The in vivo efficacy of streptomycin (STR), doxycycline (DOX), rifampin (RIF), ciprofloxacin (CIP), and their combinations was evaluated for a Brucella melitensis experimental infection in a mouse model. Animals were infected with 2 x 10(4) to 4 x 10(4) CFU of B. melitensis intraperitoneally on day 0 and were randomized to receive, starting on day 7, STR alone at 75, 150, or 300 mg/kg of body weight per day intraperitoneally or DOX at 6 mg/kg/day orally, RIF at 3 mg/kg/day orally, or CIP at 200 mg/kg/day orally, each of the last three drugs alone or in combination with STR at 75, 150, or 300 mg/kg/day, for 14 days. Therapy failure (defined as nonsterile spleens) was observed in all animals treated with STR at all doses and with CIP given as monotherapy. Mean log CFU isolated from the spleens remaining infected following monotherapy with STR or CIP were not different from those in control mice. RIF at a low dose did not have an effect on cure rates; however, a reduction in CFU relative to the CFU in untreated animals was obtained. DOX at low levels achieved a 35% cure rate and a reduction in CFU in animals not cured. All animals treated with DOX or RIF combined with any STR dose were cured, but none of the animals receiving the STR-CIP combinations was cured, and the splenic CFU remained similar to those in the controls. These results demonstrate that the combinations DOX-STR and RIF-STR are synergistic against B. melitensis, while the combination STR-CIP is indifferent and ineffective in the management of acute murine brucellosis. The results also appear to support the clinical superiority of combination drug therapy over monotherapy.