Cefditoren, a third generation orally administered aminothiazolyl cephalosporin, has demonstrated bactericidal activity against many Gram positive and negative bacterial pathogens and stability against clinically important β-lactamases. Cefditoren was compared to cefaclor, cefixime, and penicillins against 1 435 recently isolated strains of streptococci (312 Streptococcus pneumoniae, 165 viridans group streptococci, 142 β-haemolytic streptococci), Haemophilus influenzae (521 strains), and Moraxella catarrhalis (295 strains). Streptococcus pneumoniae and viridans group streptococci had penicillin nonsusceptible rates of 37.8 and 35.8%, respectively. Cefditoren (MIC 90 in μg/ml/% susceptible) activity against all tested H. influenzae (0.03/100) and M. catarrhalis (0.06–0.5/100) was comparable to cefixime and significantly greater than cefaclor. Cefditoren (MIC 90, 0.5 μg/ml) was 4- to 128-fold more active than comparison β-lactams against the pneumoococci and was the most potent β-lactam (including penicillin) versus β-haemolytic streptococci. Cefditoren pharmacokinetics demonstrate a T 1/2 of 1.5–2 h and C max values of 2.8 and 4.6 μg/ml, respectively with 200 or 400 mg doses of cefditoren pivoxil; plasma concentrations exceed 1 μg/ml for 4 to 6 hours (33–50% of dosing interval). Consequently, a susceptible MIC of ≤ 1 μg/ml or ≤ 2 μg/ml was proposed with zone diameter correlates of ≥ 18 and ≥ 15 mm (5-μg disk) for all cited fastidious species tested. Categorical agreement between MIC and disk tests was 94.6 to 100% with a correlation coefficient (r) range of 0.50 to 0.90 for streptococci. H. influenzae intermethod comparison results using the same interpretive criteria were in complete agreement, but exhibited a low r = 0.39. Cefditoren clearly possesses the most potent activity among currently studied oral cephalosporins or penicillin against commonly isolated bacterial pathogens causing bronchitis, pneumonia, sinusitis, or pharyngitis and was active against nearly all penicillin-resistant streptococci at ≤ 0.5 μg/ml. Expanded clinical investigations seem warranted.