This class of medications is structurally related to beta-lactam antibiotics with a broad spectrum of activity that includes most gram-negative rods (including P aeruginosa), gram-positive organisms, and anaerobes. Carbapenems are inactive against Burkholderia cepacia, S maltophilia, E faecium, methicillin-resistant S aureus, and methicillin-resistant Staphylococcus epidermidis. There are four carbapenem antibiotics: imipenem, meropenem, doripenem, and ertapenem.
Meropenem, doripenem, and imipenem have a similar spectrum of activity and pharmacology. Of particular importance, the carbapenems are the most reliable agents in the treatment of infection secondary to ESBL-producing E coli and Klebsiella spp. The emergence of CRE throughout the world is of particular concern because limited options are available to treat these infections, which are associated with high morbidity and mortality.
Meropenem and doripenem are less likely to be associated with seizures when compared with imipenem, although the risk of seizures is low with imipenem if dosage is appropriately adjusted for kidney dysfunction. Meropenem and doripenem are associated with less nausea and vomiting than imipenem, a feature of importance when high doses must be used, as in the treatment of Pseudomonas infection in patients with cystic fibrosis. The usual dose for meropenem is 1–2 g intravenously every 8 hours. Dosage adjustment is required in kidney dysfunction. Doripenem (500 mg–1 g intravenously every 8 hours) is used in the treatment of intra-abdominal infection and pyelonephritis. Unlike meropenem, doripenem is not approved for the treatment of other serious hospital-acquired infections. In the treatment of ventilator-associated pneumonia, doripenem (administered for 7 days) was associated with increased mortality when compared with imipenem (administered for 10 days). Unlike meropenem and doripenem, imipenem is co-formulated with cilastatin, an enzyme that enhances the pharmacokinetics and minimizes the nephrotoxic effects of imipenem. The dose and dosing interval of imipenem/cilastatin vary depending on the pathogen susceptibility profile and kidney function.
Ertapenem is similar to the other carbapenems in its activity against aerobic gram-positive and anaerobic organisms, but it is inactive against Pseudomonas and Acinetobacter. Because of its long half-life (4 hours), it can be administered once daily. The usual dose is 1 g intravenously every 24 hours, and adjustments are needed for kidney dysfunction.
The carbapenems should not be routinely used as first-line therapy unless the pathogen is multidrug-resistant and is known to be susceptible to these agents. In patients hospitalized for a prolonged period with presumed infection with a multidrug-resistant organism, empiric use of carbapenems is reasonable. However, ertapenem should not be used if Pseudomonas and Acinetobacter are suspected. Pseudomonas may rapidly develop resistance to carbapenems, but combination definitive therapy for the treatment of Pseudomonas is not routinely recommended. The use of imipenem or meropenem alone appears to be as effective as combination therapy in patients with febrile neutropenia and certain polymicrobial infections such as peritonitis and pelvic infections.
The most common adverse effects of carbapenems are diarrhea, reactions at the infusion site, and skin rashes. Seizures, nausea, and vomiting are more commonly observed with imipenem. Patients allergic to penicillins may be allergic to imipenem and meropenem as well. While earlier studies suggested substantial cross-reactivity between penicillin and imipenem in patients with confirmed IgE-mediated reactions to penicillin, more data strongly suggest the cross-reactivity is less than 1%.
Meropenem is available as a coformulated product with a novel beta-lactamase inhibitor vaborbactam. Results from the TANGO II trial found meropenem-vaborbactam monotherapy was superior to the best available therapies (polymyxins, carbapenems, aminoglycosides, tigecycline, or ceftazidime-avibactam) in the treatment of CRE infections. Imipenem-cilastatin in combination with relebactam, a beta-lactamase inhibitor, is approved for the treatment of complicated urinary tract and intra-abdominal infections. Relebactam is structurally similar to avibactam with similar activity against beta-lactamases such as ESBLs and KPC-producing Enterobacteriaceae. These carbapenem-beta-lactamase inhibitors offer valuable options over more toxic agents, such as colistin. The adverse event profile of these combination products mimics that of the parent carbapenem antibiotic.
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