For almost three decades, physicians have recognized that C. difficile (C. diff) infection is the main cause of bacterial diarrhea during or following antibiotic treatment of other infections. Outbreaks of C. diff infection have been reported in many countries around the world in recent years. An anaerobic bacterium commonly found in hospitals and long-term care facilities but also in the feces of 3 percent of patients outside of hospital, C. diff produces toxins which can cause diarrhea, colitis, sepsis and death. Clostridia are spore-forming bacteria; diarrheal patients in hospitals or other settings shed thousands of spores. These spores are resistant to most germicidal agents and can persist in hospital and nursing home wards for long periods of time. There is also concern that C. diff infection is becoming more prevalent outside of hospital settings (community-acquired), and that infection can occur in the absence of prior antibiotic exposure.

To review recent research and treatment experiences related to C. diff, a group of leading infectious disease specialists from around the world met recently in San Francisco. These experts offered a range of perspectives from clinical settings in the U.S., Canada and the European Union related to pathophysiology, disease epidemiology, recurrence, prevention, standardized incidence reporting, treatment and prospects for future treatment.

The Antibiotic Link

C. difficile-associated disease (CDAD) is often triggered by the use of antibiotic therapy, which can disrupt the normal balance of flora in the intestine, making it possible for the C. diff bacterium to flourish. As a result, the first strategy of intervention in treating C. diff. infection is to stop treatment with antibiotics. As much as 23 percent to 30 percent of symptomatic patients recover simply by suspending the antibiotic therapy that is disrupting the balance of flora in the colon.

If diarrhea continues despite stopping antibiotics, or if the diarrhea is severe, patients with C. diff are treated with antibiotics including metronida-zole or oral vancomycin. Thus, C. diff infection is distinctive as one of the few health problems that is both caused by and treated with antibiotic therapy. Metronidazole is used as a first course of therapy and for more moderate cases of C. diff infection. Vancomycin, a more powerful therapy, is usually prescribed for more severe cases.

Experts agree that current standards of treating CDAD can be improved. Premature cessation of antibiotic therapy can result in persistence of the original infection, e.g., pneumonia. Also, because only a minority of patients experience resolution of CDAD when antibiotics are stopped, most patients diagnosed with CDAD will require treatment with metronidazole or vancomycin. Furthermore, for both treatments of CDAD with metronidazole or vancomycin, between 10 percent and 20 percent of patients fail to respond. In addition, 15 percent to 21 percent of patients who do respond develop recurrence of diarrhea (relapse), most often within a week to a month after treatment of the CDAD. Recent studies have demonstrated that response rates to metronidazole treatment are falling, and relapse rates are higher than observed in the past.

While treatment with vancomycin tends to result in lower rates of failure, experts have expressed concern that over-use of vancomycin could promote the selection for vancomycin-resistant bacteria, i.e. select for superbugs, particularly vancomycin-resistant Enterococci (bowel streptococci) and Staphylococci (staph bugs).

Although the C. diff bacterium remains sensitive to both metronidazole and vancomycin, resistance to commonly used antibiotics such as cipro-floxacin (a fluoroquinolone) and clindamycin is on the rise. Researchers recently identified a new epidemic strain of C. diff, known as NAP1/ B1 or PCR ribotype 027, which produces 20 times more toxin in the test tube than other strains. This new strain has been shown to be resistant to the newer fluoroquinolones, gatifloxacin and moxifloxacin, and over-use of these quinolones have been shown to be associated with outbreaks of CDAD.

While CDAD is almost exclusively associated with prior antibiotic exposure, there are recent reports of patients developing CDAD in the absence of antibiotic exposure, implying that the C. diff bug is more virulent and can cause disease despite an intact and presumably healthy bowel flora.

Two recent studies from the same General Practice Research Database in the United Kingdom provide a case in point. In these studies, only between 37 percent and 55 percent of patients with symptomatic C. diff infection reported treatment with antibiotics within the previous 90 days. While it is possible that some of these patients could have received undocumented antibiotic therapy, these results indicate that previous antibiotic exposure may not be universally valid as a precondition for developing CDAD. Community and hospital surveillance to diagnose CDAD may require testing without regard to a history of prior antibiotic exposure.

Other Risk Factors

Aside from the issue of prior exposure to antibiotics, clinicians are able to identify several other potential risk factors in C. diff infection. The apparent rise in cases of CDAD acquired outside of hospital settings has drawn attention to the risk among residents in nursing homes and other extended-care facilities. People age 65 and older are especially vulnerable to C. diff infection, and the likelihood of infection increases exponentially when elderly patients are treated with antibiotic therapy and exposed to environments where C. diff is prevalent. In one study, among patients over age 90 who were treated in hospital environments where C. diff was known to be present, 7.4 percent developed CDAD and 14 percent of those patients died as a result of the infection.

At present the interaction between the C.diff bacterium and the bodys immune defenses is poorly understood. The majority of patients who have ingested the spores of C. diff remain well. It has been shown that patients who develop antibodies to C. diff after the bacterium is present in the bowel are less likely to develop CDAD. While most cases of CDAD are mild to moderately severe, it is not clear why some cases are fulminant, resulting in rapid progression to severe and fatal disease. Furthermore, the transition of mild disease to fatal infection is unpredictable. Age, immune responsiveness, type of antibiotic exposure, anti-cancer chemotherapy, strain differences in toxin production, delays in diagnosis and treatment are thought to be factors affecting the outcome of infection. Factors leading to relapse of CDAD are also not well understood at present; persistent imbalance of the normal bowel bacteria is suspected to be one of many possible causes of relapse. It is well known that the spores of C. diff persist in the colon following successful treatment of the diarrhea.

While many of these patients in hospitals and extended-care facilities will not go on to develop CDAD, they may contribute to the spread of C. diff spores throughout the environment. In any ward where patients are infected with C. diff, transmission can be facilitated in a process that infectious disease specialists call "active disease pressure." Bacterial spores are continually spread by infected patients between patients or via the environment or the hands of healthcare workers.

As a result, a virtual "film" of C. diff spores can develop on multiple surfaces in a patient's environment, especially in bathrooms. Thus the relative level of environmental contamination is another risk factor for infection. High case rates of CDAD tend to maintain the status quo.

Currently there are many deficiencies in tracking CDAD cases and outbreaks. The infection is not reportable to public health agencies in most countries. Also, the standard test for CDAD, detection of C. diff. toxins in fecal samples, is only about 75 percent (+15 percent) accurate. Therefore, repeat testing of highly suspected cases is routinely done. The vast majority of microbiology laboratories do not culture for the organism, and instead rely on toxin testing alone. Growing the bacterium from stool samples is required to determine strain types and antibiotic resistance in C. diff bacteria, key tests required to control outbreaks.

Experts agree that accurate and consistent reporting will be essential to C. diff prevention and control in the years ahead. As the rates of both hospital and community-acquired infection incidence rise, active and accurate reporting practices in the U.S., Canada and the European Union countries are clearly needed. Ohio is currently the only U.S. state that requires mandatory reporting of C. diff, and medical health professionals, administrators, and public health officials are considering it as a critical test-case of mandatory reporting. In Canada, Manitoba and Quebec actively track cases and several spot surveys at participating hospitals across Canada have been done, but comprehensive and continuous surveillance is not done. For patients age 65 or older in United Kingdom hospitals, stool sampling has been performed regularly for C. diff isolation and typing since 2004. As a result, hospitals in the United Kingdom are being categorized according to strain-specific analyses, though it remains to be seen whether and how this will affect public perceptions relative to quality of care.

Strategies for Disease Control and Prevention

Heightened awareness of C. diff could help clinicians, hospital administrators and public health officials develop more effective preventative strategies to combat infection. The disease control ideas presented during the roundtable discussion ranged from the complex (e.g., restructuring hospital architecture to provide more private rooms to prevent transmission of infection) to the basic (e.g., more frequent handwashing and barrier precautions by healthcare workers and patients).

Overall, experts agree that the latter strategy, calling for increased attention to personal hygiene, is the most practical method for controlling the spread of C. diff infection. Because the primary means of transmission seems to be via the hands of healthcare workers and patients and between patients through shared facilities, thorough handwashing with soap and water and consistent use of barriers such as gloves are considered by many infectious disease experts to be the most effective measures for disease control. Prompt isolation of diarrheal patients pending the results of stool toxin testing is helpful in reducing the spread of the organism.

Because C. diff spores can collect on surfaces in contaminated environments, regular and thorough cleaning of patient rooms with the proper antibacterial agents can also be an effective countermeasure. In this regard, hospital and extended-care facility staff should pay special attention to patient bathrooms, where bacterial spores tend to accumulate in the greatest concentrations. For best results, experts recommend the use of bleach at a 1:10 dilution in water to kill C. diff spores in the environment.

Because CDAD is almost always associated with prior use of antibiotics, infectious disease specialists are calling for more stringent prescriptive guidelines to limit unnecessary and inappropriate antibiotic therapy. Limiting the overuse of the most common inducers of C. diff (i.e., the cephalosporins, clindamycin and more recently, the quinolones) should help. New research on novel methods of treating CDAD, including more selective antibiotics that would have less impact on the normal gut bacteria, the use of non-antibiotics to bind and neutralize the toxins produced by C. difficile, or neutralization of toxin by antibodies, could help reverse the rising tide of disease in the near future. Non-antibiotic alternatives should reduce the selective pressure driving antibiotic resistance.

Improved and standardized information reporting and sharing methods could also improve the ability of clinicians to respond quickly and effectively to future outbreaks of CDAD. Timely action is especially important in the case of C. diff infection because of the unpredictable nature of transmission and disease progression. The implementation of broader reporting requirements for hospitals and extended-care facilities would be one way to increase awareness of CDAD issues among medical professionals and medical and long-term care facilities managers. More rigorous reporting standards that target both incidence and severity of CDAD cases could also make it easier to identify highly transmissible strains of C. diff known as "hyper-spreaders." While the costs of mandatory C. diff surveillance will be an issue for already overburdened health care systems, clinical laboratories, working in partnership with state and provincial laboratories and the public health departments can provide the necessary medical intelligence to control the threat of CDAD.

Further Areas of Research

In future research, many clinicians and researchers call for a focus on the increasing use of fluoroquinolone antibiotics which, as noted, may be adding to the resistance of and selection for certain C. diff strains, as in the case of NAP1/B1. The extensive use of proton pump inhibitors (PPIs), which also alter the normal balance of intestinal flora, is another target for further clinical investigation. Widely used for patients with ulcers and other GI illnesses, PPIs may enable C. diff to survive and flourish in the stomach by stopping the production of stomach acid, which under normal circumstances kills microbes. But it remains to be seen exactly how PPIs affect intracolonic events leading up to disease.

Broader understanding of strain virulence in C. diff itself could also have a significant impact on the effectiveness of prevention and treatment strategies. Not much is currently known about the relationship if any between strain virulence, disease transmission and disease severity. More-over, while the disease-causing role of toxins A and B associated with C. diff is established, additional research is necessary to assess the role of a binary toxin in humans.

Finally, many experts conclude that the incidence of community-acquired CDAD should be monitored closely, particularly those cases in which outbreaks are not preceded by antibiotic therapy. If, as suspected, this trend is on the rise, new strategies in public health policy, public awareness, disease prevention and treatment may be required.

Thomas J. Louie, MD, is from the University of Calgary, Departments of Medicine and Microbiology and Infectious Diseases.