Burkholderia pseudomallei is the causative agent of melioidosis, a disease endemic in tropical and subtropical regions of South-East Asia and Northern Australia. Antimicrobial therapy regimens for treatment of acute septicemic melioidosis are of variable efficacy. Ceftazidime is the current antibiotic of choice and is commonly administered with other agents such as cotrimoxazole or doxycycline. The emergence of resistant strains of B. pseudomallei and the persistence of high mortality rates prompted the present study. Using an established mouse model of acute disseminated B. pseudomallei infection, we compared the efficacy of ceftazidime versus cefpirome in combination with cotrimoxazole or chloramphenicol therapy in vivo. Control mice that were infected but did not receive antibiotic therapy died within 96 hours of infection. No deaths occurred in treatment groups receiving either cephalosporin or cotrimoxazole, despite the demonstrated resistance of B. pseudomallei to cotrimoxazole in vitro. The mortality rate in treatment groups receiving either cephalosporin and chloramphenicol was 66%. These results demonstrate a comparable level of efficacy between ceftazidime and cefpirome for treatment of acute B. pseudomallei infection in mice.