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Impact of Concu..

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Initiation of antibiotic therapy alters normal gut flora and creates an opportunity for Clostridium difficile colonization and infection. The Infectious Diseases Society of America and Society for Healthcare Epidemiology of America treatment guidelines1 recommend removing the inciting agent as soon as possible; however, patients will often require concurrent antimicrobials during and shortly after treatment of Clostridium difficile infection (CDI) to treat other ongoing infections.

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Recently, two large phase III trials2,3 compared fidaxomicin 200mg twice daily, a new bacteriocidal macrocyclic antibiotic approved for the treatment of CDI in adults,4 and vancomycin 125mg four times daily for 10 days. The number of subjects evaluated for clinical and global cure (sustained response) was 999. Both trials found fidaxomicin noninferior to vancomycin for initial clinical cure (88.2% vs 85.5% and 91.7% vs 90.6%), decreased recurrence rates (15.4% vs 25.3%, p = 0.05 and 12.7% vs 26.9%, p < 0.001), and significantly higher sustained response in the 4-week period after the end of therapy (74.6% vs 64.1%, p = 0.06 and 76.6% vs 63.4%, p = 0.001).

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Mullane and colleagues5 published a subgroup analysis of the 275 study participants (27.5%) who received concomitant antibiotics during the treatment course (days 1-10) and during the follow-up period (days 11-40) of the previously mentioned phase III trials. Concomitant antibiotics in all patients were associated with lower clinical cure rates (84.38% vs 92.57%, p < 0.01) and lower global cure rates (65.82% vs 74.72%, p = 0.005). There were no differences in recurrence rates during the treatment or follow-up periods. The time to resolution of diarrhea was delayed in those subjects receiving concomitant antibiotics (97 vs 54 hours, p < 0.001). However in subjects receiving concomitant antibiotics, fidaxomicin, when compared to vancomycin, was associated with higher clinical cure rates (90% vs 79.41%, p = 0.04), lower recurrence rates (16.85% vs 29.17%, p = 0.048), and overall was superior in global cure rates (72.73% vs 59.44%, p = 0.02). There was no significant difference in all three endpoints between fidaxomicin and vancomycin in the subjects who received concomitant antibiotic classes classified as having a high risk of contributing to symptomatic CDI. A limitation of this study is that patients with life-threatening CDI were excluded from the study, and these patients often require concomitant and potentially prolonged courses of antibiotics.

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Although concomitant antibiotics would ideally be avoided in all patients who are currently or have recently been treated for CDI, patients often require additional empiric antibiotics or treatment for other confirmed infections. Fidaxomicin has the advantage of relatively good selective activity against Clostridium difficile and poor activity against normal enteric colonizing anaerobic gram negative bacteria. Fidaxomicin also has a longer postantibiotic effect of 5.5 – 10hr has compared to 0 – 1.5 hours with vancomycin.4 These unique properties of fidaxomicin may allow it to serve as an alternative in patients requiring concomitant antibiotics, however more research is needed in patients with life-threatening CDI.

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1. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Cont Hosp Ep 2010;31:431-55.   [PubMed: 20307191]
2. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-31.   [PubMed: 21288078]
3. Crook D, Weiss K, Cornerly O, et al. Randomized clinical trial (RCT) in Clostridium difficile infection (CDI) confirms equivalent cure rate and lower recurrence rate of fidaxomicin (FDX) versus vancomycin (VCN). In: Program and abstracts of the 20th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). (Vienna, Austria). Basel, Switzerland: European Society of Clinical Microbiology and Infectious Diseases, 10-13 April 2010.
4. Venugopal AA, Johnson S. Fidaxomicin: A novel macrocyclic antibiotic approved for treatment of Clostridium difficile infection. Clin Infect Dis 2011. DOI 10.1093/cid/cir830.   [PubMed: 22156854]
5. Mullane KM, Miller MA, Weiss K, et al. Efficacy of fidaxomicin versus vancomycin as ...

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