Search intensifies for new, more effective C. difficile treatments

Intestinal superbug surpasses MRSA as most deadly, difficult to treat hospital-acquired infection.

Once regarded as a nuisance illness, Clostridium difficile infections have more than doubled since 1996, causing damage in the gastrointestinal tracts of patients on multiple continents and perplexing the physicians who treat them.

In the early 2000s, hospitals in Canada, Europe and the US experienced large, epidemic outbreaks of C. difficile infection, marking the emergence of a new, hypervirulent strain. “The predominant strain when the organism was cultured and subjected to typing was a unique strain referred to as BI/NAP1/027 by the three most common typing methods,” Stuart Johnson, MD, who has studied C. difficile for more than 25 years, told Infectious Disease News.

Although the BI/NAP1/027 strain was first documented in the US and Europe in the 1980s, several mutations, including those with resistance to fluoroquinolone antibiotics and the ability to produce as much as 20 to 30 times more of the toxins responsible for diarrhea and inflammation, have helped fuel its spread, said Johnson, a staff physician at the Edward Hines, Jr. Veteran Affairs Hospital in Illinois and an infectious disease professor at Loyola University Chicago – Stritch School of Medicine.

“Disease onset is much more rapid, it is much more fatal and it runs a much quicker, more severe course,” Mark A. Miller, MD, chief of the department of microbiology, head of the infectious diseases division and chair of the Infection Prevention and Control Committee at the Jewish General Hospital in Montreal, said in an interview.

Mandatory disease reporting instituted during an outbreak that affected 12 Quebec hospitals revealed that the number of C. difficile cases increased from 3,263 to 7,004 from 2001 to 2004. During the same time, mortality increased 60%, with the number of deaths attributable to C. difficile increasing from 398 to 1,270.

“The outbreaks in Montreal were a wake-up call for a lot of physicians,” Johnson said. “Ten to 15 years ago in a large tertiary care center, we would see one, maybe two severe cases a year. In Montreal, this was happening on a weekly, if not daily basis.”

Although no uniform C. difficile reporting system exists in the US, the CDC estimates that mortality increased by 35% each year between 1999 and 2004, and may now be responsible for as many as 15,000 deaths each year.

Ed Kuijper, MD, PhD, of the department of medical microbiology at the Leiden University Medical Center in Leiden, the Netherlands, said in Europe, C. difficile mortality now surpasses mortality rates associated with methicillin-resistant Staphylococcus aureus.

Johnson said although diarrhea is the hallmark of C. difficile infection, the spectrum of illness is wide.

“The severity of disease is variable. Most patients present with abdominal symptoms and non-dehydrating, but bothersome diarrhea,” he said. “Other patients have a toxic appearance and life-threatening colitis in which their colon dilates and essentially shuts down. Some go on to die, and others have their colon removed in desperation.”

Despite drastic changes in C. difficile epidemiology, treatment and management options for these infections have been at a near standstill for more than 30 years, Miller said. Infectious disease specialists, clinicians and researchers have been struggling to come up with solutions to four pivotal, unmet challenges:

• Improving prevention approaches for at-risk patients;
• Resolving symptoms faster;
• Achieving higher cure rates and lower complications among severely ill patients; and
• Reducing post-therapy recurrence rates.

Identifying at-risk patients

Exposure to C. difficile spores and antiobiotics are two essential elements for any C. difficile infection, said Herbert L. DuPont, MD, chief of medicine at St. Luke’s Episcopal Hospital in Houston and an Infectious Disease News Editorial Board member.

Although infectious disease specialists are not exactly sure how antibiotics trigger C. difficile infections, they know that some antibiotics are worse than others. “Fluoroquinolones, second- and third-generation cephalosporins and clindamycin are the worst drugs,” DuPont said. “The fluoroquinolones deplete gut flora dramatically, and are emerging as one of the most important factors driving infection.”

Johnson compared the current situation with a clindamycin-resistant C. difficile “J strain” that was prevalent in the early 1990s. “We saw numerous outbreaks across the US, where clindamycin was a specific risk factor for infection with the J strain. Not only was clindamycin disruptive of the host flora, but it resulted in a specific advantage for the highly clindamycin-resistant J strain. There’s a parallel to this with the new fluoroquinolone- resistant epidemic BI/NAP1/027 strain and fluoroquinolones,” he said.

Because antibiotics play such a large role in C. difficile pathogenesis, it is not surprising that older, hospitalized patients account for most infections. These patients often have higher rates of underlying diseases and have more frequent and prolonged visits to health care facilities. “This is a disease that is driven by age,” Miller said. “For every decade past the age of 65 years, patients are at increased risk for infection, more severe disease and mortality.”

Data from a small case study suggest that the antibiotics commonly prescribed for C. difficile may have reduced efficacy in elderly patients. In a letter to the editor published in the April 2009 issue of The Journal of Hospital Infection, Thomas Parks, MD, of the Oxford Radcliffe Hospitals NHS Trust in the United Kingdom, and colleagues described prolonged C. difficile infection in patients aged 80 to 90 years.

Among 66 patients who were admitted to the department of medicine for the elderly at Addenbrooke’s Hospital in Cambridge, 34 patients who were treated with metronidazole, vancomycin or both had diarrhea for more than 12 days (median 21 days).

Patients enrolled in clinical trails for the two agents that indicated a more than 80% cure rate had a mean age closer to 60 years, according to the researchers. “Our data suggest that the natural history of C. difficile infection in frail, elderly patients is different from that in younger adults,” the researchers wrote, adding that specific management protocols must be developed for these patients.

Another barrier to efficient treatment may be that physicians in certain specialties are not as aware of the risks associated with C. difficile and the challenges that it poses.

“What we’ve noticed is that a certain group of physicians are aware of the risk for C. difficile and they can easily recognize and diagnose the disease, such as those in internal medicine or surgery,” Kuijper said. “There are also specialists who do not have many experiences with C. difficile infection, that just think that C. difficile infection is a side effect of the standard treatments that the patient is receiving.”

Other common risk factors include recent hospitalization for an extended period, residence in a nursing home or long-term care facility, recent abdominal surgery or gastrointestinal procedure, history of colon disease such as inflammatory bowel disease or colorectal cancer, chemotherapy and proton pump inhibitor use.

Yet, there are a number of younger, otherwise healthy individuals without any known risk factors who are becoming sick with community-associated C. difficile, and this number is rising.

According to data from a study by

Preeta K. Kutty, MD, MPH, of the CDC, and colleagues published in Emerging Infectious Diseases, of the 241 confirmed cases of community-associated strains, 36% had no history of antibiotic use within the 3 months before symptom onset; 25% had no underlying medical condition or recent hospital admission; and most were aged younger than 45 years.

Recommended treatment

Between 20% and 30% of patients who have an initial episode of C. difficile infection experience a relapse or recurrent infection. The debate continues in several treatment areas, including which antibiotics are best for initial infections and the efficacy of strategies, such as prescribing pulse-tapered doses of vancomycin or higher doses for an extended duration for recurrent diarrhea.

Currently, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America (SHEA) recommend only two antibiotics to treat C. difficile infections — metronidazole and vancomycin.

“Vancomycin is the only FDA-indicated treatment for this disease, but metranodizole has been used heavily because of its low cost and apparent efficacy,” Johnson, a member of the IDSA/SHEA committee that recently updated the organizations’ C. difficile treatment guidelines, told Infectious Disease News.

Clinical trial results from 2004 indicate that metranidazole and vancomycin are both more than 90% effective for first mild

C. difficile infection and demonstrate similar recurrence rates. However, results from a more recent prospective clinical study have shown that vancomycin is superior to metronidazole in severe C. difficile infections.

It is because of this evidence that the IDSA/SHEA revised guidelines encouraging physicians to take a risk-stratified approach to treatment. Patients with a first mild episode of C. difficile infection should be prescribed 500 mg of oral metronidazole, three times daily, for 10 to 14 days. For patients with severe C. difficile-associated diarrhea, the guidelines recommend initial antibiotic therapy with 125 mg oral vancomycin, four times daily.

In the event of a first relapse or recurrence, clinicians should repeat the initial antibiotic regimen, prescribing the same dose of metronidazole for mild infections or vancomycin for moderate-to-severe infections. If a third relapse or recurrence occurs, the guidelines recommend for physicians treating mild infections to switch to 125 mg oral vancomycin, four times daily, and those treating severe infections should try prolonged tapered or pulsed doses of vancomycin.

Most patients with mild C. difficile infection will get better with metronidazole in about 3 to 4 days, Stuart H. Cohen, MD, another IDSA/SHEA guideline co-author, and professor and director of hospital epidemiology and infection control at University of California Davis Health System, told Infectious Disease News.

Distinguishing which cases are mild and which are moderate-to-severe is an area that Johnson and Cohen said continues to be tenuous. “There’s a clinical gestalt that can help you determine this, but in the guidelines, we suggest that a white blood cell count greater than 15,000 (cells/mm³) and creatinine elevated 1.5 times baseline are the markers for severe illness,” Johnson said.

Cohen said these severity markers are generally inclusive, and this definition usually applies to many people aged older than 65 years, particularly those with a fever.

Others question whether metronidazole should be recommended at all, citing results from recent clinical studies that suggest that treating even mild infections with metronidazole may prolong patient recovery.

In a 2008 study published in Clinical Infectious Diseases, researchers found that among 52 patients, those treated with vancomycin were less likely to have detectable levels of C. difficile in stool samples compared with those treated with metronidazole (adjusted HR=3.99; 95% CI, 1.41-11.3) and more likely to have symptom resolution (adjusted HR=4.17; 95% CI, 1.53-11.40) within the first 5 days of therapy.

“We have our doubts about metronidazole because more research is suggesting that it is inferior to vancomycin, not only for severe disease but also for mild infections,” Kuijper said. “It is possible that in the future, metronidazole will be completely replaced by other antibiotics.”

Burke A. Cunha, MD, chief of the infectious disease division at Winthrop University Hospital in Mineola, N.Y., and an Infectious Disease News Editorial Board member, said he prefers starting treatment with 250 mg of oral vancomycin every 6 hours for 5 to 7 days.

“If you use an adequate dose,” Cunha said. “If you start with 250 mg, the response is usually apparent in 2 to 3 days. If no decrease in diarrhea in 72 hours, I increase the dose to 500 mg every 6 hours to complete 7 to 10 days of therapy.”

Relapses and recurrences

Most patients who experience C. difficile relapses or recurrences do so within 2 weeks to a month, and once a patient has a second episode, they are more susceptible to additional episodes.

The IDSA/SHEA guidelines recommend pulse-tapered vancomycin doses for these patients. “With the taper-pulse strategy, you decrease the dose over the course of 6 weeks and then alter to an every-other-day therapy, and then an every third day therapy to try and wean patients off the antibiotic that way,” Cohen said.

Johnson concurs with the treatment. “The idea is that this would hopefully allow for a return of the normal flora of the gut, so the normal microbiota might have a chance to recover,” he said.

Yet, the evidence base for pulse-tapered vancomycin is anecdotal, and no specific treatment regimens exist. There are only two published case series: one from 1982 that involved 11 patients and another from 1985 that involved 22 patients, both published in The American Journal of Gastroenterology.

Cunha said pulse-tapered vancomycin often fails. The vegetative form of C. difficile is producing the toxin in the colon not the spores. Therefore, a high, prolonged dose, rather than a tapered dose to allow C. difficile spores to germinate is most effective in eradicating the bacteria.

In his hospital, for patients who experience recurrences of C. difficile diarrhea, Cunha recommends 500 mg oral vancomycin, four times daily, for 1 month. If a patient relapses, he recommends extending treatment or the same dose for 2 or 3 months.

DuPont also raised the question of whether the typical 10- to 14-day antibiotic regimens are long enough to eradicate spore-forming bacteria and said recommended treatment for Bacillus anthracis is significantly longer at 2 months.

“There’s no downside to patients, except the cost,” Cunha said. “Vancomycin is not absorbed, so there are no side effects, and orally doesn’t change the fecal flora or predispose to VRE, so there is no risk for the patient.”

DuPont said current drugs are only approved for shorter courses, so reimbursement for longer courses may not occur unless studies are performed and the FDA approves a new indication.

Musher and colleagues conducted a prospective, randomized, double blind study that involved 142 patients with C. difficile-associated infections and found that administering two daily 500 mg doses of nitazoxanide for 7 or 10 days resulted in similar response rates as a 250-mg dose of metronidazole administered four times daily for 10 days (90% vs. 82%).

Cunha said he likes to add an antibiotic, such as tigecycline (Tygacil, Pfizer Pharmaceuticals), to treatment regimens for patients who have C. difficile colitis to kill other colon flora. Thus far, only small case reports have shown that the drug is effective in severe C. difficile infections, and more clinical trials are necessary to determine its role in therapy.

Newer treatment options

Despite treatment challenges, clinicians are optimistic about several new treatment options, including bacteriotherapy, and several new therapies currently undergoing clinical investigation such as antibiotics, monoclonal antibodies and even a vaccine.

Bacteriotherapy, or fecal transplantation, is a therapy currently being used in a growing number of patients with multirecurrent C. difficile infection. The procedure involves taking a fecal sample from a donor — usually a spouse or parent — mixing it with saline solution and administering it to the patient at either end of the gastrointestinal tract using colonoscopy or a nasogastric tube.

“In a desperate group of patients who have a recurrence every month or two, we in the Netherlands and Europe offer fecal transplantation as an alternative option because all of the other treatments are doubtful,” Kuijper said.

The rationale behind bacteriotherapy is that microganisms in feces may be beneficial in reintroducing healthy gut microbiota that offer protection against subsequent C. difficile infection. Although published data are only available in about 100 patients, results indicate that the therapy is about 90% effective.

“It looks like [bacteriotherapy] works and it makes sense,” Cohen said. “If the pathogenesis of C. difficile is that the gut microbiology has been disrupted, then it makes more sense to give back the normal gut flora than it does to keep trying to control the infection without replenishing what was protecting people in the first place,” Cohen said.

Antibiotics in the pipeline

Earlier this year, the FDA granted fast-track status to fidaxomicin (Optimer Pharmaceuticals), a narrow spectrum antibiotic that is the first of its kind in a new class of macrocyclic antibiotics, as a potential new treatment for C. difficile infections.

Cohen said fidaxomicin is promising but may cost more than vancomycin if approved. If that is the case, hospitals may use the antibiotic for recurrences, rather than initial C. difficile infections, even though clinical trials have not assessed the drug in that capacity.

The FDA is scheduled to meet and discuss fidaxomicin this month. If approved, it is possible that the drug could be available in the US by the end of 2011.

Two other antibiotics, ramoplanin and CB-183315, are currently in phase 2 clinical trials. Ramoplanin is a glycolipodepsipeptide with activity against C. difficile and other vancomycin-resistant enteroccocci. Preliminary phase 2 trial results suggest cure rates for two doses of the drug (200 mg or 400 mg, twice daily) comparable to vancomycin and similar recurrence rates. Cubist Pharmaceuticals is currently recruiting patients in phase 2 clinical trials of CB-183315.

Immunologic approaches

Two immunologic approaches, monoclonal antibodies directed at toxin A and B and an injectable C. difficile toxoid vaccine, also show promise.

Results from a randomized, placebo-controlled clinical trial published in The New England Journal of Medicine indicated that patients who had adjunctive therapy with two monoclonal antibodies in addition to vancomycin and metronadizole had better recurrence rates compared with those treated with antibiotics alone (7% vs. 25%; P?.001).

A phase 2 clinical trial is currently under way to assess a vaccine intended to prevent recurrent C. difficile infections. Preliminary trials indicated that the vaccine is safe in humans and induced vigorous serum antibody responses in healthy adults.

In the meantime, clinicians should follow these simple steps to help reduce the spread of C. difficile infection within health care settings: Institute appropriate infection control measures — good hand hygiene with soap and water, disinfect medical equipment and cleaning patient rooms and the hospital environment with bleach and practice good antimicrobial stewardship.

“The fewer antibiotics you use, the more likely it is that C. difficile will disappear from your institution,” Kuijper said.

- by Nicole Blazek

For more information:

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• Eggertson L. CMAJ. 2004;171:1331-1332.
• Johnson S. Clin Infect Dis. 2007;44:846-848.
• Jump RL. Emerg Infect Dis. 2010;16:827-829.
• Kutty PK. Emerg Infect Dis. 2010;16:197-204.
• Louie TJ. N Engl J Med. 2011;364:422-431.
• Lowy I. N Engl J Med. 2010;362:197-205.
• Musher DM. Clin Infect Dis. 2009;48:e41-46.
• Parks T. J Hosp Infect. 2010;e74:403-405.
• Tedesco FJ. Am J Gastroenterol. 1982;77:220-221.
• Tedesco FJ. Am J Gastroenterol. 1985;80:867-868.

Disclosure: Dr. Cohen is a paid consultant for Optimer. Drs. Cunha, DuPont, Johnson and Kuijper report no relevant financial disclosures. Dr. Miller is a paid consultant for Optimer, Iroko, Merck and Pfizer.

Do you recommend probiotics for recurrent C. difficile in your patients?

I recommend probiotics, but the evidence is limited

I often get emails from physicians who are at their wits end because they have patients whose Clostridium difficile-associated diarrhea keeps recurring asking me, “What can I do?” I recommend trying probiotics.

There are some probiotics that have specifically been developed for C. difficile: Saccharomyces boulardii (Florastor, Biocodex) is a yeast that produces a protease or an enzyme that attacks C. difficile toxins. It’s very specific to this pathogen. Other strains have been tried as well, but the caveat with probiotics is that not all strains are effective for all diseases – some probiotics are better than others for certain illnesses. Data from two large phase 3 studies have shown that S. boulardii may be beneficial as an adjunctive therapy for recurrent C. difficile. Vancomycin or metronidazole treats the initial episode fairly well in 60% to 80% of patients; the other 20% to 30% will have one recurrence, but once a patient has a second recurrence, there is a 65% chance that they are going to continue to have multiple episodes.

The problem is that the evidence for probiotics is limited, because to empirically prove that probiotics work for C. difficile, researchers need to enroll lots of patients in clinical trials.

In the meantime, if a patient would like to try probiotics, physicians can advise that they look for certain components on the label: the specific bacteria or yeast strain, the number of colony-forming units or organisms per gram, so that an oral dose per day can be calculated; the product manufacturer and the expiration date. If these items are not listed, this is a red flag that the manufacturer probably does not have very good quality control.

Lynne V. McFarland, PhD, research health science specialist with the Puget Sound Veterans Affairs in Seattle, Washington. She has co-authored the book, The Power of Probiotics, with colleague Gary W. Elmer, professor emeritus in the department of medicinal chemistry at the University of Washington. Disclosure: Dr. McFarland has received lecture fees from Acambis, Biocodex, Danone, Massachusetts Biologic Laboratories, Osel.

Probiotics are not the way to go for prevention

One of the key reasons that a patient develops C. difficile infection is because there is a reduction in the number and diversity of protective colonic flora, which occurs usually after taking an antibiotic. Given that a significant number and a variety of bacteria are needed to prevent development of C. difficile infection, taking probiotics is like a ‘drop in a bucket’. There are so many diverse bacteria in the gut and to administer one or two strains of bacteria has a significantly limited utility when there are millions of different species. I do not think probiotics are the way to go for routine prevention and certainly not for treatment of C. difficile, and I would not promote their use for recurrent C. difficile infections. Manufacturers [of probiotics] do not go through the same rigorous process that is used to approve prescription medications. The probiotics that are out on the market may not even contain viable organisms, and none have undergone high-quality clinical trials to determine the efficacy in preventing or treating C. difficile infection. To test probiotics to determine if they have a role in preventing C. difficile infection, researchers would need a very large cohort study to show a difference as approximately 10% of individuals who receive antibiotics go on to develop C. difficile infection. At this time, there really is no evidence to support routine use of probiotics for the prevention, treatment or management of C. difficile infections.

Christine Lee, MD, is an associate professor of pathology and molecular medicine at McMaster University, infectious diseases physician, medical microbiologist and the medical director for Infection Prevention and Control at St. Joseph’s Healthcare in Hamilton, Ontario, Canada. Disclosure: Dr. Lee had no financial disclosures.