Consider Newer Therapies to Treat New Strain of C. difficile

STOWE, VT. — Although Clostridium difficile-associated diarrhea is now more severe and more drug resistant than before, because of the evolution of a recently identified and more robust strain, a variety of new agents are in the pipeline.

And in some patients, several current treatments can effectively eliminate the organism, according to Dr. Samuel Pegram, who spoke at an emergency medicine update sponsored by the University of Vermont.

C. difficile, first identified in 1935, has evolved from a fairly benign bacterium to a multidrug-resistant pathogen that is responsible for an increasing portion of pediatric and adult cases of severe diarrhea, known as C. difficile-associated diarrhea or disease (CDAD), said Dr. Pegram, professor of medicine at Wake Forest University, Winston-Salem, N.C.

Currently, the pathogen is present in up to 30% of patients who have antibody-associated diarrhea, he said, and up to 65% of patients with antibody-associated colitis test positive for the bacterium. He cited a recent study that found that among children presenting to an emergency department with diarrhea, 47% had a bacterial pathogen, and nearly 7% were infected with C. difficile (Clin. Infect. Dis. 2006;43:807–13).

Moreover, a new strain is responsible for greater symptom severity and is resistant to many traditional therapies. This strain is known by various names, including BI, NAP1, ribotype 027, and toxinotype II, depending on what type of analysis is used to identify it in a particular laboratory. This new variant produces 16 times the amount of toxin A as prior strains and 23 times the amount of toxin B as toxinotype 0 strains, said Dr. Pegram, who is also the director of the Infectious Diseases Specialty Clinic at the university. In addition, the new subtype shows resistance to fluoroquinolones, including ciprofloxacin.

Several new treatments are in the developmental pipeline, however. They include tolevamer, a nonantibiotic toxin-binding polymer expected go on the market this year, and the antibiotic ramoplanin (Oscient Pharmaceuticals), which is in phase III trials, as is the novel macrocycle OPT-80 (Optimer Pharmaceuticals). An antibiotic called Rifalazil (ActivBiotics Inc.) is in phase II development, along with a monoclonal antibody to toxin A and B (Medarex Inc.). In addition, a toxoid vaccine is in phase I development (Acambis).

Yet the mainstream therapies for infection are still viable in many patients, though they have various abilities to overcome recurrence and come with a wide range of treatment costs, Dr. Pegram noted.

The least expensive treatment, at $18 for a 10-day course, is generic metronidazole 500 mg orally three times daily, he said, although a brand formulation also exists (Flagyl, Pfizer Inc.), costing $147 for the same treatment duration. Vancomycin (Vancocin, Viropharma Inc.), for which no generic exists, costs $611 for 10 days. Dr. Pegram estimated recurrence rates to be 20%–25% with metronidazole or vancomycin. Toxin-binding resins currently available include cholestyramine and colestipol.

Other weapons in the physician's arsenal are the oral antibiotic rifaximin (Xifaxan, Salix Pharmaceuticals), approved for E. coli-associated traveler's diarrhea in patients at least 12 years old, and nitazoxanide (Alinia, Romark Laboratories), approved for treatment of diarrhea caused by Giardia lamblia orCryptosporidium parvum.

Probiotic agents including yogurt, yeast, and oral lactobacillus may also be effective, he noted. Brands of lactobacillus include Lactinex (Becton Dickinson) and Culturelle (Kirkman). Yeast products include Saccharomyces boulardii and Florastor (Biocodex Inc.), which he said can be given in a dosage of two 250-mg capsules daily for 4–6 weeks.

In addition to pharmacologic and probiotic therapy, there remains the option of fecal transplantation to replenish the decimated gut flora, Dr. Pegram said. This can be done by collecting 30–50 g of fresh stool from a healthy donor and delivering it in a saline vehicle via either an enema or a nasogastric tube. Despite the perhaps unsettling nature of this treatment, “it certainly has worked,” Dr. Pegram said, although it carries a risk of transmitting other pathogens to the recipient. Thus, this option “is less desirable,” he said.

Intravenous immunoglobulin is also an option, he said. “Half the people sitting in this audience will have detectable antitoxin to toxins A and B,” said Dr. Pegram. Thus “pooled intravenous immune globulin might work. You give it as a one-time dose—a large dose and very expensive—400 mg/kg. And it's actually proven to be a very valuable asset when adding on therapy to the very sick patient.”

He noted that research is underway to develop a “hyper-immune globulin” by using plasmapheresis to cull these antibodies from persons with high antibody levels.

Dr. Pegram also noted that the Centers for Disease Control and Prevention has outlined steps that health care providers can take to prevent the spread of C. difficile. Perhaps most surprising is the admonition to use soap and water instead of alcohol-based sanitizers—which, he pointed out, can kill other hardy bacteria, such as methicillin-resistant Staphylococcus aureus, but not C. difficile.

A polymerase chain reaction test for detection of C. difficile toxin will likely be introduced this year, Dr. Pegram said.

STOWE, VT. — Although Clostridium difficile-associated diarrhea is now more severe and more drug resistant than before, because of the evolution of a recently identified and more robust strain, a variety of new agents are in the pipeline.

And in some patients, several current treatments can effectively eliminate the organism, according to Dr. Samuel Pegram, who spoke at an emergency medicine update sponsored by the University of Vermont.

C. difficile, first identified in 1935, has evolved from a fairly benign bacterium to a multidrug-resistant pathogen that is responsible for an increasing portion of pediatric and adult cases of severe diarrhea, known as C. difficile-associated diarrhea or disease (CDAD), said Dr. Pegram, professor of medicine at Wake Forest University, Winston-Salem, N.C.

Currently, the pathogen is present in up to 30% of patients who have antibody-associated diarrhea, he said, and up to 65% of patients with antibody-associated colitis test positive for the bacterium. He cited a recent study that found that among children presenting to an emergency department with diarrhea, 47% had a bacterial pathogen, and nearly 7% were infected with C. difficile (Clin. Infect. Dis. 2006;43:807–13).

Moreover, a new strain is responsible for greater symptom severity and is resistant to many traditional therapies. This strain is known by various names, including BI, NAP1, ribotype 027, and toxinotype II, depending on what type of analysis is used to identify it in a particular laboratory. This new variant produces 16 times the amount of toxin A as prior strains and 23 times the amount of toxin B as toxinotype 0 strains, said Dr. Pegram, who is also the director of the Infectious Diseases Specialty Clinic at the university. In addition, the new subtype shows resistance to fluoroquinolones, including ciprofloxacin.

Several new treatments are in the developmental pipeline, however. They include tolevamer, a nonantibiotic toxin-binding polymer expected go on the market this year, and the antibiotic ramoplanin (Oscient Pharmaceuticals), which is in phase III trials, as is the novel macrocycle OPT-80 (Optimer Pharmaceuticals). An antibiotic called Rifalazil (ActivBiotics Inc.) is in phase II development, along with a monoclonal antibody to toxin A and B (Medarex Inc.). In addition, a toxoid vaccine is in phase I development (Acambis).

Yet the mainstream therapies for infection are still viable in many patients, though they have various abilities to overcome recurrence and come with a wide range of treatment costs, Dr. Pegram noted.

The least expensive treatment, at $18 for a 10-day course, is generic metronidazole 500 mg orally three times daily, he said, although a brand formulation also exists (Flagyl, Pfizer Inc.), costing $147 for the same treatment duration. Vancomycin (Vancocin, Viropharma Inc.), for which no generic exists, costs $611 for 10 days. Dr. Pegram estimated recurrence rates to be 20%–25% with metronidazole or vancomycin. Toxin-binding resins currently available include cholestyramine and colestipol.

Other weapons in the physician's arsenal are the oral antibiotic rifaximin (Xifaxan, Salix Pharmaceuticals), approved for E. coli-associated traveler's diarrhea in patients at least 12 years old, and nitazoxanide (Alinia, Romark Laboratories), approved for treatment of diarrhea caused by Giardia lamblia orCryptosporidium parvum.

Probiotic agents including yogurt, yeast, and oral lactobacillus may also be effective, he noted. Brands of lactobacillus include Lactinex (Becton Dickinson) and Culturelle (Kirkman). Yeast products include Saccharomyces boulardii and Florastor (Biocodex Inc.), which he said can be given in a dosage of two 250-mg capsules daily for 4–6 weeks.

In addition to pharmacologic and probiotic therapy, there remains the option of fecal transplantation to replenish the decimated gut flora, Dr. Pegram said. This can be done by collecting 30–50 g of fresh stool from a healthy donor and delivering it in a saline vehicle via either an enema or a nasogastric tube. Despite the perhaps unsettling nature of this treatment, “it certainly has worked,” Dr. Pegram said, although it carries a risk of transmitting other pathogens to the recipient. Thus, this option “is less desirable,” he said.

Intravenous immunoglobulin is also an option, he said. “Half the people sitting in this audience will have detectable antitoxin to toxins A and B,” said Dr. Pegram. Thus “pooled intravenous immune globulin might work. You give it as a one-time dose—a large dose and very expensive—400 mg/kg. And it's actually proven to be a very valuable asset when adding on therapy to the very sick patient.”

He noted that research is underway to develop a “hyper-immune globulin” by using plasmapheresis to cull these antibodies from persons with high antibody levels.

Dr. Pegram also noted that the Centers for Disease Control and Prevention has outlined steps that health care providers can take to prevent the spread of C. difficile. Perhaps most surprising is the admonition to use soap and water instead of alcohol-based sanitizers—which, he pointed out, can kill other hardy bacteria, such as methicillin-resistant Staphylococcus aureus, but not C. difficile.

A polymerase chain reaction test for detection of C. difficile toxin will likely be introduced this year, Dr. Pegram said.

STOWE, VT. — Although Clostridium difficile-associated diarrhea is now more severe and more drug resistant than before, because of the evolution of a recently identified and more robust strain, a variety of new agents are in the pipeline.

And in some patients, several current treatments can effectively eliminate the organism, according to Dr. Samuel Pegram, who spoke at an emergency medicine update sponsored by the University of Vermont.

C. difficile, first identified in 1935, has evolved from a fairly benign bacterium to a multidrug-resistant pathogen that is responsible for an increasing portion of pediatric and adult cases of severe diarrhea, known as C. difficile-associated diarrhea or disease (CDAD), said Dr. Pegram, professor of medicine at Wake Forest University, Winston-Salem, N.C.

Currently, the pathogen is present in up to 30% of patients who have antibody-associated diarrhea, he said, and up to 65% of patients with antibody-associated colitis test positive for the bacterium. He cited a recent study that found that among children presenting to an emergency department with diarrhea, 47% had a bacterial pathogen, and nearly 7% were infected with C. difficile (Clin. Infect. Dis. 2006;43:807–13).

Moreover, a new strain is responsible for greater symptom severity and is resistant to many traditional therapies. This strain is known by various names, including BI, NAP1, ribotype 027, and toxinotype II, depending on what type of analysis is used to identify it in a particular laboratory. This new variant produces 16 times the amount of toxin A as prior strains and 23 times the amount of toxin B as toxinotype 0 strains, said Dr. Pegram, who is also the director of the Infectious Diseases Specialty Clinic at the university. In addition, the new subtype shows resistance to fluoroquinolones, including ciprofloxacin.

Several new treatments are in the developmental pipeline, however. They include tolevamer, a nonantibiotic toxin-binding polymer expected go on the market this year, and the antibiotic ramoplanin (Oscient Pharmaceuticals), which is in phase III trials, as is the novel macrocycle OPT-80 (Optimer Pharmaceuticals). An antibiotic called Rifalazil (ActivBiotics Inc.) is in phase II development, along with a monoclonal antibody to toxin A and B (Medarex Inc.). In addition, a toxoid vaccine is in phase I development (Acambis).

Yet the mainstream therapies for infection are still viable in many patients, though they have various abilities to overcome recurrence and come with a wide range of treatment costs, Dr. Pegram noted.

The least expensive treatment, at $18 for a 10-day course, is generic metronidazole 500 mg orally three times daily, he said, although a brand formulation also exists (Flagyl, Pfizer Inc.), costing $147 for the same treatment duration. Vancomycin (Vancocin, Viropharma Inc.), for which no generic exists, costs $611 for 10 days. Dr. Pegram estimated recurrence rates to be 20%–25% with metronidazole or vancomycin. Toxin-binding resins currently available include cholestyramine and colestipol.

Other weapons in the physician's arsenal are the oral antibiotic rifaximin (Xifaxan, Salix Pharmaceuticals), approved for E. coli-associated traveler's diarrhea in patients at least 12 years old, and nitazoxanide (Alinia, Romark Laboratories), approved for treatment of diarrhea caused by Giardia lamblia orCryptosporidium parvum.

Probiotic agents including yogurt, yeast, and oral lactobacillus may also be effective, he noted. Brands of lactobacillus include Lactinex (Becton Dickinson) and Culturelle (Kirkman). Yeast products include Saccharomyces boulardii and Florastor (Biocodex Inc.), which he said can be given in a dosage of two 250-mg capsules daily for 4–6 weeks.

In addition to pharmacologic and probiotic therapy, there remains the option of fecal transplantation to replenish the decimated gut flora, Dr. Pegram said. This can be done by collecting 30–50 g of fresh stool from a healthy donor and delivering it in a saline vehicle via either an enema or a nasogastric tube. Despite the perhaps unsettling nature of this treatment, “it certainly has worked,” Dr. Pegram said, although it carries a risk of transmitting other pathogens to the recipient. Thus, this option “is less desirable,” he said.

Intravenous immunoglobulin is also an option, he said. “Half the people sitting in this audience will have detectable antitoxin to toxins A and B,” said Dr. Pegram. Thus “pooled intravenous immune globulin might work. You give it as a one-time dose—a large dose and very expensive—400 mg/kg. And it's actually proven to be a very valuable asset when adding on therapy to the very sick patient.”

He noted that research is underway to develop a “hyper-immune globulin” by using plasmapheresis to cull these antibodies from persons with high antibody levels.

Dr. Pegram also noted that the Centers for Disease Control and Prevention has outlined steps that health care providers can take to prevent the spread of C. difficile. Perhaps most surprising is the admonition to use soap and water instead of alcohol-based sanitizers—which, he pointed out, can kill other hardy bacteria, such as methicillin-resistant Staphylococcus aureus, but not C. difficile.

A polymerase chain reaction test for detection of C. difficile toxin will likely be introduced this year, Dr. Pegram said.