title: Pharmacokinetic-pharmacodynamic modelling of meropenem against VIM-producing Klebsiella pneumoniae isolates: clinical implications.
abstract: VIM-producing Klebsiella pneumoniae isolates are usually associated with high MICs to carbapenems. Preclinical studies investigating the pharmacokinetic-pharmacodynamic (PK-PD) characteristics of carbapenems against these isolates are lacking. The in vitro antibacterial activity of meropenem against one WT and three VIM-producing K. pneumoniae clinical isolates (median MICs 0.031, 8, 16 and 128 mg l- 1) was studied in a dialysis-diffusion PK-PD model and verified in a thigh infection neutropenic animal model by testing selected strains and exposures. The in vitro PK-PD target associated with bactericidal activity was estimated and the target attainment for different dosing regimens was calculated with Monte Carlo analysis. The in vitro model was correlated with the in vivo data, with log10CFU/ml reduction of < 1 for the VIM-producing (MIC 16 mg l- 1) and >2 for the WT (MIC 0.031 mg l- 1) isolates, with %f T >MIC 25 and 100%, respectively. The in vitro bactericidal activity for all isolates was associated with 40 % f T>MIC and attained in >90% of cases with the standard 1 g q8 0.5 h infusion dosing regimen only for isolates with MICs up to 1 mg l- 1. For isolates with MICs of 2-8 mg l- 1, prolonged infusion regimens (4 h infusion q8 or 2 h infusion q4) of standard (1 g) and higher (2 g) doses or continuous infusion regimens (3-6 g) are required. For isolates with a MIC of 16 mg l- 1 the unconventional dosing regimen of 2 g as 2 h infusion q4 or 12 g continuous infusion will be required. Prolonged and continuous infusion regimens of meropenem may increase efficacy against VIM-producing K. pneumoniae isolates.
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Marilena
authors.initials: M
authors.lastname: Tsala
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Sophia
authors.initials: S
authors.lastname: Vourli
authors.affiliation: Laboratory of Bacteriology, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Stathis
authors.initials: S
authors.lastname: Kotsakis
authors.affiliation: First Department of Propaedeutic Medicine, Laikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: George L
authors.initials: GL
authors.lastname: Daikos
authors.affiliation: Department of Microbiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Tzouvelekis
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Loukia
authors.initials: L
authors.lastname: Zerva
authors.affiliation: Laboratory of Bacteriology, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Vivi
authors.initials: V
authors.lastname: Miriagou
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.|Department of Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy / Q000382:microbiology*; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000378:metabolism; D000077731:Meropenem; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009010:Monte Carlo Method; D013845:Thienamycins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D001618:beta-Lactamases; D000077731:Meropenem