Background: Evidence supports therapeutic drug monitoring of polymyxin B, but clinical data for establishing an area under the concentration–time curve across 24 h at steady state (AUC_ss,24 h) threshold are still limited. This study aimed to examine exposure–response/toxicity relationship for polymyxin B to establish an AUC_ss,24 h threshold in a real-world cohort of patients. Methods: Using a validated Bayesian approach to estimate AUC_ss,24 h from two samples, AUC_ss,24 h threshold that impacted the risk of polymyxin B-related nephrotoxicity and clinical response were derived by classification and regression tree (CART) analysis and validated by Cox regression analysis and logical regression analysis. Results: A total of 393 patients were included; acute kidney injury (AKI) was 29.0%, clinical response was 63.4%, and 30-day all-cause mortality was 35.4%. AUC_ss,24 h thresholds for AKI of > 99.4 mg h/L and clinical response of > 45.7 mg h/L were derived by CART analysis. Cox and logical regression analyses showed that AUC_ss,24 h of > 100 mg h/L was a significant predictor of AKI (HR 16.29, 95% CI 8.16–30.25, P < 0.001) and AUC_ss,24 h of ≥ 50 mg h/L (OR 4.39, 95% CI 2.56–7.47, P < 0.001) was independently associated with clinical response. However, these exposures were not associated with mortality. In addition, the correlation between trough concentration (1.2–2.8 mg/L) with outcomes was similar to AUC_ss,24 h. Conclusions: For critically ill patients, AUC_ss,24 h threshold of 50–100 mg h/L was associated with decreased nephrotoxicity while assuring clinical efficacy. Therapeutic drug monitoring is recommended for individualizing polymyxin B dosing.

Pharmacokinetics/pharmacodynamics is the foundation for guiding the rational application of antibiotics in clinical practice, so it is necessary to establish quantitative methods for accurate drug concentration determination. This study aimed to develop a rapid and simple ultrahigh‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) method for simultaneous quantification of 14 antibiotics (amikacin, etimicin, ceftazidime, cefepime, cefoperazone, ceftriaxone, daptomycin, latamoxef, linezolid, meropenem, biapenem, ampicillin, norvancomycin, and vancomycin) in human plasma and cerebrospinal fluid. Antibiotics were chromatographically separated on a Waters ACQUITY UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) via gradient elution within 3 minutes and were monitored using positive ion fitted with multiple reaction monitoring. The lower limit of quantification was 0.05–2.0 μg·mL⁻¹. The method was verified according to the FDA bioanalysis method validation guidelines, which showed excellent accuracy (from 86.75% to 110.85%) and precision (from 0.46% to 10.97%). At last, this method was successfully applied to therapeutic drug monitoring in 113 patients under antibiotics treatment.

Purpose: Limited data are available on the characteristics, risk factors, and antimicrobial treatment of critically ill pediatric patients with carbapenem-resistant Enterobacteriaceae (CRE) infections. This study was to identify the risk factors for 30-day mortality in pediatric intensive care unit (PICU) patients with CRE infections and compare the clinical outcomes of different antimicrobial regimens. Methods: A retrospective, observational cohort study was performed on patients admitted to the PICU with positive CRE cultures between January 2016 and December 2021. Results: For the 56 patients, the overall 30-day mortality was 50% (n=28). Multivariable logistic regression analysis revealed that pediatric critical illness score (PCIS; HR = 0.879; 95% CI, 0.827– 0.935; P < 0.001) and serum albumin levels (HR = 0.921; 95% CI, 0.860– 0.987; P = 0.019) were independently associated with 30-day mortality. At the same time, there was no significant difference in 30-day mortality (42.9% versus 45.5%, P = 0.854) or clinical efficiency rate (53.4% versus 40.9%, P = 0.374) between with and without polymyxin B therapy. Conclusion: The study revealed PCIS and serum albumin levels were the independent mortality-related risk factors of CRE infections in critically ill pediatric patients. Treatment with polymyxin B could not reduce 30-day mortality. Future prospective cohort studies are needed to investigate the optimal antimicrobial regimens for CRE infection in PICU patients.