The Evolving Treatment of Clostridium Difficile Infection

Prabin Sharma
Department of Internal Medicine, Yale New Haven Health-Bridgeport Hospital
prabin.sharma@bpthosp.org

Clostridium difficile infection (CDI) rates have been increasing, with a corresponding rise of morbidity and mortality. The primary treatment modality of CDI includes standard-of-care oral antibiotics, although the recurrent infection rate is high and newer treatment methods are being explored. Here is a summary of four studies focussing on the evolving treatment methods of severe and recurrent CDI.

Vancomycin: First-line Therapy for Severe Clostridium Difficile Infection
In this retrospective propensity matched study, Stevens et al.1 focussed on the recurrence of CDI and all-cause 30-day mortality from CDI in order to strengthen the evidence that vancomycin-treated CDI patients tend to have better long term outcomes. Recurrence was defined as a second positive test for CDI within 8 weeks of the initial episode. Death from any underlying cause within 30 days of the first episode was defined as all-cause 30-day mortality. Data was sourced from the U.S. Department of Veterans Affairs (VA) healthcare system and was collected from January 1st 2005–December 31st 2012. In this study, 47,471 patients (95.9% men and 4.1% women) who developed CDI were treated with either vancomycin or metronidazole. 2,068 (4.4%) patients managed with vancomycin for the first episode were matched with 8,069 metronidazole-treated patients. Subgroup analysis based on the severity of the disease was also performed. The authors did not note any significant difference in the CDI recurrence risk between vancomycin-treated versus metronidazole-treated patients and no significant mortality risk difference between the two groups was found with mild-to-moderate CDI. However, mortality benefit was seen in the vancomycin-treated group with severe CDI who had a significant reduction in 30-day mortality. This study highlights and reaffirms the treatment guidelines recommending vancomycin as the initial therapy for severe CDI. The strength of the study is its large scale and large number of patients included within its analysis. As acknowledged by the authors, observational and retrospective study design, lack of randomisation, unmeasured confounding factors, lack of information on treatment changes over time, and absence of treatment-data outside of the VA health system are the limitations of this study.

Metronidazole is the current initial recommended therapy for mild-to-moderate CDI, but studies have shown superiority of vancomycin while treating severe cases of CDI. Despite this, a significant number of patients with severe CDI are still treated with metronidazole leading to higher rates of recurrence and mortality. Authors highlight higher vancomycin-related treatment cost and fear of vancomycin resistant enterococcal infection as the most likely treatment barrier, however, a lack of awareness of treatment guidelines may also be playing a role.

Human Monocolonal Antibodies for the Treatment of Recurrent Clostridium Difficile Infection?
Wilcox et al.2 present data from two double-blind, randomised, placebo-controlled, Phase III trials in this pharmaceutical-funded study; MODIFY I and MODIFY II. Actoxumab and bezlotoxumab are two human monoclonal antibodies against toxin A and B of Clostridium difficile. Undergoing treatment for a first or recurrent episode of CDI as per current treatment guidelines, 2,655 patients were divided into different groups in a 1:1:1:1 ratio to receive bezlotoxumab (10 mg/kg body weight), actoxumab plus bezlotoxumab (10 mg/kg body weight each), or placebo (0.9% saline) and an additional group which received actoxumab alone included in MODIFY I (which was later discontinued). In a modified intention-to-treat analysis, recurrent CDI within 12 weeks of infusion was the primary endpoint. In both MODIFY I and II, patients treated with bezlotoxumab alone compared to placebo had a significantly lower rate of recurrent CDI. Addition of actoxumab did not result in positive treatment outcomes. Adverse events occurred at the same rates in all treatment groups, the most common being nausea and diarrhoea. Limitations of the study, as acknowledged by the authors, included: lack of standardisation in the selection of standard-of-care antibiotics, a broad time interval between the time of study infusion relative to the onset of symptoms, underestimation of baseline severity of CDI due to the standard-of-care antibiotic treatment of 90% of the patients, lack of data on the combined effect of bezlotoxumab with other agents used for treatment of recurrent CDI, and limited assessments of adverse events. Despite the limitations, the authors conclude that in CDI patients, either primary or recurrent who are receiving standard-of-care antibiotics, a single infusion of bezlotoxumab is associated with lower recurrence rates and results show a similar safety profile as placebo for up to 12 weeks. It is now US Food and Drug Administration (FDA) approved and is soon to be made available for treatment of recurrent CDI. The biggest limiting factor is going to be its cost, with each infusion costing up to $4,000 USD.

Heterologous versus Autologous Fecal Microbiota Transplantation for Recurrent Clostridium Difficile Infection?
In a randomised, double-blind, controlled trial, funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIH) and conducted at two academic medical centers by Kelly et al.,3 46 patients were included with a history of ≥3 recurrences of CDI, with the most recent episode treated with a full course of vancomycin. Resolution of diarrhoea without any further need for treatment during the follow-up period of 8 weeks was the primary endpoint of the study and intervention was autologous (stool from self) or heterologous (stool from donor) fecal microbiota transplantation (FMT). The treatment data on safety, including adverse events, serious adverse events, and the evolution of new medical conditions, was obtained across the following 6 months. The fecal microbiota composition was analysed for all patients before and after the FMT. Limitations included a small sample size, exclusion of sicker patients including those of an older age (>75 years) and those immunocompromised, and the inclusion of patients with >3 recurrences only. The authors reported that heterologous FMT compared to autologous FMT was associated with a restoration of fecal floral diversity close to that of the healthy donors used. They recommend FMT with donor stool as a safe and efficacious modality to prevent recurrence of CDI. Further studies including a larger number of patients are needed to validate their findings.

Freeze-Dried Encapsulated Microbiota for oral administration?
FMT has developed over the years for the restoration of gut microbiota in patients with recurrent CDI. Oral preparation is preferred compared to colonoscopic or nasogastric administration and has shown good results. However, there are concerns in terms of uniformity of the flora and its storage, particularly with frozen liquid capsules. In this study by Staley et al. 4, the authors developed a lyophilization protocol in order to ensure viability and diversity of the bacteria in FMT. 49 patients received the treatment, of which 88% had no recurrence over 2 months and this was defined as clinical success. Fecal microbiota analyzed after treatment revealed near normalization within 1 month of treatment. The authors suggest that recurrent CDI can be managed successfully by administration of single dose of encapsulated, freeze-dried microbiota from a healthy donor. They also add that low dose formulations (2-4 capsules) are as effective as high dose formulations (24-27 capsules). Again this was a small, single center study and it doesn’t compare capsules with other forms of treatment in terms of efficacy and adverse outcomes. Further studies will be needed to probe into these areas.

References

  1. Stevens VW et al. Comparative Effectiveness of Vancomycin and Metronidazole for the Prevention of Recurrence and Death in Patients With Clostridium difficile Infection. JAMA Intern Med. 2017. [Epub ahead of print].
  2. Wilcox MH et al., MODIFY I and MODIFY II Investigators. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017;376(4):305-17.
  3. Kelly CR et al. Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial. Ann Intern Med. 2016;165(9):609-16.
  4. Staley C et al. Successful Resolution of Recurrent Clostridium difficile Infection using Freeze-Dried, Encapsulated Fecal Microbiota; Pragmatic Cohort Study. Am J Gastroenterol. 2017. doi: 10.1038/ajg.2017.6. [Epub ahead of print].

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