In Vitro Activity of Rifampin Alone and in Combination with Nafcillin and Vancomycin Against Pathogenic Strains of Staphylococcus aureus

Abstract

Twenty strains of Staphylococcus aureus isolated from patients with endocarditis were examined in vitro for susceptibility to rifampin, nafcillin, and vancomycin and to combinations of rifampin with nafcillin or vancomycin. Minimum bactericidal concentrations of rifampin ranged from 0.0031 to 0.0125 yg/ml, of nafcillin ranged from 0.078 to 0.312 ,ug/ml, and of vancomycin ranged from 0.312 to 1.25 pg/ml. The combination of rifampin with nafcillin was synergistic for 12 strains; the combination of rifampin plus vancomycin was synergistic for 5 of the isolates.Although penicillins resistant to penicillinase are currently the drugs of choice for treatment of Staphylococcus aureus infections, there is a need for more effective agents and/or therapeutic regimens. With limited clinical experiences (9), synergistic combinations of penicillinase-resistant penicillins with aminoglycoside (3,(11)(12)(13)(14) offer some promise. Rifampin, which has high activity against S. aureus in vitro (5, 7), is another possibility for either a single or combination drug regimen (2, 4, 10). The current study deals with the activity of rifampin, nafcillin, and vancomycin, singly and in combination, against strains of S. aureus known to be pathogenic for man. MATERIALS AND METHODSTwenty strains of coagulase-positive S. aureus recently isolated from patients with endocarditis were studied. Nafcillin sodium, vancomycin hydrochloride, and rifampin were supplied by Wyeth Laboratories Inc., Eli Lilly and Co., and Ciba Pharmaceutical Co., respectively. Standard stock solutions of each antibiotic, prepared by dissolving the lyophilized powders in sterile solutions per the manufacturer's instructions, were stored at -70°C and thawed immediately before use. At the time of each study, drug dilutions were done in brain heart infusion (BHI) broth.Minimal inhibitory concentrations and minimal bactericidal concentrations (MBCs) of nafcillin, vancomycin, and rifampin alone and in combination were determined in vitro using a microtiter checkerboard dilution method (8,15). Nafcillin concentrations ranged from 2.5 to 0.02 ,g/ml, vancomycin concentrations ranged from 5.0 to 0.039 ug/ml, and rifampin concentrations ranged from 0.01 to 0.0004 gsg/ml. An The MBC was read as the lowest concentration of drug in which there was no growth of the test organism after plating 10 A1 of solution from each well and reincubating at 37°C for 18 to 24 h. Since the MBC was always within one dilution of the minimal inhibitory concentration, all data are based on MBCs.Drug combinations were considered "fully synergistic" if inhibition occurred at one-fourth or less of the MBC for both drugs. If inhibition had occurred with concentrations exceeding the MBC of either drug, "antagonism" between the two antibiotics would have been demonstrated. "Partial synergism" was judged to have occurred when the MBC of one of the antibiotics in the combination was at least one-fourth of the MBC of that antibiotic alone, whereas the MBC of the second antibiotic was only one-half of the concen...

Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus

“…Rifampin never achieved a bactericidal effect in either phase. While rifampin has usually been considered an antistaphylococcal bactericidal agent (28,35,41), some authors have reported results consistent with our own (3, 9, 17). In contrast, levofloxacin reached a potent killing rate in the log phase and it also showed bactericidal activity in the stationary phase, although higher concentrations than those for the exponential phase were required.…”

Rifampin Combination Therapy for Nonmycobacterial Infections

“…For example, vancomycin penetration into lung tissue is not sustained, and the same was seen for the meninges and infected bone, whereas rifampin easily penetrates these tissues (61,109,120). The rifampin-vancomycin in vitro interaction appears to range from antagonistic to indifferent, with very few synergistic studies (25,26,112,119,158,218,246,251,258,261). Tuazon et al showed that the rifampin-vancomycin combination had "partial synergism" with only 25% of the MSSA isolates, with the remainder being indifferent, while the nafcillin-rifampin combination had "partial synergism" for 60% of the isolates (246).…”

“…The rifampin-vancomycin in vitro interaction appears to range from antagonistic to indifferent, with very few synergistic studies (25,26,112,119,158,218,246,251,258,261). Tuazon et al showed that the rifampin-vancomycin combination had "partial synergism" with only 25% of the MSSA isolates, with the remainder being indifferent, while the nafcillin-rifampin combination had "partial synergism" for 60% of the isolates (246). Watanakunakorn and Guerriero showed antagonism for 43 of 50 S. aureus strains using the rifampin-vancomycin combination.…”

“…A microtiter checkerboard dilution method was used to determine the MICs and MBCs of the drugs used either alone or in combination. Their definitions of synergy were not standardized with other in vitro studies, as they had a category of "partial synergy" and "indif- ference" based on the combination of the drug's relationship to the MBC of the individual drugs (246). Those authors reported "full synergy" for 3 of the 20 (15%) isolates and partial synergy for 9 (45%) other isolates with the rifampin-nafcillin combination (246).…”

“…The combinations of rifampin with ␤-lactam antibiotics, especially nafcillin, oxacillin, and cephalothin, have been the most frequently studied in vitro combinations for the treatment of MSSA infections (199). Tuazon et al evaluated the nafcillin-rifampin combination against 20 strains of MSSA from patients with endocarditis (246). A microtiter checkerboard dilution method was used to determine the MICs and MBCs of the drugs used either alone or in combination.…”