Importance of Antibiotic Stewardship in Healthcare Settings

#### **Chapter 1**

## Introductory Chapter: Antimicrobial Stewardship – Antibiotics Usage Optimization to Reduce the Microbial Resistance Burden

*Hafiza Salaha Mahrosh and Ghulam Mustafa*

#### **1. Introduction to antimicrobial stewardship**

Antimicrobial stewardship (AMS) refers to interventions and control programs for the optimization of antibiotic usage. Antimicrobial stewardship is growing fastly in numbers with diverse contexts ranging from hospitals to the veterinary community [1]. Despite much acceptance, the term is still facing many challenges in different communities. There are different ways to view antimicrobial stewardship such as a collection of coordinated interventions, a program, a philosophy, and an ethic [1]. Antimicrobial stewardship policies are mainly focused on the optimization of antibiotic usage to reduce antimicrobial resistance and improvement of patients' outcomes and hospital hygiene in different healthcare centers. This may involve creating criteria for the use of antibiotics, such as limiting their use to specific indications or restricting certain antibiotics to specific patient populations [2]. Various antimicrobial stewardship strategies have been mentioned in **Figure 1**.

Antimicrobial stewardship programs (ASPs) are typically led by multidisciplinary teams of healthcare professionals, including infectious diseases specialists, pharmacists, and microbiologists. These teams work together to develop and implement strategies for promoting the appropriate use of antimicrobial agents [3]. The primary strategies of ASPs include prospective auditing and feedback, pre-authorization, dose optimization, hospital education, computer monitoring, and antibiotic restriction. Regular evaluation of outcomes of these programs can help identify areas to further improve and ensure that the programs are meeting their desired goals [4].

Antimicrobial stewardship policies are important for promoting the responsible use of antibiotics and reducing the risk of antibiotic resistance. By implementing these policies, healthcare providers can help ensure that antibiotics remain effective for future generations. In this current article, the policies to cope with the ongoing problems with uprising challenges have been discussed for the understanding of the importance of antimicrobial stewardship in the medical sector for the management of antibiotic resistance.

**Figure 1.** *Various antimicrobial stewardship strategies used to overcome antimicrobial resistance.*

#### **2. Antimicrobial resistance**

Antimicrobial resistance is the ability of microorganisms to withstand the effects of antimicrobial drugs and it develops when an antibiotic loses its ability to effectively stop microbial growth. Antibiotic resistance is a growing global health concern, as it can lead to longer hospital stays, higher healthcare costs, and increased mortality rates. When antibiotics are overused or misused, bacteria are exposed to drugs unnecessarily, and those that survive develop resistance to the antibiotics used [5]. Antimicrobial resistance (AMR) jeopardizes not only public health but also economic growth and security. Based on high-level predictions and global reports, AMR has the potential to result in 10 million fatalities worldwide by 2050 [6]. The Centers for Disease Control and Prevention (CDC) has estimated that antibiotic resistance increases direct healthcare expenditures in the United States by \$20 billion annually, excluding the estimated \$35 billion in productivity losses [7].

The wide spread of antimicrobials has resulted in the expression of resistance to these antimicrobial agents. Resistance-encoding genes have been probably present for thousands of years, either as a defense against antibiotics or for unknown purposes, and the incorporation of these genes by human commensal and pathogenic flora has been quickly followed [8]. The mass production of antimicrobials has provided humanity with a temporary advantage in the battle against microorganisms however, if the current rate of increase in antimicrobial resistance continues, we may enter the postantibiotic era [8].

*Introductory Chapter: Antimicrobial Stewardship – Antibiotics Usage Optimization to Reduce… DOI: http://dx.doi.org/10.5772/intechopen.112116*

Various programs and strategies have been developed over the years to reduce antimicrobial resistance and promote the proper and effective use of antibiotics [9]. The antimicrobial stewardship programs (ASPs) have attracted a lot of attention as one of the most important strategies for combating AMR. Antimicrobial stewardship is a coordinated approach to promote the appropriate use of antibiotics and other antimicrobial agents in healthcare settings [3].

#### **3. History**

Since the 1940s, different educational programs, management strategies, clinical protocols, and guidelines have been developed by infectious-disease organizations to control and prevent microbial infections in various sectors [10]. In the United States, the Centers for Disease Control and Prevention (CDC) launched the first educational program in 2009 to advocate for the rational use of antibiotics in acute-care settings, and improved antibiotic use as a strategy was adopted in 2013 to address the problem [11]. In 2015, World Health Organization (WHO) issued a global action plan (GAP) on the appropriate use and effects of antibiotics on humans and animals along with the validity of antibiotics for future generations as the main aim of GAP [12].

AMS has a positive impact in hospitals with shorter lengths of stay, shorter treatment duration without an increase in mortality, and a decrease in colonization and infection with resistant bacteria. Many studies have been conducted on interventions aimed at outpatient prescribers proving the prominent reduction in antibiotic prescriptions and resistance rates [11, 13]. The government urged in 2017 that all hospitals include stewardship programs in their organizational mandates. In 2017, European Commission issued reports that highlighted the successful implementation of AMS in clinical communities of different countries [14].

#### **4. Need for antimicrobial stewardship programs**

Antimicrobial resistance has been increased by the indiscriminate and injudicious use of antibiotics. Bacterial strains are adapted to new resistance mechanisms due to the abuse of sophisticated antibiotics. Bacteria have developed innovative strategies to combat the currently available antibiotics. Many antibiotics have become ineffective due to the modification of penicillin-binding proteins, and the development of betalactamases [15]. The term antimicrobial stewardship refers to appropriate measures and a set of coordinated guidelines for the optimization and selection of antimicrobial usage. The professionals should know the duration and type of antibiotics based on pathogenic identification. The chemists, microbiological labs, and infection control agents should work together to guide and assist decision-making persons about antibiotics, dose, and administration routes for maximum output. The global interdisciplinary committee has been trying to optimize the consumption of antibiotics through different antimicrobial stewardship programs to restrict resistance patterns [16].

#### **5. Antimicrobial stewardship strategies**

Antimicrobial stewardship consists of two main strategies and the most effective programs typically combine both of them. The first pre-prescription approach includes


#### **Table 1.**

*Core approaches for antimicrobial stewardship programs [17].*

the strict authorization and prescription of certain antimicrobials by a selected group of clinicians. These antimicrobial drugs need special approval and a specific time duration which depends on local microbial resistance patterns in different microbial infections. The other post-prescription approach mainly deals with perspective feedback and reviews for prescribed antibiotics to observe the outcomes for dose optimization (**Table 1**). Based on the available microbiology data and the clinical aspects of different cases, the antimicrobial steward analyses current antimicrobial treatments and offers clinicians the to continue, modify, change, or stop the medication [18].

#### **6. Evaluation of antimicrobial stewardship**

Patient risk factors and subjectivity should be considered as the major factor for the prescription of antibiotics. Antimicrobial stewardship needs to be followed up and assessed using relevant and acceptable outcome indicators such as intensity of antibiotics consumption, antibiotics resistance and consumption rate, financial condition, and morbidity and mortality rates [19].

Recent meta-analyses and systematic reviews on antimicrobial stewardship policies show the possibility of lowering comparable outcomes in a variety of healthcare settings (**Table 2**).

#### **7. Antimicrobial stewardship programs**

The purpose of antimicrobial stewardship programs is to optimize the use of antimicrobial drugs in healthcare facilities such as hospitals, long-term care homes,


*Introductory Chapter: Antimicrobial Stewardship – Antibiotics Usage Optimization to Reduce… DOI: http://dx.doi.org/10.5772/intechopen.112116*

**Table 2.**

*Recent interventions on antimicrobial stewardship programs in hospitals.*

and outpatient clinics. These initiatives aim to raise patients' outcomes, control the spread of antibiotic resistance, and cut back on medical expenses.

#### **7.1 Healthcare facility**

A list of core components for healthcare facilities has been developed to assist facility management in creating the frameworks required to implement sustainable AMS programs. The core elements are comprised of financial funding, a multidisciplinary dedicated team, health professionals, up-to-date standard treatment recommendations, regular feedback and reviews, and an AMS action plan that sets priorities, evaluates performance, and establishes accountability, collaboration with

other programs, a list for healthcare facilities that include a list of restricted antibiotics, basic training for optimal antibiotics use, monitoring quality, susceptibility, types, and resistance rate of antibiotics and medical records and prescription records for the institution (**Figure 2**).

#### **7.2 AMS planning programs**

AMS programs should be interlinked with other programs for the optimization of antibiotic usage. A large tertiary hospital with many different specialties will have a larger and more sophisticated AMS program than a local hospital. The deployment of an AMS program is a dynamic and step-by-step process where each facility is built on the infrastructure that already exists [26]. AMS programs conduct situational analysis and faculty action plans based on core elements to identify the missing elements. The situational analysis consists of opportunities, barriers, and enablers at different levels for the participation of clinical professionals. The AMS committee can function independently or it can be integrated into an existing framework such as the infection control, patient safety, drugs and therapeutics committee to define the scope of the work. An infectious disease specialist with interest and experience in infectious illnesses can give expertise to the infection management team. This individual serves as the primary hand for the AMS team for helping with drug prescription, diagnosis, and patient management for the optimization of antibiotics to treat infections [27].

*Introductory Chapter: Antimicrobial Stewardship – Antibiotics Usage Optimization to Reduce… DOI: http://dx.doi.org/10.5772/intechopen.112116*

Patients care should be taken by nurses and expert staff of hospitals because they know the entire first-hand disease history of the patients [28]. This AMS team member should be focused on the timely administration of antibiotics without delaying any dose, therapeutic drug monitoring, high-quality microbiological sampling, and results discussion to promote the accurate prescription of antibiotics. Moreover, nurses should cooperate to monitor the patient's clinical progress, antibiotic consumption intensity, and identify the conditions to shift the route of antibiotics from intravenous (IV) to oral, educate patients, and handle the data collection for feedback and reviews [17].

#### **7.3 Selection and dosing of appropriate antibiotics**

The infectious disease workers should recommend the correct duration of treatment with an optimized drug dosage to secure the target more accurately in the shortest period with minimal toxicity. The IV drugs should be shifted to the oral route of administration to shorten the patient's stay at the hospital to avoid catheterassociated infections. The infectious diseases team should follow evidence-based recommendations for the duration of the treatment. The treatment plan for grampositive and gram-negative bacteria is also established based on the identified pathogen(s) to avoid unnecessary prolonged treatments [29].

Understanding and utilizing pharmacokinetics and pharmacodynamics by hospital and clinical pharmacists is necessary for choosing appropriate antibiotic doses that can help to reduce the use of unnecessary drugs for double therapy. Nursing staff can help explore alternative medicines by accurately documenting and updating antibiotic allergies on a regular basis [30].

#### **8. Antimicrobial stewardship challenges**

The antimicrobial stewardship program is challenging due to limited human resources, formal programs, and policies. Antimicrobial stewardship programs require a significant investment of time, money, and resources to implement and maintain.

#### **8.1 Healthcare challenges**

The healthcare sector faces major challenges due to lack of equipment, improper infrastructure, large patient burden, and shortage of hospital facilities. These challenges were frequently reported in rural areas due to irrelevant antibiotic prescriptions and malpractices in the healthcare system [31]. In developed countries, hospitals have special antibiotics committees that monitor the antibiotics usage, treatment plans, and evaluate the implementation of hospital's stewardship interventions [32].

#### **8.2 Diagnostic challenges**

High burden of infectious diseases has limited the availability of microbiology diagnostic laboratories [33]. There is a dire need for necessary equipment, standard operating protocols, well-trained staff, and quality control systems in diagnostic laboratories [34]. Correct pathogen identification and susceptibility testing are difficult due to the large number of antibiotics that could potentially be tested, the multiple techniques and media needed, and the analysis and validation of unlikely resistance

profiles. High testing threshold, lack of experienced microbiologists, and habitat culture media are the main crises due to financial constraints [35].

#### **8.3 Educational challenges**

The lack of professional clinical staff has been recorded as the main problem in the path of antimicrobial stewardship practice. In rural areas, antibiotics are prescribed and/or provided in many cases by a diverse group of people including healthcare workers with different learning backgrounds (e.g., nurses, dispensers, chemists, and midwives) as well as local vendors. Many healthcare providers may not have adequate education and training on appropriate antimicrobial use. This can make it difficult for them to make informed decisions about prescribing antimicrobials [36].

Antimicrobial stewardship should be a core element for healthcare workers to fully access over risks of antibiotic misuse and its outcomes for the patients. The development of protocols and guidelines is a mandatory step for the education of medical students and clinical workers. Providers may be educated on the principles of antimicrobial stewardship, appropriate prescribing practices, and the risks associated with inappropriate antibiotic use [13].

#### **8.4 Limited access to antibiotics**

Many underdeveloped countries have poor access to different antibiotics in rural and remote areas due to a lack of financial aid, transport, storage, and reliable drug supply system. Limited access to antibiotics can lead to increased morbidity and mortality rates, as well as the spread of infectious diseases [37]. The widespread of non-prescribed antibiotics is another potentially challenging threat for the public sector. Many drugs may be difficult to trace in terms of their sources, quality, and supply chain and the pharmaceutical corporations' influence is frequently neither visible nor regulated [38]. Moreover, US Food and Drug Administration and the European Medicines Agencies have little or no medical access in low- and middleincome countries [39].

#### **9. International guidelines and approaches**

The World Health Organization (WHO) has set different roadmaps to monitor the establishment of antimicrobial stewardship policies. The necessity for monitoring and investigation, infection prevention, and control strategies such as immunization and the development of an economic argument for long-term investment in antibiotics have all been mentioned by them as being important components of a complete approach. The availability of affordable and high-quality diagnostic kits and tools, continuous surveillance, and equal distribution of antibiotics is urgently needed as core elements of AMS [12].

The WHO provides a framework for creating National Action Plans (NAP) and analysis systems for a country's progress evaluation. The US Center for Disease Dynamics, Economics and Policy (CDDEP) is funding the establishment of multisectoral national-level working groups in low- and middle-income countries to comprehend and document antibiotic use in human and animal populations in the national context as well as of developing evidence-based interventions [13].

*Introductory Chapter: Antimicrobial Stewardship – Antibiotics Usage Optimization to Reduce… DOI: http://dx.doi.org/10.5772/intechopen.112116*

The global action plan extends current efforts on smart drug use and national medicines policy including the use of essential pharmaceutical lists, concerning the regulation of antibiotic availability, quality, and use at the national level. For instance, despite increasing antibiotic resistance in many countries, national essential drug lists in many underdeveloped countries still do not include specific antibiotics such as carbapenems, glycopeptides, or polymyxins. Moreover, programs such as the Global Antibiotic Research and Development Partnership (GARDP), which aims to use partnership models rather than a pharmaceutical industry-driven strategy to create novel antibiotic treatments may be capable of ensuring ethical use and unlimited access to different antibiotics [40].

Targeted strategies such as shifting from intravenous to dosage form, improving surgical antibiotic prophylaxis, and introducing standard antibiotic formulations might be taken into consideration. Improving antibiotic hang time is another easy approach to improving patients' outcomes [41].

#### **10. Case studies**

Hospital-based antimicrobial stewardship programs (ASPs) use several coordinated strategies to optimize the use of antibiotics. Verma et al., [42] have reported pre- and post-intervention study designs that compared the outcomes of AMS on patients admitted from November 2017 to January 2018. Daily assessments and feedbacks, restrictions on the use of antibiotics, daily bedside evaluations, and educational activities to raise awareness among residents and nurses were part of the ASP interventions. The study involved the prescription of 1331 antibiotics to 695 patients. Prophylactic antibiotic use was decreased by 11% (*p* = 0.001) in this period. In terms of length, choice, indication, and method of administration, the prescription pattern was considerably improved in the intervention phase compared to the preintervention phase by 8%, 14%, 2%, and 8%, respectively. The outcomes of this study indicated positive feedback on the implementation of AMS in hospital units for the optimization of antibiotic dosage.

Jones et al., [43] presented the hypothesis of the positive relationship of professional healthcare workers with the success of AMS. During six months intervention period, antibiotic consumption was lowered by 6.5% compared to previous years' reports. A daily review of antibiotics prescription and administration documentation was significantly improved.

Similarly, [44] conducted telehealth-based antimicrobial stewardship programs in two hospitals. In six months duration, 1419 proposals were presented and 1262 (88.9%) of them were followed through with a 24.4% decrease in broad-spectrum antibiotic consumption. Antimicrobial expenses were estimated to save \$1,42,629.83 annually. An intensive ASP strategy enabled in the community hospital context *via* telehealth resulted in a lower broad-spectrum antibiotic usage and minimum antimicrobial expenses.

#### **11. Conclusion**

The rising frequency of antibiotic resistance in hospitals as well as communities is an urgent issue as hospitalized patients become more difficult to treat. To address the problem(s) of AMR, it is important to promote the appropriate use of antimicrobial

drugs, develop new and more effective drugs, and improve infection prevention and control practices in healthcare settings and the community. Antimicrobial stewardship practices, concepts, and interventions are the key stages in the prevention and control of antimicrobial resistance. Antimicrobial stewardship may offer every professional the tools they need to use valuable resources.

#### **Author details**

Hafiza Salaha Mahrosh<sup>1</sup> and Ghulam Mustafa<sup>2</sup> \*

1 Department of Biochemistry, University of Agriculture Faisalabad, Faisalabad, Pakistan

2 Department of Biochemistry, Government College University Faisalabad, Faisalabad, Pakistan

\*Address all correspondence to: drghulammustafa@gcuf.edu.pk

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Introductory Chapter: Antimicrobial Stewardship – Antibiotics Usage Optimization to Reduce… DOI: http://dx.doi.org/10.5772/intechopen.112116*

#### **References**

[1] Dyar O et al. What is antimicrobial stewardship? Clinical Microbiology and Infection. 2017;**23**(11):793-798

[2] Schuts EC et al. Current evidence on hospital antimicrobial stewardship objectives: A systematic review and meta-analysis. The Lancet Infectious Diseases. 2016;**16**(7):847-856

[3] Ababneh MA, Nasser SA, Rababa'h AM. A systematic review of antimicrobial stewardship program implementation in middle eastern countries. International Journal of Infectious Diseases. 2021;**105**: 746-752

[4] Barlam TF et al. Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clinical Infectious Diseases. 2016; **62**(10):e51-e77

[5] Nadeem SF et al. Antimicrobial resistance: More than 70 years of war between humans and bacteria. Critical Reviews in Microbiology. 2020;**46**(5): 578-599

[6] Nathwani D et al. Value of hospital antimicrobial stewardship programs [ASPs]: A systematic review. Antimicrobial Resistance & Infection Control. 2019;**8**:1-13

[7] Dadgostar P. Antimicrobial resistance: Implications and costs. Infection and drug resistance. 2019;**12**: 3903-3910

[8] MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clinical Microbiology Reviews. 2005;**18**(4): 638-656

[9] Pollack LA, Srinivasan A. Core elements of hospital antibiotic stewardship programs from the Centers for Disease Control and Prevention. Clinical Infectious Diseases. 2014;**59** (suppl\_3):S97-S100

[10] Rosenblatt-Farrell N. The landscape of antibiotic resistance. Environmental Health Perspectives. 2009;**117**(6):A244- A250

[11] Davey P, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database of Systematic Reviews. 2017;**2**: 14651858

[12] World Health Organization. Global action plan on antimicrobial resistance. Geneva, Switzerland: World Health Organization; 2015. ISBN 978 924 1509763

[13] Cox JA et al. Antibiotic stewardship in low-and middle-income countries: The same but different? Clinical Microbiology and Infection. 2017;**23**(11): 812-818

[14] Majumder MAA et al. Antimicrobial stewardship: Fighting antimicrobial resistance and protecting global public health. Infection and drug resistance. 2020;**13**:4713-4738

[15] Rice LB. Antimicrobial stewardship and antimicrobial resistance. Medical Clinics. 2018;**102**(5):805-818

[16] Sahra S, Jahangir, De Chavez V. Antimicrobial stewardship: A review for internal medicine physicians. Cureus. 2021;**13**(4):e14385

[17] World Health Organization. Antimicrobial Stewardship Programmes in Health-Care Facilities in Low- and Middle-Income Countries. Geneva, Switzerland: A Who Practical Toolkit; 2019. ISBN 978-92-4-151548-1

[18] Doron S, Davidson LE. Antimicrobial stewardship. Mayo Clinic Proceedings. 2011;**86**(11):1113-1123

[19] Horikoshi Y et al. Sustained pediatric antimicrobial stewardship program with consultation to infectious diseases reduced carbapenem resistance and infection-related mortality. International Journal of Infectious Diseases. 2017;**64**: 69-73

[20] Xiao Y et al. Change in antibiotic use in secondary and tertiary hospitals nationwide after a national antimicrobial stewardship campaign was launched in China, 2011–2016: An observational study. The Journal of Infectious Diseases. 2020;**221**(Supplement\_2):S148-S155

[21] Mardani M, Abolghasemi S, Shabani S. Impact of an antimicrobial stewardship program in the antimicrobial-resistant and prevalence of clostridioides difficile infection and amount of antimicrobial consumed in cancer patients. BMC Research Notes. 2020;**13**(1):1-5

[22] Savoldi A et al. Impact of implementing a non-restrictive antibiotic stewardship program in an emergency department: A four-year quasi-experimental prospective study. Scientific Reports. 2020;**10**(1):1-8

[23] Wee LE et al. Who listens and who doesn't? Factors associated with adherence to antibiotic stewardship intervention in a Singaporean tertiary hospital. Journal of Global Antimicrobial Resistance. 2020;**22**:391-397

[24] Abubakar U, Syed Sulaiman SA, Adesiyun AG. Impact of pharmacist-led antibiotic stewardship interventions on compliance with surgical antibiotic prophylaxis in obstetric and gynecologic surgeries in Nigeria. PLoS One. 2019; **14**(3):e0213395

[25] Wang H et al. Impact of antimicrobial stewardship managed by clinical pharmacists on antibiotic use and drug resistance in a Chinese hospital, 2010–2016: A retrospective observational study. BMJ Open. 2019; **9**(8):e026072

[26] Mendelson M et al. How to start an antimicrobial stewardship programme in a hospital. Clinical Microbiology and Infection. 2020;**26**(4):447-453

[27] Goff DA, Rybak MJ. Global antimicrobial stewardship: challenges and successes from frontline stewards. 2015;**4**(Suppl 1):S1S3

[28] Brink AJ et al. Passing the baton to pharmacists and nurses: New models of antibiotic stewardship for South Africa?: Guest editorial. South African Medical Journal. 2016;**106**(10):947-948

[29] Sampathkumar P. Reducing catheter-associated urinary tract infections in the ICU. Current Opinion in Critical Care. 2017;**23**(5):372-377

[30] Satterfield J, Miesner A, Percival K. The role of education in antimicrobial stewardship. Journal of Hospital Infection. 2020;**105**(2):130-141

[31] Zhang C et al. The professional status of infectious disease physicians in China: A nationwide cross-sectional survey. Clinical Microbiology and Infection. 2018;**24**(1):82. e5-82. e10

[32] Howard P et al. An international cross-sectional survey of antimicrobial stewardship programmes in hospitals.

*Introductory Chapter: Antimicrobial Stewardship – Antibiotics Usage Optimization to Reduce… DOI: http://dx.doi.org/10.5772/intechopen.112116*

Journal of Antimicrobial Chemotherapy. 2015;**70**(4):1245-1255

[33] Feikin DR et al. The burden of common infectious disease syndromes at the clinic and household level from population-based surveillance in rural and urban Kenya. PLoS One. 2011;**6**(1): e16085

[34] Barbé B et al. Implementation of quality management for clinical bacteriology in low-resource settings. Clinical Microbiology and Infection. 2017;**23**(7):426-433

[35] Om C et al. "If it'sa broad spectrum, it can shoot better": Inappropriate antibiotic prescribing in Cambodia. Antimicrobial Resistance & Infection Control. 2016;**5**(1):1-8

[36] Morgan DJ et al. Non-prescription antimicrobial use worldwide: A systematic review. The Lancet Infectious Diseases. 2011;**11**(9):692-701

[37] Pulcini C et al. Ensuring universal access to old antibiotics: A critical but neglected priority. Clinical Microbiology and Infection. 2017;**23**(9):590-592

[38] Parry J. Former Head of GSK China Is Charged with Bribery. British Medical Journal Publishing Group; 2014

[39] Collignon P, et al. Antimicrobial resistance: the major contribution of poor governance and corruption to this growing problem. PloS one. 2015;**10**(3): e0116746

[40] World Health Organization. WHO Model List of Essential Medicines, 20th List (March 2017, Amended August 2017). Geneva, Switzerland: World Health Organization; 2017

[41] Messina AP, van den Bergh D, Goff DA. Antimicrobial stewardship with pharmacist intervention improves timeliness of antimicrobials across thirty-three hospitals in South Africa. Infectious Diseases and Therapy. 2015;**4**: 5-14

[42] Verma M et al. Antimicrobial stewardship programme in a trauma Centre of a tertiary care hospital in North India: Effects and implementation challenges. Journal of Global Antimicrobial Resistance. 2019;**17**: 283-290

[43] Jones AS, et al. Impact of positive feedback on antimicrobial stewardship in a pediatric intensive care unit: A quality improvement project. Pediatric quality & safety. 2019;**4**(5):e206

[44] Shively NR et al. Impact of a telehealth-based antimicrobial stewardship program in a community hospital health system. Clinical Infectious Diseases. 2020;**71**(3):539-545

#### **Chapter 2**

## Antibiotic Stewardship: How It Is Implemented in Primary Healthcare Facility

*Rini S. Handayani and Vita Pertiwi*

#### **Abstract**

Antibiotic stewardship plays an important role in controlling antibiotic resistance. The problem of antibiotic resistance in primary healthcare has not been given much attention, so far, the focus has been on the hospital. Antibiotic resistance control needs to start from primary healthcare facilities such as community health centers, clinics, and independent doctor practices because patients who enter the hospital are often already resistant. Therefore, it is necessary to identify things that can be done to control antibiotic resistance in primary health care facilities. Things that can be done include making policies or regulations that support antibiotic stewardship in primary healthcare, optimizing available facilities and infrastructure, improving facilities that support antibiotic stewardship, increasing capable human resources, monitoring and evaluating antibiotic prescribing, and building system information on antibiotic resistance that is easily accessible to health workers in primary health care facilities.

**Keywords:** antibiotic stewardship, primary healthcare, resistance policy, primary care provider, stewardship implementation

#### **1. Introduction**

According to World Health Organization (WHO), antibiotic stewardship is a comprehensive integrated series of activities to promote the responsible and appropriate use of antibiotics so that patients get optimal treatment results. These strategies are reducing antibiotic utilization by increasing the rational use of antibiotics and reducing the incidence of infectious diseases by carrying out immunizations. The irrational use of antibiotics includes inaccuracies in diagnosis, dosage, interval, and duration. Prescribing antibiotics recklessly is a predisposing factor for the emergence of antibiotic resistance. In primary health facilities, antibiotics are widely prescribed for acute Upper Respiratory Tract Infections (URTI), even though URTI is mostly caused by viruses and antibiotic is not a proper drug choice. Using broad-spectrum antibiotics too frequently is also not recommended. The existence of guidelines for prescribing appropriate antibiotics with the application of evidence-based interventions helps clinicians to use antibiotics wisely. Besides, the proper management of antibiotics also plays a role in controlling antibiotic-resistant bacteria and saving costs. Therefore, doctors and pharmacists in primary health facilities play

an important role in overcoming inappropriate antibiotic prescribing problems and antibiotic stewardship is a key strategy to maintain the effectiveness of antibiotics in the future [1–9]. Implementation of antibiotic stewardship will be effective if it is carried out cross-sectorally from the national level to the regional level by involving all parties such as local health offices, hospitals, primary health facilities, health workers like doctors, pharmacists, and the community.

#### **2. Problems**

Currently, the antibiotic stewardship strategy is mostly carried out in hospitals, especially referral hospitals, rather than primary health facilities [1]. In contrast to referral hospitals, the primary health center has limited human resources, facilities, and infrastructure. It is estimated that about 80% of antimicrobials are consumed in primary health facilities. Therefore, antibiotic stewardship must be started in primary health facilities immediately. Limited sources should not be used as a barrier to initiating antibiotic stewardship. Although it is not yet ideal, it is hoped that antibiotic stewardship in primary health facilities will play an important role in controlling antibiotic resistance. Besides limited resources, the understanding of antibiotic resistance among health workers is not comprehensive. Lack of risk awareness of antibiotic resistance among health workers like doctors and pharmacists is also one of the leading factors for increasing antibiotic resistance. Therefore, interventions to increase the awareness of doctors and pharmacists in primary health centers about using antibiotics wisely need to be carried out. This intervention will help increase rational antibiotic utilization. Other factors include physician non-compliance with antibiotic utilization management, limited access to microbiological testing to support diagnosis, lack of support and coordination with local policymakers, and limited access to antibiotic resistance data in the community [5, 10]. Even though policymakers have made several interventions by developing antibiotic indication and utilization regulation, for example in the case of URTI, the rate of inappropriate antibiotic prescribing is still high [3]. Optimal antibiotic stewardship implementation is expected to reduce inappropriate antibiotic prescribing. Antibiotic stewardship programs and activities can be successful if the challenges faced by primary health facilities can be overcome [3, 7]. Therefore, challenges or obstacles to the implementation of antibiotic stewardship in primary health facilities must be minimized, considering that inappropriate antibiotic prescribing often occurs in primary health facilities.

#### **3. Antibiotic stewardship implementation in primary healthcare facilities**

#### **3.1 Antibiotic stewardship policies in primary health care facility**

In developing countries, enforcement of policies prohibiting the free sale of antibiotics is often not optimal. This allows people to self-medicate using antibiotics that are not needed [11]. Improvements across the health system and drug supply chain are needed to tackle the problem of antibiotic resistance [9]. In addition, the government needs to make policies to strengthen the role of primary healthcare facilities in controlling antibiotic resistance because they are the ones dealing with the most patients. Antibiotic stewardship policy needs to start from the upstream to primary healthcare facilities to have a significant impact. Antimicrobial stewardship programs *Antibiotic Stewardship: How It Is Implemented in Primary Healthcare Facility DOI: http://dx.doi.org/10.5772/intechopen.113102*

in the form of education, clinical support, supervision, and policy have reduced rates of prescription writing and inappropriate prescribing [12]. The government needs to immediately make national policies related to antibiotics following WHO recommendations, including the Access, Watch, and Reserve (AWaRe) classification in national guidelines for antibiotics application [13].

The Ministry of Public Health in Qatar developed the NAP (National Plan of Action) to Fight Antimicrobial Resistance (AMR) in collaboration with the WHO Regional Office for the Eastern Mediterranean (WHO/EMRO)) [14]. Indonesia, through the Ministry of Health, has established rational drug prescription indicators for URTI and diarrhea at Public Health Centers. Tolerance to the use of antibiotics in URTI is at 20% and in diarrhea is at 8%. This is based on the fact that antibiotics are often given to treat diarrhea and acute respiratory infections, although in most cases these conditions are caused by viruses and do not require antibiotics [9]. This target is stated in the Regulation of the Coordinating Minister for Human Development and Culture of the Republic of Indonesia number 7 of 2021 concerning the national action plan for controlling antimicrobial resistance for 2021–2024. The Indonesian Ministry of Health has also made pharmacists as the agents of change which are part of the Community Movement to Use Drug Intelligently program. One of the goals of this program is to educate health workers and the public to use antibiotics wisely and be aware of the antibiotic resistance dangers. Another important component of the program is comprehensive surveillance of antibiotic prescription and antimicrobial resistance. This data is intended to help antibiotic stewardship efforts be more precise and wise [12].

#### **3.2 Optimizing primary healthcare's facilities to support the antibiotic stewardship program**

In developing countries, facilities and infrastructure in primary healthcare facilities are often limited, especially in rural and remote areas. There is a shortage of diagnostic tools so that the diagnosis becomes inaccurate and inappropriate antibiotic prescribing occurs when the patient does not need antibiotics [11]. Rapid diagnostic tests will allow doctors to prescribe specific antibiotics rather than broad-spectrum antibiotics and to differentiate between viral and bacterial infections [9].

The lack of human resources, the inaccessibility of diagnostic tests, and the cheap price of antibiotics resulted in a tendency to give treatment with empiric antibiotics directly without conducting cultures because they were considered more efficient economically [9, 15]. General practitioners in developed countries commonly use the rapid antigen detection test for the diagnosis of streptococcal pharyngitis. The C-reactive protein (CRP) kit is used to differentiate serious respiratory infections [16].

In addition to the absence of a rapid diagnostic test, inappropriate application of guidelines, unavailability of specific antibiogram data, and the short consultation time due to many patients are also factors triggering the irrational use of antibiotics [14]. Public understanding of the dangers of antibiotic resistance plays an important role in controlling the spread of antibiotic resistance. Unfortunately, people often believe that antibiotics will help cure colds and flu caused by viruses. Whereas viral infections generally do not require antibiotics [11].

Poor sanitation in primary healthcare facilities also facilitates spreading of the microbes that are resistant to antibiotics. To control the spread of antibioticresistant microbes in the environment, primary healthcare facilities must be clean. Contamination in water supplies is driving the spread of antibiotic-resistant microbes. This clean primary healthcare can be achieved if it is supported by community health workers who are competent in environmental sanitation. Adequate water, good sanitation, and public health workers implementing effective infection prevention and control procedures will control the spread of antibiotic-resistant microbes. Unfortunately, many primary health care facilities do not follow basic sanitation measures such as aseptic technique, hand washing, and the use of personal protective equipment, such as gloves and masks. Without clean water and good sanitation in primary healthcare facilities, they become infection exposure points for patients and the staff. These inadequate facilities can be the starting point for transmission of antimicrobial resistance in the community [9].

A comprehensive assessment of primary healthcare facilities in resource-limited settings is essential to strengthening the Infection Prevention and Control (IPC) measures and Antibiotic Stewardship Programs (ASP) activities. This approach for assessing existing IPC and ASP activities will provide relevant data for establishing further policies regarding adequate facilities and infrastructure in primary healthcare facilities to support the Antibiotic Stewardship Program [17].

#### **3.3 Increase health worker's capacity in primary healthcare**

Some health workers consider antibiotic resistance as a national and even international problem but sadly this does not affect their daily practice in primary healthcare facilities. The others do not understand and have full awareness about antibiotic resistance. Some doctors in primary healthcare facilities may prescribe antibiotics out of habit or are reluctant to follow the new policy in prescribing antibiotics. Therefore, antibiotic prescribing varies greatly [9, 18]. Other health workers like pharmacists and informal health service providers, especially in countries and regions where there is relatively free access to antibiotics also contribute to antibiotic resistance [12]. Raising awareness and understanding the antibiotic resistance must start with professional education, and continue to any other advanced education program. This continuing education is carried out with the hope of behavior changes in health workers [16]. Besides educational interventions, it is necessary to audit and give feedback because it will increase the rational use of antibiotics. If needed, policy changes and an information system are formed to remind and promote the rational use of antibiotics in primary healthcare facilities [10, 18].

In Indonesia, especially in rural and remote areas, the prescription of antibiotics is also carried out by nurses or midwives due to the absence of general practitioners. Therefore, education interventions about the dangers of antibiotics should also be given to nurses or midwives. Unfortunately, continuing education for health workers in primary healthcare facilities is not yet intensive. Poor management of antibiotics in primary healthcare facilities also has a role in antibiotic resistance [7].

In addition to the health workers mentioned above, pharmacists also play a role in controlling antibiotic resistance. Pharmacists have a significant role in ensuring the proper consumption of antibiotics. Unfortunately, pharmacists often lack the education about advanced antibiotic resistance even though have an important role in the Antibiotic Stewardship Program. Another crucial point is the lack of collaboration between health workers such as doctors, nurses, midwives, and pharmacists [19].

Apart from health workers, understanding and being aware of the antibiotic resistance danger is also crucial for patients. The public also needs to be educated regarding this matter. Unawareness of the public regarding the proper use of antibiotics and free access to antibiotics is a potential risk for antibiotic resistance [10–12]. People

#### *Antibiotic Stewardship: How It Is Implemented in Primary Healthcare Facility DOI: http://dx.doi.org/10.5772/intechopen.113102*

believe that antibiotics can cure diseases caused by viral infections such as the common cold or flu [11]. People often self-medicate using leftover antibiotics that have been previously prescribed for diseases that are not necessarily caused by bacteria. Non-compliance with the dosage and rules of use that doctors have prescribed is one of the factors for the development of antibiotic resistance in a community [12]. This behavior needs to be changed, they must be taught to only use antibiotics according to the doctor's instructions and not self-medicate using antibiotics [18]. Effective education and communication to the public to increase public awareness is part of the Antibiotic Stewardship Program [7]. Public education about antibiotic utilization and the dangers of antibiotic resistance can be carried out through talk shows with pharmacists and doctors through electronic media such as TV, radio, YouTube, and other mass media [16]. Besides educating health workers, raising awareness and educating the public about antibiotic resistance also needs to be done.

Although doctors are the most influential health professionals in addressing the problem of antibiotic resistance in primary healthcare facilities, treatment decisions are sometimes influenced by patient demands and are often driven by an unfounded belief in getting the 'quickest cure' with antibiotics [10–12]. Inappropriate use of antibiotics and demands on doctors to prescribe antibiotics can result from a poor understanding of the implications of antibiotic abuse, limited access to trained doctors, limited resources, and health literacy [12]. General practitioners often feel that patients with URTI consult with the hope of getting antibiotics [18]. Even though doctors understand the dangers of antibiotic resistance, sometimes doctors prescribe antibiotics to maintain good relations with patients and avoid patient dissatisfaction. This paradox still occurs and may be one of the main contributors to the continued over-prescribing of antibiotics for URTI [11, 18]. The gap in knowledge about antibiotic resistance that contributes to the continuation of this antibiotic resistance needs to be eliminated. Therefore, better communication skills are needed for patients and the wider community. Continuing education materials apart from material on the rational use of antibiotics, the dangers of antibiotic resistance are also material on communicative ways of communicating to patients and the wider community. Communicative communication with patients is the key to making joint decisions to use antibiotics rationally. This has been shown to reduce antibiotic prescriptions for URTI in several studies [18, 20].

Given a lot of factors cause antibiotic resistance, the high risk of antibiotic resistance, and the involvement of many parties, this antibiotic resistance must be overcome by all parties in collaboration. Working together to tackle antibiotic resistance, both from the sector in humans and livestock, (one health priority agenda) will be more successful than doing it alone [11, 21]. Doctors and pharmacists in primary healthcare can be the spearheads of the "one health priority agenda" because primary healthcare does not only provide health services but also has the functions and duties of carrying out health promotion and preventive programs.

#### **3.4 Antibiotic monitoring and evaluation**

Monitoring and evaluation of antibiotic prescribing and resistance are very important in controlling antibiotic resistance. This is necessary as a feedback basis for primary healthcare facilities, an intervention that needs to be carried out by the local health authority (public health office) or on a national scale by the Ministry of Health. The results of monitoring and evaluation are also needed as a reference for improving antibiotic prescribing guidelines.

Comprehensive surveillance of antibiotic prescription and resistance is an important component of the Antibiotic Stewardship Program [12]. WHO issued the "Global Antimicrobial Resistance and Use Surveillance System (GLASS)" program on October 22, 2015. This GLASS program is the first global collaborative effort to standardize AMR surveillance. Surveillance is a way to obtain data as a basis for assessing the spread of AMR and to inform and monitor the impact of local, national, and global strategies. Based on the surveillance results, infection prevention, control responses, and policy improvements are determined. GLASS was compiled by combining data from AMR monitoring in humans, namely monitoring of microbial resistance and antimicrobials utilization including in the food chain (use of antimicrobials in animal husbandry and fisheries) and resistant microbes in the environment [22]. Unfortunately, this can only be done at the hospital level, it cannot be done yet in primary health facilities due to the absence of microbiological examination facilities and limited infrastructure, as well as health human resources to carry out antimicrobial resistance tests. Collaboration with hospitals is needed to overcome this problem. Besides the surveillance program, data on antibiotic consumption at the primary healthcare is also needed for monitoring and evaluating antibiotic management. Community-level resistance and consumption data are needed to monitor resistance, inform treatment guidelines and patient care, and understand prescribing patterns. For evaluating and monitoring antibiotic utilization, WHO classifies antibiotics into three groups, namely Access, Watch, and Reserve. The Access group is a group of antibiotics that have activity against a wide range of commonly encountered susceptible bacteria while also having lower resistance potential than other groups. This group of antibiotics is recommended as the first or second choice of infectious disease treatment. Therefore, the Access group should be the most widely available antibiotics in primary healthcare [9]. There is a direct correlation between antibiotic use and resistance. High consumption of antibiotics leads to high levels of resistance [16]. In Indonesia, monitoring of antibiotic use in primary healthcare facilities is carried out on the use of antibiotics in non-pneumonic URTI and non-specific diarrhea. The Indonesian government has also established a national formulary that includes a list of antibiotics used in primary healthcare facilities. Community Health Centers were asked to report the use of antibiotics in non-pneumonic URTI and non-specific diarrhea to the local public health office and then they will report to the Ministry of Health, meanwhile, an evaluation of the suitability types of antibiotics prescribed at the primary healthcare with the national formulary had not been carried out.

#### **3.5 Building an information system on antibiotic resistance**

An obstacle in making the right diagnosis in primary healthcare facilities is the absence of microbiological examination to determine whether the cause of infection is bacteria or virus. This situation makes choosing precise antibiotics harder. Microbiological examination currently only exists in hospitals, so collaboration with hospitals is needed. Building an antibiotic-resistant information system that is easily accessible to health workers in primary healthcare facilities can be a solution to overcome this [9].

An information system coordinated by the local health authority (public health office) in collaboration with hospitals is urgently needed considering that the hospital has antibiotic resistance data as well as laboratory facilities and human resources for the microbiology examination laboratory. Primary healthcare facilities will provide information on the use of antibiotics. A comprehensive information system involving

#### *Antibiotic Stewardship: How It Is Implemented in Primary Healthcare Facility DOI: http://dx.doi.org/10.5772/intechopen.113102*

hospitals, primary healthcare facilities, and health offices will be effective in increasing rational antibiotic prescribing [9].

Data on antibiotic utilization and antibiotic resistance that are integrated into a system can monitor antibiotic use and emerging resistance so that future antibiotic prescribing can be based on local resistance patterns and results with more accurate diagnosis and therapy. This information system can also be accessed by primary healthcare facilities in rural areas, given that internet access is now quite extensive in rural areas. This will overcome the problem of health workers in rural areas who lack information about local resistance patterns. This application should not be too complicated so that it can be accessed by smartphone. An app launched in South Africa in late 2017, provides information to patients about their diagnosis, proper use of antimicrobials, and infection prevention; physicians can enter patient characteristics and symptoms to obtain guidance on their diagnosis and local prevalence of resistance [9].

This information system can also be used by the health office to monitor and provide feedback to primary healthcare facilities. This comprehensive information will assist doctors in prescribing appropriate antibiotics or not prescribing antibiotics for patients with viral infections who usually do not require antibiotics [9]. Information systems that are supported by interventions can provide a better result of antibiotic resistance prevention, but this information and interventions are very specific regionally, so they will vary depending on the region [10].

In addition to the information system intended for health workers, the public health office can create an information system intended for the community. This system will be useful for socializing about the danger of antibiotic resistance with interesting content for the public. The Internet can be one of the media because it is widely accessed by the public. There were an estimated 4.90 billion social media users worldwide in 2017 and is projected to increase to 5.85 billion in 2027 [23]. Public health offices can promote proper use of antibiotics, and hygiene practices to the public as part of antibiotic stewardship activity. Besides, this information system can be used against media that provide wrong information about health problems, such as the use of antibiotics to treat colds and influenza and the dangers of vaccines [9].

#### **4. Conclusion**

An Antibiotic Stewardship Program is necessary to solve antibiotic resistance. Focus programs need to change from hospital-based to primary healthcare-based due to their large coverage. An implementation that can be done in primary healthcare is forming a solid policy, optimizing its infrastructure, upgrading human resources, monitoring and evaluating antibiotic use routinely, and building an information system. Cooperation between primary healthcare, hospitals, and public health offices made a comprehensive and powerful antibiotic stewardship program.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Antimicrobial Stewardship – New Insights*

#### **Author details**

Rini S. Handayani1 and Vita Pertiwi<sup>2</sup> \*

1 National Research and Innovation Agency, Jakarta, Indonesia

2 Prambanan Public Hospital, Yogyakarta, Indonesia

\*Address all correspondence to: vitapertiwi96@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Antibiotic Stewardship: How It Is Implemented in Primary Healthcare Facility DOI: http://dx.doi.org/10.5772/intechopen.113102*

#### **References**

[1] WHO. Policy Guidance on Integrated Antimicrobial Stewardship Activities. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO

[2] WHO. Antimicrobial Stewardship Programmes in Health-Care Facilities in Low- and Middle-Income Countries. A Practical Toolkit. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO

[3] Avent ML, Cosgrove SE, Price-Haywood EG, et al. Antimicrobial stewardship in the primary care setting: From dream to reality? BMC Family Practice. 2020;**21**(134):1-9. DOI: 10.1186/ s12875-020-01191-0

[4] Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clinical Infectious Diseases. 2016;**62**(10):51-77. DOI: 10.1093/cid/ciw118

[5] WHO. Antimicrobial Stewardship Interventions: A Practical Guide. Copenhagen: WHO Regional Office for Europe; 2021. Licence: CC BY-NC-SA 3.0 IGO

[6] Aslam B, Wang W, Arshad MI, et al. Antibiotic resistance: A rundown of a global crisis. Infection and Drug Resistance. 2018;**11**:1645-1658. DOI: 10.2147/IDR.S173867

[7] Engler D, Meyer JC, Schellack N, et al. Antimicrobial stewardship activities in public healthcare facilities in South Africa: A baseline for future direction. Antibiotics (Basel). 2021;**10**(8):996. DOI: 10.3390/antibiotics10080996

[8] Gi Mancuso G, Midiri A, Gerace E, et al. Bacterial antibiotic resistance:

The most critical pathogens. Pathogens. 2021;**10**(10):1310. DOI: 10.3390/ pathogens10101310

[9] WHO. Antimicrobial Resistance and Primary Health Care, Technical Series on Primary Health Care. Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO

[10] Yao L, Yin J, Huo R, et al. The effects of the primary health care providers' prescription behavior interventions to improve the rational use of antibiotics: A systematic review. Global Health Research and Policy. 2020;**5**:45. DOI: 10.1186/s41256-020-00171-2

[11] Dadgostar P. Antimicrobial resistance: Implications and costs. Infection and Drug Resistance. 2019;**12**:3903-3910. DOI: 10.2147/IDR. S234610

[12] Yau JW, Thor SM, Tsai D, et al. Antimicrobial stewardship in rural and remote primary health care: A narrative review. Antimicrobial Resistance & Infection Control. 2021;**10**(105):1-33. DOI: 10.1186/ s13756-021-00964-1

[13] Sulis G, Adam P, Nafade V, et al. Antibiotic prescription practices in primary care in low- and middleincome countries: A systematic review and meta-analysis. PLoS Medicine. 2020;**17**(6):1-20. DOI: 10.1371/journal. pmed.1003139

[14] Sharaf N, Al-Jayyousi GF, Radwan E, et al. Barriers of appropriate antibiotic prescription at PHCC in Qatar: Perspective of physicians and pharmacists. Antibiotics (Basel). 2021;**10**(3):317. DOI: 10.3390/ antibiotics10030317

[15] Chinemerem Nwobodo D, Ugwu MC, Oliseloke Anie C, et al. Antibiotic resistance: The challenges and some emerging strategies for tackling a global menace. Journal of Clinical Laboratory Analysis. 2022;**36**(9):1-10. DOI: 10.1002/ jcla.24655

[16] Llor C, Bjerrum L. Antimicrobial resistance: Risk associated with antibiotic overuse and initiatives to reduce the problem. Therapeutic Advances in Drug Safety. 2014;**5**(6):229-241. DOI: 10.1177/2042098614554919

[17] Harun MGD, Anwar MMU, Sumon SA, et al. Rationale and guidance for strengthening infection prevention and control measures and antimicrobial stewardship programs in Bangladesh: A study protocol. BMC Health Services Research. 2022;**22**(1):1-11. DOI: 10.1186/ s12913-022-08603-0

[18] Hansen MP, Hoffmann TC, McCullough AR, et al. Antibiotic resistance: What are the opportunities for primary care in alleviating the crisis? Frontiers in Public Health. 2015;**3**(35):1- 5. DOI: 10.3389/fpubh.2015.00035

[19] Luhraimaduretnoasvinigita B, Kristina S, Ika PS. Antibiotics stewardship practice among community pharmacists in Indonesia: A cross-sectional survey. International Journal of Pharmaceutical Research. 2020;**11**(4):176-180. DOI: 10.31838/ ijpr/2019.11.04.028

[20] Medina-Perucha L, García-Sangenís A, Moragas A, et al. Autonomy, power dynamics and antibiotic use in primary healthcare: A qualitative study. PLoS One. 2020;**15**(12):1-21. DOI: 10.1371/journal.pone.0244432

[21] WHO. A One Health Priority Research Agenda for Antimicrobial Resistance. Geneva: World Health

Organization, Food and Agriculture Organization of the United Nations, United Nations Environment Programme and World Organisation for Animal Health; 2023. Licence: CC BY-NC-SA 3.0 IGO

[22] WHO. Global Antimicrobial Resistance and Use Surveillance System (GLASS) [Internet]. 2022. Available from: https://www.who.int/initiatives/ glass [Accessed: August 12, 2023]

[23] Ruby D. Social Media Users in 2023 (Global Demographics) [Internet]. 2023. Available from: https://www. demandsage.com/social-mediausers/#:~:text=Social%20Media%20 Users%202023%20(Top,base%20 with%202.99%20billion%20users [Accessed: August 01, 2023]

#### **Chapter 3**

## Applications of Antimicrobial Stewardship and Natural Product Chemistry in Tackling Antimicrobial Resistance

*Khalifa Musa Muhammad and Mansurat Oluwatoyin Shoge*

#### **Abstract**

Antimicrobial resistance (AMR) is a major concern for global health security because of its impact on human, environment, and animal health. This tendency of AMR was corroborated by Alexander Fleming who discovered the first antibiotic. This chapter focuses on the global concern of AMR, its causes, and solutions. Antimicrobial stewardship (AMS) is one of the solutions employed globally to tackle the challenge of AMR. The objective of the AMS includes: reducing antibiotic abuse, lowering healthcare costs, and tackling AMR. Therefore, it is pertinent to decrease AMR and protect global health. Many countries are implementing antimicrobial stewardship programs (ASPs) in order to reduce AMR. The misuse of antibiotics is one of the major factors that cause AMR. To reduce antibiotic abuse pharmacists have a key role to play. Finding new drugs to treat resistant pathogens is another solution to AMR. Plants have contributed immensely to traditional medicine and drug discovery due to the presence of bioactive secondary metabolites. They have the potential to contribute immensely to tackling AMR.

**Keywords:** antimicrobial resistance, antimicrobial stewardship, global health, plants, secondary metabolites

#### **1. Introduction**

Antibiotics are considered as a substance of biological origin or produced by a microorganism that can be lethal to other organisms or inhibit their growth [1]. In 1928 Alexander Fleming discovered the first antibiotic from fungi and by 1940 other useful antibiotics were discovered from bacteria [2]. The period of 1930–1960 is regarded as the antibiotics golden era due to the discovery of many antibiotics [3].

The drugs that are most prescribed across the globe are antibiotics [4]. It is estimated that by 2030 the use of antibiotics will increase up to 67% in highly populated countries around the world [5]. Antibiotics have contributed immensely by reducing mortality and morbidity rates, especially in developing countries [6]. However, there is a need for new antibiotics due to the existence of resistant bacteria and the advent of new diseases [2].

Antibiotics mechanism of action includes:


Antibiotics have played an unparalleled role in the advancement of society and medicine, and they are now a requirement in all healthcare systems. Antibiotic treatment has contributed to controlling bacterial infections; enhancing major surgeries; cancer therapy; and other successful aspects of modern medicine [5].

It is pertinent to sustain the effectiveness of present antibiotics in order to prevent any retrogression recorded in dialysis, surgery, and chemotherapy among others [7]. If the challenge of antimicrobial resistance (AMR) is not tackled then gains recorded in controlling/treating illnesses like HIV, TB, and malaria would be in dire situation [4].

#### **1.1 Antimicrobial resistance**

The case of methicillin-resistant S*taphylococcus aureus* was reported in the 1950s [8]. *Salmonella*, *Shigella*, and *Escherichia coli* were intestinal bacteria that were resistant to various antimicrobial treatments in the late 1950s and early 1960s. These resistant strains led to significant life, financial, and clinical loss, primarily in developing countries. However, it was seen as a minor health issue limited to intestinal bacteria in the developed world. This false belief was dispelled in the 1970s when it was discovered that *Haemophilus influenzae* and *Neisseria gonorrhoeae* are ampicillin-resistant, with *Haemophilus* also being reported to be resistant to tetracycline and chloramphenicol [5]. Antibiotics destroy delicate germs, but they leave behind resistant pathogens, which eventually proliferate and flourish due to natural selection [9].

AMR is the main issue when treating a certain disease for a long time. AMR occurs when microorganisms stop responding to medications that once killed them. The rise in AMR is caused by both microbial behavior and how people take antimicrobial medications. This resistance could be extremely harmful since it might make some illnesses impossible to cure, which could result in serious consequences or even death. To combat AMR, researchers are striving to create novel therapeutics [9].

Bacteria can develop antibiotic resistance in addition to the intrinsic mechanism of resistance. Other mechanisms may also contribute to the development of antibiotic resistance in bacteria. These include antibiotic efflux or poor drug penetration that lowers the antibiotic's intracellular concentration, modification of the antibiotic's target site caused by posttranslational target modification or genetic target mutation, and inactivation of the antibiotic through modification or hydrolysis [5].

*Applications of Antimicrobial Stewardship and Natural Product Chemistry in Tackling… DOI: http://dx.doi.org/10.5772/intechopen.113185*

#### *1.1.1 Virulence*

Human skin, mucous membranes, and internal organs all contain bacteria. The ability of bacteria to cause disease is known as pathogenicity, and a pathogen carries a number of elements known as virulence that enable the bacterium to enhance its level of pathogenicity. Toxicity and invasiveness are two of a pathogen's most crucial characteristics that aid in the development of a disease. Both virulence and the state of the host's immune system have the potential to affect the final balance of a bacterial illness course. The coevolution of the host and bacterium may have occurred over a period of millions of years. During this time, pathogens have altered their virulence to adapt to the host's immune system [10].

#### **1.2 Global concern of AMR**

AMR is an increasing challenge to the global economy, human health, and sustainable development due to the indisposition, death, and economic cost it causes [7, 11]. AMR is a global challenge; however, antibiotics have contributed immensely to medicine by treating bacterial infections in animals [5]. Inappropriate use of antibiotics is widely regarded to contribute to the growing challenge of resistant bacteria [12]. Sir Alexander Fleming, who discovered antibiotics, had cautioned that the public would demand antibiotics and this would begin an era of abuses. Therefore, the primary driver of resistance development is the overuse of antibiotics [9].

The infections that are caused by multidrug-resistant pathogens are linked with a high rate of mortality [13, 14]. The coronavirus pandemic has led to an increase in multidrug-resistant pathogens and this heightens the challenge of AMR [15]. The resistance of antibiotics is associated with: pumping antibiotics out of cell, decreasing uptake of antibiotics, distorting the target to reduce the binding of antibiotics with the target, and enzyme inactivation [16].

By 2050, AMR-related mortality is estimated to outpace diseases like cancer and diabetes, killing 10 million people annually [17, 18]. Major concerns about the security of the global health system include the escalation of AMR and the dearth of novel medications to treat drug-resistant bacterial illnesses [7]. The World Economic Forum, the World Health Organization (WHO), the Centre for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America have all identified antibiotic resistance as a global public health concern [19, 20]. The World Health Assembly asked WHO to submit a worldwide action plan to address the issue of antibiotic resistance [21].

People in the UK have voted for a government-sponsored \$10 million award (longitude award challenge) to find new ways to prevent antibiotic resistance [22, 23]. According to the US President's Council of Advisors on Science and Technology's recommendations, President Barack Obama in the United States instructed the National Security Council to create a comprehensive national action plan (NAP) to combat antibiotic resistance by 2015 [24, 25]. Multidrug-resistant (MDR) bacterial infections have been linked to over 8 million hospital stays and are currently costing healthcare systems over \$20 billion, according to research by the WHO [26].

AMR is a critical issue that needs to be addressed on a global scale since it has a detrimental influence on patient safety, public health, and clinical outcomes. It also poses a threat to the advancements made in contemporary medicine, as it makes it difficult to treat severe infectious diseases effectively given how infrequently new

antibiotics are being developed [27]. This places a significant load on healthcare systems all across the world [28]. Many nations have created and are putting into practice their NAPs for AMR [29].

#### **1.3 Causes of AMR**

Microbial resistance results because of improper antibiotic usage [30]. The overuse of antibiotics is discouraged nevertheless overprescription is still practiced around the world [31]. The misuse of antibiotics is facilitated by self-medication behaviors and the unrestricted procurement of antibiotics without prescriptions, particularly in low-income nations [31, 32]. It is pertinent to control AMR because of its potential to incur US \$1 trillion in healthcare costs by 2050 if left unchecked [33, 34]. The improper use of antibiotics is present in hospitalized patients and community [35, 36]. About 62% of antibiotics sold in community pharmacies around the world are given out with no prescription [37]. Community pharmacists frequently give antibiotics without a prescription due to a variety of factors including complacency, patient pressure, and fear of losing customers [38, 39]. There are various studies that have confirmed inappropriate prescription of antibiotics [40, 41]. A meta-analysis revealed that in a particular community pharmacy setting, 62% of antibiotics were dispensed without a prescription to treat illnesses that do not even require antibiotic therapy [42].

Furthermore, infection control guidelines, sanitation settings, water hygienic practices, diagnostic and treatment procedures, drug quality, and travel or migration quarantine are additional significant factors that have the potential to cause antibiotic resistance. The exchange of genetic material between organisms enhances the spread of antibiotic resistance, in addition to the mutation of numerous genes located on the chromosome of the microbe [5]. Resistance results from diverse genetic mutations and alterations that make microorganisms less sensitive to certain types of antibiotics. As a result, infections become more difficult to treat and rates of transmission, sickness severity, and mortality considerably rise [43, 44]. Antibiotic resistance has resulted because bacterial infections are becoming more challenging to treat because of pharmaceutical industry's failure to produce new medications [40].

The lack of antimicrobials has made AMR a serious global problem. The cost of medications, the length of hospital stays, and the overall cost of healthcare services all rise as a result of AMR [45]. AMR is associated with poverty and the WHO has posited that by 2050 about 28 million could be pushed into extreme poverty [46]. Inappropriate management of antimicrobial agents has been shown to have a substantial impact both in developed and developing nations worldwide. The population's general lack of awareness and perhaps the prescribers' lack of knowledge are the main factors in the misuse of antibiotics. This may cause them to select the wrong treatment course or therapeutic agent, increasing the likelihood of the emergence of microbial resistance [47, 48].

#### **1.4 Solution to AMR**

Despite the WHO's repeated warnings new antibiotics are needed to address the growing threat of antibiotic resistance [49]. The rise of AMR rates has prompted calls from the WHO and UN urging nations to create NAPs [50]. Otherwise, AMR rates will increase significantly, having a negative influence on death, morbidity, and expenditures [51, 52].

*Applications of Antimicrobial Stewardship and Natural Product Chemistry in Tackling… DOI: http://dx.doi.org/10.5772/intechopen.113185*

Five strategic goals are outlined in the Global Action Plan on AMR as a guide for nations creating their NAPs on AMR:

Objective 1: Improve public knowledge and comprehension of AMR through effective outreach, instruction, and training.

Objective 2: Through observation and research, strengthen the body of information and evidence.

Objective 3: Reduce the likelihood of infection by implementing efficient sanitation, hygiene, and infection prevention practices.

Objective 4: Optimize the use of antimicrobial drugs for both human and animal health.

Objective 5: Develop the financial justification for long-term investments that consider the requirements of all nations and boost spending on innovative drugs, diagnostic equipment, vaccinations, and other interventions [53].

Utilizing antimicrobial drugs sparingly and for the shortest possible time is a crucial step in preventing and reducing resistance [54]. To promote appropriate antibiotic use in community settings, approaches like encouraging prescribers to include the diagnosis on the prescription, implementing delayed prescribing, point-of-care testing, and creating collaborative practice agreements can be effective options [55, 56]. A global action plan on antibiotic resistance is necessary in order to enrich public perceptions of antibiotic resistance, lowering the frequency of infections, stepping up monitoring and research efforts, and maximizing the use of antibiotics [57]. To ensure the best possible use of antibiotics in the public, proper dispensing procedures at community pharmacies are crucial in this situation [58]. To clarify, analyze, and examine pharmacists' and patients' perspectives, beliefs, and feelings, qualitative research methods are useful in pharmacy studies [59].

A distinct and fruitful strategy to combat AMR could be the use of alternative medicines for the treatment and control of infectious diseases. These treatments include vaccinations (against MRSA and MDR *Mycobacterium tuberculosis*), biological therapy (application of monoclonal antibodies, insulin, erythropoietin, etc.), and anti-virulence techniques (to manipulate the virulence components of bacteria) [60, 61]. Additionally, herbal remedies have illusive properties; yet, there is a strong argument that they might be a workable alternative [5].

#### **2. Antimicrobial stewardship**

One of the methods for reducing antibiotic resistance is known as antimicrobial stewardship (AMS) [62]. It ensures that the best antimicrobial therapies are chosen, administered, and continued for the shortest possible time to produce the best therapeutic results with the least amount of chance that the patient may experience adverse effects or the emergence of AMR [63]. Succinctly, AMS programs work to raise the success rates of treating infections, decrease treatment failures, and correctly prescribe therapy and prophylaxis [64]. The WHO has pushed for and taken the lead in developing frameworks for antimicrobial stewardship programs (ASPs) by working with other professional, national, and international organizations [53, 65]. AMS is accomplished by preventing the unnecessary use of medications and by offering focused, targeted care when it is appropriate in order to raise the standard of patient care [66].

Antibiotic stewardship is a method that makes sure antibiotics are used correctly and in sufficient amounts when necessary. Additionally, this assures that antibiotic use yields the most advantages, stops the spread of infections, and improves both health and economic benefits [67]. Evidence demonstrates that antibiotic stewardship initiatives are successful in encouraging judicious antibiotic usage and enhancing clinical results in the hospital context [68]. Reviews have demonstrated the effectiveness of ASPs in boosting antibiotic policy adherence; reducing the length of antibiotic therapy; decreasing antibiotic resistance, morbidities, mortalities, healthcare-associated infections, costs, and extended hospital stays [69]. ASPs help to promote achieving the sustainable development goals (SDGs) [70]. A thorough stewardship program should include constant monitoring and audit of antibiotic consumption patterns with clinician feedback; the development of an antibiotic formulary; nonstop educational initiatives; antibiotic de-escalation to ease the switch from broad spectrum to narrow spectrum antibiotics; the development of infection treatment guidelines; antibiotic restriction programs; and the enforcement of proper medication regimens [71].

Medical professionals, clinical microbiologists, pharmacists, nurses, and/or administrative staff typically make up multidisciplinary teams for ASPs and the interventions they use can vary greatly depending on the healthcare system and cultural context [72]. ASPs must be implemented in order to improve the prudent use of antibiotics in healthcare facilities and the general public [73, 74].

#### **2.1 Objectives of AMS**

Reduced antibiotic abuse, lower healthcare costs, improved clinical outcomes, and a decrease in AMR are the objectives of AMS [62]. The ASPs are targeted to ensure the responsible use and continuous efficacy of available antimicrobials through a wide range of treatments incorporating quality improvement efforts [4].

#### **2.2 Role of pharmacists in AMS**

According to the CDC and the American Society of Health-System Pharmacists (ASHP), pharmacists have a significant role to play in infection prevention and control programs which are important to AMS [75, 76]. Pharmacists contribute to AMS programs in the following ways: leading of AMS programs in healthcare facilities, formulary development; automatic change and stop orders; dose optimization therapeutic drug monitoring; and providing empirical antimicrobial guidance [62]. Additionally, AMS activities led by pharmacists maximize patient clinical outcomes, enhance the proper administration of antibiotics, and lower the cost of antibiotics [68, 77, 78].

Lack of training and information are among the major obstacles that affect the participation of pharmacists in AMS [62, 79]. Patient education relies heavily on pharmacists and numerous studies have demonstrated the benefits of instructing patients on proper antibiotic usage [70]. Therefore, it is advised that undergraduate pharmacy students should be trained in the areas of antimicrobial therapy, AMR, and AMS [62]. Pharmacists play critical roles in ASPs like: taking part in antimicrobial ward rounds; editing and writing antimicrobial guidelines; keeping track of antimicrobial consumption and spending; and educating healthcare professionals about antimicrobials [79]. Community pharmacies are the best place to introduce ASPs because of the effect antibiotic resistance has on the patient's condition and the cost to society [80]. Community pharmacists play a crucial role in patient management since

#### *Applications of Antimicrobial Stewardship and Natural Product Chemistry in Tackling… DOI: http://dx.doi.org/10.5772/intechopen.113185*

they are frequently the first healthcare providers that people see about their condition [81]. They are crucial stewards of antibiotics and play a significant role in informing, educating, and counseling patients and healthcare professionals on how to use antibiotics properly [82].

In Sub-Saharan Africa (SSA), there is a shortage of infectious disease pharmacists. However recent studies have demonstrated that with the right training, pharmacists in SSA can create and oversee AMS programs that are comparable to those in the UK or the USA [4]. Existing research indicates that pharmacists are crucial in developing and managing antimicrobial guidelines and policies; evaluating individual patient regimens to optimize therapy; auditing antimicrobial consumption outcomes both prospectively and retrospectively; and training clinical teams and patients [83]. Additionally, it has been noted that doctors frequently rely on the advice and knowledge of pharmacists about antibiotic stewardship [84]. Studies have shown that AMS with a pharmacist reduced antibiotic consumption compared [85].

#### **2.3 Implementation of AMS across the globe**

Due to the growing concern about AMR and the drying up of the supply of new antibiotics, there has been a global push for the implementation of ASPs [72]. More detailed instructions on how to set up, carry out, and assess efficient AMS programs at the national and healthcare facility level are increasingly needed, particularly in developing countries [53]. The adoption of AMS principles in the real world is thought to depend heavily on education [86]. Healthcare systems around the world have embraced AMS as a crucial strategy for combating AMR [87].

The implementation of AMS in Nigerian hospitals is insufficient even though AMS is a part of the Nigerian National Antimicrobial Resistance Action Plan 2017–2022 [79]. The enforcement of a law banning the distribution of antibiotics without a prescription among community pharmacists in Saudi Arabia dramatically reduced such malfeasance [88]. In 2007, the Thailand Ministry of Public Health started a campaign "Antibiotic Smart Use" to encourage prudent antibiotic use in Thailand hospitals. In 2016, the Royal Thai Government released a National Strategic Plan on AMR [64].

According to a study conducted in Australia, clinical leaders' involvement and executive-level support were essential for the successful implementation of AMS programs [89]. In order to implement a comprehensive and sustainable ASP it is pertinent to take into consideration the following: the need for developing formal AMS policies and incorporating them into the clinical governance structure; establishing a multidisciplinary approach to AMS with clear roles and responsibilities for each team member and importance of organizational investment in staffing, information management systems, and staff education [64].

#### **3. Plants contribution to medicine**

Traditional medicine is acknowledged by the WHO as an essential alternative healthcare delivery system for the majority of the global population [90]. According to WHO, more than 80% of people in developing nations still rely on herbal medicine to treat diseases [91]. Globally, herbal medicine either forms the backbone of healthcare delivery or works in tandem with it [92]. Numerous plants have secondary metabolites also referred to as bioactive metabolites because of their antimicrobial properties [93].

The large and diverse groups of organic compounds that make up the secondary metabolites in plants are produced in small amounts, and they play no direct role in vital processes like photosynthesis and respiration [94]. The primary function of a plant's secondary metabolites is to defend itself against pathogens and predators. These secondary metabolites have significant applications in modern medicine as they are useful for treating or preventing some human ailments [95]. Examples of secondary metabolites include: tannins, flavonoids, terpenoids, and saponins and they possess antibacterial properties [90].

The combination of compounds known as secondary metabolites found in plants is primarily responsible for the good therapeutic effects of plant materials [96]. Secondary metabolites are efficient and more affordable than conventional drugs. They have been seen to be the preferred first-line therapy option for people, particularly traditional healers, in treating infections and other disorders [97]. About 25% of drugs produced are derived from plants and even synthetic drugs derive their structures from natural products. This is because plant secondary metabolites provide protection against microbial infection and insects [2].

Plant defense mechanisms vary depending on their unique needs and are influenced by physiological conditions, climatic changes, and environmental factors [98, 99]. Secondary metabolites can treat diseases by themselves or in conjunction with other substances or metabolites. Numerous studies have shown that such combinations can improve the effectiveness of a disease's treatment [100]. Due to their bioactivity, secondary metabolites have historically been employed in medical systems across the globe [101].

Natural products derived from medicinal plants give room for the discovery of new drugs [102]. There are many medications made of various secondary metabolites that have the potential to address the issue of drug resistance and open up a new avenue for researchers to find new medications [101]. Concern over antibiotic resistance is now widespread. The rise of MDR bacteria poses a danger to the therapeutic efficacy of several currently available medications. Treatment relies heavily on the use of plant extracts and phytochemicals, both of which have well-known antibacterial effects [103]. In order to survive and thrive in the natural environment, plants produce a variety of biologically active substances that shield them from pests, abiotic stress and disease infections [104]. In developed and developing nations, there is increased interest in medicinal plants due to their potential to cure infectious diseases [105].

#### **3.1 Pharmacological activities of secondary metabolites**

Secondary metabolites perform biological activity that neutralizes bacteria or animal cells by interacting with specific targets within those structures. However, the variety of metabolic routes that plants take to produce these metabolites ensures the presence of unique structures in these defense molecules that can be used to create new medications and pharmaceuticals. Because of this, plants are a significant source of compounds that can be utilized to enhance health and/or treat ailments [94]. Secondary metabolite chemicals found in many plants such as phenolics, alkaloids, carotenoids, and anthocyanins that accumulate in vegetables and fruit, may act as antioxidants. Antioxidants have the potential to lessen the oxidative and structural harm brought on by free radical molecules, and they are crucial in the prevention of cancer, the slowing of aging, UV protection, and the reduction of tissue inflammation in maintaining human health [105].

#### *Applications of Antimicrobial Stewardship and Natural Product Chemistry in Tackling… DOI: http://dx.doi.org/10.5772/intechopen.113185*

The antibacterial action of polyphenols is based on their capacity to prevent the development, reproduction, respiration, and any other essential function of microbes. This effect is caused by the oxidation of particular enzymes, which also inhibit several vital processes like respiration. Additionally, it has been claimed that polyphenols inhibit the creation of proteins in bacteria by binding to DNA chains. According to some scientists, certain polyphenols may be able to rupture the cell walls of microorganisms, leading to cell apoptosis. Due to their lipophilic character, monoterpenes are also known to interact with the phospholipids found in the cell membranes of numerous bacteria [94].

The most common characteristic for bacteria to live in an unfavorable environment are bacterial biofilms. Due to their high antibiotic tolerance, biofilms are one of the causes of chronic, nosocomial, and medical device-related infections, which present a significant challenge to the healthcare system. Several plant-derived substances, including phenylpropanoids, terpenoids, betulinic and ursolic acids, and alkaloids, such as berberine, indole, and chelerythrine, exhibited anti-biofilm activity toward *Pseudomonas aeruginosa*, *Klebsiella pneumoniae* and *staphylococcus* biofilms. The disruption of intercellular communication, disturbance in cell-to-cell coaggregation, inhibition of cell mobility, inactivation of bacterial adhesins, or stimulation of bacterial dispersal are the suggested mechanisms of plants' secondary metabolites in inhibiting bacterial biofilm [106]. The screening of plant extracts and natural products for antimicrobial activity has revealed that medicinal plants are a potential source of novel anti-infective medicines [107].

#### **3.2 Mechanism of action of secondary metabolites**

Secondary metabolites can affect the microbial cell in a variety of ways, including disruption of the cytoplasmic membrane's efflux system, interaction with membrane proteins, impacting DNA/RNA synthesis and function, impairing enzyme synthesis, causing cytoplasmic constituents to coagulate, and interfering with normal cell communication (quorum sensing) [106]. Terpenoids, alkaloids, and flavonoids are some of the substances that are currently utilized as medications or dietary supplements to treat or prevent a variety of illnesses like cancer. According to estimates, 14–28% of higher plant species are used medicinally, and research into ethno-medical plant use led to the discovery of 74% of pharmacologically active plant-derived components [108].

As a result, we are aware that the alkaloids have the capacity to intercalate with DNA, interrupting transcription and replication, and that they can also suppress cell division, leading to cell death. For instance, when *Streptococcus agalactiae* interacts with berberine it can severely disrupt the structure of bacterial cell membranes and prevent the creation of proteins and DNA. The action of flavonoids on the membrane of the microbial cell is what gives them their antibacterial properties; they interact with membrane proteins found on bacterial cell walls, making the membrane more permeable and disrupting it. Terpenes possess the capacity to damage microbial membranes and this is largely responsible for their antimicrobial effects [96].

#### **3.3 Potential of natural products for combating AMR**

The chemistry of natural drug products versus synthetic pharmaceuticals differs greatly, with natural products having a wider diversity of chemicals. The nitrogen, phosphorus, sulfur, and halogen content of natural products is lower, while their

structural complexity, scaffold variation, stereochemistry, ring system diversity, and carbohydrate content are increased [106]. Compared to current antibiotics, crude extracts from medicinal plants have proven to be more therapeutically efficacious and less harmful. The defense against free radicals and pathogenic bacteria is greatly aided by phytochemical substances, particularly flavonoids and other natural compounds. In order to tackle infectious disorders linked to drug-resistant microbes and oxidative stress, there is a compelling need to investigate new and more effective antimicrobial/ antioxidant substances of natural origin [107].

Natural plant extracts have a lower likelihood of developing resistance since they include numerous and complex phytochemicals [109]. A single plant contains a variety of phytochemicals so plant extracts can fight infections in a variety of ways. *Thymus vulgaris* essential oil has been shown to be effective against *Haemonchus contortus* that is resistant to benzimidazoles, macrocyclic lactones and imidazothiazoles. It can target different stages of the parasite's life cycle, including the ability to inhibit egg hatching, larvae motility, and development [110]. Natural plant extracts and compounds can be used with conventional antibiotics to increase the antibacterial efficacy in addition to having multiple modes of action. It was discovered that the alkaloid berberine, which is found in many plants, works in conjunction with fluconazole to combat *Candida albicans* that are resistant to the drug. Fluconazole may raise the intracellular content of berberine by rupturing the fungal cell membrane and this would enhance the effect of berberine [111]. Disruptions of cell membrane structures and function are mechanisms that some plant bioactive compounds like geraniol, monoterpene linalool, cinnamaldehyde, eugenol, and carvacrol, show their antifungal activity [106].

#### **4. Future perspectives**

Some antimicrobial metals kill MDR bacteria and selectively disrupt metabolic pathways [112]. Metal nanoparticles have the potential to threaten bacterial survival and antimicrobials containing silver can impact physical stress on cells of bacteria [113]. Also, gallium can interfere with the metabolic pathways of bacteria [114]. Genetically engineered bacteria can be used to target pathogens. A good example is the use of *E. coli* to secrete antimicrobial peptides in response to quorum-sensing molecules released by *P. aeruginosa* [113]. Furthermore, synthetic drugs can be combined with natural products to tackle AMR. The combination of fluconazole and berberine may be an effective combination to boost fluconazole's effectiveness in fluconazoleresistant *C. tropicalis* [106].

#### **5. Conclusion**

Antibiotics have played a crucial role in medicine by reducing morbidity and mortality rates. Without antibiotics, some successful aspects of modern medicine may not have been achieved. However, the inappropriate use of antibiotics has resulted in to the development of AMR. This poses a threat to human health, global economy, and sustainable development. World Economic Forum and WHO have labeled AMR as a matter of global public concern and many nations have taken stance on tackling this menace. This has led to increased efforts to tackle the challenge of AMR. AMS has been identified as one of the methods of reducing AMR. The method is focused on

#### *Applications of Antimicrobial Stewardship and Natural Product Chemistry in Tackling… DOI: http://dx.doi.org/10.5772/intechopen.113185*

preventing unnecessary use of antibiotics in order to prevent the occurrence of AMR. Some of the objectives of the ASPs are: reducing antibiotic use and lowering healthcare costs. Multidisciplinary teams are used to champion the ASPs and pharmacists play crucial roles in these teams. Another way to tackle AMR is the development of new antibiotics. Plants have contributed immensely to healthcare delivery across the globe since prehistoric times. Bioactive secondary metabolites have pharmacological functions for treating diseases and they possess the potential to contribute to tackling AMR. The study also highlights future perspectives that should be considered in combating AMR.

### **Author details**

Khalifa Musa Muhammad\* and Mansurat Oluwatoyin Shoge Department of Chemistry, Air Force Institute of Technology, Kaduna, Nigeria

\*Address all correspondence to: mkhalifam14@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Etebu E, Arikekpar I. Antibiotics: Classification and mechanisms of action with emphasis on molecular perspectives. International Journal of Applied Microbiology and Biotechnology Research. 2016;**4**:90-101

[2] Demain AR. Antibiotics: Natural products essential to human health. Medicinal Research Reviews. 2009;**29**(6):821-842. DOI: 10.1002/ med.20154

[3] Nathan C, Cars O. Antibiotic resistance-problems, progress, and prospects. New England Journal of Medicine. 2014;**371**(19):1761-1763

[4] Otieno PA, Campbell S, Maley S, Arunga TO, Okumu MO. A systematic review of pharmacist-led antimicrobial stewardship programs in Sub-Saharan Africa. International Journal of Clinical Practice. 2022:3639943. DOI: 10.1155/2022/3639943

[5] Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, et al. Antibiotic resistance: A rundown of a global crisis. Infection and Drug Resistance. 2018;**11**:1645-1658

[6] Van Boeckel TP, Brower C, Gilbert M, Grenfell BT, Levin SA, Robinson TP, et al. Global trends in antimicrobial use in food animals. Proceedings of the National Academy of Sciences. 2015;**112**(18):5649- 5654. DOI: 10.1073/pnas.1503141112

[7] World Health Organization. Antimicrobial Resistance: Global Report on Surveillance. Geneva, Switzerland: World Health Organization; 2014

[8] Saga T, Yamaguchi K. History of antimicrobial agents and resistant bacteria. Journal of the Japan Medical Association. 2008;**137**(3):513-517

[9] Babu PC, Meeravali SN, Azad S, Kumar KR. An overview on microbial infections and their antimicrobial resistance. Indo American Journal of Pharmaceutical Sciences. 2020;**7**(3):457-462

[10] Martinez JL, Baquero F. Interactions among strategies associated with bacterial infection: Pathogenicity, epidemicity, and antibiotic resistance. Clinical Microbiology Reviews. 2002;**15**(4):647-679

[11] Laxminarayan R, Duse A, Wattal C, Zaidi AKM, Wertheim HFL, Sumpradit N, et al. Antibiotic resistance—The need for global solutions. The Lancet Infectious Disease. 2013;**13**:1057-1098. DOI: 10.1016/ s1473-3099(13)70318-9

[12] Bell BG, Schellevis F, Stobberingh E, Goossens H, Pringle M. A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. BMC Infectious Disease. 2014;**14**:1-25

[13] Abubakar U, Tangiisuran B, Elnaem MH, Sulaiman SA, Khan FU. Mortality and its predictors among hospitalized patients with infections due to extended spectrum beta-lactamase (ESBL) Enterobacteriaceae in Malaysia: A retrospective observational study. Future Journal of Pharmaceutical Sciences. 2022;**8**(1):1-8

[14] Abubakar U, Zulkarnain AI, Rodríguez-Baño J, Kamarudin N, Elrggal ME, Elnaem MH, et al. Treatments and predictors of mortality for carbapenem-resistant gram-negative bacilli infections in Malaysia: A retrospective cohort study. Tropical Medicine and Infectious

*Applications of Antimicrobial Stewardship and Natural Product Chemistry in Tackling… DOI: http://dx.doi.org/10.5772/intechopen.113185*

Disease. 2022;**7**(12):1-12. DOI: 10.3390/ tropicalmed7120415

[15] Abubakar U, Al-Anazi M, Rodríguez-Baño J. Impact of COVID-19 pandemic on multidrug resistant gram positive and gram negative pathogens: A systematic review. Journal of Infection and Public Health. 2023;**16**(3):320-331

[16] Singh SB, Barrett JF. Empirical antibacterial drug discovery-foundation in natural products. Biochemical Pharmacology. 2006;**71**:1006-1015

[17] de Kraker MEA, Stewardson AJ, Harbarth S. Will 10 million people die a year due to antimicrobial resistance by 2050? PLOS Medicine. 2016;**13**(11):1-6. DOI: 10.1371/journal.pmed.1002184

[18] O'Neill J. Tackling drug-resistant infections globally: Final report and recommendations. The Review on Antimicrobial Resistance. 2016:1-84

[19] Michael CA, Dominey-Howes D, Labbate M. The antimicrobial resistance crisis: Causes, consequences, and management. Frontiers in Public Health. 2014;**2**:145

[20] Spellberg B, Srinivasan A, Chambers HF. New societal approaches to empowering antibiotic stewardship. Journal of the American Medical Association. 2016;**315**(12):1229-1230. DOI: 10.1001/jama.2016.1346

[21] Hoffman SJ, Caleo GM, Daulaire N, Elbe S, Matsoso P, Mossialos E, et al. Strategies for achieving global collective action on antimicrobial resistance. Bulletin of the World Health Organization. 2015;**93**(12):867-876

[22] Payne DJ, Miller LF, Findlay D, Anderson J, Marks L. Time for a change: Addressing R&D and commercialization challenges for antibacterials.

Philosophical Transactions of the Royal Society B Biological Science. 2015;**370**(1670):1-12. DOI: 10.1098/ rstb.2014.0086

[23] Luepke KH, Mohr JF. The antibiotic pipeline: Reviving research and development and speeding drugs to market. Expert Review of Anti Infective Therapy. 2017;**15**(5):425-433. DOI: 10.1080/14787210.2017.1308251

[24] Ventola CL. The antibiotic resistance crisis: Part 1: Causes and threats. Pharmacy and Therapeutics. 2015;**40**(4):277-283

[25] Landers T, Kavanagh KT. Is the presidential advisory council on combating antibiotic resistance missing opportunities? American Journal of Infection Control. 2016;**44**(11):1356-1359

[26] Nasr Z, Paravattil B, Wilby KJ. The impact of antimicrobial stewardship strategies on antibiotic appropriateness and prescribing behaviours in selected countries in the Middle East: A systematic review. Eastern Mediterranean Health Journal. 2017;**23**(6):430-440. DOI: 10.26719/2017.23.6.430

[27] Gillani SW, Shahwan MKS, Szollosi DE. A questionnaire based survey among pharmacy practitioners to evaluate the level of knowledge and confidence towards antimicrobial stewardship. Pharmacy Practice. 2023;**21**(1):1-9. DOI: 10.18549%2FPharmPract. 2022.4.2757

[28] MacBrayne CE, Williams MC, Levek C, et al. Sustainability of handshake stewardship: Extending a hand is effective years later. Clinical Infectious Diseases. 2020;**70**(11):2325-2332. DOI: 10.1093/cid/ciz650

[29] Antimicrobial Resistance: A Manual for Developing National Action Plans. Geneva: World Health Organization; 2016

[30] Holmes AH, Moore LS, Sundsfjord A, Steinbakk M, Regmi S, Karkey A, et al. Understanding the mechanisms and drivers of antimicrobial resistance. The Lancet. 2016;**387**:176-187. DOI: 10.1016/ s0140-6736(15)00473-0

[31] Roca I, Akova M, Baquero F, Carlet J, Cavaleri M, Coenen S, et al. The global threat of antimicrobial resistance: Science for intervention. New Microbes and New Infections. 2015;**6**:22-29. DOI: 10.1016/j.nmni.2015.02.007

[32] Al-Hamad A. Over-the-counter delivery of antibiotics: Are we sending the right message? American Journal of Infection Control. 2012;**40**:81-81

[33] Byrne MK, Miellet S, McGlinn A, Fish J, Meedya S, Reynolds N, et al. The drivers of antibiotic use and misuse: The development and investigation of a theory driven community measure. BMC Public Health. 2019;**19**:1-11. DOI: 10.1186/s12889-019-7796-8

[34] World Health Organization. Briefing to WHO Member States. 2023. Available from: https://apps.who.int/gb/MSPI/ pdf\_files/2023/03/Item1\_22-03.pdf

[35] Abubakar U, Sulaiman SAS, Adesiyun AG. Utilization of surgical antibiotic prophylaxis for obstetrics and gynaecology surgeries in Northern Nigeria. International Journal of Clinical Pharmacy. 2018:**40**(5):1037-1043. DOI: 10.1007/s11096-018-0702-0

[36] Abubakar U, Amir O, Rodríguez-Baño J. Healthcare-associated infections in Africa: A systematic review and metaanalysis of point prevalence studies.

Journal of Pharmaceutical Policy and Practice. 2022;**15**(1):1-12. DOI: 10.1186/ s40545-022-00500-5

[37] Auta A, Hadi MA, Oga E, Adewuyi EO, Abdu-Aguye SN, Adeloye D, et al. Global access to antibiotics without prescription in community pharmacies: A systematic review and meta-analysis. Journal of Infection. 2019;**78**:8-18

[38] Zapata-Cachafeiro M, González-González C, Váquez-Lago JM, López-Vázquez P, López-Durán A, Smyth E, et al. Determinants of antibiotic dispensing without a medical prescription: A crosssectional study in the north of Spain. Journal of Antimicrobial Chemotherapy. 2014:**69**(11):3156-3160. DOI: 10.1093/jac/dku229

[39] Zawahir S, Lekamwasam S, Aslani P. A cross-sectional national survey of community pharmacy staff: Knowledge and antibiotic provision. PLoS One. 2019:**14**(4):1-15

[40] Abubakar U, Tangiisuran B. Knowledge and practices of community pharmacists towards non-prescription dispensing of antibiotics in Northern Nigeria. International Journal of Clinical Pharmacy. 2020;**42**(2):756-764. DOI: 10.1007/s11096-020-01019-y

[41] Abubakar U. Practices and perceptions of Nigerian community pharmacists toward antimicrobial stewardship program. International Journal of Pharmacy and Pharmaceutical Sciences. 2020;**12**(4):37-42

[42] Al-Shami HA, Abubakar U, Hussein MSE, Hussin HFA, Al-Shami SA. Awareness, practices and perceptions of community pharmacists towards antimicrobial resistance and antimicrobial stewardship in Libya: A cross-sectional study. Journal of

*Applications of Antimicrobial Stewardship and Natural Product Chemistry in Tackling… DOI: http://dx.doi.org/10.5772/intechopen.113185*

Pharmaceutical Policy and Practice. 2023;**16**(46):1-10

[43] Munita JM, Arias CA. Mechanisms of antibiotic resistance. Microbiology Spectrum. 2016;**4**:481-511. DOI: 10.1128/ microbiolspec.VMBF-0016-2015

[44] World Health Organization. Antimicrobial Resistance. 2020. Available from: https://www.who. int/news-room/fact-sheets/detail/ antimicrobial-resistance

[45] Ababneh MA, Nasser SA, Rababa'h AM. A systematic review of antimicrobial stewardship program implementation in Middle Eastern countries. International Journal of Infectious Diseases. 2021;**105**:746-752

[46] Antimicrobial Resistance and Primary Health Care. World Health Organization; 2018. Available from: https://apps.who.int/iris/bitstream/ handle/10665/328084/WHO-HIS-SDS-2018.57-eng.pdf

[47] Pinder RJ, Berry D, Sallis A, et al. behaviour change and antibiotic prescribing in healthcare settings: Literature review and behavioural analysis. Public Health England. 2015. Available from: https://assets.publishing. service.gov.uk/government/uploads/ system/uploads/attachment\_data/ file/774129/Behaviour\_Change\_for\_ Antibiotic\_Prescribing\_-\_FINAL.pdf

[48] Yu B, Wang S, Yin X, Bai J, Gong Y, Lu Z. Factors associated with doctors' knowledge on antibiotic use in China. Scientific Reports. 2016;**6**(1):1-5. DOI: 10.1038/srep23429

[49] Woolhouse M, Waugh C, Perry MR, Nair H. Global disease burden due to antibiotic resistance state of the evidence. Journal of Globalization and Health. 2016;**6**(1):1-5

[50] Saleem Z, Hassali MA, Hashmi FK. Pakistan's National Action Plan for antimicrobial resistance: Translating ideas into reality. The Lancet Infectious Diseases. 2018;**18**:1066-1067

[51] Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: Mortality, length of hospital stay, and health care costs. Clinical Infectious Diseases. 2006;**42**:S82-S89

[52] Founou RC, Founou LL, Essack SY. Clinical and economic impact of antibiotic resistance in developing countries: A systematic review and metaanalysis. PLoS One. 2017;**12**:1-18

[53] World Health Organization. Antimicrobial Stewardship Programmes in Health-Care Facilities in Low-And Middle-Income Countries: A WHO Practical Toolkit. Geneva, Switzerland: World Health Organization; 2019

[54] Burgera M, Fouriea J, Lootsa D, Mnisia T, Schellacka N, Bezuidenhouta S, et al. Knowledge and perceptions of antimicrobial stewardship concepts among final year pharmacy students in pharmacy schools across South Africa. South African Journal of Infectious Diseases. 2016;**1**(1):1-7

[55] Dobson EL, Klepser ME, Pogue J, Labreche MJ, Adams AJ, Gauthier TP, et al. SIDP community pharmacy antimicrobial stewardship task force, outpatient antibiotic stewardship: Interventions and opportunities. Journal of the American Pharmacists Association. 2017;**57**:464-473. DOI: 10.1016/j.japh.2017.03.014

[56] Bishop C, Yacoob Z, Knobloch MJ, Safdar N. Community pharmacy interventions to improve antibiotic stewardship and implications for pharmacy education: A narrative

overview. Research in Social & Administrative Pharmacy. 2019;**15**:627- 631. DOI: 10.1016/j.sapharm.2018.09.017

[57] Alkadhimi A, Dawood OT, Hassali MA. Dispensing of antibiotics in community pharmacy in Iraq: A qualitative study. Pharmacy Practice. 2020;**18**(4):1-9

[58] Torres NF, Solomon VP, Middleton LE. Pharmacists' practices for non-prescribed antibiotic dispensing in Mozambique. Pharmacy Practice. 2020;**18**(3):1-13. DOI: 10.18549/ pharmpract.2020.3.1965

[59] Amin MEK, Nørgaard LS, Cavaco AM, Witry MJ, Hillman L, Cernasev A, et al. Establishing trustworthiness and authenticity in qualitative pharmacy research. Research in Social & Administrative Pharmacy. 2020;**16**(10):1472-1482. DOI: 10.1016/j. sapharm.2020.02.005

[60] Escaich S. Antivirulence as a new antibacterial approach for chemotherapy. Current Opinion in Chemical Biology. 2008;**12**(4):400-408

[61] Rex JH, Eisenstein BI, Alder J, et al. A comprehensive regulatory framework to address the unmet need for new antibacterial treatments. The Lancet Infectious Diseases. 2013;**13**(3):269-275. DOI: 10.1016/S1473-3099(12)70293-1

[62] Abubakar U, Sha'aban A, Mohammed M, Muhammad HT, Sulaiman SAY, Amir O. Knowledge and self-reported confidence in antimicrobial stewardship program me among final year pharmacy undergraduate students in Malaysia and Nigeria. Pharmacy Education. 2021;**21**(1):298-305

[63] Gerding DN. The search for good antimicrobial stewardship. The on Quality Improvement. 2001;**27**:403-404. DOI: 10.1016/S1070-3241(01)27034-5

[64] van Gulik N, Hutchinson A, Considine J, Driscoll A, Malathu K, Botti M. Barriers and facilitators to integrating antimicrobial stewardship into clinical governance and practice: A Thai case study. International Journal of Infection Control. 2020;**16**(2):1-11

[65] Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: Guidelines by the infectious diseases society of America and the society for healthcare epidemiology of America. Clinical Infectious Diseases. 2016;**62**:e51-e77

[66] Charani E, Holmes AH. Antimicrobial stewardship programmes: The need for wider engagement. BMJ Quality and Safety. 2013;**22**(11):885-887

[67] Abushaheen MA, Muzaheed, Fatani AJ, Alosaimi M, Mansy W, George M, et al. Antimicrobial resistance, mechanisms and its clinical significance. Disease-a-Month. 2020;**66**:1-21

[68] Abubakar U, Syed Sulaiman SA, Adesiyun AG. Impact of pharmacist-led antibiotic stewardship interventions on compliance with surgical antibiotic prophylaxis in obstetric and gynecologic surgeries in Nigeria. PLoS One. 2019;**14**(3)

[69] Davey P, Brown E, Charani E, McNeil K, Brown E, Gould IM, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database of Systematic Reviews. 2013;**30**(4):1-371. DOI: 10.1002/14651858.cd003543.pub4

[70] Drug-resistant Infections: A Threat to Our Economic Future. World Bank Report. Available from: https:// documents1.worldbank.org/curated/ en/323311493396993758/pdf/finalreport.pdf

*Applications of Antimicrobial Stewardship and Natural Product Chemistry in Tackling… DOI: http://dx.doi.org/10.5772/intechopen.113185*

[71] Aryee A, Price N. Antimicrobial stewardship—Can we afford to do without it? British Journal of Clinical Pharmacology. 2015;**79**(2):173-181

[72] Chung GW, Wu JE, Yeo CL, Chan D, Hsu LY. Antimicrobial stewardship: A review of prospective audit and feedback systems and an objective evaluation of outcomes. Virulence. 2013;**4**(2):151-157

[73] MarkGilchrist M, Wade P, Ashiru-Oredope D, Howard P, Sneddon J, Whitney L, et al. Antimicrobial stewardship from policy to practice: Experiences from UK antimicrobial pharmacists. Infectious Disease Therapy. 2015;**4**:51-64

[74] Sanchez GV, Fleming-Dutra KE, Roberts RM, Hicks LA. Core elements of outpatient antibiotic stewardship. Mobidity and Mortality Weekly Report. 2016;**65**:1-12. Retrieved from: https:// www.cdc.gov/mmwr/volumes/65/rr/ rr6506a1.htm

[75] Ponto JA. ASHP statement on the pharmacist's role in antimicrobial stewardship and infection prevention and control. American Journal of Health-System Pharmacists. 2010;**67**:575-577. DOI: 10.2146/sp100001

[76] Centers for Disease Control and Prevention. Core Elements of Hospital Antibiotic Stewardship Programs. 2014. Available from: https://www.cdc.gov/ antibiotic-use/healthcare/pdfs/coreelements.pdf

[77] Wang J, Dong M, Lu Y, Zhao X, Li X, Wen A. Impact of pharmacist interventions on rational prophylactic antibiotic use and cost saving in elective cesarean section. International Journal of Clinical Pharmacology and Therapeutics. 2015;**53**(8):1-11

[78] Brink AJ, Messina AP, Feldman C, Richards GA, Becker PJ, Goff DA, et al. Antimicrobial stewardship across 47 South African hospitals: An implementation study. The Lancet Infectious Diseases. 2016;**16**(9):1017-1025. DOI: 10.1016/ S1473-3099(16)30012-3

[79] Abubakar U, Tangiisuran B. Nationwide survey of pharmacists' involvement in antimicrobial stewardship programs in Nigerian tertiary hospitals. Journal of Global Antimicrobial Resistance. 2020;**21**:148-153

[80] Paravattil B, Zolezzi M, Nasr Z, Benkhadra M, Alasmar M, Hussein S. et al. An interventional call-back service to improve appropriate use of antibiotics in community pharmacies. Antibiotics. 2021;**10**:1-8

[81] Saleem Z, Hassali MA, Hashmi FK, Godman B, Saleem F. Antimicrobial dispensing practices and determinants of antimicrobial resistance: A qualitative study among community pharmacists in Pakistan. Family Medicine and Community Health. 2019;**7**:1-9. DOI: 10.1136/fmch-2019-000138

[82] American Society of Health-System Pharmacists. ASHP statement on the pharmacist's role in primary care. American Journal of Health-System Pharmacists. 1999;**56**:1665-1667. DOI: 10.1093/ajhp/56.16.1665

[83] Liaskou M, Duggan C, Joynes R, Rosado H. Pharmacy's role in antimicrobial resistance and stewardship. Clinical Pharmacy. 2018;**10**

[84] Mohiuddin AK. Pharmacistled antimicrobial stewardship. ACTA Scientific Medical Sciences. 2019;**3**(10):112-116

[85] Mahmood RK, Gillani SW, Saeed MW, Vippadapu P, Alzaabi MJMA. Impact of pharmacist-led services on antimicrobial stewardship programs: A meta-analysis on clinical outcomes. Journal of Pharmaceutical Health Services Research. 2021;**12**(4):615-625

[86] Saleh D, Abu-Farha R, Mukattash TL, Barakat M, Alefishat E. Views of community pharmacists on antimicrobial resistance and antimicrobial stewardship in Jordan: A qualitative study. Antibiotics. 2021;**10**(4):1-11. DOI: 10.3390/antibiotics10040384

[87] Thomas B, Abdulrouf P, Elkassem W, Al Hail F, Nazar Z, Nasr Z, et al. Clinical and economic impact of antimicrobial stewardship interventions reported among hospital inpatients in the Middle East: A systematic review protocol. 2020. DOI: 10.21203/rs.3.rs-50679/v1

[88] Alrasheedy AA, Alsalloum MA, Almuqbil FA, Almuzaini MA, Aba Alkhayl BS, Albishri AS, et al. The impact of law enforcement on dispensing antibiotics without prescription: A multi-methods study from Saudi Arabia. Expert Review of Anti-Infective Therapy. 2020;**18**(1):87-97

[89] Loh JAM, Darby JD, Daffy JR, Moore CL, Battye MJ, Lorenzo YSP, et al. Implementation of an antimicrobial stewardship program in an Australian metropolitan private hospital: Lessons learned. Healthcare Infection. 2015;**20**:134-140. DOI: 10.1071/HI15015

[90] Mohammed H, Muhammad HL, Hussaini MA. Comparative secondary metabolite compositions and antimicrobial properties of n-hexane and ethyl-acetate fractions of Nelsonia campestris. GSC Biological and Pharmaceutical Sciences. 2019;**9**(1):046-052

[91] Adeyemi MM, Habila JD, Enemakwu TA, Okeniyi SO, Salihu L. Antimalarial activity of leaf extract, fractions and isolation of sterol from Alstonia boonei. Tropical Journal of Natural Product Research. 2019;**3**(7):221-224

[92] Okoro IO, Auguster O, Edith OA. Antioxidant and antimicrobial activities of polyphenols from ethnomedicinal plants of Nigeria. African Journal of Biotechnology. 2010;**9**:2989-2993

[93] Pandey A, Kumar S. Antibiotic activity of antimicrobial metabolites produced from soil microorganisms: An overview. International Journal of Pharmaceutical Research & Allied Sciences. 2015;**4**(4):28-32

[94] Mera IFG, Falconí DEG, Córdova VM. Secondary metabolites in plants: Main classes, phytochemical analysis and pharmacological activities. Revista Bionatura. 2019;**4**:1000-1009 DOI: 10.21931/RB/2019.04.04.11

[95] Roopan SM, Madhumitha G. Bioorganic Phase in Natural Food: An Overview. Cham, Switzerland: Springer; 2018. DOI: 10.1007/978-3-319-74210-6

[96] Gorlenko CL, Kiselev HY, Budanova EV, Zamyatnin AA Jr, Ikryannikova LN. Plant secondary metabolites in the battle of drugs and drug-resistant bacteria: New heroes or worse clones of antibiotics? Antibiotics. 2020;**9**:1-19. DOI: 10.3390/ antibiotics9040170

[97] Manzo LM, Moussa I, Ikhiri K, Yu L. Toxicity studies of *Acacia nilotica* (L.): A review of the published scientific literature. Journal of Herbmed Pharmacology. 2019;**8**:163-172

[98] Ballhorn DJ, Kautz S, Heil M, Hegeman AD. Analyzing plant defenses in nature. Plant Signaling & Behavior. 2009;**4**(8):743-745

*Applications of Antimicrobial Stewardship and Natural Product Chemistry in Tackling… DOI: http://dx.doi.org/10.5772/intechopen.113185*

[99] Samuni-Blank M, Izhaki I, Dearing MD, Gerchman Y, Trabelcy B, Lotan A, et al. Intraspecific directed deterrence by the mustard oil bomb in a desert plant. Current Biology. 2012;**22**(13):1218-1220

[100] Wink M. Modes of action of herbal medicines and plant secondary metabolites. Medicine. 2015;**2**(3):251-286

[101] Kaushik B, Sharma J, Yadav K, Kumar PS, A. Phytochemical properties and pharmacological role of plants: Secondary metabolites. Biosciences Biotechnology Research Asia. 2021;**18**(1):23-35

[102] Hassan LG, Yusuf AJ, Muhammad N, Ogbiko C, Mustapha MD. In vitro phytochemical screening and anti-snake venom activity of the methanol leaf and stem bark extracts of *Leptadenia hastata* (Asclepiadaceae) against *Naja nigricollis*. Asian Pacific Journal of Health Sciences. 2020;**7**(3):11-14

[103] Jain C, Khatana S, Vijayvergia R. Bioactivity of secondary metabolites of various plants: A review. International Journal of Pharmaceutical Sciences and Research. 2019;**10**(2):494-504

[104] Tamasi AA, Shoge MO, Adegboyega TT, Chukwuma EC. Phytochemical analysis and in-vitro antimicrobial screening of the leaf extract of *Senna occidentalis* (Fabaceae). Asian Journal of Natural Product Chemistry. 2021;**19**(2):57-64

[105] Dhaniaputri R, Suwono H, Amin M, Lukiati B. Introduction to plant metabolism, secondary metabolites biosynthetic pathway, and in-silico molecular docking for determination of plant medicinal compounds: An overview. Advances in Biological Sciences Research, Volume 22. In: 7th

International Conference on Biological Science (ICBS 2021). 2021. pp. 373-382

[106] Arip M, Selvaraja M, Mogana, Tan LF, Leong MY, Tan PL, et al. Review on plant-based management in combating antimicrobial resistance - Mechanistic perspective. Frontiers in Pharmacology. 2022. DOI: 10.3389/ fphar.2022.879495

[107] Tsamo DLF, Tamokou JDD, Kengne IC, Ngnokam CDJ, Djamalladine MD, Voutquenne-Nazabadioko L, et al. Antimicrobial and antioxidant secondary metabolites from *Trifolium baccarinii* Chiov. (Fabaceae) and their mechanisms of antibacterial action. BioMed Research International. 2021;**3099428**:1-15

[108] Pagare S, Bhatia M, Tripathi N, Pagare S, Bansal YK. Secondary metabolites of plants and their role: Overview. Current Trends in Biotechnology and Pharmacy. 2015;**9**(3):293-304

[109] Gupta PD, Birdi TJ. Development of botanicals to combat antibiotic resistance. Journal of Ayurveda Integrative Medicine. 2017;**8**:266-275. DOI: 10.1016/j.jaim.2017.05.004

[110] Ferreira LE, Benincasa BI, Fachin AL, França SC, Contini SSHT, Chagas ACS, et al. *Thymus vulgaris* L. essential oil and its main component thymol: Anthelmintic effects against *Haemonchus contortus* from sheep. Veterinary Parasitology. 2016;**228**:70-76. DOI: 10.1016/j.vetpar.2016.08.011

[111] Li DD, Xu Y, Zhang DZ, Quan H, Mylonakis E, Hu DD, et al. Fluconazole assists berberine to kill fluconazoleresistant *Candida albicans*. Antimicrobial Agents and Chemotherapy. 2013;**57**:6016- 6027. DOI: 10.1128/AAC.00499-13

[112] Lemire JA, Harrison JJ, Turner RJ. Antimicrobial activity of metals: Mechanisms, molecular targets and applications. Nature Reviews Microbiology. 2013;**11**:371-384

[113] Lobanovska M, Pilla G. Penicillin's discovery and antibiotic resistance: Lessons for the future? Yale Journal of Biology and Medicine. 2017;**90**:135-145

[114] Minandri F, Bonchi C, Frangipani E, Imperi F, Visca P. Promises and failures of gallium as an antibacterial agent. Future Microbiology. 2014;**9**(3):379-397

#### **Chapter 4**

## Implementing Antimicrobial Stewardship in Various Healthcare Settings

*Olanrewaju O. Popoola*

#### **Abstract**

Antimicrobial resistance is a global health problem associated with mortality, morbidity, and socioeconomic losses. Given the rapid evolution of microorganisms and the scarcity of novel antimicrobials, it is important to implement strategies that promote appropriate, evidence-based use of antimicrobials to preserve their efficacy. These strategies and interventions are collectively referred to as antimicrobial stewardship (AMS). AMS interventions are focused on ensuring that the right antimicrobials are given at the right dose to the right patient, through the right route and for the right duration of time in order to improve patient outcomes, reduce side effects from inappropriate antimicrobial use and reduce the cost of therapy. AMS interventions include providing patient and public education; educating health professionals; ensuring evidence-based antimicrobial use; strengthening infection prevention and control practices; and prioritizing "one health" focused strategies to mitigate AMR in humans, animals, and the environment. Successful antimicrobial stewardship programs possess seven core elements as recommended by the CDC- leadership commitment, education of health professionals, accountability, drug expertise, action-oriented implementations, regular tracking of adherence to stewardship processes, and reporting. Stewardship interventions are successfully implemented when healthcare workers and stakeholders perceive the benefits of the program to be more than the effort required to implement the change.

**Keywords:** antimicrobial resistance, antimicrobial stewardship, interventions, one health, antibiotic resistance

#### **1. Introduction**

Antimicrobial resistance (AMR) is a global public health challenge that has continued to thrive, accounting for mortality, morbidity, and significant socioeconomic losses from prolonged illness, multiple therapies, and healthcare-associated infections. Microorganisms develop resistance to antimicrobials naturally in an effort to preserve their existence, however, antimicrobial misuse, poor infection control practices, and lack of adequate diagnostic tools have accelerated the emergence and spread of AMR [1]. AMR was the direct cause of 1.27 million deaths and played a role in 4.95 million deaths in 2019 [2]. If urgent interventions are not initiated, it could cause about \$100 million in socioeconomic loss by 2050 [3].

Antibiotic stewardship (AMS) interventions are programs and strategies set up to reduce the emergence and incidence of AMR - related infections, improve antimicrobial use, and optimise patient outcomes. Antimicrobial stewardship programs ensure that the right antimicrobials are given at the right dose to the right patient, through the right route for the right duration of time [1]. These interventions are aimed at improving patient outcomes, reducing side effects from inappropriate antimicrobial use, and reducing the cost of therapy. Antimicrobial stewardship interventions should be implemented in all healthcare and nonhealthcare settings including but not limited to hospitals (both in-patient and out-patient units), intensive care units, pharmacies, primary healthcare settings, nursing homes, veterinary hospitals, agricultural farms, animals houses, and in the community [1].

#### **2. Antimicrobial stewardship interventions**

To effectively implement antimicrobial stewardship interventions, you need to understand these interventions and how they can be implemented, here are some essential stewardship interventions.

#### **2.1 Patient and public education**

The general public is a major consumer of antimicrobials and should be educated on the appropriate use of antimicrobials, the administration, storage, and proper disposal of antimicrobials [4]. Awareness of AMR and its effect on morbidity, mortality, and socioeconomic impact should be explained. Information for the public should clearly address negative antimicrobial use practices observed over time and present proper alternative practices that promote proper antimicrobial use. Several studies have identified that people in many developing low- and middle-income countries (LMIC) stop using antimicrobials on feeling better, keep antibiotics at home for future use and use antibiotics based on recommendations from friends and family and this inappropriate use corresponds to the prevalence of AMR in such settings [5]. Educating the public about AMR and AMS can be done using broadcast media like television, radio, internet-based communication channels like certified websites dedicated to information on AMR and AMS, and social media. Additionally, print and multimedia materials can be made available to the public. All information materials should be presented in a simple, easy-tounderstand manner, should be translated into the community's local language(s), and should be tailored to the local cultural context in which they are used. The public should be educated on inappropriate antibiotic use for viral infections like influenza, and the wrong use of antibiotics as growth promoters in agriculture. Patients and the general public should be educated on how AMR develops and spreads, as well as interventions to stop AMR [6]. Integration of the proper use of antimicrobials into high school curricula may promote awareness and change behaviour toward antimicrobial use at an early age [1].

Likewise, direct health professional to patient education should be encouraged. All health practitioners with direct access to patients using antibiotics such as doctors, nurses, pharmacists, primary care nurses, and infection control specialists should educate patients on proper antibiotic use, and debunk myths and false information on AMR [4].

#### **2.2 Education of health professionals**

Antimicrobial stewardship intervention requires a multidisciplinary approach involving doctors, pharmacists, nurses, infection control experts, data scientists, laboratory technicians and specialists, dentists, surgeons, veterinary doctors, and primary care doctors. They should be educated on proper antibiotic prescribing and dispensing, evidence-based prescription guidelines, antimicrobial surveillance, and the importance of the "one health" approach to address antimicrobial resistance [6]. Educational modules on AMR and AMS should be included in continuing professional development (CPD) programs. In-person educational sessions have been proven to have a greater and longer-lasting effect on prescribing behaviour than printed materials [1].

Locally-adapted presentations, workshops, simulations, and lectures on AMS should be encouraged within health facilities and institutions as part of CPD. Print materials and online learning on AMS should also be encouraged. Regional health authorities should provide timely information on recent and changing trends in AMR patterns to help health facilities tailor information sessions to represent the present reality. Education on infection prevention control practices should be made compulsory to limit the occurrence and spread of healthcare-associated infection and limit patient-to-staff disease transmission and vice versa [7]. Health authorities should promote multidisciplinary teamwork among all health practitioners to ensure effective AMR reporting, surveillance, and implementation of AMS programs.

#### **2.3 Ensuring appropriate antimicrobial use**

The inappropriate use of antimicrobials, especially antibiotics has accelerated antimicrobial resistance, therefore many antimicrobial stewardship interventions focus on limiting antimicrobial use and encouraging evidence-based use when necessary [4]. Most of the several strategies to improve antimicrobial use are focused on appropriate antimicrobial prescribing and dispensing, a few are discussed below.

#### *2.3.1 Promoting adherence to regional and/or facility-specific antimicrobial prescribing guidelines*

Information from antimicrobial stewardship surveillance reports should be used to develop region and facility-specific clinical guidelines. These guidelines are to provide evidence-based prescription practices. The adherence of physicians to prescription guidelines has been found to improve the quality of care [8]. Additionally, computerised decision support systems (CDSS) can help improve adherence to prescription guidelines and provide case-specific treatment plans when needed. Technology-integrated prescription guidelines are an improved effort toward evidence-based prescription of medicines and physicians should be encouraged to embrace and utilise such innovations [8].

#### *2.3.2 Promoting evidence-based antimicrobial prescribing*

Accurate laboratory testing provides evidence for diagnosis and treatment. When available, laboratory test results help identify disease-causing pathogens which aid diagnosis. This in turn ensures optimal antimicrobial use, limits the occurrence of

drug toxicity, and prevents the occurrence of subsequent antimicrobial resistance [9]. Strengthening laboratory capacity to provide prompt diagnosis and antimicrobial susceptibility test results are strategies emphasised by the World Health Organisation (WHO) to improve accurate antimicrobial prescribing [9]. The flow of samples from the patient to the laboratory and the feedback of test results should be optimised to provide timely care. The laboratory staff should periodically provide a facility cumulative antibiotic resistance report, called an "antibiogram". This antibiogram will be used to update prescription guidelines and provide evidence-based antimicrobial treatment plan pending antimicrobial susceptibility results.

#### *2.3.3 Reducing the prescription of broad-spectrum antibiotics*

Broad-spectrum antibiotics (for example vancomycin, amikacin, and meropenem) have been proven to be effective against many species of both gram-positive and gram-negative organisms. The inappropriate use of these broad-spectrum antibiotics has been associated with the emergence of multidrug-resistant organisms [MDRO] [5, 10]. Therefore, to preserve the effectiveness of these broad-spectrum antibiotics, their prescription and use should be limited, and be determined by the approval of an infectious disease expert or consultant. Narrow-spectrum antibiotics that are only effective against a specific subset of organisms should be prescribed instead of broadspectrum antibiotics.

#### *2.3.4 Implementing delayed antimicrobial prescribing*

This involves prescriptions issued by a doctor to a patient to be used at a later date if symptoms worsen. This intervention has been shown to reduce antibiotic use [11–13]. Within the period of delayed prescribing, non-pharmaceutical interventions can be recommended.

#### *2.3.5 Restricting the use of antimicrobials*

Restrictive antimicrobial use requires limiting the use of certain "reserve" antimicrobials (like carbapenems, vancomycin, piperacillin/tazobactam, and echinocandin antifungals) until authorised according to approved criteria. This is usually done to preserve the effectiveness of these broad-spectrum and last-line antimicrobials, and reduce the cost of therapy and potential toxicity associated with the use of these antimicrobials. These restricted antimicrobials can only be used when:


It is important that the use of these "reserve" antimicrobials are closely monitored, reviewed and reported. This strategy is usually implemented within a hospital, health

*Implementing Antimicrobial Stewardship in Various Healthcare Settings DOI: http://dx.doi.org/10.5772/intechopen.112456*

facility, or at a regional level. An antimicrobial restriction policy and procedure document should be created to ensure compliance with restricting antimicrobial use, making it clear who is authorised to approve the use of the restricted antimicrobials and how approvals can be obtained [14, 15]. The WHO's AWaRe categorisation alongside hospital/regional antimicrobial surveillance reports can be used to formulate antimicrobial restrictive formulary [16, 17].

#### **2.4 Strengthen infection control practices**

Infection prevention and control (IPC) strategies can be implemented at health facilities and in the community. Infection prevention programs in health facilities are mostly focused on reducing healthcare-associated infections. At the core of infection prevention practices are rapid microbial diagnosis to quickly identify multidrug-resistant organisms, and rapid intervention to curb its spread. Infection control practices are optimised when healthcare providers are well educated on the importance of these practices and their compliance are regularly monitored [18].

Infection control activities in health facilities involve regular hand washing; use of protective, sterilised gloves, masks, eye protection devices (goggles), and other personal protective equipment (aprons and gowns) when interacting with patients; appropriate disinfection of medical equipment; regular environmental cleaning and disinfection; investigating potential disease outbreak and implementing control measures; identifying and vaccinating susceptible workers against vaccine preventative diseases; appropriate infectious waste management; and the installation of high-efficiency particulate absorbing (HEPA) filters into the building's construction to limit the spread of airborne infections.

The objective of Infection prevention and control at the community level is to minimise infection occurrence and spread between people. IPC strategies in the community focus on ensuring good hygiene and sanitation; promoting vaccination; encouraging the use of insect repellants; avoiding contact with confirmed cases of infectious diseases; practising safe sex; and ensuring appropriate use of medication [18].

#### **2.5 Regulation of antimicrobial prescription, supply, and use**

Suboptimal antimicrobial prescription practices have been linked with the emergence of resistant microorganisms, especially in LMICs [19]. Therefore, adherence to prescription guidelines and evidence-based antimicrobial prescribing based on laboratory analysis and data from antimicrobial resistance surveillance should be prioritised.

Pharmacists should ensure the continuous supply of antimicrobials and formulate a restricted antimicrobial formulary based on antimicrobial resistance patterns and the WHO's AWaRe classification. The shortage of essential narrow-spectrum antibiotics have contributed to the increased, suboptimal use of newer and broad-spectrum antibiotics potentially promoting an increase in antimicrobial resistance [20].

All health facilities should have access to continuous supply of antimicrobials. The antimicrobial stewardship pharmacists must ensure proper selection, procurement, and distribution of antimicrobials on the prescription formularies, including the reserved antimicrobials. Pharmacists should ensure that antimicrobials are of appropriate standard and properly stored to preserve efficacy. A critical antimicrobial formulary can be developed based on infectious disease epidemiology, antimicrobial resistance patterns, and drug availability. Tools for accurate antimicrobial use projections and inventory management should be employed to prevent shortages of these

essential medicines [21]. Comprehensive procurement systems and robust supply chains should be engaged to ensure that antimicrobials are readily available and affordable [22]. Regulatory authorities should discourage pharmaceutical companies from advertising antimicrobials, especially broad-spectrum antibiotics to decrease patient demand for such medicines and prevent abusive use [23].

#### **2.6 Implementation of a "one health" approach to limit AMR**

The term "One health" refers to interdisciplinary, multi-sectoral initiatives to guarantee the best possible well-being for people, animals, and the environment. Antimicrobials are rightly used in humans and animals to treat diseases, however, the prolonged use of antimicrobials for prophylaxis in humans and animals; the mass administration of antimicrobials to animals (especially antibiotics that are critical to humans like third generation cephalosporins); and the unregulated use of antibiotics (e.g colistin) at low sub-therapeutic doses as growth promoters in agriculture, have accelerated the development of antimicrobial resistance – making animals reservoirs for antimicrobial resistant organisms and antimicrobial resistant genes. These resistant organisms and genes can easily be passed into the environment when excreted in urine and faeces [24]. Antimicrobials are used in aquaculture in feeds, given as injections, and sometimes directly applied to the water to prevent or treat diseases. When the water is released into the environment, it contaminates the environment with antimicrobials [25]. Wastewater from the production of antibiotics in pharmaceutical industries can contain traces of these antibiotics and are released directly into the environment [26]. Correspondingly, the improper disposal of expired antimicrobials (of which up to 90% of the active pharmaceutical ingredient may be present) also contributes to the direct deposits of antimicrobials into the environment [27]. Farmers have also been found to use antibiotics to preserve fruits from bacterial infections, leaving them with antibiotic residues.

When antimicrobials and their metabolites are in the environment (soil, water, or air), they are mostly present at sub-therapeutic concentrations, creating selective pressure on organisms around them, resulting in these organisms becoming resistant, making the environment a reservoir of antimicrobial resistant organisms and antibiotic resistant genes. Humans interact with animals and with the environment, this interdependence creates opportunities for antimicrobial resistant organisms and antimicrobial resistant genes to be transmitted within and between humans, animals, and the environment.

It is important that wastewater and solid waste contaminated with antibiotics or their metabolites are properly treated. Wastewater and sewage sludge can be treated to remove antimicrobials and pollutants chemically by coagulation and flocculation; by adsorption using activated charcoal; by physicochemical methods – electrochemical oxidation, ozone-based antibiotic degradation, and ultraviolet rays; using membrane technology like ultrafiltration, nanofiltration, and microfiltration; biological treatments [27], liming and composting [28].

#### *2.6.1 One health focused strategies to limit AMR*

1.Farmers, veterinarians, agriculturists, aquaculturists, and all stakeholders in the food industry need to be educated on antimicrobial resistance and how improper use of antibiotics contributes to it. They should be discouraged from using antimicrobials for prophylaxis unless recommended by a veterinarian or infection control expert. They should be encouraged to apply good agricultural principles, use clean

water, and observe good sanitation and hygiene to prevent infection in plants and animals. Veterinarians should be specially trained on antimicrobial stewardship practices, and encourage their clients to practice the same. Educative information on AMR may be disseminated through specific outreaches to farmers, publications in food, agro- and aqua industries, and professional development programs.


#### **3. Antimicrobial stewardship programs (ASPs)**

Antimicrobial Stewardship Programs (ASPs) are consciously coordinated programs that promote the appropriate use of antimicrobials [29]. The goals of ASPs [1] are to;


7.Ensure cost-effective therapy and reduce unnecessary health costs [21].

ASP can be implemented in all settings where antimicrobials are prescribed, dispensed, or used such as hospitals, nursing homes, intensive care units, pharmacies, and primary healthcare settings.

#### **3.1 Core elements of antimicrobial stewardship programs**

All ASPs must possess certain elements that are key to the success of such interventions. These elements are a broad category of strategies needed for the success of an ASP. The Centre for Disease Control (CDC) has highlighted seven core elements of successful antimicrobial stewardship programs [29].

#### *3.1.1 Leadership commitment*

The success of any ASP relies on the support of the leadership of the health facility, regulatory institutions, pharmaceutical industries, scientists, and health insurance.

Leaders support ASPs by providing adequate human resources, financial support, and information technology for the successful implementation of such programs. Executives of health organisations need to be well informed of the benefit of ASPs and their potential impact on patient outcomes. Leaders, managers, and board of directors can support ASPs by:


Leadership at the regional and national level are also required to support ASPs to ensure multi-sectoral collaborations and formulation of regional or national action plans that align with the goals and activities of the ASP.

#### *3.1.2 Accountability*

ASPs require a leader or co-leaders, who are accountable for programs' management and outcomes. Co-leadership of a physician and pharmacists have been shown to be effective [29]. Clinical staff are better suited to lead ASPs than non-clinical staff. These leaders must possess effective leadership, management, and communication skills.

Leaders of ASPs should have regular stewardship rounds where they interact with physicians on their choice of antimicrobials, reasons for prescriptions, and preauthorisation of the use of restricted antimicrobials. These rounds encourage a critical review and evaluation of antimicrobial choices and assessment of physician's adherence to prescription guidelines. Face-to-face interactions give physicians and the antimicrobial stewardship team a chance to exchange ideas in an open forum and offer real-time feedback when necessary [30]. These stewardship rounds provide an opportunity for learning and development, and can increase the confidence of physicians when prescribing antimicrobials especially when the antimicrobial stewardship team confirms their choice of antimicrobials [31], and reduce inappropriate use of broad-spectrum antimicrobials [32]. Leaders of ASPs should also provide reports of stewardship activities, interventions, and impact to the health facility and regional health leadership [33].

#### *3.1.3 Drug expertise*

Successful ASPs have a pharmacist leader or co-leader taking responsibility for appropriate antimicrobial use. Clinical pharmacists with training in antimicrobial stewardship and infectious diseases are more suitable and highly effective for this role [29]. After evaluating the patient's diagnostic results, pharmacists can offer clinical information to support decisions regarding the patient's antimicrobial medication regimen and length of treatment [34]. Additionally, they can help develop guidelines for the management of specific infections and particular organisms (such as multidrugresistant *Staphylococcus aureus*) as well as educate health professionals on the use of evidence-based antimicrobial prescribing, and contribute to antimicrobial surveillance efforts [35].

#### *3.1.4 Action*

This involves Implementing recommended stewardship interventions like reducing the prescription of broad-spectrum antibiotics; restricting certain "reserve" antimicrobials to pre-authorisation from the antimicrobial stewardship team; and re-evaluating and assessing antimicrobial prescription 36–72 h after first administration- considering culture and antimicrobial sensitivity results, clinical scenario and patients response to therapy [33]. The reassessing of antibiotic prescription after 36–72 h after initiation is referred to as an "antibiotic timeout", and has been associated with reduced antimicrobial use, and improved patient outcomes [36–38]. During an antibiotic timeout, changes could be made to the antibiotic selected, duration of antibiotic use, route of administration such as the transmission of intravenous antibiotics to oral antibiotics, and/or dosage such as dose optimisation in patients with organ dysfunction. Pharmacists can also raise alerts when potential antibiotic related drug–drug interactions are observed (such as interactions between fluoroquinolones and metals like calcium, iron, and aluminium- and magnesium-containing antacids), monitor patient's drug levels, prevent unnecessary repetition of antibiotic prescriptions, and ensure antibiotics are not used beyond a reasonable time. Microbiological consultations are important for optimal antimicrobial selection and use, aseptic techniques should be employed to prevent contamination of laboratory cultures. Specific guidelines should be established to cater for infections caused by specific organisms like methicillin-resistant *S. aureus* (MRSA), multidrug-resistant *Clostridium difficile,* and specific conditions like community-acquired pneumonia [29]. Prospective audits of antimicrobial use which involves the review of antimicrobial use by an external expert is required periodically, to further improve antimicrobial use.

#### *3.1.5 Tracking*

This entails assessing the processes and outcomes of ASPs, such as adherence to prescription guidelines (process). And outcomes like a decrease in the use of broad-spectrum antibiotics, a drop in the number of antimicrobial days of therapy (DOT) per 1000 patient days, and an improvement in overall patient outcomes [29]. Additionally, antimicrobial use at a facility level, and the emergence of antimicrobial resistant diseases should be collated and monitored, and forwarded to regional and national health authorities [33]. Auditing of ASPs can help identify areas where more education or focused attention is needed, evaluate the effectiveness of AMS interventions and provide feedback on resistance patterns to regional authorities.

#### *3.1.6 Reporting*

Reports on antimicrobials prescribed, purchased, and dispensed should be made available to physicians, nurses, pharmacists, and relevant staff, along with specific action points. Information gotten from antimicrobial use audits should be shared with prescribers along with specific action points to drive compliance to guidelines. Antimicrobial resistance patterns should be evaluated and shared with the infectious disease and antimicrobial stewardship team to improve guidelines and drug formulary. Sharing reports can be used as a tool to increase compliance to prescribing guidelines and motivation to engage in antimicrobial stewardship activities. Facility-based data should also be made available to the hospital board, the ministry of health, and other regional or national health authorities to drive evidence-based interventions.

#### *3.1.7 Education*

Members of the healthcare team, including doctors, nurses, pharmacists, microbiologist, and laboratory staff should be well educated on the mechanisms and drivers of antimicrobial resistance; appropriate antimicrobial prescribing; individual roles in antimicrobial stewardship; benefits of antimicrobial stewardship; antimicrobial prescribing guidelines; antimicrobial pre-authorisation requirements; and the importance of antimicrobials stewardship intervention like antibiotic timeouts and antimicrobial use audits. Education can be done in formal and informal settings through lectures, posters, newsletters, case scenarios, educational video games, or electronic communications about antibiotic use with relevant departments [33, 39]. Education is most effective when initiated with interventions and monitored outcomes [33]. Patients should also be educated on appropriate antimicrobial use, the importance of antimicrobials, and potential side effects. Information to patients should be simple, adapted to the local language, and easy to understand.

#### **3.2 Implementing antimicrobial stewardship programs**

The first step in implementing an ASP is to form an antimicrobial stewardship committee. This committee should consist of a clinical doctor (preferably with training in infectious diseases and AMS, with keen interest in antimicrobial use and patient safety), a pharmacist (with training in infection prevention and control and antimicrobial stewardship), a nurse, a clinical microbiologist, infection control physician/expert, data analyst, information technology expert. Each member has unique roles and responsibilities.

#### *3.2.1 Role of a physician in a stewardship team*

Physicians are to develop treatment guidelines in collaboration with the infection control team and pharmacist, and also adhere to appropriate prescription practices and guidelines to ensure proper antimicrobial prescription and use. They are to ensure evidence-based decisions for infection management utilising data on antimicrobial susceptibility and laboratory diagnosis. When prescribing antimicrobials, physicians need to account for antimicrobial allergies, such as penicillin allergies, to limit adverse drug events. Physicians de-escalate the use of broad-spectrum and reserved antimicrobials to simple, narrow-spectrum regimens based on laboratory diagnosis, antimicrobial culture, and sensitivity. It is also important that they shorten

#### *Implementing Antimicrobial Stewardship in Various Healthcare Settings DOI: http://dx.doi.org/10.5772/intechopen.112456*

the duration of antimicrobial therapy for surgical prophylaxis. In relating with patients, physicians can advise patients on appropriate antimicrobial use and how best to prevent infections. Senior physicians are to influence the prescribing of other physicians and facilitate peer-to-peer learning for improved adherence to established guidelines. Physicians are to take co-leadership of ASPs and communicate with facility leadership and stakeholders on the importance and impact of ASPs [40, 41].

#### *3.2.2 Role of a pharmacist in a stewardship team*

During antibiotic timeouts, pharmacists should assess and, if necessary, convert intravenous antibiotic regimens to oral regimens. As medicine experts, they are required to ensure the appropriate selection of antimicrobials based on laboratory test results and individualise dosing in accordance with clinical presentations, administration route, genetics, laboratory analysis, organ dysfunction, and comorbidities. Additionally, pharmacists are to collaborate with the infectious control team to develop treatment guidelines for specific infections (like community-acquired pneumonia) and specific organisms like vancomycin-resistant enterococci (VRE). Pharmacists participate in "antimicrobial timeouts" to assess the efficacy of antimicrobial prescribing practices, and "antimicrobial audits" to evaluate overall antimicrobial prescribing and dispensing practices. Based on antimicrobial susceptibility patterns, pharmacists are to create facility- and/or region-specific antibiogram to guide antimicrobial prescribing. They are also well skilled to formulate facility-based essential antimicrobial lists and restrictive formularies based on the WHO's AWaRe classification and regional antimicrobial resistance patterns [16]; intervene and prevent drug-drug and drug-food interactions; and ensure continuous availability of essential antimicrobials [34, 35].

#### *3.2.3 Role of nurses in a stewardship team*

Nurses must ensure the aseptic collection of laboratory specimens for laboratory investigations. Laboratory specimens must be handled with aseptic techniques to prevent contamination, which could result in the use of antimicrobials where there is no medical indication for their use. They can collaborate with the pharmacist to review laboratory results to help guide antimicrobial selection. They are to administer antimicrobials promptly and record antimicrobial use. Nurses monitor patients' progress and report signs of infection (including sepsis), allergies, and observed adverse drug events (like diarrhoea) to the physician and pharmacist. They serve as a vital communication channel between patients and doctors and assess patients' capacity to transition from intravenous drug therapy to oral therapy [42, 43].

#### *3.2.4 Role of microbiologist in a stewardship team*

To optimise the selection and use of antimicrobials, microbiologists conduct antimicrobial sensitivity tests and interpret laboratory test results. They evaluate novel diagnostic techniques and recommend their use in healthcare settings. Diagnostic tests that are affordable, sensitive, specific, and support rapid identification of organisms and possible resistance patterns should be prioritised. They review antibiograms based on antimicrobial surveillance reports, and report cases of antimicrobial resistance throughout the healthcare system. Lastly, they educate other members of the healthcare team on standard laboratory practices for optimal antimicrobial prescribing [44].

#### *3.2.5 Infection control specialist*

These specialists are to instil infection prevention and control measures that minimise infection risk. They promote the use of personal protective equipment. They develop and implement isolation guidelines and procedures for highly infectious and critical disease cases. And ensure aseptic techniques and strategies that prevent contamination of laboratory specimens, and limit exposure of the blood and body fluids of patients. Likewise, they ensure proper waste management, environmental hygiene, disinfection, and sterilisation as well as provide education and training on proper infection prevention and control strategies to healthcare professionals [18].

#### *3.2.6 Role of data analyst in a stewardship team*

Data provides evidence for effective decision-making and should not be trivialised. Data analysts collect, validate, clean, and analyse data on the antibiotic supply, prescription, and use. They inform health facility management, regional surveillance systems, and national surveillance systems of the findings of significant data analysis. They monitor and evaluate the outcomes of ASPs in line with predetermined indicators.

#### *3.2.7 Role of information technology expert in a stewardship team*

In broad terms, information technology experts essentially digitalise systems, structures, and processes for effective storage, timely communication and intervention. They integrate electronic records into the health system to facilitate efficient data collection, and rapid sharing of necessary information, like laboratory results, among health workers and the antimicrobial stewardship team. They maintain databases of antimicrobial resistance trends, and information on antimicrobial prescribing, purchase, and use. Similarly, they promote technology-aided drug prescribing and integrate computer provider order entry [CPOE] across the health facility for multidisciplinary, holistic patient care.

#### **3.3 Strategic action plans for implementing antimicrobial stewardship programs**

ASPs are implemented in all health settings where antimicrobials are prescribed, dispensed, and used. However, there is no one size fits all approach to implementing ASPs. Below are a few essential steps in implementing ASPs, these strategies should be adopted to fit the local context of the health setting in which they are applied.

#### *3.3.1 Create an antimicrobial stewardship committee or team*

The first step is to establish the antimicrobial stewardship committee or team. The team may stand alone or be integrated into the infection control or patient safety committee. For this team to be effective, it should have the support of the leadership of the health facility, major stakeholders, and managers in the health facility. The team is to be co-led by a physician and pharmacist with training in infectious disease control, and antimicrobial stewardship. When a physician is not available, a trained pharmacist can take up the leadership role.

*Implementing Antimicrobial Stewardship in Various Healthcare Settings DOI: http://dx.doi.org/10.5772/intechopen.112456*

#### *3.3.2 Execute a facility-based SWOT analysis*

The stewardship team is to carry out a SWOT analysis of the health system to evaluate areas of strength, weaknesses, opportunities, and threats. Already existing facility or regional prescription guidelines should be reviewed, and compliance with these guidelines be evaluated. Additionally, antimicrobial use data should also be evaluated. The focus of the SWOT analysis should be on assessing the availability of the core elements of AMS at the health facility. Resources - human and capital resources needed for the program should be assessed. In cases where a specialist member of the team like a pharmacist with training in infectious disease management is not available within a facility, then another similar expert should be identified off-site within another similar facility and can be consulted to collaborate and fill that gap [45].

#### *3.3.3 Develop a focused action plan*

A well developed and planned antimicrobial stewardship intervention is needed for the success of an ASP. All core elements of antimicrobial stewardship should be well established with support from the leadership of the health facility. Senior physicians should partner with the antimicrobial stewardship team to influence other physicians to implement antimicrobial prescription and use changes that come with the ASP.

Antimicrobial stewardship activities should be identified based on facility-specific peculiarities, after a SWOT analysis has been completed. Antimicrobial stewardship programs implemented in other similar facilities can be examined and adopted to fit the local context. Action plans should focus on initiating and maintaining behavioural changes to how antimicrobials are prescribed and used. The use of antimicrobial prescription guidelines, pre-authorisation of the use of restricted antimicrobials, limiting the use of broad-spectrum antibiotics, and evidence-based antimicrobial prescriptions backed up by laboratory results should be encouraged. Pharmacists should categorise antibiotics, and restrict access to their use based on the WHO's AWaRe classification, participate in antimicrobial use review (see **Table 1**) [17].

SMART (specific, measurable, attainable, realistic, and time-bound) goals for the stewardship program should be set, each member of the stewardship committee should understand their roles, responsibilities, and expected outcomes, and should be supported with the necessary authorisation needed to execute their task. Indicators to measure the success of the ASP should be well defined, and a period of time to evaluate the ASP based on the set indicator should be decided on whether every 3–6 months. Feedback from each evaluation process should be considered and necessary adjustments should be made to the antimicrobial stewardship plan.

#### *3.3.4 Initiating sustained behavioural change in antimicrobial prescription practices*

For a change process to be successful, all stakeholders involved must perceive the benefits of the change to be greater than the required efforts to actualise the change, the greater the perceived benefit, the quicker the adoption. The antimicrobial stewardship team must be able to effectively communicate the reason and benefits of changes in antimicrobial prescribing practices, and other stewardship activities to clinicians and stakeholders. Physicians must understand the proposed benefits of antimicrobial stewardship practices to the patients and also to them. The team must take into account factors that influence wrong prescribing practices and work on addressing them. It is important that all stakeholders are


#### **Table 1.**

*WHO's AWaRe classification of antibiotics.*

consulted on the ASP and the changes that will be initiated. Having informal focus group discussions will help the stewardship team take into account the views of other health actors and limit potential resistance to stewardship programs when initiated and scaled up [45].

Behavioural changes and interventions initiated by the stewardship program will be speedily adopted and scaled up if they possess the seven CORRECT attributes.


When stewardship interventions possess these attributes, they are easily embraced and are less likely to face rigid opposition when implemented.

#### *3.3.5 Identify change agents/stewardship champions*

To effectively initiate long-lasting change, local change agents are required. These change agents (antimicrobial stewardship champions) are early adopters of the changes initiated by the AMS team. These champions lead others to adopt new practices, and transmit their commitment and enthusiasm. These champions are often well respected and have the credibility and capacity to influence others. A change agent could be a senior manager or consultant clinician working to drive the implementation of, and adherence to stewardship principles among physicians in a health facility. Change agents should be able to effectively navigate the cultural, individual, and social differences among staff that may limit the success of the ASP. They should be equipped with knowledge of antimicrobial stewardship practices and leadership skills to sustain change.

The activities of these change agents should receive positive reinforcement and support from the antimicrobial stewardship team and health facility leadership, they should be acknowledged and appreciated. These agents can also be channels of feedback on the progress of the ASP.

#### *3.3.6 Provide a favourable environment for change*

All health workers must be educated on antimicrobial stewardship practices and their benefits to them and the patients. Education can be done using clinical case studies, lectures, and e-learning materials. This can be integrated into staff mandatory development programs. When possible, a trip to another health facility where ASPs are in full effect is encouraged. Through site visits and study tours, they see for themselves changes to expect through an ASP and the real-life benefits to the patients and health practitioners. The stewardship team and health leadership should clearly state the roles and responsibilities of the different departments and staff involved in the ASP. Leadership should provide the resources and support necessary to effectively execute these tasks.

ASP requires multidisciplinary collaborations, thus, structural and organisational changes and strategies should be established to promote quick communication; encourage feedback and open discussion on challenges or important issues that arise during the programs; and advance partnership across departments.

Change agents and the AS team should work to provide continuous encouragement and technical assurance to staff that are involved in the day-to-day activities of the AS processes. Health leadership must positively enforce their commitment to change processes initiated by the AS team. Their attitudes and statement should clearly communicate "This change is necessary, and we support it".

It's commonly said that "perfect is the enemy of good", it is important that ASPs are initiated as soon as possible and are not delayed till when the situation is "perfect".

#### *3.3.7 Monitor and evaluate stewardship programs*

Adherence to stewardship interventions should be monitored and evaluated periodically. ASP can be evaluated by the stewardship team every 3–6 months (or at a frequency agreed upon by the stewardship team), and the impact can be shared with stakeholders to further obtain their support and approval of the program. Results should also be discussed with the health workforce and various departments, to provide possible solutions to challenges encountered while initiating the stewardship interventions.

Antimicrobial prescription and antimicrobial use audits should be initiated regularly, antibiograms and drug formularies should be updated regularly based on data from antimicrobial resistance and susceptibility surveillance. Monitoring and evaluation practices provide an opportunity to obtain feedback from clinicians and stakeholders on ASP, address challenges and encourage further compliance with stewardship interventions. SMART goals and indicators agreed on at the beginning of the intervention process will be valuable during monitoring and evaluation. Information regarding the success of ASP, and patterns of antimicrobial susceptibility can be shared with regional and national surveillance teams and health authorities.

#### *3.3.8 Implement feedback*

Important information gotten from the monitoring and evaluation process, and antibiotic audits should be shared with the health professionals and leadership and should be implemented. Identified challenges should be discussed and practical solutions should be initiated.

#### **4. Conclusion**

The problem of antimicrobial resistance possesses a global threat to health, finance, and food security, and although only a few "new" antimicrobials have been developed over the years, a combination of effective strategies have been identified to mitigate this global public health challenge. Antimicrobial stewardship programs targeted at

*Implementing Antimicrobial Stewardship in Various Healthcare Settings DOI: http://dx.doi.org/10.5772/intechopen.112456*

implementing evidence-based antimicrobial use, restricting the use of "broad-spectrum" and "reserve" antimicrobials, limiting the occurrence of AMR-related infections, and promoting infection prevention and control practices should be implemented in all settings where antimicrobials are prescribed and used. A "One health" approach to tackle AMR should be prioritised considering the interaction and interdependence between and among humans, animals, and the environment. Stewardship interventions have been proven to be effective in improving antimicrobial use and patient outcomes, and are readily accepted and implemented when they are presented to be beneficial to the health practitioner and the patient; made easy to understand and implement; and unequivocally supported by health leadership and important stakeholders.

### **5. Additional resources**

#### **5.1 ASP in the hospital**


#### **5.2 ASP in the ICU**


#### **5.3 ASP in nursing homes**

• Crnich CJ, Jump R, Trautner B, Sloane PD, Mody L. Optimising antibiotic stewardship in nursing homes: A narrative review and recommendations for improvement. *Drugs Ageing*. 2015;32(9):699–716. doi: 10.1007/s40266-015-0292-7.

• McElligott M, Welham G, Pop-Vicas A, Taylor L, Crnich CJ. Antibiotic stewardship in nursing facilities. *Infectious Disease in Clinical North America*. 2017;31(4):619–638. doi: 10.1016/j.idc.2017.07.008.

### **Author details**

Olanrewaju O. Popoola1,2

1 Obafemi Awolowo University, Ile-Ife, Nigeria

2 HealthPlus Pharmacy Limited, Nigeria

\*Address all correspondence to: popoolalanre8@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Implementing Antimicrobial Stewardship in Various Healthcare Settings DOI: http://dx.doi.org/10.5772/intechopen.112456*

#### **References**

[1] British Society for Antimicrobial Chemotherapy. Antimicrobial stewardship from principles to practice. 2018. Available from: https://www.bsac. org.uk/antimicrobialstewardshipebook/ BSAC-AntimicrobialStewardship-FromPrinciplestoPractice-eBook.pdf [Accessed: April 25, 2023]

[2] Murray CJ, Ikuta KS, Sharara F, Swetschinski L, Robles AG, Gray A, et al. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. The Lancet. 2022;**399**(10325):629-655. DOI: 10.1016/S0140-6736(21)02724-0

[3] World Bank Group. Drug-Resistant Infections: A Threat to Our Economic Future. Washington, DC: World Bank Group; 2017. Available from: https:// www.worldbank.org/en/topic/health/ publication/drug-resistant-infectionsa-threat-to-our-economic-future [Accessed: May 3, 2023]

[4] World Health Organization (WHO). Antimicrobial Stewardship Interventions: A Practical Guide. Copenhagen: WHO Regional Office for Europe; 2021. Available from: https:// apps.who.int/iris/handle/10665/340709 [Accessed: May 3, 2023]

[5] Ayukekbong JA, Ntemgwa M, Atabe AN. The threat of antimicrobial resistance in developing countries: Causes and control strategies. Antimicrobial Resistance and Infection Control. 2017;**6**:47. DOI: 10.1186/ s13756-017-0208-x

[6] WHO. Global Action Plan on Antimicrobial Resistance. Geneva: World Health Organization; 2015. Available from: https://www.who.int/ publications/i/item/9789241509763 [Accessed: May 7, 2023]

[7] Bankar NJ, Ugemuge S, Ambad RS, Hawale DV, Timilsina DR. Implementation of antimicrobial stewardship in the healthcare setting. Cureus. 2022;**14**(7):e26664. DOI: 10.7759/cureus.26664

[8] Catho G, Centemero NS, Catho H, Ranzani A, Balmelli C, Landelle C, et al. Factors determining the adherence to antimicrobial guidelines and the adoption of computerised decision support systems by physicians: A qualitative study in three European hospitals. International Journal of Medical Informatics. 2020;**141**:104233. DOI: 10.1016/j. ijmedinf.2020.104233

[9] Morency-Potvin P, Schwartz DN, Weinstein RA. Antimicrobial stewardship: How the microbiology laboratory can right the ship. Clinical Microbiology Reviews. 2017;**30**:381-407. DOI: 10.1128/CMR.00066-16

[10] Bharadwaj A, Rastogi A, Pandey S, Gupta S, Sohal JS. Multidrug-resistant Bacteria: Their mechanism of action and prophylaxis. BioMed Research International. 2022;**2022**:5419874. DOI: 10.1155/2022/5419874

[11] Tonazzi S, Prenovost L, Scheuermann S. Delayed antibiotic prescribing to reduce antibiotic use: An urgent care practice change. BMJ Open Quality. 2022;**11**:e001513. DOI: 10.1136/ bmjoq-2021-001513

[12] Llor C, Moragas A, Cots JM. Implementation of the delayed antibiotic prescribing strategy. Prospective observation study in primary care. Revista Espanola de Quimioterapia. 2022;**35**(2):213-217 10.37201/ req/141.2021

[13] Ghebrehewet S, Shepherd W, Panford-Quainoo E, Shantikumar S, Decraene V, Rajendran R, et al. Implementation of a delayed prescribing model to reduce antibiotic prescribing for suspected upper respiratory tract infections in a hospital outpatient department, Ghana. Antibiotics (Basel). 2020;**9**(11):773. DOI: 10.3390/ antibiotics9110773

[14] National Centre for Antimicrobial Stewardship (NCAS). Antimicrobial Stewardship. 2020. Available from: https://www.ncas-australia.org/ antimicrobial-formulary-and-restrictions [Accessed: May 10, 2023]

[15] Public Health Ontario (PHO). Antimicrobial Stewardship Strategy: Formulary restriction. Available from: https://www.publichealthontario. ca/apps/aspstrategies/data/pdf/ ASP\_Strategy\_Formulary\_Restriction.pdf [Accessed: May 15, 2023]

[16] WHO. Executive Summary: The Selection and Use of Essential Medicines 2019. Geneva: World Health Organization; 2019. Available from: https://apps.who.int/iris/ handle/10665/325773

[17] WHO. The WHO AWaRe (Access, Watch, Reserve) Antibiotic Book. Geneva: World Health Organization; 2022. Available from: https:// www.who.int/publications/i/item/ WHO-MHP-HPS-EML-2022.02

[18] Taplitz RA, Ritter ML, Torriani FJ. Infection prevention and control, and antimicrobial stewardship. Infectious Diseases. 2017;**2017**:54-61. DOI: 10.1016/ B978-0-7020-6285-8.00006-X

[19] Kpokiri EE, Taylor DG, Smith FJ. Development of antimicrobial stewardship programs in low and middleincome countries: A mixed-methods

study in Nigerian Hospitals. Antibiotics (Basel). 2020;**9**(4):204. DOI: 10.3390/ antibiotics9040204

[20] Pulcini C, Beovic B, Béraud G, Carlet J, Cars O, Howard P, et al. Ensuring universal access to old antibiotics: A critical but neglected priority. Clinical Microbiology and Infection. 2017;**23**(9):590-592. DOI: 10.1016/j.cmi.2017.04.026

[21] Pan American Health Organization (PAHO). Florida International University. Recommendations for Implementing Antimicrobial Stewardship Programs in Latin America and the Caribbean: Manual for Public Health Decision-Makers. Washington, D.C.: PAHO; 2018. Available from: https://iris.paho.org/ handle/10665.2/49645

[22] Malan L, Labuschagne Q, Brechtelsbauer E, Goff DA, Schellack N. Sustainable access to antimicrobials; a missing component to antimicrobial stewardship—A tale of two countries. Frontiers in Public Health. 2018;**6**:324. DOI: 10.3389/fpubh.2018.00324

[23] Dyar OJ, Huttner B, Schouten J, Pulcini C, ESGAP (ESCMID Study Group for Antimicrobial stewardshiP). What is antimicrobial stewardship? Clinical Microbiology and Infection. 2017;**23**(11):793-798. DOI: 10.1016/j. cmi.2017.08.026

[24] McEwen SA, Collignon PJ. Antimicrobial resistance: A one health perspective. Microbiology Spectroscopy. 2018;**6**(2):1-13. DOI: 10.1128/ microbiolspec.ARBA-0009-2017

[25] Chowdhury S, Rheman S, Debnath N, Delamare-Deboutteville J, Akhtar Z, Ghosh S, et al. Antibiotics usage practices in aquaculture in Bangladesh and their associated

*Implementing Antimicrobial Stewardship in Various Healthcare Settings DOI: http://dx.doi.org/10.5772/intechopen.112456*

factors. One Health. 2022;**15**:100445. DOI: 10.1016/j.onehlt.2022.100445

[26] Larsson DGJ, Flach CF. Antibiotic resistance in the environment. Nature Reviews. Microbiology. 2022;**20**(5):257-269. DOI: 10.1038/ s41579-021-00649-x

[27] Sagaseta de Ilurdoz M, Sadhwani JJ, Reboso JV. Antibiotic removal processes from water & wastewater for the protection of the aquatic environment a review. JWPE. 2022;**2022**:45. DOI: 10.1016/j.jwpe.2021.102474

[28] Goulas A, Livoreil B, Grall N, et al. What are the effective solutions to control the dissemination of antibiotic resistance in the environment? A systematic review protocol. Environmental Evidence. 2018;**7**:3. DOI: 10.1186/s13750-018-0118-2

[29] CDC. Core Elements of Hospital Antibiotic Stewardship Programs. Atlanta, GA: US Department of Health and Human Services, CDC; 2019. Available from: https://www.cdc.gov/ antibiotic-use/core-elements/hospital. html. Accessed May 10th 2023.

[30] Zembles TN, Nakra N, Parker SK. Extending the reach of antimicrobial stewardship to pediatric patients. Infectious Disease and Therapy. 2022;**11**(1):101-110. DOI: 10.1007/ s40121-022-00590-3

[31] McCreary ML, Tse-Chang A, Forbes KL, Foulds JL. Physician experiences implementing antimicrobial stewardship rounds in pediatric hospital medicine: An exploratory, qualitative study. Antimicrobial Steward Healthcare Epidemiology. 2021;**1**(1):e11. DOI: 10.1017/ash.2021.175

[32] Renk H, Sarmisak E, Spott C, Kumpf M, Hofbeck M, Hölzl F. Antibiotic stewardship in the PICU: Impact of ward rounds led by paediatric infectious diseases specialists on antibiotic consumption. Scientific Reports. 2020;**10**(1):8826. DOI: 10.1038/ s41598-020-65671-0

[33] Hwang S, Kwon KT. Core elements for successful implementation of antimicrobial stewardship programs. Infectious Chemotherapy. 2021;**53**(3):421-435. DOI: 10.3947/ ic.2021.0093

[34] Royal Pharmaceutical Society. The Pharmacy Contribution to Antimicrobial Stewardship. 2017. Available from: https://www.rpharms. com/Portals/0/RPS%20document%20 library/Open%20access/Policy/ AMS%20policy.pdf [Accessed: May 17, 2023].

[35] Jantarathaneewat K, Camins B, Apisarnthanarak A. The role of the clinical pharmacist in antimicrobial stewardship in Asia: A review. Antimicrobial Steward Healthcare Epidemiology. 2022;**2**(1):e176. DOI: 10.1017/ash.2022.310

[36] Mishima Y, Nawa N, Asada M, Nagashima M, Aiso Y, Nukui Y, et al. Impact of antibiotic time-outs in multidisciplinary ICU rounds for antimicrobial stewardship program on patient survival: A controlled beforeand-after study. Crital Care Exploration. 2023;**5**(1):e0837. DOI: 10.1097/ cce.0000000000000837

[37] Wirtz AL, Burns AN, Lee BR, Frank TS, Fitzmaurice L, Ogden RK, et al. Effectiveness and safety of mandatory antimicrobial indications and durations and a pharmacist-driven 48-hour time-out in a pediatric hospital. American Journal of Health-System Pharmacy. 2020;**77**(8):614-621. DOI: 10.1093/ajhp/zxaa029

[38] Paulson CM, Handley JF, Dilworth TJ, et al. Impact of a systematic pharmacist-initiated antibiotic timeout intervention for hospitalized adults. Journal of Pharmacy Practice. 2022;**35**(3):388-395. DOI: 10.1177/0897190020980616

[39] Satterfield J, Miesner AR, Percival KM. The role of education in antimicrobial stewardship. The Journal of Hospital Infection. 2020;**105**(2):130-141

[40] Sahra S, Jahangir A, De Chavez V. Antimicrobial stewardship: A review for internal medicine physicians. Cureus. 2021;**13**(4):e14385. DOI: 10.7759/ cureus.14385

[41] Ostrowsky B, Banerjee R, Bonomo RA, Cosgrove SE, Davidson L, Doron S, et al. Infectious diseases physicians: Leading the way in antimicrobial stewardship. Clinical Infectious Diseases. 2018;**66**(7):995- 1003. DOI: 10.1093/cid/cix1093

[42] Van Huizen P, Kuhn L, Russo PL, Connell CJ. The nurses' role in antimicrobial stewardship: A scoping review. International Journal of Nursing Studies. 2021;**113**:103772. DOI: 10.1016/j. ijnurstu.2020.103772

[43] Gotterson F, Buising K, Manias E. Nurse role and contribution to antimicrobial stewardship: An integrative review. International Journal of Nursing Studies. 2021;**117**:103787. DOI: 10.1016/j. ijnurstu.2020.103787

[44] Palavecino EL, Williamson JC, Ohl CA. Collaborative antimicrobial stewardship: Working with microbiology. Infectious Disease Clinics of North America. 2020;**34**(1):51-65. DOI: 10.1016/j.idc.2019.10.006

[45] WHO. Antimicrobial Stewardship Programs in Health-Care Facilities in Low- and Middle-Income Countries. A Practical Toolkit. Geneva: World Health Organization; 2019. Available from: https://apps.who.int/iris/ handle/10665/329404

#### **Chapter 5**

## Antimicrobial Stewardship in Resource-Limited Settings

*Simeon Chijioke Amadi, Faithful Miebaka Daniel, Sokeipirim Ikiroma and Ibinabo Laura Oboro*

#### **Abstract**

Antimicrobials are very important for the treatment of patients. With decades of haphazard prescription and inappropriate use, antimicrobial resistance (AMR) has emerged as a global public health threat. In resource-limited settings, besides AMR, there is also the issue of access to antibiotics and increased healthcare costs. In the past, the discovery of new drugs and the modification of older ones helped to counter antimicrobial resistance. Since the 1970s, only a handful of new agents (a few of which are novel) have been introduced into clinical practice periodically. This makes the existing antibiotics to be a limited resource. Antibiotics must, therefore, be used more responsibly and managed carefully to extend their usefulness while being made available to the patients who truly need them. Antimicrobial stewardship (AMS) refers to systematic actions or interventions that inculcate sustainable, rational, and evidence-based antibiotic prescription and use patterns in healthcare institutions. Implementation of AMS programmes would be an appropriate step towards improving patient outcomes, reducing AMR and its adverse economic impact, and building the best-practices capacity of healthcare professionals, among others. Despite these seemingly beneficial benefits, the implementation of antimicrobial stewardship programmes (ASPs) remains relatively limited and faces complex challenges in resourcepoor healthcare settings.

**Keywords:** antimicrobial, stewardship, resource, limited, setting

#### **1. Introduction**

Today's world is a product of continuous change driven by research, industry and innovation to address humanity's greatest needs. The development of antimicrobials has been an ongoing process dating back to ancient civilisations that utilised plant extracts and mouldy bread to treat infections [1]. Alexander Fleming's serendipitous discovery of penicillin in 1928 ushered in an era of growing interest in antimicrobial formulation and its ability to save millions of lives [1]. Since then, synthetic chemistry and modern drug discoveries have become the norm. However, the world faces an even more significant threat that may upend the progress made over the years: antimicrobial resistance [1, 2].

Scientists have striven to utilise research and innovation to combat emerging drug resistance and the evolving challenges of infectious diseases [2]. Antimicrobial resistance (AMR) is a primary global public health concern. It occurs when microorganisms develop the ability to evade the effects of antimicrobial medication, resulting in a reduction or loss of the medications' effectiveness in treating infections [2]. The main drivers of AMR are the inappropriate use and overuse of antimicrobials, which can stem from factors such as poor infection control practices, inadequate surveillance systems, improper prescription practices, inadequate patient education, limited diagnostic facilities, unauthorised sale of antimicrobials, lack of appropriate functioning drug regulatory mechanisms, and non-human use of antimicrobials such as in animal production [2, 3]. The challenges posed by AMR require a comprehensive and coordinated approach to promote responsible antimicrobial use, develop new drugs, strengthen infection prevention and control practices, and enhance surveillance [3]. To this end, antimicrobial stewardship is a crucial strategy that aims to optimise the use of antimicrobial medicines while minimising the development of AMR. It involves a multidisciplinary approach that includes healthcare professionals, policymakers, and patients [4].

Addressing the global threat of resistant infections requires a concerted effort to tackle AMR and promote antimicrobial stewardship. Antimicrobial stewardship is the practice of optimising the use of antimicrobial drugs to combat the growing issue of antimicrobial resistance [4]. It is essential to ensure the responsible use of these drugs. However, resource-poor settings face unique challenges in implementing effective antimicrobial stewardship programmes due to limited resources, infrastructure, and funding [3]. These challenges include limited access to healthcare, inadequate diagnostic capabilities, scarcity of essential medicines, and difficulties in implementing infection prevention and control measures [5]. Innovative solutions and a commitment to ensuring access to essential medicines and healthcare services for all are necessary to address these challenges.

#### **2. The significance of antimicrobial stewardship**

Addressing antimicrobial stewardship in resource-poor settings is vital as it directly affects vulnerable populations, decreases the economic burden of inappropriate antimicrobial use, and controls the spread of antimicrobial resistance [5–7]. In this chapter, we will delve deeper into the topic, exploring the specific challenges faced by resource-poor settings and underscoring the importance of implementing effective antimicrobial stewardship programmes.

Antimicrobial stewardship programmes in resource-poor settings face several unique challenges that hamper their effectiveness. One of the critical challenges is the limited access to healthcare. In many low- and middle-income countries, most people live in rural areas with scarce healthcare facilities. This limited access to healthcare facilities makes it difficult for patients to receive proper diagnosis and treatment for infectious diseases, leading to the inappropriate use of antimicrobials and the development of resistance [5–7].

Another significant challenge is inadequate diagnostic capabilities. Diagnostic tests such as blood cultures, microbiological cultures, and susceptibility testing are essential for identifying the causative agent of an infection and determining the appropriate antimicrobial therapy [5–7]. However, many resource-poor settings lack the necessary diagnostic capabilities to perform these tests, leading to the widespread use of broad-spectrum antimicrobials and the development of resistance [5–7].

#### *Antimicrobial Stewardship in Resource-Limited Settings DOI: http://dx.doi.org/10.5772/intechopen.114057*

The scarcity of essential medicines is another challenge faced by resource-poor settings. Essential drugs, including antimicrobials, are often unavailable or in short supply in these settings due to a lack of funding, poor infrastructure, and limited supply chains [5–7]. This scarcity of essential medicines can lead to inappropriate antimicrobials, contributing to the development of resistance [5–7]. Implementing infection prevention and control measures significantly challenges antimicrobial stewardship in resource-poor settings [5–7]. Lack of basic amenities such as clean water, sanitation facilities, and waste management systems can rapidly spread infectious diseases, making it difficult to control outbreaks.

To overcome these challenges, effective antimicrobial stewardship programmes must be implemented in resource-poor settings. These programmes should focus on improving access to healthcare, strengthening diagnostic capabilities, ensuring the availability of essential medicines, and implementing infection prevention and control measures [8]. Improving access to healthcare can be accomplished by deploying community health workers who can provide critical diagnostic and treatment services to patients in rural areas [5]. Rapid diagnostic tests that do not require sophisticated laboratory facilities can also help improve diagnostic capabilities in resource-poor settings [7]. Ensuring the availability of essential medicines requires a coordinated effort between governments, international organisations, and the private sector [6]. This effort should focus on improving supply chain management, increasing funding for research and development of new antimicrobial drugs, and reducing the cost of existing medications [7]. Implementing infection prevention and control measures requires basic amenities such as clean water, sanitation facilities, and waste management systems. These amenities can be provided through public–private partnerships focusing on improving infrastructure in resource-poor settings [5].

To sum up, antimicrobial stewardship is crucial in addressing the global threat of antimicrobial resistance. Nonetheless, implementing effective antimicrobial stewardship programmes in resource-poor settings requires a comprehensive and coordinated effort to address these settings' unique challenges. Improving access to healthcare, strengthening diagnostic capabilities, ensuring the availability of essential medicines, and implementing infection prevention and control measures are vital steps towards achieving this goal.

#### **3. Understanding antimicrobial resistance in resource-poor settings**

The issue of antimicrobial resistance (AMR) is a pressing global public health crisis with far-reaching implications for healthcare systems worldwide [9]. The emergence and spread of antimicrobial resistance significantly threaten our ability to treat infectious diseases effectively, increasing morbidity, mortality, and healthcare costs [10, 11]. The challenges in combating AMR are even more pronounced in resource-poor settings, characterised by poor resources, limited infrastructure, and scarce funding [10, 12, 13]. These settings face unique obstacles in addressing AMR, including limited access to healthcare, inadequate diagnostic capabilities, scarcity of essential medicines, and challenges in implementing infection prevention and control measures [10, 12–14]. These factors contribute to inappropriate use of antimicrobials, such as overprescribing, inadequate dosing, and misuse, leading to severe consequences, including treatment failures, increased morbidity and mortality, and disproportionate impacts on vulnerable populations [10, 12–14]. Addressing AMR in resource-poor settings is, therefore, mitigating the effects and preventing the further spread of resistance.

However, the challenges in addressing antimicrobial resistance in resource-poor settings are further compounded by the fragility of health systems. Fragile health systems, characterised by weak characteristics, limited resources, and inadequate governance, pose a significant barrier to effectively combating antimicrobial resistance [15]. The fragility of these health systems undermines efforts to address AMR and poses challenges in addressing other health priorities and achieving global health goals. Many resource-poor settings struggle with fragile health systems, further hampering their ability to address AMR [15, 16]. The World Health Organisation (WHO) has identified six building blocks of health systems: leadership and governance, health workforce, health information systems, access to essential medicines, financing, and service delivery [17]. Addressing these building blocks is critical for improving healthcare infrastructure, human resources, and laboratory capacity, which is necessary for managing antimicrobial resistance in these settings [17].

Therefore, comprehensive strategies should be implemented to improve access to healthcare, enhance diagnostic capabilities, ensure the availability of essential medicines, and strengthen infection prevention and control measures. Additionally, capacity building and education initiatives are vital to promote responsible antimicrobial use and raise awareness about the significance of AMR [9]. By addressing both the challenges in resource-poor settings and the fragility of health systems, we can contribute to safeguarding the effectiveness of antimicrobials, protecting vulnerable populations, and preserving the efficacy of these life-saving drugs for future generations.

#### **4. Challenges and barriers to antimicrobial stewardship in resource-poor settings**

The global healthcare context in resource-poor settings is often characterised by limited resources, infrastructure, and funding to adequately meet the population's healthcare needs [15, 17]. This scenario poses unique challenges when it comes to addressing antimicrobial stewardship. Limited access to healthcare facilities and professionals, inadequate diagnostic capabilities, scarcity of essential medicines, and difficulties implementing infection prevention and control measures are some of the challenges faced in these settings [18].

The lack of reliable and timely diagnostic tools hampers accurate determination of the cause of infection and appropriate antimicrobial therapy selection [19]. Addressing antimicrobial stewardship in resource-poor settings is essential due to its impact on vulnerable populations, the economic burden of inappropriate antimicrobial use, and the potential for spreading antimicrobial resistance [16, 19]. Inadequate stewardship can result in treatment failures, increased morbidity and mortality, and disproportionately affect vulnerable populations. The emergence and spread of antimicrobial resistance are particularly concerning in resource-poor settings, where limited access to healthcare, inadequate diagnostics, and infection prevention and control challenges can contribute to its development [5, 19].

The limitations to antimicrobial stewardship in resource-poor settings can be attributed to several factors, including the lack of trained healthcare professionals and awareness, financial constraints, limited resources, and cultural and behavioural factors affecting antimicrobial use [16, 19]. The need for more trained healthcare professionals in resource-poor settings poses a significant challenge to implementing effective antimicrobial stewardship programmes. Financial constraints and limited resources also play a crucial role in inhibiting antimicrobial stewardship efforts.

#### *Antimicrobial Stewardship in Resource-Limited Settings DOI: http://dx.doi.org/10.5772/intechopen.114057*

Cultural beliefs, practices, and patient expectations may influence the demand for antimicrobials, leading to their inappropriate use [20]. For instance, in some cultures, antibiotics are considered a miracle cure, and their use is expected for any illness, regardless of whether bacteria or viruses cause it [20]. Additionally, limited health literacy and understanding of the risks of antimicrobial misuse among community members can perpetuate the problem. Therefore, addressing these factors is crucial in implementing effective antimicrobial stewardship programmes in resource-poor settings.

Several interventions can be implemented to ensure effective antimicrobial stewardship in resource-poor settings. Firstly, there is a need for increased investment in healthcare infrastructure, particularly in diagnostic capabilities and infection prevention and control measures [19]. This investment should be accompanied by appropriate training of healthcare workers on antimicrobial stewardship and infection control practices. Secondly, there is a need for increased awareness campaigns to educate the public on the proper use of antimicrobials and the risks associated with their misuse [14].

Thirdly, there is a need to develop guidelines and protocols for the appropriate use of antimicrobials in resource-poor settings. Such policies should be context-specific, considering the unique challenges faced in resource-poor settings [5, 19]. Fourthly, there is a need for increased surveillance of antimicrobial use and resistance patterns to guide the development and implementation of effective stewardship programmes [18, 21].

In conclusion, antimicrobial stewardship in resource-poor settings is crucial to prevent the emergence and spread of antimicrobial resistance and ensure the appropriate use of antimicrobials. Addressing the challenges these settings face requires a multi-pronged approach that involves increased investment in healthcare infrastructure, proper training of healthcare workers, increased public awareness campaigns, and developing context-specific guidelines and protocols. These interventions will go a long way in ensuring effective antimicrobial stewardship in resource-poor settings.

#### **5. Strategies for implementing antimicrobial stewardship in resource-poor settings**

Antimicrobial stewardship programmes (ASPs) are crucial in promoting responsible antimicrobial use and combating AMR. However, implementing effective ASPs in resource-poor settings is challenging due to the need for more resources and infrastructure. To address these challenges, multiple aspects of healthcare delivery must be addressed. Building local capacity and training healthcare professionals is crucial [22–24]. This means providing education and training on antimicrobial stewardship principles, appropriate use, and infection prevention and control measures [25]. It is also essential to strengthen healthcare infrastructure, including improving access to diagnostics such as laboratory facilities and point-of-care tests [5, 26, 27]. This enables accurate diagnosis of infections and facilitates appropriate antimicrobial prescribing. Developing guidelines and protocols for antimicrobial use tailored to the specific context of resource-poor settings helps standardise practices and promote responsible prescribing [4, 25, 26].

ASPs also require a cultural shift in the healthcare system. Promoting rational prescribing practices and patient education is crucial in shifting cultural and behavioural factors contributing to antimicrobial misuse [20]. Public awareness campaigns and educating patients about the risks of inappropriate antimicrobial use and the importance of completing prescribed treatments are vital strategies [23].

Engaging stakeholders, including healthcare professionals, policymakers, and community leaders, fosters collaboration and creates a supportive environment for implementing ASPs [28–30]. Experts in the field have identified nine key strategies to enhance antimicrobial stewardship (AMS) [28]. These include implementing quality improvement measures, promoting peer learning across different disciplines, assigning AMS leads, carrying out individual-level prescribing audits, creating practical tools for prescribing audits, improving induction processes for new prescribers, standardising local approaches to antibiotic prescribing, providing online AMS training to all patient-facing staff, and increasing staff time devoted to AMS work through the standardisation of AMS-related roles [28].

Implementing ASPs in resource-poor settings is challenging and requires a comprehensive and coordinated approach. Developing national action plans and policies can provide a framework for implementing ASPs and ensuring sustainability [31, 32]. Additionally, funding and technical support from international organisations and donor agencies can provide critical resources to support ASP implementation [25, 33, 34].

In conclusion, addressing AMR in resource-poor settings requires a comprehensive approach that includes strengthening healthcare infrastructure, improving access to essential medicines, enhancing diagnostic capabilities, and implementing effective infection prevention and control measures. Capacity building and education for healthcare professionals and the community are vital in promoting responsible antimicrobial use. Promoting rational prescribing practices and patient education is crucial in shifting cultural and behavioural factors contributing to antimicrobial misuse. Engaging stakeholders and developing national action plans and policies can provide a framework for implementing ASPs and ensuring sustainability [31, 32]. Like the National Action Plan for AMR developed in India [35]. In 2019, a framework for addressing AMR was designed to be an ongoing and adaptable process that responds to contextual factors, allowing for continuous improvement and refinement of national action plans [36]. This was to address the need for a systematic approach to the governance of national plans [36]. By systematically addressing these strategies, resource-poor settings can enhance their ability to combat antimicrobial resistance and improve patient outcomes.

#### **6. Lessons from case studies**

The successful implementation of antimicrobial stewardship programmes in resource-poor settings has been the subject of various studies. These studies have demonstrated the potential for positive outcomes, such as significantly reducing inappropriate antimicrobial prescribing and improving guideline adherence [26, 35]. The key to success lies in tailored training and education programmes considering resource-poor settings' specific contexts and challenges [26]. Additionally, developing and implementing evidence-based local guidelines and protocols can considerably reduce the prevalence of antimicrobial resistance and improve patient outcomes. Continuous monitoring and feedback to healthcare professionals also play a vital role in ensuring responsible antimicrobial use [18, 21]. These successful initiatives challenge the notion that limited resources are insurmountable barriers to implementing effective antimicrobial stewardship programmes in resource-poor settings.

Numerous studies have explored the implementation of antimicrobial stewardship programmes in resource-poor settings, revealing their potential to reduce

#### *Antimicrobial Stewardship in Resource-Limited Settings DOI: http://dx.doi.org/10.5772/intechopen.114057*

inappropriate antimicrobial prescribing and improve adherence to guidelines. The key to success lies in tailored training and education programmes that address the unique challenges of such settings [15, 22, 23, 31]. Evidence-based local procedures and protocols are crucial in tackling antimicrobial resistance and enhancing patient outcomes.

Despite limited resources, establishing active antimicrobial stewardship programmes in resource-poor settings is achievable through a collaborative approach involving healthcare professionals, policymakers, and the community [30]. It is essential to provide tailored training and education programmes that cater to the specific challenges faced by healthcare professionals [30]. Developing and implementing context-specific guidelines and protocols based on evidence can considerably reduce antimicrobial resistance and improve patient outcomes [20]. Regular monitoring and feedback to healthcare professionals are critical for responsible antimicrobial use.

The successful implementation of antimicrobial stewardship programmes in resource-poor settings challenges the notion that limited resources are insurmountable barriers. By adopting an evidence-based, context-specific approach, healthcare professionals and policymakers can effectively address the issue of antimicrobial resistance in such settings.

#### **7. Overcoming challenges and sustainability of antimicrobial stewardship programmes**

Antimicrobial resistance (AMR) is a pressing global health issue that threatens the effective prevention and treatment of infections caused by bacteria, viruses, fungi, and parasites [9]. The misuse and overuse of antimicrobial agents, poor infection prevention and control practices, and inadequate access to clean water, sanitation, and hygiene are major drivers of AMR. Resource-poor settings, where access to healthcare and essential medicines is limited, are particularly vulnerable to the negative impact of AMR. Antimicrobial stewardship programmes (ASPs) are crucial interventions to address AMR and promote the rational use of antimicrobial agents [31]. However, the implementation and sustainability of ASPs in resource-poor settings face several challenges that must be addressed [31]. Financial constraints and limited resources are significant obstacles to implementing and sustaining ASPs in resource-poor settings. External funding from international organisations, donor organisations, and philanthropic foundations can help overcome these constraints [33, 34]. Advocating for increased healthcare budgets and prioritising allocating ASPs can also contribute to addressing and identifying innovative approaches for funding, resource mobilisation and partnerships, which can provide additional resources and expertise [37].

Partnerships with organisations, institutions, and pharmaceutical companies can also provide access to expertise, resources, and funding. Collaborating with local communities and engaging community leaders can promote sustainability by fostering ownership and support for ASPs [30]. Engaging patients and their families in antimicrobial stewardship efforts can also increase awareness and guideline adherence [23]. Integrating ASPs into existing healthcare systems is crucial for long-term sustainability [17, 24, 38]. This can be achieved by incorporating antimicrobial stewardship principles and training into medical and nursing curricula and establishing

dedicated antimicrobial stewardship teams or committees within healthcare facilities [24]. Collaboration between healthcare professionals, policymakers, and regulators is essential to develop and enforce antimicrobial prescribing guidelines and policies that align with national and international recommendations [38]. Furthermore, leveraging existing healthcare infrastructure and systems, such as electronic medical records and surveillance systems, can facilitate monitoring and evaluating antimicrobial use and resistance patterns [21].

Ensuring the long-term sustainability and scalability of ASPs is a critical consideration. This can be achieved by establishing monitoring and evaluation mechanisms to assess the programmes' impact and identify areas for improvement [38]. Continuous education and training of healthcare professionals on antimicrobial stewardship principles and practices is essential to maintain awareness and adherence to guidelines [24]. Fostering a culture of accountability and responsibility among healthcare professionals and the community is crucial for sustaining the momentum of ASPs. Engaging stakeholders, including policymakers, healthcare professionals, patients, and community members, in discussions and decision-making processes can contribute to the sustainability and scalability of ASPs [27].

Finally, implementing and sustaining ASPs in resource-poor settings requires addressing frequent constraints, forming partnerships, integrating stewardship into existing healthcare systems, and focusing on long-term scalability. When implemented in a coordinated and comprehensive manner, these strategies can contribute to the successful implementation and long-term impact of antimicrobial stewardship initiatives in resource-poor settings.

#### **8. Future directions and recommendations**

The field of antimicrobial stewardship in resource-poor settings presents several areas for further exploration. To ensure the sustained effectiveness and sustainability of antimicrobial stewardship programmes, research should investigate the long-term impact of such programmes on antimicrobial resistance patterns, patient outcomes, and healthcare costs [39]. Additionally, evaluating the effectiveness of different strategies and interventions used in antimicrobial stewardship programmes, including education and training programmes, guidelines and protocols, and electronic decision support systems, is essential [39, 40]. Understanding the social and behavioural factors influencing antimicrobial use in these settings is also crucial. Policymakers should prioritise developing and implementing national antimicrobial stewardship policies and guidelines and advocate for increased funding and resources to support programme implementation and sustainability [31, 32, 35, 36]. Global collaboration and knowledge sharing can also advance antimicrobial stewardship efforts in resource-poor settings. By addressing these areas, resource-poor locations can strengthen their antimicrobial stewardship programmes and contribute to the global fight against antimicrobial resistance.

Antimicrobial resistance (AMR) is a growing concern globally, and it is especially significant in resource-poor settings. In these locations, the prevalence of infectious diseases is high, and antibiotics are often the primary treatment option. Unfortunately, the misuse and overuse of antibiotics have led to the emergence of resistant strains of bacteria, making infections difficult to treat [6]. The World Health Organisation (WHO) has recognised the importance of antimicrobial stewardship programmes, which aim to reduce the inappropriate use of antibiotics, improve prescribing practices, and optimise patient outcomes.

#### *Antimicrobial Stewardship in Resource-Limited Settings DOI: http://dx.doi.org/10.5772/intechopen.114057*

One area that requires further exploration is the long-term impact of antimicrobial stewardship programmes on antimicrobial resistance patterns, patient outcomes, and healthcare costs [40, 41]. While it is clear that such programmes can reduce the development of antimicrobial resistance, the long-term effects still need to be better understood. Research should investigate the impact of stewardship programmes over extended periods to determine their sustained effectiveness and sustainability. This information can help policymakers and healthcare providers make informed decisions about resource allocation and programme implementation.

Another critical area for exploration is the evaluation of the effectiveness of different strategies and interventions used in antimicrobial stewardship programmes [42]. These may include education and training programmes, guidelines and protocols, and electronic decision support systems [42, 43]. By evaluating these strategies, healthcare providers can identify the most effective ways to reduce inappropriate antibiotic use and improve patient outcomes. This information can help providers tailor their programmes to the unique needs of their patients and communities.

Understanding the social and behavioural factors influencing antimicrobial use in resource-poor settings is also crucial [44]. While healthcare providers can significantly reduce inappropriate antibiotic use, patients and their families also have a role to play. Cultural beliefs, practices, and limited access to healthcare facilities and diagnostics can contribute to inappropriate antibiotic use [43]. By understanding these factors, healthcare providers can develop targeted interventions to address them.

In conclusion, the importance of antimicrobial stewardship in addressing the global challenge of AMR cannot be overstated. In resource-poor settings, the challenges of implementing effective stewardship programmes are significant but manageable. By addressing research, evaluation, social and behavioural factors, policymaking, and collaboration, resource-poor locations can strengthen their antimicrobial stewardship programmes and contribute to the global fight against AMR. The health of populations in resource-poor settings, as well as future generations, depends on collective action by policymakers, healthcare providers, and researchers to develop and implement effective antimicrobial stewardship programmes.

### **Author details**

Simeon Chijioke Amadi1 \*, Faithful Miebaka Daniel<sup>2</sup> , Sokeipirim Ikiroma1 and Ibinabo Laura Oboro3

1 Department of Obstetrics and Gynaecology, Rivers State University/Rivers State University Teaching Hospital, Port Harcourt, Rivers State, Nigeria

2 Community and Clinical Research Division, First On-Call Initiative, Port Harcourt, Nigeria

3 Department of Medical Microbiology, Rivers State University/Rivers State University Teaching Hospital, Port Harcourt, Rivers State, Nigeria

\*Address all correspondence to: amachijio@yahoo.com

© 2024 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Rahman M, Sarker SD. Antimicrobial natural products. In: Annual Reports in Medicinal Chemistry. United States: Elsevier; 2020. pp. 77-113

[2] Dyary HO, Faraj GJ, Saeed NM. History, Current Situation, and Future Perspectives on Antibiotics and Antibiotic Resistance. One Heal Triad. Vol. 2. Faisalabad, Pakistan: Unique Scientific Publisher; 2023. pp. 109-118

[3] Ayukekbong JA, Ntemgwa M, Atabe AN. The threat of antimicrobial resistance in developing countries: Causes and control strategies. Antimicrobial Resistance and Infection Control. 2017;**6**(1):1-8

[4] Fishman N. Antimicrobial stewardship. American Journal of Infection Control. 2006;**34**(5):S55-S63

[5] Kakkar AK, Shafiq N, Singh G, Ray P, Gautam V, Agarwal R, et al. Antimicrobial stewardship programs in resourceconstrained environments: Understanding and addressing the need of the systems. Frontiers in Public Health. 2020;**8**:140

[6] Cox JA, Vlieghe E, Mendelson M, Wertheim H, Ndegwa L, Villegas MV, et al. Antibiotic stewardship in low-and middle-income countries: The same but different? Clinical Microbiology and Infection. 2017;**23**(11):812-818

[7] Hijazi K, Joshi C, Gould IM. Challenges and opportunities for antimicrobial stewardship in resourcerich and resource-limited countries. Expert Review of Anti-Infective Therapy. 2019;**17**(8):621-634

[8] Caron WP, Mousa SA. Prevention strategies for antimicrobial resistance: A systematic review of the literature.

Infection and Drug Resistance. 2010;**3**:25-33

[9] Ferri M, Ranucci E, Romagnoli P, Giaccone V. Antimicrobial resistance: A global emerging threat to public health systems. Critical Reviews in Food Science and Nutrition. 2017;**57**(13):2857-2876

[10] Roope LSJ, Smith RD, Pouwels KB, Buchanan J, Abel L, Eibich P, et al. The challenge of antimicrobial resistance: What economics can contribute. Science (80-). 2019;**364**(6435):eaau4679

[11] Cars O, Nordberg P. Antibiotic resistance–the faceless threat. The International Journal of Risk & Safety in Medicine. 2005;**17**(3-4):103-110

[12] Tenover FC. Mechanisms of antimicrobial resistance in bacteria. The American Journal of Medicine. 2006;**119**(6):S3-S10

[13] Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: Mortality, length of hospital stay, and health care costs. Clinical Infectious Diseases. 2006;**42**(Supplement\_2):S82-S89

[14] DiazGranados CA, Cardo DM, McGowan JE Jr. Antimicrobial resistance: International control strategies, with a focus on limited-resource settings. International Journal of Antimicrobial Agents. 2008;**32**(1):1-9

[15] Akilimali A, Awuah WA, Cakwira H, Mirindi MK, Masimango G, Amani T, et al. Antimicrobial resistance in Democratic Republic of Congo: The way forward. In: IJS Global Health. Vol. 6. Netherlands: Wolters Kluwer; 2023. p. e0150

[16] MacPherson EE, Reynolds J, Sanudi E, Nkaombe A, Phiri C, Mankhomwa J, et al. Understanding antimicrobial resistance through the lens of antibiotic vulnerabilities in primary health care in rural Malawi. Global Public Health. 2022;**17**(11):2630-2646

[17] World Health Organization (WHO). Monitoring the Building Blocks of Health Systems: A Handbook of Indicators and their Measurement Strategies [Internet]. Geneva, Switzerland: World Health Organization; 2010. Available from: https://www.google.com/url?sa=t&rct= j&q=&esrc=s&source=web&cd=&cad =rja&uact=8&ved=2ahUKEwij6Ifn59S AAxXgV0EAHRi8AcEQFnoECCUQAQ &url=https%3A%2F%2Fapps.who.int% 2Firis%2Fbitstream%2Fhandle%2F106 65%2F258734%2F9789241564052-eng. pdf&usg=AOvVaw1VUvLpCAGxolA87\_ WiE

[18] Iskandar K, Molinier L, Hallit S, Sartelli M, Hardcastle TC, Haque M, et al. Surveillance of antimicrobial resistance in low and middle-income countries: A scattered picture. Antimicrobial Resistance and Infection Control. 2021;**10**(1):1-19

[19] Gebretekle GB, Haile Mariam D, Abebe W, Amogne W, Tenna A, Fenta TG, et al. Opportunities and barriers to implementing antibiotic stewardship in low and middleincome countries: Lessons from a mixed-methods study in a tertiary care hospital in Ethiopia. PLoS One. 2018;**13**(12):e0208447

[20] Charani E, Smith I, Skodvin B, Perozziello A, Lucet JC, Lescure FX, et al. Investigating the cultural and contextual determinants of antimicrobial stewardship programmes across low-, middle-and high-income countries—A qualitative study. PLoS One. 2019;**14**(1):e0209847

[21] Simonsen GS, Tapsall JW, Allegranzi B, Talbot EA, Lazzari S. The antimicrobial resistance containment and surveillance approach-a public health tool. Bulletin of the World Health Organization. 2004;**82**(12):928-934

[22] Prentiss T, Weisberg K, Zervos J. Building capacity in infection prevention and antimicrobial stewardship in lowand middle-income countries: The role of partnerships inter-countries. Current Treatment Options in Infectious Diseases. 2018;**10**:7-16

[23] Virhia J, Gilmour M, Russell C, Mutua E, Nasuwa F, Mmbaga BT, et al. If you do not take the medicine and complete the dose… it could cause you more trouble: Bringing awareness, local knowledge and experience into antimicrobial stewardship in Tanzania. Antibiotics. 2023;**12**(2):243

[24] World Health Organization. Health Workers' Education and Training on Antimicrobial Resistance: Curricula Guide. Geneva, Switzerland: WHO; 2019

[25] Majumder MAA, Rahman S, Cohall D, Bharatha A, Singh K, Haque M, et al. Antimicrobial stewardship: Fighting antimicrobial resistance and protecting global public health. Infection and Drug Resistance. 2020;**13**:4713-4738

[26] Rolfe R, Kwobah C, Muro F, Ruwanpathirana A, Lyamuya F, Bodinayake C, et al. Barriers to implementing antimicrobial stewardship programs in three low-and middleincome country tertiary care settings: Findings from a multi-site qualitative study. Antimicrobial Resistance and Infection Control. 2021;**10**:1-11

[27] World Health Organization. Diagnostic Stewardship: A Guide to Implementation in Antimicrobial Resistance Surveillance Sites. Geneva, *Antimicrobial Stewardship in Resource-Limited Settings DOI: http://dx.doi.org/10.5772/intechopen.114057*

Switzerland: World Health Organization; 2016

[28] Borek AJ, Wanat M, Sallis A, Ashiru-Oredope D, Atkins L, Beech E, et al. How can national antimicrobial stewardship interventions in primary care be improved? A stakeholder consultation. Antibiotics. 2019;**8**(4):207

[29] Wathne JS, Kleppe LKS, Harthug S, Blix HS, Nilsen RM, Charani E, et al. The effect of antibiotic stewardship interventions with stakeholder involvement in hospital settings: A multicentre, cluster randomized controlled intervention study. Antimicrobial Resistance and Infection Control. 2018;**7**:1-12

[30] Logan AY, Williamson JE, Reinke EK, Jarrett SW, Boger MS, Davidson LE. Establishing an antimicrobial stewardship collaborative across a large, diverse health care system. Joint Commission Journal on Quality and Patient Safety. 2019;**45**(9):591-599

[31] Frumence G, Mboera LEG, Sindato C, Katale BZ, Kimera S, Metta E, et al. The governance and implementation of the National Action Plan on antimicrobial resistance in Tanzania: A qualitative study. Antibiotics. 2021;**10**(3):273

[32] Charani E, Mendelson M, Pallett SJC, Ahmad R, Mpundu M, Mbamalu O, et al. An analysis of existing national action plans for antimicrobial resistance— Gaps and opportunities in strategies optimising antibiotic use in human populations. The Lancet Global Health. 2023;**11**(3):e466-e474

[33] Wernli D, Harbarth S, Levrat N, Pittet D. A 'whole of United Nations approach' to tackle antimicrobial resistance? A mapping of the mandate and activities of international organisations. BMJ Global Health. 2022;**7**(5):e008181

[34] Tattevin P, Levy Hara G, Toumi A, Enani M, Coombs G, Voss A, et al. Advocacy for increased international efforts for antimicrobial stewardship actions in low-and middle-income countries on behalf of alliance for the prudent use of antimicrobials (APUA), under the auspices of the International Society of Antimicrobial Chemotherapy (ISAC). Frontiers in Medicine. 2020;**7**:503

[35] Ranjalkar J, Chandy SJ. India's National Action Plan for antimicrobial resistance–an overview of the context, status, and way ahead. Journal of Family Medicine and Primary Care. 2019;**8**(6):1828

[36] Anderson M, Schulze K, Cassini A, Plachouras D, Mossialos E. A governance framework for development and assessment of national action plans on antimicrobial resistance. The Lancet Infectious Diseases. 2019;**19**(11):e371-e384

[37] Uzochukwu BSC, Ughasoro MD, Etiaba E, Okwuosa C, Envuladu E, Onwujekwe OE. Health care financing in Nigeria: Implications for achieving universal health coverage. Nigerian Journal of Clinical Practice. 2015;**18**(4):437-444

[38] World Health Organization. Antimicrobial Stewardship Interventions: A Practical Guide. Geneva, Switzerland: World Health Organization; 2021

[39] Saubolle MA. Antimicrobial resistance: Current status and future direction. American Journal of Rhinology. 2006;**20**(6):667-671

[40] Engler D, Meyer JC, Schellack N, Kurdi A, Godman B. Antimicrobial

stewardship activities in public healthcare facilities in South Africa: A baseline for future direction. Antibiotics. 2021;**10**(8):996

[41] Newland JG, Banerjee R, Gerber JS, Hersh AL, Steinke L, Weissman SJ. Antimicrobial stewardship in pediatric care: Strategies and future directions. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2012;**32**(8):735-743

[42] Same RG. The current state and future directions of inpatient pediatric antimicrobial stewardship. Infectious Disease Clinics. 2022;**36**(1):173-186

[43] Briggs DC, Oboro IL, Bob-Manuel M, Amadi SC, Enyinnaya SO, Lawson SD, et al. Antibiotic prescription patterns in paediatric wards of Rivers state university teaching hospital, southern Nigeria: A point prevalence survey. The Nigerian Health Journal. 2023;**23**(3):837-843

[44] Bassetti M, Giacobbe DR, Vena A, Brink A. Challenges and research priorities to progress the impact of antimicrobial stewardship. Drugs Context. 2019;**8**:212600

#### **Chapter 6**

## Improving Antimicrobial Stewardship in Human Health Using Probiotics and Their Derivatives

*Nesisa Nyathi, Duduzile Ndhlovu, Esma Rabvukwa and Abigarl Ndudzo*

#### **Abstract**

Since antimicrobial resistance poses the biggest risks to human health, antimicrobial stewardship implies a strategy of responsible management. To lessen antimicrobial resistance and its impacts, a number of antimicrobial stewardship strategies are being used. One such crucial tactic is the use of probiotics and their derivatives, which directly affect the gut microbiota and have been linked to the development and management of a number of human diseases. Undoubtedly, the gut microbiota has a significant impact on the host immunological response, defense against pathogen overgrowth, biosynthesis, and metabolism. There is a rising need to incorporate strategies for altering the gut microbiota as a means of therapy or infection prevention in routine clinical practice as our understanding of the connections between the gut microbiota and host immunity and infectious illnesses deepens. Probiotics and their derivatives influence the development of various species in the gut microbiome to support the host's health. This review aims to investigate how the gut microbiota is modulated by probiotics, ghost probiotics, postbiotics, and synbiotics, and what this means for infection prevention and antibiotic stewardship.

**Keywords:** probiotics, ghost probiotics, synbiotics, postbiotics, antimicrobial resistance, antimicrobial stewardship

#### **1. Introduction**

The maintenance of a healthy and diverse gut microbiota plays an important role in the prevention and acquisition of antimicrobial resistance, and strategies that modulate its composition have great potential in impacting human health [1]. By limiting the detrimental effects of antimicrobials on the gut flora, the principles of antimicrobial stewardship are strengthened. Antimicrobial stewardship refers to a logical sequence of steps that confirms the effective therapeutic availability of antimicrobials when required [1]. Antimicrobial stewardship has three objectives.

The first objective is to collaborate with medical professionals to ensure that each patient receives the best antibiotic at the right dosage and for the right amount of time. The correct drug, dose, de-escalation to pathogen-directed therapy, and length of therapy are essential components of the best antimicrobial therapy [2]. Preventing misuse, abuse, and overuse of antibiotics is the second objective. Reduction of the emergence of antimicrobial resistance is the third objective [3].

Antimicrobials are the foundation upon which the health system is standing and are regarded as a global public good that has boosted health care, saved lives, and increased economic advantages [4]. Antimicrobial stewardship optimizes patient antimicrobial functioning to enhance outcomes and lowers antimicrobial resistance. In addition to encouraging the use of agents that are less likely to select for resistant microorganisms, it aids in the development of techniques and interventions that aim to reduce the unnecessary use of antimicrobials. Its initiatives lower prices, antimicrobial resistance, and toxicity [5]. According to Shiffen et al. [6], antimicrobial resistance is the modification of bacteria that renders them resistant to an antimicrobial. Antimicrobial resistance is one of the top ten global public health problems now facing the world [7].

In order to maintain antibiotic effectiveness and prevent the emergence and spread of infections that are antibiotic-resistant, antimicrobial stewardship promotes the cautious application of antimicrobials [8]. Antimicrobial treatments can cause microbes including viruses, fungi, and parasites to adapt and develop resistance. For instance, bacteria that are exposed to antibiotics develop a resistance that allows them to proliferate in the presence of antibiotics and pass on their resistance genes to their progeny [9]. As time goes on, highly resistant strains of microbes develop which are difficult or impossible to treat with available antimicrobials [10]. For antimicrobial therapies to be effective, antimicrobial stewardship programs promote the appropriate use of antibiotics, which includes proper prescription of drugs, the right dose for the right duration, and only when it is necessary [11]. As a result, the selective pressure driving the formation of antimicrobial resistance is reduced. It ensures that these drugs successfully treat infections and reduces the risk of microbial resistance, which is connected to morbidity and mortality [12].

Focus should be placed on the antimicrobial potential of probiotics against pathogenic microbes and host immunity when considering the current pandemic scenario. It has been said that the gut microbiota is an underappreciated organ that constantly establishes bi- or multidirectional interactions with other organs [13]. Therefore, the modification of the human immune system, gut microbiota, and treatment of illness by probiotics and their derivatives has a strong positive impact on reducing antimicrobial resistance and thereby increasing antimicrobial stewardship. The capacity of a healthy microbiota to limit the spread of potentially harmful bacteria is known as colonization resistance [1]. Probiotics play a crucial role in antimicrobial stewardship by maintaining or re-establishing colonization resistance by regulating the gut microbiota to prevent infection [6].

#### **2. Probiotics**

Probiotics are living organisms that, when consumed in sufficient proportions, help the host's health, however, the dead bacteria and their components can also exhibit probiotic properties [14]. They help with gastrointestinal health, immune system stimulation, and infection risk reduction [15]. By upsetting the normal

*Improving Antimicrobial Stewardship in Human Health Using Probiotics and Their Derivatives DOI: http://dx.doi.org/10.5772/intechopen.112497*

equilibrium of gut flora, they reduce antibiotic-associated diarrhea [16]. Additionally, they prevent an infection, which is an objective of antimicrobial stewardship, which reduces the need for antimicrobials. Microbiome therapy aims to modify the gut microbiome by applying native or artificially created bacteria in an additive, subtractive, or modulatory manner. [17]. Probiotic bacteria have the additional capacity to create and release antimicrobial substances like chemical compounds [7].

#### **2.1 Mechanisms of action of probiotics**

Probiotics function by:


#### **2.2 Effects of probiotics on the gut microbiota**

By encouraging the growth of helpful bacteria like *Lactobacillus* and *Bifidobacterium* and suppressing the growth of pathogenic bacteria like *Clostridium difficile*, probiotics can alter the balance of bacteria in the gut [20]. This can help safeguard against certain illnesses while enhancing intestinal health. Depending on the probiotic, harmful bacteria may be killed or its growth may be inhibited [19]. By doing so, the danger of infection can be decreased and pathogenic bacteria in the gut cannot develop [21]. By encouraging the creation of mucus and tight junction proteins, which can help stop harmful bacteria from entering the bloodstream, probiotics can enhance the intestinal barrier [19]. By increasing the production of anti-inflammatory cytokines and decreasing the production of pro-inflammatory cytokines, probiotics can also modify the immune system [20]. This may lessen intestinal inflammation and enhance gut health. A number of infectious and non-infectious diseases can be effectively treated using probiotics and their derivatives.

#### **2.3 Role of probiotics in antimicrobial stewardship**

The World Health Organization [11] has come to the conclusion that probiotics are the second-most important immune defense mechanism when frequently advised antimicrobials are unsuccessful against a limited number of pathogens. A number of beneficial intestinal bacteria, including *Lactobacillus*, *Bifidobacterium*, and *Enterococcus*, as shown in **Table 1**, contribute to the improvement of gut microbiota stability [28]. Probiotics can be found in food, beverages, and dietary supplements. Additionally, consuming fermented foods, which are probiotic bacteria's natural habitat, is of immense importance which eventually helps in the better treatment of several diseases, including gut-related disorders [28].


**Table 1.** *Roles of probiotics.* *Improving Antimicrobial Stewardship in Human Health Using Probiotics and Their Derivatives DOI: http://dx.doi.org/10.5772/intechopen.112497*

If it happens that once in the human body the probiotics die, they can no longer have a positive effect on health therefore scientists are conducting research to formulate technologies that produce dead and broken-down bacteria which are like probiotics or better in terms of immune enhancing properties [29].

#### **3. Ghost probiotics**

It has recently been discovered that ghost probiotics, or inactivated or heat-killed probiotic cells, can be used in place of live probiotics. In both animals and people, they have demonstrated effectiveness in modifying anti-inflammatory and proinflammatory immune responses [30]. Ghost probiotics, commonly referred to as para-probiotics, are beneficial microorganisms that have been rendered inactive. They can either be whole or broken [8]. Provoking the human immune system, promoting a favorable immunological response, and having anti-inflammatory effects in both people and animals are all impacts of ghost probiotics [31]. They are favored because they have a longer shelf life, which makes it easier to distribute them without refrigeration to various locations. In immune-compromised people, the use of ghost probiotics lowers the likelihood of contamination, microbial translocation, or heightened inflammatory immune responses [8, 32].

#### **3.1 Mechanisms of action of ghost probiotics**

Probiotics that have been inactivated may influence immunological responses by interacting with the immune system. A study suggested that the beneficial effects of ghost probiotics on gut microbiota may be due to the release of soluble factors such as cell membrane fragments and metabolites that can modulate immune function and promote the growth of beneficial bacteria [4]. These immuno-modulatory actions might suppress immune-related disorders and control immune response and inflammation. In the stomach, they fight against harmful microbes for adhesion sites and nutrition. They might hinder the attachment and proliferation of harmful bacteria by occupying these locations. In another study, researchers discovered that supplementation with ghost probiotics derived from *Lactobacillus plantarum* had positive effects on gut microbiota, including an increase in beneficial bacteria such as *Bifidobacterium* and *Lactobacillus* and a decrease in potentially harmful bacteria such as *Clostridium* [17].

They might help keep the intestinal barrier healthy and functioning properly. They are able to interact with gut epithelial cells, enhancing tight junction protein production and preserving the integrity of the gut barrier. Inactivated probiotics can aid in preventing the transfer of hazardous chemicals from the gut into the circulation by enhancing the barrier function [33]. Even in their non-viable state, inactivated probiotics may retain some antimicrobial properties. They may produce antimicrobial compounds such as organic acids, bacteriocins, or antimicrobial peptides that can inhibit the growth of pathogenic bacteria in the gut. These antimicrobial effects contribute to maintaining a balanced gut microbiota [8]. Inactivated probiotics may still have metabolic effects. They can interact with dietary components and release bioactive compounds such as short-chain fatty acids (SCFAs) or other metabolites. SCFAs, for example, can provide energy to colon cells, support the gut barrier function, and have systemic effects on metabolism [32].


#### **Table 2.**

*Roles of ghost probiotics.*

#### **3.2 Roles of ghost probiotics in antimicrobial stewardship**

In antimicrobial stewardship, ghost probiotics are used as a possible remedy in fighting against antimicrobial resistance [34], as illustrated in **Table 2**. A study by Thursby and Juge [40], revealed a significant decrease in the number of infections in the treatment group compared to the control group when the efficacy of a ghost probiotic formula in preventing respiratory tract infections in a population of elderly individuals in a nursing home was tested. In 2019, another study investigated the potential use of ghost probiotics as a preventive strategy against *Clostridium difficile* infections in a mouse model. Researchers found that a ghost probiotic formula of *Lactobacillus reuteri* DSM 17938 significantly shortens the duration of acute infectious diarrhea and reduces abdominal pain in patients with colitis [19, 41].

### **4. Synbiotics**

The term synbiotics describes probiotics and prebiotics that have been combined in dietary supplements or food ingredients to create a synergistic effect. According to Wang et al. [42], prebiotics are common foods that strengthen the immune system while encouraging the development of probiotic bacteria in the human stomach.

*Improving Antimicrobial Stewardship in Human Health Using Probiotics and Their Derivatives DOI: http://dx.doi.org/10.5772/intechopen.112497*

Prebiotics, which are necessary for the development and function of microorganisms, should not be mistaken with probiotics. Supplements and specific foods like yogurt, whole grains, and sauerkraut contain synbiotics [43]. *Bifidobacterium*, *Lactobacillus*, *Saccharomyces boulardii*, *Bacillus cougulans*, and prebiotics like Inulin and XOS are the most widely utilized synbiotics [44]. The most popular fibers that are typically utilized in conjunction with probiotics are fructans. Synbiotics were created in order to get over potential probiotic survival issues [43]. Synbiotics play a significant role in gut bacterial balance, which benefits the human immune system, metabolism, and gut health [43].

#### **4.1 Effects of synbiotics on gut microbiota**

The gut microbiota appears to play a role in the pathogenesis of obesity and associated diseases. Therefore, gut microbiota can also be considered a promising target in the comprehensive dietary approach to the prevention and treatment of obesity, including weight loss and weight maintenance [45]. Synbiotic supplementation increases the abundance of gut bacteria associated with positive health effects, especially *Bifidobacterium* and *Lactobacillus*, and it also appears to increase the gut microbiota richness [45].

According to Roy and Dhaneshwar [46], synbiotics can aid in enhancing the integrity of the intestinal barrier, which may lessen intestinal inflammation and enhance immunological function. Short chain fatty acids (SCFAs) are vital energy sources for colonocytes and have anti-inflammatory characteristics. Synbiotics help to boost production of SCFAs [47]. According to Phavichitr et al. [45], synbiotics can determine the abundance of harmful bacteria in the stomach, including *Escherichia coli* and *Clostridium difficile*. Additionally, synbiotics may enhance cholesterol, glucose, and inflammation metabolism, which could be advantageous for metabolic health [44].

#### **4.2 How do synbiotics work?**

Synbiotics work by combining prebiotics and probiotics to provide a synergistic effect that promotes optimal gut health. The probiotic adds beneficial bacteria that greatly benefit the gut microbiome. The prebiotic fuels the beneficial bacteria that is already present in the gut microbiome. There are two types of synbiotics which are synergistic synobiotics and complementary synbiotics [43]. Synergistic synbiotics are formulated to have live probiotics fueled by the prebiotic substrate that is co-administered in the product, allowing the two elements to work together as a self-contained whole [44]. Complementary synbiotics are formulated so that both elements work independently, with the prebiotic chosen to target resident microorganisms in the gut [44].

Synbiotics help to promote the growth of beneficial bacteria in the gut, leading to improved gut microbiome balance and overall gut health. A study by Palai *et al.* [43], supported that symbiotic supplements used in clinical trial modulate human gut microbiota by increasing abundance of potentially beneficial microbial species. Synbiotics have been shown to boost immune function by promoting the growth of beneficial bacteria that can help fight off harmful pathogens. A study showed that a synbiotic consisting of *Lactobacillus acidophilus* and Inulin improved the immune response in elderly individuals by increasing the production of immunoglobulin A and reducing the levels of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha [44].

Synbiotics can improve digestion by promoting the growth of beneficial bacteria that aid in the breakdown and absorption of nutrients. They display positive effects on digestion and enzymatic activity, which may help alleviate many of the symptoms associated with lactose intolerance. For instance, the synbiotic of *Lactobacillius acidophilus* and Inulin improves the digestion of lactose in lactose-intolerant individuals by increasing the population of lactase-producing bacteria in the gut [47]. Also, probiotics like *Bifidobacterium lactis* combined together with fructooligosaccharides (FOS) improve the digestion of protein and fat in healthy adults by enhancing the production of pancreatic enzymes. Synbiotics have been shown to have anti-inflammatory effects, which can help to reduce inflammation in the gut and throughout the body. For example, research showed that a synbiotic consisting of *Lactobacillus acidophilus* and FOS reduces levels of C-reactive protein, a cause of inflammation [48].

#### **4.3 Roles of synbiotics in antimicrobial stewardship**

Synbiotics play a valuable role in antimicrobial stewardship by reducing the need for antimicrobial agents and preventing the development of antibiotic resistance. Synbiotics can be used to prevent and treat a number of conditions that are often treated with antimicrobials, such as *Clostridium difficile* infection, inflammatory bowel disease, and irritable bowel syndrome [49]. *Lactobacillus acidophilus* and *Bifidobacterium lactis* with FOS have been shown to reduce the incidence of antibioticassociated diarrhea and *Clostridium difficile* infection in hospitalized patients efficiently [47]. *Lactobacillus rhamnosus* GG and inulin have been shown to reduce the incidence of antibiotic-associated diarrhea in children [47]. *Akkermansia muciniphila* and prebiotic fibers have been shown to improve gut barrier function and reduce inflammation in obese and overweight adults [49].

#### **5. Postbiotics**

Postbiotics are metabolic by-products of probiotic bacteria [34]. These byproducts include short-chain fatty acids, enzymes, peptides, and other compounds that can have various health benefits. Postbiotics play a role in maintaining gut health, regulating the immune system, providing anti-inflammatory effects and potentially reducing the risk of certain diseases [2]. Postbiotics can be naturally produced by the probiotic bacteria that live in our gut and they can also be produced through fermentation of certain foods such as yogurt, kefir, sauerkraut, and kimchi [50].

#### **5.1 Roles of postbiotics in antimicrobial stewardship**

Postbiotics, such as peptides and organic acids, have been shown to have beneficial effects on gut microbiota as shown in **Table 3**. Certain peptides produced by *Lactobacillus* species have been shown to inhibit the growth of pathogenic bacteria such as *Escherichia coli* and *Salmonella enteritidis* [9]. Organic acids such as acetic acid and lactic acid, which are produced by some probiotic bacteria, can help to lower the pH of the gut, creating an environment that is less favorable for the growth of harmful bacteria [2]. Short-chain fatty acids (SCFAs) are produced by the fermentation of dietary fiber by gut bacteria and have been shown to have antimicrobial properties. They can help to inhibit the growth of harmful bacteria such as *Clostridium difficile*, which is a common cause of antibiotic-associated diarrhea. By promoting the growth of beneficial *Improving Antimicrobial Stewardship in Human Health Using Probiotics and Their Derivatives DOI: http://dx.doi.org/10.5772/intechopen.112497*


**Table 3.** *Roles of postbiotics.*

bacteria and reducing the need for antibiotics, SCFAs can help to reduce the overall use of antimicrobials and limit the development of antimicrobial resistance [50].

Bacteriocins are antimicrobial peptides produced by some probiotic bacteria that can help to inhibit the growth of pathogenic bacteria. For example, nisin, a bacteriocin produced by *Lactococcus lactis*, has been shown to be effective against a range of Gram-positive bacteria, including *Staphylococcus aureus* and *Streptococcus pneumoniae* [57]. By using bacteriocins instead of antimicrobials to target specific pathogens, postbiotics can help to reduce the overall use of antimicrobials and limit the development of antimicrobial resistance.

Exopolysaccharides are complex carbohydrates produced by some probiotic bacteria that can have prebiotic effects, meaning they can promote the growth of beneficial bacteria in the gut [50]. Peptidoglycans are complex molecules found in the cell walls of bacteria that can modulate the immune system and have anti-inflammatory effects. Cell surface proteins are proteins found on the surface of probiotic bacteria that can interact with host cells and modulate immune responses [33].

#### **6. Issues surrounding the use of probiotics and their derivatives in antimicrobial stewardship**

To be considered a probiotic, a supplement needs to meet all the requirements set forth by the 2002 Food and Agriculture Organization/World Health [57].

The requirements stipulate that a probiotic must be a live microorganism, needs to be administered and should have a health benefit. Additionally, a probiotic must be safe and void of vectors that can transfer resistance to antibiotics [14]. One issue surrounding the use of probiotics in antimicrobial stewardship is the potential for interactions between probiotics and antibiotics. Some studies have suggested that probiotics may reduce the effectiveness of antibiotics by competing with them for absorption in the gut or by producing antibacterial substances that can neutralize antibiotics. This could lead to suboptimal treatment outcomes and the emergence of antibiotic-resistant strains of bacteria [58]. However, other studies have shown that probiotics can enhance the effectiveness of antibiotics by improving the gut microbiota and reducing the risk of antibiotic-associated diarrhea and other side effects. Another issue is the lack of standardization in the production and labeling of probiotics [57]. There is significant variability in the quality and efficacy of probiotic products, and there are currently no widely accepted standards for the selection, testing, and labeling of probiotics. This makes it difficult for healthcare providers to make informed decisions about which probiotics to use and for what indications [59].

### **7. Conclusion and future perspectives**

In the midst of the ongoing antibiotic resistance challenge, using probiotics, postbiotics, ghost probiotics, and synbiotics offers a secure alternative to treating microbial infections. In order to research future potential uses of probiotics in both human and animal diseases, it is vital to update our knowledge in this area. As a result, this work may be used as a reference to understand naturally occurring probiotic compounds and their prospective applications for the treatment and management of numerous human diseases, providing a significant contribution to antimicrobial stewardship. Probiotics and their derivatives that exhibit powerful activity, both alone and in combination, must therefore be researched in the future.

### **Author details**

Nesisa Nyathi1 \*, Duduzile Ndhlovu1 , Esma Rabvukwa1 and Abigarl Ndudzo1,2

1 Department of Applied Biotechnology, Lupane State University, Zimbabwe

2 Department of Molecular Biology and Biotechnology, Pan African University of Basic Sciences and Technology, Jomo Kenyatta University of Agriculture and Technology, Juja, Kenya

\*Address all correspondence to: nesisamdluli@gmail.com

© 2024 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Improving Antimicrobial Stewardship in Human Health Using Probiotics and Their Derivatives DOI: http://dx.doi.org/10.5772/intechopen.112497*

#### **References**

[1] Zawistowska-Rojek A, Tyski S. Are probiotic really safe for humans? Polish Journal of Microbiology. 2018;**67**(3): 251-258. DOI: 10.21307/pjm-2018-044

[2] Aguilar-Toala JE, Garcia-Varela R, Garcia HS, Mata- Haro V, Gonzalez-Cordova AF, Vallejo-Cordoba B. Postbiotics: An evolving term within the functional foods field. Trends Food Science and Technology. 2018;**75**:105-114. DOI: 10.1016/j.tifs.2018.03.009

[3] Jeong K, Kim M, Jeon SA, Kim YH, Lee S. A randomized trial of *lactobacillus rhamnosus* IDCC 3201 tyndallizate (RHT3201) for treating atopic dermatitis. Pediatric Allergy and Immunology. 2020;**31**:783-792. DOI: 10.1111/pai.13269

[4] Arboleya S, Merinero MC, Solis G. Ghost probiotics with a combined regimen: A novel approach for the prevention and treatment of neonatal sepsis. Beneficial Microbes. 2021;**12**(1). DOI: 10.3920/BM2020.0079

[5] Hoarau C, Martin L, Faugaret D, Baron C, Dauba A, Aubert-Jacquin C, et al. Supernatant from Bifidobacterium differentially modulates transduction signaling pathways for biological functions of human dendritic cells. PLoS One. 2018;**3**(7):E2753. DOI: 10.1371/ journal.pone.0002753

[6] Sniffen JC, McFarland LV, Evans CT, Goldstein EJC. Choosing appropriate probiotic product for your patient: An evidence based particular guide. PLoS One. 2018;**13**(12):e0202205. DOI: 10.1371/journal.pone.0209205

[7] Szczerbiec D, Piechoka J, Glowacki R, Torzewska A. Organic acids secreted by lactobacillus spp. isolated from

urine and their antimicrobial activity against Uropathogenic *Proteus mirabilis*. Molecules. 2022;**27**:5557. DOI: 10.3390/ molecules27175557

[8] Kim WK, Jang YJ, Han DH, Jeon K, Lee C, Han HS. *Lactobacillus paracasei* KBL382 administration attenuates atopic dermatitis by modulating immune response and gut microbiota. Gut Microbes. 2020;**12**:1-14. DOI: 10.1080/19490976. 2020.1819156

[9] Chang CM, Tsai MH, Liao WC, Yang PH, Li SW, Chu SM, et al. Effects of probiotics on gut microbiomes of extremely preterm infants in the neonatal intensive care unit: A prospective cohort study. Nutrients. 2022;**14**(15):3239. DOI: 10.3390/nu14153239

[10] Sun M, Luo J, Liu H, Xi Y, Lin Q. Can mixed strains of *lactobacillus* and *Bifidobacterium* reduce eczema in infants under three years of age? A meta-analysis. Nutrients. 2021;**13**. DOI: 10.3390/ nu13051461

[11] World Health Organisation. Antimicrobial Stewardship Programmes in Health Care Facilitating Low- and Middle Income Countries: A WHO Practical Toolkit. 2019. Available from: https://apps.who.int/iris/bitstream/han dle/10665/329404/9789241515481-eng. pdf [Accessed: 20 May 2023]

[12] Azim-Majumder MA, Rahman S, Cohall D, Bharatha A, Singh K, Haque M, et al. Antimicrobial stewardship: Fighting antimicrobial resistance and protecting global public health. Infection and Drug Resistance. 2020;**13**:4713-4738. DOI: 10.2147/IDR. S290835

[13] Halluran K, Underwood MA. Probiotics mechanisms of action. Early Human Development. 2019;**135**:58-65. DOI: 10.1016/j.earlhumdev.2019.05.010

[14] Plaza-Diaz J, Ruiz-Ojeda FJ, Gil-Campos M, Gil A. Mechanisms of action of probiotics. Advanced Nutrition. 2019;**10**. DOI: 10.1093/advances/nmy063

[15] Reid G, Gadir AA, Dhir R. Probiotics: Reiterating what they are and what they are not. Frontiers in Microbiology. 2019;**10**. DOI: 10.3389/fmicb.2019.00424

[16] Blaabjerg S, Artzi DM, Aabenhus R. Probiotics for the prevention of antibiotic-associated diarrhea in outpatients- a systematic review and meta-analysis. Antibiotics. 2017;**6**(4). DOI: 10.3390/antibiotics6040021

[17] Yadav M, Chauhan NS. Microbiome therapeutics: Exploring the present scenario and challenges. Gastroenterology Report. 2021;**10**:goab046. DOI: 10.1093/gastro/ goab046

[18] Li Y, Xia S, Jiang X, Feng C, Gong S, Ma J, et al. Gut microbiota and diarrhea: An updated review. Frontiers in Cellular and Infection Microbiology. 2021;**11**. DOI: 10.3389/ fcimb.2021.625210

[19] Wu J, Zhang Y, Ye L, Wang C. The anti-cancer effects and mechanisms of lactic acid bacteria exopolysaccharides in vitro: A review. Carbohydrate Polymers. 2021;**253**:117308. DOI: 10.1016/j. carbpol.2020.117308

[20] Divakar D, Poonam SN. The gut microbiota influenced by the intake of probiotics and functional foods with prebiotics can sustain wellness and alleviate certain ailments like gutinflammation and colon cancer. 2022. DOI: 10.3390/microorganisms10030665 [21] Case I. The Regulation of Probiotics. Degree Candidate for Masters of Science in Regulatory Science. Johns Hopkins University.Available from: https:// www.jhsph.edu/research/centers-andinstitutes/center-of-excellence-inregulatory-science-and-innovation/ training/Iris; 2021 [Accessed 24 May 2023]

[22] George Kerry R, Patra JK, Gouda S, Park Y, Shin H, Das G. Benefaction of probiotics for human health: A review. Journal of Food and Drug Analysis. 2018;**26**(3):927-939. DOI: 10.1016/j. jfda.2018.01.002

[23] Chen M, Lin W, Li N, Wang Q, Zhu S, Zeng A, et al. Therapeutic approaches to colorectal cancer via strategies based on modulation of gut microbiota. Frontiers in Microbiology. 2022;**13**:945533. DOI: 10.3389/ fmicb.2022.945533

[24] Bozomitu L, Miron I, Adam Raileanu A, Lupu A, Paduraru G, Marcu FM, et al. The gut microbiome and its implication in the mucosal digestive disorders. Biomedicine. 2022;**10**(12):3117. DOI: 10.3390/biomedicines10123117

[25] Mazziotta C, Tognon M, Martini F, Torreggiani E, Rotondo JC. Probiotics mechanism of action on immune cells and beneficial effects on human health. Cell. 2023;**12**(1). DOI: 10.3390/ cells12010184

[26] Aponte M, Murru N, Shoukat M. Therapeutic, prophylactic, and functional use of probiotics: A current perspective. Frontiers in Microbiology. 2020;**11**:562048. DOI: 10.3389/ fmicb.2020.562048

[27] Gunaratnam S, Millette M, McFarland LV, DuPont HL, Lacroix M. Potential role of probiotics in reducing Clostridioides difficile virulence:

*Improving Antimicrobial Stewardship in Human Health Using Probiotics and Their Derivatives DOI: http://dx.doi.org/10.5772/intechopen.112497*

Interference with quorum sensing systems. Microbial Pathogenesis. 2021;**153**:104798. DOI: 10.1016/j. micpath.2021.104798

[28] Prakoeswa C, Bonita L, Karim A, Herwanto N, Umborowat MA, Setyaningrum T. Beneficial effect of *lactobacillus plantarum* IS-10506 supplementation in adults with atopic dermatitis: A randomized controlled trial. Journal of Dermatological Treatment. 2022;**33**:1491-1498. DOI: 10.1080/09546634.2020.1836310

[29] Marco ML, Heeney D, Binda S, Cifelli CJ, Cotter PD, Foligne B, et al. Health benefits of fermented foods: Microbiota and beyond. Current Opinions in Biotechnology. 2017;**44**:94- 102. DOI: 10.1016/j.copbio.2016.11.010

[30] Siciliano RA, Reale A, Mazzeo MF, Morandi S, Silvetti T, Brasca M. Paraprobiotics: A new perspective for functional foods and nutraceuticals. Nutrients. 2021;**13**(4). DOI: 10.3390/ nu13041225

[31] Hasan A, Paray BA, Hussain A, Qadir FA, Attar C, Aziz FM. A review on the cleavage priming of the spike protein on coronavirus by angiotensinconverting enzyme-2 and furin. Journal of Biomolecular Structure and Dynamics. 2021;**39**(8):3025-3033. DOI: 10.1080/07391102.2020.1754293

[32] Ndudzo A, Ndlovu S, Nyathi N, Makuvise-Sibanda A. Unlocking the potential of ghost probiotics in combating anti-microbial resistance. In: The Global Antimicrobial Resistance Epidemic: Innovative Approaches and Cutting Edge Solutions. London, UK: IntechOpen; 2022. DOI: 10.5772/ intechopen.10426

[33] Kim D, Kim YJ, Kim SH, Yang JS. Short-chain fatty acids produced by

*lactobacillus plantarun* strain Lp27 inhibit *Escherichia coli* 0157:H7 and *salmonella Typhimurium* in vitro. Journal of Microbiology and Biotechnology. 2019;**29**(8):1195-1205

[34] Aguilar-Toalá JE, Cuevas-Gonzalez P, Liceaga A. Postbiotics and Parabiotics: From concepts to applications. Food Research International. 2020;**136**:109502. DOI: 10.1016/j.foodres.2020.109502

[35] Amara AA, Shibl A. Role of probiotics in health improvement, infection control and disease treatment and management. Saudi Pharmaceutical Journal: SPJ. 2015;**23**(2):107-114. DOI: 10.1016/j.jsps.2013.07.001

[36] Incrocci R, Negris O, McGrath S, Swartzendruber JA. Bacillus subtilis provides long-term protection in a murine model of allergic lung disease by influencing bacterial composition. Allergie. 2023;**3**(1):1-10. DOI: 10.3390/ allergies3010001

[37] Li HY, Zhou DD, Ren Y, Huang S, Zhao C, Shang A, et al. Effects and mechanisms of probiotics, prebiotics, synbiotics and post biotics on metabolic diseases targeting. Gut Microbiota. 2021;**13**(9):3211. DOI: 10.3390/nu13093211

[38] Kechagia M, Basoulis D, Konstantopoulou S, Dimitriadi D, Gyftopoulou K, Skarmoutsou N, et al. Health benefits of probiotics: A review. ISRN Nutrition. 2013. DOI: 10.5402/2013/481651

[39] Patangia DV, Ryan CA, Dempsey E, Ross RP, Stanton C. Impact of antibiotics on the human microbiome and consequences for host health. Microbiology Open. 2022;**11**(1). DOI: 10.1002/mbo3.1260

[40] Thursby E, Juge N. Introduction to the human gut microbiota. The

Biochemical Journal. 2017;**474**(11):1823- 1836. DOI: 10.1042/BCJ20160510

[41] Saviano A, Brigida M, Migneco A, Gunawardena G, Zanza C, Candelli M, et al. *Lactobacillus Reuteri* DSM 17938 (*Limosilactobacillus reuteri*) in diarrhea and constipation: Two sides of the same coin? Mecina (Kaunas). 2021;**57**(7):643. DOI: 10.3390/ medicina57070643

[42] Wang HT, Anvari S, Anagnostou K. The role of probiotics in preventing allergic disease. Children (Basel, Switzerland). 2019;**6**(2):24. DOI: 10.3390/children6020024

[43] Palai S, Derecho CMP, Kesh SS, Egbuna C, Onyeike PC. Prebiotics, probiotics, synbiotics and its importance in management of diseases. Chapter 10. In: Functional Foods and Neutraceuticals. Springer; 2020. DOI: 10.1007/978-3-030-42319-3\_10

[44] Thilagavathi T. Probiotics, prebiotics, synbiotics and its health benefits, International Journal of Current Microbiology and Applied Sciences. 2020 DOI: 10.20546

[45] Phavichitr N, Wang S, Chomoto S, Tantibhaedhyangkul R, Kakourou A, Intarakhao S, et al. Impact of Synbiotics on gut microbiota during early life: A randomized double-blind study. Scientific Reports. 2021;**11**(1):3534. DOI: 10.1038/s41598-021-83009-2

[46] Roy S, Dhaneshwar S. Role of prebiotics, probiotics, and synbiotics in management of inflammatory bowel disease: Current perspectives. World Journal of Gastroenterology. 2023;**29**(14):2078-2100. DOI: 10.3748/ wjg.v29.i14.2078

[47] Chatchatee P, Way SL, Eugenia C, Kosuwon P, Simaakachorn N, Yavuz Y, et al. Effects of growing up supplemented with prebiotics and LCPUFAS on infectious in young children. 2018. DOI: 10.1097/MPG.0000000000000252

[48] Xie A, Chen A, Chen Y, Luo Z, Jiang S, Chen D, et al. *Lactobacillus* for the treatment and prevention of atopic dermatitis: Clinical and experimental evidence. Frontiers in Cellular and Infection Microbiology. 2023;**13**:1137275. DOI: 10.3389/fcimb.2023.1137275

[49] Depommier C, Everard A, Druart C, Plovier H, Van Hul M, Vieira-Silva S, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: A proof-of-concept exploratory study. Nature Medicine. 2019;**25**(7):1096-1103. DOI: 10.1038/ s41591-019-0495-2

[50] Zhang L, Chen H, Wang Y, Yu L. Antimicrobial activity of acetic acid produced by lactobacillus plantarum JD-15 against foodborne pathogens. Journal of Agricultural and Food Chemistry. 2019;**67**(43):12059-12067. DOI: 10.3390%2Ffoods10123131

[51] Delgado S, Sánchez B, Margolles A, Ruas-Madiedo P, Ruiz L. Molecules produced by probiotics and intestinal microorganisms with immunomodulatory activity. Nutrients. 2020;**12**(2). DOI: 10.3390/nu12020391

[52] Moon A, Sun Y, Wang Y, Huang J, Zafar Khan MU, Qiu H. Lactic acid bacteria as mucosal immunity enhancers and antivirals through Oral delivery. Applied Microbiology. 2022;**2**(4):837-854. DOI: 10.3390/applmicrobiol2040064

[53] Francisco D, Alexis J, Rubén J. Bacteriocins: An overview of antimicrobial, toxicity, and biosafety assessment by in vivo models. Frontiers in Microbiology. 2021;**12**:630695. DOI: 10.3389/fmicb.2021.630695

*Improving Antimicrobial Stewardship in Human Health Using Probiotics and Their Derivatives DOI: http://dx.doi.org/10.5772/intechopen.112497*

[54] Buzas EI. The roles of extracellular vesicles in the immune system. Nature Reviews Immunology. 2023;**23**(4):236- 250. DOI: 10.1038/s41577-022-00763-8

[55] Ma L, Tu H, Chen T. Postbiotics in human health: A narrative review. Nutrients. 2023;**15**(2). DOI: 10.3390/ nu15020291

[56] Hou K, Wu Z, Chen X, Wang J, Zhang D, Xiao C, et al. Microbiota in health and diseases. Signal Transduction and Targeted Therapy. 2022;**7**(1):1-28. DOI: 10.1038/s41392-022-00974-4

[57] FDA. 2017. Food Labeling: Revision of the Nutrition and Supplement Facts Label. Available form: https://www. regulations.gov/document/FDA-2012-N-1210-0875 [Accessed 19 May 2023]

[58] de Simone C. The unregulated probiotic market. Clinical Gastroenterology and Hepatology. 2019;**17**(5):809-817. DOI: 10.1016/j. cgh.2018.01.018

[59] Grebow J. Will FDA Ever Provide a Practical Regulatory Path for Probiotics? Panel Discusses at NPS's the Big Natural Conference. 2020. Available from: https://www.nutritionaloutlook. com/view/will-fda-ever-provide-apractical-regulatory-path-forprobioticspanel-discusses-at-npa-s-the-bignatural-conference [Accessed: 19 May 2023]

#### **Chapter 7**

## Laboratory Information Management System (LIMS) Analysis: A Lucrative Tool to Support the Control of Antimicrobial Resistance (AMR)

*Maryam Nasrumminallah and Fatima Rehan*

#### **Abstract**

Globally, antimicrobial resistance (AMR) poses a real risk to people's health. To ascertain the burden, implications, and trends of AMR and to track the results of interventions, surveillance is a crucial activity. High-quality laboratory data must be efficiently collected and shared with surveillance systems. Particularly in LMICs with high disease loads, the capacity of laboratories is being dramatically increased. Building capacity for effective laboratory data administration is still a resourceconstrained issue that, if left unresolved, may hamper development toward comprehensive AMR surveillance in LMICs. The absence of an open-source, useful lab tests database is particularly concerning. In this Personal View, we present an overview of the laboratory data management practices in Lower Middle Income Countries (LMIC) laboratories, a snapshot of the technological requirements for microbiological lab data management, and a description of the critical remedial measures. Current efforts to boost capability for AMR surveillance in LMICs would not be entirely successful without strategies for upgrading information technology equipment and information management systems in microbial labs.

**Keywords:** laboratory information management, AMR, bacterial antigen, antibiotics, surveillance resistance, patient care

#### **1. Introduction**

Worldwide, antibiotic use has spared millions of souls. However, overuse of antibiotics over the past 60 years has resulted in the evolution of antibiotic-resistant bacteria, hastening the spread of fatal infectious diseases and burdening society with financial costs. Even though this issue is frequently thought of as a worldwide one, some parts of the world are ignorant of its true extent [1]. AMR, an evolving danger to the general population, is caused by resistant strains of antibiotics. is making it harder to treat and prevent bacterial infections with today's drugs.

Antibiotic-resistant organisms have emerged due to widespread antibiotic use during the past 60 years, accelerating the spread of fatal diseases and adding to the financial burden on society. There is no denying that this problem exists on a worldwide scale, yet in some regions of the world its scope is not quite evident [1].

The tendency of microorganisms to resist treatment or control via antimicrobial drugs adopted to do so is known as antibiotic resistance. Antimicrobial resistance (AMR) could pose a serious worldwide issue. Information on the rate of bacteria immune to antibiotics in countries of low- and middle socioeconomic status is scarce. Antibiotic resistance, however, is a significant international and domestic problem in West Pakistan, one of South Asia's growing nations [2]. Recent discoveries of MDR (multi-drug resistant) and highly drug resistant microbes have both been made in Pakistan. The enterobacteriaceae family has developed quinolone resistance in Pakistan [3]. In addition, 93.7% of strains were found to be resistant to third-generation cephalosporins in a research on blood stream infections (BSI) [4]. The theory, which is commonly backed by a number of studies, contends that patients' inaccurate indefinite consumption is to fault, along with irrational advice, incentives for overprescribing, self-treatment, less trained personnel, and a lack of professional training and standard examinations.

Suboptimal antimicrobial use can be caused by a number of things, including a general overreliance on empirical antimicrobial therapy with a concomitant disregard for microbiological outcomes, errors in testing at the lab, inability to bring in suitable samples for culture, unauthorized use of microbes in order assets and the absence of a microbiologically verified evaluation.

#### **1.1 What is an antimicrobial stewardship program?**

The Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), and the pediatric Infectious Diseases Society (PIDS), all agree that antibiotic stewardship involves collaborative efforts to encourage the selection of the best medication regimen, including the administration, time span, and route of administration. The purpose of these interventions is to measure and enhance the proper use of antibiotics [5].

The implementation of evidence-based treatments that maximize the use of antibiotics while limiting the emergence of resistance is the focus of ASPs. These programs include the creation of guidelines as well as regulatory and policy measures. Practically speaking, ASPs could be considered as the right course of action for employing antibiotics in a way that provides ongoing access to efficient treatment while minimizing side effects [5].

#### **1.2 What is needed to set up an AMR surveillance system?**

AMR surveillance typically requires a supportive environment and a commitment to delivering high-quality care in order for specialists from various facets of the medical field to follow good clinical practice, connect effectively, coordinate customs, and complete projects in the shortest possible time. Based on an effective infectious disease diagnostic cycle, this multifaceted or collaborative strategy includes clinicians who collect clinical samples for the microbiology lab and submit them there, a bacteriology lab that can perform species recognition and AST, as well as a system to report, collect, analyze, and analyze facts so that those who must take action are informed [6]. The uniform and verified information gathered from an effective

AMR surveillance system can help countries create practical therapy recommendations, based on research public health policies, and other actions. There are a few key components for creating an AMR surveillance system. The system can grow gradually once these foundational pieces are in place [6].

#### **1.3 Justification for surveillance of antimicrobial resistance**

Data from AMR surveillance programs are used to track how bacteria respond to various antibiotic agents. Regular data distribution can aid in the revision of case management guidelines for healthcare facilities and aid in the methodical eradication of AMR. Additionally, this information can be utilized to educate the public, regulators, pharmacists, and medical professionals. To prove the effectiveness of treatment when treating communities during outbreaks, AMR surveillance is essential. It is crucial for both identifying the formation of novel resistance patterns and tracking the effectiveness of measures meant to reduce the burden and spread of AMR. It is obvious that in order to lower infectious disease-related mortality and morbidity, an effective surveillance system for AMR, which is a component of IDSR implementation and health systems improvement, is required [7].

In a national bacteriology reference laboratory, WHO handbook seeks to give background knowledge and outline the essential stages for countries conducting AMR surveillance for meningitis, bacteremia, and common enteric epidemic-prone Diseases. The adaptation of this guide to the national context and its acceptance would help to reduce the spread of AMR among these microorganisms, even though it encourages the sharing of laboratory data on AMR for high priority bacterial infections as meningitis, cholera, salmonellosis, and shigellosis [7].

#### **1.4 Purpose and benefits of antimicrobial stewardship programs**

The goal of ASPs is aimed at improving the clinical use of prescription antibiotics, which includes proper drug choice, a sufficient/balanced range, and use at the optimal moment, in the ideal amount, using the proper technique, and at appropriate periods [5]. There is growing evidence that ASPs improve the handling of disease, reduce complications linked to the use of antimicrobial agents, and enhance patient safety and quality of care [5].

#### **1.5 Antimicrobial stewardship programs in different parts of the world**

The Infectious Diseases Study Group for Antimicrobial Stewardship (ESCMID/ ESGAP) and the Antimicrobial Stewardship Working Group of the International Society of Antimicrobial Chemotherapy (ISC) collaborated to conduct a global survey on antimicrobial stewardship in hospitals between March and September 2012. There were 67 participating nations from six different continents. 103 replies out of 660 came from Central and South America. Hospital AMS requirements differed from nation to nation. A total of 46% of hospitals already have an ASP, compared to 58% of hospitals worldwide, 66% of hospitals in Europe, and 67% of hospitals in North America [5].

At the local level, some initiatives have been created, such as mandated prescriptions for the purchase of antibiotics at pharmacies. Brazil and Mexico enacted laws in 2010, Chile in 1999, Colombia in 2005, and Chile in 1999, all of which were successful in lowering antibiotic consumption. A 12% decline in penicillin consumption was

realized in Mexico. Following the implementation of the legislation, the large seasonal variation in penicillin consumption also decreased, indicating that antibiotics were previously not used appropriately for the treatment of transmissible infections of the respiratory system, a common example of antimicrobials abuse. Antimicrobial resistance reduction or stabilization (87%), a decrease in the amount of antibiotic prescriptions (53%), and clinical outcome improvement (49%) were the three main goals of ASPs across all nations [5].

#### **1.6 Antimicrobial stewardship programs and WHO Global Action Plan**

The WHO Global Action Plan on Antimicrobial Resistance and the PAHO Regional Action Plan both include antimicrobial stewardship programs [5]. In fact, suggestions for maximizing the use of antimicrobial medications in human and animal health are included in Objective 4 of the WHO Global Action Plan. The same goal specifically mentions that Member States must set up stewardship programs "that monitor and promote optimization of antimicrobial use at national and local levels in accordance with international standards to ensure the correct choice of antimicrobials at the right dose, based on evidence" [5].

#### **2. Laboratory data management system**

Systems for managing and evaluating large volumes of data from antimicrobial resistance (AMR) monitoring systems are called laboratory information management systems (LIMS). A crucial tool for informing policies and infection prevention and control measures is surveillance. A Laboratory Information Management System (LIMS) is used by the majority of labs. Laboratory information management systems (LIMS) are used in real time to monitor sample flow, automatically enter laboratory results, manage quality (for as by keeping an eye on reporting times), or highlight unexpected results. To investigate AMR patterns and trends, information should even be questioned at the regional, national, and international levels. To ensure that laboratory results are directly linked to other patient data, such as admission date and outcome data, laboratory information management systems (LIMS) should ideally be able to exchange data with hospital and patient data systems [8]. The majority of labs utilize a single LIMS for all types of samples. A single sample may yield multiple results in bacteriology (positive or negative, identification of the organism or organisms, multiple AST results, and additional testing like minimum inhibitory concentration (MIC)), and the workflows are more complicated (one sample may need to be handled over the course of several days). These are frequently not the best for bacteriology because they were created for hematology and biochemistry. The actual data from potential testing, such as zone widths or MIC values, are frequently not retained by many LIMS; rather, they can only retain the interpretations, such as resilient, intermediate, or prone. It is challenging to analyze data over time and look for trends because break-points and recommendations are frequently modified [9].

#### **2.1 Laboratory capacity and quality management**

Quite frequently, the limitation in AMR surveillance is laboratory full capacity. To build this capacity and ensure quality, it is crucial to implement internal quality assurance, take part in external quality assessment (EQA) programs in research facilities,

#### *Laboratory Information Management System (LIMS) Analysis: A Lucrative Tool to Support… DOI: http://dx.doi.org/10.5772/intechopen.113344*

develop and keep up with national standards of operation (SOPs) to guarantee consistency and integration of lab practices, and regularly train and inspire personnel [6]. In order to perform and/or regulate the aforementioned tasks, countries should establish a central coordinating laboratory. Assuring uniformity in picking out of samples, living things, and drugs to be tested is another benefit of using monitoring criteria [6].

Working with sponsored locations to make sure they have a functional LIMS is a fundamental responsibility of the Fleming Fund Country Grants. Country Grantees must also make sure that procedures are in place that can collect data and submit it to Global Antimicrobial Resistance and Use Surveillance System (GLASS) and national surveillance systems [6].

Antimicrobial resistance (AMR) still exists in Pakistan despite the country's creation of a national action plan (NAP) to address inappropriate antimicrobial use and high antimicrobial resistance (AMR) rates there. The NAP was made public from the Department of National Health Services in May 2017. As a result, patient and LIMS are very necessary that will shape and strengthen the collection, management, and sharing of biological science information in lower middle income countries (LMICs) and boost screening of illnesses with public health significance such as antibiotic resistance (AMR). This can change how information is used to direct patient care, support information accessibility and usage for decision-making, and enable trend comparison on a regional and international level [6].

#### **2.2 Elements of a laboratory-based surveillance system for AMR**

The main method of identifying new drug resistance in the populace is surveillance, which enables prompt and effective response. Therefore, nations should improve their capability for the early detection and identification of resistant organisms that cause fetal diseases for public health [7].

Drug resistance monitoring national laboratories must staff qualified technologists, scientists, and pathologists. They should have the necessary tools and supplies to generate accurate results that will enable medication resistance surveillance. For informed decision-making, the information produced should be routinely shared with stakeholders and national authorities. Additionally, a laboratory must continually invest in purchasing supplies, media, and reagents, ensuring quality control, along with providing regular training for staff members and carrying out external quality assessment or proficiency testing, in order to successfully carry out the duties of isolation, identification, and antimicrobial susceptibility testing. A summary of the key findings from the national surveillance as well as clinical information from sentinel locations should be included in the AMR surveillance report [7]. Without requesting further information from hospitals, a nation with limited resources may carry out laboratory-based monitoring first, collecting data on susceptibility for widespread or epidemic-prone bacterial infections. Additional data may be prospectively collected if appropriate resources are available and the laboratory has experience tracking medication resistance, which should aid in enhancing AMR documentation [7].

#### **2.3 Laboratory-based surveillance has several requirements**

a.Prioritization of organisms to be observed, taking into mind the severity of the disease in the nation;


#### **2.4 Core components of LIMS**

The specimen evaluation, custom executions, and storage space group make up the three main parts of an ideal LIMS. Think of a lab where different researchers track measurements in a variety of ways, from pen and paper to a sizable spreadsheet. It would be very challenging to guarantee that human error has not tainted your data; missing data, mistakes, and discrepancies in the data collected can all exacerbate any error. Let us examine the three parts of a LIMS in greater detail and discuss how they complement one another to help study participants and lab executives (**Figure 1**) [10].

#### *2.4.1 Recording samples using a LIMS software*

The primary function of a LIMS is to record an item from the point that it arrives the laboratory by means of evaluation & preservation. In order to achieve this, all relevant evidence about the samples must be recorded at the time of first annexation, including the sample's ID, origin, collect date, and estimating information (such as concentration, volume, and particle quantity). As the laboratory item progresses over its process, further data is noted, and this data is likewise preserved in the LIMS. This comprises test results, produced data samples, and statistics for immediate research [10].

**Figure 1.** *Core components of LIMS.*

#### *Laboratory Information Management System (LIMS) Analysis: A Lucrative Tool to Support… DOI: http://dx.doi.org/10.5772/intechopen.113344*

Each lab study's specific data is recorded by a LIMS, together with details on the people involved and the environment it has been in throughout its existence. Adding a sample to a section or combining it with different materials under scrutiny in the lab are also possible. This necessitates the employment of both an exterior barcode label on the test tube and a chemical "index" in addition to it. It can therefore be differentiated from the other specimens in the pool. All of this significant sample monitoring data is kept in the LIMS technique [10].

#### *2.4.2 Protocol execution with a LIMS*

The centralization of lab's process flows and fundamental guidelines, methods, and phases is yet another key role of LIMS software. Despite of the truth, who holds the material or doing the analysis and in order to get a precise and consistent outcome, it is of the utmost importance to make sure every research individual adheres to the particulars of a given SOP (standard operating procedure). By scanning every phase in methods and standards, a LIMS supports standardization among the research group. That makes certain all of the laboratory's personnel does the right actions, in the correct order, while subject is placed accurately by means of an exam [10].

The adoption of LIMS software, which can manage trial allocations, enables an object to be assigned the appropriate procedure as soon as it reaches a testing facility. A LIMS may also provide a lab stronger code implementation restrictions, granting access to study or clinical groups, depending on who is authorized to carry out the activity. Lab test results may be taken down, transmitted through the appropriate authorization line, and then followed by relevant collaborators [10].

#### *2.4.3 Storage organization with a LIMS*

The 3rd vital part of a LIMS is to keep a record of a specimen's movements throughout its study career. The LIMS registers the location of the tube with the specimen or a container in a particular box (for example, slot A1 or B5) for each and every lab specimen. The system then keeps track of the shelf and slot that each package is on. The system also monitors the region and tier in which the chiller is located.

In busy labs, finding data fast depends on this "storage hierarchy" (Sample > Position > Box > Drawer > Rack > Shelf > Freezer > Room). Teams of researchers that are conscious of the precise location of lab samples remain useful, structured, and effective [10].

#### **2.5 How laboratory information management system control antimicrobial resistance**

LIMS can help control antimicrobial resistance in several ways:


it can provide alerts or warnings when certain drugs are being overprescribed or when there are prescribing errors. This aids in stopping the emergence and expansion of resilience.


### **3. Conclusion**

Think about combining a variety of complementary programs and technologies to increase a Laboratory Information Management Systems (LIMS) capacity for addressing issues related to antibiotic resistance and enhancing patient care. Additional software can improve data administration and analysis in addition to the drawbacks mentioned by Sayed and colleagues. These include powerful Database Management Systems (DBMS) like MySQL or PostgreSQL, machine learning and AI algorithms for predictive analytics, and data analysis and visualization tools like R or Python. While laboratory automation software improves workflow efficiency, electronic health record (EHR) integration software guarantees smooth data transmission between clinical and laboratory records. Tools for encryption and cybersecurity are necessary to protect sensitive healthcare data. While cloud computing platforms provide scalability and cost-effectiveness, geographic information system (GIS) software aids in the identification of spatial patterns. A full LIMS ecosystem includes collaboration and communication tools, regulatory compliance software, quality control and assurance tools, mobile data gathering apps, and middleware for data integration and interoperability. Solutions for data backup, user education, and documentation guarantee data integrity and user competence. The combination of these software elements enables a comprehensive strategy to tackle antibiotic resistance and improve patient care.

### **Conflict of interest**

None of the author's interests are in conflict.

*Laboratory Information Management System (LIMS) Analysis: A Lucrative Tool to Support… DOI: http://dx.doi.org/10.5772/intechopen.113344*

#### **Author details**

Maryam Nasrumminallah and Fatima Rehan\* Dow University of Health Sciences, Karachi, Pakistan

\*Address all correspondence to: rehanfatima4@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Bilal H, Khan MN, Rehman T, Hameed MF, Yang X. Antibiotic resistance in Pakistan: A systematic review of past decade. BMC Infectious Diseases. 2021. Available from: https:// bmcinfectdis.biomedcentral.com/ articles/10.1186/s12879-02105906-1

[2] Hussain S, Khan RA, Ain NU, Haider H, Riaz S. Prevalence of extended-spectrum-βlactamaseproducing Enterobacteriaceae: First systematic meta-analysis report from Pakistan. Antimicrobial Resist Infection Control. 2018;**7**(1):26. Available from: https://aricjournal.biomedcentral. com/articles/10.1186/s13756-018-0309-1

[3] Yasmin F, Akhtar N, Hameed A. In vitro synergistic effect of ciprofloxacin with aminoglycosides against multidrug resistant-Pseudomonas aeruginosa. Pakistan Journal of Pharmaceutical Sciences. 2013;**26**(5):1-3. Available from: https://pubmed.ncbi.nlm.nih. gov/24035966/

[4] Latif S, Anwar MS, Ahmad I. Bacterial pathogens responsible for blood stream infection (BSI) and pattern of drug resistance in a tertiary care hospital of Lahore. Biomédica. 2009;**25**(2):2-3. Available from: https://pdfs. semanticscholar.org/e089/45412f8d65ab5 9660d27f26cb9a9bb7cd9fd.pdf

[5] Da Silva JB Jr, Espinal M, Ramón-Pardo P. Antimicrobial resistance: Time for action. Revista Panamericana de Salud Pública. 2020;**44**:e131. DOI: 10.26633/ RPSP.2020.131

[6] Malania L, Wagenaar I, Karatuna O, Andrasevic AT, et al. Setting up laboratory-based antimicrobial resistance surveillance in low- and

middle-income countries: Lessons learned from Georgia. Clinical Microbiology and Infection. 2021;**27**:2

[7] Global Antimicrobial Resistance and Use Surveillance System (GLASS). Available from: https://www.who.int/ initiatives/glass

[8] Tools of the Trade: Data Management Software in AMR Surveillance. 2020. Available from: https://www. flemingfund.org/publications/tools-ofthe-trade-datamanagement-software-inamr-surveillance/

[9] Fleming Fund: Supporting Surveillance Capacity for Antimicrobial Resistance. Overview of the Antimicrobial Resistance Surveillance Systems for Ghana, Malawi, Nepal and Nigeria. Available from: www. flemingfund.org

[10] Third Wave Analytics. What is a Lims and What are They Used for? Third Wave Analytics. 2023. Available from: https:// thirdwaveanalytics.com/blog/what-doesa-lims-do/ [Accessed: 15 October 2023]

### Section 2
