Combination Antimicrobial Therapy Against Metallo-β-Lactamase-Producing Pathogens

Metallo-β-lactamases (MBLs) represent a class of enzymes that confer resistance to virtually all β-lactam antibiotics, posing a severe threat to global public health. Unlike serine β-lactamases, MBLs employ zinc ions at their active sites to hydrolyse the β-lactam ring, rendering traditional carbapenems and cephalosporins ineffective. Combination antimicrobial therapy seeks to overcome this enzymatic defence by pairing agents that are intrinsically resistant to MBL hydrolysis—such as aztreonam—with potent β-lactamase inhibitors or adjuvants that neutralise co-produced serine β-lactamases and efflux mechanisms. Recent efforts have focused on dual or multitarget strategies: co-administration of aztreonam with novel inhibitors like avibactam, relebactam or vaborbactam; innovative efflux pump blockers; and phyto-derived scaffolds that bind multiple resistance determinants. Preclinical and clinical data indicate that such combinations can restore susceptibility in Enterobacterales and Pseudomonas aeruginosa strains harbouring New Delhi metallo-β-lactamase (NDM), Verona integron-encoded metallo-β-lactamase (VIM) or imipenem-resistant mechanisms. This approach not only broadens the therapeutic window of legacy antibiotics but also mitigates the selective pressure for emerging resistance when deployed judiciously. Clinical case reports and systematic in vitro assessments underline the global significance of these regimens, especially in regions with high carriage rates of MBL genes. Ongoing challenges include optimising dosing regimens, refining diagnostic synergy tests, and developing next-generation inhibitors with expanded spectra and minimal toxicity.

Research from Nature Portfolio

Clinical experience with pandrug-resistant Klebsiella pneumoniae emphasises the potential of aztreonam combined with ceftazidime-avibactam. In a documented case of infective endocarditis on a cardiovascular implant, the pathogen carried NDM-1, OXA-48 and additional β-lactamases, alongside resistance determinants for aminoglycosides and colistin. Traditional therapy failed to clear the infection despite prolonged courses of colistin, gentamicin and meropenem. The introduction of aztreonam plus ceftazidime-avibactam achieved rapid bactericidal synergy, leading to clinical resolution. Genomic analysis confirmed that the combination overcame both metallo- and serine-β-lactamase activity and circumvented non-β-lactam resistance mechanisms, demonstrating a proof-of-concept for treating high-risk MBL-producing infections with tailored dual-β-lactam strategies.

Combination Antimicrobial Therapy Against Metallo-β-Lactamase-Producing Pathogens publication trend

The graph below shows the total number of articles in combination antimicrobial therapy against metallo-β-lactamase-producing pathogens across all publications each year (not limited to Nature Index journals).

Technical terms

Metallo-β-lactamase (MBL): A zinc-dependent enzyme that hydrolyses most β-lactam antibiotics, including carbapenems, leading to high-level resistance.

β-lactamase inhibitor: A compound that binds to and inactivates β-lactamase enzymes, thereby protecting β-lactam antibiotics from hydrolysis.

Aztreonam: A monobactam antibiotic inherently resistant to metallo-β-lactamase hydrolysis, commonly used in combination regimens.

Minimum inhibitory concentration (MIC): The lowest concentration of an antimicrobial that visibly inhibits bacterial growth in vitro.

Synergy: The interaction of two or more agents resulting in enhanced antimicrobial activity compared with each agent alone.

References

1. Successful treatment of infective endocarditis due to pandrug-resistant Klebsiella pneumoniae with ceftazidime-avibactam and aztreonam. Scientific Reports (2021).
2. Potentiation of Antibiotic Activity of Aztreonam against Metallo-β-Lactamase-Producing Multidrug-Resistant Pseudomonas aeruginosa by 3-O-Substituted Difluoroquercetin Derivatives. Pharmaceutics (2024).
3. Aztreonam Combinations with Avibactam, Relebactam, and Vaborbactam as Treatment for New Delhi Metallo-β-Lactamase-Producing Enterobacterales Infections—In Vitro Susceptibility Testing. Pharmaceuticals (2024).
4. The Revival of Aztreonam in Combination with Avibactam against Metallo-β-Lactamase-Producing Gram-Negatives: A Systematic Review of In Vitro Studies and Clinical Cases. Antibiotics (2021).