We compared the pharmacology ofcefamandole and cephalothin in six healthy adult male volunteers. After a 1-g, 20-min intravenous (i.v.) infusion, the average peak blood level of cefamandole was 87.6 versus 64.1 ,ug/ml for cephalothin. An i.v. infusion of 500 mg/h for 2 h (after a loading dose of 750 mg) gave an average steady-state blood level of 28.5 ,g/ml for cefamandole and 18.2 ug/ml for cephalothin. Mean peak serum levels after 1 g intramuscularly were similar for the two antibiotics (about 21 ,ug/ml), but with cefamandole they persisted longer, and the area under the blood level curve was about 25% greater. The average ti as determined from both i.v. studies was 34 min for cefamandole versus 30 min for cephalothin. The mean serum clearance for cephalothin, due to its partial conversion to a metabolite, was much greater than for cefamandole (425 versus 272 ml/min per 1.73 m2), but the renal clearances were similar for the two antibiotics (268 versus 257 ml/min per 1.73 m2). Other values for cefamandole and cephalothin were: 24-h urinary excretion, 80 and 66%; serum protein binding, 74 and 70%; and apparent volume of distribution, 12.8 and 18.5 liters/1.73 m2, respectively. Thus, the pharmacology of the two antibiotics was similar. Blood levels were somewhat higher with cefamandole i.v., but the results suggest that dosage regimens should be the same for the two antibiotics.

These studies extend the recent observation that cefazolin is inactivated to a greater extent than cephaloridine by some strains of penicillinase-producing Staphylococcus aureus, whereas cephalothin undergoes little if any inactivation. In Mueller-Hinton broth (inoculum, 3 x 106) 100 recently isolated strains had minimal inhibitory concentrations (MICs) c 2 ,ug/ml for cephalothin and cephaloridine, whereas in Trypticase soy broth (TSB) 50% had MICs > 2 ,ug/ml and 10% (designated "resistant" strains) were >8 ,ug/ml for cephaloridine but remained c2 ,ug/ml for cephalothin. A large inoculum (3 x 107) of strains with high MICs in TSB almost completely inactivated 50 ,ug of cefazolin per ml in 6 h, with progressively less inactivation, in the following order, of cephaloridine, cephalexin, cephradine, cephapirin, and cefamandole; cefoxitin and cephalothin underwent little if any inactivation. The greater inactivation in TSB than in Mueller-Hinton broth appeared to be due to a greater production of ,3-lactamases by each colony-forming unit, since the inoculum size in the two broths was not significantly different. In contrast, "susceptible" strains (MICs s 2 ,ug/ml in both broths) inactivated cephaloridine more than cefazolin, and equal amounts of powdered bacterial extracts confirmed the fact that qualitatively different (3-lactamases were produced by the susceptible and resistant strains. Disk diffusion tests were unreliable in separating the two groups of staphylococci. The clinical significance of inactivation by strains with high MICs is not known but, unless susceptibility can be clearly established, cephalothin appears preferable for severe staphylococcal infections, since it undergoes little if any inactivation by any strains of staphylococci.Benner et al. (2) showed in 1965 that 50%o of strains of Staphylococcus aureus had minimal inhibitory concentrations (MICs) higher than 2 gg/ml for cephaloridine and that large inocula of these relatively resistant strains caused inactivation of the antibiotic. With cephalothin, in contrast, the MICs were invariably 2 ,ug/ml or less and there was little if any inactivation. It has subsequently been recommended by some authorities that cephaloridine be used in the treatment of severe staphylococcal infections only when susceptibility of the infecting strains can be reliably established in vitro (8). Regamey et al. (7) have recently reported that cefazolin is even more rapidly degraded by strains that inactivate cephaloridine. This study compares the relative susceptibility to inactivation of eight cephalosporins and further differentiates the characteristics of strains that cause marked destruction of cephaloridine from those that do not.

Cefazolin was more susceptible than cephaloridine and cephalothin to in vitro inactivation by coagulase-positive, penicillinase-producing strains of Staphylococcus aureus. Inactivation (which was greater with methicillin-resistant than with methicillin-sensitive strains) was demonstrated by assay of the antibiotics in broth cultures with simultaneous colony counts and by exposure of the antibiotics to penicillinase powders extracted from S. aureus. Cefazolin was destroyed to a greater extent than was cephaloridine, whereas cephalothin underwent little, if any, destruction. The clinical implications of this degradation, thought by some to be of importance for cephaloridine, might also apply to cefazolin.

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