Carbapenems, Monobactams, and Carbapenem-Resistant Organisms

Imipenem is always formulated with cilastatin, an inhibitor of a renal tubular enzyme that otherwise rapidly inactivates imipenem, preventing adequate systemic concentrations. Cilastatin has no antibacterial activity; it is a pharmacokinetic enabler. Imipenem has the broadest gram-positive spectrum of the carbapenems, including methicillin-susceptible Staphylococcus aureus, Streptococcus species, and Enterococcus faecalis, but lacks coverage of methicillin-resistant Staphylococcus aureus and Enterococcus faecium. Its Pseudomonas aeruginosa activity is inferior to meropenem.

The most clinically important adverse effect unique to imipenem is seizure, occurring in approximately 1–3% of patients—substantially more frequently than with other carbapenems. Seizure risk is highest with renal impairment (drug accumulation), high doses, and pre-existing central nervous system pathology. This seizure liability makes imipenem a poor choice for meningitis and contraindicated in patients with active seizure disorders.

Meropenem is the most widely used carbapenem and the reference agent for serious gram-negative infections. Unlike imipenem, meropenem is stable to renal tubular degradation and does not require a co-administered enzyme inhibitor. Meropenem has superior Pseudomonas aeruginosa and Acinetobacter baumannii activity compared to imipenem, achieves clinically adequate central nervous system penetration with inflamed meninges, and has substantially lower seizure potential. It is the carbapenem of choice for gram-negative meningitis and for extended-infusion therapy targeting Pseudomonas aeruginosa with elevated minimum inhibitory concentrations. Meropenem requires renal dose adjustment in significant renal impairment.

Ertapenem is distinguished by one critical absence: it has no activity against Pseudomonas aeruginosa or Acinetobacter baumannii. This narrower gram-negative spectrum makes it a useful carbapenem-sparing agent for extended-spectrum beta-lactamase infections when Pseudomonas coverage is not required. Ertapenem has the longest half-life of the carbapenems (approximately 4 hours) due to extensive protein binding, enabling once-daily dosing—its principal pharmacokinetic advantage for outpatient parenteral antibiotic therapy. It is used for community-acquired extended-spectrum beta-lactamase infections, complicated urinary tract infections, and as step-down therapy from meropenem in extended-spectrum beta-lactamase bacteremia after clinical stability is achieved.

Doripenem has a spectrum similar to meropenem with antipseudomonal activity and low seizure potential. Its use in current practice has declined significantly relative to meropenem; it is approved for complicated urinary tract infections and complicated intra-abdominal infections but not for ventilator-associated pneumonia in the United States.

Carbapenem resistance in Enterobacteriaceae arises through three mechanisms that may coexist. The first and most clinically significant is carbapenemase production: enzymatic hydrolysis by Klebsiella pneumoniae carbapenemase (Class A), metallo-beta-lactamases including New Delhi metallo-beta-lactamase (Class B), or OXA-48-type enzymes (Class D). The second is non-carbapenemase-mediated resistance: loss of outer membrane porins combined with upregulation of extended-spectrum beta-lactamases or AmpC, creating intermediate or low-level carbapenem resistance without a carbapenemase. The third is efflux pump upregulation, which contributes to but rarely causes high-level resistance alone.

Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae is the dominant epidemic strain in the United States and much of Europe. New Delhi metallo-beta-lactamase-producing organisms predominate in South Asia and are increasingly prevalent worldwide, spreading on mobile plasmids across diverse Enterobacteriaceae species.

Three approved combinations specifically target carbapenem-resistant Enterobacteriaceae. Ceftazidime-avibactam (discussed in Module 2) covers Klebsiella pneumoniae carbapenemase, AmpC, and OXA-48 but not New Delhi metallo-beta-lactamase or Verona integron-encoded metallo-beta-lactamase. Meropenem-vaborbactam covers Klebsiella pneumoniae carbapenemase and AmpC but not New Delhi metallo-beta-lactamase or OXA-48. Imipenem-cilastatin-relebactam covers Klebsiella pneumoniae carbapenemase and AmpC and has enhanced anti-Pseudomonas aeruginosa activity.

None of these three combinations reliably treats New Delhi metallo-beta-lactamase-producing organisms. For New Delhi metallo-beta-lactamase producers, aztreonam-avibactam or aztreonam combined with ceftazidime-avibactam are the primary options; cefiderocol may be used as salvage therapy.

Cefiderocol is a novel cephalosporin that bypasses outer membrane permeability barriers, giving it activity against organisms with porin-loss resistance, and is stable against hydrolysis by all classes of beta-lactamases including metallo-beta-lactamases. It has demonstrated activity against carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and metallo-beta-lactamase-producing Enterobacteriaceae in clinical trials. However, a higher all-cause mortality signal was observed in Acinetobacter baumannii infections in one trial compared to best available therapy, and clinical use should be guided by infectious disease consultation.

Carbapenem-resistant Acinetobacter baumannii is designated a critical priority pathogen by the World Health Organization, reflecting near-total resistance of many isolates to conventional antibiotics. Resistance is driven predominantly by OXA-type Class D carbapenemases combined with porin loss and efflux pump upregulation. Sulbactam-durlobactam (sulbactam combined with a novel inhibitor that protects it from OXA-type carbapenemase hydrolysis) is the first specifically approved agent for carbapenem-resistant Acinetobacter baumannii and exploits sulbactam's intrinsic antibacterial activity against Acinetobacter through direct penicillin-binding protein binding.