Pasteurella multocida causes a wide variety of infections and is the most common localized soft tissue infection after animal bite injuries. Penicillin or amoxicillin has been considered agent of choice for therapy. Reported beta-lactamase production by some isolates, the therapeutic dilemma of the penicillin allergic patient, and the polymicrobial nature of some infections led to this study of alternate antimicrobial agents. The in vitro activity of ampicillin, amoxicillin/clavulanate, cefprozil, cefuroxime, erythromycin, clarithromycin, trimethoprim/sulfamethoxazole, ciprofloxacin, and tetracycline were compared to penicillin against 73 geographically diverse isolates of P. multocida from human infections collected since 1991. MIC90 (microgram/mL) were as follows: penicillin < or = 0.06; ampicillin < or = 0.5; amoxicillin/clavulanate < or = 0.5; cefaclor 1.0; cefprozil 1.0; cefpodoxime 0.06; cephalothin 2.5; cefuroxime < or = 0.25; erythromycin 2.0; azithromycin 1.0; clarithromycin 4.0; trimethoprim/sulfamethoxazole < or = 0.5/9.5; ciprofloxacin < or 0.25; tetracycline < or = 2.0. No beta-lactamase producing isolates were found in this study. This in vitro study has identified alternate oral agents to penicillins that may be appropriate for therapy of P. multocida infections.