Combination Therapy for Carbapenem-Resistant Klebsiella pneumoniae Infections

Carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a major global health threat owing to its capacity to evade last-line β-lactam antibiotics. Combination therapy seeks to harness synergistic interactions between two or more antimicrobial agents to overcome resistance mechanisms such as carbapenemase production and efflux pump upregulation. Regimens often pair carbapenems with polymyxins, aminoglycosides or novel β-lactamase inhibitors, exploiting complementary modes of action to enhance bacterial killing, prevent resistance emergence and improve clinical outcomes. In vitro studies demonstrate that certain combinations can restore activity against planktonic and biofilm-embedded CRKP, while observational clinical cohorts report reduced mortality and higher rates of microbiological eradication. Key challenges include optimising dosing to maximise synergy and minimise toxicity, selecting partners based on local resistance profiles and confirming efficacy in randomised trials. Emerging strategies such as double carbapenem therapy, ceftazidime–avibactam plus aztreonam and triple-agent regimens highlight the dynamic evolution of combination approaches. As new agents become available, integrated pharmacokinetic/pharmacodynamic modelling and robust clinical evidence will be essential to guide practice and curb the spread of CRKP.

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Combination Therapy for Carbapenem-Resistant Klebsiella pneumoniae Infections publication trend

The graph below shows the total number of articles in combination therapy for carbapenem-resistant klebsiella pneumoniae infections across all publications each year (not limited to Nature Index journals).

Technical terms

Carbapenem-resistant: Bacteria not inhibited by carbapenem antibiotics due to enzymatic degradation or membrane alterations.

Combination therapy: Concurrent use of two or more antimicrobial agents to enhance efficacy and suppress resistance.

Synergy: Interaction between drugs that produces an effect greater than the sum of their individual activities.

Bactericidal: Capability of an agent or regimen to kill bacteria rather than merely inhibiting their growth.

Biofilm: Structured microbial community attached to a surface and embedded in a protective extracellular matrix, often exhibiting increased drug tolerance.

Klebsiella pneumoniae carbapenemase (KPC): Enzyme produced by some K. pneumoniae strains that hydrolyses carbapenems and other β-lactams, conferring high-level resistance.

References

1. Meropenem plus Ertapenem and Ceftazidime–Avibactam plus Aztreonam for the Treatment of Ventilator Associated Pneumonia Caused by Pan-Drug Resistant Klebsiella pneumonia. Antibiotics (2024).
2. In Vitro antibiotic combinations of Colistin, Meropenem, Amikacin, and Amoxicillin/clavulanate against multidrug-resistant Klebsiella pneumonia isolated from patients with ventilator-associated pneumonia. BMC Microbiology (2023).
3. Double carbapenem as a rescue strategy for the treatment of severe carbapenemase-producing Klebsiella pneumoniae infections: a two-center, matched case–control study. Critical Care (2017).