Tag Archives: fidaxomicin

A C difficile two-fer

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Two recent review articles on Clostridium difficile are quite useful:

  • Mezoff EA, Cohen MB. J Pediatr 2013; 163: 627-30.
  • Dupont HL. Clin Gastroenterol Hepatol 2013; 11: 1216-23.

The first publication reviews acid suppression and the risk of C difficile infection (CDI).  It starts off with  a terrific piece of advice from Sir William Osler: “One of the first duties of the physician is to educate the masses not to take medicine.”  The authors note that pH above 4 has been shown to increase bacterial survival, including  C perfringe spores in a mouse model.  In addition, the article notes that there have been concerns as early as 1982 that acid suppression could be a risk factor for CDI.  Several recent studies were summarized, including the following:

  • A recent meta-analysis (Kwok CS et al. Am J Gastroenterol 2012; 107: 1011-9) with 42 studies (N= 313,000 patients) “found an association between PPI use and risk of CDI (OR1.74, 05%CI 1.47-2.85).”
  • A review of the literature (Deshpande A et. Clin Gastroenterol Hepatol 2012; 10: 225-33) between 1990-2010 found an overall increase in CDI risk with PPIs to be OR 2.15 (95% CI 1.81-2.55). No prospective studies were identified.
  • In pediatrics, a study (Turco et al. Alimentary Pharmacol Therapeut 2010; 31: 754-9) with 910 children admitted for abdominal pain and diarrhea identified 68 with CDI.  Compared with control patients, use of PPIs was significantly higher in CDI patients (OR 4.52, 95% CI 1.4-14.4).

The FDA has stated that PPIs may be associated with an increased risk of CDI.  In addition, the use of antibiotics “appear to act synergistically with PPIs.”  Thus, the authors recommend stopping PPIs in those who do not need them.  Periodic ‘holidays’ or dosing step-downs may help assess continued need for PPIs.

The second publication succinctly reviews the diagnosis and management of CDI.  The various diagnostic methods are compared in Table 1.  Therapeutic options for 1st time infection are reviewed in Table 2.  For adults with mild-to-moderate infections, metronidazole (500 mg TID for 10 days) is preferred.  Vancomycin or Fidaxomicin are recommended for more severe infections.

Table 3 lists treatment options for recurrent CDI.  Repeat course of any of the 1st round treatments can be considered depending on patient’s illness severity.  In addition, other potential treatments included the following:

  • vancomycin tapered dose (week 1: 125 mg 4 times/day, week 2: 125 mg 2 times/day, week 3: 125 mg once/day, week 4: 125 mg every other day, week 5 & 6: 125 mg every third day)
  • rifaximin (550 mg BID x 20 days)
  • high-dose vancomycin (250-500 mg 4 times/day for 10 days) followed by S boulardii (2 capsules BID for 28 d)
  • fecal microbiota transfer (FMT) –“although family member stool donors have been used, the current movement is toward volunteer donor pools.”  [I do not think ‘current movement’ was intended as a pun by the authors.]  Volunteer donors could lower the screening costs.
  • intravenous immunoglobulin (small clinical trials have failed to show efficacy)
  • monoclonal antibodies to toxins A/B

Related blog posts:

What’s the best medical therapy for Clostridium difficile?

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More data on the superiority of fidaxomicin versus vancomycin in adult patients has been published (Lancet 2012; 12: 281-9).  While this study was a ‘double-blind, non-inferiority, randomized controlled trial,’ the data tilt in favor of fidaxomicin.  This study enrolled 535 patients from 45 sites in Europe and 41 sites in U.S.

On an intention-to-treat basis, a clinical cure was noted in 88% of fidaxomicin group (200 mg BID x 10 days) and 86% of vancomycin group (125 mg QID x 10 days).  Clinical cure was defined as resolution of diarrhea and no need for further treatment.  The big difference was in recurrence risk:  13% of patients receiving fidaxomicin compared with 27% of patients receiving vancomycin.  Recurrence was defined as development of three unformed bowel movements in 24 h, a positive stool toxin, and need for retreatment within 30 days of treatment completion.  A sustained response (=”global cure”) was noted in 77% with fidaxomicin compared with 63% of vancomycin group.

Both groups of patients had similar variables: severity of illness, frequency of B1/027 strains, geographic distribution, concomitant antibiotics, previous C difficile infection, age, and inpatient status.  In the group with concomitant antibiotics, fidaxomicin outperformed vancomycin with respect to cure rate: 90% versus 73%.  Adverse reactions were similar as well (Table 7).

To underscore the severity of C difficile in this population, there was a significant mortality rate in both groups.  8% of patients receiving at least one dose of fidaxomicin died compared with 7% of vancomycin-treated patients.

Why does fidaxomicin have a lower recurrence rate?  Probably due to a more narrow antibiotic spectrum and minimal effect on commensal gut flora.  Fidaxomicin also has roughly eight times more potency in vitro than vancomycin against clinical isolates of C difficile.

Previous related blog entries/reference:

Clostridium difficile -Current Battlelines

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The most recent how to treat Clostridium difficile with fecal microbiota transplantation is described in a review article, Clinical Gastroenterology & Hepatology; 2011: 9:1044-49.  This article details the rationale and effectiveness of this approach.  Indications include 2-3 recurrent episodes or moderate/severe episode not responding to conventional treatment. Workup for donors to minimize the risk of transmission is discussed.  The article points out that fecal transplantation can be accomplished by nasogastric or transpyloric tubes or can be delivered directly via colonoscope or via retention enema.

Additional information on this topic:

–Am J Gastro 2000; 95: 3283-5.
–Clin Inf Dis 2003; 36: 580-5.

More C difficile references:

  • –NEJM 2010; 364: 422, 473. Fidaxomicin – a macrocytic abx –more effective than vancomycin (92% vs. 90%) and with lower recurrence (15% vs 25%). Dose 200mg BID. n=629.
  • –NEJM 2010; 362: 197, 264 (editorial). 1st article: n=200. Rx with monoclonal antibodies (against toxins A & B) -single infusion (10mg/kg) –reduced recurrence rate from 25% vs 7% & among those with previous recurrence, the rate was reduced from 38% to 7%.
  • –NEJM 2011; 365: 1693. Host/pathogen factors. n=4143.
  • –Gastro 2009; 136: 1152, 1206. “reining in recurrent C. diff”
  • –JPGN 2009; 48 suppl 2: S63-65. Cohen MB. ~35% of patients now w/o antibiotic exposure.
  • –Curr Opin Gastro 2008; 25: 24-35. Use of sacchromyces boulardii(1gm/d)x 2 weeks w Vanco may reduce recurrence by >50&.
  • –Journal of Pediatrics 2009; 154: 607. n=198.  Virulent NAP1 strain present in~19% from 2 children’s hospitals.
  • –NEJM 2009; 360: 637. C diff (even toxigenic strains) present in ~50% of healthy newborns. Not convincingly associated with any illnesses in newborns –possibly due to lack of receptor in infants (J Clin Invest 1992; 90: 822-9).