Background Severe infections in critically ill patients due to P. aeruginosa require timely and appropriate antibiotic treatment. Pharmacokinetics (PK) and pharmacodynamics (PD) both affect dosing antibiotic regimens. The minimum inhibitory concentration (MIC) becomes a PD surrogate for microbiological cure for the combination of infecting bacteria and drug. Monte Carlo simulations facilitate theoretical forecasting of the probability of PK/PD targets being attained. Regarding carbapenems, the PK/PD index to be optimised is the time for which the free serum drug concentration exceeds the MIC: fTSS>MIC.
Purpose To use Monte Carlo simulations to evaluate the appropriateness of extended intravenous infusions (EIs) of meropenem (MEP) in patients critically ill with P. aeruginosa infections.
Materials and methods For each dose regimen (MEP 1 g intravenous q8h-q6h and different lengths of infusion), 5000 PK profiles were simulated (NONMEM v.6) based on previous PK data and creatinine clearance (CLcr). A range of MICs was studied: S ≤2 mg/L, I 4 mg/L and R >8 mg/L, according to the EUCAST cut-off for P. aeruginosa for MEP. The likelihood of target attainment (PP50: fTSS>MIC>50%), was calculated for each EI while keeping the interdose interval of 6h, 8h or 12h.
Results In patients with CLcr 80 mL/min and MICs ≤2 mg/L, high doses of MEP 1 g intravenous for 30 min/6h were needed to reach the goal (PP50>90%). For higher MICs, this high dose was clearly inadequate (eg, MIC=4 and 8 mg/L PP50 were 76.5% and 38.8%, respectively). The PP50 could be markedly increased by using longer EIs (eg, for MIC=4 mg/L PP50=85.2%, 94.8% and 100% for EIs of 1h, 2h and 3h, respectively). Lower MEP doses could be prescribed without loss of efficacy (PP50 89.7%, 95.1% and 99.1% using MEP 1 g intravenous/8h for 1h, 2h and 3h, respectively), for MICs ≤2 mg/L. The length of infusion had less effect on PP50 in moderate/severe renal impairment. For MIC≤2 mg/l, PP50 remained >90% while Clcr=40 ml/min for q6–8 h.
Conclusion The probability of attaining PP50 for a given MIC rises as long as the infusion time increases. MEP administered as an EI (3h) might increase the likelihood of a favourable microbiological and clinical outcome in ICU patients when P. aeruginosa. has a high MIC.
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