Activities of tobramycin and azlocillin alone and in combination against experimental osteomyelitis caused by Pseudomonas aeruginosa

Abstract

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...

Use of Quinolones for the Treatment of Osteomyelitis and Septic Arthritis

“…No increase in the MIC for the isolated strain of P. aeruginosawas observed in this study. These results were better than those recorded previouslywith carbenicillin, azlocillin, and sisomycin [18].…”

Evaluation of combination chemotherapy in a lightly anesthetized animal model of Pseudomonas pneumonia

“…had improved survival when treated with synergistic combinations of antibiotics as compared to those treated with aminoglycosides or beta-lactams given alone (1). Other investigators have failed to demonstrate an advantage to synergistic drug combinations in experimental sepsis, pneumonia, and osteomyelitis in animals with normal host defenses (7,20,24). In this experiment we studied ceftazidime and tobramycin in the therapy of P. aeruginosa pneumonia.…”

Antibiotic combinations: should they be tested?

“…However, not all studies clearly indicate advantages of synergistic regimens. Norden and Shaffer (140) found no benefit of combination therapy for P. aeruginosa osteomyelitis in comparison with single-drug therapy despite documentation of in vitro synergism by two methods.…”