Recent Developments Promise New Guidelines for Management of C. difficile
This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.
PRIORITY PRESS - 23rd European Congress on Clinical Microbiology and Infectious Diseases
Berlin, Germany / April 27-30, 2013
Berlin - Broad initiatives now underway are poised to stem the morbidity and mortality driven by a persistent rise in the incidence of Clostridium difficile infection (CDI). Due to progress in understanding risk factors and an expansion of treatment options, a committee was convened during the 2013 ECCMID to generate new guidelines, which are expected before the end of 2013. These guidelines are likely to capture many of the initiatives to control CDI that were described in a series of symposia and presentations at the 2013 ECCMID. These include a greater focus on treatment strategies that not only provide clinical cure but minimize risk of recurrence as well as on broader and more aggressive implementation of infection control.
Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec
At ECCMID, newly reported European survey data found that rates of CDI climbed 50% (6.6 vs. 4.1 per 10,000 patient bed days) since 2008. In the US, CDI among hospitalized patients ≥65 years of age increased 200% over a recent 10-year period (MMWR 2011;60:1171). In Canada, data from the Canadian Nosocomial Infection Surveillance Program (CNISP) have tracked a similar rise in CDI at participating hospitals. These and other data have encouraged aggressive efforts at CDI control.
“We now test every diarrhea sample,” reported Dr. Thomas Louie, Professor of Microbiology, Immunology, and Infectious Disease, University of Calgary, Alberta. Referring to a standard practice now put in place at most Canadian hospitals, Dr. Louie suggested at ECCMID that prompt detection and cure represent the fundamental steps for infection control. Although such practices are also underway in Europe, they appear to be further behind. In the recently released EUCLID (European multicentre prospective biannual point prevalence study of Clostridium difficile infection in hospitalized patients with diarrhea) survey, only 10.6% of hospitals were testing all in-patient diarrhea samples.
Screening of diarrhea samples is particularly important in CDI, because early detection and treatment reduces production of toxins and spores, which are both critical factors in the vicious cycle of recurrent CDI. Even with successful CDI treatment, spores which survive for months in the absence of adequate decontamination, can increase risk of recurrence and trigger outbreaks.
At ECCMID, preventing recurrence not just treating acute disease was emphasized. Although clinical cure can be readily achieved with metronidazole in mild cases and with vancomycin in severe or recurrent infections, recurrences occur in up to 25% of patients within 3 months with greater rates in the most severe cases. Two options appear to improve recurrence rates. In the trial that led to approval of fidaxomicin for CDI, its major advantage over vancomycin was a significantly lower rate of recurrence. More recently, a study with fecal transplant was found to offer similar protection against recurrence.
Relative to vancomycin “fidaxomicin has several advantages, including less disruption of the microflora in the gut and prolonged activity,” reported Dr. John Coia, Royal Infirmary, Glasgow, UK. In the two similarly designed multinational trials instrumental to its approval, including one led by Dr. Louie (N Engl J Med 2011;364:422-31), fidaxomicin was found non-inferior to vancomycin for clinical cure but recurrence rates were lower. In the trial which included centres in Canada, recurrence rates fell from 25.3% to 15.4% (P=0.005) on the intention-to-treat analysis and from 24% to 13.3% (P=0.004) in the per-protocol analysis for those receiving fidaxomicin relative to vancomycin.
Similar results were reported in a subsequent similarly designed multinational trial that was conducted primarily in Europe (Cornley et al. Lancet Infect Dis 2012;12:281-9). Global cure, an end point capturing the absence of recurrence, was also significantly improved with fidaxomicin in both trials.
Insights into Novel Antimicrobial
Insight into the relative advantage of fidaxomicin in the clinical trials was generated by new in-vitro data reported at ECCMID. In a human gut model, fidaxomicin was found to adhere to spores and to persist in gut biofilm for more than 2 weeks. In a study led by Dr. Caroline H. Chilton, University of Leeds, UK, the ability of fidaxomicin to adhere to spores, preventing subsequent growth of CDI, was consistent across all ribotypes evaluated, including 027, which is considered one of the most virulent.
“In an earlier set of studies with the same model, we observed that fidaxomicin activity persisted over a much longer time than vancomycin. Most of that time, C. difficile spores could not be detected, which was a phenomenon not observed following vancomycin,” Dr. Chilton reported. This more recent study of spore adherence appears to explain the previous observations and “may be the primary explanation for the greater efficacy of fidaxomicin relative to vancomycin for preventing CDI recrudescence.”
Similar prolonged protection against the germination, outgrowth and sporulation of CDI was identified in independent studies at the University of Nottingham, UK. In a study led by Dr. Daniela Heeg, Centre for Biomolecular Sciences, fidaxomicin was able to inhibit in vitro growth of CDI at minimum inhibitory concentrations (MICs) as low as 0.01 μg. Again, the ability to inhibit growth was consistent across strains including 027.
“We observed impaired spore formation at sub-MIC levels of fidaxomicin,” Dr. Heeg reported. “The inability of spores to return to a cell growth state in the presence of fidaxomicin may provide an explanation for the reduced risk of recurrence on this therapy relative to vancomycin.”
Option of Fecal Transplant
Fecal transplant is an option still in development. According to recent guidelines, fecal transplant tends to be considered when all else fails, evaluation of the cost effectiveness and further investigation of the therapeutic potential is warranted (http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317138914904).
A recent study demonstrated superiority of fecal transplant to vancomycin for protection against recurrence (van Nood et al. N Engl J Med 2013;368:407-15), The relative difference in efficacy for the end point of resolution of CDI (83% vs. 31% for vancomycin alone and 23% for vancomycin plus bowel lavage; P<0.001 for either comparison) was so great that the study was stopped at the interim analysis. Although evidence of benefit from fecal transplant in CDI dates back to 1958, Dr. Coia believes the randomized trial will draw greater attention to this option.
“Fecal transplant is not suitable for a substantial proportion of patients, including those who are immunocompromized or who are taking antibiotics for another reason, but it is effective,”Dr. Coia noted. “I think one potential problem will be patient acceptance, but for those who have frequent CDI recurrences, any option may be acceptable.”
Vectors of Transmission
Better therapies are one approach to lowering the morbidity and mortality of CDI, but better strategies for infection control are needed and may depend on better understanding of vectors of transmission. Persistent outbreaks at institutions where stringent infection control practices are already in place emphasize the need to better understand the spread of CDI.
Of new data at ECCMID regarding transmission, one study suggested that some transmission may emanate from asymptomatic carriers. In a study presented by Dr. Prameet Sheth, Mount Sinai Hospital, Toronto, Ontario, 1549 rectal swabs from 474 admitted patients were cultured for C. difficile. Of these, 50 (10.6%) were found to be positive for CDI on polymerase chain reaction analysis. Of the patients with rectal swabs positive for C. difficile, nearly half were colonized at admission.
Of the 29 samples characterized using Modified Multiple Loci Variable Number Tandem Repeat Analysis, 21 (72%) were found to harbour toxigenic strains of C. difficile. Perhaps more importantly, 15% of those positive for C. difficile appear to have been colonized from an asymptomatic carrier. Providing evidence that at least some nosocomial transmissions originate in asymptomatic patients, Dr. Sheeth indicated that these results, which need further verification, have implications for designing new strategies to strengthen infection control.
The CDI epidemic is not expected to abate soon. Citing evidence that the risk of CDI is greater in diseases associated with aging, including chronic kidney disease, Dr. Louie predicted that “the baby boom bulge will increase the number of cases” despite advances in therapy and more aggressive efforts at infection control. He suggested that these trends increase pressure on institutions to develop protocols which detect cases early, prevent spread and lower recurrence rates.
New therapeutic strategies to reduce the risk of recurrence are considered essential to broad efforts to stem the growing toll in morbidity and mortality of CDI. In an aging population, the incidence of CDI is expected to rise even if efforts to improve early detection and treatment are successful. While recent advances appear likely to influence new treatment guidelines now in development, the identification of effective evidence-based strategies to reduce recurrence appear to provide an immediate opportunity to lessen the toll of this disease.