Guest commentary: Promising novel therapies for CDI and the need for better management strategies

Issue: October 2015

In this guest commentary, Dale N. Gerding, MD, professor of medicine at Loyola University Chicago Stritch School of Medicine, discusses several presentations at ICAAC 2015 that focused on new approaches to the treatment of Clostridium difficile infection and recurrence and the need for more effective C. difficile management strategies.

Dale N. Gerding

The recent Interscience Conference on Antimicrobial Agents and Chemotherapy and International Congress of Chemotherapy and Infection meeting focused considerable attention on Clostridium difficile infection (CDI), which the CDC has categorized as one of three “urgent public health threats.” In February, the CDC reported that in 2011 CDI caused almost half a million infections and more than 29,000 deaths, mostly among people aged 65 years and older.

Perhaps the most encouraging CDI news from the meeting is the progress being made in developing promising novel therapies to combat this formidable foe. These include advances in bacteriotherapy and the use of a single monoclonal antibody (MAB) to passively neutralize C. difficile toxin B. Successful demonstration of MAB suggests the eventual development of active immunity with C. difficile vaccines may also be successful.

The need for more efficacious therapies has grown especially dire following the emergence of the epidemic C. difficile strain 027/B1/NAP1, which has greatly increased the risk for severe infections and outcomes. The incidence and severity of CDI have risen significantly in the United States, Canada and Europe over the past decade, leading to an increase in hospitalizations, health care costs and mortality.

A retrospective, population-based cohort study of 1.165 million Medicare beneficiaries presented by Andrew F. Shorr, MD, MPH, of the Washington Hospital Center, quantified the enormous burden CDI places on both patients and our health care system. The study found that CDI is associated with a near-doubling in adjusted mortality (from 23.4% to 42.6%) and health care costs during the year following a CDI episode. This translates to 46,000 all-cause deaths annually and a $27,000 increase in total annual per patient costs among 240,000 Medicare patients with CDI-associated disease.

Continued surveillance and molecular typing of C. difficile are important for identifying epidemic and emerging strains nationally and worldwide. Through its Emerging Infections Program (EIP), the CDC analyzed 2,630 isolates from 10 EIP sites nationwide in 2012-2013 and detected 208 different C. difficile ribotypes (RT), with RT 027 the most prominent (18%) — a much lower frequency than in previous surveys, whereas RT 106, a previously epidemic strain in the United Kingdom, appears to be on the increase in the U.S.

Emerging approaches to treating CDI and reducing the risk for recurrence

A major paradox in the management of CDI is that the use of antimicrobial agents (metronidazole, vancomycin or Dificid [fidaxomicin, Merck]) for treatment runs the risk for prolonged gut microbiota perturbation and infection recurrence. Recurrence rates range from 15% to 35% in adult patients, and those who have a recurrence of CDI are at high risk for having multiple recurrences.

At ICAAC, fecal microbiota transplantation (FMT), which is an experimental treatment, was a high-profile topic for treating recurrent CDI. FMT is rapidly evolving and multiple recurrent CDI remains the major successful application of FMT. In randomized controlled trials, FMT success rates are in the 75% to 80% range for a single FMT rather than exceeding 90% in earlier observational studies. Thomas J. Louie, MD, of the University of Calgary, noted that multiple approaches are now available for FMT administration, including fecal microbes in condensed, capsulized form given orally either fresh, frozen or freeze dried. The method of administration (orally or rectally) does not seem to affect efficacy.

In addition to several new narrow-spectrum CDI antibiotics under study, other microbial and nonmicrobial biological approaches are in development. Although all differ from each other on a mechanistic level, most are grounded on the principle of attempting to spare, protect or repair the endogenous gut flora.

Stuart Johnson, MD, of the Stritch School of Medicine at Loyola University, presented data on different CDI treatment approaches, including a toxin-binding polymer tolevamer (Genzyme), which was unsuccessful compared with metronidazole and vancomycin treatment. This study, however, did demonstrate superiority of vancomycin vs. metronidazole treatment for all CDI patients. In a biotherapeutic approach, a phase 2 trial published earlier this year in JAMA showed a CDI recurrence rate of 2% among 86 patients who were successfully colonized with nontoxigenic C. difficile strain M3 (NTCD-M3) given as an adjunct after treatment of first episode or first recurrence of CDI with vancomycin or metronidazole. With all the progress made in biotherapeutics, it is highly likely that new novel strains will be found that will prevent some of the unintended consequences of antibiotic therapy.

Mark H. Wilcox, MD, FRCPath, of Leeds Teaching Hospitals and the University of Leeds, and I presented top-line results from two global, phase 3 studies on the use of two fully human MABs (actoxumab and bezlotoxumab alone and in combination) to prevent CDI recurrence. These two MABs directed at toxin A and toxin B, respectively, were used as an adjunctive therapy to antibiotic treatment. Both MODIFY (Monoclonal Antibodies for C. difficile Therapy) studies demonstrated that in patients receiving standard of care antibiotics for CDI, bezlotoxumab and the combination of actoxumab and bezlotuxumab were superior to placebo in prevention of CDI recurrence, the primary study endpoint, but were not different from each other. Actoxumab alone was ineffective and dropped from the study. Based on these results, Merck plans to submit new drug applications seeking regulatory approval of bezlotoxumab alone in the U.S., European Union and Canada in 2015.

Adopting more effective CDI management strategies

A presentation by Erik Dubberke, MD, MSPH, of Washington University School of Medicine, identified three variables that contribute to poor clinical outcomes — host factors (age, severity of illness, immune response), C. difficile (germination, toxin production, binary toxin) and management (time to treatment, treatment selection, concomitant antimicrobials). Of these, management of the disease is the only variable physicians can affect.

Yet despite our growing understanding of what needs to be done to more effectively manage CDI, numerous ICAAC presentations provided evidence that hospitals have been slow to incorporate this knowledge into clinical practice. This can partially be attributed to current Society for Healthcare Epidemiology of America/Infectious Diseases Society of America CDI treatment guidelines, which are based on limited and outdated information and have not been updated since 2010, though they are in the process of being revised. For example, the guidelines recommend metronidazole as the drug of choice for mild to moderate CDI, while accumulating data now indicate that metronidazole is inferior to vancomycin. In the aforementioned MODIFY studies, 50% of physicians selected metronidazole as their CDI standard of care. The guidelines also make little mention of FMT, and none at all of fidaxomicin, which was approved after guideline publication and has been shown to be noninferior to vancomycin for initial cure in CDI patients and is associated with a lower recurrence rate and superior sustained clinical response.

Johnson stated that most patients with recurrent CDI can be effectively managed with vancomycin and fidaxomicin through the use of novel treatment regimens. He presented alternative dosing strategies with tapered and/or pulsed regimens of vancomycin followed by a fidaxomicin “chaser.” A small study of alternative fidaxomicin dosing regimens for patients who on average had five prior CDI episodes resulted in a cure rate of 82%, which is similar to FMT success rates. He also noted that physicians too often increase dosages and extend dosing treatments for vancomycin, both of which can harm the patient.

Educating the medical community and general public

Although we have made significant advances in its treatment, C. difficile is a serious health problem that too often is still underdiagnosed, misunderstood and mismanaged. Greater education is paramount throughout the health care system, not only for ID physicians but for the internists, hospitalists and general practitioners who treat most cases of CDI. Hospital executives also should be more informed about the impact of CDI on costs and patients. I have had patients who have had open-heart surgery followed by CDI tell me that they would rather have their surgery again than get CDI again.

We need to do more to make the public aware that CDI is a more common and significant health care infection than Staphylococcus aureus or MRSA. Greater awareness in health care facilities and the community will focus more attention — and hopefully resources — toward improving disease prevention, diagnosis and treatment and accelerating the development of more effective therapies. Ideally, this could ultimately result in a CDI vaccine for long-lasting protection and improved biotherapeutics and immunologics such as MABs for short-term protection of patients. – by Dale N. Gerding, MD

References:

Crowther GS, et al. Infect Drug Resist. 2015;8:333-337.

Dubberke ER. Recognizing Factors Associated with Poor Clinical Outcomes in CDI. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Gerding DN, et al. Phase 3 Double-Blind Study of Bezlotoxumab (BEZ) Alone & with Actoxumab (ACT) for Prevention of Recurrent C. difficile Infection (rCDI) in Patients on Standard of Care (SoC) Antibiotics (MODIFY II). Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Johnson SJ. Integrating the New with the Old when Managing CDI. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Karlsson M, et al. Abstract C-579. Molecular Epidemiology of Clostridium difficile Isolated in the United States, 2012-2013. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Lessa FC, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1408913.

Louie TJ. New Perspectives on CDI Pathogenesis and How This Translates to Therapy. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Wilcox MH, et al. Phase 3 Double-blind Study of Actoxumab (ACT) & Bezlotoxumab (BEZ) for Prevention of Recurrent C. difficile Infection (rCDI) in Patients on Standard of Care (SoC) Antibiotics (MODIFY I). Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Zilberberg MD, et al. Clostridium difficile-associated Disease Nearly Doubles Mortality and Healthcare Costs in Medicare Population. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Disclosure: Gerding is a scientific adviser to Merck.