Comparative Pharmacokinetics of the Carbapenems

Abstract

During the last few decades, several carbapenems have been developed. The major characteristic of the newer drugs, such as MK-826, is a prolonged half-life. Alternatively, some carbapenems have been developed that can be given 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 dehydropeptidase-1 and reduce nephrotoxicity, the newer drugs such as meropenem, biapenem and lenapenem are relatively stable towards that enzyme. Structural 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 slightly 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 extracellular body-water, as observed both from the volumes of distribution and from blister studies. Some carbapenems have a better penetration in cerebrospinal fluid than others. In patients with renal dysfunction, doses have to be adjusted, and special care must be taken with imipenem/cilastatin and panipenem/betamipron to prevent accumulation of the co-drugs, as the pharmacokinetic properties of the co-drugs differ from those of the drugs themselves. However, toxicity of the co-drugs has not been shown. The carbapenems differ in proconvulsive activity. Imipenem shows relatively the highest proconvulsive activity, especially at higher concentrations. Pharmacodynamic studies have shown that the major surrogate parameter for antimicrobial efficacy is the percentage of time of the dosage interval above the minimum inhibitory concentration (MIC). The minimum percentage percentage of time above the MIC (TaM) needed for optimal effect is known in animals (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 about 50% at 4 mg/L, which is the current 'susceptible' breakpoint determined by the National Committee for Clinical Laboratory Standards (NCCLS) for most micro-organisms. Dosage regimens in patients with reduced renal clearance should be based on the TaM. The increased half-life of the newer carbapenems will probably lead to less frequent administration, although continuous infusion may still be the optimal mode of administration for these drugs. The availability of oral carbapenems will have a profound effect on the use of carbapenems in the community.

A Beneficial Interaction between Imipenem and Piperacillin Possibly through Their Renal Excretory Process

“…Most carbapenems exhibit relatively short elimination half-lives after administration. 17) If the renal clearance of other carbapenems is efficiently mediated by OAT, PIPC may also be beneficial in modulating such clearance.…”

Microdialysis Study of Imipenem Distribution in Skeletal Muscle and Lung Extracellular Fluids of Noninfected Rats

“…As opposed to elimination, the IPM distribution was not altered in the anesthetized rats. Carbapenem antibiotics are usually considered to be distributed within the extracellular body water (24). Accordingly, the IPM volume of distribution in rats was previously found (12,20) to be almost equal to the mean value (297 ml · kg Ϫ1 ) of the extracellular fluid in rats (8).…”

Occurrence of PER-1 Producing Clinical Isolates of Pseudomonas aeruginosa in Japan and their Susceptibility to Doripenem

“…The differences of susceptibility between PER-1 producers might be due to the amount of production of PER-1. Doripenem and meropenem can be used clinically without a dehydropeptidase-I inhibitor due to their high stability to human renal dehydropeptidase-I [22,33]. Doripenem is also more stable against murine dehydropeptidase-I than meropenem and imipenem, and the therapeutic efficacy by single administration of doripenem against various infection models has been found to be comparable to or better than that of the combinational administration of meropenem : cilastatin and imipenem : cilastatin [14,16].…”

“…All test antibiotics were subcutaneously administered at 1, 3 and 5 hours after infection. For the carbapenem antibiotics doripenem, meropenem and imipenem, equal amounts of cilastatin was simultaneously administered to prevent the degradation of carbapenem antibiotics by renal dehydropeptidase-I [22,23]. Seven mice were used at each dosage of the compound.…”