Optimization of polymyxin B regimens for the treatment of carbapenem-resistant organism nosocomial pneumonia: a real-world prospective study

Abstract

Background: Polymyxin B is the first-line therapy for Carbapenem-resistant organism (CRO) nosocomial pneumonia. However, clinical data for its pharmacokinetic/pharmacodynamic (PK/PD) relationship are limited. This study aimed to investigate the relationship between polymyxin B exposure and efficacy for the treatment of CRO pneumonia in critically ill patients, and to optimize the individual dosing regimens.

Methods: Patients treated with polymyxin B for CRO pneumonia were enrolled. Blood samples were assayed using a validated high-performance liquid chromatography-tandem mass spectrometry method. Population PK analysis and Monte Carlo simulation were performed using Phoenix NLME software. Logistic regression analyses and receiver operating characteristic (ROC) curve were employed to identify the significant predictors and PK/PD indices of polymyxin B efficacy.

Results: A total of 105 patients were included, and the population PK model was developed based on 295 plasma concentrations. AUC_{ss,24 h}/MIC (AOR = 0.97, 95% CI 0.95-0.99, p = 0.009), daily dose (AOR = 0.98, 95% CI 0.97-0.99, p = 0.028), and combination of inhaled polymyxin B (AOR = 0.32, 95% CI 0.11-0.94, p = 0.039) were independent risk factors for polymyxin B efficacy. ROC curve showed that AUC_{ss,24 h}/MIC is the most predictive PK/PD index of polymyxin B for the treatment of nosocomial pneumonia caused by CRO, and the optimal cutoff point value was 66.9 in patients receiving combination therapy with another antimicrobial. Model-based simulation suggests that the maintaining daily dose of 75 and 100 mg Q12 h could achieve ≥ 90% PTA of this clinical target at MIC values ≤ 0.5 and 1 mg/L, respectively. For patients unable to achieve the target concentration by intravenous administration, adjunctive inhalation of polymyxin B would be beneficial.

Conclusions: For CRO pneumonia, daily dose of 75 and 100 mg Q12 h was recommended for clinical efficacy. Inhalation of polymyxin B is beneficial for patients who cannot achieve the target concentration by intravenous administration.

Keywords: Carbapenem-resistant organism; Dosing optimization; Nosocomial pneumonia; Pharmacokinetic/pharmacodynamic; Polymyxin B.

Fig. 1

Goodness-of-fit plots for the final population pharmacokinetic model. A Polymyxin B concentration versus population predicted concentrations (PRED); B Polymyxin B concentration versus individual predicted concentrations (IPRED); C Conditional weighted residuals versus population predicted concentrations (CWRES vs. PRED); D Conditional weighted residuals versus time (CWRES vs. Time); The blue lines in panels (C, D) represent smoothed regression lines

Fig. 2

The prediction corrected-visual predictive check (pc-VPC) of the final population PK model. The red and black lines represent the 5th, 50th and 95th quantiles of the observed and predicted concentration, and the shaded area represents the simulation-based 90% confidence intervals

Fig. 3

ROC of the final multivariate logistic regression model

Fig. 4

The area under the ROC curve of polymyxin B PK/PD indices in prediction of clinical efficacy

Fig. 5

Comparison of clinical efficacy rates of polymyxin B in different subgroups. IV, intravenous polymyxin B; IH, inhaled polymyxin B; * represented p < 0.05

Fig. 6

Probability of target attainment (PTA) for polymyxin B regimens on day 1 (A) and day 4 (B)