ISSUE: FEBRUARY, 2008 VOLUME: 35:2
Vancomycin May Win Fight Against Severe C. Difficile Charlotte Huff
DENVER—After years of relying on metronidazole as the primary agent to treat worrisome Clostridium difficile strains, recent data indicate that clinicians should instead consider oral vancomycin when the infection is severe, according to a presentation on C. difficile treatment at the American College of Clinical Pharmacy (ACCP) meeting.
To make his point, Joseph Guglielmo, PharmD, chair of the Department of Clinical Pharmacy at the University of California, San Francisco (UCSF), cited two recent analyses, one published in Clinical Infectious Diseases (CID) and another presented in September 2007 at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).
The CID study (2007;45:302-307), a prospective, randomized, double-blind analysis, was particularly enlightening, Dr. Guglielmo said. Of the 150 patients who completed the trial, researchers determined that metronidazole and oral vancomycin were equally effective in treating mild disease. Yet in cases of severe infection, vancomycin was significantly more successful, with a clinical cure 97% of the time compared with 76% among patients taking metronidazole.
“If you have severe disease, I think it’s a different world right now,” Dr. Guglielmo said in a subsequent interview with Pharmacy Practice News. “Now, as opposed to anecdotes, I think by evidence we can see that the drug of choice for severe disease should be vancomycin—it should not be metronidazole.”
C. difficile–associated disease (CDAD) was a major focus at the ACCP meeting, with researchers presenting posters delving into strategies to better test, prevent and treat the challenging and potentially fatal diarrheal infection. A widely discussed study in The New England Journal of Medicine (2005;353:2433-2441) heightened concerns when researchers described the spread of a new, previously uncommon strain that produces more toxins and is more resistant to fluoroquinolones.
“As a clinician, C. difficile diarrhea is always concerning,” said Steven Martin, PharmD, professor and chair of the Department of Pharmacy Practice at the University of Toledo College of Pharmacy in Ohio. “But particularly now, with this newer strain, it would appear that there is higher morbidity and mortality associated with this strain than the older strain.”
Another, more recent study published in CID (2007;45:992-998) found that a significant amount of C. difficile may be lurking undiagnosed. In the study, half of 68 asymptomatic patients living in long-term care settings were carriers of toxigenic C. difficile.
Treatment Challenges
Traditionally, metronidazole has been considered a first-line treatment for C. difficile because of its lower cost and because of concerns about the proliferation of vancomycin-resistant organisms. But in recent communications, officials at the Centers for Disease Control and Prevention left the door open regarding the use of vancomycin, acknowledging that the new, more toxic strain of C. difficile may not respond as well to treatment with metronidazole.
In the earlier CID study, patients were classified based on the severity of their infection. To be classified as having severe C. difficile, patients at Saint Francis Hospital, a teaching facility affiliated with the University of Illinois at Chicago, had to meet two or more of the following criteria: age greater than 60 years, temperature higher than 38.3 C, albumin level below 2.5 mg/dL or peripheral white blood cell count greater than 15,000 cells/mm within 48 hours of enrollment. When classifying patients with either mild or severe disease, two factors—endoscopic evidence of colitis or treatment in the ICU—classified the patient as suffering from severe C. difficile.
Dr. Martin noted that those criteria for severe disease are relatively broad, such as the inclusion of all ICU patients. Clinicians, moreover, don’t typically stage C. difficile amid a busy practice, he said. Still, he described the University of Illinois findings as thought-provoking.
“I think we need to rethink our strategy with C. difficile–related diarrhea in patients [who] are seriously ill,” said Dr. Martin, a member of the Pharmacy Practice News editorial advisory board. “We might have a lower threshold of going to vancomycin.”
In his presentation at ACCP, Dr. Guglielmo also described some of the data presented at the recent ICAAC meeting as potentially illuminating in terms of the metronidazole-vancomycin question. The Phase III study (abstract K-425a), designed to assess Genzyme’s investigational drug tolevamer and involving more than 500 patients, had determined that the drug was not as effective as metronidazole or vancomycin.
But when the severity of C. difficile disease was broken down, an intriguing difference emerged between metronidazole and vancomycin, said Dr. Guglielmo, who also directs the Antimicrobial Management Program at UCSF Medical Center. The ICAAC data showed that in severe cases, vancomycin was more effective than metronidazole, with a clinical success rate of 84.8% versus 64.9%, he said.
Making an Impact
In addition to Dr. Guglielmo’s presentation, the fall 2007 ACCP meeting also featured a number of abstracts that delved into other challenges associated with C. difficile, from diagnosis to the potential influence of other medications, such as gastric acid suppressants.
One presentation (abstract 119), involving researchers at Scripps Mercy Hospital in San Diego, Calif., provided some insights into diagnostic accuracy and the need to start treatment with the optimal medication regimen.
The researchers, who conducted a medical record review of positive diagnoses from January through July 2006, found that diagnosis wasn’t an easy task. Three-fourths of the 98 patients were diagnosed after one test. Yet in some cases, a positive confirmation required three or more tests. By the third test, 92% of the infections had been identified. In one case, as many as a dozen tests were required, said Lisha Kronmann, PharmD, lead researcher on the project and a clinical pharmacist at Scripps Mercy. “If we had just stopped at one test, we’d only have caught three-quarters of our positive patients,” she said.
Moreover, the data also indicated the significance of the first choice of treatment regimen, Dr. Kronmann said. Of the patients initially treated with an inappropriate regimen, 30% suffered a severe outcome—either colectomy or death. By comparison, only 9.6% of those who were appropriately treated suffered a similar result, she said. When reviewing regimens, one of the most common missteps was prescribing metronidazole, but not necessarily at the correct frequency, she said.
A second poster presentation at ACCP scrutinized another recurring issue, the potential relationship between C. difficile and gastric acid suppressants. Several recent studies have already pointed to an association between acid-suppressive therapy and C. difficile, said Paul Juang, PharmD, BCPS, the ACCP poster’s lead researcher and assistant professor of pharmacy practice at St. Louis College of Pharmacy in St. Louis, Mo. Dr. Juang pointed to one study, published in the Journal of the American Medical Association (2005;294:2989-2995), which involved two population-based case-control studies and found a link between gastric acid suppressants—in particular, proton-pump inhibitors—and C. difficile.
In his own poster at the ACCP meeting, Dr. Juang took a smaller snapshot of the relative influence of gastric acid suppressants. The retrospective analysis, involving 50 patients admitted to Missouri Baptist Medical Center, St. Louis, in 2005, was not sufficiently large to determine if there is an increased risk for C. difficile in patients who receive the gastric acid suppressants, he said. But it did identify a longer length of stay in patients taking the medications: 14.6 days compared with 9.5 days for those who were not. The duration of C. difficile antibiotic treatment also was longer: 7.9 days versus 4.3 days in patients not taking the suppressants.
“It’s more hypothesis-generating,” Dr. Juang said about his results. “In patients with C. difficile, we should probably think [carefully] about the use of gastric acid suppressants.”
Keeping clinicians up to speed regarding the latest findings on C. difficile is almost a moving target, clinicians say. In the wake of the Scripps Mercy findings regarding repeat testing and other issues, Dr. Kronmann conducted grand rounds education in the spring of 2007 for clinicians there. She has not analyzed the data since then but believes she has seen anecdotal evidence that clinicians have improved their testing and treatment approaches. In the months since that talk, the results from the University of Illinois had been published in CID. By year’s end, Dr. Kronmann was contemplating another grand rounds to educate clinicians about the potential benefits of oral vancomycin in combating severe C. difficile disease.
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