TREATMENT Clostridium difficile Infection PRIMARY CDI
When possible, discontinuation of any ongoing antimicrobial administration is recommended as the first step in treatment of CDI. Earlier studies indicated that 15–23% of patients respond to this simple measure. However, with the advent of the current epidemic strain and the associated rapid clinical deterioration of some patients, prompt initiation of specific CDI treatment has become the standard. Empirical treatment is appropriate if CDI is strongly suspected on clinical grounds. General treatment guidelines include hydration and the avoidance of antiperistaltic agents and opiates, which may mask symptoms and possibly worsen disease. Nevertheless, antiperistaltic agents have been used safely with vancomycin or metronidazole for mild to moderate CDI.
Oral administration of vancomycin, fidaxomicin, or metronidazole is recommended for CDI treatment. IV vancomycin is ineffective for CDI, and fidaxomicin is available only for oral administration; when IV metronidazole is administered, fecal bactericidal drug concentrations are achieved during acute diarrhea; however, in the presence of adynamic ileus, IV metronidazole treatment of CDI has failed. Two large clinical trials comparing vancomycin and fidaxomicin indicated comparable resolution of diarrhea (~90% of patients) as well as significantly reduced rates of recurrent CDI with fidaxomicin from rates with vancomycin. In previous randomized trials, diarrhea response rates to oral therapy with vancomycin or metronidazole were ≥94%, but four observational studies found that response rates for metronidazole had declined to 62–78%. Although the mean time to resolution of diarrhea is 2–4 days, the response to metronidazole may be much slower. Treatment should not be deemed a failure until a drug has been given for at least 6 days. On the basis of data for shorter courses of vancomycin and the results of two large-scale clinical trials, it is recommended that vancomycin, fidaxomicin, and metronidazole be given for at least 10 days. Metronidazole is not approved for CDI by the U.S. Food and Drug Administration (FDA), but most patients with mild to moderate illness respond to 500 mg given by mouth three times a day for 10 days; extension of the treatment period may be needed for slow responders. In addition to the reports of increases in metronidazole failures, a prospective, randomized, double-blind, placebo-controlled study has demonstrated the superiority of vancomycin over metronidazole for treatment of severe CDI. The severity assessment score in that study included age as well as laboratory parameters (elevated temperature, low albumin level, or elevated WBC count), documentation of PMC by endoscopy, and treatment of CDI in the intensive care unit. Although a validated severity score is not available, it is important to initiate treatment with oral vancomycin for patients who appear seriously ill, particularly if they have a high WBC count (>15,000/μL) or a creatinine level that is ≥1.5 times higher than the premorbid value (Table 31-2). In addition, a randomized blinded trial compared a toxin-binding polymer, tolevamer, with two antibiotic regimens for treatment of CDI and showed that vancomycin was superior to metronidazole for all patients regardless of severity. Small randomized trials of nitazoxanide, bacitracin, rifaximin, and fusidic acid for treatment of CDI have been conducted. These drugs have not been extensively studied, shown to be superior, or approved by the FDA for CDI, but they provide potential alternatives to vancomycin, fidaxomicin, and metronidazole. RECURRENT CDI
Overall, ~15–30% of successfully treated patients experience recurrences of CDI, either as relapses caused by the original organism or as reinfections following treatment. Rates of CDI recurrence are significantly lower among patients treated with fidaxomicin rather than vancomycin. Rates of recurrence are comparable with vancomycin and metronidazole. Recurrence rates are higher among patients ≥65 years old, those who continue to take antibiotics while being treated for CDI, and those who remain in the hospital after the initial episode of CDI. Patients who have a first recurrence of CDI have a high rate of second recurrence (33–65%). In the first recurrence, re-treatment with metronidazole is comparable to treatment with vancomycin (Table 31-2), and fidaxomicin is superior to vancomycin in reducing the risk of further recurrences in patients who have had one recurrence. Recurrent CDI, once thought to be relatively mild, has now been documented to pose a significant (11%) risk of serious complications (shock, megacolon, perforation, colectomy, or death within 30 days). There is no standard treatment for multiple recurrences, but long or repeated metronidazole courses should be avoided because of potential neurotoxicity. The use of vancomycin in tapering doses or with pulse dosing every other day for 2–8 weeks may be the most practical approach to treatment of patients with multiple recurrences. Other approaches include the administration of vancomycin followed by the yeast Saccharomyces boulardii; the administration of vancomycin followed by a fecal microbiota transplant given via nasoduodenal tube, colonoscope, or enema; and the intentional colonization of the patient with a nontoxigenic strain of C. difficile. None of these biotherapeutic approaches has been approved by the FDA for use in the United States. Other non-FDA-approved antibiotic strategies include (1) sequential treatment with vancomycin (125 mg four times daily for 10–14 days) followed by rifaximin (400 mg twice daily for 14 days) and (2) treatment with nitazoxanide (500 mg twice daily for 7 days). IV immunoglobulin, which has also been used with variable success, presumably provides antibodies to C. difficile toxins. SEVERE COMPLICATED OR FULMINANT CDI
Fulminant (rapidly progressive and severe) CDI presents the most difficult treatment challenge. Patients with fulminant disease often do not have diarrhea, and their illness mimics an acute surgical abdomen. Sepsis (hypotension, fever, tachycardia, leukocytosis) may result from severe CDI. An acute abdomen (with or without toxic megacolon) may include signs of obstruction, ileus, colon-wall thickening and ascites on abdominal CT, and peripheral-blood leukocytosis (≥20,000 WBCs/μL). With or without diarrhea, the differential diagnosis of an acute abdomen, sepsis, or toxic megacolon should include CDI if the patient has received antibiotics in the past 2 months. Cautious sigmoidoscopy or colonoscopy to visualize PMC and abdominal CT are the best diagnostic tests in patients without diarrhea.
Medical management of fulminant CDI is suboptimal because of the difficulty of delivering oral fidaxomicin, metronidazole, or vancomycin to the colon in the presence of ileus (Table 31-2). The combination of vancomycin (given via nasogastric tube and by retention enema) plus IV metronidazole has been used with some success in uncontrolled studies, as has IV tigecycline in small-scale uncontrolled studies. Surgical colectomy may be life-saving if there is no response to medical management. If possible, colectomy should be performed before the serum lactate level reaches 5 mmol/L. The incidence of fulminant CDI requiring colectomy appears to be increasing in the evolving epidemic; however, morbidity and death associated with colectomy may be reduced by performing instead a laparoscopic ileostomy followed by colon lavage with polyethylene glycol and vancomycin infusion into the colon via the ileostomy.