Carbapenems and aztreonam

Carbapenems and aztreonam

The spread of organisms that had developed various forms of resistance to the early penicillins and cephalosporins lead to a search for other β-lactam antibiotics that avoided these resistance problems. Many naturally occurring and synthetic compounds were examined but only a few were developed to become marketed products, and the most useful of these were the carbapenems. This group may be considered as penicillin or cephalosporin derivatives in which the sulphur atom has been replaced with a carbon. The nomenclature is confusing because some reference sources used terms like carbapenems, olivanic acids and thienamycins as if they were synonymous. In fact, carbapenems is the generic term for the group which includes olivanic acids (of which there are no products in therapeutic use) and the thienamycins. The earliest thienamycins were discovered in the 1970s but proved difficult to develop because of their poor stability. The N-formimidoyl derivative of thienamycin, which was named imipenem (Figure 11.6A), proved to combine the desirable properties of in vitro stability, a broad spectrum of antimicrobial activity and good resistance to almost all of the then known β-lactamases. Its only shortcoming was poor in vivo-stability because it was vulnerable to hydrolysis by mammalian renal dipeptidase, but this was solved by the development of a renal dipeptidase inhibitor, cilastatin, with which imipenem was marketed. Meropenem, marketed more recently, is more stable than imipenem to dipeptidase and may thus be administered without cilastatin; its chemical structure is depicted in Figure 11.6B. Ertapenem (Figure 11.6C) has properties similar to those of meropenem but affords the additional advantage of once daily dosing.

Examination of the structure-activity relationships of the early β-lactam antibiotics led to an expectation that molecules possessing only the β-lactam ring without a second ring fused to it would have no antimicrobial activity. This proved not to be so when such naturally occurring antibiotics, termed monobactams, were discovered, and found not only to possess activity, but to exhibit good resistance to β-lactamases. The naturally occurring monobactams were not developed for clinical use, but an analogue, aztreonam, produced totally by conventional chemical synthesis, was marketed in 1986. It is highly active against most Gram-negative bacteria and stable to most types of β-lactamases, although its resistance to staphylococcal β-lactamases is irrelevant because it is inactive against all strains of Staph. aureus as well as other Gram-positive species and anaerobes. Like the carbapenems, it is formulated as an intravenous injection and, as such, it tends to be limited to use in hospitals for the treatment of serious Gram-negative infections, including those due to Ps. aeruginosa. As with the carbapenems and third generation cephalosporins, it exhibits synergy with aminoglycosides like gentamicin and tobramycin, and these combinations are employed for the treatment of Pseudomonas lung infections in cystic fibrosis.