Τίτλος:
Pharmacokinetic–pharmacodynamic modelling of meropenem against vim-producing Klebsiella pneumoniae isolates: Clinical implications
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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-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-1) and.2 for the WT (MIC 0.031 mg-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. For isolates with MICs of 2–8 mg-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 mg1 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. © 2015 The Authors.
Συγγραφείς:
Tsala, M.
Vourli, S.
Kotsakis, S.
Daikos, G.L.
Tzouvelekis, L.
Zerva, L.
Miriagou, V.
Meletiadis, J.
Περιοδικό:
Journal of Medical Microbiology
Εκδότης:
Microbiology Society
Λέξεις-κλειδιά:
creatinine; cyclophosphamide; meropenem; antiinfective agent; beta lactamase; meropenem; thienamycin derivative, animal experiment; antibacterial activity; Article; bacterial count; bacterial strain; bacterium isolate; colony forming unit; continuous infusion; controlled study; creatinine blood level; creatinine clearance; drug clearance; drug efficacy; drug half life; female; in vitro study; Klebsiella pneumoniae; male; maximum plasma concentration; minimum inhibitory concentration; nonhuman; priority journal; protein binding; rat; sex ratio; vim producing Klebsiella pneumoniae; animal; antibiotic resistance; biological model; drug effects; genetics; human; Institute for Cancer Research mouse; Klebsiella Infections; Klebsiella pneumoniae; metabolism; microbial sensitivity test; microbiology; Monte Carlo method; mouse, Animals; Anti-Bacterial Agents; beta-Lactamases; Drug Resistance, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Models, Biological; Monte Carlo Method; Thienamycins
DOI:
10.1099/jmm.0.000214
