Is all free time above the minimum inhibitory concentration the same: implications for beta-lactam in vivo modelling.
Previously, ertapenem 50 mg/kg every 6h given subcutaneously to mice achieved a similar 24-h cumulative free time above the minimum inhibitory concentration (fT>MIC) to 1g every 24h in humans. However, this simplified regimen (SR) does not provide a superimposable concentration-time profile to that observed in humans, thus allowing concentrations to fluctuate above and below the minimum inhibitory concentration (MIC) throughout the 24-h period. Herein, we compared a complex regimen (CR; 9 various mg/kg doses over 24 h) providing a near superimposable concentration-time profile with the SR to determine implications on bacterial kill against eight extended-spectrum beta-lactamase (ESBL)-producing isolates over a wide MIC range. The CR resulted in a similar (+/-5%) 24-h cumulative fT>MIC to ertapenem 1 g every 24h in humans over an MIC range of 0.032 mg/L to 16 mg/L. Similar bacterial kill was observed with both regimens against all eight ESBL-producing isolates examined. In mouse models, it appears that the 24-h cumulative fT>MIC and not the distribution of the fT>MIC over 24 h drives efficacy.
DeRyke
C Andrew
CA
Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
Nicolau
David P
DP
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077727:Ertapenem; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D001618:beta-Lactamases / Q000096:biosynthesis; D047090:beta-Lactams / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D001618:beta-Lactamases; D000077727:Ertapenem