Guest Commentary: Updated guidelines for C. difficile infection may change clinical practice

Issue: March 2018

Kathleen Mullane

In this guest commentary, Kathleen Mullane, DO, PharmD, an infectious disease specialist at the University of Chicago Medicine, discusses new clinical practice guidelines for Clostridium difficile infection in children and adults. The guidelines, published in Clinical Infectious Diseases, include changes in diagnostics and therapy.

The updated clinical practice guidelines for Clostridium difficile infection, or CDI, in adults and children are potentially practice-changing in that they reflect an altered treatment paradigm, strengthened infection control procedures, and the accentuated importance of antimicrobial stewardship. The updated guidelines, issued by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America, were prompted by extensive research published since the release of the 2010 guidelines that has enhanced our understanding of CDI management and the impact of antibiotic therapy on the fecal microbiome, and that better qualifies the incidence and outcomes of recurrent CDI.

In addition to treatment recommendations based on controlled studies demonstrating differences in outcomes, the new guidelines include recommendations for managing CDI in children. In addressing the management of recurrent CDI (rCDI), the guidelines include use of fecal microbiota transplantation (FMT), highlighting the importance of strategies to repopulate a healthy microbiome for protection against rCDI.

The guidelines also address differentiating C. difficile colonization or carriage from active CDI. Because enzyme immunoassay (EIA) tests are associated with high rates of false-negative results (missing active CDI in 30%-70% of cases), previous guidelines recommended increased use of nucleic acid amplification testing (NAAT/PCR) to diagnose CDI. However, these tests identify the presence of the gene that produces toxin and not the toxin itself; therefore, individuals colonized or carrying C. difficile may be falsely diagnosed as having active CDI. Concerns of overtreatment of CDI, and of hospitals reporting CDI rates that may be inflated, led to the new recommendation that individuals who do not meet the criterion of diarrhea (> 3 unformed stools within a 24-hour period) not be tested. The guidelines also recommend the adoption of multistep algorithms to enhance sensitivity of C. difficile testing when appropriately submitted stool specimens cannot be guaranteed. In cases in which an in-house algorithm for screening acceptable specimens cannot be implemented, the guidelines recommend a testing and validation approach with:

glutamate dehydrogenase (GDH) antigen testing, followed by toxin testing in specimens testing positive;
GDH, followed by toxin testing of positive specimens, arbitrated by NAAT in the case of discordance; or
NAAT-positive specimens verified by toxin testing.

European guidelines recommend similar approaches. Algorithmic approaches may reduce the rate of false-positive results and, by extension, overtreatment and overreporting of CDI.

The guidelines mention, but do not recommend, multiplex PCR platforms that include C. difficile as part of a panel detecting enteric pathogens. It is yet unclear whether these tests will enhance screening sensitivity or lead to overtreatment of CDI.

For managing CDI in adults, a notable change in the newest guidelines is the recommendation of vancomycin or Dificid (fidaxomicin, Merck) and the dropping of metronidazole as first-line treatment. This recommendation is based on publications demonstrating higher initial cure rates with vancomycin and fidaxomicin compared with metronidazole in patients experiencing a first episode or, in the case of fidaxomicin, first recurrence of CDI. Metronidazole is still recommended in adults who are unable to take oral therapy or having an ileus or toxic megacolon (these patients represent < 5% of CDI cases). Fidaxomicin, although more expensive than vancomycin, may be more cost-effective by virtue of reducing the frequency of rCDI and readmissions, which are costly burdens on the health care system ($34,104 per admission). Widespread adoption of fidaxomicin vs. use in specific populations at risk for CDI will depend on changing attitudes among physicians, payers and pharmacies, who will need to consider overall costs of CDI management to the health care system and not medication costs alone. Usage patterns will likely be closely monitored in the coming years.

The 2017 guidelines include new recommendations for the treatment of rCDI. For a first recurrence, the guidelines recommend:

oral vancomycin as a tapered or pulsed regimen rather than a second, standard 10-day course of vancomycin;
a 10-day course of fidaxomicin; or
a standard 10-day course of vancomycin rather than a second course of metronidazole if the latter agent was used for the primary episode.

In patients with more than one recurrence, the guidelines recommend either tapered or pulsed oral vancomycin, a standard course of oral vancomycin, followed by rifaximin, or fidaxomicin. Although published too late to be included in these guidelines, extended pulsed- dose fidaxomicin was found to be superior to tapered vancomycin for sustained cure in individuals with relapsing CDI in the phase 3b/4 EXTEND trial. Notably, the guidelines recommend FMT for patients with multiply rCDI in whom “appropriate antibiotic treatments” have failed.

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Although FMT currently lacks FDA approval, it is increasingly used in the community. The availability of stool banks providing FMT specimens tested for pathogenic organisms from donors who were prescreened for bloodborne pathogens enhances the safety, availability and cost-effectiveness of FMT. The cost of a colonoscopy needs be included in the cost of endoscopically administered FMT. Long-term effects of donor-FMT on the gut microbiome of recipients are still unknown. Randomized controlled trials to better define efficacy and possible acute and long-term toxicities associated with this process are needed. The “ick factor” may be alleviated by oral FMT capsules currently under investigation.

The new guidelines mention but do not recommend Zinplava (bezlotoxumab, Merck), a monoclonal antibody directed against C. difficile toxin B because pivotal clinical trial results became available after the stop-date of the literature review. Bezlotoxumab is FDA-approved as an adjunct to CDI therapy to reduce rCDI. Although expensive, bezlotoxumab may be a reasonable addition to antibiotic therapy in patients unable to produce antibodies against the C. difficile toxin, such as those with multiple comorbidities, or those who are at risk for rCDI due to advanced age or being immunocompromised.

These guidelines highlight infection prevention to reduce the spread of C. difficile, including pre-emptive contact isolation for those with diarrheal illnesses until CDI is ruled out. They also recommend incorporating measures to assess the effectiveness and ensure the quality of environmental cleaning of hospital rooms previously housing patients with CDI.

A notable update is an increased emphasis on antibiotic stewardship programs (ASP) to minimize the frequency and duration of high-risk antibiotic therapy and the number of antimicrobial agents prescribed. Implementation of an ASP includes targeting use of antibiotics based on local epidemiology and the C. difficile strains present. The guidelines also recommend restrictions on the use of fluoroquinolones, clindamycin and cephalosporins — antibiotics largely responsible for epidemic strains of C. difficile.

New to the guidelines are recommendations on epidemiologic surveillance, diagnosis and treatment of CDI in children. Babies up to the age of 2 years carry C. difficile but do not develop CDI because they lack mature gut receptors that bind toxin. However, infants can transmit the organism, possibly leading to CDI in their contacts. Diagnostic workup by colonoscopy for CDI is rarely done as frequently in children as it is in adults. Children with certain conditions (eg, cancer, inflammatory bowel disease, transplantation) undergoing treatments that alter their gut microbiome are at risk for CDI, and one should therefore consider aggressive diagnostic evaluation. The recommendation of metronidazole or vancomycin as first-line therapy in children reflects the paucity of data on the treatment of pediatric CDI. To remedy this situation, studies are needed to evaluate pediatric outcomes to different therapeutic interventions.

With continued robust CDI research, it is hoped the next update will come expediently as the results of these trials are reported. More focused interim recommendations, as opposed to broad guidelines that include all the aspects in the latest publication, may be a consideration. In the meantime, the 2017 guidelines will serve as an extremely useful guidance for practicing clinicians, infection control practitioners and testing labs.

References:

Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;doi:10.1086/651706.

Debast SB, et al. Clin Microbiol Infect. 2014;doi:10.1111/1469-0691.12418.

Guery B, et al. Lancet Infect Dis. 2017;doi:10.1016/S1473-3099(17)30751-X.

McDonald LC, et al. Clin Infect Dis. 2018;10.1093/cid/cix1085.

Rodrigues R, et al. Infect Control Hosp Epidemiol. 2017;doi:10.1017/ice.2016.246.

For more information:

Kathleen Mullane, DO, PharmD, is an infectious disease specialist at the University of Chicago Medicine. She can be reached at: kmullane@medicine.bsd.uchicago.edu.

Disclosure: Mullane reports grants and/or personal fees from Astellas, Chimerix, ContraFect, Crestovo, Gilead Sciences, GlaxoSmithKline, Leonard Merlin Biopharm Inc., Nohla, Medimmune, Merck, Sage, Shire and Synexis, outside the submitted work.