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Is all free time above the minimum inhibitory concentration the same: implications for beta-lactam in vivo modelling

C Andrew DeRyke1, David P Nicolau

  • 1Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.

International Journal of Antimicrobial Agents
|January 16, 2007
PubMed

Insights

A complex regimen (CR) of ertapenem in mice matched human dosing, showing that the total 24-hour exposure above the minimum inhibitory concentration (MIC) drives bacterial kill, not dose timing.

Area of Science:

  • Pharmacology and Microbiology
  • Antimicrobial Resistance

Background:

  • Ertapenem dosing in mice previously achieved similar 24-hour cumulative free time above minimum inhibitory concentration (fT>MIC) to human dosing.
  • However, simplified mouse regimens (SR) do not replicate human concentration-time profiles, leading to fluctuations above and below the minimum inhibitory concentration (MIC).

Purpose of the Study:

  • To compare a complex regimen (CR) with a near-superimposable concentration-time profile to the SR in mice.
  • To determine the impact of CR versus SR on bacterial kill against extended-spectrum beta-lactamase (ESBL)-producing isolates.

Main Methods:

  • Mice were administered ertapenem via a complex regimen (CR; 9 varied doses over 24h) and a simplified regimen (SR).
  • Bacterial kill was assessed against eight ESBL-producing isolates across a wide MIC range (0.032 mg/L to 16 mg/L).
  • Pharmacokinetic/pharmacodynamic (PK/PD) parameters, specifically 24-h cumulative fT>MIC, were compared between regimens.

Main Results:

  • The CR achieved a 24-h cumulative fT>MIC similar (+/-5%) to human ertapenem 1g every 24h dosing.
  • Both CR and SR demonstrated comparable bacterial kill against all eight ESBL-producing isolates.
  • Efficacy was driven by the 24-h cumulative fT>MIC, irrespective of dose distribution over the 24-hour period.

Conclusions:

  • In mouse models, the 24-hour cumulative exposure of ertapenem above the MIC is the primary determinant of efficacy against ESBL-producing bacteria.
  • The timing of drug concentrations within the 24-hour period is less critical than the overall cumulative exposure for achieving bacterial kill.

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