Search continues 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.

Prevalence of C. difficile colonization in a cohort of infants and young children can vary between 3% and 62%, according to data from a 2000 study by Lynne V. McFarland, PhD, and colleagues. Results of the study indicated that colonized infants and young children were more likely to have symptoms than those who were not colonized. In contrast, older children have similar rates of colonization to adults with similar rates of symptoms among colonized and uncolonized individuals.

Challenges in diagnosis of CDI

Andi L. Shane, MD, MPH, assistant professor of pediatric infectious diseases, Emory University School of Medicine, said the most commonly utilized C. difficile toxin assays available in hospital and commercial laboratories has a turn-around time for toxin results of 24 to 48 hours. Because of easy access to testing, these toxin assays are frequently ordered in hospitalized children and outpatients with diarrhea. Despite easy access, interpretation of test results is more challenging.

“Awareness of the morbidity and mortality of C. difficile disease has increased both in the scientific and lay press, resulting in increased testing and increased detection of toxin and, therefore, reporting of C. difficile infection,” she said.

In the early 2000s, hospitals in Canada, Europe and the US experienced large, epidemic outbreaks of CDI, 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 30 years, told Infectious Diseases in Children.

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 one with 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. VA Hospital in Illinois and an infectious disease professor at Loyola University Chicago – Stritch School of Medicine.

“[In these cases] 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.

Increases in cases

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 severe case 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 associated with 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 CDI, 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 colons dilate and essentially shut down. Some go on to die, and others have their colons removed in desperation.”

Management of children

The management of children from whom C. difficile toxin is detected is complex, according to Shane.

“The detection of C. difficile toxin represents a perturbation of bowel flora from a pathogen, antimicrobial, toxin or underlying disease. It is important to consider the context in which the test was obtained and whether or not C. difficile disease explains all of the child’s symptoms,” Shane told Infectious Diseases in Children. “Additional evaluation may be necessary to ensure that the child does not have a concomitant infectious or a non-infectious process.”

Shane also said this can be particularly challenging in young children who more frequently experience viral and bacterial gastroenteritis and non-infectious diarrhea.

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.

At-risk patients

Although infectious disease specialists are not exactly sure how antibiotics trigger CDI, they know that some antibiotics are worse than others.

“The antibiotics most important in children are cephalosporins and penicillins,” said Herbert L. DuPont, MD, chief of medicine at St. Luke’s Episcopal Hospital in Houston. “In contrast to adults where fluoroquinolones are important as predisposing agents for CDI, this class of drugs is unusual in children and is an unusual source of CDI.”

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 strain. Not only was it disruptive of the flora, but it was drawing a specific advantage for highly antibiotic-resistant strains. There’s a parallel to this with the new epidemic BI/NAP1/027 strain and fluoroquinolones,” he said.

Common risk factors include recent hospitalization for an extended period, residence in a long-term care facility, recent abdominal surgery or gastrointestinal procedure, history of inflammatory bowel disease or colorectal cancer and exposure to chemotherapy.

“Children with the greatest risk are hospitalized for various medical problems, including cancer and inflammatory bowel disease. Infants and young children aged younger than 2 years rarely experience CDI and are often colonized by the organism, which may provide some protection against disease,” DuPont said, adding that CDI is also occurring with increasing frequency in children in the outpatient setting.

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 CDI 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.

The mainstay of treatment of C. difficile disease in children, according to Shane, is discontinuation or narrowing of antimicrobial therapy to cover the underlying pathogen or pathogens.

“This will facilitate repopulation of the colonizing flora that may, in turn, serve as competition for the C. difficile. Oral metronidazole and oral vancomycin are recommended antimicrobial agents for treatment,” Shane said, adding that approximately 25% of children may experience a relapse in symptoms after treatment. “Reduction or discontinuation of broad-spectrum antimicrobial therapy is the mainstay of both treatment and retreatment. A second course of oral metronidazole or oral vancomycin may result in a clinical response.”

According to Shane, additional agents that have been shown to be effective in managing C. difficile disease include nitazoxanide (Alinia, Romark Pharmaceuticals), rifaximin (Xifaxan, Salix Pharmaceuticals), tinidazole (Tindamax, Mission Pharmacal), immune globulin therapy and restoration of intestinal tract flora with probiotic supplementation.

She said although empiric antimicrobials will eliminate bacterial organisms from children’s stools, they may promote the activity, including toxin production of C. difficile.

“A child with salmonellosis or shigellosis may have a culture-negative stool after a few doses of antimicrobials. However, C. difficile toxin, if present, could be detected for a greater duration than the original bacterial pathogen, especially if broad spectrum antimicrobials are administered,” she said. “A similar situation may occur with viral gastroenteritis in which the viral etiology may or may not be detected. Perturbation of the gut flora from viral pathogenesis may also result in the continued detection of C. difficile toxin both in symptomatic and asymptomatic children.” Post-infectious symptoms may also develop in children, in which the original pathogen(s) are no longer isolated and C. difficile toxin detection may be noted intermittently with repeated testing. These are challenging situations that require an individual approach and may benefit from input from infectious disease and gastroenterology colleagues.

Follow-up testing for C. difficile toxin is not recommended in an asymptomatic child, according to Shane.

Antibiotics in the pipeline

The FDA in May granted approval for fidaxomicin (Dificid, Optimer Pharmaceuticals) in adults (aged 18 years and older) for treatment of C. difficile-related diarrhea. The 200-mg tablets should be taken twice daily for 10 days. Fidaxomicin is a narrow-spectrum antibiotic that is the first of its kind in a new class of macrocyclic antibiotics to be used as potential new treatment for CDIs.

Before the drug’s approval, the FDA granted orphan drug designation in January for fidaxomicin for the treatment of CDI in pediatric patients aged 16 years and younger. The FDA said in its Anti-Infective Drugs Advisory Committee meeting briefing document in April that additional safety and efficacy studies in children aged 2 to 18 years are planned. However, the drug indication remains for adults only and the labeling reflects that the safety and effectiveness of fidaxomicin has not been studied in patients aged younger than 18 years.

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

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

In the meantime, clinicians should follow these simple steps to help reduce the spread of CDI within health care settings: Institute appropriate infection control measures — good hand hygiene with soap and water, disinfect medical equipment, clean patient rooms and the hospital environment with bleach, and practice good antimicrobial stewardship, paying particular attention to restriction of the antibiotics known to be associated with C. difficile disease.

“The fewer antibiotics you use, the more likely it is that C. difficile will disappear from your institution,” Kuijper said. – by Nicole Blazek and Cassandra A. Richards

For more information:

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Disclosure: Dr. Shane reports no relevant financial disclosures. Dr. Miller is a paid consultant for Optimer, Iroko, Merck and Pfizer. Dr. Cohen is a paid consultant for Optimer. Dr. Zilberberg received grant funding from ViroPharma Inc.

Do you recommend probiotics for children with C. difficile?

I recommend probiotics, and studies show it is effective.

I often get emails from physicians who are at their wits’ end because they have patients whose Clostridium difficile-associated diarrhea keeps recurring, and they ask 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.

Lactobacillus rhamnosus GG (Culturelle, Amerifit) has also been used, but there have been no studies large enough to be able to show that L. rhamnosus GG is effective for C. difficile infections.

Adding a probiotic to standard antibiotic therapy is like using a double-barrel shot gun. Vancomycin or metronidazole kills off the active bacteria in the gut, but this does not do anything for spores that may cause future problems. The spores sit there in the colon, twiddling their bacterial thumbs, waiting for the antibiotics to go away, and that is why there is this problem with recurrences.

In the past, the only way to get probiotics to patients was to seek FDA licensure as a biologic. Several companies were doing this until the Dietary Supplement Health and Education Act was passed in 1994. The impetus for doing research went away. Why would a drug company pay millions of dollars to do a clinical trial when it does not have to?

Because of this, many companies are not producing good quality probiotics. Quality control studies indicate that 50% of probiotics on the market do not contain the ingredients listed on the label. But good quality probiotic clinical trials are coming out of Europe and Asia, where manufactures are still incentivized to have these products approved by the government.

However, compared with studies in adults, a great deal of research has been done in children using different types of probiotics to prevent and treat diarrhea. And probiotics have been used safely with children. The only time there has been any issue with using probiotics is with children who have been really sick, including children in the ICU, and those with central catheters because they sometimes get septicemia. Those children respond well to antifungals or antibiotics, depending on what kind of probiotic they’re taking.

Probiotics are particularly helpful because many cases of pediatric diarrhea are caused by viral infection. Therefore, antibiotics aren’t effective, and many children are treated with oral rehydration therapy. This option is fine because it rehydrates them, but it doesn’t do anything to help them recover. Studies of probiotics have shown that children in these situations have responded well. And unlike antibiotics, probiotics basically help boost the immune system.

If a patient/parent 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 good quality control. Also, research the reputation of the company. If it produces other FDA-regulated products, it probably has a good quality control system in place. Also, I recommend lyophilized formulations because they are more stable at room temperature than heat-dried formulations, which have a shorter shelf-life and need to be refrigerated to retain live bacteria.

Lynne V. McFarland, PhD, is a research health science specialist with the Puget Sound Veterans Affairs in Seattle. 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, and Osel.

The evidence on probiotics is limited.

The issue of probiotic use to either prevent or treat C. difficile infection is contentious. Most of the studies on probiotic use are small and not adequately controlled (Bauer MP. Clin Microbiol Infect. 2009;15:1067-1079). A large study on administration of a probiotic yogurt drink to prevent antibiotic-associated diarrhea was published in the BMJ in 2007 (Hickson M. BMJ. 2007;335:80). Unfortunately, the results of the study are not widely applicable, as claimed by the authors (Wilcox MH. BMJ. 2007;335:171). Crucially, the design of the study was fundamentally flawed because they gave a milk-based preparation to “placebo” recipients, which may have increased the chance of diarrhea and made the yogurt drink appear more effective.

A recent large study claimed that a combination of Lactobacillus acidophilus and L. casei was effective at preventing antibiotic-associated diarrhea and C. difficile-associated diarrhea (Gao XW. Am J Gastroenterol. 2010;105:1636-1641). However, nearly one-quarter of the placebo recipients were claimed to have C. difficile-associated diarrhea, which is a remarkably high figure that does not reflect normal experience.

It is possible, of course, that some probiotics may be effective and some are not. Rational design/choice of probiotic microorganisms is desirable, and adequately designed studies are needed to determine if some are beneficial. Of particular note with probiotics preparations is the consistency of product use, and therefore results. The yeast S. boulardii has, in particular, been extensively examined, but yielded conflicting results. Notably, S. boulardii isolates obtained from varied commercial sources were found to differ in virulence in a mouse model, suggesting a lack of uniformity of yeast strains in such preparations (McCullough MJ. J Clin Microbiol. 1998;36:2613-2617).

It must also be remembered that there are risks associated with administering live bacteria. Cases of fungemia have been reported in immunocompromised and immunocompetent patients following administration of S. boulardii (Cherifi S. Acta Clin Belg. 2004;59:223-224). Cases of cross infection have also been reported (ie, from a S. boulardii-treated patient), highlighting the potential virulence of this yeast in humans (Muñoz P. Clin Infect Dis. 2005;40:1625-1634).

Mark Wilcox is a consultant and clinical director of microbiology/pathology at Leeds Teaching Hospitals NHS Trust and professor of medical microbiology at University of Leeds, UK. He is also Health Protection Agency (England) Lead on Clostridium difficile. Disclosure: Wilcox reports no relevant financial disclosures.

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