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C. difficile epidemiology changing, cases and virulence increase
New drugs in the pipeline address a pressing clinical need: Doctors have been using the same two drugs for 25 years.
ATLANTA — If it feels as if you are seeing more cases of Clostridium difficile in your facility, that its virulence is increasing and that treatments may not be working as well as they did 25 years ago, you may be right, according to several speakers at the 2006 International Conference on Emerging Infectious Diseases.
The rate of cases is increasing, both in the United States and Canada, where Vivian G. Loo, MD, MSc, practices. Cases are also rising in the Netherlands and the United Kingdom, said Loo, who is associate professor, McGill University Health Center, Montreal, Quebec. In a study published in Emerging Infectious Diseases, researchers found that a discharge diagnosis of infection by Clostridium noted in charts of U.S. hospitals to approximately 60 discharges per 100,000 population in 2003 compared with 30 discharges in 1996, she said.
In addition, a Canadian survey found a four- to fivefold increase in mortality from the disease. Loo’s group has found a new genotype NAP1, which is proving to be more virulent in Canada, she said, and research in the Netherlands, the United Kingdom and the United States supports this.
Clinical problems
Dale N. Gerding, MD, said he sees four clinical problems associated with C. difficile today: an inability to prevent C. difficile–associated disease (CDAD) in high-risk settings; lack of a sensitive and rapid diagnostic test for CDAD; the inability to prevent recurrence of CDAD; and an inability to effectively treat fulminate disease.
The tests for C. difficile are only about 60% to 70% sensitive, he said, which can confuse the diagnosis. “You need to use good clinical judgment: If it looks like C. diff, smells like C. diff and acts all the world like C. diff, you should not be intimidated by the negative test results,” said Gerding, who is associate chief of staff for research at Hines Veterans Affairs Hospital and professor of medicine at Loyola University Chicago Stritch School of Medicine.
Culture, with its sensitivity of 89% to 100%, is the best diagnostic method, but most laboratories find it cumbersome. Instead, they use an enzyme immunoassay (EIA) test for toxin A. “It is not the best test, but labs like it because it is more rapid and less labor intensive than other tests,” he said.
Some use an EIA that looks for toxins A and B. “We continue to see problems with these tests. In addition, we are anecdotally becoming aware of a number of incidences where it appears these toxin A/B tests are reporting false-positives,” he said.
This is of concern because there are patients being diagnosed with C. difficile who do not have risk factors, and it is difficult to decide if this is a change in epidemiology or they do not have CDAD in the first place. One should do backup cultures and should be careful about making the diagnosis solely on the test results, he suggested.
Treatment
Treatment is a problem.
“I’m afraid there isn’t much new to offer. We’ve had the same two drugs to treat this disease for 25 years now,” Gerding explained.
Both metronidazole and vancomycin disrupt the normal flora during treatment, leaving 20% of patients susceptible to relapse and recurrence. And relapses are very hard to treat.
The recurrence rates are similar for both metronidazole (20%) and vancomycin (19%), but metronidazole saw a higher failure rate (13% vs. 4%), according to Gerding.
Another issue is whether the drugs stop diarrhea. “You can see in the earlier trials, 95% to 94% of diarrhea stopped with treatment. More recent trials found only about 74% to 78% of diarrhea stopped, which is about a 20% reduction in efficacy,” he said.
The relapse rate with the current epidemic strain of NAP1 is higher than in patients without the epidemic strain, he said. “It appears that there is some drop off in response rate and increase in recurrence rates with this more recent data associated with an epidemic strain,” he said. “Overall response time with C. diff was slower with metronidazole than vancomycin.”
However, there are treatments in the pipeline: narrow-spectrum antimicrobials targeting C. difficile that do not disrupt the normal flora, toxin target binding agents, biological agents and vaccines. It will be years, however, before they will be available for practice.
“Multiple recurrences of C. difficile remain a problem. Once you have a recurrence, the probability of another one is about 40%,” he said. Recurrences are aggressive, and occur mostly in elderly women. “There are various strategies to dealing with it: tapering drugs, pulsed dosing, combining with rifampin,” he said. “We’ve used all of them, and sometimes they work and sometimes they don’t.”
Probiotics, IV immune globulin, toxin binding agents and fecal reconstitution have all been tried. “Fecal reconstitution using donor stool from closely related relatives, while esthetically unappealing, actually has very high efficacy, if you can find someone who can do it,” he said, adding that the overall lack of efficacy leads to desperate measures.
Better management is sorely needed. “We need controlled trials for management of C. diff patients, and an algorithm for when to take them to surgery,” he suggested.
Loo said that she has real problems controlling outbreaks in her facility because it is more than 100 years old. The hospital features rooms with four beds and a shared bathroom, so the logistics make infection control difficult.
Infection control is a serious problem in many institutions, agreed John M. Boyce, MD, chief of infectious diseases at the Hospital of St. Raphael and clinical professor of medicine at Yale University School of Medicine.
He said that the noncontroversial strategies are limiting the use of antimicrobials associated with a high risk of CDAD, rapidly detecting CDAD and isolating or cohorting patients, replacing electronic thermometers with disposable devices, and wearing gloves when caring for CDAD patients. These practices are supported by good evidence.
“Wearing gowns when caring for C. diff patients is widely used, although the evidence of that is not as strong,” he said.
Alcohol vs. soap
Where the controversy starts is at the hands of health care workers. “Transmission of C. difficile via the transiently contaminated hands of a health care worker is considered to be an important mode of spread, and in six studies, C. diff has been recovered from anywhere from 2% to 59% of health care workers,” Boyce said.
The controversy lies in which type of hand hygiene product to recommend: chlorhexidine gluconate soaps and water or alcohol-based hand rubs. Studies have found no difference between plain soap and water vs. chlorhexidine gluconate soap for removing C. difficile, he said, but the alcohol products, which are more popular with staff, did not fair as well.
One study examined chlorhexidine soap and water vs. three alcohol-based hand rubs. Researchers applied a nontoxigenic strain of C. difficile to the hands of health care workers, and then hand cultures were done before they used the products and then after use. They also studied how frequently C. difficile remaining on the hands after using an alcohol-based hand rub was transmitted by shaking hands. The chlorhexidine had a 2.5 log10 reduction in C. difficile, while the alcohol-based hand rubs saw only a 1.7 to 1.9 log10 reduction.
“They also found that after using an alcohol-based hand rub, an average of 36% of C. diff spores were transferred by handshaking,” said Boyce. “So, they concluded that hand washing with chlorhexidine was significantly more effective in removing C. diff from the hands than using alcohol-based hand rubs.”
The reduction of C. difficile from the hands using alcohol-based hand rubs was higher than they expected, however, and more study should be done.
Some experts blame the alcohol-based hand rubs for the recent increases in C. difficile rates, said Loo. But Boyce said that in five studies, “the incidence of C. difficile disease decreased slightly or remained the same as it had been before the introduction of the alcohol-based hand rubs.”
And in most institutions, hand hygiene compliance increases with the introduction of alcohol-based products, which is an important consideration.
“Hospitalwide use of alcohol-based hand rubs for a period of three to four years is not associated with an increase of C. difficile,” Boyce said, adding that an epidemic strain or increase in quinolones use is more likely the reason for increases in CDAD.
“I think in terms of recommending hand hygiene measures, if an institution is experiencing an outbreak of C. difficile disease, then it’s prudent to wash hands with soap and water after caring for patients with CDAD. However, we should continue to use alcohol-based hand rubs for routine hand hygiene when caring for all of the other patients.”
Decontamination
Once the environment becomes contaminated, it is difficult to decontaminate it, Boyce said, because the organism lives on many types of surfaces, including commodes, tile floors, bedrails, bedpans, room floors, windowsills, call buttons, etc.
“The amount of contamination depends on who has been in the room,” he said. “If you go to hospital rooms where there have been no recent C. diff patients, about 2.6% to 8% of the surfaces that you culture will be positive. If you go into rooms where there have been patients with asymptomatic C. diff colonization, 7% to 29% of the cultures will be positive, and if you go into rooms where the patient has active diarrhea, 20% to almost 50% of the surfaces will be contaminated with C. diff.”
There is some suggestive evidence that surface contamination contributes to transmission by health care workers, because their hands become contaminated by touching surfaces, and the frequency of hand contamination increases with increasing environmental contamination.
“So the environment may contribute to transmission by serving as the source for which health care workers contaminate their hands,” he said.
Routine cleaning may not eliminate the C. difficile spores, he added. Detergents are not very effective. In contrast, bleach is effective at a dilution of 1:10. Phosphate buffered hypochlorite was more effective, but the stability is reduced. Some alternatives to bleach include acidified nitrite, peracetyl ions, hydrogen peroxide and chlorine dioxide, but they are not recommended for routine cleaning and more studies are needed.
A Connecticut hospital saw an increase of incidence of C. difficile from the Nap1 strain, despite good control measures, such as limiting antimicrobial use, isolating patients, using soap and water for hand hygiene and cleaning the environment with 1:10 bleach dilution. The researchers initiated a prospective, collaborative trial of hydrogen peroxide vapor (HPV) biodecontamination (Bioquell, PLC). They “blitzed” three affected wards and nurse stations after the patients were moved. The process takes about three hours for each room, according to Boyce. They continued to perform HPV biodecontamination in additional patient rooms, but other nursing stations were not included. They cultured the rooms before and after decontamination. Of the 165 swab cultures of various surfaces before biodecontamination, 5% grew C. difficile, even though many of the surfaces had been cleaned with bleach. In contrast, of 155 cultures performed after decontamination, none grew C. difficile.
Of 45 cultures done before room decontamination, 24% grew C. difficile. Of 35 done after decontamination, none grew C. difficile.
They did daily laboratory surveillance for C. difficile and found that the rate of nosocomial C. difficile significantly decreased over the preceding year. Although HPV was effective, there were no contemporary control wards, admitted Boyce, and this limits the interpretation of the results. He said continued evaluation of this and other disinfection methods is needed.
“Evidence suggested that reducing the level of environmental contamination may contribute to reducing transmission of C. difficile,” he said. – by Marie Rosenthal
For more information:
- Loo VG. The changing epidemiology of Clostridium difficile associated disease.
- Gerding D. Recommended approaches to diagnosis and treatment.
- Boyce JM. Infection control issues and controversies.
- All presented at: 2006 International Conference on Emerging Infectious Diseases; March 19-22, 2006; Atlanta.