Fighting C. Difficile

Clostridium difficile-associated diarrhea has re-emerged in hospitals with a vengeance, causing physicians to worry about higher morbidity and mortality from the hard-to-eradicate pathogen. “I think what we're seeing is very, very concerning. It used to be unusual to see people die of this,” said Trish M. Perl, MD, a professor of medicine and pathology at Johns Hopkins University School of Medicine in Baltimore. “Over the past 20 years, C. difficile has become the most frequent cause of nosocomial diarrhea.” C. difficile is a gram positive, spore-forming pathogen that infects the colon, causing a spectrum of disease from diarrhea and toxic mega colon, which may require colostomy, to death in severe cases. It is currently treated with metronidazole or vancomycin, but relapses are common. Clinical research on a vaccine is underway. (See box.) Dr. Perl, also the director of hospital epidemiology and infection control at Johns Hopkins Hospital, said at a recent news briefing sponsored by the National Foundation for Infectious Diseases in Washington, D.C., that the prevalence of C. difficile in the United States ranges between one percent and 11 percent of hospitalized patients, about 350,000 cases per year. “It colonizes the GI tract; it's very hard to remove,” she said. “Almost all neonates are colonized.” Most worrisome, she said, is that the reported increased incidence of Clostridium difficile-associated diarrhea (CDAD) suggests a changing epidemiology for this bacterium. “What happened is that this disease remade itself,” Dr. Perl said. “We are seeing a new toxin. It's associated with resistance to antibiotics, especially the fluoroquinolones.” Dr. Perl cited a large outbreak of CDAD in Quebec, with a mortality rate about three times the norm. “The Quebec strain has infiltrated the U.S.,” she said. “There is increased morbidity and mortality with this disease” that is moving into the community. She said rates of CDAD are three to four times higher in both acute and long-term care facilities than they were 10 years ago, and that the annual costs of this disease may exceed $1.1 billion. She added that CDAD lengthens a patient's stay in the hospital by about four days, and can increase a patient's medical costs by about $3600. Risk Factors for CDAD “We're very concerned about this,” said Richard J. Duma, MD, PhD, the director of infectious diseases at Halifax Medical Center in Daytona Beach, FL, who moderated the Washington briefing. “One of the most common questions I am asked by physicians is, ‘What do we do about C. difficile?’” Dr. Perl said risk factors for CDAD have been described in the medical literature, but that these risk factors now may be changing, in part reflecting an aging population. She said risk factors of developing C. difficile colonization or infection are increasing age, underlying renal failure, severity of illness, interhospital transfer from a nursing home, extended length of stay in the hospital, gastrointestinal surgery, transplantation, and enteral tube feedings. In addition, she said, data suggest that contamination of the environment has been linked to nosocomial transmission. “The existence of the organism in a high rate among patients æ in other words, the colonization pressure æ is also considered a risk factor for developing infection,” Dr. Perl said. Many studies link the incidence of CDAD to use of antimicrobial therapy, said Dr. Perl. The classic link was clindamycin, but she said many other antimicrobial drugs also increase the risk of CDAD, including cephalosporins, vancomycin, and the fluoroquinolones. “Given that the incidence of CDAD is increasing, the association of fluoroquinolones with CDAD is both intriguing and concerning,” she said. “The data implicating fluoroquinolones, agents that are widely prescribed for myriad in- and outpatient conditions, are of epidemiologic interest,” she added. “These agents represent a substantial if not increasing portion of antimicrobial agents prescribed.” Unfortunately, said Dr. Perl, “Prevention and control of CDAD has been difficult in health care settings.” She cited several factors to explain the challenges of controlling CDAD in hospitals: The organism contaminates the environment. Because C. difficile is a spore-forming organism, it is likely to be relatively resistant to chemical disinfectants. Cross-contamination in hospitals occurs because of shared equipment (due to limited resources) that has not or cannot be cleaned. Antimicrobial resistance that is reportedly increasing may contribute to the emergence of the organism in high-risk patients. Widespread use of antimicrobials contributes to the incidence of CDAD. “CDAD has a unique association with antibiotics. Multiple studies suggest that in addition to traditional infection control measures, antimicrobial stewardship and formulary manipulation are needed to control disease,” she said. Dr. Perl said the hallmarks of CDAD prevention and control strategies include: Fastidious use of barrier precautions. Implementation of cleaning procedures with environmental disinfectants, preferably those with anti-sporocidal action. Use of disposable equipment. Use of private rooms for patients infected with CDAD or putting those infected together. Isolation of patients with CDAD, especially if they are incontinent. Use of gloves for handling body fluids. Scrupulous hand hygiene with soap and water, not alcohol-based hand cleaners. Antimicrobial formulary manipulation or restriction to reduce the risk of colonization. “Controversy exists about which of these procedures is most effective and most important,” said Dr. Perl. “Bleach clearly works very well, but it's destructive to equipment.” She said in the future there will be new cleaning technologies using hydrogen peroxide. The re-emergence of CDAD is part of a pattern of hard-to-control pathogens that cause disease in hospitalized patients, noted Dr. Perl. “In 2006, multi-drug-resistant pathogens continue to cause disease in hospitalized patients and continue to spread into patients in the community not traditionally thought to be at risk,” she noted. She said the ultimate weapon against CDAD would be a vaccine, and that she considers current research on a vaccine “very promising.” C. difficile Vaccine Research Progressing In February 2006, Acambis plc, a company based in Cambridge, United Kingdom, and Cambridge, MA, announced the results of a Phase I study of its investigational C. difficile vaccine. In the study, 37 subjects received the vaccine, and a control group of 13 received a placebo. Antibody responses (against toxins A and B, which cause CDAD) were seen in all subjects who received the vaccine, said the company, and vaccination was well tolerated in all doses in all subjects. At four weeks after the first injection of the highest vaccine dose, anti-toxin A and anti-toxin B immunoglobulin G levels were 10-fold higher in vaccinated subjects than those reported in another study of unvaccinated patients who had recovered from natural CDAD infection and did not have recurrent disease. Vaccine side effects included mild tenderness, redness, and pain at the vaccine site, and headaches. Acambis is testing the vaccine in another Phase I trial of healthy elderly adults, and expects to launch Phase II trials on its investigational vaccine before the end of the year. — Peggy Eastman

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