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C. difficile infection remains among most costly, morbid nosocomial infections
Recent advances have been achieved in the prevention and treatment of Clostridium difficile infection, but it continues to be the most frequently reported nosocomial pathogen in the United States.
Recently, Daniel A. Leffler, MD, and J. Thomas Lamont, MD, AGAF, both from Beth Israel Deaconess Medical Center at Harvard Medical School, co-wrote a review article on the changing epidemiology of C. difficile infection, risk factors, prevention, treatments and emerging disease control strategies.
Daniel A. Leffler
“Despite overall good tests and treatments for acute C. difficile infection, this infection remains one of the most costly and morbid nosocomial infections,” Leffler told Healio Gastroenterology. According to the review, 453,000 C. difficile infections and 29,000 subsequent deaths occurred in the United States in 2011. Furthermore, nosocomial C. difficile infection increases hospitalization costs more than fourfold, representing an annual increase of $1.5 billion in expenditures nationwide.
New risk factors
The major risk factor for C. difficile infection is antibiotic use, but others include increasing age, inflammatory bowel disease, organ transplantation, chemotherapy, chronic kidney disease, immunodeficiency, or exposure to an infant carrier or infected adult. Acid suppression may increase risk for C. difficile infection, but the data are conflicting.
Risk factors in hospitals and long-term care facilities include environmental contamination and frequent antibiotic use. Community-acquired infections have risen during the past decade to account for up to one-third of new cases, but more research is required to determine modes of acquisition and risk factors. Risk factors for severe and recurrent C. difficile infection include older age, a severe initial infection and ongoing antibiotic use.
Improving diagnostics
DNA-based tests have recently displaced enzyme immunoassay as the diagnostic gold standard for C. difficile infection because they have higher sensitivity and specificity. “In the future, highly sensitive quantitative toxin assays may also contribute to diagnostic algorithms,” the authors wrote.
Delayed diagnosis may result from the heterogeneity of tests and lack of clinical suspicion, and although sequential testing with polymerase chain reaction assay and enzyme immunoassay is advocated, diarrhea and a positive result from either test are sufficient for treatment.
Stool testing should be restricted to patients with diarrhea, and although testing after treatment does not have a role in confirming eradication, it can help to differentiate recurrent C. difficile infection from other causes of diarrhea after treatment.
Challenges in prevention
Without a vaccine for C. difficile infection, preventive efforts focus on minimizing antibiotic use, infection containment and probiotics.
“Currently, we rely on prevention of infection through antibiotic stewardship and isolation of infected cases, along with prompt diagnosis and antibiotic therapy,” Leffler said. Study data demonstrate the effectiveness of antibiotic stewardship, although it is labor-intensive, and isolation of infected patients is important due to the ineffectiveness of alcohol-based hand sanitizers in reducing viable spores.
“At present, probiotics have an uncertain effect on the prevention of C. difficile infection, and their routine use for the prevention or treatment of active infection is not recommended,” the authors wrote.
Current treatments
Metronidazole and oral vancomycin have been the standard treatments for acute C. difficile infection for decades, although a variety of recent data, metronidazole’s more frequent adverse effects, and generic vancomycin’s decreasing costs have resulted in increasing use of vancomycin.
The cure rate for acute infection with Dificid (fidaxomicin, Cubist Pharmaceuticals), approved by the FDA in 2011, was shown to be nearly equivalent to vancomycin in phase 3 trials, but with a lower risk of recurrence (except in patients with the BI/NAP1/027 strain). Its higher cost has limited its use; however, recent data suggest fidaxomicin may be superior to vancomycin in preventing further episodes after first recurrence.
Repeat metronidazole or vancomycin is effective about half of the time for treating initial recurrence, and further recurrences are treated with fidaxomicin or tapered and pulsed dosing of vancomycin.
In terms of surgical treatments, “emergency colectomy for fulminant C. difficile infection is associated with mortality as high as 80%, although a diverting ileostomy and a colonic lavage with vancomycin may be an effective alternative,” the authors wrote.
Other antibiotics are effective but not recommended except in rare cases due to limited data, high costs, poor safety profile and resistance to C. difficile.
Emerging therapies
Fecal microbial transplant has been recently accepted as a treatment for recurrent C. difficile infection. It was approved by the FDA for this indication without an investigational new drug application and has demonstrated a 90% success rate. Ongoing research focuses on using FMT to treat primary C. difficile infection, bacterial cultures as substitutes for stool, and orally administered capsules.
“With further refinement, FMT will most likely become the standard of care for recurrent infection,” the authors wrote.
Findings from animal studies involving immunization with toxoids TcdA and TcdB, and from human trials involving protective immunoglobulin G antitoxins indicate potential for the development of vaccines. Passive immunization with monoclonal antibodies also have demonstrated substantial and cost-effective protection from recurrent infection.
“In the near future, vaccines, passive immunotherapy and microbiome therapies will likely both reduce rates of infection and improve outcomes,” Leffler said.
“Until such time, C. difficile infection will continue to be a common and highly morbid consequence of antibiotic use,” the authors concluded. – by Adam Leitenberger
Disclosure: Leffler and Lamont report no relevant financial disclosures.