Prevention of emergence of bacterial resistance by combination of two antibiotics: rifampicin and trimethoprim

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Abstract
Experiments have been performed using rifampicin (RIF) and trimethoprim (TRIM) to establish whether the use of the combination prevents the emergence of bacterial resistance to either drug. Experiments were performed using repeated 4 h cycles of exposure of large bacterial populations to varying concentrations of the antibiotics for up to 1 week in order to reproduce ‘in vitro’ either the conditions of treatment of a systemic infection in man, or of exposure of commensal bacteria in the bowel flora during treatment. In the treatment experiments, organisms sensitive to RIF and to TRIM were eliminated from the test cultures after 28 h by RIF + TRIM without emergence of resistance, whereas TRIM-resistant cultures exposed to RIF alone, doubly sensitive strains exposed to RIF alone, or TRIM-resistant bacteria exposed to RIF + TRIM, all became RIF-resistant in 12 to 24 h. RIF-resistant strains exposed to TRIM alone, doubly sensitive strains exposed to TRIM alone, or RIF-resistant bacteria exposed to RIF + TRIM, all became TRIM-resistant in 20 to 96 h. It is clear that under the test conditions the combination of RIF + RIM prevented the emergence of bacteria resistant to RIF or TRIM which was seen when each antibiotic was acting alone. It is argued that the test methods used are more likely to be reliable in predicting the emergence or non-emergence of resistance to antibacterial agents during combined chemotherapy than is the traditional single exposure culture technique. The experimental method described has a general applicability to all combinations of two antibiotics.

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