RANDOMIZED DOUBLE-BLINDED TRIAL OF RIFAMPIN WITH EITHER NOVOBIOCIN ORTRIMETHOPRIM-SULFAMETHOXAZOLE AGAINST METHICILLIN-RESISTANT STAPHYLOCOCCUS-AUREUS COLONIZATION - PREVENTION OF ANTIMICROBIAL RESISTANCE ANDEFFECT OF HOST FACTORS ON OUTCOME

Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen in hospitals. Current antimicrobial regimens for eradicating colonizi ng strains are not well defined and are often complicated by the emerg ence of resistance. The combination of novobiocin plus rifampin in vit ro and in vivo was found to prevent the emergence of resistant populat ions of initially susceptible strains of MRSA, particularly resistance to rifampin. We therefore studied, in a randomized, double-blind, mul ticenter comparative trial, the combination of novobiocin plus rifampi n versus trimethoprim-sulfamethoxazole (T/S) plus rifampin in order to determine the efficacy of each regimen in eradicating MRSA colonizati on and to further characterize the host factors involved in the respon se to this antimicrobial therapy. Among the 126 individuals enrolled i n the study, 94 (80 patients; 14 hospital personnel) were evaluable. A mong the 94 evaluable subjects, no significant demographic or medical differences existed between the two treatment groups. Successful clear ance of the colonizing MRSA strains was achieved in 30 of 45 (67%) sub jects receiving novobiocin plus rifampin, whereas successful clearance was achieved in 26 of 49 (53%) subjects treated with T/S plus rifampi n (P = 0.18). The emergence of resistance to rifampin developed more f requently in 14% (7 of 49) of subjects treated with T/S plus rifampin than in 2% (1 of 45) of subjects treated with novobiocin plus rifampin (P = 0.04). Restriction endonuclease studies of large plasmid DNA dem onstrated that the same strain was present at pretherapy and postthera py in most refractory cases (24 of 29 [83%] subjects). Among the 56 su ccessfully treated subjects, clearance of MRSA was age dependent: 29 o f 36 (80%) subjects in the 18- to 49-year-old age group, 19 of 35 (54% ) subjects in the 50- to 69-year-old age group, and 8 of 23 (35%) in t he 70- to 94-year-old age group (P < 0.01). Clearance was also site de pendent; culture-positive samples from wounds were related to a succes sful outcome in only 22 (48%) of 46 subjects, whereas culture-positive samples from sites other than wounds (e.g., nares, rectum, and sputum ) were associated with a success rate of 34 of 48 (71%) subjects (P = 0.02). Foreign bodies in wounds did not prevent the eradication of MRS A by either regimen. T/S plus rifampin was less effective in clearing pressure wounds compared with other wounds, whereas novobiocin plus ri fampin was equally effective in clearing both pressure and other wound s. There were no significant differences in toxicity between the two r egimens. Thus, the combination of novobiocin plus rifampin, in compari son with T/S plus rifampin, was more effective in preventing the emerg ence of resistance to rifampin and demonstrated a trend toward greater activity in clearing the MRSA carrier state. The response to either c ombination depended on host factors, particularly age and the site of MRSA colonization.