Burkholderia cepacia complex (Bcc) is an opportunistic pathogen, posing little risk to healthy individuals. The presentation of Bcc can vary from a virtually asymptomatic chronic infection, to an acute, life-threatening necrotizing pneumonia, acute respiratory distress syndrome, and bacteremia (cepacia syndrome) associated with a mortality rate up to 75%. We present the successful treatment of a 17-year-old male with chronic granulomatous disorder who presented with cepacia syndrome and confirmed Bcc pneumonia using a novel antimicrobial approach. Despite initial IV antimicrobial therapy, our patient continued to decline, developing hypotension requiring pressor support and eventually extracorporeal membrane oxygenation. An aggressive, multimechanistic approach including the combination of nebulized tobramycin, IV sulfamethoxazole-trimethoprim, ceftazidime, enteral minocycline, and corticosteroids was implemented. This multimechanistic antimicrobial approach in combination with systemic corticosteroids led to the successful treatment of cepacia syndrome in the setting of necrotizing pneumonia due to B cepacia with full respiratory recovery. We suggest that in patients with cepacia syndrome who continue to decline despite IV antimicrobial therapy, using multiple antimicrobial mechanisms of action may improve clinical outcomes.