The antibacterial activity of cefamandole was evaluated against 120 methicillin-susceptible and methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococcal strains, using both large (108 CFU per ml) and small (104 CFU per ml) inocula. Cefamandole appeared superior to cephalothin against tnethicillin-resistant strains, displaying at 10 ,ug/ml a bacteriostatic and for some strains a bactericidal action against a large inoculum of bacteria.The cross-resistance reported between methicillin and cephalosporins for both coagulase-positive and coagulasenegative staphylococcal strains (1, 6, 10, 13, 15) represents a major therapeutic problem, as it precludes the use of cephalosporins in patients affected with methicillin-resistant (MR) strains. Hospital outbreaks of infection caused by multiplyresistant staphylococcus strains, even in countries where they have never been isolated previously (4,7,12,18), have renewed interest in this problem. Among the newer cephalosporins with a broadened spectrum of activity against gramnegative bacteria, only a few (e.g., cefamandole and cefazolin) maintain good antistaphylococcal activity comparable to that of cephalothin (2, 9, 11). We undertook to evaluate whether the generally observed cross-resistance between methicillin and cephalosporins is-valid for the second-generatlon cephalosporin cefamandole. For this purpose the bacteriostatic and bactericidal activities of cefamandole and cephalothin against methicillin-susceptible (MS) and MR staphylococci were studied.Sixty-six Staphylococcus aureus (36 MS and 30 MR) and 54 coagulase-negative staphylococci (18 MS and 36 MR) strains isolated from clinical specimens at the microbiology laboratory, Perugia University Medical School, Italy, were tested. Most of the isolates were fromn patients who had not received antibiotic prophylaxis or therapy.The Staphylococcus species were identified on the basis of conventional tests (8) visible growth after 24 h of incubation at 37°C, and then 0.1 ml was subcultured from wells containing the lower inoculum, and 0.001 ml was subcultured from wells containing the higher inoculum. After 48 h of incubation at 37°C, 99.9%killing was determined as the lowest antibiotic concentration yielding no growth on subculture of the wells containing the lower inoculum and 100 colonies or less from wells containing the higher inoculum.The results are reported in Table 1. Nearly all the MS strains were inhibited by the two antibiotics, which both lacked bactericidal activity at the large inoculum. The median MICs were two to three times higher for cefamandole, whereas the reverse was noted for the MBCs for S. aureus. For MR strains at the smiall inoculum, the median MICs were all in the therapeutic range, but 100% strains were susceptible to 10 ,ug of cefamandole per ml, whereas 13.3% S. aureus and 22.3% coagulase-negative staphylococci were resistant to 10 ,ug of cephalothin per ml.At the large inoculum, the median MICs of cephalothin were out of the therapeutic range (58.3 ,ug/ml for S. a...