Joseph R. Guarini

SK&F 75073, New Parenteral Broad-Spectrum Cephalosporin with High and Prolonged Serum Levels

SK&F 75073, a new parenteral cephalosporin, was found to have broad in vitro and in vivo antibacterial activity including isolates usually resistant to cephalothin and cefazolin. This activity included indole-positive Proteus and Enterobacter species and some Serratia isolates. Proteus mirabilis strains were particularly susceptible, as were Haemophilus influenzae and Neisseria species. The activity of SK&F 75073 against gram-positive bacteria was poorer than that of the control cephalosporins. This cephalosporin is highly bound to serum proteins, and a loss in in vitro activity was observed in the presence of serum. Parenteral administration of SK&F 75073 to experimental animals (mice, dogs, squirrel monkeys) resulted in high and prolonged serum levels when compared with cefazolin and other injectable cephalosporins. This favorable serum profile was reflected in the excellent protection observed in mice infected with pathogenic bacteria.

Disk Susceptibility Studies with Cefazolin and Cephalothin

Cefazolin and cephalothin disk susceptibility and minimal inhibitory concentration determinations were conducted on 591 clinical isolates. Cefazolin demonstrated superior activity, as shown by lower minimal inhibitory concentrations, and a greater percentage of isolates inhibited in the disk susceptibility test. The cephalothin antibiotic class disk by the standard Bauer-Kirby method failed to detect susceptibility to cefazolin in a significant percentage of Escherchia coli, Enterobacter species, and Enterococcus isolates. A separate cefazolin disk with a susceptibility cut-off point of 18 mm is recommended. An alternative to a separate cefazolin disk would be a reinterpretation of the cephalothin susceptibility disk zone diameters so that it would more adequately predict cefazolin activity.

Relationships between in vitro susceptibility and efficacy in experimental mouse infection-protection assay of cefazolin and cephalothin using Escherichia coli strains.

The disc sensitivity and minimal inhibitory concentrations (MIC) of cefazolin and cephalothin were compared against a series of Escherichia coli isolates. These data were correlated with the mouse protective doses of the 2 cephalosporins in animals infected with E. coli strains selected according to their various degrees of in vitro sensitivity to the 2 cephalosporins. The overwhelming majority of E. coli strains showed a significantly higher degree of susceptibility and lower MIC values for cefazolin than for cephalothin. There has been found a good correlation between the inhibition zones and especially the MIC values and the ED50 results for both cephalosporins. Using E. coli clinical isolates, cefazolin was found to be superior to cephalothin not only in vitro experiments but also more potent in protecting the experimentally infected mice.