Werner Tosch

Penems: In Vitro and In Vivo Experiments

A mong the plethora of new antibiotics discovered in the last 10 to 15 years, the penems and carbapenems, or “non-classic” beta-lactams as they have been dubbed,1 doubtless belong to the few that not only presented an extraordinary challenge to chemists but also aroused wide interest among medical microbiologists and clinicians. Although related in denomination and structure, they are intrinsically distinct inasmuch as the carbapenems are naturally occurring fermentation products, whereas the penems are fully synthetic. The first penem (Figure 1) was synthesized at the Woodward Research Institute in Basle, Switzerland, in 1975.23 It displayed a certain, albeit unsatisfactory, activity against gram-positive bacteria, but was unstable, probably because of its acyl side chain at C-6. The synthesis of this compound, however, marked the realization of Woodward’s original idea of constructing antibiotics that would combine the beta-lactam-activating properties of the five-membered ring of the penicillins with the reactivity-enhancing double bond similarly located to that in the six-membered ring of the cephalosporins (Figure 2). It was not, however, until the molecule-stabilizing hydroxyethyl substituent at C-6, already known from thienamycin, was introduced that beta-lactamase-resistant and chemically stable penems with a promising activity profile were obtained. The penems (and carbapenems) possess a number of special antibiotic properties not shared by most other beta-lactams. Some of these are indicated in Table I and are the subject of this brief review; for the most part they are exemplified by data relating to the well-known penems SCH 29482 and SCH 34343 (Schering-Plough), FCE 22101 and FCE 22891 (Farmitalia Carlo Erba) and the carbapenem imipenem (Merck, Sharp & Dohme) (Figure 3); findings made with some new penems of Ciba-Geigy are also included.