Higher Dose for Severe C. diff Speeds Response

SAN FRANCISCO – Two small studies suggest that treating severe Clostridium difficile infection with a higher initial dose of vancomycin may work better than the recommended dose of 125 mg every six hours.

The most recent study, presented in a poster at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, surprised the investigators.

"Pharmacodynamically, the concentrations in stool of the standard dose of 125 mg are about 500-1,000 times greater than the MIC [minimum inhibitory concentration]," Yleana T. Garcia, Pharm.D., said in an interview. "So, we have enough concentration in the stool. We wanted to see that we have similar outcomes with patients who are treated with standard doses as with higher doses."

CDC/D. Holdeman

Instead, the retrospective review of 62 patients with severe diarrhea who received oral vancomycin for at least 3 days found that symptoms resolved significantly quicker in 19 patients who got 250 mg every 6 hours compared with 43 patients who got 125 mg every 6 hours, she and her associates reported.

Symptoms resolved by day 3 in nine patients (47%) on the high dose and six patients (15%) on the conventional dose, said Dr. Garcia, a palliative care fellow at the James J. Peters Veterans Affairs Medical Center, Bronx, N.Y.

There also were statistically nonsignificant trends toward a higher likelihood of clinical cure, shorter length of stay, and reduced risk of recurrence in patients with the higher dose. An increased death rate in the higher-dose group also was not statistically significant, and might be due to greater severity of illness at baseline in patients who got the higher dose of vancomycin, she said at the meeting, sponsored by the American Society for Microbiology.

The findings support those of a small prospective study that analyzed levels of vancomycin in feces collected from 15 patients with presumed or confirmed C. difficile infection. Drug concentrations were high in patients who got 250 or 500 mg q.i.d. but were inadequate in at least one patient on the first day of treatment with 125 mg q.i.d. (BMC Infect. Dis. 2010;10:363).

"Higher doses like 250-500 mg may be warranted to reach adequate concentrations in the stool in the first 24-48 hours," Dr. Garcia said. "I’m not saying to use 250 for the whole treatment course, but there may be a role for a loading dose of 250 mg q6 for the first 24-48 hours, and then switching to 125 mg q6 for the remainder of the treatment course. We know that 125 does have adequate fecal concentration; it just may not be adequate on day 1."

The 2010 update to clinical practice guidelines for C. difficile infection in adults recommends treating severe C. difficile infection with oral vancomycin 125 mg every 6 hours or using 500 mg every 6 hours for patients with severe disease complicated by ileus, megacolon, or hypotension (Infect. Control Hosp. Epidemiol. 2010;31:431-55).

Severe C. difficile infection generally is defined as the presence of the organism plus leukocytosis with a white blood cell count of 15,000 cells/microL or greater, or a serum creatinine level at least 1.5 times baseline. The study reviewed records of patients who received vancomycin for these indications or hypotension, shock, ileus, megacolon, or evidence of colitis. The study excluded patients who were treated with any other medication besides metronidazole.

The study is continuing in order to increase the number of patients reviewed and the power of the findings.

Dr. Garcia reported having no financial disclosures.

SAN FRANCISCO – Two small studies suggest that treating severe Clostridium difficile infection with a higher initial dose of vancomycin may work better than the recommended dose of 125 mg every six hours.

The most recent study, presented in a poster at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, surprised the investigators.

"Pharmacodynamically, the concentrations in stool of the standard dose of 125 mg are about 500-1,000 times greater than the MIC [minimum inhibitory concentration]," Yleana T. Garcia, Pharm.D., said in an interview. "So, we have enough concentration in the stool. We wanted to see that we have similar outcomes with patients who are treated with standard doses as with higher doses."

CDC/D. Holdeman

Instead, the retrospective review of 62 patients with severe diarrhea who received oral vancomycin for at least 3 days found that symptoms resolved significantly quicker in 19 patients who got 250 mg every 6 hours compared with 43 patients who got 125 mg every 6 hours, she and her associates reported.

Symptoms resolved by day 3 in nine patients (47%) on the high dose and six patients (15%) on the conventional dose, said Dr. Garcia, a palliative care fellow at the James J. Peters Veterans Affairs Medical Center, Bronx, N.Y.

There also were statistically nonsignificant trends toward a higher likelihood of clinical cure, shorter length of stay, and reduced risk of recurrence in patients with the higher dose. An increased death rate in the higher-dose group also was not statistically significant, and might be due to greater severity of illness at baseline in patients who got the higher dose of vancomycin, she said at the meeting, sponsored by the American Society for Microbiology.

The findings support those of a small prospective study that analyzed levels of vancomycin in feces collected from 15 patients with presumed or confirmed C. difficile infection. Drug concentrations were high in patients who got 250 or 500 mg q.i.d. but were inadequate in at least one patient on the first day of treatment with 125 mg q.i.d. (BMC Infect. Dis. 2010;10:363).

"Higher doses like 250-500 mg may be warranted to reach adequate concentrations in the stool in the first 24-48 hours," Dr. Garcia said. "I’m not saying to use 250 for the whole treatment course, but there may be a role for a loading dose of 250 mg q6 for the first 24-48 hours, and then switching to 125 mg q6 for the remainder of the treatment course. We know that 125 does have adequate fecal concentration; it just may not be adequate on day 1."

The 2010 update to clinical practice guidelines for C. difficile infection in adults recommends treating severe C. difficile infection with oral vancomycin 125 mg every 6 hours or using 500 mg every 6 hours for patients with severe disease complicated by ileus, megacolon, or hypotension (Infect. Control Hosp. Epidemiol. 2010;31:431-55).

Severe C. difficile infection generally is defined as the presence of the organism plus leukocytosis with a white blood cell count of 15,000 cells/microL or greater, or a serum creatinine level at least 1.5 times baseline. The study reviewed records of patients who received vancomycin for these indications or hypotension, shock, ileus, megacolon, or evidence of colitis. The study excluded patients who were treated with any other medication besides metronidazole.

The study is continuing in order to increase the number of patients reviewed and the power of the findings.

Dr. Garcia reported having no financial disclosures.

SAN FRANCISCO – Two small studies suggest that treating severe Clostridium difficile infection with a higher initial dose of vancomycin may work better than the recommended dose of 125 mg every six hours.

The most recent study, presented in a poster at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, surprised the investigators.

"Pharmacodynamically, the concentrations in stool of the standard dose of 125 mg are about 500-1,000 times greater than the MIC [minimum inhibitory concentration]," Yleana T. Garcia, Pharm.D., said in an interview. "So, we have enough concentration in the stool. We wanted to see that we have similar outcomes with patients who are treated with standard doses as with higher doses."

CDC/D. Holdeman

Instead, the retrospective review of 62 patients with severe diarrhea who received oral vancomycin for at least 3 days found that symptoms resolved significantly quicker in 19 patients who got 250 mg every 6 hours compared with 43 patients who got 125 mg every 6 hours, she and her associates reported.

Symptoms resolved by day 3 in nine patients (47%) on the high dose and six patients (15%) on the conventional dose, said Dr. Garcia, a palliative care fellow at the James J. Peters Veterans Affairs Medical Center, Bronx, N.Y.

There also were statistically nonsignificant trends toward a higher likelihood of clinical cure, shorter length of stay, and reduced risk of recurrence in patients with the higher dose. An increased death rate in the higher-dose group also was not statistically significant, and might be due to greater severity of illness at baseline in patients who got the higher dose of vancomycin, she said at the meeting, sponsored by the American Society for Microbiology.

The findings support those of a small prospective study that analyzed levels of vancomycin in feces collected from 15 patients with presumed or confirmed C. difficile infection. Drug concentrations were high in patients who got 250 or 500 mg q.i.d. but were inadequate in at least one patient on the first day of treatment with 125 mg q.i.d. (BMC Infect. Dis. 2010;10:363).

"Higher doses like 250-500 mg may be warranted to reach adequate concentrations in the stool in the first 24-48 hours," Dr. Garcia said. "I’m not saying to use 250 for the whole treatment course, but there may be a role for a loading dose of 250 mg q6 for the first 24-48 hours, and then switching to 125 mg q6 for the remainder of the treatment course. We know that 125 does have adequate fecal concentration; it just may not be adequate on day 1."

The 2010 update to clinical practice guidelines for C. difficile infection in adults recommends treating severe C. difficile infection with oral vancomycin 125 mg every 6 hours or using 500 mg every 6 hours for patients with severe disease complicated by ileus, megacolon, or hypotension (Infect. Control Hosp. Epidemiol. 2010;31:431-55).

Severe C. difficile infection generally is defined as the presence of the organism plus leukocytosis with a white blood cell count of 15,000 cells/microL or greater, or a serum creatinine level at least 1.5 times baseline. The study reviewed records of patients who received vancomycin for these indications or hypotension, shock, ileus, megacolon, or evidence of colitis. The study excluded patients who were treated with any other medication besides metronidazole.

The study is continuing in order to increase the number of patients reviewed and the power of the findings.

Dr. Garcia reported having no financial disclosures.