Comparative pharmacodynamics of meropenem using an in-vitro model to simulate once, twice and three times daily dosing in humans.
An in-vitro pharmacokinetic model was used to study the antibacterial activity of meropenem. Strains of Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus were exposed to meropenem concentrations likely to be produced in an adult by rapid iv infusion of 3 g once a day (q24h regimen), 1.5 g twice a day (ql2h regimen) or 1 g three times a day (q8h regimen). Each of these three dosing regimens produced a rapid reduction in viable bacterial count over the first 16 h after dosing. There were no differences in the pattern of reduction in viable count with the q24h, q12h or q8h regimens with any of the three bacterial strains tested over the first 16 h. However, reduction in viable counts was poorer at 24 h with the q24h than q12h or q8h regimens. A simulation lasting 48 h of the q24h dosing regimen indicated a reduction in bacterial count below the limit of detection from the model with E. coli but not with P. aeruginosa or S. aureus. The time for which the meropenem concentration was higher than the MIC for the bacteria correlated best with the reduction in viable bacterial count at 24 h. The AUC for the bacterial time-kill curve, which may be a better measure of antibacterial efficacy, was not related to the length of time for which the concentration was above the MIC or the peak concentration/MIC ratio. The antibacterial effect of the conventional q8h dosing simulation was indistinguishable from that given by the q12h simulation, and both the q8h and q12h regimens offered minor advantages over a q24h regimen. Dosing of meropenem 12 hourly or 24 hourly in humans should be investigated.
Bowker
K E
KE
Bristol Centre for Antimicrobial Research and Evaluation, Southmead Health Services NHS Trust and University of Bristol, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, UK.
Holt
H A
HA
Lewis
R J
RJ
Reeves
D S
DS
MacGowan
A P
AP
D000328:Adult; D019540:Area Under Curve; D015169:Colony Count, Microbial; D003198:Computer Simulation; D004334:Drug Administration Schedule; D004926:Escherichia coli / Q000187:drug effects / Q000302:isolation & purification; D006801:Humans; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000302:isolation & purification; D013211:Staphylococcus aureus / Q000187:drug effects / Q000302:isolation & purification; D013845:Thienamycins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors
D013845:Thienamycins; D000077731:Meropenem