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This article is also available for rental through DeepDyve. View Metrics. Email alerts Article activity alert. Advance article alerts. New issue alert. Receive exclusive offers and updates from Oxford Academic. Of concern, the number of infections caused by methicillin-resistant S aureus MRSA continues to rise. Furthermore, treatment failure with standard therapies for MRSA is common. Rifampin, a broad-spectrum antimicrobial agent that is bactericidal against S aureus , achieves high intracellular levels and is one of the few antimicrobial agents that can penetrate biofilms and kill organisms in the sessile phase of growth.
Combination therapy with rifampin has been used to treat S aureus infections. To our knowledge, there has been no attempt to synthesize the literature that has examined the efficacy of rifampin therapy against S aureus. To this aim, we conducted a systematic review of the use of rifampin as adjunctive therapy to treat S aureus infections.
To identify in vitro, animal, and human subject data regarding the efficacy of rifampin as adjunctive therapy for the treatment of S aureus , 2 independent reviewers J. These terms were used to avoid ignoring articles with permutations of the words Staphylococcus and rifampin , eg, Staph aureus or rifampicin. All abstracts were printed for review. The search was limited to English-language articles published between January 1, , and January 31, We reviewed only manuscripts relating to S aureus and not coagulase-negative staphylococci.
We also contacted several experts in the field of adjunctive rifampin therapy to determine if there were any pertinent recently published meeting abstracts or published articles that we missed by our systematic review. An investigation was included in our systematic analysis if it met each of the following criteria: 1 the organism under study was S aureus ; 2 the study design compared the efficacy of 1 or more antibiotics alone and in combination with rifampin; 3 the study outcome assessed quantitative bacterial measurements, cure rates or eradication of colonization , or staphylococcal-related mortality; and 4 outcome data were explicitly reported.
By the nature of our methods, we excluded studies reporting the efficacy of rifampin therapy alone compared with other antibiotics, the efficacy of rifampin as prophylaxis to prevent infections in uninfected hosts, or the use of rifampin-impregnated devices or catheters.
Also excluded were articles not containing original research eg, reviews, editorials, case reports, abstracts, and letters. We also examined the bibliographies of selected review articles for original research articles that may have contained references of articles that were missed by our search criteria. Each investigator was blinded to the other investigator's data extraction.
The 2 reviewers independently rejected or accepted each abstract based on the inclusion and exclusion criteria. Article texts of selected abstracts were reviewed, as were article texts of abstracts that could not be excluded based on abstract review alone. All disagreements between the abstractors as to whether the article should be included were settled by a third independent reviewer L.
Data from each trial were entered onto a standardized form, verified for accuracy, and input into a computerized database. Information extracted included study design, antibiotics tested, number of subjects, year of publication, duration of follow-up, clinical setting in vitro, animal, or human , and intervention dosage, frequency, and duration of therapy or exposure.
Abstracted data included the outcome eg, mortality, clinical failure, and colony count after treatment and the time of evaluation of treatment outcome. Discrepancies in data between abstractors were identified and resolved via discussion among the investigators.
For human studies, 2 independent reviewers M. For investigations that did not perform statistical analyses but reported results, we attempted to perform statistical analyses. For studies comparing means, if standard deviations and group sample sizes were available, we performed Wilcoxon rank sum test. We did not perform analyses from investigations that reported results of statistical tests or contained inadequate information for us to perform tests of significance.
We initially planned to perform a meta-analysis of results but abandoned this method because study outcome heterogeneity was substantial eg, in vivo studies variably used outcomes of cure rates, proportion of sterile cultures, decrease in colony-forming units [CFUs], and others. The results of the literature search and the reasons for exclusion from the systematic review are summarized in the Figure.
To facilitate review of our findings, results are summarized herein as in vitro investigations, animal investigations, and human investigations. We identified 72 publications comparing antibiotic efficacy with and without rifampin using in vitro models Table 1 A and Table 1 B.
Of individual antibiotic trials in these 72 publications, 41 trials tested both methicillin-susceptible S aureus and MRSA strains. We found that methods used to determine the nature of the antibiotic interactions were heterogeneous and included E test, time-kill curves, checkerboard assays, serum bactericidal activity, and ex vivo intracellular bactericidal activity. Methodological variability was reflected in the inconsistent interactions reported.
Many studies using time-kill assays failed to report results in terms of synergy or antagonism, presenting the data only graphically and without statistical analysis. Some authors noted that different concentrations of antibiotics changed the nature of the interaction. In the animal models, between-study differences included the dosing route, dosing frequency, antibiotic dosages, S aureus strain used, animal model investigated, timing of outcome assessment, end point studied eg, microbiologic or cure , and duration between bacterial inoculation and therapy initiation Table 2.
Many studies did not report statistical analyses. To facilitate description of the animal investigations, we first stratified models by disease and then by primary antibiotic treatment. In peritonitis models, we identified 3 studies. Of 2 investigations of fluoroquinolones, one noted that combination therapy resulted in a larger decrease in CFUs per milliliter and sterilization of fluid but did not report a statistical analysis.
Two investigations examined skin and soft-tissue infections without hardware. One abscess model demonstrated that adjunctive rifampin with teicoplanin resulted in diminished CFU decrease compared with teicoplanin monotherapy. Of 16 antibiotics used in 12 publications pertaining to endocarditis, 7 showed superiority of combination therapy, 4 showed superiority of monotherapy, and 5 showed no difference. Dual therapy was superior in terms of decreases in CFUs or valve sterilization in trials using vancomycin, 48 cloxacillin, 52 ciprofloxacin, 23 quinupristin-dalfopristin, 52 teicoplanin, 51 and daptomycin.
In S aureus bacteremia models, an investigation showed a benefit to adding rifampin to methicillin or trimethoprim. In osteomyelitis models, 16 antibiotic trials were reported in 8 publications. Statistical analyses revealed significant reductions in positive bone cultures, 56 increases in sterile bone cultures, 35 , 37 , 56 - 58 or reductions in CFUs per gram.
Nine treatment comparisons presented in 4 publications of device- or hardware-associated infections with adjunctive rifampin therapy were identified. In an abscess model with implanted foreign material, dual therapy with rifampin and either vancomycin, ciprofloxacin, fleroxacin, or teicoplanin showed superiority in terms of cure rate.
Patients treated with rifampin had longer hospital length-of-stay: On multivariate analysis, only cerebral emboli odds ratio [OR] 2. Conclusions: A large proportion One-year survival and relapse rates were similar in patients treated with or without rifampin.
Keywords: endocarditis; mortality; prosthetic valve; relapse; rifampin. More than half of all rifampin recipients 22 experienced clinically significant, previously unrecognized drug—drug interactions. Evaluating treatment outcomes in a retrospective study like this one is difficult because rifampin might have been used in sicker patients or those with persistent bacteremia.
However, the high resistance rates among bacteremic patients, the previously unrecognized drug—drug interactions, and the hepatotoxicity observed in this study are concerning. Clinicians should consider these risks carefully, particularly because there are no good data to substantiate any benefits of rifampin in native-valve endocarditis.
Riedel DJ et al. Addition of rifampin to standard therapy for treatment of native valve Staphylococcus aureus infective endocarditis.
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