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C. difficile epidemic continuing to spread
Strains similar to those in the United States are now showing a presence in Europe.
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Rates of Clostridium difficile diarrhea continue to increase in the United States, and the epidemic has now jumped to Europe.
C. difficile is an anaerobic bacteria gram-positive rod with the ability to produce spores. Its spores can persist in the environment and spread the infection through health care workers and the environment itself, which is the key to its success, according to Dale N. Gerding, MD, associate chief of staff for research and development at the Hines Veterans Affairs Hospital, and professor of medicine at the Stritch School of Medicine at Loyola University, Chicago.
“This is a difficult organism to manage in the health care environment – much like the previous outbreaks of anthrax in the postal services was difficult to manage because of its ability to contaminate the environment,” said Gerding, who is also an infectious disease specialist and hospital epidemiologist.
Year in review
Recent studies show that the increased rates of C. difficile diarrhea were caused by a common epidemic strain that circulated in the United States and Canada, Gerding said during the recent 2006 Annual Meeting of the Association for Professionals in Infection Control and Epidemiology. The strain was also recently found in Europe.
“There are at least four or five European countries that have had the same strain that has circulated in the United States and Canada and continues to be present,” Gerding said.
The epidemic is evidenced through the increased incidence of cases. Data from Veterans Affairs hospitals in 2000 showed that the rate of C. difficile was about five cases per 1,000 discharges. In 2004, the rate of C. difficile diarrhea in VA hospitals was more than 10 per 1,000 discharges. These numbers include primary and secondary diagnoses of C. difficile.
National rates have more than doubled since 2000. The disease primarily occurs in patients older than 65, with a rate of 20 cases per 1,000 discharges; the rate is also rising in younger patients, but not as significantly, according to Gerding.
A recent study showed that C. difficile outbreaks that occurred in six states during 2004 were caused by a common strain. The same strain continues to circulate, but testing for C. difficile is still not occurring frequently enough to truly track the epidemic, Gerding said.
Canada has also reported an increased rate of C. difficile. A Montreal study revealed rates in that region to be 22.5 cases per 1,000 discharges during the height of the epidemic.
More recent data from Montreal, however, show that hospitals now have reduced rates of C. difficile. The data also reported a much lower rate last winter, which is attributed to myriad infection-control measures, according to Gerding.
A new toxin
According to Gerding, an organism is considered toxigenic because of toxins A and B. The pathogenicity is located in a locus of five genes that are located in the same place of the chromosome. Generally, the strains either possess the entire package of five genes, or they lack it entirely and do not cause disease.
However, new data indicate a few strains that include atypical or variant genes and are able to produce disease, including Pseudomembranous colitis. Binary toxin, a new third toxin was first encountered about 10 years ago, and the significance of that is still unknown. It is present in these current epidemic strains, Gerding said.
Schematically, the pathogenicity locus is about 20,000 base pairs long and consists of a gene called an alternate sigma factor for promotion of toxin production. The new epidemic strains have deletions in the gene. By either PCR or amplification of this gene in a non-toxigenic strain, 115 base pairs of DNA would be present and have no function in terms of toxin production. The outbreak strain, however, is different.
This epidemic strain is known by several names, depending on the diagnostic testing, according to Gerding. When the strain is toxinotyped by amplifying portions of the pathogenicity locus or by restriction nonucleus analysis, it is known as the BI group. When done with pulsed-field analysis, as done at the CDC, they are known as the North American Pulsed Field 1 (NAP1). In Europe where PCR ribotyping is done, they carry the name O27.
“All of these are very closely related, if not absolutely identical,” he said.
A collaborative typing study is underway, and these isolates are being exchanged as a way of determining how closely related the strains are, according to Gerding.
Characteristics
The epidemic strains are characterized by three things. The first is production of binary toxin, an ADP ribosome transferase that is found in other organisms like C. perfringens. Only about 5% to 6% of C. difficile strains have this.
The genes for this strain are located in a different part of the chromosome, far away from the pathogenicity locus. All the epidemic strains have different variations of binary toxins, but are largely 18 base-pair deletions.
Secondly, data have suggested that something else is present to stop production of the TCDC protein. Finally, the epidemic strains have resistance to the new fluoroquinolones, such as gatifloxacin and moxifloxacin.
These epidemic strains are not new. They have been collected since about 1980, according to Gerding. The binary toxin is fairly new, but its role remains unknown.
“We actually had typed these back in the 1980s and early 90s and classified them as BI 1-5. They are identical in every aspect except the fluoroquinolone resistance. That part is new in the new epidemic strains,” he said. “Everything else – the 18 base-pair deletion and the TCDC gene and the binary toxin were present in the 1980s but they did not cause epidemics. The question is what has happened between 1980 and now that we are seeing this strain spread widely?
“It appears that we have this toxin but we don’t know exactly what it’s doing in terms of pathogenicity of the organism. There is also an association of binary toxin with isolates that are coming from the community and that relationship needs to be further explored as well,” Gerding said.
Quinolone resistance
Fluoroquinolone resistance is the only known difference between the current epidemic strains and the historic strains, and is a risk factor for the current epidemic. When an organism becomes resistant to gatifloxacin and moxifloxacin, the MIC90 level to ciprofloxacin and levofloxacin also goes up.
“You generate much higher resistance to all the drugs, not just to gatifloxacin and moxifloxacin,” Gerding said.
According to Gerding, data from a long-term care facility in Atlanta showed big increases in C. difficile rates when it switched from using levofloxacin to gatifloxacin. The facility returned to using levofloxacin and the rate decreased, despite a reported resistance to levofloxacin. More data are needed on whether there is risk to fluoroquinolones, according to Gerding.
One contradictory report indicated risks with using levofloxacin. The odds ratio (OR) was only two, but they had significantly increased their use of this drug prior to the outbreak. A high proportion of patients received levofloxacin. A risk associated with use of cephalosporins and clindamycin was also present.
A similar study in Canada found that use of any quinolone was associated with an OR of 3.4, but ciprofloxacin was the facility’s most frequently used drug, followed by levofloxacin, both of which had a slightly lower risk. The hospital had a low rate of gatifloxacin and moxifloxacin use.
An article in Morbidity and Mortality Weekly Report alerted clinicians to community-associated C. difficile cases and some peripartum C. difficile cases. One woman miscarried her pregnancy and then died herself as a result of C. difficile diarrhea. They calculated the rate of a community in Philadelphia at a minimum of 7.6 per a 100,000 population. That actually is lower than the rate of a previous community study in Boston.
Community vs. hospital
Gerding said a striking finding was that 25% of patients reported no antibiotic use in the prior three months.
“That would be distinctly unusual and needs verification,” he said. “Also unusual would be exposure to another C. difficile case. Normally you do not have antibiotic-exposed contacts to another C. difficile patient. We think antibiotics are the entryway into the patients becoming susceptible.”
Only two isolates were recovered and both had the binary toxin gene. One had the TCDC gene deletion but neither were the epidemic strains found in hospitals, according to Gerding.
“We desperately need more of these isolates from the community to try and figure out what’s going on and figure out if the rate really is increasing and figure out if the risk is present without antibiotics,” he said.
Another study, published in the Journal of the American Medical Association made some startling observations in a study population from the United Kingdom, according to Gerding. The research team collected the C. difficile cases and matched them to 10 controls in the database and found that community-associated C. difficile had increased from 1 per a 100,000 population to 22 per a 100,000 population in the10-year observation period.
The researchers found that proton-pump inhibitors (PPIs) were used in 23% of the C. difficile cases and in 8% of controls (OR=2.9), which implicated the PPIs. They also found that H2-receptor antagonists were associated with increased risk, as were anti-inflammatory agents, which were the most commonly used drugs.
Antibiotics were found in only 37% of patients vs. 13% of controls, according to Gerding. The CDC is currently conducting further study on this topic.
More data is needed on PPIs and C. difficile diarrhea because additional studies that support PPIs as a risk factor also exist, as do studies that show no risk with PPIs, according to Gerding.
Handwashing or alcohol?
Much controversy exists around handwashing vs. alcohol to remove C. difficile spores. Gerding’s team conducted a study of 10 volunteers whose hands were seeded with 10,000 C. difficile spores. They tested three alcohol products and compared them with handwashing using chlorhexidine. They conducted a terminal transfer experiment after using the alcohol products by having the volunteers shake hands with a second volunteer to see if the spores would transfer.
A mean of 30% of spores were transferred. Gerding said there could be study limitations, but the alcohol gels removed a significant amount of spores from the hands. There were no differences between alcohol gel products, but chlorhexidine was significantly better than the gels at removing the C. difficile spores.
“Soap works just as well as chlorhexidine,” Gerding said.
The spores were prepared for the experiment by heating them, but not to the high temperature that is usually used for enriching spores. It is possible that some non-spore organisms were present in the preparation. Gerding speculated that might be the reason significant reductions in spore count were seen with alcohol gels, because those findings were unexpected.
Treatment
Computed tomography (CT) scans are becoming more common for patients with C. difficile diarrhea. The scans have shown a markedly thickened colon wall contrasting in the colon, which physicians have termed as Pseudomembranous colitis.
Clinicians are becoming accustomed to looking for neutrophil high white blood cell counts. One study revealed that white counts of more than 15,000 were present in 16% of patients with C. difficile and 25% had white counts of more than 30,000.
Another study showed 58% of 60 patients with an unexplained white count of more than 15,000 had C. difficile toxin in their stool.
“Be aware of a high white count, particularly a high white count that continues to rise during therapy. That is very bothersome and indicates the need to consider changing therapy,” Gerding said.
Patients with a classic case of C. difficile diarrhea are best treated with either vancomycin or metronidazole. The cocktail used by Gerding for difficult-to-manage patients starts with oral vancomycin, then metronidazole IV, followed by enema with vancomycin.
IVIG is a possible treatment consideration if the patient is suspected of having an antibody problem, according to Gerding. In addition, there are new drugs in the pipeline that will be helpful in treating fulminate C. difficile disease, including some already available but with indications for other diseases.
Several studies have indicated metronidazole failure in treating C. difficile diarrhea and have been associated with relapses, Gerding said. However, it is possible, based on other data, that metronidazole works, but at a slower rate than vancomycin.
In treating relapsing patients, metronidazole can be used and it is just as effective as vancomycin for the first relapse. Recurrent cases of C. difficile can be treated with the same drug as the first case, or a different drug. However, complications of the relapses may be much higher than anticipated. – by Cassandra A. Richards
For more information:
- Gerding D. Review and update of Clostridium difficile. Session 3205. Presented at the 2006 Annual Meeting of the Association for Professionals in Infection Control and Epidemiology. Tampa, Fla. June 10-14, 2006.