Beta-lactamase inhibitors are available only in fixed combinations with specific penicillins and cephalosporins. (The fixed combinations available in the USA are listed in Preparations Available.) An inhibitor extends the spectrum of its companion β-lactam provided that the inactivity against a particular organism is due to destruction by a β-lactamase and that the inhibitor is active against the β-lactamase that is produced. Thus, ampicillin-sulbactam is active against β-lactamase-producing S aureus and H influenzae but not against Serratia, which produces a β-lactamase that is not inhibited by sulbactam. Similarly, if a strain of P aeruginosa is resistant to piperacillin, it is also resistant to piperacillin-tazobactam because tazobactam does not inhibit the chromosomal β-lactamase produced by P aeruginosa.
Beta-lactam–β-lactamase inhibitor combinations are frequently used as empirical therapy for infections caused by a wide range of potential pathogens in both immunocompromised and immunocompetent patients. Adjustments for renal insufficiency are made based on the β-lactam component.
The carbapenems are structurally related to other β-lactam antibiotics (Figure 43–1). Doripenem, ertapenem, imipenem, and meropenem are licensed for use in the USA. Imipenem, the first drug of this class, has a wide spectrum with good activity against most 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 resistant. Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations. Consequently, it is administered together with an inhibitor of renal dehydropeptidase, 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 dehydropeptidase and do not require an inhibitor. Unlike the other carbapenems, ertapenem does not have appreciable activity against P aeruginosa and Acinetobacter species. It is not degraded by renal dehydropeptidase.
Carbapenems penetrate body tissues and fluids well, including the cerebrospinal fluid for all but ertapenem. 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 1or 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 the drug is formulated with 1% lidocaine for administration by this route.