Carbapenems - Beta Lactam Drugs

CARBAPENEMS

The carbapenems are structurally related to β-lactam antibiotics (Figure 43–1). Doripenem, ertapenem, imipenem, and meropenem are licensed for use in the USA. Imipenem, the firstdrug of this class, has a wide spectrum with good activity against many gram-negative rods, including P aeruginosa, gram-positive organisms, and anaerobes. 

It is resistant to most β lactamases but not carbapenemases or metallo-β lactamases. Enterococcus faecium, methicillin-resistant strains of staphylococci, Clostridium difficile, Burkholderia cepacia, and Stenotrophomonas maltophilia are resis-tant. Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations. Consequently, it is administered together with an inhibitor of renal dehydropepti-dase, cilastatin, for clinical use. Doripenem and meropenem are similar to imipenem but have slightly greater activity against gram-negative aerobes and slightly less activity against gram-positives. They are not significantly degraded by renal dehydro-peptidase and do not require an inhibitor. Ertapenem is less active than the other carbapenems against P aeruginosa and Acinetobacter species. It is not degraded by renal dehydropeptidase.

Carbapenems penetrate body tissues and fluids well, including the cerebrospinal fluid. All are cleared renally, and the dose must be reduced in patients with renal insufficiency. The usual dosage of imipenem is 0.25–0.5 g given intravenously every 6–8 hours (half-life 1 hour). The usual adult dosage of meropenem is 0.5–1 g intravenously every 8 hours. The usual adult dosage of doripenem is 0.5 g administered as a 1- or 4-hour infusion every 8 hours. Ertapenem has the longest half-life (4 hours) and is administered as a once-daily dose of 1 g intravenously or intramuscularly. Intramuscular ertapenem is irritating, and for that reason the drug is formulated with 1% lidocaine for administration by this route.

A carbapenem is indicated for infections caused by susceptible organisms that are resistant to other available drugs, eg, P aeruginosa, and for treatment of mixed aerobic and anaerobic infections. Carbapenems are active against many penicillin-non-susceptible strains of pneumococci. Carbapenems are highly active in the treatment of enterobacter infections because they are resistant to destruction by the β lactamase produced by these organisms. Clinical experience suggests that carbapenems are also the treat-ment of choice for infections caused by extended-spectrum β-lactamase-producing gram-negative bacteria. Ertapenem isinsufficiently active against P aeruginosa and should not be used to treat infections caused by that organism. Imipenem, meropenem, or doripenem, with or without an aminoglycoside, may be effec-tive treatment for febrile neutropenic patients.

The most common adverse effects of carbapenems—which tend to be more common with imipenem—are nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites. Excessive levels of imipenem in patients with renal failure may lead to seizures. Meropenem, doripenem, and ertapenem are much less likely to cause seizures than imipenem. Patients allergic to penicil-lins may be allergic to carbapenems as well.