Chemical and Microbiologic Aspects of Penems, a Distinct Class of β-Lactams: Focus on Faropenem

Jeremy M. T. Hamilton-Miller, D.Sc., FRCPath


Pharmacotherapy. 2003;23(11) 

In This Article

In Vivo Studies

There are relatively few published data on the use of penems in vivo, since, for commercial as well as scientific reasons, few of these molecules have reached the late stages of clinical development. Furthermore, evaluations of penems in animal models are complicated because of differing properties and tissue distribution of DHP in different species. In humans, this enzyme is much less extensively expressed, but renal DHP causes rapid breakdown of early carbapenems (e.g., thienamycin and imipenem[32]), necessitating coadministration of DHP inhibitors such as cilastatin with these agents. Penems have a superficially similar structure to that of carbapenems but offer the advantage of increased stability to DHP, negating the need for coadministration with inhibitors in humans. For example, in one study, 52.1-57.1% of an intravenous dose of the penem CGP 31608 was eliminated, intact, in urine.[33] By contrast, when the carbapenem imipenem was administered without a DHP inhibitor, only 12-42% of the dose was eliminated intact, with a large proportion of the drug undergoing hydrolysis by renal DHP.[32]

Most penems are not available in an oral formulation and must be administered parenterally. However, in many cases this has been overcome by the development of prodrugs that can be taken orally. The pharmacokinetics of penems are similar to those of other β-lactams, with a half-life typically around 1 hour, elimination principally by the kidney, and protein binding determined mainly by the substitution at C2.[3]

Sulopenem has been tested in a number of animal models of infection. In mice, sulopenem was more effective that meropenem, ceftazidime, and flomoxef against systemic infections of S. aureus and S. pneumoniae, and less effective than imipenem-cilastatin against systemic infections of S. aureus, K. pneumoniae, and Acinetobacter calcoaceticus.[34] In a murine model of mixed systemic infection with E. coli and Bacteroides fragilis, sulopenem had a lower effective dose for 50% of organisms than that of imipenem.[35] In a guinea pig model of lung infection with K. pneumoniae, sulopenem was more effective than cefuzonam and cefotiam.[35]

BRL 42715 also demonstrated efficacy in vivo, with effective inhibition of β-lactamases secreted by S. marcescens US 20 and E. coli 41548 in the rat peritoneum, enhancing the efficacy of cefazolin and piperacillin, respectively.[36]

Ritipenem has been studied in several conditions in humans, including uncomplicated cystitis, in which it proved less effective than norfloxacin and was particularly associated with loose stools and diarrhea.[37] It also was tested in exacerbations of chronic obstructive pulmonary disease, where significant improvements in symptoms and lung function were seen, although it was not effective against H. influenzae and was associated with gastrointestinal disturbances.[38] In other studies, ritipenem was compared with cefotiam against lower respiratory tract infections and bacterial pneumonia.[39,40] In these studies, ritipenem had a similar efficacy to that of cefotiam (with excellent or good efficacy in 85% and 91.8%, respectively) and did not present any safety issues.