New recommendations for the treatment of C. difficile infections

Infections with Clostridium difficile are unfortunately common in cancer patients, leading to substantial morbidity and increased health care costs. Recently, new treatment guidelines were published by the Infectious Diseases Society of American and the Society for Healthcare Epidemiology of American.

C. difficile infections (CDI) have been increasing in frequency and severity for the past several years due to both increased numbers of patients at risk, as well as increased nosocomial transmission. In addition, the emergence of the hyper-virulent strain NAP1/BI/027 has increased the burden of this disease.

Presentation is that of watery diarrhea, up to 10 to 15 times per day; although, symptoms can range from an asymptomatic carrier state to ileus, toxic megacolon and bowel perforation. Other symptoms can include leukocytosis, fever, and abdominal pain and cramping. Patients may also experience dehydration and electrolyte abnormalities, hypotension, renal failure and sepsis.

Lisa Lohr

CDIs occur when gastrointestinal colonization occurs after alteration of the normal gut flora. Asymptomatic carriers serve as reservoir for nosocomial acquisition from fecal-oral transmission. It is estimated that up to 20% of patients in acute care hospitals and up to 50% of elderly patients in long-term care are carriers of C. difficile. The incubation period is thought to be about 2 to 3 days after exposure.

Diagnosis of CDI requires the demonstration of a toxin-positive stool sample in the context of watery diarrhea (or colonoscopy findings), but initiation of treatment usually precedes the diagnostic confirmation. Unfortunately, about 25% of patients experience recurrent symptoms, which are usually a relapse of the initial infection.

Risk factors

The greatest risk factor for CDI is antimicrobial therapy through the alteration of normal gastrointestinal flora. Although most antibiotics have been associated with CDI, it is reported in higher frequency after the administration of fluoroquinolones, broad spectrum penicillins and cephalosporins, and clindamycin.

In addition, a longer duration of antibiotics and exposure to multiple antibiotics increase the risk of CDI. Another significant risk factor is advanced age; the risk is three- to fourfold greater in patients older than 65 years.

Hospitalization and the duration of hospitalization increase the risk by increasing the duration of nosocomial exposure. Other risk factors include cancer chemotherapy, gastric acid suppression through administration of proton pump inhibitors, and manipulation or surgery of the gastrointestinal tract.

Treatment

Treatment of CDI should start with providing appropriate supportive care, including rehydration and correction of electrolyte abnormalities. If possible, offending antimicrobial agents should be stopped or switched to agents with a narrower spectrum. Antidiarrheal agents that slow peristalsis should be avoided, as they may lead to ileus and toxic megacolon.

Treatment of initial episodes of mild-to-moderate CDI should be started with oral metronidazole. The recommended dose is 500 mg by mouth three times a day for 10 to 14 days. The usual adverse effects include nausea, usual/metallic taste, and rarely neurotoxicity and central nervous system symptoms. Vancomycin has not been shown to be superior to metronidazole in mild-to-moderate cases. Therefore, metronidazole is the preferred agent for these cases to avoid the high cost of vancomycin and the potential selective pressure for vancomycin-resistant enterococci.

For severe cases of CDI, vancomycin has been shown to be superior in efficacy. The recommended dose of vancomycin is 125 mg by mouth four times a day for 10 to 14 days. Adverse effects include bitter taste, nausea and vomiting.

In severe, complicated cases of CDI or in the presence of ileus, additional measures must be taken to deliver medications to the site of infection. In these cases, vancomycin may be administered as a retention enema, in a dose of 500 mg in NS 100 mg every 6 hours. Metronidazole should be added, given IV in a dose of 500 mg IV every 8 hours. Metronidazole depends on enterohepatic circulation and biliary excretion and may take a few days to get adequate levels to the gut lumen.

Treatment of recurrent CDI

Unfortunately, about 25% of patients will experience a recurrence of CDI. The recommended treatment for the first recurrence episode is the same as for the first episode, adjusted for severity of disease. For the second or subsequent recurrences, metronidazole is not recommended, partly due to the potential for neurotoxicity with prolonged administration.

The recommended treatment for the second recurrence is oral vancomycin, followed by a tapering and pulsed fashion. This vancomycin regimen is given in the following steps: 125 mg by mouth four times a day × 10 to14 days, then 125 mg by mouth twice a day × 7 days, then 125 mg by mouth daily ×7 days, then 125 mg by mouth every 2 to 3 days for 2 to 8 weeks.

In one small study, good results were found in treating patients with multiply recurrent CDIs by administering rifaximin “chaser” therapy as 400 mg by mouth twice a day × 2 weeks after completion of vancomycin therapy. Rifaximin is an antimicrobial agent that has been used for the treatment of traveler’s diarrhea and hepatic encephalopathy.

CDIs cause great suffering and distress to patients, and appropriate therapy is necessary to minimize the morbidity and consequences of these infections. These new recommendations will help guide therapy choices for individual patients.

Lisa Lohr, PharmD, BCPS, BCOP, is clinical pharmacist in oncology and bone marrow transplantation the department of pharmacy services at the University of Minnesota Medical Center and is the HemOnc Today Pharmacology Section Editor.

For more information:

• Bauer MP. Curr Opin Infect Dis. 2009:22:517-524.
• Cohen SH. Infect Control Hosp Epidemiol. 2010;I.C.:10.1086/651706.