**7. Prevention and control of microorganisms in cystic fibrosis**

Despite the development of antibiotics and vaccines, patients with CF are still faced with many debilitating and fatal infections, which demonstrate the adaptability of microbial pathogens [44]. The choice of antibiotic depends on in vitro sensitivity patterns. Physicians treating patients with CF are increasingly faced with infection with multidrug-resistant strains of *Pseudomonas aeruginosa*. Also, innately resistant organisms such as *Burkholderia cepacia*, *Stenotrophomonas maltophilia*, and *Achromobacter xylosoxidans* become more prevalent [45].

Additionally, many studies resulted in strong indicator for a relevant importance of mutators in bacterial populations especially in infectious diseases. High prevalence and mutators are recorded environmentally in chronic respiratory infection with *Pseudomonas aeruginosa* in CF patients [46].

#### **7.1 Strategies and guidelines for bacterial infection control within CF patients**

Guidelines on infection control developed for general patient populations are applicable to CF patients. Historically, before 1998, guidelines on infection control were applied to acute-care hospitals. Recently it includes for non-acute-care settings. Also, it has shifted from hospitals to home and outpatient clinics to reduce days of hospitalization and provide chronic suppressive treatments. Infection control in CF guidelines has been developed by Healthcare Infection Control Practices Advisory Committee (HICPAC) and Centers for Disease Control and Prevention (CDC) [47].

Common pathogens that infect the lungs of CF patients include *Staphylococcus aureus*, *Haemophilus influenzae*, *Pseudomonas aeruginosa*, and *Burkholderia cepacia*. Aggressively treating pulmonary infection with antibiotics has contributed to improved survival in patients with CF but has also promoted multiple drug-resistant bacteria [48].

Antibiotic therapy leads to improvement in lung function, the best predictor of survival in CF patients which treat CF lung disease morbidity based on decisions with which antibiotics are selected according to broad empirical and based on the severity of the patient's pulmonary exacerbation, the colonizing microorganisms, and the patient's age [49].

A range of anaerobic bacterial species are present in huge numbers in the lungs of CF patients, which contribute significantly to infection and inflammation in the CF lung. So, informed alterations of antibiotic treatment to target anaerobes is done, in addition to the primary infecting pathogens, may improve management [50].

A positive approach to the protection of the lung from early in life seems to be the only way to change the slope of the survival curves [51]. Ticarcillin can be used

**29**

*Recent Approach in Microbial Pathogen Complications in Patients with Cystic Fibrosis*

**7.2 Inhalational antibiotics for the treatment of** *Pseudomonas aeruginosa*

recent isolation of *Pseudomonas aeruginosa* from sputum [60].

filamentous fungi which is resistant to many antifungal agents [62].

**7.3 Antifungal therapy to control yeasts and filamentous fungi with CF patients**

Antifungal therapy is usually considered when the deteriorating respiratory function is not responding to antibacterial therapy and *A. fumigatus* is growing and identified in sputum cultures [61]. Long-term antifungal treatment with mold active azoles, the only class of antifungals with an oral formulation, is not without risk of toxicity and adverse events and should be carefully balanced against its benefit [10]. *A. fumigatus* can grow in sputum cultures, and antifungal therapy is not effective [61]. Also, *Scedosporium* sp. is the second most frequent cystic fibrosis associated

In CF, *Candida albicans* causes 95% of all *Candida* infections, whereas the remainder is caused by *Candida glabrata*, *Candida parapsilosis*, and *Candida krusei*. Also, *Candida dubliniensis* has been isolated in CF; however, little is known about its

Respiratory viruses associated with exacerbations in CF patients and upper respiratory symptoms are strong predictors for their presence. Some studies have

potential for virulence, and treatment modality is not clearly defined [63].

**7.4 Antiviral therapy to control respiratory viruses with CF patients**

in the treatment of pulmonary exacerbations of cystic fibrosis due to susceptible

Also, *Alcaligenes* bacterial strains are characterized as motile, Gram-negative, producing oxidase enzyme. The most common is *Alcaligenes xylosoxidans* known as *Achromobacter xylosoxidans*. The bacterial genus is composed of three main species such as *Achromobacter piechaudii*, *Achromobacter xylosoxidans*, and *Achromobacter faecalis.* These bacterial strains observed multiple antibiotic resistance especially grouped of aminoglycosides and recorded sensitivity to cephalosporins (third

In recent years, there are emergences of inhaled antibiotics to treat patients with Gram-negative bacterial infection such as *P. aeruginosa* infection. The benefits of

Inhaled tobramycin, inhaled colistin, and inhaled aztreonam are used to control chronic *P. aeruginosa* infections in patients with CF [57]. In CF, tobramycin inhalation solution contributed to improved survival and reduced lung function decline [58]. Subsequently, the development of antibiotic agents can achieve high tissue concentrations to control bacterial infection that is difficult to treat in hosts [59]. Inhaled tobramycin achieves a sputum concentration of drug at least 25 times the MIC, with a median serum/sputum concentration of 0.01. Such high concentrations are required for the effective killing of *P. aeruginosa* because aminoglycosides bind to mucins in sputum and reduce the availability of effective antibiotic. Also, early randomized, double-blind, placebo-controlled trials conducted in patients with CF were short-term but demonstrated positive results with the use of aztreonam solution for inhalation compared to placebo. Colistin is bactericidal and active against Gram-negative bacteria including *P. aeruginosa*. Nebulized colistin is a preferred inhaled therapy for patients with CF and chronic *P. aeruginosa* [59]. Inhaled levofloxacin was studied in patients with CF and *P. aeruginosa* lung infection. Also, nebulized levofloxacin solution (MP-376) is a novel therapy that is currently being evaluated in phase I, II, and III clinical trials among patients with stable CF and

*DOI: http://dx.doi.org/10.5772/intechopen.91635*

strains of *Pseudomonas aeruginosa* [52, 53].

which are explained below [55, 56].

generation) [54].

*Recent Approach in Microbial Pathogen Complications in Patients with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.91635*

in the treatment of pulmonary exacerbations of cystic fibrosis due to susceptible strains of *Pseudomonas aeruginosa* [52, 53].

Also, *Alcaligenes* bacterial strains are characterized as motile, Gram-negative, producing oxidase enzyme. The most common is *Alcaligenes xylosoxidans* known as *Achromobacter xylosoxidans*. The bacterial genus is composed of three main species such as *Achromobacter piechaudii*, *Achromobacter xylosoxidans*, and *Achromobacter faecalis.* These bacterial strains observed multiple antibiotic resistance especially grouped of aminoglycosides and recorded sensitivity to cephalosporins (third generation) [54].

#### **7.2 Inhalational antibiotics for the treatment of** *Pseudomonas aeruginosa*

In recent years, there are emergences of inhaled antibiotics to treat patients with Gram-negative bacterial infection such as *P. aeruginosa* infection. The benefits of which are explained below [55, 56].

Inhaled tobramycin, inhaled colistin, and inhaled aztreonam are used to control chronic *P. aeruginosa* infections in patients with CF [57]. In CF, tobramycin inhalation solution contributed to improved survival and reduced lung function decline [58]. Subsequently, the development of antibiotic agents can achieve high tissue concentrations to control bacterial infection that is difficult to treat in hosts [59]. Inhaled tobramycin achieves a sputum concentration of drug at least 25 times the MIC, with a median serum/sputum concentration of 0.01. Such high concentrations are required for the effective killing of *P. aeruginosa* because aminoglycosides bind to mucins in sputum and reduce the availability of effective antibiotic. Also, early randomized, double-blind, placebo-controlled trials conducted in patients with CF were short-term but demonstrated positive results with the use of aztreonam solution for inhalation compared to placebo. Colistin is bactericidal and active against Gram-negative bacteria including *P. aeruginosa*. Nebulized colistin is a preferred inhaled therapy for patients with CF and chronic *P. aeruginosa* [59]. Inhaled levofloxacin was studied in patients with CF and *P. aeruginosa* lung infection. Also, nebulized levofloxacin solution (MP-376) is a novel therapy that is currently being evaluated in phase I, II, and III clinical trials among patients with stable CF and recent isolation of *Pseudomonas aeruginosa* from sputum [60].

#### **7.3 Antifungal therapy to control yeasts and filamentous fungi with CF patients**

Antifungal therapy is usually considered when the deteriorating respiratory function is not responding to antibacterial therapy and *A. fumigatus* is growing and identified in sputum cultures [61]. Long-term antifungal treatment with mold active azoles, the only class of antifungals with an oral formulation, is not without risk of toxicity and adverse events and should be carefully balanced against its benefit [10].

*A. fumigatus* can grow in sputum cultures, and antifungal therapy is not effective [61]. Also, *Scedosporium* sp. is the second most frequent cystic fibrosis associated filamentous fungi which is resistant to many antifungal agents [62].

In CF, *Candida albicans* causes 95% of all *Candida* infections, whereas the remainder is caused by *Candida glabrata*, *Candida parapsilosis*, and *Candida krusei*. Also, *Candida dubliniensis* has been isolated in CF; however, little is known about its potential for virulence, and treatment modality is not clearly defined [63].

#### **7.4 Antiviral therapy to control respiratory viruses with CF patients**

Respiratory viruses associated with exacerbations in CF patients and upper respiratory symptoms are strong predictors for their presence. Some studies have

*Cystic Fibrosis - Heterogeneity and Personalized Treatment*

respiratory morbidity in CF patients [43].

influenza, para influenza, and adenovirus which is RSV and influenza infection leading to decreases in lung function [41]. Also, viral respiratory infections show pronounced and long-lasting effects on patients with CF, resulting in significant declines in forced vital capacity (FVC), forced expiratory volume in 1 second (FEV-1), and significant increases of both the frequency and duration of hospitalizations especially that the frequency of viral respiratory infections is closely associated with pulmonary deterioration in patients with CF [42]. Additionally, viral respiratory infections occur in equal frequency in CF patients and healthy controls which in CF patients viral upper respiratory tract infections are associated with lower respiratory tract symptoms in 31–76%. Viral infections cause long-term

**7. Prevention and control of microorganisms in cystic fibrosis**

*Achromobacter xylosoxidans* become more prevalent [45].

with *Pseudomonas aeruginosa* in CF patients [46].

Despite the development of antibiotics and vaccines, patients with CF are still faced with many debilitating and fatal infections, which demonstrate the adaptability of microbial pathogens [44]. The choice of antibiotic depends on in vitro sensitivity patterns. Physicians treating patients with CF are increasingly faced with infection with multidrug-resistant strains of *Pseudomonas aeruginosa*. Also, innately resistant organisms such as *Burkholderia cepacia*, *Stenotrophomonas maltophilia*, and

Additionally, many studies resulted in strong indicator for a relevant importance of mutators in bacterial populations especially in infectious diseases. High prevalence and mutators are recorded environmentally in chronic respiratory infection

**7.1 Strategies and guidelines for bacterial infection control within CF patients**

Guidelines on infection control developed for general patient populations are applicable to CF patients. Historically, before 1998, guidelines on infection control were applied to acute-care hospitals. Recently it includes for non-acute-care settings. Also, it has shifted from hospitals to home and outpatient clinics to reduce days of hospitalization and provide chronic suppressive treatments. Infection control in CF guidelines has been developed by Healthcare Infection Control Practices Advisory Committee (HICPAC) and Centers for Disease Control and Prevention

Common pathogens that infect the lungs of CF patients include *Staphylococcus aureus*, *Haemophilus influenzae*, *Pseudomonas aeruginosa*, and *Burkholderia cepacia*. Aggressively treating pulmonary infection with antibiotics has contributed to improved survival in patients with CF but has also promoted multiple drug-resis-

Antibiotic therapy leads to improvement in lung function, the best predictor of survival in CF patients which treat CF lung disease morbidity based on decisions with which antibiotics are selected according to broad empirical and based on the severity of the patient's pulmonary exacerbation, the colonizing microorganisms,

A range of anaerobic bacterial species are present in huge numbers in the lungs of CF patients, which contribute significantly to infection and inflammation in the CF lung. So, informed alterations of antibiotic treatment to target anaerobes is done, in addition to the primary infecting pathogens, may improve management [50]. A positive approach to the protection of the lung from early in life seems to be the only way to change the slope of the survival curves [51]. Ticarcillin can be used

**28**

(CDC) [47].

tant bacteria [48].

and the patient's age [49].

suggested a role played by respiratory viruses in exacerbation of CF. The impact of respiratory viruses is likely to be underestimated due to the low detection rate by conventional laboratory methods. Molecular techniques such as multiplex PCR have improved their diagnostic accuracy identifying respiratory viruses in CF patients which are important in clinical decision-making and are potentially important as new antivirals are becoming readily available [64]. A few therapeutic options recorded to treat virus-induced CF pulmonary exacerbations include macrolide antibiotic (azithromycin). It has antiviral properties of the human bronchial epithelial cells and stimulates antiviral mechanisms in bronchial epithelial cells within the CF airway control infection with rhinovirus by reducing rhinovirus replication as an interferon pathway [65]. Also, there are exciting prospects such as antiviral host defense peptides in development and can be novel therapeutics targeting rhinovirus [66].

Additionally, CF patients infected with influenza A(H1N1) showed increased case fatality rate (CFR) and morbidity compared to patients with other chronic respiratory diseases, so, early antibiotic and antiviral treatment strategies are important to control it in CF patients [67].

### **8. Conclusion**

This chapter concludes that complications of microorganisms associated with cystic fibrosis disease are very high and can lead to patient death. Pathogenic microorganisms isolated from CF patients included Gram-negative bacteria, Grampositive bacteria, unicellular fungi, multicellular fungi, and viruses.

The most common Gram-negative bacterial pathogens are *Pseudomonas aeruginosa* and *Haemophilus influenzae*. Also, the most common Gram-positive bacterial pathogen is *Staphylococcus aureus* especially MRSA. Other bacterial pathogens are isolated from CF patients, such as NTM species, *Alcaligenes xylosoxidans*, and *Burkholderia cenocepacia*.

In addition, *Candida albicans* is the most common unicellular fungi, and *Aspergillus fumigatus* is the most common filamentous fungi. Influenza A and B viruses are major viruses in causing respiratory exacerbations in CF, and both viruses are more commonly detected during pulmonary exacerbations.

To prevent this microbial complication, appropriate antimicrobials can be used to treat bacterial infections, antifungal therapy for treating pathogenic fungi and antiviral to manage viral infections. With prospects, researchers must work to produce new therapeutic options to control multidrug-resistant bacteria and resistant fungi and virus. These new treatment options may further enhance the prognosis in patients with CF.

### **Acknowledgements**

Firstly, great thanks and appreciation to Prof. Dr. Mamdouh Salem Elgamal and Prof. Dr. Ayman Farrag Ahmed for their support and encouragement. Finally, I wish to thank my mother, brother, sisters, children (Khalid and Mohammed), and everyone in my family for their continual guidance.

**31**

**Author details**

Salah Abdelbary

abdelbary\_salah@azhar.edu.eg

provided the original work is properly cited.

Cairo, Egypt

*Recent Approach in Microbial Pathogen Complications in Patients with Cystic Fibrosis*

CFTR cystic fibrosis transmembrane conductance regulator gene

Botany and Microbiology Department, Faculty of Science, Al-Azhar University,

© 2020 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,

\*Address all correspondence to: salah.micro87@gmail.com;

MRSA methicillin-resistant *Staphylococcus aureus*

NTM nontuberculous mycobacteria

*DOI: http://dx.doi.org/10.5772/intechopen.91635*

CF cystic fibrosis

CFR case fatality rate

**Abbreviations**

#### **Conflict of interest**

The author declares no conflict of interest.

*Recent Approach in Microbial Pathogen Complications in Patients with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.91635*
