e1-03: Other Beta-Lactam Medications

Aztreonam is the sole marketed monobactam, so named due its monocyclic beta-lactam ring resistant to many beta-lactamases. Aztreonam is active against gram-negative organisms (including Pseudomonas) but has no activity against gram-positive organisms or anaerobes. Aztreonam resembles ceftazidime with its gram-negative activity. Thus, it is generally strong against E coli, Klebsiella, Proteus, and Pseudomonas spp, but its activity is unpredictable against Acinetobacter, Enterobacter, and Citrobacter spp. Clinical uses of aztreonam are limited because of the availability of third-generation cephalosporins with a broader spectrum of activity and minimal toxicity. However, the clinical role of aztreonam may expand; it is being investigated in combination with the beta-lactamase inhibitor avibactam for the management of metallo-beta-lactamase–producing Enterobacteriaceae (eg, E coli, Klebsiella, Proteus), for which few other therapies are available. Considering its activity against P aeruginosa, aztreonam is also useful in the management of patients with cystic fibrosis as an inhaled dose of 75 mg administered three times daily. Despite the structural similarity of aztreonam to penicillin, IgE cross-reactivity does not exist, and it can therefore be used in patients with IgE-mediated penicillin allergy.

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.

In patients hospitalized for a prolonged period or with presumed infection caused by 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; however, combination anti-pseudomonal therapy does not decrease the rate of resistance. 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, although it is likely the cross-reactivity is less than 1%.

Meropenem is also available coformulated with vaborbactam, a novel beta-lactamase inhibitor. Results from the TANGO II trial revealed meropenem-vaborbactam 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, intra-abdominal infections, and hospital-acquired or ventilator-associated bacterial pneumonia. 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.