Definition of Antibiotic Synergy
Antibiotic synergy occurs when the combined effect of two or more antimicrobial agents exceeds the additive effects of the individual components when used alone. 1
Core Concept
- Synergistic action is present when the antimicrobial effect of a combination is greater than simply adding together the effects of each drug individually. 1
- This differs fundamentally from an additive effect, where the combination equals the sum of individual effects, or indifference, where the combination equals only the most active component. 1
Mathematical Quantification
The European Society of Clinical Microbiology and Infectious Diseases defines synergy using the Fractional Inhibitory Concentration (FIC) Index: 1
For two antibiotics A and B:
- FIC_A = (MIC_A in presence of B) / (MIC_A alone)
- FIC_B = (MIC_B in presence of A) / (MIC_B alone)
- FIC Index (ΣFIC) = FIC_A + FIC_B 1
Synergy is typically defined as ΣFIC ≤ 0.5, though specific threshold criteria are provided in standardized tables. 1
Clinical Context and Mechanisms
Three main mechanisms produce synergistic antimicrobial activity: 2
- Cell wall synthesis inhibitors combined with aminoglycosides (e.g., penicillin G with gentamicin against enterococci shows synergistic bactericidal effects) 3, 2
- Beta-lactamase inhibitors combined with beta-lactam antibiotics 2
- Agents acting on sequential steps in bacterial metabolic pathways 2
Important Caveats
- These synergistic effects are demonstrated in vitro, and their clinical significance remains unclear. 1
- Synergy is relatively rare—only 0.3% of tested isolate-antibiotic combinations show true synergy, while 87.1% are additive and 11.6% are antagonistic. 4
- Synergistic interactions can be isolate-specific within the same bacterial species, ranging from antagonistic to synergistic for a given antibiotic combination. 4
- Clinical studies show that synergistic combinations in vitro correlate with significantly better therapeutic responses (P < 0.01) in severe gram-negative infections. 5
Alternative Testing Methods
Beyond FIC calculations, synergy can be demonstrated using: 1