Combination Therapy for Multidrug-Resistant Bacterial Infections

Combination therapy employs two or more antimicrobial agents with complementary mechanisms of action to overcome bacterial resistance, enhance bactericidal activity and prevent the emergence of resistant subpopulations. By pairing drugs that target distinct pathways—such as cell-wall synthesis, protein synthesis and membrane integrity—clinicians can achieve synergistic killing while minimising toxicity through dose reduction. This approach is particularly critical for infections caused by carbapenemase-producing Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii, where monotherapy options are rapidly diminishing. Beyond conventional antibiotics, combinations may include β-lactamase inhibitors, antibiotic adjuvants or repurposed non-antibiotic compounds that disrupt resistance mechanisms. Preclinical models and observational studies suggest that optimised combinations can suppress mobile resistance elements, reduce pathogen burden in biofilms and improve clinical outcomes in bloodstream and pulmonary infections. Global implementation requires integration of rapid diagnostics, antimicrobial stewardship and pharmacokinetic/pharmacodynamic modelling to tailor regimens to pathogen profile, infection site and patient factors.

Research from Nature Portfolio

Systematic analysis of randomised and observational studies has demonstrated that combination antimicrobial regimens confer a mortality benefit over monotherapy for infections due to multidrug-resistant Gram-negative bacteria. The greatest reduction in death rates was observed in bloodstream infections and when at least two agents were active in vitro. While data from case-control studies and limited clinical trials remain heterogeneous, subgroup analyses indicate superior outcomes with dual or triple therapy in high-risk settings, particularly for carbapenemase-producing Enterobacteriaceae. The review underscores the need for high-quality trials to define optimal agent pairs, dosing strategies and duration of therapy.

Combination Therapy for Multidrug-Resistant Bacterial Infections publication trend

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

Technical terms

Multidrug-resistant (MDR) bacteria: Bacterial strains non-susceptible to at least one agent in three or more antimicrobial classes.

Synergy: Interaction between drugs resulting in greater combined antimicrobial effect than the sum of their individual effects.

Resistome: The collection of all antibiotic-resistance genes present in a microbial community.

Antibiotic adjuvant: A non-antibiotic compound that enhances the activity of an antimicrobial agent or inhibits resistance mechanisms.

Hollow-fibre infection model: An in vitro system that mimics human drug pharmacokinetics to study antimicrobial efficacy and resistance evolution over time.

References

1. A metagenomic analysis for combination therapy of multiple classes of antibiotics on the prevention of the spread of antibiotic-resistant genes. Gut Microbes (2023).
2. Drug repurposing for next-generation combination therapies against multidrug-resistant bacteria. Theranostics (2021).
3. Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and blaNDM-5: Preparation for a Postantibiotic Era. mBio (2017).
4. Monotherapy versus combination therapy for multidrug-resistant Gram-negative infections: Systematic Review and Meta-Analysis. Scientific Reports (2019).