A rabbit perforated-capsule model was utilized to study antimicrobial efficacy in treating 2-week-old Staphylococcus aureus abscesses. Animals received either ciprofloxacin (30 mg/kg), cefazolin (100 mg/kg), or ciprofloxacin (30 mg/kg) plus rifampin (20 mg/kg) every 8 h for 8 days or no antibiotic. Antibiotic levels within the abscess exceeded the MIC for the test organism. At the end of treatment, ciprofloxacin was no more effective than the control, animals receiving cefazolin had a mean log1o fall of 2.41 CFU/ml, and animals receiving ciprofloxacin plus rifampin had a mean loglo reduction of 5.06 CFU/ml (P s 0.01). Six days after completion of therapy, all abscesses in animals receiving ciprofloxacin plus rifampin were culture negative. Surviving organisms in animals receiving ciprofloxacin or rifampin did not develop resistance to the treatment antibiotics. In vitro time-kill curves performed with logarithmic-and stationary-phase organisms in broth, serum, and abscess fluid supernatants did not correlate with the in vivo results. Neutrophil killing studies of S. aureus pretreated with antibiotics revealed greater killing of organisms pretreated with ciprofloxacin plus rifampin than of those pretreated with cefazolin or ciprofloxacin alone. In conclusion, ciprofloxacin plus rifampin was effective therapy in this staphylococcal abscess model, compared with the moderate efficacy of cefazolin and no effect observed with ciprofloxacin alone. Enhanced neutrophil killing of S. aureus pretreated with antibiotics may be an important mechanism by which bacteria are killed in suppurative infections.
Clinical reports and animal models have demonstrated that cefazolin may have decreased efficacy against some strains of Staphylococcus aureus because of type A 1-lactamase-mediated hydrolysis. We sought to measure biologically active cefazolin concentrations within abscesses with high concentrations of S. aureus and compare the concentrations with those of cefmetazole, a j3-lactamase-stable cephamycin. A type A 13-lactamaseproducing strain of S. aureus with a demonstrated inoculum effect against cefazolin (MIC at an inoculum of 5 x 10' CFU/ml, 1.0 ,ug/ml; MIC at an inoculum of 5 x 107 CFU/ml, 32.0 ,ug/ml) but not cefmetazole (MICs at inocula of 5 x 105 and 5 x 107 CFU/ml, 2.0 ,g/ml) was used. Cefazolin or cefmetazole (100 mg/kg of body weight every 8 h for 8 days) was administered to rabbits with infected tissue cages. No differences in the concentrations of the two drugs in the uninfected tissue cages were observed. Higher concentrations of cefmetazole than cefazolin were found in infected tissue cages at day 3 (5.9 0.7 versus 2.2 + 0.3 ,ug/ml; P < 0.01), day 5 (9.1 + 2.6 versus 3.6 + 0.7 ,ug/ml; P = 0.02), and day 8 (9.4 + 1.4 versus 4.8 + 0.9 tig/ml; P = 0.01) after infection. Cefazolin and cefmetazole were equally effective in reducing the bacterial concentration in the abscess. In vitro experiments demonstrated greater cefazolin than cefmetazole degradation by S. aureus, but the differences were greater in serum than in abscess fluid supernatants. We conclude that abscess cefazolin concentrations are diminished by type A P-lactamase-producing S. aureus, but this did not affect drug efficacy in this model. Some cephalosporins, especially cefazolin and cephaloridine, are relatively more susceptible in vitro to staphylococcal P-lactamases (20). Despite reports of cephalosporin failure in the treatment of Staphylococcus aureus infections in humans (3) and in animal models (5, 9), the relevance of these findings remains controversial, in part because of the presence of conflicting reports (4).Some of the discrepancies reported may be due to differences in staphylococcal ,B-lactamases. Zygmunt et al. (27) demonstrated that type A ,B-lactamase more efficiently hydrolyzes cefazolin and cephaloridine than cefamandole and cefuroxime. In contrast, type B and type C 13-lactamases more efficiently hydrolyze cefamandole than cefazolin. A small number of clinical trials also suggest that P-lactamase activity may be clinically important. Although conflicting data have been reported (6), some studies of cephalosporins used as prophylaxis in cardiac surgery have indicated that either cefamandole (13, 22) or cefuroxime (22) is more effective than cefazolin in prophylaxis of S. aureus wound infections. In addition, Kernodle et al. (14) demonstrated that staphylococcal type A ,B-lactamase production is associated with a greater number of clean wound infections with cefazolin prophylaxis than with cefamandole prophylaxis. No studies have measured the degree of staphylococcal 1-lactamase inactivation at the infection site and cor...
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