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Pharmacodynamic Attainment of the Synergism of Meropenem and Fosfomycin Combination against Pseudomonas aeruginosa Producing Metallo-ß-Lactamase.
Albiero, James; Mazucheli, Josmar; Barros, Juliana Pimenta Dos Reis; Szczerepa, Marcia Maria Dos Anjos; Nishiyama, Sheila Alexandra Belini; Carrara-Marroni, Floristher Elaine; Sy, Serubbabel; Fidler, Matthew; Sy, Sherwin K B; Tognim, Maria Cristina Bronharo.
Afiliación
  • Albiero J; Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Paraná, Brazil.
  • Mazucheli J; Programa de Pós-Graduação em Bioestatística, Departamento de Estatística, Universidade Estadual de Maringá, Paraná, Brazil.
  • Barros JPDR; Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Paraná, Brazil.
  • Szczerepa MMDA; Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Paraná, Brazil.
  • Nishiyama SAB; Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Paraná, Brazil.
  • Carrara-Marroni FE; Departamento de Patologia, Análises Clínicas e Toxicológicas, Universidade Estadual de Londrina, Paraná, Brazil.
  • Sy S; Department of Chemical Engineering, University of Waterloo, Waterloo, Ontario, Canada.
  • Fidler M; Novartis Pharmaceuticals Corporation, Fort Worth, Texas, USA.
  • Sy SKB; Programa de Pós-Graduação em Bioestatística, Departamento de Estatística, Universidade Estadual de Maringá, Paraná, Brazil.
  • Tognim MCB; Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Paraná, Brazil mcbtognim@uem.br.
Article en En | MEDLINE | ID: mdl-30910903
Fosfomycin combined with other antimicrobials has shown good efficacy against multidrug-resistant (MDR) bacteria in both in vitro and clinical studies; however, the activity of fosfomycin combined with other antimicrobials against metallo-ß-lactamase (MBL)-producing Pseudomonas aeruginosa strains has not been tested. The objective of this study was to determine the synergism and optimal intravenous dosing regimens of fosfomycin with meropenem against MDR and MBL-producing P. aeruginosa strains. The MICs of both antimicrobials were determined by the checkerboard method and analyzed by two synergism tests with 19 clones of P. aeruginosa isolates, 10 of which were MBL producers. A pharmacodynamic (PD) analysis was performed for meropenem (administered at 1 g every 8 h [q8h], 1.5 g every 6 h [q6h], and 2 g q8h) and fosfomycin (administered at 4 g q8h, 4 g q6h, 6 g q8h, and 8 g q8h) regimens with a dose reduction for renal impairment by determining the probability of target attainment (PTA) for target PD indices of meropenem (the percentage of the time in a 24-h duration at which the free drug concentration remains above the MIC [fT>MIC], ≥40%) and fosfomycin (the ratio of the area under the free drug concentration-versus-time curve over 24 h and the MIC [fAUC/MIC], ≥40.8). The combination reduced the MIC50 and MIC90 by 8-fold. Seven (44%) isolates with MICs in the intermediate or resistant ranges became sensitive to meropenem. For the MBL-producing isolates, the combination resulted in 40% of isolates becoming sensitive to meropenem. The meropenem regimens reached a PTA of ≥90% (MIC = 4 µg/ml) in 6 (32%) isolates when they were used as monotherapy and 13 (68%) isolates when they were combined with fosfomycin. None of the fosfomycin monotherapy regimens reached the PTA of ≥90% (MIC = 16 µg/ml). When combined with meropenem, the fosfomycin regimens reached the PTA of ≥90% in 14 (74%) isolates. The increase in pharmacodynamic activities resulting from the synergistic action of meropenem with fosfomycin demonstrates the potential relevance of this combination to fight infections caused by MDR and MBL-producing P. aeruginosa strains.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pseudomonas aeruginosa / Infecciones por Pseudomonas / Beta-Lactamasas / Fosfomicina / Meropenem / Antibacterianos Límite: Adult / Female / Humans / Male Idioma: En Revista: Antimicrob Agents Chemother Año: 2019 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pseudomonas aeruginosa / Infecciones por Pseudomonas / Beta-Lactamasas / Fosfomicina / Meropenem / Antibacterianos Límite: Adult / Female / Humans / Male Idioma: En Revista: Antimicrob Agents Chemother Año: 2019 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Estados Unidos