Two Steps Forward: Improving the Management of Cystic Fibrosis Pulmonary Exacerbations

In this issue of the Journal, Goss and colleagues (pp. 1295–1305) report the findings of the STOP2 (Standardized Treatment of Pulmonary Exacerbations) study, a randomized trial of antimicrobial duration for cystic fibrosis (CF) pulmonary exacerbation (PEx) treatment (1). Adults with CF experiencing PExs treated with intravenous antibiotics were enrolled at presentation and assessed at an interim time point (7–10 days into antibiotic therapy) for clinical response based on lung function and symptom improvement. Early responders were randomized to either 10 or 14 days of total antibiotic treatment duration, whereas non–early responders were randomized to 14 or 21 days’ duration. The primary outcome was the change in FEV₁ from the start of antibiotics to 2 weeks after antibiotic cessation. Almost 1,000 patients with CF were randomized in the study; among the approximate one-third of early responders, 10 days was not inferior to 14 days of antibiotics, and among the remaining non–early responders, 21 days was not shown to be superior to 14 days of antimicrobial therapy.

The STOP2 trial represents a landmark study in the treatment of CF pulmonary exacerbations as it is the first to be adequately powered to compare varying lengths of antibiotic courses. The choice of antibiotic duration in the treatment of infectious diseases is frequently guided by clinical experience or observational studies rather than by evidence from comparative randomized controlled trials (2). Recent randomized controlled trials have examined shorter antimicrobial regimens for the treatment of ventilator associated or community acquired pneumonia, intraabdominal sepsis, and gram-negative bacteremia and found that shorter courses were not inferior to longer courses (3, 4). Prolonged antimicrobials are associated with an increased number of days in hospital, central line–associated thrombotic complications, toxicity such as ototoxicity secondary to aminoglycoside use, and drug hypersensitivity reactions, to name a few. Although the study by Goss and colleagues did not identify a statistically significant difference in adverse events between treatment arms, it is important to remember that antimicrobial side effects are cumulative over the lifespan of a patient with CF who will require repeated antibiotic courses to treat pulmonary infections. In addition, although not assessed in this study, increased antimicrobial exposure invariably leads to antimicrobial resistance, which ultimately limits the long-term effectiveness of antibiotic therapy in patients with CF (5). By demonstrating that shorter courses are not inferior to longer courses (and in the case of non–early responders, longer ones are not superior), the authors have provided valuable data in the guidance of antimicrobial stewardship (6). The main strength of this study is thus its clinical relevance, as the results have the potential to directly impact the care of individuals with CF.

Another strength of the study was its feasibility and pragmatic design. The management of CF PExs is often complex and variable with no universally accepted definition or complete understanding of the etiology of the condition (7). The investigators are to be commended on the institution of a management protocol that resulted in only 6–16% deviations, proving that standardized approaches are clinically feasible. The advantage of such protocols is the resulting ability to study other interventions aimed at improving the outcomes of PExs without having to control for an endless number of variables. Standardized approaches to the management of CF PExs will become increasingly important as the decreased incidence of exacerbations associated with highly effective modulator therapy limits the sample size available for study (8). Although there will always be certain patients requiring unique, individualized treatment plans, the guidance provided by Goss and colleagues on antibiotic treatment duration will aid in the design of future CF PEx trials.

The choice of primary outcome in this study, change in FEV₁ from start of antibiotics to 2 weeks after ending antibiotics, has certain limitations. Although the absolute change in FEV₁ from start to end of therapy may be the most direct measure of an intervention, the primary driver of this change is the initial drop in FEV₁ from baseline, with greater drops associated with greater increases from Day 0 to end of treatment (9, 10). Within the early responders and non–early responders, the FEV₁ drop from baseline was similar between treatment arms. However, between the groups, the drop was very different, on average 9% in the early responder group and 2% in the non–early responder group. These data highlight the differences between the two study populations and, as the authors correctly point out, does not mean that one can infer that 10 days would be equivalent to 21 days of antibiotic treatment. These differences also beg the question as to why intravenous antibiotics were initially started in the non–early responder group with only a 2% drop in FEV₁ from baseline and whether an increase in FEV₁ was the appropriate measure of clinical response. The non–early responders would seem to represent a different exacerbation phenotype, perhaps not driven by an infective process, given the minimal change in lung function with prolonged antibiotic therapy. Clinical assessment of lung function and symptom scores should thus occur at the interim time point 7–10 days into antibiotic treatment to distinguish these patient populations and apply the findings of the current study.

We still do not know whether these observations apply to patients with frequent, recurrent exacerbations, those with end-stage lung disease, or children with CF, our most vulnerable populations. Nor do we know how to improve the outcomes of those who do not respond to traditional PEx antimicrobial therapy. However, by defining a standardized antibiotic duration for CF PExs, the results of the STOP2 trial by Dr. Goss and colleagues have the potential to improve quality of life for individuals with CF by minimizing antimicrobial exposure as well as providing the infrastructure on which to investigate new treatment modalities. Two steps forward.