Increased Clostridium difficile Virulence Demands New Treatment Approach

The rapid spread of a particularly virulent strain of Clostridium difficile has prompted the development of new clinical guidelines that focus on how physicians should tailor treatment based on patients' disease severity.

Earlier guidelines, published 15 years ago, suggested that metronidazole and vancomycin were equally effective treatment for patients with C difficile infection. But clinical data that have emerged following recent reports of increased incidence, more severe symptoms, and higher death rates from C difficile demonstrated the need to reexamine existing treatment recommendations.

The new guidelines, compiled by an expert panel from the Society of Healthcare Epidemiology (SHEA) and the Infectious Diseases Society of America, recommend that patients with mild to moderate symptoms receive metronidazole, but that those with severe disease be given oral vancomycin (http://www.journals.uchicago.edu/doi/pdf/10.1086/651706).

“We now have better data showing that, for patients who are severely ill, the efficacy of metronidazole is significantly less than that of vancomycin,” said Dale Gerding, MD, of the Edward Hines Jr Veterans Affairs Hospital in Hines, Ill, who is an author of the new guidelines and was lead author of the 1995 guidelines.

“The issue here is that C difficile now is a different disease than it was in 1995,” added Stuart Johnson, MD, also of Hines and an author of both sets of guidelines.

During the past decade, mutations in the bacterium have transformed C difficile from a rare nosocomial infection to one that can spread rapidly in hospitals and has spilled out into the community. Now, infection of healthy individuals with few or no risk factors is not uncommon, and increasing recurrence rates have been reported. The main symptoms include watery diarrhea, fever, and nausea. But infection also can lead to pseudomembranous colitis, toxic megacolon, colon perforations, and, in rare cases, death.

“We're in the midst of an epidemic of C difficile that's caused by a newer strain,” said Neil Fishman, MD, president of SHEA. “There are certain mutations in the genes that allow this strain to produce much more toxin than the older strain of C difficile.”

Based on molecular characteristics, the epidemic strain is known as NAP1/BI/027. The guidelines summarize its emergence, beginning in 2001 with a spike in US acute care hospital discharges with C difficile infection codes. Over the next 5 years, unusually severe, recurrent hospital outbreaks were reported throughout Quebec, Canada. Investigators found nearly identical strains of NAP1/BI/027 in patients in the US and Quebec outbreaks (McDonald LC et al. N Engl J Med. 2005;353[23]:2433-2441; Loo VG et al. N Engl J Med. 2005;353[23]:2442-2449).

Even though NAP1/BI/027 caused infrequent infections in North America and Europe in the 1980s, examination of isolates from more recent outbreaks shows higher resistance to fluoroquinolones. The expert panel noted that the increasing use of fluoroquinolones in North American hospitals “likely promoted dissemination of a once-uncommon strain.”

The NAP1/BI/027 strain has caused infections in 40 states and 7 Canadian provinces, as well as outbreaks in England, other European countries, and Asia, the panel added.

Stuart Cohen, MD, of the University of California at Davis and lead author of the new guidelines, said that even though the epidemic strain is linked to the high volume of fluoroquinolone use, that level of use is not necessarily inappropriate. “That's always the toughest call to make,” he said. “You’ll only know that within your own facility.”

But Fishman of SHEA, also an infectious disease physician at the University of Pennsylvania in Philadelphia, disagreed. He noted that research in the late 1960s showed that approximately 50% of prescriptions for antibiotics were inappropriate or unnecessary.

“Here we are, almost a half-century later, and that number is still hovering between 35% and 50%,” he said. “I don't think physicians recognize that it's not the same as prescribing a nonsteroidal or proton pump inhibitor, because there is this ecological impact of causing both antimicrobial resistance and other unanticipated consequences like C difficile.”

The major change in the new recommendations advises physicians to choose an antibiotic based on patients' disease severity. Definitions of mild to moderate and severe disease given in the guidelines are based on white blood cell counts and serum creatinine levels. Complicated severe disease includes the presence of hypotension or shock, ileus, or megacolon. Those definitions are based on symptoms and outcomes of patients in the Canadian outbreaks, but Cohen said that severe disease still is not very well defined.

Perhaps the most controversial part of the guidelines process was developing recommendations for diagnostic testing. The new recommendations note that stool culture is the most sensitive method, but turnaround time is slow. Enzyme immunoassays for C difficile toxins A and B are rapid but not very sensitive.

While they do not recommend a specific testing method, the guidelines say stool culture followed by toxigenic culture is “the standard against which other clinical test results should be compared.” In time, said Cohen, experts hope that polymerase chain reaction will emerge as the preferred testing method.

Management and prevention of recurrent infections also remain challenging. The guidelines indicate that between 6% and 25% of patients have a recurrence. Retreatment with metronidazole or vancomycin will not affect patients' chances of having a second recurrence. But if the infection does recur a second time, treatment usually is a tapered or pulsed regimen of oral vancomycin. For patients who do not respond to treatment or have repeated recurrences, options are not clear-cut. “We still need new treatments to tackle that problem,” said Fishman.

He noted that 2 existing medications currently indicated for other conditions appear promising as treatment for C difficile infection. One is rifaximin, used as postvancomycin therapy in patients with multiple recurrences. In a small study with 6 patients, Johnson and Gerding of Hines reported that this approach alleviated diarrhea in 4 patients (Johnson S et al. Anaerobe. 2009;15[6]:290-291). Also, a randomized trial of 50 patients showed that nitazoxanide may be as or slightly more effective than vancomycin in patients with mild to moderate and severe disease (Musher DM et al. Clin Infect Dis. 2009;48[4]:e41-e46).

As C difficile has emerged as a more significant clinical problem (see Box), the need for innovation has become more apparent. “There have been zero new drugs for C difficile in the entire history of this disease,” said Gerding, who noted that studies for new therapies are under way.

Infections with methicillin-resistant Staphylococcus aureus (MRSA) may have grabbed headlines the last few years, but a new study shows that Clostridium difficile infection rates have surpassed those of MRSA in at least 1 group of community hospitals.

Researchers at the Duke University Medical Center in Durham, NC, showed that during an 18-month period in 2008 and 2009, C difficile infections were 25% more common than MRSA infections in a network of 28 community hospitals in the southeastern United States. The report, presented in late March at the Fifth Decennial International Conference on Healthcare-Associated Infections 2010 in Atlanta, Ga, also showed that C difficile infections were just as common as hospitalwide bloodstream infections.

Lead author Becky Miller, MD, said her research team was surprised by the findings. “We knew C difficile was out there, but none of our hospitals [in the Duke Infection Control Outreach Network] had called us and said, ‘We think our C difficile rates are more than they used to be,’” said Miller.

Experts say the study is notable because it is the first to use patient surveillance data rather than hospital discharge diagnosis codes to compare C difficile and MRSA infection rates. Miller and her colleagues calculated infection rates based on the number of cases per 1000 patient-days. The results showed the C difficile infection rate was 0.28 cases per 1000 patient-days compared with MRSA's 0.23 cases. Documented rates are difficult to obtain because C difficile is not a reportable infection.

“This is probably the best-documented report we have,” said noted C difficile researcher Stuart Johnson, MD, of the Edward Hines Jr Veterans Affairs Hospital in Hines, Ill. “We’ve known this for some time, but it has not been well documented.”—R.V.

Gerding is a coauthor of a study published earlier this year that reported results of a phase 2 randomized trial in 200 patients assessing 2 monoclonal antibodies developed against C difficile toxins A and B vs placebo. When administered together as a single infusion in patients receiving metronidazole or vancomycin, the antibodies reduced recurrence rates in patients with the NAP1/BI/027 strain and in those with recurrent infections (Lowy I et al. N Engl J Med. 2010;362[3]:197-205). The antibody combination has been licensed to Merck & Co, Inc.

Another promising therapy is what Gerding calls “something akin to a vaccine, but more of a biotherapeutic.” The approach uses a naturally occurring strain of C difficile that does not produce the disease-causing toxins. “When patients have these strains in their gut, they're able to keep out the toxigenic strain,” Gerding explained.

“We think that the nontoxigenic C difficile is entering the body and colonizing the gut in the same manner that a toxigenic strain does,” he added. “So it's probably either adhering to some sites in the gut itself or it is utilizing some key nutrients that become available because of taking an antibiotic by the patient. That's how we're approaching it.” Phase 2 clinical trials are expected to begin this fall.

Additional treatment approaches are in the pipeline. Investigators in the United States and the United Kingdom are enrolling patients in a phase 2 trial examining the efficacy of a C difficile toxoid vaccine. Phase 3 clinical trial results presented in early April at the European Congress of Clinical Microbiology and Infectious Diseases in Vienna, Austria, showed that the narrow-spectrum antibiotic fidaxomicin resulted in lower recurrence rates than vancomycin therapy. “Our optimism about new agents coming out is fairly high,” said Johnson.