In vivo exposure-response relationship of meropenem against metallo-ß-lactamase-harbouring Pseudomonas aeruginosa: an assessment using MICs from conventional and zinc-limited broth.

OBJECTIVES: Previous investigations into metallo-ß-lactamase (MBL)-harbouring Enterobacterales suggest that susceptibility testing in zinc-limited media may be more appropriate in predicting ß-lactam in vivo activity. There are limited data with MBL-harbouring Pseudomonas aeruginosa. METHODS: Forty-three MBL-harbouring P. aeruginosa isolates (IMP, n = 11; VIM, n = 12; NDM, n = 10; SPM, n = 10) and two P. aeruginosa control isolates (KPC, n = 1; WT, n = 1) were evaluated. Meropenem activity was evaluated in the murine neutropenic thigh model using humanized exposures. Susceptibility testing was conducted in conventional CAMHB, EDTA-supplemented CAMHB (3-300 mg/L EDTA) and Chelex-treated CAMHB (0-1.0 mg/L re-supplemented zinc), resulting in a range of meropenem MIC values for each isolate. A sigmoidal Emax model was fitted to fT>MIC versus change in log10 cfu/thigh to estimate the goodness of fit (R2). RESULTS: Increasing EDTA concentrations or limiting the amount of zinc in broth resulted in several-fold reductions in MIC among the majority of the MBL-harbouring P. aeruginosa while the MICs for the KPC and WT isolates were unchanged. Bacterial killing in vivo was variable, with the range of killing spanning -3.29 to +4.81 log10 change in cfu/thigh. Addition of 30 mg/L EDTA and Chelex-treated CAMHB (with no zinc supplementation) provided broth conditions for susceptibility testing that best predicted in vivo efficacy (R2 > 0.7). CONCLUSIONS: Among MBL-harbouring P. aeruginosa, meropenem in vivo efficacy is best represented by the pharmacodynamic profile generated using MICs determined in EDTA-supplemented or zinc-limited broth. In addition to previous data with Enterobacterales, antibiotic susceptibility testing in media that approximates physiological conditions makes it possible to uncover potential and existing therapeutic agents.

Unresolved issues in the identification and treatment of carbapenem-resistant Gram-negative organisms.

PURPOSE OF REVIEW: Carbapenem-resistant organisms (CROs), including Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacterales, are a threat worldwide. This review will cover mechanisms of resistance within CROs and challenges with identification and treatment of these organisms while pointing out unresolved issues and ongoing challenges. RECENT FINDINGS: The treatment of CROs has expanded through newer therapeutic options. Guided utilization through genotypic and phenotypic testing is necessary in order for these drugs to target the appropriate mechanisms of resistance and select optimal antibiotic therapy. SUMMARY: Identification methods and treatment options need to be precisely understood in order to limit the spread and maximize outcomes of CRO infections.