The critical relationship of antibiotic dose and bacterial contamination in experimental infection.
Even though the usefulness of prophylactic antimicrobial administration for potentially contaminated operations is widely accepted, infection continues to occur in a finite number of cases. This study examined whether potential infection due to an increasing bacterial inoculum can be prevented or controlled by increasing antimicrobial doses. In an initial set of experiments, Sprague-Dawley rats were given various doses of cefazolin (15, 30, 60, 120 mg/kg) intraperitoneally, then serum and tissue levels were quantified. Serum and tissue drug concentrations correlated with the dose given. In another set of experiments, rats were given doses of either 0, 30 (standard dose), 60, or 120 mg/kg of cefazolin 30 min prior to subcutaneous inoculation of various doses of Staphylococcus aureus. After 6 days, inoculum sites were examined for abscess formation and size. At low levels of contamination, increasing in antibiotic dose to 30, 60, and 120 mg/kg, abscess formation was eliminated at 50, 80, and 92% of inoculum sites, respectively. At moderate levels of contamination, abscesses formed at all inoculum sites, but abscess size was significantly smaller as the dose increased. When a high inoculum of S. aureus was given, large doses of antibiotics provided no additional benefit. These data suggest that the risk of infection in this model of experimental infection is significantly related to the size of the bacterial inoculum. Increasing the dose of an effective antimicrobial increases drug concentration at the site of contamination and reduces the risk of infection. Administration of higher doses of prophylactic antimicrobials may be more effective when larger amounts of bacterial contamination are anticipated.