Septicemic melioidosis is often fatal despite treatment with antibiotics such as ceftazidime to which Burkholderia pseudomallei, the causal pathogen, is sensitive in vitro. We report a near-fatal case of septicemic melioidosis with persistent B. pseudomallei bacteremia despite intravenous ceftazidime in which combination therapy with meropenem and ciprofloxacin, splenectomy and correction of metabolic acidosis allowed for hospital discharge. The choice of antibiotic agents was supported by intracellular minimum inhibitory concentration analysis using B. pseudomallei co-culture in Acanthamoeba trophozoites. The patient's B. pseudomallei isolates were indistinguishable by pulsed-field gel electrophoresis from clinical and environmental isolates previously analyzed during investigation of a Western Australian melioidosis outbreak. A combination of antibiotics known to possess intracellular activity against B. pseudomallei, surgery and supportive critical care may provide a means of improving the probability of survival in persistent septicemic melioidosis.