An Observational Cohort Study of Targeted Antibiotic Treatments of Cystic Fibrosis Exacerbations

Cystic fibrosis (CF) pulmonary exacerbations shorten survival. Treatment guidelines omit minimal inhibitory concentration (MIC)-based antibiotic dose selection. We tested whether MIC-guided intravenous antibiotic strategies prolong time between exacerbations.

We retrospectively studied randomly chosen intravenous antibiotic-treated pulmonary exacerbations from 2015 to 2018, followed through 2021. Using pre-admission sputum culture-derived MICs to select dosing targets, we estimated measured:target ratios for β-lactam steady-state and aminoglycoside area under the curve pharmacokinetics. We used Kaplan-Meier and Cox proportional hazards methods to test whether measured:target ratios were associated with time to next exacerbation. We evaluated serial laboratory measurements with linear mixed-effects models for adverse events. We tested model sensitivities to concurrent treatments and severe acute respiratory syndrome coronavirus 2 pandemic-related events.

Compared with measured:target ratios ≤1, β-lactam ratios >1 were associated with a median of 19 more (from 204 to 223) exacerbation-free days (91 exacerbations; hazard ratio [HR], 0.60; 95% CI, 0.37-0.99; P = .045); aminoglycoside ratios >1 were associated with a median of 83 more (from 153 to 236) exacerbation-free days (65 exacerbations; HR, 0.54; 95% CI, 0.31-0.93; P = .026); both antibiotic ratios >1 simultaneously were associated with a median of 210 more (from 185 to 396) exacerbation-free days (60 exacerbations; HR, 0.33; 95% CI, 0.15-0.71; P = .004). No toxic antibiotic levels and few adverse laboratory or clinical events occurred. Models were insensitive to other treatments and pandemic events.

MIC-guided antibiotic dosing prolongs time between pulmonary exacerbations with few adverse events. Reduced exacerbation frequency predicts better survival and may improve quality of life for people with CF.