A better adherence to evidence-based guidelines can improve the outcome of Clostridium difficile infection and waiting for the latest therapeutic options
Stefano Di Bella MD
Nicola Petrosillo MD
National Institute for Infectious Diseases
Clostridium difficile is recognised as the major cause of antibiotic-associated diarrhoea and has recently emerged as the most common agent of healthcare-associated infections in US.1 The epidemiology of Clostridium difficile infection (CDI) has dramatically evolved over the last two decades, in terms of incidence, mortality and therapeutic failure, and spread of hypervirulent strains.2 Indeed, during the last few years an epidemic strain BI/NAP1/027 spread in several countries, accounting for an increased morbidity and mortality. This strain has been recognised to be characterised by higher toxin production and high-level floroquinolone resistance. Moreover, recently a new type of toxin A-negative, toxin B-positive C. difficile strain has been identified; this strain has a variant type of pathogenicity locus and might not be detected by molecular tests.3
The best standard laboratory test for diagnosis of CDI has not been clearly established. There are two main issues regarding CDI diagnostics: the lack of clinical suspicion and the level of sensitivity and/or specificity of the tests. The EUCLID study assessed the burden of under-diagnosis for CDI analysing data from 482 European hospitals. This study demonstrated that 23% of samples positive for C. difficile were not diagnosed because of an absence of clinical suspicion.4 The second issue is related to level of sensitivity and specificity of diagnostic tools: the use of a two- or three-stage algorithm, with the use of a first test with high sensitivity followed by more specific tests is encouraged by the scientific community in order to avoid false negative tests.5
Increasing trend of treatment failures and recurrent episodes of CDI
During the last 15 years the rate of treatment failures and recurrent CDI episodes have increasingly been reported. The reason for treatment failure is likely related to microbial evolution and changing epidemiology of CDI, with circulation of ribotypes that are more difficult to treat.2
The increase in recurrence rate is likely due to the ageing of the population and the increasing prevalence of immunosuppressed individuals (for example, transplanted patients receiving chronic immunosuppressant regimens, hypogammaglobulinaemic patients, etc) alongside the distribution of specific ribotypes associated with a higher rate of recurrence.
a. First episodes of CDI
The first step in the management of CDI is withdrawing precipitating antibiotics. When this is not possible, it should be considered to shift to antibiotics with no effect on anaerobes.
The current pharmacological management on CDI depends on disease severity. The definition of “severe CDI”, although similar, is not identical according to different guidelines. However, marked leukocytosis (≥15000 cells/mm3), hypoalbuminaemia (<3g/dl) and the rise in creatinine level (≥1.5 times the premorbid level) are commonly used to discriminate severe from mild disease.5–7
Metronidazole is still recommended for mild CDI, while vancomycin is the mainstay for severe CDI. This comes from studies that showed superiority of vancomycin over metronidazole in severe episodes of CDI. When oral treatment is not possible intravenous tigecycline is an alternative option to intravenous metronidazole and enteral vancomycin, even if the quality of evidence is poor.
b. Recurrent episodes of CDI
In patients with multiple recurrences, vancomycin administered with a tapered and/or pulsed regimen or fidaxomicin is the preferred regimen.
Moreover the so-called “chaser” regimens have been attempted for the management of recurrent CDI. These regimens consist of a second antibiotic given after a first course of a different one. Fidaxomicin and rifaximin have been used for this reason after a course of vancomycin demonstrating to be effective in preventing recurrences, even if this evidence comes from few case series.8–9
The non-pharmacological treatment for recurrent CDI relies on faecal microbiota transplantation (FMT). This procedure has proven to have an efficacy of ~90% for CDI.10 The trial comparing vancomycin followed by FMT and vancomycin alone was stopped after an interim analysis because of clear superiority of the FMT over vancomycin alone.11 It is likely that in the future this procedure will be used also for the management of the initial episodes of CDI.
c. Complicated CDI episodes
A complicated CDI is considered when there are signs of infection including hypotension, ileus or megacolon.6 In these cases vancomycin is the preferred antimicrobial. Monitoring lactate levels is a helpful tool prognostic of progression toward a complicated course of the disease. It is very important to obtain a surgical evaluation in patients with complicated CDI. The two main surgical options are the colectomy and the loop ileostomy with intraoperative colon lavage.
Currently four Phase III trials on anti-C. difficile drugs are ongoing; these studies include the following molecules: cadazolid (a oxazolidinone-type antibiotic), surotomycin (a cyclic lipopeptide antibiotic), MK-6072 and MK-3415A (two monoclonal antibodies) and H-030-012 (a toxoid vaccine).
Results of these studies are not yet available. The near future appears related to the full introduction in the clinical practice of FMT and treatment with monoclonal antibodies. FMT is already a recommended treatment for recurrent CDI even if its application lacks a widespread utilisation (recent evidences show its efficacy also in immunocompromised patients). The obstacle to FMT availability in many centres derives from the difficulty for many centres to combine the screening of the donor and the endoscopic instillation procedure.
A suitable way to overcome these difficulties could be derived from a recent preliminary feasibility study that evaluated the administration of oral, capsulised, frozen FMT in patients with recurrent CDI. The authors demonstrated an overall 90% rate of clinical resolution of diarrhoea (70% after the first treatment) without serious adverse event.12 This study seems to open a different way of administration of FMT that could pave the way to the widespread use of FMT.
Regarding monoclonal antibodies, in a Phase II study published by Lowy et al. in 2010 the combination of two monoclonal antibodies (actoxumab and bezlotoxumab) was given with standard-of-care therapy: the rate of recurrence of CDI was lower among patients treated with monoclonal antibodies (7% versus 25%).13
In conclusion, even though in the last few years there have been advances in diagnosis and clinical management CDI remains a severe disease, sometimes with a poor prognosis. Waiting for newest therapeutical options, a better adherence to evidence guided diagnostic and clinical management may help to improve the success rate and to reduce the spread of infection in the healthcare settings.
- Magill SS et al. Multistate point-prevalence survey of health care-associated infections. N Engl J Med 2014;370:1198–208.
- Freeman J et al. The changing epidemiology of Clostridium difficile infections. Clin Microbiol Rev 2010;23:529–49.
- Janezic S et al. A new type of toxin A-negative, toxin B-positive Clostridium difficile strain lacking a complete tcdA gene. J Clin Microbiol 2015;53:692–5.
- Davies KA et al. Underdiagnosis of Clostridium difficile across Europe: the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID). Lancet Infect Dis 2014;14:1208–19.
- Debast SB et al. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014;20 Suppl 2:1–26.
- Cohen SH 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 Control Hosp Epidemiol 2010;31:431–55.
- Surawicz CM et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013;108:478–98.
- Johnson S et al. Rifaximin Redux: treatment of recurrent Clostridium difficile infections with rifaximin immediately post-vancomycin treatment. Anaerobe 2009;15:290–1.
- Johnson S et al. Fidaxomicin “chaser” regimen following vancomycin for patients with multiple Clostridium difficile recurrences. Clin Infect Dis 2013;56:309–10.
- Cammarota G et al. Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review. J Clin Gastroenterol 2014;48:693–702.
- van Nood E et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407–15.
- Youngster I et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014;312:1772–8.
- Lowy I et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010;362:197–205.