title: Pharmacodynamic Evaluation of the Potential Clinical Utility of Fosfomycin and Meropenem in Combination Therapy against KPC-2-Producing Klebsiella pneumoniae.
abstract: KPC-producing Klebsiella pneumoniae causes serious infections associated with high death rates worldwide. Combination therapy consisting of fosfomycin and a carbapenem is better than monotherapy to combat multidrug-resistant microorganisms, but no dosages for the combination have been defined. The MICs of meropenem and fosfomycin were evaluated against 18 clinical isolates of KPC-2-producing K. pneumoniae The activities of combination antimicrobials were also determined by the checkerboard method. The MIC50 and MIC90 of each agent alone and in combination were challenged against short (1.5-h) or prolonged (3-h) infusion regimens of meropenem (1 g every 8 h [q8h], 1.5 g q6h, 2 g q8h) and fosfomycin (4 g q8h, 6 g q6h, 8 g q8h) by Monte Carlo simulation to evaluate the time above the MIC of the free drug concentration as a percentage of the dosing interval (fT>MIC). The monotherapy MIC50s and MIC90s were 32 and 256 mg/liter for meropenem and 64 and 512 mg/liter for fosfomycin, respectively. Antimicrobial combination increased bacterial susceptibility to 1/4 the MIC50s and to 1/8 to 1/16 the MIC90s of monotherapy. The antimicrobial combination demonstrated a synergistic effect for at least two-thirds of the isolates. In combination therapy, fosfomycin regimens of 6 g q6h and 8 g q8h as a 3-h infusion against the MIC50 and MIC90 had better chances of achieving ≥90% probability of target attainment (PTA) of 70% fT>MIC. Meropenem regimens of 1.5 g q6h and 2 g q8h in prolonged infusion can achieve close to 90% PTA of 40% fT>MIC for MIC50 but not MIC90 The significant reduction in the MIC values and the achievement of appropriate PTA demonstrated that regimens containing fosfomycin with meropenem can be effective against KPC-2-producing K. pneumoniae.
authors.affiliation: Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, PR, Brazil jamesalbiero1@gmail.com mcbtognim@uem.br.
authors.forename: James
authors.initials: J
authors.lastname: Albiero
authors.affiliation: Programa de Pós-Graduação em Bioestatística, Departamento de Estatística, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: Sherwin K B
authors.initials: SK
authors.lastname: Sy
authors.affiliation: Programa de Pós-Graduação em Bioestatística, Departamento de Estatística, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: Josmar
authors.initials: J
authors.lastname: Mazucheli
authors.affiliation: Departmento de Farmacologia e Terapêutica, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: Silvana Martins
authors.initials: SM
authors.lastname: Caparroz-Assef
authors.affiliation: Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: Bruno Buranello
authors.initials: BB
authors.lastname: Costa
authors.affiliation: Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: Janio Leal Borges
authors.initials: JL
authors.lastname: Alves
authors.affiliation: Laboratório Alerta, Divisão de Doenças Infecciosas, Departamento de Medicina Interna, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Gales
authors.affiliation: Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, PR, Brazil jamesalbiero1@gmail.com mcbtognim@uem.br.
authors.forename: Maria Cristina Bronharo
authors.initials: MC
authors.lastname: Tognim
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D005578:Fosfomycin / Q000494:pharmacology*; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology*; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D013845:Thienamycins / Q000494:pharmacology*; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D005578:Fosfomycin; D001618:beta-Lactamases; D000077731:Meropenem