Carbapenems and Carbacephems

CARBAPENEMS AND CARBACEPHEMS

The newest classes of β-lactam antibiotics are the car-bapenems and carbacephems. Their mechanism of action is the same as those of the other β-lactam antibi-otics.

Imipenem

The first carbapenem, imipenem–cilastatin (Primaxin), is a chemically stable analogue of thienamycin pro-duced by Streptomyces cattleya. The antibacterial spec-trum of imipenem is among the broadest of all of the β-lactam antibiotics. Imipenem is active against most gram-positive, gram-negative, and anaerobic bacteria. When compared with the in vitro activities of third-generation cephalosporins, imipenem is more potent against E. faecalis, B. fragilis, and P. aeruginosa. Imipenem’s stability against β-lactamases is attributa-ble to the trans position of the 6-hydroxyethyl side chain on the β-lactam ring. Organisms resistant to imipenem include E. faecium, Stenotrophomonas mal-tophilia, and MRSA.

Imipenem–cilastatin is only available for intramus-cular or intravenous administration because oral bioavailability is poor. The enzyme, dehydropeptidase I, present in renal tubules, converts imipenem to an inac-tive metabolite. To decrease metabolic clearance, imipenem is combined with cilastatin, an inhibitor of dehydropeptidase I. Additional pharmacokinetic infor-mation appears in Table 45.2.

Imipenem–cilastatin is one of the drugs of first choice for the empirical therapy of many polymicrobial pulmonary, intraabdominal, and soft tissue infections. The notable adverse effect of imipenem–cilastatin is seizures affecting 1% of patients. Risk factors for seizures are old age, head trauma, previous seizure dis-order, cerebrovascular accident, and renal failure. Among patients with a history of penicillin allergy, 10% are cross-sensitive to imipenem–cilastatin.

Meropenem

Meropenem (Merrem) is another carbapenem antibi-otic with a broad spectrum of activity comparable to that of imipenem. A methyl group attached at the one-position on the five-member ring confers stability to de-hydropeptidase I. Consequently, meropenem does not require administration with cilastatin. When compared in human trials, imipenem–cilastatin and meropenem achieve similar clinical outcomes in patients with seri-ous intraabdominal and soft tissue infections. Both imipenem–cilastatin and meropenem are used to treat infections caused by highly resistant Klebsiella pneumo-niae producing ESBLs. The major clinically relevant dis-tinction between imipenem–cilastatin and meropenem is the lower likelihood of seizures associated with meropenem.

Loracarbef

Loracarbef (Lorabid) is a synthetic β-lactam antibiotic of the carbacephem class. The chemical structure of lo-racarbef is similar to that of cefaclor. Selected pharma-cokinetic information appears in Table 45.2. Lora-carbef’s spectrum of antibacterial activity resembles those of the second-generation cephalosporins. Com-parative clinical trials reveal similar outcomes in pa-tients treated with cefaclor, cefprozil, and loracarbef.