The emergence of beta-lactamase-mediated resistance to established beta-lactum antibiotics prompted the development of beta-lactamase inhibitors for co-administration. Ampicillin has been combined with sulbactam for both parenteral and oral (as the mutual pro-drug sultamicillin) administration. The combination is active in vitro against a wide variety of Gram-positive and Gram-negative pathogens, including aerobic and anaerobic organisms. In clinical trials, ampicillin/sulbactam has proved clinically and bacteriologically effective against a variety of frequently encountered pediatric infections, including mild-to-moderate upper respiratory tract infections (acute otitis media, sinusitis, pharyngitis, and tonsillitis), severe postoperative and intra-abdominal infections, periorbital infections (which, left untreated, can lead to blindness, brain abscess, or death), acute epiglottitis, bacterial meningitis, and brain abscess. Ampicillin/sulbactam has also proved effective in the prevention of post-operative surgical infections in pediatric patients. The clinical efficacy profile of ampicillin/sulbactam and sultamicillin, combined with their excellent tolerability profile, make these agents attractive options for the management of many life-threatening infections in pediatric patients.