Effect of Inoculum and of Beta-Lactamase on the Anti-Staphylococcal Activity of Thirteen Penicillins and Cephalosporins

Abstract

Because there are few persuasive data for selecting one semisynthetic penicillin or cephalosporin over another for treatment of serious staphylococcal infections, 118 recent clinical isolates of Staphylococcus aureus were studied to determine to what extent the presence of fl-lactamase affected the relative anti-staphylococcal activity of six penicillins and seven cephalosporins. In addition, the effect of inoculum was studied for its possible effect on the anti-staphylococcal activity of the 13 ,8-lactam antibiotics. By all criteria, methicillin and nafcillin were clearly more resistant to both the inoculum effect and the production of staphylococcal ,B-lactamase, whereas benzylpenicillin and cephaloridine (especially benzylpenicillin) were the most susceptible to these effects. Cephazolin was clearly more susceptible to staphylococcal #-lactamase and heavy inocula than the other cephalosporins (with the exception of cephaloridine), whereas cephalothin was the most resistant cephalosporin to these factors. The minimal inhibitory concentration for benzylpenicillin for tests with undiluted inoculum, compared to results with inoculum diluted 10-4, differed by a factor up to 16,384, whereas with methicillin and nafcillin the differences were rarely more than twofold. Ratios for the other 10 antibiotics fell between these extremes. These results suggest that methicillin or nafcillin is most stable to staphylococcal ,-lactamase, and that benzylpenicillin and cephaloridine are the most susceptible.

Transferable beta-lactamase. A new mechanism for in vitro penicillin resistance in Streptococcus faecalis.

“…Growth at a high inoculum was not observed with 30 other S. faecalis examined in this laboratory nor with numerous others in the literature (12)(13)(14); the MIC of penicillin for a representative strain, HH54 (also highly resistant to gentamicin), is also shown in Table I. The production of penicillinase, suggested by this inoculum effect (15)(16), was confirmed by demonstrating that HH22 inactivates penicillin (Fig. 1).…”

In Vitro Antibacterial Activity of AM-715, a New Nalidixic Acid Analog

“…Cross-resistance was not observed between AM-715 and various other antibiotics. The antibacterial activity of most /B-lactam antibiotics is known to be influenced by inoculum size (12,13). In contrast, the effect of inoculum sizes on the MICs and MBCs of AM-715, pipemidic acid, nalidixic acid, and miloxacin was found to be small, and that of AM-715 was smaler than those of other nalidixic acid analogs.…”

Use of a Heavy Inoculum in the In Vitro Evaluation of the Anti-Staphylococcal Activity of 19 Cephalosporins

“…Other in vitro studies showed large inoculum effects with cephalosporins (5,14), but in this study only cephaloridine and 87/312 consistently showed marked decreased anti-staphylococcal activity when tested against a heavy inoculum of methicillin-susceptible staphylococci.…”

“…However, most of the standard in vitro studies have shown little or no difference in the anti-staphylococcal activity of those newest cephalosporins in comparison with other cephalosporins that have been available for several years or more (5,15,17). Previous studies (3,14) have already established a certain correlation between the susceptibility of various cephalosporins to staphylococcal ,B-lactamase and the magnitude of the effect of the inoculum size when those same cephalosporins were tested against large and small inocula of staphylococci. In 1946, Luria showed that penicillinase-producing staphylococci, when diluted to the point that individual colonies were formed on agar plates, were almost as susceptible to penicillin G as were penicillinase-negative strains (9).…”