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Quadruple-Checkerboard: A Modification of the Three-Dimensional Checkerboard for Studying Drug Combinations
Published on: July 24, 2021
Advances and updates in antibiotic combination therapy
Claudia Bartalucci1, Chiara Sepulcri1, Federica Portunato2
1Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.
Introduction:
While antibiotic combination therapy remains a common clinical practice, its scientific foundation is fragile. The available evidence is fragmented, biased, and fails to capture the complexity of modern infectious disease scenarios. This perspective reinterprets the role of combination therapy through a critical lens, challenging current dogmas and proposing a pathogen-specific approach, focusing also on severe acute infections.
Areas Covered:
This Critical Perspective focused on selected studies from 2018 to 2025 identified through a focused PubMed search on the place in therapy and efficacy of antibiotic combinations on main gram-positive (Streptococcus spp. Enterococcus spp. and Staphylococcus aureus) and gram-negative (Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia) pathogens.
Expert Opinion:
After reviewing the current available literature, in our opinion, a strong indication to use antibiotic combination therapy can be only for specific situations and clinical syndromes (such as endocarditis, toxic shock syndrome due to S. pyogenes, or persistent bacteremia due to S. aureus and few others). However, especially in severe infections due to gram negatives, clinical trial and strong data are insufficient to draw definite clinical indications. Consequently, further randomized clinical trial should be performed, and they should include new antibiotics to define the potential role of combination therapy.
Insights
Antibiotic combination therapy lacks strong evidence for broad use. A pathogen-specific approach is needed, with more clinical trials required to define its role in severe gram-negative infections.
Area of Science:
- Infectious Diseases
- Pharmacology
- Clinical Microbiology
Background:
- Antibiotic combination therapy is a common practice but lacks a robust scientific foundation.
- Existing evidence is fragmented and does not fully address complex modern infectious disease scenarios.
Purpose of the Study:
- To critically re-evaluate the role of antibiotic combination therapy.
- To propose a pathogen-specific approach for antibiotic use, particularly in severe infections.
Main Methods:
- Focused PubMed search of studies from 2018-2025.
- Review of antibiotic combinations for key gram-positive and gram-negative pathogens.
Main Results:
- Strong indications for combination therapy are limited to specific syndromes like endocarditis or toxic shock.
- Insufficient data exists for definite clinical indications in severe gram-negative infections.
Conclusions:
- Antibiotic combination therapy should be reserved for specific clinical situations.
- Further randomized clinical trials, including novel antibiotics, are necessary to clarify its role, especially for gram-negative pathogens.
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