Antimicrobial effects of continuous versus intermittent administration of carbapenem antibiotics in an in vitro dynamic model

Abstract

In an in vitro dynamic model we compared the antimicrobial effects of two carbapenems, imipenem (MIC, 1 microg/ml) and meropenem (MIC, 0.25 microg/ml) on Pseudomonas aeruginosa. The antibiotics were administered either as short-time infusions once or three times a day or as continuous infusions with steady-state levels ranging from 0.5 to 20 microg/ml. From the resulting kill curves the period of time until the onset of bacterial death (dt), the rate constant of bacterial death (ka), the maximal reduction of CFU (mr), and the period of time until bacterial regrowth occurred (tr) were determined. Additionally, the occurrence of bacterial resistance during the simulations (rq) and the postantibiotic effect (PAE) were recorded. For both investigated carbapenems no significant difference in dt, ka, mr, and PAE values between the short-time infusions and continuous infusions with steady-state levels above 2 microg/ml could be detected. The tr was longest with continuous infusions of over approximately 24 h, corresponding to steady-state levels of 3 microg/ml for imipenem and 2.5 microg/ml for meropenem. An increase in MIC was observed only during continuous infusions with steady-state levels below 2 microg/ml. Independent of the chosen method of application and despite the lower MIC of meropenem, imipenem was slightly more effective than meropenem.

Single-Dose Pharmacokinetics of Meropenem during Continuous Venovenous Hemofiltration

“…No dosage recommendations for meropenem are available for patients undergoing continuous renal replacement therapy. Because beta-lactam drug levels need to be above the minimal inhibitory concentration (MIC) for the organism (6,10) during at least 40 to 50% of the dosing interval for optimal efficacy, underdosing might impair clinical outcome.…”

Trough serum concentrations of β-lactam antibiotics in cancer patients: inappropriateness of conventional schedules to pharmacokinetic/pharmacodynamic properties of β-lactams

“…Increasing drug concentrations above this target concentration provides no added benefit. Some in vitro [30] and in vivo [22,31] experiments appear to indicate that IMP may be active at lower serum concentrations. Moreover, the percentage of the dosage interval during which the serum concentration should exceed the MIC to produce a bacteriostatic effect was smaller with IMP than with CAZ [32].…”

<p>An investigation of the stability of meropenem in elastomeric infusion devices</p>

“…Manning et al considered the pharmacokinetic issues 10. To achieve optimum pharmacodynamic activity and to optimize the time-dependent killing of meropenem, the steady-state concentration should be at least three to four fold the MIC for a majority, if not all, of the dosing interval 1,2,4,23. At a meropenem concentration of 10 mg/mL (intended for CI; equivalent to a daily dose of 2.4 g), a population pharmacokinetic model determined the median, 2.5th centile and 97.5th centile steady-state meropenem plasma concentrations, which were compared to breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa 10.…”

“…It exhibits a time-dependent antibacterial effect with antibacterial activity related to the time for which the free concentration is maintained above the minimum inhibitory concentration (MIC) during a dosing interval 1,2. Administering meropenem via continuous infusion (CI) maintains serum drug concentrations above the MIC for susceptible bacteria3,4 thereby optimising pharmacodynamic targets in plasma, especially against less susceptible bacteria, such as Pseudomonas aeruginosa 5. Comparative studies between meropenem administered via CI and intermittent infusion have shown that CI improves infection eradication and requires a shorter duration of treatment 2…”