Beta-Lactam Treatment Options for Carbapenem-Resistant Organisms: A Practical Guide
- Benjamin Heymans
- Jan 7
- 3 min read
Antimicrobial resistance poses a growing global threat to public health, directly causing an estimated 1.27 million deaths in 2019 alone (1). In clinical practice, this rise in resistance means clinicians will increasingly encounter infections where carbapenems - the once, reliable last-line agents - are ineffective. Since resistance mechanisms can often be determined before susceptibility results are available, this blog provides a schematic overview of beta-lactam treatment options for carbapenem-resistant organisms.
1) Activity of ‘new’ beta-lactam antibiotics against key beta-lactamases
2) IDSA treatment recommendations for carbapenem-resistant gram-negative infections
3) Beta-lactam/beta-lactamase inhibitors in development
1) Activity of ‘new’ beta-lactam antibiotics against key beta-lactamases
The table below summarizes the activity of some of the newer beta-lactam antibiotics against key Ambler Class A, B and D beta-lactamases.
Remarks:
Resistance to cefiderocol among NDM-producing Enterobacterales has been reported even without prior exposure (2). IDSA thus recommends susceptibility testing for cefiderocol before initiating therapy in suspected NDM-producing Enterobacterales infections (2).
Prior to the FDA approval of aztreonam-avibactam in 2025 (7), clinical data on its antimicrobial activity were primarily derived from studies using the combination of ceftazidime-avibactam with aztreonam (5). Both regimens are likely to have similar efficacy (5). However, pharmacokinetic data suggest a more optimal avibactam dosing in aztreonam-avibactam as its is administered as a 3-hour infusion of 500 mg every 6 hours (instead of a 2-hour infusion of 500 mg every 8 hours with ceftazidime-avibactam) (3).
2) IDSA Treatment Recommendations for Carbapenem-Resistant Gram-Negative Infections
Based on the IDSA guidance of 2024, the following beta-lactam treatment options are recommended in case of carbapenem-resistant gram-negative infections (2):
Remarks:
P. aeruginosa possesses multiple non-enzymatic resistance mechanisms to aztreonam, in addition to pseudomonal AmpC enzymes (2). Since avibactam does not overcome these mechanisms, the combination of aztreonam and avibactam offers no substantial benefit and is not recommended for difficult-to-treat P. aeruginosa infections (2).
Pharmacokinetic/pharmacodynamic data indicate that sulbactam-durlobactam should be effective against carbapenem-resistant A. baumanii (CRAB) (4). However, in the ‘large’ randomized controlled ATTACK trial, CRAB-infections were treated with sulbactam/durlobactam combined with imipenem-cilastatin (10). This combination targets additional penicillin-binding proteins, potentially enhancing potency (4). Given ongoing uncertainty about monotherapy with sulbactam/durlobactam, IDSA currently suggests adding a carbapenem (2).
3) Beta-Lactam/Beta-Lactamase Inhibitors in Development
Several beta-lactam/beta-lactamase inhibitors are currently in development. Whereas meropenem-nacubactam remains in a phase 1 trial, the other combinations are currently recruiting for phase 3-trials (8). The table below summarizes their anticipated spectra.
Suggested reading:
• How to treat Stenotrophomonas maltophilia?https://www.infectiousdigest.com/post/stenotrophomonas-maltophilia-the-common-but-unknown-story
• Can piperacillin-tazobactam still be used in case of ESBL? https://www.infectiousdigest.com/post/is-piperacillin-tazobactam-still-a-valid-option-for-treating-infections-by-esbl-producing-bacteria-w
References:
1. Katsarou A, Stathopoulos P, Tzvetanova ID, et al. β-Lactam/β-Lactamase Inhibitor Combination Antibiotics Under Development. Pathogens. 2025 Feb 8;14(2):168.
2. Tamma PD, Heil EL, Justo JA, et al. Infectious Diseases Society of America 2024 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections. Clin Infect Dis. 2024 Aug 7:ciae403.
3. Grabein B, Arhin FF, Daikos GL, et al. Navigating the Current Treatment Landscape of Metallo-β-Lactamase-Producing Gram-Negative Infections: What are the Limitations? Infect Dis Ther. 2024 Nov;13(11):2423-2447.
4. Pogue JM, Harrington J, Wangchinda W, et al. New Perspectives on Antimicrobial Agents: Sulbactam-durlobactam. Antimicrob Agents Chemother. 2025 Oct;69(10):e0108624.
5. Pina-Sánchez M, Rua M, Candel FJ, et al. Therapeutic optimization against bacteria carrying metalloenzymes: the battle for class B. Rev Esp Quimioter. 2025 Oct 24;38 Suppl 1(Suppl 1):51-58.
6. Outeda-García M, Arca-Suárez J, Lence E, et al. Advancements in the fight against globally distributed OXA-48 carbapenemase: evaluating the new generation of carbapenemase inhibitors. Antimicrob Agents Chemother. 2025 Feb 13;69(2):e0161424.
7. Daikos GL, Cisneros JM, Carmeli Y, et al. Aztreonam-avibactam for the treatment of serious infections caused by metallo-β-lactamase-producing Gram-negative pathogens: a Phase 3 randomized trial (ASSEMBLE). JAC Antimicrob Resist. 2025 Jul 28;7(4):dlaf131.
8. Katsarou A, Stathopoulos P, Tzvetanova ID, et al. β-Lactam/β-Lactamase Inhibitor Combination Antibiotics Under Development. Pathogens. 2025 Feb 8;14(2):168.
9. Kaye KS, Shorr AF, Wunderink RG, Du B, Poirier GE, Rana K, Miller A, Lewis D, O'Donnell J, Chen L, Reinhart H, Srinivasan S, Isaacs R, Altarac D. Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK). Lancet Infect Dis. 2023 Sep;23(9):1072-1084.
Comments