Vancomycin was used alone and in combination with rifampin in the treatment of experimental osteomyelitis due to Staphylococcus aureus in rabbits. Treatment with 60 mg of vancomycin/kg of body weight twice a day for 28 days was ineffective in sterilizing infected rabbit bones. Rifampin (40 mg/kg) injected once a day for 28 days sterilized 57% of infected rabbit bones. Treatment with a combination of vancomycin and rifampin for either 14 or 28 days was significantly more effective than either drug used alone, sterilizing 84% and 90%, respectively, of the infected bones of treated animals. A possible explanation for the failure of vancomycin when used alone may be that its in vitro activity against the infecting strain of S. aureus (as measured by minimal inhibitory concentrations or minimal bactericidal concentrations) was substantially less under anaerobic conditions (that is, at partial pressures of oxygen analogous to those in osteomyelitic bones) than under aerobic conditions.

Aziocillin and tobramycin were used alone and in combination in the treatment of chronic osteomyelitis due to Pseudomonas aeruginosa in rabbits. This combination showed in vitro synergy measured by both the checkerboard technique and time-kill curves. A marked inoculum effect was demonstrated in vitro with azlocillin and the infecting strain of P. aeruginosa. The minimal inhibitory concentration of azlocillin, with an inoculum of 105 organisms, was 12.5 ,ug/ml; when the inoculum size was increased to 107 organisms, the minimal inhibitory concentration rose to more than 500 ,ug/ml. In therapeutic trials, the combination of azlocilhin and tobramycin, given for 28 days, was significantly better than either no therapy or azlocillin alone, but was not significantly better than tobramycin alone. Even after 4 weeks of combined therapy with azlocillin and tobramycin, P. aeruginosa was recovered from the bones of 60% of the treated rabbits.A previous study in an experimental model of osteomyelitis caused by Pseudomonas aeruginosa showed that the combination of carbenicillin and sisomicin was significantly more effective (when administered for 4 weeks) than either agent alone (5). However, that combination failed to sterilize the bones of 30% of the rabbits treated, and it was apparent that a more effective regimen would be desirable. Azlocillin and tobramycin were selected for further testing in this experimental model. Tobramycin is as active in vitro as sisomicin against the infecting strain of P. aeruginosa; azlocillin showed considerably greater activity than carbenicillin in initial in vitro testing against the infecting strain of P.aeruginosa. It seemed plausible that azlocillin, either alone or in combination with tobramycin, might be an effective regimen for treatment of experimental osteomyelitis caused by P. aeruginosa. The present study measured the efficacy of azlocillin and tobramycin alone and in combination in this model. This combination, given for 28 days, was more effective than either no therapy or azlocillin alone, but failed to sterilize the bones of 60% of the treated rabbits.MATERIALS AND METHODS Production of osteomyelitis. The technique for production of osteomyelitis has been described previously (5). New Zealand white rabbits (weight 1.5 to 2 kg) received an intramedullary injection into the tibia of sodium morrhuate and 2 x 107 colony-forming units (CFU) of P. aeruginosa (5). The strain used was isolated from a patient with osteomyelitis. It was sensitive to polymyxin, carbenicillin, azlocillin, gentamicin, tobramycin, sisomicin, and amikacin. It was resistant to bacteriolysis when tested with fresh serum from five normal individuals.Determination of MICs. An inoculum (0.5 ml containing either 10' or 107 CFU of P. aeruginosa per ml in Mueller-Hinton broth) was added to 0.5 ml of serial dilutions of antibiotic standards. The mixture was incubated at 37°C for 18 h and then observed for turbidity. The lowest concentration of antibiotic for which no growth was visible was the minimal inhibitory co...

Forty beta-lactamase producing Gram-negative organisms were tested with mezlocillin plus an isoxazolyl penicillin for synergy. With standard chequerboard techniques, the combination showed enhanced activity, when compared to either drug alone, against 30 strains. Eighteen of these 30 strains showed synergism at concentrations of mezlocillin and isoxazolyl penicillins which were attainable in the serum (7 strains of Morganella morganii, 8 strains of Eschericia coli and 3 strains of Serratia marcescens).

Mezlocillin was used alone and in combination with cloxacillin in the treatment of chronic experimental osteomyelitis due to Morganella morganii. This combination showed in vitro synergy as measured by the checkerboard technique. A marked inoculum affect was demonstrated in vitro with mezlocillin and the infecting strain of M. morganii. In therapeutic trials, mezlocillin administered for 28 days was totally ineffective. The combination of mezlocillin and cloxacillin (at 800 and 400 mg/kg, respectively, 4 times a day) given for 28 days was significantly better than either no therapy or therapy with mezlocillin alone. However, even after 4 weeks of combined therapy with mezlocillin and cloxacillin M. morganii was recovered from the bones of 55% of the treated rabbits.