Host risk factors for rifamycin-resistant clostridium difficile infection: A case control study

Objective. To evaluate the host risk factors associated with rifamycin-resistant Clostridium difficile (C. diff) infection in hospitalized patients compared to rifamycin-susceptible C.diff infection.^ Background. C. diff is the most common definable cause of nosocomial diarrhea affecting elderly hospitalized patients taking antibiotics for prolonged durations. The epidemiology of Clostridium difficile associated disease is now changing with the reports of a new hypervirulent strain causing hospital outbreaks. This new strain is associated with increased disease severity and mortality. The conventional therapy for C. diff includes metronidazole and vancomycin but high recurrence rates and treatment failures are now becoming a major concern. Rifamycin antibiotics are being developed as a new therapeutic option to treat C. diff infection after their efficacy was established in a few in vivo and in vitro studies. There are some recent studies that report an association between the hypervirulent strain and emerging rifamycin resistance. These findings assess the need for clinical studies to better understand the efficacy of rifamycin drugs against C. diff.^ Methods. This is a hospital-based, matched case-control study using de-identified data drawn from two prospective cohort studies involving C. diff patients at St Luke's Hospital. The C. diff isolates from these patients are screened for rifamycin resistance using agar dilution methods for minimum inhibitory concentrations (MIC) as part of Dr Zhi-Dong Jiang's study. Twenty-four rifamycin-rifamycin resistant C. diff cases were identified and matched with one rifamycin susceptible C. diff control on the basis of ± 10 years of age and hospitalization 30 days before or after the case. De-identified data for the 48 subjects was obtained from Dr Kevin Garey's clinical study at St Luke's Hospital enrolling C. diff patients. It was reviewed to gather information about host risk factors, outcome variables and relevant clinical characteristic.^ Results. Medical diagnosis at the time of admission (p = 0.0281) and history of chemotherapy (p = 0.022) were identified as a significant risk factor while hospital stay ranging from 1 week to 1 month and artificial feeding were identified as an important outcome variable (p = 0.072 and p = 0.081 respectively). Horn's Index assessing the severity of underlying illness and duration of antibiotics for cases and controls showed no significant difference.^ Conclusion. The study was a small project designed to identify host risk factors and understand the clinical implications of rifamycin-resistance. The study was underpowered and a larger sample size is needed to validate the results.^

Does prior receipt of a rifamycin antibiotic increase the risk of acquiring an infection due to a rifamycin-resistant strain of Clostridium difficile?

Objectives. To examine the association between prior rifamycin exposure and later development of C. difficile infection (CDI) caused by a rifamycin-resistant strain of C. difficile , and to compare patient characteristics between rifamycin-resistant strains of C. difficile infection and rifamycin-susceptible strains of C. difficile infection. ^ Methods. A case-control study was performed in a large university-affiliated hospital in Houston, Texas. Study subjects were patients with C. difficile infection acquired at the hospital with culture-positive isolates of C. difficile with which in vitro rifaximin and rifampin susceptibility has been tested. Prior use of rifamycin, demographic and clinical characteristics was compared between case and control groups using univariate statistics. ^ Results. A total of 49 C. difficile strains met the study inclusion criteria for rifamycin-resistant case isolates, and a total of 98 rifamycin-susceptible C. difficile strains were matched to case isolates. Of 49 case isolates, 12 (4%) were resistant to rifampin alone, 12 (4%) were resistant to rifaximin alone, and 25 (9%) were resistant to both rifampin and rifaximin. There was no significant association between prior rifamycin use and rifamycin-resistant CDI. Cases and controls did not differ according to demographic characteristics, length of hospital stay, known risk factors of CDI, type of CDI-onset, and pre-infection medical co-morbidities. Our results on 37 rifaximin-resistant isolates (MIC ≥32 &mgr;g/ml) showed more than half of isolates had a rifaximin MIC ≥256 &mgr;g/ml, and out of these isolates, 19 isolates had MICs ≥1024 &mgr;g/ml. ^ Conclusions. Using a large series of rifamycin-non-susceptible isolates, no patient characteristics were independently associated with rifamycin-resistant CDI. This data suggests that factors beyond previous use of rifamycin antibiotics are primary risk factors for rifamycin-resistant C. difficile. ^

Rifaximin-mediated changes to the epithelial cell proteome: 2-D gel analysis

Diarrhea remains a significant cause of worldwide morbidity and mortality. Over 4 million children die of diarrhea annually. Although antibiotics can be used as prophylaxis or for treatment of diarrhea, concern remains over antibiotic resistance. Rifaximin is a semi-synthetic rifamycin derivative that can be used to treat symptoms of infectious diarrhea, inflammatory bowel syndrome, bacterial overgrowth of the small bowel, pouchitis, and fulminant ulcerative colitis. Rifaximin is of particular interest because it is poorly adsorbed in the intestines, shows no indication of inducing bacterial resistance, and has minimal effect on intestinal flora. In order to better understand how rifaximin functions, we sought to compare the protein expression profile of cells pretreated with rifaximin, as compared to cells treated with acetone, rifamycin (control antibiotic), or media (untreated). 2-D gel electrophoresis identified 38 protein spots that were up- or down-regulated by over 2-fold in rifaximin treated cells compared to controls. 16 of these spots were down-regulated, including keratin, annexin A5, intestinal-type alkaline phosphatase, histone h4, and histone-binding protein RbbP4. 22 spots were up-regulated, including heat shock protein HSP 90 alpha, alkaline phosphatase, and fascin. Many of the identified proteins are associated with cell structure and cytoskeleton, transcription and translation, and cellular metabolism. A better understanding of the functionality of rifaximin will identify additional potential uses for rifaximin and determine for whom the drug is best suited. ^