Studies of in vitro and in vivo bactericidal interactions of vancomycin plus rifampin against Staphylococcus aureus have yielded conflicting results. In this study the efficacy of this drug combination in experimental endocarditis due to a methicillin-resistant strain of S. aureus was investigated. Left-sided endocarditis was induced in 84 rabbits by an infecting strain that had been found to be synergistically killed by vancomycin plus rifampin in vitro when tested by the timed-kill curve technique; in contrast, the checkerboard technique had indicated that the two drugs were antagonistic against this strain. Infected animals received no therapy, vancomycin alone (30 mg/kg per day), rifampin alone (20 mg/kg per day), or both drugs (in the same doses). The combination was significantly more effective than the single-drug regimens in terms of (1) reduction of mean methicillin-resistant S. aureus vegetation titers (P less than .05-.0005), (2) rate and incidence of sterilization of vegetations (P less than .0005), and (3) rate of "radical" cure of endocarditis (P less than .005). Vancomycin alone and vancomycin plus rifampin were equally effective in reducing mortality and sterilizing renal abscesses. The use of vancomycin prevented the in vivo development of resistance to rifampin. No evidence that rifampin exerted an antagonistic effect on the in vivo bactericidal activity of vancomycin was found.

The in vitro bactericidal interactions of penicillin G, cefotaxime, or vancomycin in combination with gentamicin were compared against 20 group G streptococci by the timed kill curve method. Synergy was noted at the following frequences: penicillin plus gentamicin, 80%; cefotaxime plus gentamicin, 85%; vancomycin plus gentamicin, 90%. There was no bactericidal antagonism observed.Serious infections due to Lancefield group G streptococci (GGS) have been increasingly reported in the recent literature (4,5,7,10). Despite exquisite in vitro susceptibility of GGS to penicillin G (1, 5, 12), the in vivo responses have often been suboptimal, particularly in cases of GGS endocarditis and septic arthritis (4,5,7,10 and gentamicin, used in subsequent synergy testing, for the 20 GGS strains were determined. The microtiter broth dilution technique was employed (1, 12). Volumes of 50 R1 of each antibiotic in twofold serial dilutions were added to a separate microtiter row of wells. A 50-RIl sample of each GGS isolate grown in Todd-Hewitt broth to the logarithmic phase of growth was added to each antibiotic-containing well to achieve a final concentration of _105 CFU/ml. The final drug concentrations (in micrograms per milliliter) in the wells were as follows: penicillin G, 0.0025 to 2.5; cefotaxime, 0.005 to 5; vancomycin, 0.01 to 10; gentamicin, 0.01 to 10. These concentrations were chosen to encompass levels of each agent readily attainable in serum at standard clinical dosages. For each isolate tested, one microtiter well contained only GGS in antibiotic-free Todd-Hewitt broth as a growth control. After inoculation, all plates were incubated for 24 h at 37°C. The MIC was then read as the lowest antibiotic concentration yielding no visible turbidity. At this time, 25-,ul portions were taken from all visibly clear wells and subcultured onto antibiotic-free Todd-Hewitt agar. After 24 h of incubation at 37°C, the MBC was read as the lowest antibiotic concentration which yielded no visible GGS colonies on subculture.The timed kill curve technique was utilized in synergy studies (8). Logarithmic-phase cells of each GGS isolate in Todd-Hewitt broth were added to antibiotic-containing tubes to achieve a final inoculum of -5 x 106 CFU/ml. The relatively high in vitro inoculum was chosen to approximate the in vivo inocula seen in endocarditis and septic arthritis (3, 9), the most problematic clinical syndromes caused by GGS (4, 5, 7, 10). Penicillin G (0.02 ,ug/ml), cefotaxime (0.02 ,ug/ml), and vancomycin (1.25 ,ug/ml) were tested alone or in combination with gentamicin (1.25 ,ug/ml) against each GGS isolate. These final drug concentrations were chosen to represent levels of each agent readily achievable in serum; in addition, the single agents at these drug concentrations did not effect a rapid kill of the GGS within 4 to 24 h in pilot studies in our laboratory. For each GGS isolate tested, an antibiotic-free broth tube was inoculated as described above as a growth control. All inoculated tubes were incubated at 37°C in a water ...

We investigated the efficacy of a potent new antipseudomonal /3-lactam agent, ceftazidime, in a model of right-sided Pseudomonas endocarditis in 72 rabbits. Animals received either: no therapy (controls), amikacin (15 mg/kg/day), ceftazidime (100 mg/kg/day) or amikacin + ceftazidime. Amikacin + ceftazidime was significantly more effective than single-drug regimens in terms of reduction of mortality (p < 0.01), prevention of pulmonary infarction (p < 0.05), reduction of mean vegetation titers of Pseudomonas aeruginosa (p < 0.05-p < 0.0005), sterilization of vegetations (p < 0.0005) and reduction in prevalence of bacteriologic relapses after therapy (p < 0.005). There was no development of resistance in vivo to either amikacin or ceftazidime.

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Right-sided infective endocarditis due to Pseudomonas aeruginosa was induced in 130 rabbits. Animals received either: (1) no therapy (controls); (2) standard-dose amikacin (AMK) (15 mg/kg/day) plus ticarcillin (300 mg/kg/day), or (3) high-dose AMK (20 or 25 mg/kg/day) plus ticarcillin, for 20 days. Animals in each treatment group were evaluated at 10 days after therapy for bacteriologic relapse. Both standard-and high-dose AMK regimens significantly decreased mortality and Pseudomonas aeruginosa vegetation titers versus controls (p < 0.01, p < 0.05, respectively). Despite significantly higher serum AMK levels at 25 mg/kg/day, there was no significant difference in mean vegetation titers, percent of vegetations sterilized, or posttherapy bacteriologic relapse in the three treatment groups. AMK at 20 or 25 mg/kg/day (but not at 15 mg/kg/ day) significantly reduced the incidence of pulmonary infarction versus untreated controls (p < 0.01).