title: Evaluation of meropenem regimens suppressing emergence of resistance in Acinetobacter baumannii with human simulated exposure in an in vitro intravenous-infusion hollow-fiber infection model.
abstract: The emergence of resistance to carbapenems in Pseudomonas aeruginosa can be suppressed by optimizing the administration of meropenem. However, whether the same is true for Acinetobacter baumannii is not fully understood. We assessed the bactericidal activity of meropenem and its potency to suppress the emergence of resistance in A. baumannii with human simulated exposure in an in vitro intravenous-infusion hollow-fiber infection model (HFIM). Two clinical strains of carbapenem-susceptible multidrug-resistant A. baumannii (CS-MDRAB), CSRA24 and CSRA91, were used, and their MICs and mutant prevention concentrations (MPCs) were determined. Six meropenem dosage regimens (0.5, 1.0, or 2.0 g given every 8 h [q8h] with a 0.5-h or 3-h infusion for seven consecutive days) were simulated and then evaluated in the HFIM. Both the total population and resistant subpopulations of the two strains were quantified. Drug concentrations were measured by high-performance liquid chromatography. All dosage regimens, except for the lowest dosage (0.5 g for both the 0.5-h and 3-h infusions), showed 3-log CFU/ml bacterial killing. Dosage regimens of 2.0 g with 0.5-h and 3-h infusions exhibited an obvious bactericidal effect and suppressed resistance. Selective amplification of subpopulations with reduced susceptibility to meropenem was suppressed with a percentage of the dosage interval in which meropenem concentrations exceeded the MPC (T>MPC) of ≥20% or with a ratio of T>MPC to the percentage of the dosage interval in which drug concentrations are within the mutant selection window of ≥0.25. Our in vitro data support the use of a high dosage of meropenem (2.0 g q8h) for the treatment of severe infection caused by CS-MDRAB.
authors.affiliation: Clinical Application Research Center of Antibiotics, The Third Hospital of Changsha, Changsha, Hunan, China School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Clinical Application Research Center of Antibiotics, The Third Hospital of Changsha, Changsha, Hunan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Clinical Application Research Center of Antibiotics, The Third Hospital of Changsha, Changsha, Hunan, China.
authors.forename: Xian-Jia
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Clinical Application Research Center of Antibiotics, The Third Hospital of Changsha, Changsha, Hunan, China.
authors.forename: Wei-Tao
authors.initials: WT
authors.lastname: Gong
authors.affiliation: Clinical Application Research Center of Antibiotics, The Third Hospital of Changsha, Changsha, Hunan, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Clinical Application Research Center of Antibiotics, The Third Hospital of Changsha, Changsha, Hunan, China.
authors.forename: Ying-Qun
authors.initials: YQ
authors.lastname: Zhu
authors.affiliation: Clinical Application Research Center of Antibiotics, The Third Hospital of Changsha, Changsha, Hunan, China lwlwtg@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D013845:Thienamycins / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D013845:Thienamycins; D000077731:Meropenem