Inhaled antibiotics for the treatment of chronic bronchopulmonary Pseudomonas aeruginosa infection in cystic fibrosis: systematic review of randomised controlled trials

Introduction: Inhaled antibiotics are probably the safest and most effective therapy for Pseudomonas aeruginosa chronic lung infection in cystic fibrosis (CF) patients.

Areas covered: To summarise the available evidence, a systematic review of the three currently available inhaled antibiotics (aztreonam lysine (AZLI), colistin (COL) and tobramycin (TOB)) was performed. The three AZLI placebo-controlled studies showed that the improvements in FEV₁ and mean sputum P. aeruginosa density were statistically significant better than with placebo. The two COL placebo-controlled studies involved few patients but showed that COL was better than placebo in terms of maintenance of some pulmonary function parameters. The tobramycin inhalation solution (TIS) and tobramycin inhalation powder studies showed that the efficacy of both formulations was similar but significantly better than placebo. In the comparative studies, TIS showed more efficacy than COL solution, colistin inhalation powder showed non-inferiority to TIS and AZLI was superior to TIS.

Expert opinion: Placebo-controlled and comparative clinical trials have shown that clinical evidence of inhaled antibiotics is very different. The choice of treatment for each individual CF patient must be based on the features of the drug (clinical evidence on efficacy and safety), the inhalation system and the patient characteristics. Development of new inhaled antibiotics will allow new end points of efficacy and therapy regimens to be assessed.     

Inhaled aztreonam lysine: an evidence-based review

Introduction: Chronic airway infection in cystic fibrosis (CF) is linked with progressive loss of pulmonary function and is the primary cause of mortality. Treatment regimens have generally focused on the use of chronic antibiotic therapy to target Pseudomonas aeruginosa (PA), a major pathogen associated with a decline in FEV₁%. Specifically, inhaled antibiotic therapy provides high antibiotic sputum concentrations and decreases bacterial burden.

Areas covered: This article describes the pharmacology, pharmacodynamics/pharmacokinetics, clinical efficacy, microbiology and safety of aztreonam lysine (AZLI, Cayston), an inhaled antibiotic indicated for use in CF patients with PA. Articles were identified using MEDLINE (1966 – June 13, 2013) and EMBASE (1947 – June 13, 2013). Abstracts from the annual meeting (2011 – 2012) of the North American Cystic Fibrosis Conference were searched to identify additional publications.

Expert opinion: AZLI is an additional product that can be used in the management of CF and will likely play a major role in the suppression of PA. Clinical trials have demonstrated improvements in pulmonary function and patient reported symptoms. AZLI may therefore be used as an alternative to traditional inhaled antibiotics in patients with moderate-to-severe CF and PA colonization. Further investigation is warranted into use of AZLI in mild lung disease and for PA eradication.     

Long-term safety of tobramycin inhalation powder in patients with cystic fibrosis: phase IV (ETOILES) study

Objective: Long-term treatment with inhaled antibiotics is recommended for chronic Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients. The ETOILES study (Clinicaltrials.gov identifier: NCT01519661) evaluated the safety of tobramycin inhalation powder (TIP) for 1 year.

Research design and methods: This single-arm, open-label, multicenter, phase IV trial, enrolled CF patients aged ≥6 years, with baseline FEV₁ ≥25%–≤75% predicted and Pa infection, and assessed the safety of TIP over six cycles in terms of the incidence of treatment-emergent adverse events (AEs) and serious AEs (SAEs). Secondary endpoints included presence of airway reactivity, relative change in FEV₁% predicted, and change in sputum Pa density (log₁₀ colony forming units/g sputum).

Results: A total of 157 patients were enrolled, and 96 patients (61.1%) completed the study. The most commonly reported AE was infective pulmonary exacerbation of CF (55.4%). Cough was reported as an AE in 23.6% of patients; a majority were mild or moderate and two were severe (1.3%). SAEs were reported by 31.2% of patients. No deaths were reported during the study. There were no clinically meaningful changes reported in airway reactivity. Most frequently reported post-inhalation event was cough at all time points; however, it was of short duration (<4?minutes) and decreased over the course of the study, possibly due to patients becoming more experienced with the administration of TIP. The post-inhalation events resolved without intervention in most cases. FEV₁% predicted remained stable from Cycles 1 to 4 and tended to decrease thereafter, although it was not statistically significant (change from baseline to study end mean [SD] = ?1.9% [14.55]; P?=?0.199).

Conclusions: This was one of the largest studies with long-term TIP exposure. The majority of patients enrolled were adults with more advanced CF lung disease than those in previous TIP studies. No new emerging safety signals were seen and efficacy was sustained during the year.     

Pseudomonas aeruginosa biofilm infections in cystic fibrosis: insights into pathogenic processes and treatment strategies

Importance of the field: CF airway mucus can be infected by opportunistic microorganisms, notably Pseudomonas aeruginosa. Once organisms are established as biofilms, even the most potent antibiotics have little effect on their viability, especially during late-stage chronic infections. Better understanding of the mechanisms used by P. aeruginosa to circumvent host defenses and therapeutic intervention strategies is critical for advancing novel treatment strategies.

Areas covered in this review: Inflammatory injury in CF lung, role of neutrophils in pathogenesis, P. aeruginosa biofilms, mucoidy and its relationship with poor airway oxygenation, mechanisms by which P. aeruginosa biofilms in the CF airway can be killed.

What the reader will gain: An understanding of the processes that P. aeruginosa undergoes during CF airway disease and clues to better treat such infections in future.

Take home message: The course of CF airway disease is a process involving host and microbial factors that often dictate frequency of pulmonary exacerbations, thus affecting the overall course. In the past decade significant discoveries have been made regarding the pathogenic processes used by P. aeruginosa to bypass the immune system. Many new and exciting features of P. aeruginosa now illuminate weaknesses in the organism that may render it susceptible to inexpensive compounds that force its own destruction.     

Anaerobic Pseudomonas aeruginosa and other obligately anaerobic bacterial biofilms growing in the thick airway mucus of chronically infected cystic fibrosis patients: an emerging paradigm or “Old Hat”?

Introduction: The cystic fibrosis (CF) airway mucus is an ideal niche in which many bacteria can develop antibiotic- and phagocyte-resistance in unique structures known as “mode II biofilms” where bacteria are embedded within the mucus, yet unattached to airway epithelial cells. Pseudomonas aeruginosa is the dominant CF pathogen, yet herein the authors provide burgeoning evidence that obligate anaerobic bacteria (e.g., Prevotella) actually thrive within the CF mucus, a paradigmatic shift that chronic CF is an “aerobic” disease. Interestingly, CF organisms repress virulence factor production (e.g., P. aeruginosa) while others (e.g., S. aureus) increase them under anaerobic conditions.

Areas covered: The authors shed additional light on (i) the anoxic nature of the CF airway mucus, (ii) the relative commonality of anaerobic bacteria isolated from CF sputum, (iii) virulence factor production and cross-talk between obligate anaerobes and P. aeruginosa relative to disease progression/remission, (iv) the role of mucoidy in CF, and (v) the role of nitrosative stress in activation of bacteriophage and pyocins within biofilms.

Expert opinion: The authors conclude with insight as to how we might treat some CF bacteria during mode II biofilm infections that utilizes a metabolite of bacterial anaerobic respiration and an aerobic oxidation product of airway-generated NO, acidified NO₂ ^-.     

Inhaled colistin for lower respiratory tract infections

Introduction: Lower respiratory tract infections, due to Pseudomonas aeruginosa or Acinetobacter baumannii, are frequently encountered in patients with cystic fibrosis (CF) or in patients developing nosocomial pneumonias. Both of these conditions bear a high mortality risk and aggressive antibiotic therapy is necessary. Inhaled antibiotics might represent an effective therapeutic approach for these diseases as it has demonstrated good bactericidal efficacy and safety in both preclinical and clinical studies. This colistin formulation might be useful particularly in patients with respiratory tract infections due to multidrug-resistant Gram-negative bacteria. Its main advantages are a better safety profile with a minimal or absent risk of nephrotoxicity.

Areas covered: This paper discusses the available systemic formulations of colistin, with pharmacokinetic and safety profiles, followed by an overview of inhaled antibiotics in lower respiratory tract infections.

Expert opinion: Inhaled colistin should be used selectively as monotherapy in chronic infections with P. aeruginosa in CF patients, whereas in patients with hospital/ventilator-acquired pneumonia (HAP/VAP), it should be used in a combined regimen with systemic antibiotics.     

Baseline airway inflammation may be a determinant of the response to ozone exposure in asthmatic patients

Abstract

Context: It is well known that ozone exposure decreases lung function and increases airway neutrophilia, but large variability has been observed among asthmatic patients.

Objective: To find possible predictors of functional and inflammatory airway response to ozone in asthmatic patients.

Materials and methods: We studied 120 patients with mild-to-moderate asthma, randomly exposed to either air or ozone (0.3?ppm for 2?h) in a challenge chamber. Symptoms and pulmonary function test (PFT) were measured before and immediately after exposure. Six hours after exposure, induced sputum was collected. Patients were evaluated according to their functional (FEV₁ responders) or neutrophilic (neutrophil responders) response to ozone. We considered, as possible predictors of response: age, baseline FEV₁, previous treatment with inhaled corticosteroids (ICS), baseline sputum neutrophils, baseline sputum eosinophils, methacholine responsiveness, atopy and smoking habit.

Results: FEV₁ responders had lower baseline FEV₁, and a lower percentage of these had received ICS treatment. Neutrophil responders were younger, with lower baseline sputum inflammation and greater methacholine responsiveness. These results were confirmed by multivariate logistic analysis.

Discussion and conclusion: Patients not previously treated with ICS and patients with lower FEV₁ are more prone to functional response to ozone. Lower baseline airway inflammation and greater bronchial hyperresponsiveness may predict neutrophilic airway response to ozone in asthmatic patients. Thus, determinants of functional and inflammatory responses to ozone are different.     

From pipeline to patient: new developments in cystic fibrosis therapeutics

Introduction: Cystic fibrosis (CF) is an inherited rare disease characterised by recurrent pulmonary infection, pancreatic malabsorption and a number of other multisystem effects. In the past few years new drugs specifically designed to treat CF have entered the pipeline, and some are now used in clinical practice.

Areas covered: Clinical trial results from CF trials reported or ongoing within the last 3 years are discussed. A literature and trials registry search of trials and meta-analyses involving patients with CF was conducted, from which the most exciting developments were selected.

Expert opinion: Drugs to address the basic defect in CF have finally come to market, albeit for a limited number of patients with a specific genotype. Traditional areas of CF therapeutics continue to be developed, with modest success, including drugs to modulate the airway surface liquid, new pancreatic supplements, antibiotics and new treatments for endocrine complications of CF.     

Lumacaftor/ivacaftor,a novel agent for the treatment of cystic fibrosis patients who are homozygous for the F580del CFTR mutation

Introduction: Cystic Fibrosis (CF) is an autosomal recessive disease affecting up to 90,000 people worldwide. Approximately 73% of patients are homozygous for the F508del cystic fibrosis transmembrane conductance regulator [CFTR] mutation. Traditionally treatment has only included supportive care. Therefore, there is a need for safe and effective novel therapies targeting the underlying molecular defects seen with CF.

Areas covered: In 2016, the Food and Drug Administration and the European Commission approved LUM/IVA (Orkambi), a CFTR modulator that includes both a CFTR corrector and potentiator, for CF patients homozygous for the F508del CFTR mutation. This article reviews the pharmacologic features, clinical efficacy, and safety of LUM/IVA and summarize the available pre-clinical and clinical data of LUM/IVA use.

Expert commentary: LUM/IVA showed modest, but significant improvements from baseline in percent predicted FEV₁ (ppFEV₁) as well as a reduction in pulmonary exacerbations by 35% It was shown to be safe for short- and long-term use. Currently, LUM/IVA is the only oral agent in its class available and represents a milestone the development of therapies for the management of CF. Nonetheless, pharmacoeconomic data are necessary to justify its high cost before is use becomes standard of care.     

Challenges with current inhaled treatments for chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis

Abstract

Background:

Pseudomonas aeruginosa (Pa) is the predominant pathogen infecting the airways of patients with cystic fibrosis (CF). Initial colonization is usually transient and associated with non-mucoid strains, which can be eradicated if identified early. This strategy can prevent, or at least delay, chronic Pa infection, which eventually develops in the majority of patients by their late teens or early adulthood. This article discusses the management and latest treatment developments of Pa lung infection in patients with CF, with a focus on nebulized antibiotic therapy.     

Emerging therapies for cystic fibrosis lung disease

Importance of the field: Cystic fibrosis (CF), one of the major respiratory diseases, is caused by mutations in a gene encoding for a chloride channel. Abnormal transepithelial ion transport leads to a reduced volume of the airway surface liquid layer and reduced mucociliary clearance.

Areas covered in this review: There is currently no cure for CF and CF lung disease remains a major contributor to morbidity and mortality. However, most current treatments for CF lung disease do not address the underlying pathology. We describe here new therapeutic developments aiming to identify or generate compounds that counteract the effects of cystic fibrosis transmembrane conductance regulator (CFTR) on the airway.

What the reader will gain: This review summarizes the current state of new developments in the treatment of CF lung disease. These drugs include nebulized and inhaled osmotically active agents, but also modifiers of ion channels other than CFTR, such as activators of alternative chloride channels or inhibitors of sodium absorption, and compounds in development aim to correct or improve impaired CFTR function directly. First clinical trials with new drugs including ion channel modifiers and CFTR pharmacotherapeutics have revealed very promising results.

Take home message: CF drug therapy is moving rapidly from symptomatic therapy to treatment of the underlying pathophysiology.     

New drug developments in the management of cystic fibrosis lung disease

Introduction: Therapies for cystic fibrosis (CF) pulmonary disease have, until recently, all targeted downstream manifestations rather than the root cause of the disease. A step-change in our approach has been achieved in the last few years, with novel small-molecule CFTR modulating drugs entering the clinic.

Areas covered: In this article, we will discuss the field of drug development for CF lung disease. The case will be made for the potential benefits of basic defect-targeted strategies, which will be described in detail. Novel therapies directed at the downstream pulmonary manifestations of CF – infection, inflammation, and mucus impaction – will be reviewed. Finally, we will speculate on future directions and challenges.

Expert opinion: CF drug development is in an exciting phase, catalysed by the impressive results seen in patients with ivacaftor-responsive CFTR mutations. The research field is active with trials of novel therapies targeting the basic defect, alongside drugs targeting downstream effects. In order to detect potentially small improvements due to novel therapies, especially in the context of treating young patients with early disease, sensitive outcome measures and the coordinated efforts of collaborative research networks are crucial.     

Pharmacotherapy for lower respiratory tract infections

Introduction: Bacterial infections play an important role as etiological agents in acute exacerbations of chronic obstructive pulmonary disease (AECOPD), and exacerbations of non-cystic fibrosis (CF) bronchiectasis. In acute bronchitis and asthma exacerbations their role is less well defined than with patients with COPD. The clinical features, causative pathogens and therapies of common acute respiratory tract infections are detailed in this review.

Areas covered: This article covers medical literature published in any language from 2000 to 2014, on ‘lower respiratory tract infections’, identified using PubMed, MEDLINE and ClinicalTrial.gov. The search terms used were ‘COPD exacerbations’, ‘bronchiectasis’, ‘macrolides’ and ‘inhaled antibiotics’.

Expert opinion: Given that almost half of AECOPD are caused by bacteria, administration of antibacterial agents is recommended for patients with severe exacerbations or severe underlying COPD. Chronic prophylactic use of macrolides seems to be of benefit, particularly in patients with bronchiectasis and chronic mucous hypersecretion. In an effort to manage chronic airway infection non-CF bronchiectasis due to drug-resistant pathogens, aerosolized antibiotics may be of value, and the data from recent studies are examined to demonstrate the potential value of this therapy, which is often used as an adjunctive measure to systemic antimicrobial therapy.     

Montelukast in asthmatic patients 6 years–14 years old with an FEV1 > 75%

SUMMARY

Objectives: Montelukast is a potent leukotriene receptor antagonist effective for treating asthma symptoms in adult and pediatric patients. The purpose of this analysis was to assess the clinical efficacy of montelukast, a potent leukotriene-receptor antagonist, in a subgroup analysis of patients aged 6?years–14?years with milder asthma, defined as a percentage predicted forced expiratory volume in 1?s (FEV₁) > 75% using data from a clinical trial of pediatric patients with a broad range of asthma severities.

Research design and methods: The original previously published clinical trial was an 8-week multi-center, randomized, double-blind, parallel-group study conducted in 47 centers in the United States and Canada. The study compared the efficacy of once daily montelukast 5?mg to placebo in patients 6?years–14?years old with persistent asthma and an FEV₁ ranging from 50% to 85% of predicted. A total of 87 patients in the montelukast group and 51 patients in the placebo group were selected from the original cohort of 336 patients based on percentage predicted FEV₁ of > 75%. The primary endpoint was percentage change in FEV₁ from baseline compared with placebo over 8?weeks of active treatment.

Results: Montelukast significantly improved the primary endpoint of percentage change in FEV₁ compared with placebo (?p = 0.005). Other efficacy endpoints were significantly improved on montelukast similar to efficacy in the original study.

Conclusion: Montelukast significantly improved FEV₁, clinic measured peak expiratory flow (PEF), reduced nocturnal awakenings, and improved quality of life in children with milder persistent asthma defined as an FEV₁ > 75% of predicted.     

2016—2018年南京市儿童医院铜绿假单胞菌的分布及耐药性分析

目的 回顾性分析2016—2018年南京市儿童医院铜绿假单胞菌的分布及其耐药特点。方法 对送检标本进行分离和培养,并对分离出的铜绿假单胞菌的分布及耐药性进行分析。结果 2016—2018年分离出铜绿假单胞菌分别为379、455和483株,检出率分别为4.17%、4.76%、5.15%,呈逐年递增。分离菌株数量最多的科室是普外科,共分离317株（24.07%）;标本来源以痰液为主,共737株（55.96%）。铜绿假单胞菌对大部分抗菌药物的耐药率较低,对环丙沙星、左氧氟沙星的耐药率仅为0.30%、0.53%;对亚胺培南、氨曲南、哌拉西林的耐药率较高,但也仅为20.88%、17.62%、11.62%,对其余抗菌药物的耐药率均小于10%。共检出158株多重耐药铜绿假单胞菌,平均检出率为12%,检出较多的科室为新生儿重症监护室。结论 铜绿假单胞菌是儿童医院感染的常见致病菌,易产生多重耐药性,了解其临床分布和耐药性变迁,以期为临床治疗提供最新的耐药性资料,以便更好地控制铜绿假单胞菌的感染。     

Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a double-blind,randomized, placebo- and active-controlled trial

ABSTRACT

Objective: To evaluate the efficacy and safety of levalbuterol metered dose inhaler (MDI) in children aged 4-11 years (n = 173).

Research design and methods: Multicenter, randomized, double-blind 28‐day study of QID levalbuterol 90?µg, racemic albuterol 180?µg, and placebo (2:1:1 ratio). Serial spirometry was performed on Days 0, 14, and 28. The primary endpoint was the double-blind average peak percent (%) change in FEV₁ from visit pre-dose; the primary comparison was with placebo. Secondary endpoints included the area under the FEV₁ percent change from pre-dose curve and peak % predicted FEV₁. Safety endpoints included adverse events, laboratory tests, rescue medication use, and electrocardiograms.

Results: Levalbuterol significantly improved the least square mean peak percent change in FEV₁ compared with placebo (levalbuterol 25.6% ± 1.3% [p < 0.001]; racemic albuterol 21.8% ± 1.8% [p = ns]; placebo 16.8% ± 1.9%). Results for levalbuterol were similar for the other spirometry endpoints (?p < 0.05 vs. placebo). No levalbuterol-treated patients had a peak percent change in FEV₁ < 10% (compared with 15.8% of racemic albuterol-treated patients and 30.3% of placebo-treated patients). The incidence of adverse events was 43.4% for levalbuterol, 56.4% for racemic albuterol, and 51.4% for placebo. The rate of discontinuation was 1.3% for levalbuterol, 2.6% for racemic albuterol, and 8.6% for placebo. The rate of asthma attacks (10.5%, 12.8%, 14.3%, respectively) was similar among treatments. Levalbuterol and racemic albuterol both reduced rescue medication use (?p < 0.01 vs. placebo) and produced changes in ventricular heart rate and QT_c‐F that were similar to placebo.

Conclusions: In this study, levalbuterol administered via MDI significantly improved airway function in comparison with placebo in asthmatic children aged 4–11 years with a safety profile that was similar to placebo.     

Successful Use of Ceftolozane‐Tazobactam to Treat a Pulmonary Exacerbation of Cystic Fibrosis Caused by Multidrug‐Resistant Pseudomonas aeruginosa

Ceftolozane‐tazobactam, a novel β‐lactam/β‐lactamase inhibitor, was recently approved for the treatment of complicated urinary tract and intraabdominal infections, as monotherapy and in combination with metronidazole, respectively. Ceftolozane‐tazobactam exhibits a wide spectrum of activity against both gram‐positive bacteria, gram‐negative bacteria including multidrug‐resistant (MDR) Pseudomonas aeruginosa, and some anaerobic bacteria. Although not currently approved for any pulmonary indication, studies have demonstrated excellent distribution to epithelial lining fluid, indicating that it may be an alternative agent to use in the treatment of respiratory tract infections caused by MDRP. aeruginosa. Unfortunately, data are lacking regarding the use of ceftolozane‐tazobactam in the treatment of respiratory tract infections including patients with cystic fibrosis (CF). We describe the first case report, to our knowledge, of a 25‐year‐old white man successfully treated with ceftolozane‐tazobactam for a pulmonary exacerbation of his CF caused by MDRP. aeruginosa. He was admitted for his fourth hospitalization in 7 months for a pulmonary exacerbation of his CF. After blood and sputum were cultured, prednisone, cefepime, inhaled tobramycin, and intravenous ciprofloxacin were started. On day 4, after no signs of clinical improvement, respiratory cultures revealed nonmucoid MDRP. aeruginosa, susceptible only to colistin. β‐Lactam therapy was subsequently changed to ceftolozane‐tazobactam 3 g intravenously every 8 hours while continuing ciprofloxacin and inhaled tobramycin. Ceftolozane‐tazobactam susceptibility was determined by the Etest method (minimum inhibitory concentration 1.5 μg/ml). By day 3 of therapy, the patient showed signs of clinical improvement and was discharged after completion of a 12‐day course of antibiotics. Until additional research is available, we hope this evidence will provide consideration of ceftolozane‐tazobactam for this novel off‐label indication.     

Antibacterial/Antibodies: A Monoclonal Antibody to the Endotoxin A of Pseudomonas Aeruginosa is Therapeutically Useful

Summary

Novelty: A hybridoma which secretes an antibody specific for the exotoxin A of Pseudomonas aeruginosa is described. The antibodies can be used for therapy of P. aeruginosa infection. The exotoxin A is a potent toxin related to diphtheria toxin and is secreted by all pathogenic strains of P. aeruginosa.

Biology: The antibody recognises an amino acid sequence from 591-613 of exotoxin A and results in neutralisation of the toxin. A human monoclonal antibody generated by EBV transformation is described.     

MP-376 (Aeroquin) for chronic Pseudomonas aeruginosa infections

Introduction: The chronic airway infection with Pseudomonas aeruginosa (PA) is a risk factor for rapid disease progression in various chronic pulmonary diseases including cystic fibrosis or chronic obstructive pulmonary disease. Inhaled antibiotics are able to treat effectively such chronic airway infections, and MP-376 is currently in late-stage clinical development for such an indication.

Areas covered: Review of the existing preclinical and clinical data on MP-376, with a focus on the efficacy and safety of the compound on chronic airways infections due to PA.

Expert opinion: Chronic airways infection with PA represents a therapeutic challenge because of its own complex mechanisms of defense, because of the rapid development of antibiotic resistance and by the fact that systemic antibiotics are not always able to achieve appropriate concentrations at lung level. Inhaled antibiotics (tobramycin, aztreonam, etc.) represent optimal alternatives to their systemic homologs due to their better penetrability in the lungs and due to the lower systemic exposure. Inhaled levofloxacin which is currently investigated for chronic airways infection might be another possible antipseudomonal inhaled therapy.     

An update on new and emerging therapies for cystic fibrosis

Introduction: Cystic fibrosis (CF) is a genetic disorder that results in a multi-organ disease with progressive respiratory decline that ultimately leads to premature death. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for the CFTR anion channel. Established CF treatments target downstream manifestations of the primary genetic defect, including pulmonary and nutritional interventions.

Areas covered: CFTR modulators are novel therapies that improve the function of CFTR, and have been approved in the past five years to mitigate the effects of several CF-disease causing mutations. This review summarizes currently approved CFTR modulators and discusses emerging modulator therapies in phase II and III clinical trials described on clinical trials.gov as of April, 2017. Results of relevant trials reported in peer-reviewed journals in Pubmed, scientific conference abstracts and sponsor press releases available as of November, 2017 are included.

Expert opinion: The current scope of CF therapeutic development is robust and CFTR modulators have demonstrated significant benefit to patients with specific CFTR mutations. We anticipate that in the future healthcare providers will be faced with a different treatment paradigm, initiating CFTR-directed therapies well before the onset of progressive lung disease.