title: Strategies for the treatment of polymyxin B-resistant Acinetobacter baumannii infections.
abstract: In this study, the activity of meropenem (MEM), fosfomycin (FOF) and polymyxin B (PMB), alone and in combination, was analysed. In addition, optimisation of the pharmacodynamic index of MEM and FOF against six isolates of OXA-23-producing Acinetobacter baumannii (including three resistant to PMB) that were not clonally related was assessed. Antimicrobial combinations were evaluated by chequerboard analysis and were considered synergistic when the fractional inhibitory concentration index (FICI) was ≤0.5. Pharmacodynamic analyses of the MEM and FOF dosing schemes were performed by Monte Carlo simulation. The target pharmacodynamic index (%ƒT>MIC) for MEM and FOF was ≥40% and ≥70%, respectively, and a probability of target attainment (PTA) ≥0.9 was considered adequate. Among the PMB-resistant isolates, combinations of PMB+MEM and PMB+FOF+MEM showed the highest synergistic activity (FICI ≤0.125); isolates that were previously PMB-resistant were included in the susceptible category using CLSI interpretive criteria. Pharmacodynamic evaluation found that for a FOF minimum inhibitory concentration (MIC) of ≤16μg/mL, treatment both by bolus dosing and prolonged infusion achieved adequate PTA, whilst for MIC=32μg/mL only infusion achieved adequate PTA. For a MEM MIC of 4μg/mL, only the bolus treatment scheme with 1.5g q6h and the infusion schemes with 1.0g q8h, 1.5g q6h and 2.0g q8h achieved PTA ≥0.9. Results of antimicrobial and pharmacodynamic analyses can assist in treating infections caused by multidrug-resistant A. baumannii. However, in vivo clinical studies are essential to evaluate the true role of these compounds, including intravenous antimicrobial FOF therapy.
authors.affiliation: Universidade Estadual de Maringá, Avenida Colombo 5790, CEP 87020-900 Maringá, Paraná, Brazil.
authors.forename: Thatiany Cevallos
authors.initials: TC
authors.lastname: Menegucci
authors.affiliation: Universidade Estadual de Maringá, Avenida Colombo 5790, CEP 87020-900 Maringá, Paraná, Brazil.
authors.forename: James
authors.initials: J
authors.lastname: Albiero
authors.affiliation: Universidade Estadual de Maringá, Avenida Colombo 5790, CEP 87020-900 Maringá, Paraná, Brazil.
authors.forename: Letícia Busato
authors.initials: LB
authors.lastname: Migliorini
authors.affiliation: Universidade Estadual de Maringá, Avenida Colombo 5790, CEP 87020-900 Maringá, Paraná, Brazil.
authors.forename: Janio Leal Borges
authors.initials: JL
authors.lastname: Alves
authors.affiliation: Universidade Estadual de Maringá, Avenida Colombo 5790, CEP 87020-900 Maringá, Paraná, Brazil.
authors.forename: Giselle Fukita
authors.initials: GF
authors.lastname: Viana
authors.affiliation: Universidade Estadual de Maringá, Avenida Colombo 5790, CEP 87020-900 Maringá, Paraná, Brazil.
authors.forename: Josmar
authors.initials: J
authors.lastname: Mazucheli
authors.affiliation: Universidade Estadual de Londrina, Rodovia Celso Garcia Cid, Pr 445 Km 380, CEP 86.057-970 Londrina, Paraná, Brazil.
authors.forename: Floristher Elaine
authors.initials: FE
authors.lastname: Carrara-Marroni
authors.affiliation: Universidade Estadual de Maringá, Avenida Colombo 5790, CEP 87020-900 Maringá, Paraná, Brazil.
authors.forename: Celso Luiz
authors.initials: CL
authors.lastname: Cardoso
authors.affiliation: Universidade Estadual de Maringá, Avenida Colombo 5790, CEP 87020-900 Maringá, Paraná, Brazil. Electronic address: mcbtognim@uem.br.
authors.forename: Maria Cristina Bronharo
authors.initials: MC
authors.lastname: Tognim
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000302:isolation & purification; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D005578:Fosfomycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D011112:Polymyxin B / Q000493:pharmacokinetics / Q000494:pharmacology*; D013845:Thienamycins / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D005578:Fosfomycin; D000077731:Meropenem; D011112:Polymyxin B
keywords: Acinetobacter baumannii; Antimicrobial combination; Pharmacodynamic; Polymyxin B; Resistant