Drugs, Drugs, Drugs: Current Treatment Paradigms in Cystic Fibrosis Airway Infections

Abstract

Airway infections have remained a prominent feature in persons living with cystic fibrosis (CF) despite the dramatic improvements in survival in the past decades. Antimicrobials are a cornerstone of infection management for both acute and chronic maintenance indications. Historic clinical trials of antimicrobials in CF have led to the adoption of consensus guidelines for their use in clinical care. More recently, however, there are efforts to re-think the optimal use of antimicrobials for care with the advent of novel and highly effective CF transmembrane conductance regulator modulator therapies. Encouragingly, however, drug development has remained active concurrently in this space. Our review focuses on the evidence for and perspectives regarding antimicrobial use in both acute and maintenance settings in persons with CF. The therapeutic innovations in CF and how this may affect antimicrobial approaches are also discussed.

Airway infections remain a significant issue in cystic fibrosis. This review focuses on antimicrobial therapies for use in acute and chronic maintenance settings in people living with cystic fibrosis. Therapeutic innovations and perspectives regarding antimicrobial use are also discussed.

Dramatic improvements in therapeutics and longevity in persons with cystic fibrosis (CF) have not eliminated the role and impact of airway infections in this population. Both acute and chronic airway infections remain prevalent and necessitate antimicrobial therapies in combination with airway clearance and other maintenance therapies to optimize health. This review will focus on the historic and current perspectives of, and evidence for, antimicrobial use in eradicating acute infections, treatment of infective episodes, and as maintenance for suppression of chronic infections. The changing landscape of airway infection management with therapeutic innovation in the arena of anti-infective therapies and the adoption of highly effective CF transmembrane conductance regulator (CFTR) modulator therapies will also be discussed.

CF LUNG DISEASE—AN OVERVIEW OF AIRWAY INFECTION EPIDEMIOLOGY

CF is a life-shortening inherited condition that is found in persons of all races and ethnic backgrounds, but it is most prevalent in Caucasians and affects approximately 30 000 individuals in the United States and more than 70 000 worldwide [1]. Advances in care for persons with CF (pwCF) have resulted in dramatic improvements in survival, but they still have debilitating symptoms and die far too early [2, 3]. Despite an improved reported median survival to over 50 years in 2020 in the United States and Canada [4, 5], lung disease and chronic lung infections remain the most important health issue in CF. Most adult pwCF develop life-long airway infections that progressively destroy the lungs and lead to death. Data from a CF pig model suggest that altered airway lining pH and altered mucous excretion from airway glands represent 2 key defects in host immunity that may contribute to the classic bacterial infections seen in CF lower airways [6, 7].

Early in life, airway organisms more commonly noted include Staphylococcus aureus and Haemophilus influenzae. As CF children age, Pseudomonas aeruginosa becomes the dominant pathogen. Additional multiresistant pathogens also increase with age including Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cepacia complex and are depicted here (Figure 1). Pseudomonas aeruginosa accounts for ~80% of chronic lung infections in CF; roughly 90% of deaths are due to respiratory failure and almost all have P. aeruginosa infection [8]. Despite intensive research, no therapies exist that eradicate established CF infections, and even aggressive antibiotic treatment has only suppressive effects. Early infections with P. aeruginosa are commonly susceptible to antipseudomonal β-lactam antibiotics, aminoglycosides, and fluoroquinolones. However, as pwCF age, antibiotic resistance appears more frequently. At Danish CF centers, a significant increase in P. aeruginosa resistance to β-lactams was seen over 2 decades, but no correlation was found between an increase in minimum inhibitory concentration (drug concentration associated with inhibition of bacterial growth in standard susceptibility testing) and number of courses of antipseudomonal therapy [9]. Multidrug resistance (MDR), defined as in vitro susceptibility to at least 1 agent in 3 or more antimicrobial classes [10], has been reported in up to 11.6% of P. aeruginosa isolates from individuals with CF in the United States and up to 17.4% in Italy [11, 12]. Additional work noted that pwCF with MDR P. aeruginosa were more likely to have diabetes, use long-term inhaled tobramycin, and have frequent acute pulmonary exacerbations (PEx) requiring hospitalization or intravenous antibiotics [13]. Despite the challenges these isolates pose, evidence of clinical decline with MDR has not been consistently demonstrated [14, 15]. However, these multiple resistant isolates do present important clinical challenges in the care of pwCF, because of both challenges with antibiotic selections and concerns of potential person-to-person spread within this population based on the identification of some shared strains [16–21]. The chronic lung infections seen in CF are frequently polymicrobial and rarely eradicated with antimicrobial therapy. Recent data are promising that highly effective CFTR modulators may change this paradigm, but further data are needed to clearly understand the microbiologic impact of these new drugs [22, 23].

Figure 1.

The proportion of individuals by age group who cultured positive for the bacterial species indicated during 2020. Cystic Fibrosis Foundation patient registry 2020 annual data report, Bethesda, Maryland ^©2021 Cystic Fibrosis Foundation (Reprinted with permission). Caveat: 2020 prevalence proportions may be affected by the SARS-CoV-2 pandemic and effective CFTR modulator therapies.

Infection Diagnostics

The culture of respiratory tract specimens from pwCF can present challenges to microbiology laboratories unaccustomed to processing them, because of problems related to sample viscosity, the polymicrobial nature of infections, and slow bacterial growth [24]. Additionally, older commercial identification systems can be inaccurate for CF pathogens [25–27]. Given polymicrobial infections are the norm in CF airway infections, they can be problematic to culture since the organisms in the specimen may have very different growth requirements. Pseudomonas aeruginosa is often present and, because of its mucoid phenotype, frequently overgrows both gram-positive bacteria such as S. aureus and more fastidious gram-negative organisms such as H. influenzae and B. cepacia complex. Selective media, which inhibits the growth of P. aeruginosa, is very useful for the isolation of S. aureus and H. influenzae and is mandatory for the isolation of B. cepacia complex [12, 28–30]. Additionally, prolonged incubation and multiple subcultures are commonly needed by labs specializing in CF microbiology [30].

ANTIMICROBIAL DELIVERY

The selection of an antimicrobial and its route of administration (oral, intravenous [IV], and/or inhaled) is generally based on the indication for treatment (chronic maintenance/suppression, eradication, or PEx management) and the severity of clinical symptoms. Inhaled antimicrobials have been used in the care of pwCF since the early 1980s [31] and, in contrast to systemic therapy, can provide increased airway drug levels with decreased risk of systemic side effects [32–34]. Inhaled tobramycin was first approved in the United States in 1997. Intermittent (every other month) use was found to significantly improve lung function and reduce hospitalizations among pwCF with chronic P. aeruginosa endobronchial infection [35]. CF guidelines widely note that inhaled antibiotics should be considered for use in pwCF chronically infected with P. aeruginosa [36–38] either alone or in combination with systemic therapy for eradication.

While oral antimicrobials are sometimes used as part of P. aeruginosa eradication therapy, they are most frequently prescribed for outpatient PEx treatment to improve symptoms and avoid hospitalizations, despite limited data to support this practice [39, 40]. Some single-center studies identified no clinical benefit of oral antimicrobials for PEx treatment [40, 41]. Conversely, another study identified initial lung function improvement following oral antimicrobials, but up to 20% of pwCF still required hospitalization [39]. Since children with CF are more likely than adults to receive oral agents for PEx management [42], a pilot study to evaluate oral antimicrobial treatment of PEx in pwCF 6-18 years (STOP-PEDS; NCT04608019) is currently underway to determine clinical impact.

IV antimicrobials for pwCF have been utilized for P. aeruginosa eradication generally after unsuccessful attempts with inhaled and/or oral antibiotics, for PEx treatment if no success with oral antimicrobials, and in sick pwCF with more severe PEx requiring hospitalization. A recent randomized controlled trial (RCT) failed to demonstrate improved P. aeruginosa eradication with IV antimicrobials compared with oral antimicrobial therapy [43], whereas a single-center study found only a marginal improvement in eradication rates with IV antimicrobials after inhaled and oral antimicrobials were unsuccessful [44]. While PEx treatment with IV antimicrobials is recommended when outpatient PEx management fails, a 2015 Cochrane review failed to demonstrate the superiority of one antimicrobial route of administration compared to another for PEx treatment [45]. In addition, up to 25% of pwCF fail to recover to lung function baseline following IV antimicrobial therapy [46]. No data exist comparing the addition of oral antimicrobials to IV antimicrobial therapy for PEx treatment, and similarly, a recent observational study did not find any clinical benefit of adding inhaled antimicrobials to IV antimicrobial therapy in PEx [47].

APPROACH TO ANTIMICROBIAL USE IN CF—HISTORICAL AND CURRENT PERSPECTIVES

Pulmonary Exacerbations

Antimicrobials have been utilized in the treatment of CF lung disease since the 1940s. A study of 49 pwCF from 1952, for example, noted that antimicrobial treatment (including aureomycin and terramycin) led to improvements in pulmonary symptoms, nutritional status, and “overall well-being” [48]. A 1964 review article titled “A Therapeutic Regimen for Patients with Cystic Fibrosis” emphasized the prevention and treatment of pulmonary infection with frequent and sometimes continuous oral or intramuscular antimicrobial therapy [49]. Antimicrobials were initially used to target S. aureus as it was thought to be the main contributor to CF lung disease, but in the 1960s and 1970s, studies began to focus on antipseudomonals due to the increasing prevalence of P. aeruginosa endobronchial infection among pwCF [50]. In 1990, one of the first RCTs of antimicrobial use for PEx treatment demonstrated that antimicrobials plus airway clearance (compared with airway clearance alone) were associated with improved lung function and a reduction in P. aeruginosa sputum density compared with airway clearance alone [51].

Antimicrobials have since been considered a key tenet of PEx management, yet optimal treatment practices—including antimicrobial selection, route of administration, and treatment duration—remain unknown. Consensus PEx guidelines from the United States [52], Europe [53], Canada [54], and other countries exist, although evidence is lacking to support many of the recommendations. For example, US PEx guidelines note that there is insufficient evidence regarding the optimal duration of antimicrobials or whether single vs combination antibiotics are superior for P. aeruginosa infections [52].

Unsurprisingly, this lack of evidence has led to nonstandardized antimicrobial prescribing patterns for PEx management. A study of >4800 children with CF treated in-hospital for PEx identified significant variability with respect to antimicrobial selection (eg, 4 IV antibiotic pairs were used in at least 10% of PEx) and treatment duration (mean IV treatment was 10 days [interquartile range 6-14 days]) both within and between centers [55]. Prescribing patterns were also quite varied for 220 pwCF enrolled in the Standardized Treatment of Pulmonary Exacerbations in Patients with Cystic Fibrosis (STOP) observational study, as oral and inhaled antimicrobials were used concomitantly with IV agents for PEx treatment in 32% and 10% of cases, respectively [56].

In support of a more standardized approach to PEx management, several prospective interventional trials have recently been completed or are underway. STOP II was an open-label RCT designed to evaluate the efficacy of different durations of IV antimicrobial treatment among adults with CF [57]. In pwCF classified as early responders, 10 days of IV antimicrobial treatment was not inferior to 14 days. Among pwCF with a lesser treatment response, 21 days of IV antimicrobial treatment was not superior to 14 days. These investigators concluded that 14 days of IV antimicrobial treatment should be considered as a standard duration of IV antimicrobial therapy for PEx treatment. In addition, a study is currently underway to assess the acceptability and feasibility of a multicenter RCT comparing immediate (increase airway clearance/start oral antibiotics) antimicrobials vs tailored (increased airway clearance and start oral antibiotics later if not improved) therapy for PEx treatment in children 6-18 years of age (STOP-PEDS; NCT04608019). Given the impact, optimizing antimicrobial approaches to PEx treatment has been identified as a key research priority for the CF community [58].

Eradication of Airway Infections

Given the impact of chronic infections in CF, researchers began intensive investigations into antimicrobial regimens that could eradicate early infections, initially focusing on P. aeruginosa. After demonstrating that early P. aeruginosa infection could be eradicated in a small non-randomized interventional trial [59], the Early Pseudomonas Infection Control (EPIC) trial was initiated [60, 61]. The US EPIC trial demonstrated that, in early P. aeruginosa infection, using inhaled tobramycin solution (TSI) (300 mg nebulized twice a day) for 28 days could achieve eradication rates of 90%, although this was a secondary endpoint [62]. Cycling inhaled TSI did not improve the sustained eradication rate over repeat courses in the event of a positive P. aeruginosa culture. The addition of 14 days of oral ciprofloxacin was not superior to TSI alone. The EarLy Inhaled Tobramycin for Eradication (ELITE) trial had a similar design and noted that 93% (28 days inhaled TIS group) and 92% (56 days inhaled TIS group) of the pwCF were free of P. aeruginosa infection 1 month after the end of treatment [63]. A non-controlled trial employing a different inhaled antibiotic, the open-label Aztreonam Lysine for Pseudomonas Infection Eradication (ALPINE) study, also demonstrated a similar rate of P. aeruginosa eradication after treatment of 89% [64].

Eradication of early P. aeruginosa infection has since become the standard of care. The CF populations enrolled in these trials were children, but this strategy is also employed in adults. An addition of oral azithromycin to inhaled tobramycin did reduce the risk of PEx and led to sustained improvement in weight for pwCF with newly acquired P. aeruginosa but did not impact sputum microbiology [65]. Cochrane reviews on the topic concluded that nebulized antibiotics alone or in combination with oral ciprofloxacin are better than no eradication treatment for P. aeruginosa [66]. The most recent trial (TORPEDO-CF) demonstrated that IV antibiotics were not superior to oral antibiotics for new P. aeruginosa eradication in children and adults with CF [43]. Eradication of other common CF pathogens has been studied but in a less rigorous fashion. Trials have demonstrated that treatment protocols reduced microbiologic endpoints (sputum positivity) for newly acquired methicillin-resistant S. aureus (MRSA) in CF but were not powered for clear clinical endpoints [67, 68]. Additional key pathogens like B. cepacia complex have limited data supporting eradication treatment and approaches are detailed elsewhere in this series [69, 70]

Antimicrobials as Chronic Maintenance Therapies

Antimicrobial therapies are also used as either prophylaxis or chronic suppressive treatment in pwCF (Table 1). Early in life, some infants and young children are treated with pavalizumab seasonally as prophylaxis against respiratory syncytial virus (RSV) [71, 72]. CF alone is typically not an indication for RSV prophylaxis but may be considered with other risk factors for severe RSV pulmonary illness. Certain countries use prophylactic oral antibiotics early in life to prevent or suppress S. aureus airway infection, but this practice varies regionally and outcomes appear to be mixed [73]. The use of antibiotics (commonly azithromycin) in CF, however, is more widely accepted. Based on several studies, azithromycin has been demonstrated to reduce the risk of PEx and modestly increase lung function in persons with chronic P. aeruginosa infection [65, 74–77]. Retrospective analyses of CF registries in the United States and France identified an association between azithromycin use and better long-term pulmonary outcomes—particularly in those infected with P. aeruginosa [78, 79]. Chronic azithromycin use increases macrolide resistance in common upper respiratory bacterial species, but this may have little impact on antibiotic selection to treat CF PEx [80]. There are data indicating that azithromycin reduces the ability of tobramycin to kill P. aeruginosa, but no trials to date have demonstrated a clinical consequence of this apparent drug-drug interaction [81–83].

Table 1.

Chronic Maintenance Therapies for Airway Infections in PwCF

Drug	Route	Usual Dose	Indications	Approval Status
Tobramycin	Inhalation	Solution: 300 mg BID DPI: 112 mg BID NIS: 80-160 mg BID	-Pseudomonas aeruginosa eradication (grade A) -Maintenance therapy in persons aged ≥6 years and Paa	FDA, HC, EMA
Aztreonam	Inhalation	75 mg TID	-P. aeruginosa eradication -Maintenance therapy in persons aged ≥6 years and Paa	FDA, HC, EMA
Colistin	Inhalation	NIS: 75 mg BID DPI: 1 662 500 IU BID	-P. aeruginosa eradication -Maintenance therapy in persons aged ≥6 years and Pab	EMA
Levofloxacin	Inhalation	240 mg BID	Maintenance therapy in persons aged ≥6 years and Pab	FDA, HC, EMA
Amikacin	Inhalation	590 mg OD	- Maintenance therapy in persons aged ≥6 years and Pab -NTM therapy	FDA, EMA
Azithromycin	Oral	500 mg daily 3×/week	Maintenance therapy in persons aged ≥6 years with (grade B) or without P. aeruginosa (grade C)	FDA, HC, EMA

PwCF, persons with cystic fibrosis; DPI, dry powder inhalation; NIS, nebulized intravenous solution; FDA, Food and drug administration; HC, Health Canada; EMA, European Medicines Agency; BID, two times a day; TID, three times a day; OD, once daily.

^aGrade B recommendation for mild disease; grade A recommendation for moderate to severe disease.

^bLimited evidence for alternate agents.

Inhaled antibiotics are commonly used as chronic suppressive antibiotics, generally targeting P. aeruginosa. Inhaled tobramycin solution was one of the earliest chronic pulmonary therapies developed for CF. PwCF receiving TSI experienced and maintained a higher lung function, had a reduced risk of PEx over at least several months, and/or a reduction in pulmonary symptoms [35, 84–87]. Inhaled aztreonam lysine solution proved effective some years later and is the second most commonly prescribed antipseudomonal inhaled therapy in the United States [4]. More recent RCTs with inhaled antibiotics have shown positive but smaller improvements in clinical outcomes when compared with earlier studies of inhaled tobramycin solution and inhaled aztreonam lysine solution [88–90]. This distinction may have as much or more to do with better overall health status for many pwCF rather than true antimicrobial differences. Antibiotic preparations including inhaled tobramycin, inhaled liposomal amikacin, and inhaled levofloxacin have gained regulatory approval in some countries.

Inhaled antibiotics are often cycled on/off every 4 weeks, often as continuous use alternating between 2 medications to avoid time without an inhaled antibiotic therapy [91]. A trial was conducted to compare cycled inhaled tobramycin vs continuous alternating therapy with inhaled tobramycin and inhaled aztreonam lysine but was unable to enroll the planned number of participants, in part because many individuals had already adopted continuous use as a clinical strategy [92]. In parts of Europe, especially the UK, inhaled colistimethate is the most commonly selected inhaled antibiotic and is often administered chronically without cycled interruption [93]. Direct comparison in outcomes between colistimethate and antibiotics more frequently in use in the United States (eg, tobramycin) is limited [66, 94].

Novel Antimicrobial Approaches in CF

A number of research programs are working to develop new antimicrobial therapies that may be effective in pwCF. At present, over 15 such research programs are listed on the CF Foundation drug development anti-infectives pipeline largely focused on challenging infections (Figure 2). Novel strategies are being tested, including new inhaled antibiotics (eg, murepavadin), multiple agents targeting iron-dependent bacterial pathways, compounds that work against biofilms, and orally bioavailable versions of existing drugs (eg, amikacin) that may have lower toxicity. Two therapeutic strategies are being developed by multiple sponsors: augmentation of the nitric oxide pathway and bacteriophage therapy.

Figure 2.

Drug development pipeline (Reprinted with permission from the Cystic Fibrosis Foundation).

Nitrogen oxide (NO) is a chemical that occurs naturally in the body and exerts both immunomodulatory and antimicrobial effects. Lower concentrations of exhaled NO have been identified in pwCF which increase with the use of CFTR modulator therapies, suggesting a link between NO regulation and CFTR activity [95–98]. Based on this, NO augmentation as a therapy is being assessed for use in challenging infections in CF [99–101]. Although initial safety and tolerability in these pilot studies have been demonstrated, clinical efficacy and further safety data in randomized trials (Phase 2 study NCT02498535 recruitment terminated due to the SARS-CoV-2 pandemic) have yet to be established.

Bacteriophages are viruses that infect and replicate only within bacterial cells. They are the most abundant of all living things on Earth and are found throughout our bodies. Research is underway on IV and inhaled natural and synthetic bacteriophages that have been selected to target CF airway pathogens—namely P. aeruginosa but potentially other difficult-to-treat infections like mycobacteria [102–105]. Bacteriophage therapy has been used for several decades, but RCTs are yet to occur in CF. Likewise, novel approaches are being designed to work in concert with traditional antibiotics to optimally address the management of resistant infections [106]. The variety of approaches now included in bacteriophage programs for CF infections should allow us to test the promise of this novel antibiotic approach. It is hoped that bacteriophage therapy will be safe and effective in combating drug-resistant chronic infections where traditional antibiotic options are limited [107].

Antimicrobial Approaches Moving Forward

CFTR modulators have received considerable attention in recent years given their impressive clinical and biological impact for a majority of pwCF. It is unclear how improving CFTR function through modulator drug therapy will affect airway infections [108]. Studies using patient registry data report variable but significant reduction in the prevalence of P. aeruginosa-positive respiratory cultures in pwCF after starting ivacaftor [22, 109–113]. The combination drug elexacaftor/tezacaftor/ivacaftor (ETI) appears to be more effective than ivacaftor overall, and preliminary results suggest a substantial reduction in sputum density of several traditional bacterial pathogens along with a potential for culture negativity (conversion of positive to negative culture) [23, 114–116]. It will be particularly interesting to monitor the impact on airway microbiology when modulators are started early in life before many of these infections develop. With greater proportions of pwCF using modulators, the associations between chronic airway infections and poorer outcomes may also be attenuated, and approaches and utility of antimicrobial therapies as acute and maintenance strategies may shift fundamentally over time.

CONCLUSION

Antimicrobial therapies used in acute and chronic settings in pwCF are a cornerstone of care and have contributed to the improved outcomes. However, further work in the form of robust clinical trials is needed to move beyond consensus alone to hone antimicrobial use in these settings. This is of particular import in the context of novel and highly effective CFTR modulator therapies that have been adopted or are forthcoming. Encouragingly, novel antimicrobial development is ever expanding and will not only serve pwCF but also has the potential for use beyond this population.

Notes

Supplement sponsorship. This supplement was sponsored by the Cystic Fibrosis Foundation.

Potential conflicts of interest . All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.