Therapeutic management of bacterial infections often requires simultaneous use of more than one antimicrobial agent. Some of the reasons for use of multiple therapies include:
• Treating polymicrobial infections caused by organ isms with different antimicrobial resistance profiles
• Achieving more rapid bactericidal activity than may be achieved with any single agent
• Achieving bactericidal activity against bacteria for which no single agent is lethal
• Minimizing the emergence of resistant organisms during therapy
Testing the effectiveness of antimicrobial combinations against a single bacterial isolate is referred to as synergy testing. When combinations are tested, three outcome categories are possible:
• Synergy: the activity of the antimicrobial combination is substantially greater than the activity of the single most active drug alone
• Indifference: the activity of the combination is no better or worse than the single most active drug alone
• Antagonism: the activity of the combination is substantially less than the activity of the single most active drug alone (an interaction to be avoided)
The checkerboard assay and the time-kill assay are two basic methods of synergy testing. In the checkerboard method, MIC panels are set up containing two antimicrobial agents serially diluted independently and in com bination. After inoculation and incubation, the MICs obtained with the individual agents and the various combinations are recorded. By calculating the MIC ratios obtained with individual and combined agents, the drug combination in question is classified as synergistic, indifferent, or antagonistic.
With the time-kill assay, the same procedure described for testing bactericidal activity is used, except that the killing curve obtained with a single agent is compared with the killing curve obtained with antimicrobial combinations. Synergy is indicated when the combination exhibits killing that is greater by 100-fold or more than the most active single agent tested alone after 24 hours of incubation. Killing rates between the most active agent and the combination that are similar are interpreted as indifference. Antagonism is evident when the combination appears less active than the most active single agent.
The decision to use more than one antimicrobial agent may be based on antimicrobial resistance profiles or identification of particular bacterial pathogens reported by the clinical microbiology laboratory. However, the decision regarding which antimicrobial agents to combine should not rely on the results of complex synergy tests performed in the clinical laboratory. Most clinically useful antimicrobial combinations have been investigated in a clinical research setting and are well described in the medical literature. These data should be used to guide the decision for combination therapy. The technical difficulties associated with per forming and interpreting synergy tests, which at most would be performed only rarely in the clinical laboratory, precludes their utility in the diagnostic setting.
