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During the past decade there has been an increase in the percentage of resistant bacteria isolated from middle-ear effusions aspirated from infants and children who have had acute otitis media. At least nine oral antibiotics or combination agents are available for this indication. Cefixime, a third generation cephalosporin, has excellent in vitro activity against both beta-lactamase-negative and beta-lactamase-positive Haemophilus influenzae and Moraxella catarrhalis, good activity against Streptococcus pneumoniae and Streptococcus pyogenes but relatively poor activity against Staphylococcus aureus. In children cefixime is similar in effectiveness to amoxicillin and cefaclor, but diarrhea and stool changes are more common with cefixime. Amoxicillin is still preferred for initial empiric treatment of uncomplicated acute otitis media. Its major drawback is limited efficacy when beta-lactamase-producing bacteria are the causative organisms. Cefixime is a viable alternative to amoxicillin for infants and children with acute otitis media when: (1) a beta-lactamase-producing H. influenzae or M. catarrhalis is isolated from otorrhea or tympanocentesis; (2) the child has a history of delayed hypersensitivity to the penicillins but no history of hypersensitivity to the cephalosporins; (3) there is a high incidence of resistant bacteria in the community; (4) there is not clinical improvement with amoxicillin; or (5) once daily administration is more convenient.