**3.** *P. aeruginosa* **Antibiotic resistance profile around the globe**

*P. aeruginosa* inherent and adaptive antibiotic resistance character thus consequently making many existing antibiotics and anti-pseudomonal agents unusable against this bacterium and present a significant challenge for medical practitioners to treat infections. In this section, we exhibited few cases based on *P. aeruginosa* antibiotic resistance profile from different parts of the world by referring to previously published literature.

A comprehensive review by Wozniak et al., (2017), that covered the Australian data from the year 1990 till 2017, on antibiotic resistance Gram-negative bacteria [19]. Their study highlighted that *P. aeruginosa* isolates from different infection site showed resistance to many commonly used antibiotics. Among the *P. aeruginosa* isolates that were collected from surgical site between years 2002–2013, approximately 0.5%, 7.7% and 0.5% of the isolates showed resistance to fluoroquinolone, third generation cephalosporin and gentamicin respectively [20]. Survey on antibiotic resistance profile of *P. aeruginosa* isolates from patient's sputum between years 2007–2010 showed resistance to aminoglycosides (43%), beta-lactam (21%) and fluoroquinolone (30%) class of antibiotics [21]. Epidemiology studies on *P. aeruginosa* isolates from blood (years: 2001–2009) showed resistance to fluoroquinolone and meropenem about 12.7% and 14.3% respectively [22]. National Healthcare Safety Network (NHSN), USA survey on antimicrobial resistance patterns for the year 2009–2010, reported about 20% of pathogens (from 69,475 HAI's incidence) are antibiotic resistance in which 2% is carbapenem-resistant *P. aeruginosa* [23]. Microbial analysis on patients affected with Nosocomial and ventilator-associated pneumonia (VAP) in a period 2011–2012 in Georgia, USA reported *P. aeruginosa* as most prevalent Gram negative (40%) and highest prevalence of multi drug resistance [24]. Similar multi-drug resistance profile of *P. aeruginosa* was recorded in Asian countries. For example, antibiogram of total 2444 Pseudomonas species isolated from different clinical specimens (blood, pus, tracheal aspirate, urine and sputum from wards, intensive care units (ICUs) and follow up patients) of trauma patients from tertiary care hospitals in India over a period 2012–2016 revealed dominance of *P. aeruginosa* (95%) [25]. Among 69%, 68%, 67% 66%, 63% and 51% were levofloxacin, gentamicin, ciprofloxacin, ceftazidime, meropenem and tobramycin resistance, respectively [25]. Antibiotic profile of 121 *P aeruginosa* strains isolated from hospitals of Makkah and Jeddah, Saudi Arabia showed high resistance to antibiotics: meropenem (~30.6%), ticarcillin (22.3%), and imipenem (19%) [26]. A study reported that in mainland china hospitals prevalence of *P. aeruginosa* related ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia were 19.4 and 17.8% respectively [27]. National Healthcare Safety Network (NHSN) USA, reports prevalence of *P. aeruginosa* is common among possible VAP [28]. These isolates exhibited high level of resistance to antibiotics: Gentamicin (up to 51.1%), cefoperazone (50%), and about 22.5% for amikacin [28]. *P. aeruginosa* resistance to ciprofloxacin has also risen a global concern, especially in Asian countries for example, Bangladesh reported 75.5% resistance to ciprofloxacin whereas, India, Iran, Turkey, and Saudi Arabia reported 49%, 58%, 48.9% and 50.9% respectively [29–33].

*Pseudomonas aeruginosa* - Biofilm Formation, Infections and Treatments

on global public health and economy.

*Streptococcus pyogenes*, *Proteus mirabilis*, etc.) has an inheritance ability to colonize and form biofilms on biotic (e.g. mucosa, tissue) or abiotic surface (e.g. medical implants, surgical instruments, hospital beds, wash basins, sinks, bath tub, etc.). Bacterial colonization on these surfaces directly leads to the contamination of surfaces, food and water and consequently precedes to infections in host. Bacterial biofilms are liable for approximately 80% of hospital and community-associated infections [6]. The most serious concern is antibiotic/antibacterial agents' resistance by the infecting bacteria that threatens the very core of modern medicine and impose a greater burden

**2. Bacterial infection and antibiotic resistance are a global concern**

National Institutes of Health (NIH), USA statistics data reports 550,000 death a year and about \$94 billion total cost annually associated with biofilm infections in USA alone [7]. In Australia, billions of dollars expended annually dealing with antibiotic-resistant infections [8]. Statistics on antibiotic-resistance bacteria causing healthcare associated infections (HAI's) and death in European countries is alarming. Around, 8.9 million HAI recorded each year in combined hospitals and long-term care facilities and one in three bacteria associated with HAI's are antibiotic resistant [9]. In European population death associated with antibiotic resistance bacteria is estimated to be around 33,000 annually, this statistic is comparable to death associated with combined influenza, tuberculosis, HIV/AIDS [10]. Antibiotic resistance associated infections also triggers massive loss in productivity and healthcare incidentals estimated to be approximately 1.5 billion Euro's each year [11]. Bacterial resistance profile to different antibacterial agents is depends of several factors including geographical location of the strain (genetic mutations influenced by temperature, nutrient, oxygen), antibiotic prescribing practice to patients around the globe, poor hygiene and sanitation practice by common public and health care workers in hospitals. For instance, report released by Australian Commission on Safety and Quality in Health Care (Antimicrobial use and Resistance in Australia, AURA 2019) suggest more than 26.5 million antibiotic prescriptions were give out to patients [12]. The same report also highlighted that 23.5% of hospital prescribed antimicrobials in Australia are inappropriate and also community associated increase in antibiotic resistance bacteria (MRSA) are higher among old age people living in aged care facilities and in remote regions of the country [12]. Misuse or unethical use of antibiotics in agriculture, meat and poultry industry and fish farming, is a primary concern. Study published by Chinese Academy of Sciences reports use of 162,000 tons of antibiotics in the year 2013 alone in which more than half (52%) was used for animal husbandry and 48% by humans in addition, massive amount (50,000 tons) of antibiotics drained in the environment (water and soil) [13, 14]. USA also reported 10,000 tons of antibiotics annually used for livestock [15]. India, China, USA, Russia, Brazil, and South Africa are the world leaders in consuming antibiotics [16]. South China Morning Post (SCMP) Newspaper published an article in 2017 stating "Antibiotic overuse is a ticking time bomb for Asia" and health care workers act instantly to restrain misuse of antibiotics to stop public health calamity [17]. World Health Assembly, WHO, United Nations (UN), and countries respective government, local health organization and institutes are adopting a global action plan to crumb antibiotic resistance by educating common public, health care workers on effective sanitation, hygiene and infection prevention measures; and spreading awareness on responsible use

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