Assessing time to pulmonary function benefit following antibiotic treatment of acute cystic fibrosis exacerbations

Abstract

Background: Cystic Fibrosis (CF) is a life-shortening genetic disease in which ~80% of deaths result from loss of lung function linked to inflammation due to chronic bacterial infection (principally Pseudomonas aeruginosa). Pulmonary exacerbations (intermittent episodes during which symptoms of lung infection increase and lung function decreases) can cause substantial resource utilization, morbidity, and irreversible loss of lung function. Intravenous antibiotic treatment to reduce exacerbation symptoms is standard management practice. However, no prospective studies have identified an optimal antibiotic treatment duration and this lack of objective data has been identified as an area of concern and interest.

Methods: We have retrospectively analyzed pulmonary function response data (as forced expiratory volume in one second; FEV1) from a previous blinded controlled CF exacerbation management study of intravenous ceftazidime/tobramycin and meropenem/tobramycin in which spirometry was conducted daily to assess the time course of pulmonary function response.

Results: Ninety-five patients in the study received antibiotics for at least 4 days and were included in our analyses. Patients received antibiotics for an average of 12.6 days (median = 13, SD = 3.2 days), with a range of 4 to 27 days. No significant differences were observed in mean or median treatment durations as functions of either treatment group or baseline lung disease stage. Average time from initiation of antibiotic treatment to highest observed FEV1 was 8.7 days (median = 10, SD = 4.0 days), with a range of zero to 19 days. Patients were treated an average of 3.9 days beyond the day of peak FEV1 (median = 3, SD = 3.8 days), with 89 patients (93.7%) experiencing their peak FEV1 improvement within 13 days. There were no differences in mean or median times to peak FEV1 as a function of treatment group, although the magnitude of FEV1 improvement differed between groups.

Conclusions: Our results suggest that antibiotic response to exacerbation as assessed by pulmonary function is essentially complete within 2 weeks of treatment initiation and relatively independent of the magnitude of pulmonary function response observed.

Figure 1

Distribution of antibiotic treatment durations. The gray bars show the distribution of antibiotic treatment duration in days for the 95 study patients (left vertical axis). The black line represents the cumulative percentage of patients having completed treatment by a given duration (right vertical axis).

Figure 2

Treatment duration and time to peak response by subgroups. Box and whisker plots of antibiotic treatment duration (white boxes) and time to peak observed FEV₁ measure (gray boxes) among patients stratified by antibiotic treatment (ceftaz/tobra and mero/tobra) and by lung disease stage (FEV₁ ≥ 70% predicted, 40- 69% predicted, and <40% predicted).

Figure 3

Time from antibiotic treatment initiation to peak FEV₁ measure for subgroups. Panel A, Time to peak FEV₁ measure stratified by antibiotic treatment assignment. Gray line, ceftaz/tobra; black line, mero/tobra; dotted line, population treatment duration. Panel B. Time to peak FEV₁ measure stratified by baseline lung function. Gray line, patients with baseline FEV₁ ≥ 70% predicted, black line, patients with baseline FEV₁ between 40% and 69% predicted; dashed line, patients with baseline FEV₁ < 40% predicted; dotted line, population treatment duration.

Figure 4

Average daily change in FEV₁ from baseline by treatment group. Gray circles, patients treated with ceftaz/tobra. Open circles, patients treated with mero/tobra. Sample sizes for measures are in parentheses.