New Approaches Will Be Needed to Combat C difficile

June 3, 2007
Wayne Kuznar

Internal Medicine World Report, January 2006, Volume 0, Issue 0

Virulent Strain Developing Resistance to Fluoroquinolones

Washington, DC?The emergence of hypertoxin-producing strains of Clostridium difficile has heightened the urgency to find new therapeutic approaches, as the apparent increased pathogenicity of the organism is resulting in higher death rates, said James T. Louie, MD, director of infection control, University of Calgary, Alberta, at the 45th annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

His remarks were made just a few weeks after a report in Morbidity and Mortality Weekly Report (2005;54:1201-1205) des?cri?bing 33 cases of C difficile since 2003 in 33 otherwise healthy people from 4 states. None of the 33 had been in the hospital within 3 months of becoming ill, and 8 re?por??ted taking no antibiotics within that time.?

Shortly after this report, 2 articles were published in the New England Journal of Medicine (see related story on page 20] that described a virulent strain of C difficile?found in >50% of isolates taken from 8 health care facilities in 6 states. This strain was found to be developing resistance to 2 fluoroquinolones fre?quently used in hospitals?gatifloxacin (Tequin) and moxifloxacin (Avelox).

Future therapies may spare the anaerobic flora, the disruption of which by current antibiotic therapy is responsible for the high rates of relapse observed in C difficile infection.

"Intuitively, clinicians have become aware that new treatments need to be more selective in killing or neutralizing the pathogen yet allow the normal microbiota to rebalance itself," said Dr Louie.

The use of metronidazole (Flagyl) with vancomycin (Vancocin) as a backup has been common practice to treat C difficile infections for the past quarter century. A total of 85% to 90% of patients respond to these therapies, but the relapse rate is 16% to 21% and is higher in the current outbreaks. Furthermore, fulminant disease has resulted in colectomies, clinical sepsis, and death.

Investigational Therapies

Suppression of the anaerobic flora is responsible for relapsing cases, which can last months or years. With vancomycin, high concentrations in the fecal biomass are thought to contribute to suppression of normal flora, accounting for relapsing disease, said Dr Louie.

His group has investigated 2 novel therapies that may overcome the problems with current antibiotic therapy. One is tolevamer (Genzyme), a novel nonabsorbed polystyrene binder/neutralizer of the C difficile cytotoxins A and B. By binding the toxins produced by C difficile but ignoring the organism itself, "you're taking the bullets out of the gun," he said.

A large double-blind (phase 2) trial of 287 patients compared 2 dosages of tolevamer given for 14 days with vancomycin, 125 mg/day for 10 days. Clinical response to the 6-g daily dose of tolevamer (83%) was noninferior to the response obtained with vancomycin (91%). The number of pa?tients in the trial was insufficient to determine if tolevamer was associated with a lower rate of relapsing disease.

Two phase 3 studies in which tolevamer is being given as a 9-g loading dose and then at a 9-g/day dose are under way. One trial is comparing it with vancomycin therapy and the other with metronidazole. The hope is that 1040 pa?tients can be re?cruited into the studies.

The macrocyclic antibiotic PAR-101 (Optimer/Par) also appears promising in the treatment of C difficile?associated diarrhea. This agent has shown activity against C difficile that is 8- to 10-fold greater than that of vancomycin. Furthermore, activity against most members of the normal intestinal flora is limited. "This drug both kills the bug and spares the anaerobic flora," said Dr Louie.

In dose-ranging studies, a full course of PAR-101 resulted in responses in 41 of 45 patients, with only 2 relapses, both ?ap?prox?imately 1 month after therapy. Com?plete relief of symptoms was achieved in 87% of patients receiving 400 mg/day.

In another study by Dr Louie, he confirmed that Bacteroides counts were reduced at baseline in these patients with C difficile diarrhea. Patients randomized to vancomycin had severely impaired Bac?teroides counts during therapy, and although most patients recovered their counts, a minority had prolonged absence of Bacteroides. In contrast, no significant reduction in Bacteroides?counts was ob?served with any dose of PAR-101 studied.

Use of intravenous gamma globulin therapy is also being investigated, based on limited clinical studies showing improved outcomes in patients who have relapsing disease and in fulminant colitis, as are neutralizing human monoclonal antibodies.

"While the precise role of each of these new modalities for the treatment of C difficile?associated diarrhea is to be determined, it is anticipated that both metronidazole and vancomycin could be superse?ded by new treatments that have comparable or higher response rates, lesser relap?se by virtue of greater selectivity for C difficile by allowing the normal flora to return, and lesser selection of antibiotic-resistant nosocomial pathogens," said Dr Louie.

PCR Test May Lead to Faster Diagnosis

Newer tests using real-time polymerase chain reaction (PCR) to detect toxins A and/or B directly from stool should ?shorten the time to diagnosis of C difficile, said Lance R. Peterson, MD, director of microbiology and infectious diseases research, Evanston Northwestern Health?care, Evanston, Ill.

Currently, diagnosis relies on recognizing clinical risk factors, such as health care contact, antibiotic exposure, and significant diarrhea. The en?zyme ?im?munoassays (EIAs) currently used lack sensitivity and specificity.

Dr Peterson's laboratory has developed a real-time PCR assay that can provide a diagnosis in 2 hours. In a com?parison with EIA and toxigenic culture in 619 stool samples, PCR was found to have a sensitivity of 94% and a specificity of 92%, whereas EIA was 62% sensitive and 92% specific.

New Virulent Strain

National surveys conducted over the past year and a half suggest that 30% to 40% of US infectious disease physicians have perceived increases in the incidence, severity, and likelihood of C difficile?associated diarrhea recurrence, said L. Clifford McDonald, MD, an epidemiologist at the Centers for Disease Con?trol and Prevention. One possible reason for this increase in incidence and disease severity could involve the ?emergence of the virulent strain he described in his report in the New England Journal of Medicine.

"Although this strain has been isolated infrequently from US patients over the past 20 years, it has recently [since 2000] appeared as a cause of major outbreaks," he said. "One reason for this may be the emergence of increased resistance to ?fluoroquinolones in this strain, possibly providing it a selective advantage over other strains. There is also evidence to suggest that this strain produces much greater quantities of both toxins A and B and that this strain produces these toxins earlier during log phase growth."

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