CDC official is hopeful they can beat C diff infection.
Early decisions in the prevention and treatment of Clostridium difficile infection (CDI) can be matters of life and death for patients. In September, researchers, health care workers, and industry and patient advocates convened for the 4th Annual International Raising C. diff Awareness Conference and Health Expo in Atlanta. Clifford McDonald, MD, associate director for Science in the Division of Healthcare Quality Promotion at the Centers for Disease Control and Prevention (CDC), chaired the conference. In his role at the CDC, McDonald’s at the forefront of efforts to prevent and treat the infection — one the CDC has declared among the most urgent drug-resistant threats that we currently face.
“It’s my firm belief that we are on the threshold of a new era in better diagnosis, treatment, and prevention approaches. At the CDC, we deal with statistics, but there are faces behind those numbers. At the heart of every infection is a patient who deserves our competence, our empathy, and our passion,” said McDonald.
One of those faces, Roy Poole, is a volunteer advocate for the C. Diff Foundation. After retiring from a career in the Air Force, Poole led a healthy, active lifestyle as an avid outdoorsman in Colorado before antibiotics prescribed for a routine dental procedure set the stage for CDI. In the medical community, his symptoms were met with disbelief and inappropriate treatment.
“Three weeks after leaving the hospital, I walked into my (previous) primary care physician, and asked for an order to have a stool sample taken to determine if Toxins A or B were present. His response was, ‘Are you still having problems with that?’ Clearly, there is a need for more education about C. diff among physicians,” said Poole.
CDI is a formidable opponent. However, with the newly focused attention on discovering ways to disable the bacteria and cohesive public health approaches aimed at prevention, presenters from government, academia and industry offered five key reasons we can win the battle against C. diff:
1. Antibiotic stewardship efforts are gaining a foothold.
Statistics present a chilling picture: 453,000 new cases and an estimated 30,000 deaths each year. It’s likely that those numbers grossly underestimate the true impact of CDI, since it’s what we know from death certificate reporting.
However, we are seeing that rates may have peaked after a long plateau. Mark Wilcox, MD, Head of Microbiology at Leeds Teaching Hospital, Professor of Medical Microbiology at University of Leeds, and the lead on Clostridium difficile for Public Health England in the United Kingdom, has demonstrated a 70% reduction in cases in England in just 7 years. This was after a concerted effort that Wilcox spearheaded surrounding antibiotic stewardship, specifically addressing a reduction in unnecessary prescribing of fluoroquinolones and cephalosporin antibiotics.
Commonly prescribed antibiotics disrupt the protective microbiota (the normal bacteria of the gut) and leave it vulnerable for C. diff colonization. “There was a concerted effort that went beyond lip service and truly embraced the principles of improved surveillance, more accurate diagnostics, enhanced infection prevention measures to use antibiotics more wisely and to limit transmission and careful treatment,” said Wilcox.
High rates of CDI are always associated with the use of certain antibiotics: clindamycin, cephalosporin, and fluoroquinolones. Research has shown that lower respiratory tract infections and urinary tract infections account for more than 50% of all in-patient antibiotics use. But are these really necessary?
“We know that antibiotics are overused and misused across every healthcare setting. At least 30% of antibiotic prescriptions are unnecessary — and this equates to 47 million unnecessary antibiotic prescriptions per year written in doctors’ offices, hospital outpatient departments, and emergency departments. We have a lot of work to do, and CDC is actively working to reduce unnecessary antibiotic use,” said Arjun Srinivasan, MD at the CDC. “Stopping unnecessary antibiotics is the single most effective thing we can do to curb C. diff infections in the United States. This is something that we can do today.”
Srinivasan acknowledged that telling patients that they can’t have a prescription for an antibiotic might result in some pushback. “Patient satisfaction scores are a very real concern. When someone is sick and takes a day off work, they’re not leaving without a prescription — especially when the last provider wrote one for their same symptoms,” he said. “But this is a new day, and it’s up to the physician to educate their patients and stay strong.”
Hospitalists have access to accurate, inexpensive and quick diagnostic tests that can lead to targeted, effective treatment. This can arm the treating physician and patient with information that can put patients on a path to recovery without feeling like they are being dismissed.
2. Emerging guidance reflects important advances in research and development.
Most recently published in 2010, the Society for Healthcare Epidemiology of America (SHEA) and Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for C. diff are currently under review. This is critical because of the number of physicians still treating with metronidazole first, despite the fact that the largest randomized controlled clinical trial has shown that vancomycin is more effective.
“Since 2010, the landscape has changed dramatically,” said Stuart B. Johnson, MD, Professor, Department of Medicine, Loyola University, and Researcher at the Hines VA Hospital in Chicago. “The past few years have ushered in a new age of understanding how and where C. diff colonizes, and the damaging toxins A and B that it produces.”
Considering that 25-30% of patients experience a CDI recurrence, it’s evident that metronidazole unnecessarily contributes to the failed treatment outcomes for patients. Metronidazole is less expensive, but has more side effects than oral vancomycin and is less effective in treating CDI.
Johnson provided an overview of the dramatic advances this space has seen in just the past few years.
Limitations of current guidelines include:
• No mention of fidaxomicin, a narrow-spectrum antibiotic, which in 2011 was the first medication approved in 25 years for the treatment of C. diff associated diarrhea
• Limited evidence for recommendations to treat severe, complicated CDI
• Limited evidence for recommendations on recurrent CDI
• Little mention of Fecal Microbiota Transplant (FMT)
Microbiome-designed drugs in Phase 1 trials and FMT in Phase 2, toxin binding agents to preserve the microbiota of the gut and immune approaches like monoclonal antibodies that target toxin A and B are all advancing at various speeds. That the current guidelines are outdated after just a few years is an indication of just how rapidly the field of C. difficile research is evolving. Vaccines are also in the early stages of development, with a number of companies in clinical trials.
Despite relatively high awareness among the patient community, FMT is currently reserved only for people who have not responded to traditional therapies. It’s unusual in that FDA allows this still-investigational therapy to be used for recurrence. However, if patients are carefully and appropriately treated from the start, very few cases need to resort to FMT.
3. Advances in environmental sanitation demonstrate efficacy — and so does hand washing.
Education among health care providers and hospital staff about the importance of environmental sanitation demonstrates a commitment toward reducing rates of infection. Engaging workers in this effort can substantially reduce contaminated surfaces.
But the reality is, most physicians do not really know in great detail what happens in their hospitals; it’s simply not their job. Spores of C. difficile are highly resistant to most disinfectants, and bleach has become a standard disinfectant because of its sporicidal activity. Good compliance by housekeeping staff is an assumption that may or may not be correct.
Ultraviolet disinfection programs have also shown to be a promising approach, but one that needs further research. Many hospitals are using this in the hopes that CDI rates will be reduced. However, UV still needs to work in tandem with a room that was properly cleaned in the first place. Environmental sanitation as a means of infection control is everyone’s job. Where hospital-based physicians can play a role is to lobby that sanitation is a significant concern that can lead to better infection control and better patient outcomes.
At the very core, though, we know that hand hygiene works. “Keeping the importance of hand washing messages alive is a constant conversation that we need to be having,” said Srinivasan.
4. We can prevent recurrent CDI, particularly in high-risk patients.
One of the hallmarks of CDI is the high rate of recurrence, particularly among the most severe cases, where up to 30% recur. Breaking the cycle of recurrence can benefit not just the patient, but also hospitals, in terms of lower re-admission rates. Current approaches now in clinical trials include new narrow spectrum antibiotics, biotherapeutic agents such as non-toxigenic C. difficile, fecal transplants and their derivatives, monoclonal antibody and vaccines.
The closest to market is bezlotoxumab, a monoclonal antibody directed against toxin B, one of the toxins produced by C. difficile. Phase 3 results showed that bezlotoxumab reduced recurrences from 27% to 17% including among the sickest patients. The data also showed a reduction in hospital days and reduction in re-admissions. The FDA approved bezlotoxumab on October 21, 2016, to become the first non-antibiotic therapeutic to reduce recurrent CDI. The availability of bezlotoxumab will provide a valuable new approach to prevention of recurrent CDI, one of the major challenges we face with this devastating infection.
This is a notable development because there have been failures along the way among compounds that initially looked promising for CDI treatment. This speaks to the complexity of how to effectively treat CDI and prevent recurrence in high-risk and vulnerable patients.
5. Patient advocacy and awareness efforts can alter the course of CDI.
CDI survivors shared their experiences along their emotional journey — fear, disbelief, isolation, and depression. They also expressed gratitude at the validation, information and support they received from the patient advocacy community. Perhaps the greatest gift they have received is the empowerment to question their physicians about the necessity of antibiotics they have been prescribed in terms of risk of CDI.
“The hospital where I was treated initially seemed eager to have me leave. They offered no additional help. The C diff Foundation has been my greatest source of help. In turn, I feel I help myself cope best, when I help others to cope with the disease,” said Poole.
Dale Gerding, MD, FACP, FIDSA, is Professor of Medicine at Loyola University Chicago, Research Physician at the Edward Hines Jr. VA Hospital. Additionally, Gerding is an infectious disease specialist and hospital epidemiologist, past president of the Society for Healthcare Epidemiology of America and past chair of the antibiotic resistance committee of SHEA. He is a fellow of the Infectious Diseases Society of America and past chair of the National and Global Public Health Committee and the Antibiotic Resistance Subcommittee of IDSA. His research interests include the epidemiology and prevention of Clostridium difficile, antimicrobial resistance, and antimicrobial distribution and kinetics.
The paper, “Burden of Clostridium difficile Infection in the United States,” was published in the New England Journal of Medicine.
The study, "Changing epidemiology of Clostridium difficile infection following the intriduction of a national ribotyping-based surveillance scheme in England," was published in the journal Clinical Infectious Diseases.
The study, "Prevalence of antimicrobial use in US acute care hospitals," was published in JAMA.
The paper, "Vancomycin, metronidazole, or toleyamer for Clostridium difficile infection: results from two multinaionalm randomized, controlled trials," was published in Clinical Infectious Diseases.
The study, "A Randomized Placebo-controlled Trial of Saccharomyces boulardii in Combination with Standard Antibiotics for Clostridium difficile disease," was published in JAMA.