**8. Community changes associated with CFTR modulators**

In the last 5 years, treatments targeted towards correcting the underlying defect in CF have become available. Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, is licenced specifically for the treatment of people with a G551D mutation and a number of other rare gating mutations, which together account for approximately 5–10% of the CF population in the UK [60]. In this subset of the CF population, ivacaftor use has been associated with improvements in lung function, reductions in exacerbations, reductions in sweat chloride, improved weight gain and improved quality of life [61, 62]. The restoration of CFTR activity by ivacaftor and the associated clinical benefits, in particular improved lung function and reductions in exacerbation, has inevitably raised questions as to whether ivacaftor has an antimicrobial effect.

Theoretically, ivacaftor could have an antimicrobial effect in a number of ways. Firstly, the restoration of CFTR activity should result in a rehydrated airway surface layer, and this in turn will allow the mucociliary escalator to function physiologically. The improved clearance of airway secretions would then result in the elimination of bacteria. Secondly, the restoration of CFTR activity could result in a dramatic change in the local pulmonary microenvironment, turning a previously favourable environmental niche into an inhospitable one for resident

microbiota. There is evidence to support a similar effect in the GI tract, where CFTR modulation with ivacaftor was associated with improved proximal small intestinal pH, likely secondary to improved bicarbonate secretion [63]. Thirdly, a direct bactericidal effect of ivacaftor itself has been postulated given that its chemical structure contains a quinolone ring and many quinolone derivatives have antimicrobial properties [64]. This theory is supported by evidence that ivacaftor exerted in vitro antibacterial effects on clinical respiratory isolates of *S. aureus* (MSSA and MRSA) and *Streptococcus pneumoniae* [65, 66]. However, these studies found very little activity against Gram-negative organisms, which is uncharacteristic of a quinolone-based antibiotic [65]. Interestingly, the authors of the same study noted synergism of ivacaftor with antibiotics commonly used in CF, and this was recently supported by Payne et al., who again found that ivacaftor had activity against *Streptococcus* spp*.* and *S. aureus* and that the effect was potentiated in the presence of tobramycin. Again there was no evidence of direct antibacterial activity against *P. aeruginosa* [67].

Interest has since focussed on clinical microbiological outcomes of patients commenced on ivacaftor therapy in an effort to investigate differences post-treatment initiation. Interestingly, despite ivacaftor appearing to have no innate activity against *P. aeruginosa,* a number of studies have reported reductions in counts and density post initiation, perhaps suggesting that quinolone activity is not the only mechanism at play [68, 69].

In contrast to the relative lack of focus on inhaled antibiotics, a number of studies have investigated the effects of ivacaftor on the respiratory microbiome. Peleg et al. [70] conducted the only placebo-controlled trial in this field when they performed a double-blind, placebo-controlled, cross-over study of 28-day ivacaftor treatment. Sputum was collected at the start and end of each 28-day treatment period, and 16S rRNA sequencing with qPCR correlation was subsequently performed. No significant differences were observed for either total bacterial load or *P. aeruginosa* load following ivacaftor therapy, and no significant difference in the microbiota composition (based on 16S rRNA microbiome analysis) was observed between the placebo and treatment samples. However, the authors noted that when they adjusted for consistent or changing antibiotic exposure in the 28-day study period, ivacaftor was associated with a significant reduction in *P. aeruginosa* load. That is to say, changes in the microbiota induced by acute changes in antibiotic administration during the 28-day treatment periods may have masked the effect induced by ivacaftor.

In longer-term observational studies, a number of changes have been observed. Bernarde et al. [71] noted no significant changes in bacteria load and also no significant changes in overall community composition at 1 year following ivacaftor initiation. However, individual taxa were observed to change in that the relative abundance of *Streptococcus mitis* group was significantly diminished and a *Porphyromonas* OTU was significantly increased. Elsewhere, in perhaps the most comprehensive study of microbiological outcomes following ivacaftor initiation, Hisert et al. [72] found marked reductions in *P. aeruginosa* sputum densities using conventional culture and also reduced sputum inflammatory markers in regular follow-up throughout the first 2 years of ivacaftor use. These findings were mirrored in the 16S rRNA-based analysis, where decreases in mean *P. aeruginosa* relative abundance and subsequent increases in diversity measures were observed. However, no patient eradicated *P. aeruginosa*, and after 12 months of treatment, relative abundance, sputum counts and inflammatory markers began to increase again. The authors interpreted these findings to suggest that *P. aeruginosa* may adapt to a CFTR-restored environment and this clearly has implications for the need for ongoing anti-infective chemotherapy in CF.

**11**

**Table 2.**

*(NTM-PD) [73].*

Clinical (both required)

2.Appropriate exclusion of other diagnoses. Microbiologic (one of the following required)

are culture positive for NTM.

*The Pulmonary Microbiome in Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.91765*

**9. Nontuberculous mycobacteria**

Nontuberculous mycobacteria (NTM) are identified in approximately 10% of CF patients, but only a small proportion will go on to develop NTM pulmonary disease (NTM-PD) warranting treatment. First and foremost, the management of CF pulmonary disease should be optimised, including antibiotic therapy targeted to the individual's usual airway bacteria, prior to considering treatment for NTM-PD. Those who fulfil criteria for NTM lung disease may not necessarily require treatment and could be monitored expectantly if symptoms and radiographic findings are minimal or stable over a period of surveillance. However, the presence of *Mycobacterium abscessus* complex (MABSC), deteriorating lung function, worsening radiology and/or anticipated lung transplant should prompt NTM therapy initiation (**Table 2**). For CF patients with *Mycobacterium avium* complex (MAC), recommended treatment includes triple antibiotic therapy with a macrolide, rifampin and ethambutol. Azithromycin is generally the preferred macrolide of choice in CF as it is better tolerated and has fewer drug–drug interactions. An initial course of injectable amikacin or streptomycin should be considered in the presence of (i) acid-fast bacillus smear-positive respiratory tract samples, (ii) radiological evidence of lung cavitation or severe infection and (iii) systemic signs of illness. MABSC treatment is more complicated and requires an induction phase (oral macrolide and two IV agents including amikacin with one or more additional intravenous antibiotics including tigecycline, imipenem, cefoxitin) for 3 to 12 weeks as well as a maintenance phase (nebulised amikacin and a macrolide with two to three oral antibiotics including minocycline, clofazimine, moxifloxacin, linezolid). Baseline and interval testing for drug toxicity is essential. The treatment duration for both MAC and MABSC is extended 1-year post-culture conversion. However, in patients who do not achieve culture negative status but tolerate therapy, ongoing treatment for mycobacterial suppression and prevention of disease progression can be considered. There are no randomised controlled trials of MABSC therapy in the general population or in CF; however, there is MABSC treatment outcome data in non-CF populations from several clinical studies [74]. In a study of 57 non-CF

1.Pulmonary symptoms with nodular or cavitary opacities on chest radiograph or a high-resolution CT

• Positive culture results from at least two expectorated sputum samples. If the results from samples are

• Transbronchial or other lung biopsy with mycobacterial histopathological features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histopathological features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that

• Expert consultation should be obtained when either infrequently encountered NTM or those usually

• Patients who are suspected of having NTM-PD but who do not meet the diagnostic criteria should be

• Making the diagnosis of NTM-PD does not, per se, necessitate the institution of therapy, which is a

*ATS/IDSA clinical and microbiologic criteria for diagnosing nontuberculous mycobacterial pulmonary disease* 

non-diagnostic, consider repeat sputum acid-fast bacillus (AFB) smears and cultures.

scan that shows multifocal bronchiectasis with multiple small nodules

• Positive culture results from at least one bronchial wash or lavage.

representing environmental contamination are recovered.

followed up until the diagnosis is firmly established or excluded.

decision based on potential risks and benefits of therapy for individual patients.
