Clinical review: balancing the therapeutic, safety, and economic issues underlying effective antipseudomonal carbapenem use

Abstract

Antipseudomonal carbapenems have played a useful role in our antimicrobial armamentarium for 20 years. However, a review of their use during that period creates concern that their clinical effectiveness is critically dependent on attainment of an appropriate dosing range. Unfortunately, adequate carbapenem dosing is missed for many reasons, including benefit/risk misconceptions, a narrow therapeutic window for imipenem and meropenem (due to an increased rate of seizures at higher doses), increasingly resistant pathogens requiring higher doses than are typically given, and cost containment issues that may limit their use. To improve the use of carbapenems, several initiatives should be considered: increase awareness about appropriate treatment with carbapenems across hospital departments; determine optimal dosing regimens for settings where multidrug resistant organisms are more likely encountered; use of, or combination with, an alternative antimicrobial agent having more favorable pharmacokinetic, pharmacodynamic, or adverse event profile; and administer a newer carbapenem with lower propensity for resistance development (for example, reduced expression of efflux pumps or greater stability against carbapenemases).

Figure 1

Probability of attaining pharmacodynamic target during entire dosing interval (T > MIC > 30%, 50%, and 100%) as a function of MIC for imipenem and meropenem at a dosage of 500 mg q6h. The 30% and 50% targets represent conservative estimates for bacteriostatic and bactericidal activity, respectively. Each curve shows the likelihood of the drug to stay above the target MIC for the entire dosing period based on the pathogen's MIC. Note the steep declines in probabilities for MIC values between 0.5 and 4. Reproduced with permission from Kuti et al. [42].

Figure 2

Correlation between imipenem usage and imipenem resistance in P. aeruginosa in a community hospital. DDD, defined daily dose. Reproduced with permission from [78].

Figure 3

Imipenem susceptibility and carbapenem use at a Polish pediatric hospital (1993 to 2002). DDD, defined daily dose. Reprinted from Patzer and Dzierzanowska [80], with permission from Elsevier.

Figure 4

Effect of imipenem dose on the time during which serum imipenem exceeds the MIC₉₀ in healthy volunteers after a 30 minute infusion [83]. The dashed line shows the percentage of the dosing cycle required for optimal dosing.