x

1
Updated Guidance on the Management and treatment of Clostridium difficile infection. Public Health England. https://www.gov.uk/government/publications/clostridium-difficile-infection-guidance-on-management-and-treatment Accessed 23.09.14.
Supportive care should be given, including attention to hydration, electrolytes and nutrition. Antiperistaltic agents should be avoided in acute infection. This is because of the theoretical risk of precipitating toxic megacolon by slowing the clearance of C. difficile toxin from the intestine. The precipitating antibiotic should be stopped wherever possible; agents with less risk of inducing CDI can be substituted if an underlying infection still requires treatment.

Mild disease
Patients with mild disease may not require specific C. difficile antibiotic treatment. If treatment is required, oral metronidazole is recommended (dose: 400–500 mg tds for 10–14 days) as it has been shown to be as effective as oral vancomycin in mild to moderate CDI (Zar et al., 2007; Louie et al., 2007; Bouza et al., 2008).

Moderate disease
For patients with moderate disease, a 10- to 14-day course of oral metronidazole is the recommended treatment (dose: 400-500 mg tds). This is because it is cheaper than oral vancomycin and there is concern that overuse of vancomycin may result in the selection of vancomycin-resistant enterococci (HICPAC, 1995; American Society of Health-System Pharmacists, 1998; Gerding, 2005).

Severe disease
For patients with severe CDI, oral vancomycin is preferred (dose: 125 mg qds for 10–14 days). This is because of relatively high failure rates of metronidazole in recent reports and a slower clinical response to metronidazole compared with oral vancomycin treatment (Wilcox and Howe, 1995; Musher et al., 2005; Lahue and Davidson, 2007; Zar et al., 2007). Two double-blind randomised studies reported that vancomycin is superior to metronidazole in severe cases of CDI (Louie et al., 2007; Bouza et al., 2008). A pooled analysis of these two phase 3 studies has shown that metronidazole was overall inferior to vancomycin (Johnson et al., 2012).
We recommend using any of the following to indicate severe CDI and so to use oral vancomycin in preference to metronidazole:
 WCC more than 5 x109/L;
 acutely rising blood creatinine (e.g. more than 50% increase above baseline);
 temperature more than 38.5°C; or
 evidence of severe colitis (abdominal signs, radiology).

Recurrent disease
Recurrent disease may occur in up to 20% of patients, up to half of which may actually be reinfections rather than relapse. The same antibiotic can be used for a second course. After a first recurrence the risk of further recurrences is higher. For recurrent disease, a tapering course of vancomycin may be considered after the initial treatment course. There are various regimens, such as 125 mg qds for one week, 125 mg tds for one week, 125 mg bd for one week, 125 mg od for one week, 125 mg on alternate days for one week, 125 mg every third day for one week (six weeks in total) (Tedesco et al., 1985). Clearly, this may provide a considerable selective pressure for vancomycin resistance, e.g. in enterococci. Fidaxomicin should also be considered for patients with severe CDI who are considered at high risk for recurrence; these include elderly patients with multiple comorbidities who are receiving concomitant antibiotics (Hu et al, 2009; Wilcox 2012). Fidaxomicin is very expensive and may not be of additional benefit for some strains of C. difficile (e.g. ribotype 0157). Its role in multiple recurrences is unclear. Local cost-effectiveness based decision making should determine its use, or seek specialist advice.*

2
Howell MD, Novack V, Grgurich P, Soulliard D, Novack L, Pencina M, Talmor D (2010). Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med 170: 784-90. RATIONALE: There is increasing evidence that acid-suppressing medications, in particular proton pump inhibitors (PPIs) may be a risk factor for CDI. Notably, Howell et al. (2010) reported a correlation between the degree of acid suppression and risk of CDI (i.e. a ‘dose response’ effect), which ranged from none (Odds Ratio 1), to H2 receptor antagonists (OR 1.53, 95% CI 1.12-2.10) to once daily PPI (OR 1.74, 1.39-2.18) to more frequent PPI (OR 2.36, 1.79-3.11). It remains possible that these associations are confounded by other CDI risk factors (Cohen et al, 2010). However, given that acid suppression drugs, especially PPIs, may be over-prescribed and frequently not reviewed to determine if long-standing prescriptions are still justifiable, consideration should be given to stopping/reviewing the need for PPIs in patients with or at high risk of CDI.

3
Belmares J, Gerding DN, Parada JP, Miskevics S, Weaver F, Johnson S. Outcome of metronidazole therapy for Clostridium difficile disease and correlation with a scoring system. J Infect 2007;55:495-501. RATIONALE: This retrospective review of 102 patients given a 5-day course of metronidazole for clostridium difficile infection found that 70.3% responded by the end of the 5-day course. Twenty-one of the remaining 30 patients eventually responded to metronidazole, but needed longer treatment courses.

4
National Institute of Clinical Excellence (2012). Clostridium difficile infection: fidaxomicin. Available at: http://www.nice.org.uk/Advice/ESNM1 Accessed 23.09.14. RATIONALE: Until recently there were only two main alternatives (metronidazole or vancomycin) for the treatment of CDI (Cohen et al, 2010). Oral fidaxomicin was approved for the treatment of CDI in Europe in 2012 (Johnson & Wilcox, 2012; Wilcox, 2012), and has been reviewed by the National Institute for Clinical Excellence (NICE; the information published by NICE is not formal guidance) and the Scottish Medicines Consortium (SMC). Two, phase 3, multi-centred, randomised, double-blind trials had almost identical designs and compared oral fidaxomicin (dose: 200 mg bd for 10–14 days) with oral vancomycin (dose: 125 mg qds for 10–14 days) (Louie et al, 2011; Cornely et al, 2012). The studies had essentially similar results. Fidaxomicin was non-inferior to vancomycin in the initial clinical cure of CDI (relative risk (RR) 0.88 (95% CI 0.64, 1.19), p=0.396), but was superior in reducing recurrence (RR 0.54 (95% CI 0.42, 0.71), p<0.001) and sustained clinical cure (RR 0.68 (95% CI 0.56, 0.81), p<0.001) (all modified intention to treat analysis of combined study results) (Crook et al, 2012). The side-effect profile of fidaxomicin appears similar to that of oral vancomycin. The acquisition cost of fidaxomicin is considerably higher than vancomycin (which is more expensive than metronidazole). Therefore local decision makers need to take into account the benefits versus increased costs.

The POCAST project is funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Imperial College London and by the Imperial College Healthcare Charity (Grant Ref No:7006/P36U).