Colistin plasma concentrations are not associated with better clinical outcomes in patients with pneumonia caused by extremely drug-resistant Pseudomonas aeruginosa

Abstract

ABSTRACT The objective of this study was to examine the relationship between colistin plasma concentrations and clinical outcomes in patients with hospital-acquired pneumonia (HAP) caused by extensively drug-resistant Pseudomonas aeruginosa (XDR-PA). A prospective observational cohort study was conducted at a tertiary care hospital. Patients diagnosed with HAP caused by XDR-PA between January 2010 and September 2018 were included. Steady-state plasma concentrations (C ss,avg) of colistin were measured by high performance liquid chromatography (HPLC). Based on the pharmacokinetic/pharmacodynamic data of colistin in animal models, previous clinical data, and the minimum inhibitory concentration (MIC) of the most prevalent strain in our center, an area under the ROC curve (AUC)/MIC24h between 30 and 60 mg·h/L was considered optimal. The primary outcome was 30-day mortality, and the secondary outcomes were clinical cure and colistin-associated nephrotoxicity. Seventy-five patients were included. The median C ss,avg was 1.1 (0.56–1.75) mg/L and only 23 (30.7%) patients achieved an AUC/MIC24h of 30–60 mg·h/L and the 30-day mortality was 30.7%. In multivariate analysis, sequential organ failure assessment score [adjusted hazard ratio (95% confidence interval, CI) 1.19 (1.07–1.32)] and high AUC/MIC24h (hazard ratio 1.55, 95% CI 1.17–2.04, P = 0.002) were associated with increased risk of death and clinical failure. Based on the maximally selected standardized log-rank statistic, the C ss,avg cutoff point that best predicted mortality was 1.5 mg/L. Nephrotoxicity at the end of treatment was 38.7%. High colistin exposure was not associated with improved clinical outcomes in the setting of HAP caused by XDR-PA. These data suggest that caution is required with intravenous colistin for the treatment of HAP caused by XDR-PA. IMPORTANCE In some cases, colistin is the only treatment option for infections caused by the very drug-resistant Pseudomonas aeruginosa. However, in the past decade, there have been questions concerning its pharmacokinetics and concentration at the site of infection. In this scenario, its use in a difficult-to-treat infection like pneumonia is currently debatable. This is a clinical pharmacokinetic study of colistin in patients with multidrug-resistant P. aeruginosa pneumonia. Our findings demonstrate that colistin exposure is associated with worse clinical outcomes rather than better clinical outcomes, implying that other therapeutic options should be explored in this clinical setting.

Keywords

• Pseudomonas aeruginosa
• pneumonia
• colistin
• pharmacokinetics