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Pharmacokinetic-Pharmacodynamic Target Attainment Analyses as Support for Meropenem-Vaborbactam Dosing Regimens and Susceptibility Breakpoints.
Bhavnani, S M; Trang, M; Griffith, D C; Lomovskaya, O; Hammel, J P; Loutit, J S; Cammarata, S K; Dudley, M N; Ambrose, P G; Rubino, C M.
Afiliación
  • Bhavnani SM; Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.
  • Trang M; Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.
  • Griffith DC; Rempex Pharmaceuticals, San Diego, California, USA.
  • Lomovskaya O; Rempex Pharmaceuticals, San Diego, California, USA.
  • Hammel JP; Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.
  • Loutit JS; Rempex Pharmaceuticals, San Diego, California, USA.
  • Cammarata SK; Melinta Therapeutics, Inc., Lincolnshire, Illinois, USA.
  • Dudley MN; Rempex Pharmaceuticals, San Diego, California, USA.
  • Ambrose PG; Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.
  • Rubino CM; Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.
Antimicrob Agents Chemother ; 66(12): e0213021, 2022 12 20.
Article en En | MEDLINE | ID: mdl-36374023
Meropenem-vaborbactam is a fixed-dose beta-lactam/beta-lactamase inhibitor with potent in vitro and in vivo activity against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken using population pharmacokinetic models, nonclinical PK-PD targets for efficacy, in vitro surveillance data, and simulation to provide support for 2 g meropenem-2 g vaborbactam every 8 h (q8h) administered as a 3-h intravenous (i.v.) infusion, and dosing regimens adjusted for patients with renal impairment. Simulated patients varying by renal function measure (estimated glomerular filtration rate [eGFR], mL/min/1.73 m2 and absolute eGFR, mL/min) and resembling the clinical trial population (complicated urinary tract infection, including acute pyelonephritis) were generated. The PK-PD targets for meropenem, the percentage of time on day 1 that free-drug plasma concentrations were above the MIC (%T>MIC), and vaborbactam, the ratio of free-drug plasma area under the concentration-time curve (AUC) on day 1 to the MIC (AUC:MIC ratio), were calculated. Percent probabilities of achieving meropenem free-drug plasma %T>MIC and vaborbactam free-drug plasma AUC:MIC ratio targets were assessed. MIC distributions for Enterobacterales, KPC-producing Enterobacterales, and Pseudomonas aeruginosa were considered as part of an algorithm to assess PK-PD target attainment. For assessments of free-drug plasma PK-PD targets associated with a 1-log10 CFU reduction from baseline, percent probabilities of PK-PD target attainment ranged from 81.3 to 100% at meropenem-vaborbactam MIC values of 4 or 8 µg/mL among simulated patients. The results of these PK-PD target attainment analyses provide support for a dosing regimen of 2 g meropenem-2 g vaborbactam q8h administered as a 3-h i.v. infusion, with dosing regimens adjusted for patients with renal impairment and a meropenem-vaborbactam susceptibility breakpoint of ≤8 µg/mL (tested with a fixed vaborbactam concentration of 8 µg/mL) for Enterobacterales and P. aeruginosa based on these dosing regimens.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Infecciones Urinarias / Antibacterianos Límite: Humans Idioma: En Revista: Antimicrob Agents Chemother Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Infecciones Urinarias / Antibacterianos Límite: Humans Idioma: En Revista: Antimicrob Agents Chemother Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos