Treatment of Experimental Staphylococcus aureus Endocarditis: Comparison of Cephalothin, Cefazolin, and Methicillin

Abstract

The effectiveness of cefazolin in Staphylococcus aureus endocarditis has been questioned because of in vitro inactivation by staphylococcal beta-lactaase. Cefazolin, although inactivated in vitro by S. aureus beta-lactamase, was as effective as cephalothin in the treatment of left-sided S. aureus endocarditis in rabbits. Cefazolin (20 mg/kg every 6 or 8 h), cephalothin (40 mg/kg every 6 h), and methicillin (40 mg/kg every 6 h), administered intramuscularly, were compared in the treatment of left-sided endocarditis caused in rabbits by a highly penicillin-resistant strain of S. aureus. The three antibiotics were all effective in reducing titers in vegetations. However, at the dose used, methicillin reduced the titers more rapidly than cephalothin or cefazolin. Cefazolin concentrations in serum were about double those achieved with cephalothin or methicillin. However, cefazolin was only half as active as methicillin and oneeighth as active as cephalothin in vitro in a serum assay. The half life in serum of cefazolin, cephalothin, and methicillin were each about 30 min. Serum bactericidal activities of the three antibiotics were very similar.Cefazolin (CZ) is much more susceptile to inactivation by Staphylococcus aureus betalactamase than cephalothin (CF) (7), raising doubts about the usefulness of CZ in staphylococcal endocarditis (2). This study compares the efficacy of CZ, CF, and methicillin (M) in the therapy of left-sided endocarditis in rabbits, caused by a highly penicillin-resistant, methicillin-susceptible strain of S. aureus, which rapidly inactivates CZ in vitro. MATERIALS AND METHODSOrganism. A strain of S. aureus obtained from the blood of a patient with endocarditis was used in all experiments. The minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations of CZ, CF, M, and penicillin G were determined by using an antibiotic dilution method in both heart infusion broth (HIB; Difco Laboratories, Detroit, Mich.) and pooled rabbit serum (Microbiological Associates, Inc., Bethesda, Md.). The antibiotics were diluted in twofold steps in tubes containing 0.5 ml of HIB or serum. The bacterial inoculum for each tube was 0.5 ml of a 10-2 dilution in HIB or serum of an 18-h HIB culture. The MIC was considered to be the lowest concentration of antibiotic that prevented turbidity after 24 h of incubation at 370C. After the MIC was determined, 0.01 ml of each clear tube was streaked on the surface of a sheep blood agar plate with a sterile platinum loop. The minimal bactericidal concentration was the lowest concentration of antibiotic that resulted in no growth on the plate after 48 h at 370C. Stock cultures were made by incubating the organism in HIB at 37°C for 24 h and storing 1-ml portions at -20°C. For each experiment, a portion was subcultured into HIB, incubated at 37°C for 18 h, and diluted in HIB or serum.In vitro studies. The rate at which the S. aureus was killed was studied in flasks with HIB containing CZ, CF, or M. The inoculum in HIB was added to each flask and incubated at 370...

Effectiveness of Nafcillin, Methicillin, and Cephalothin in Experimental Staphylococcus aureus Endocarditis

“…These results agree with those of a previous study (3) in which M reduced titers of the same strain in vegetations more rapidly than C or cefazolin.…”

“…At time of sacrifice, right atrial blood cultures were positive for S. aureus in one of nine N-treated rabbits, 3 of 11 M-treated rabbits and 3 of 7 C-treated rabbits.…”

“…A previously studied strain of S. aureus obtained from the blood of a patient with endocarditis was used in all experiments (3). The minimal inhibitory concentrations (MICs) of N, M, and C were determined by using an antibiotic dilution method in both heart infusion broth (HIB; Difco Laboratories, Detroit, Mich.) and pooled rabbit serum (Microbiological Associates, Inc., Bethesda, Md.)…”

“…The final concentrations of antibiotics were 20 ug/ml, and the final concentrations of S. aureus were 4 x 107 celLs per ml. Samples were removed from the flasks at the start of the experiment and at 3,6, and 24 h. Each sample was serially diluted in 10-fold steps in HIB, and 0.1 ml of each dilution and 1 ml of undiluted sample were plated on the surfaces of blood agar plates. After incubation at 370C for 48 h, the numbers of colonies on the plates were counted and the colony-forming units (CFU) in the flasks were calculated.…”

“…In a previous study of experimental Staphylococcus aureus endocarditis from this laboratory, methicillin (M) seemed to sterilize vegetations more rapidly than did cephalothin (C) or cefazolin (3). The present study was undertaken to compare C with M and another penicillianaseresistant penicillin, nafcillin (N), in staphylococcal endocarditis.…”