Comparative pharmacokinetics of the carbapenems - Clinical implications

During the last few decades, several carbapenems have been developed, The m ajor characteristic of the newer drugs, such as MK-826, is a prolonged half -life, Alternatively, some carbapenems have been developed that can be give n orally, such as CS-834 and L-084. Although imipenem and panipenem have to be administered with a co-drug to prevent degradation by the enzyme dehydr opeptidase-1 and reduce nephrotoxicity, the newer drugs such as meropenem, biapenem and lenapenem are relatively stable towards that enzyme. Structura l modifications have, besides changes in pharmacology, also led to varying antimicrobial properties. For instance, meropenem is relatively more active against Gram-negative organisms than most other carbapenems, but is slight ly less active against Gram-positive organisms. Except for half-life and bioavailability, the pharmacokinetic properties of the carbapenems are relatively similar. Distribution is mainly in extracel lular body-water, as observed both from the volumes of distribution and fro m blister studies. Some carbapenems have a better penetration in cerebrospi nal fluid than others. In patients with renal dysfunction, doses have to be adjusted, and special care must be taken with imipenem/cilastatin and pani penem/betamipron to prevent accumulation of the co-drugs, as the pharmacoki netic properties of the co-drugs differ from those of the drugs themselves. However, toxicity of the co-drugs has not been shown. The carbapenems diff er in proconvulsive activity. Imipenem shows relatively the highest proconv ulsive activity, especially at higher concentrations. Pharmacodynamic studies have shown that the major surrogate parameter for a ntimicrobial efficacy is the percentage of time of the dosage interval abov e the minimum inhibitory concentration (MIC). The minimum percentage percen tage of time above the MIC (TaM) needed for optimal effect is known in anim als (30 to 50%). but not in humans. It is probably less than 100%, but may be higher than 50%. Dosage regimens currently in use result in a TaM of abo ut 50% at 4 mg/L, which is the current 'susceptible' breakpoint determined by the National Committee for Clinical Laboratory Standards (NCCLS) for mos t micro-organisms. Dosage regimens in patients with reduced renal clearance should be based on the TaM. The increased half-life of the newer carbapene ms will probably lead to less frequent administration, although continuous infusion may still be the optimal mode of administration for these drugs. T he availability of oral carbapenems will have a profound effect on the use of carbapenems in the community.