Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen in hospitals. Current antimicrobial regimens for eradicating colonizing strains are not well defined and are often complicated by the emergence of resistance. The combination of novobiocin plus rifampin in vitro and in vivo was found to prevent the emergence of resistant populations of initially susceptible strains of MRSA, particularly resistance to rifampin.We therefore studied, in a randomized, double-blind, multicenter comparative trial, the combination of novobiocin plus rifampin versus trimethoprim-sulfamethoxazole (T/S) plus rifampin in order to determine the efficacy of each regimen in eradicating MRSA colonization and to further characterize the host factors involved in the response to this antimicrobial therapy. Among the 126 individuals enrolled in the study, 94 (80 patients; 14 hospital personnel) were evaluable. Among the 94 evaluable subjects, no significant demographic or medical differences existed between the two treatment groups. Successful clearance of the colonizing MRSA strains was achieved in 30 of 45 (67%) subjects receiving novobiocin plus rifampin, whereas successful clearance was achieved in 26 of 49 (53%) subjects treated with T/S plus rifampin (P = 0.18). The emergence of resistance to rifampin developed more frequently 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 demonstrated that the same strain was present at pretherapy and posttherapy in most refractory cases (24 of 29 [83%] subjects). Among the 56 successfully treated subjects, clearance of MRSA was age dependent: 29 of 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 the 70-to 94-year-old age group (P < 0.01). Clearance was also site dependent; culture-positive samples from wounds were related to a successful 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 MRSA by either regimen. T/S plus rifampin was less effective in clearing pressure wounds compared with other wounds, whereas novobiocin plus rifampin was equally effective in clearing both pressure and other wounds. There were no significant differences in toxicity between the two regimens. Thus, the combination of novobiocin plus rifampin, in comparison with T/S plus rifampin, was more effective in preventing the emergence of resistance to rifampin and demonstrated a trend toward greater activity in clearing the MRSA carrier state. The response to either combination depended on host factors, particularly age and the site of MRSA colonization.

Randomized non-inferiority trial to compare trimethoprim/sulfamethoxazole plus rifampicin versus linezolid for the treatment of MRSA infection

“…This is in agreement with one controlled trial that demonstrated the efficacy of trimethoprim/sulfamethoxazole plus rifampicin for MRSA decolonization. 27 In the present study, the number and nature of AEs was similar in both arms and consistent with the known safety profile of the study drugs. 7,28,29 However, five more drug reactions occurred in the combination arm, although this was statistically non-significant.…”

Comparative efficacy of novobiocin and amoxicillin in experimental sepsis caused by β-lactam-susceptible and highly resistant pneumococci

“…Clinical trials conducted in the 1990s demonstrated the efficacy of novobiocin-containing combinations for eradicating the carrier state of MRSA [19,20]. Indeed, novobiocin combined with rifampicin prevented the development of resistance in MRSA to either drug even more efficiently than the combination of co-trimoxazole and rifampicin [20].…”

“…Because novobiocin displays potent activity against staphylococci, including meticillin-resistant Staphylococcus aureus (MRSA), pneumococci, enterococci and many other Gram-positive organisms [5,6], during the 1980s the suitability of clinical reevaluation of this drug was suggested [6]. Clinical trials conducted in the 1990s demonstrated the efficacy of novobiocin-containing combinations for eradicating the carrier state of MRSA [19,20]. Indeed, novobiocin combined with rifampicin prevented the development of resistance in MRSA to either drug even more efficiently than the combination of co-trimoxazole and rifampicin [20].…”

“…Regarding the side effects associated with the use of novobiocin alone or in combination, it should be stressed that many patients [19,20,22] and healthy volunteers [23,24] received this drug, mostly at 500 mg every 12 h for a variable period of time, without reporting relevant toxicity, and it has been suggested that some of the side effects could be attributed to impurities in the formulation that have since been removed [20]. Besides, novobiocin has also been administered as a modulator of alkylating agent cytotoxicity combined with cyclophosphamide, with the maximum tolerated dose being 6 g/day of novobiocin [25].…”

Occurrence of methicillin-resistant strains of Staphylococcus aureus at a goat breeding farm

“…Family members who are living with MRSA carriers are exposed to MRSA transmission (Matsumoto et al, 2001). Antibiotics were shown to be effective with eradication rates only between 53% and 85% (Roccaforte et al, 1988;Walsh, et al, 1993;Asensio et al, 1996) But antibiotics are considered to be inappropriate for patients who are only colonized and not infected with MRSA and so in view of the high likelihood that the attempts to eradicate the MRSA carriership would fail in the long run, no treatment was prescribed.…”