New treatments for recurrent C. difficile target microbiome, toxins

While new treatment strategies emerge, Clostridium difficile remains a major source of morbidity and mortality in the United States.

According to the most recent data from the CDC’s Emerging Infections Program, there were nearly half a million estimated cases of C. difficile in the country in 2011. Of these, approximately 83,000 recurred at least once, and 29,300 were associated with death within 30 days of first diagnosis.

The hospital-acquired infection often is due to the removal of healthy gut bacteria by prescribed antibiotic treatments. While this may still be the case, recent trends suggest that an increasing number of these infections are occurring outside of hospitals.

“When I started, almost 90% of all C. difficile occurred in the hospital,” Dale N. Gerding, MD, professor of medicine at Loyola University Stritch School of Medicine, told Infectious Disease News. “Today, it’s only about 25%.”

Dale N. Gerding

Of the 15,461 cases of C. difficile infection investigated by the CDC program, 65.8% were associated with health care, but only 24.2% were hospital-onset.

“Although people receiving care in hospitals made up two-thirds of all infections, two-thirds of all infections, two-thirds of those actually occurred after the patient went home,” Michael Bell, MD, deputy director of the CDC’s Division of Healthcare Quality Promotion, said during a February media briefing discussing the Emerging Infections Program data. “It’s essential that patients and their clinicians be aware that they need to take any diarrhea following antibiotic use very seriously.”

Although only one-quarter of the C. difficile infections developed while patients were hospitalized, the majority of the community cases are a result of contacts that occurred during outpatient events and exposure.

“What the CDC has been finding is that of the cases that are being diagnosed in the community, about 80% of them have actually had outpatient health care contact,” Gerding said. “I think it’s still health care-associated, but now it’s associated with outpatient contact, many of which are significant contacts such as people on dialysis, emergency room visits and outpatient surgery.”

Despite this challenge, there is evidence that the infection is in an overall decline. According to data published in this year’s National and State Healthcare-associated Infection Progress Report, there was a 6% decrease in reported C. difficile infections from 2012-2013, and a 10% decrease reported from 2011-2013. Meanwhile, the 2011 approval of Dificid (fidaxomicin, Optimer Pharmaceuticals) provided the first new drug treatment for C. difficile in nearly 25 years.

Recent research on various upcoming treatment approaches also may provide future benefits. In a 2014 study published in JAMA, Ilan Youngster, MD, MMSc, a pediatric infectious disease specialist at Boston Children’s Hospital, and colleagues examined the safety and efficacy of frozen, orally administrated fecal microbiota transplantation (FMT) in 20 patients with recurring infection. After 6 months, no serious adverse events attributed to FMT treatment were observed, and 70% (95% CI, 47%-85%) of patients had resolution of diarrhea after a single FMT. Separate findings involving FMT have shown the treatment to be cost-effective, while also capable of improving symptoms among patients with Crohn’s disease.

Other methods of restoring intestinal microbiota through noninvasive colonization also have seen early success. In a 2015 study published in JAMA, Gerding and colleagues administered a nontoxigenic strain of C. difficile to 173 adult patients following completion of a standard vancomycin or metronidazole treatment regimen. Recurrence was greatly reduced among those who received the treatment (30% vs. 11%; OR = 0.28; 95% CI, 0.11-0.69), and few adverse events were reported.

“You can see what’s trending here is definitely fecal transplants migrating to oral preparations,” Gerding said. “You don’t have to do a colonoscopy, you don’t have to do upper endoscopy to deliver these products — you’ll be able to give them by mouth.”

Approaches strengthening the immune system are being explored as well. In a 2010 study, monoclonal antibody treatments directed against C. difficile toxins appeared effective at preventing recurrence compared with controls (7% vs. 25%; 95% CI, 7%-29%), while pharmaceutical companies continue to develop potential vaccines against the infection.

Ilan Youngster

According to Gerding, many of these developing treatments still require work. No studies have yet explored the long-term effects of FMT, and further testing would be needed to determine whether monoclonal antibodies or nontoxigenic spores have a place as primary prevention strategies.

“Lots of things are happening from lots of different directions,” Gerding said. “The big interest is in the microbiome or the microbiota itself, and how changes in it can be used to modify or treat diseases. I think we’re going to see lots of use of various bacteria in the future as treatment agents for a variety of diseases. It’s a fascinating area.” – by Dave Muoio

References:

Gerding DN, et al. JAMA. 2015;doi:10.1001/jama.2015.3725.
Konijeti GG, et al. Clin Infect Dis. 2014;doi:10.1093/cid/ciu128.
Lessa FC, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1408913.
Youngster I, et al. JAMA. 2014;doi:10.1001/jama.2014.13875.

For more information:

Dale N. Gerding, MD, can be reached at dale.gerding2@va.gov.

Disclosure: Gerding reports holding patents for the prevention of C. difficile infection to ViroPharma/Shire; consultancy for Cubist, DaVolterra, MedImmune, Optimer, Pfizer, Sanofi Pasteur and ViroPharma/Shire; and membership on the advisory boards of Actelion, Merck, Rebiotix and Summit. Please see the full studies for a list of all other authors’ relevant financial disclosures.

While new treatment strategies emerge, Clostridium difficile remains a major source of morbidity and mortality in the United States.

According to the most recent data from the CDC’s Emerging Infections Program, there were nearly half a million estimated cases of C. difficile in the country in 2011. Of these, approximately 83,000 recurred at least once, and 29,300 were associated with death within 30 days of first diagnosis.

The hospital-acquired infection often is due to the removal of healthy gut bacteria by prescribed antibiotic treatments. While this may still be the case, recent trends suggest that an increasing number of these infections are occurring outside of hospitals.

“When I started, almost 90% of all C. difficile occurred in the hospital,” Dale N. Gerding, MD, professor of medicine at Loyola University Stritch School of Medicine, told Infectious Disease News. “Today, it’s only about 25%.”

Dale N. Gerding

Of the 15,461 cases of C. difficile infection investigated by the CDC program, 65.8% were associated with health care, but only 24.2% were hospital-onset.

“Although people receiving care in hospitals made up two-thirds of all infections, two-thirds of all infections, two-thirds of those actually occurred after the patient went home,” Michael Bell, MD, deputy director of the CDC’s Division of Healthcare Quality Promotion, said during a February media briefing discussing the Emerging Infections Program data. “It’s essential that patients and their clinicians be aware that they need to take any diarrhea following antibiotic use very seriously.”

Although only one-quarter of the C. difficile infections developed while patients were hospitalized, the majority of the community cases are a result of contacts that occurred during outpatient events and exposure.

“What the CDC has been finding is that of the cases that are being diagnosed in the community, about 80% of them have actually had outpatient health care contact,” Gerding said. “I think it’s still health care-associated, but now it’s associated with outpatient contact, many of which are significant contacts such as people on dialysis, emergency room visits and outpatient surgery.”

Despite this challenge, there is evidence that the infection is in an overall decline. According to data published in this year’s National and State Healthcare-associated Infection Progress Report, there was a 6% decrease in reported C. difficile infections from 2012-2013, and a 10% decrease reported from 2011-2013. Meanwhile, the 2011 approval of Dificid (fidaxomicin, Optimer Pharmaceuticals) provided the first new drug treatment for C. difficile in nearly 25 years.

Recent research on various upcoming treatment approaches also may provide future benefits. In a 2014 study published in JAMA, Ilan Youngster, MD, MMSc, a pediatric infectious disease specialist at Boston Children’s Hospital, and colleagues examined the safety and efficacy of frozen, orally administrated fecal microbiota transplantation (FMT) in 20 patients with recurring infection. After 6 months, no serious adverse events attributed to FMT treatment were observed, and 70% (95% CI, 47%-85%) of patients had resolution of diarrhea after a single FMT. Separate findings involving FMT have shown the treatment to be cost-effective, while also capable of improving symptoms among patients with Crohn’s disease.

Other methods of restoring intestinal microbiota through noninvasive colonization also have seen early success. In a 2015 study published in JAMA, Gerding and colleagues administered a nontoxigenic strain of C. difficile to 173 adult patients following completion of a standard vancomycin or metronidazole treatment regimen. Recurrence was greatly reduced among those who received the treatment (30% vs. 11%; OR = 0.28; 95% CI, 0.11-0.69), and few adverse events were reported.

“You can see what’s trending here is definitely fecal transplants migrating to oral preparations,” Gerding said. “You don’t have to do a colonoscopy, you don’t have to do upper endoscopy to deliver these products — you’ll be able to give them by mouth.”

Approaches strengthening the immune system are being explored as well. In a 2010 study, monoclonal antibody treatments directed against C. difficile toxins appeared effective at preventing recurrence compared with controls (7% vs. 25%; 95% CI, 7%-29%), while pharmaceutical companies continue to develop potential vaccines against the infection.

Ilan Youngster

According to Gerding, many of these developing treatments still require work. No studies have yet explored the long-term effects of FMT, and further testing would be needed to determine whether monoclonal antibodies or nontoxigenic spores have a place as primary prevention strategies.

“Lots of things are happening from lots of different directions,” Gerding said. “The big interest is in the microbiome or the microbiota itself, and how changes in it can be used to modify or treat diseases. I think we’re going to see lots of use of various bacteria in the future as treatment agents for a variety of diseases. It’s a fascinating area.” – by Dave Muoio

References:

Gerding DN, et al. JAMA. 2015;doi:10.1001/jama.2015.3725.
Konijeti GG, et al. Clin Infect Dis. 2014;doi:10.1093/cid/ciu128.
Lessa FC, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1408913.
Youngster I, et al. JAMA. 2014;doi:10.1001/jama.2014.13875.

For more information:

Dale N. Gerding, MD, can be reached at dale.gerding2@va.gov.

Disclosure: Gerding reports holding patents for the prevention of C. difficile infection to ViroPharma/Shire; consultancy for Cubist, DaVolterra, MedImmune, Optimer, Pfizer, Sanofi Pasteur and ViroPharma/Shire; and membership on the advisory boards of Actelion, Merck, Rebiotix and Summit. Please see the full studies for a list of all other authors’ relevant financial disclosures.