In vivo exposure-response relationship of meropenem against metallo-ß-lactamase-harbouring Pseudomonas aeruginosa: an assessment using MICs from conventional and zinc-limited broth.
J Antimicrob Chemother
; 77(7): 1938-1948, 2022 06 29.
Article
em En
| MEDLINE
| ID: mdl-35488847
ABSTRACT
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, nâ=â11; VIM, nâ=â12; NDM, nâ=â10; SPM, nâ=â10) and two P. aeruginosa control isolates (KPC, nâ=â1; WT, nâ=â1) 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 (3-300â mg/L EDTA) and Chelex-treated CAMHB (0-1.0â 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 log10â 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 +4.81â log10 change in cfu/thigh. Addition of 30â mg/L EDTA and Chelex-treated CAMHB (with no zinc supplementation) provided broth conditions for susceptibility testing that best predicted in vivo efficacy (R2â>â0.7).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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pseudomonas aeruginosa
/
Meropeném
/
Antibacterianos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Antimicrob Chemother
Ano de publicação:
2022
Tipo de documento:
Article