Medication Summary
Pharmacologic therapy should be tailored according to the severity of C difficile infection (CDI). Treatment is not indicated for asymptomatic carriers. In very mild cases (ie, patients without fever, abdominal pain, or leukocytosis), in patients who do not have other comorbidities, cessation of causative antibiotics may be the only treatment necessary.
Approximately 15-25% of patients respond to conservative therapy, which allows for the reconstitution of normal colonic flora and reduces the risk of relapse. Specific therapy aimed at eradicating C difficile is indicated if symptoms are persistent or if antibiotics cannot be discontinued safely.
Oral metronidazole and oral vancomycin have similar efficacy rates in treating diarrhea caused by C difficile in mild to moderate infection but not in severe disease. Whereas metronidazole is the recommended first-line treatment for mild to moderate disease without complications, vancomycin is recommended first-line therapy for severe infection or for patients with risk factors for adverse outcomes, such as advanced age, critical illness, overall debility, or inflammatory bowel disease (IBD). Vancomycin, rifaximin, and fidaxomicin are useful in recurrent or persistent cases.
The oral administration of these medications is the preferred route, because C difficile remains within the colonic lumen without invading the colonic mucosa. Vancomycin is poorly absorbed in the intestinal tract, thereby promoting high concentrations within the intestines while significantly reducing the prevalence of adverse systemic effects.
The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) recommend a regimen of metronidazole (500 mg PO TID for 10-14 days) as first-line therapy for mild to moderate disease without complications (lower cost and similar efficacy to PO vancomycin in these patients). [5] For patients who are unable to tolerate oral medication, intravenous metronidazole is effective.
A study by Louie et al compared vancomycin (125 mg PO QID) with fidaxomicin (200 mg PO BID). [80] The study showed that fidaxomicin therapy had a similar efficacy and resulted in a significantly lower rate of recurrence of CDI not associated with the epidemic North American Pulsed Field type 1 strains. Fidaxomicin was approved by the FDA in May 2011.
In another study, a review of 11 trials (1463 adult patients total) comparing metronidazole with vancomycin or another agent, combined agents, or placebo, neither vancomycin nor fidaxomicin were clearly superior for the initial treatment of CDI. One study in the review, however, showed CDI recurrence in only 15% of patients treated with fidaxomicin, compared with 25% of patients treated with vancomycin. [81]
As noted above, for severe cases, vancomycin (125 mg PO QID for 10 days) is the recommended first-line therapy. Higher dosing (250 mg PO [or per nasogastric tube] QID) may be used in situations such as ileus. Excretion of the drug into bile and exudation from the inflamed colon results in bactericidal levels in feces. Intravenous vancomycin is ineffective and should not be used for C difficile. The SHEA and IDSA recommend metronidazole (500 mg IV q8h) with vancomycin (500 mg PO QID and/or 500 mg PR q6h in 100 mL normal saline as a retention enema) for severe or complicated cases of CDI. [5]
In several clinical trials, 200 mg of oral fidaxomicin administered every 12 hours for 10 days has been noninferior to 125 mg of oral vancomycin administered every 6 hours for 10 days for the treatment of C difficile. [59] No difference in cure rates based on C difficile disease severity was reported. Symptomatic improvement is generally expected within 2-3 days. In January 2020, the FDA approved fidaxomicin for children aged 6 months or older with C difficile-associated diarrhea (CDAD). [60]
In a multicenter study including 1105 subjects with C difficile–associated diarrhea, 183 of whom had solid tumors or hematologic malignancies, fidaxomicin treatment was superior to vancomycin treatment in cancer patients, resulting in higher cure and sustained response rates for diarrhea, shorter time to resolution of diarrhea (TTROD), and fewer recurrences. [82, 83]
Cure rates for diarrhea in the study were lower overall in cancer patients (79.2%) than in others (88.6%). [83] Cure rates for noncancer patients were approximately the same with fidaxomicin (88.5%) as with vancomycin (88.7%); however, those for cancer patients were higher with fidaxomicin than with vancomycin (85.1% vs 74.0%), although the difference was not statistically significant. Median TTRODs in noncancer patients were 54 hours with fidaxomicin and 58 hours with vancomycin; those in cancer patients were 74 and 123 hours, respectively.
In the same study, the risk of recurrence was approximately twice as high with vancomycin as with fidaxomicin, regardless of whether the patients had cancer or not, but because cure and recurrence outcomes were better with fidaxomicin than with vancomycin in cancer patients, the relative odds of sustained response at 28 days in these patients were more than 2.5-fold higher for fidaxomicin than for vancomycin. [83]
Relapse
Relapse occurs in 20-27% of patients treated with metronidazole or vancomycin. Most recurrences occur 3 days to 3 weeks after discontinuing antibiotic treatment. Once a patient has one relapse, the risk for a second relapse is 45%.
Age greater than 65, severe underlying illnesses, and ongoing antibiotic treatments during C difficile therapy are all risk factors for recurrence. Recurrent infection tends to occur in patients who mount a poor host immune response to C difficile. Persistent disruption of the colonic microbial flora also confers an increased risk. Recurrent infection can result from reinfection with the same strain or a different strain of C difficile.
For the first relapse, the choice of antibiotic should be based on the severity of C difficile diarrhea/colitis. Mild symptoms of recurrence in patients who are otherwise well may be managed without further antibiotic therapy. Initial recurrence that is not severe can be treated with metronidazole. For subsequent recurrences, patients may benefit from vancomycin in a prolonged tapered and/or pulse regimen or fidaxomicin with or without probiotics. Rifaximin is also a potential option.
Bezlotoxumab is a human monoclonal antibody that binds to C difficile toxin B and neutralizes its effects. The FDA approved this agent for use with the standard of care antibiotics to reduce recurrence of CDI in adults who are at a high risk of recurrence. Approval was based on the results from the global MODIFY I and MODIFY II studies that showed a single dose of bezlotoxumab is superior to placebo in the prevention of CDI recurrence through 12 weeks (P = 0.0003 for both trials). [63]
Two products have been approved for fecal transplantation. The FDA approved rectal administration of microbiota for prevention of recurrent CDI. [6] The PUNCH CD3 phase 3 clinical trial reported successful treatment was 70.6% with microbiota versus 57.5% with placebo. More than 90% of the participants with successful treatment had sustained response through 6 months in both the microbiota and the placebo groups. [6] A second orally administered microbiota product (Vowst) received FDA approval in April 2023. Results from the ECOSPOR III phase 3 double-blind, randomized, placebo-controlled trial showed a decreased recurrence of C difficile infection in patients treated orally with microbiota compared with placebo (12% vs 40%, respectively; P< 0.001). [7]
Probiotics
Probiotics are not recommended as a single agent for the treatment of active CDI owing to limited data supporting their benefit and a potential risk for septicemia. [5] Use of Saccharomyces boulardii and Lactobacillus species have shown mixed results in reducing the risk of CDI relapse. However, S boulardii has generated interest for the treatment of CDI, because it seems to inhibit the effects of toxins A and B on the human colonic mucosa.
Potential therapies
Rifaximin after treatment with vancomycin may reduce the risk of relapse, but rifaximin is not yet FDA approved for this indication.
Nitazoxanide, a medication used to treat parasites, has been shown to be as effective as vancomycin in a clinical trial for the treatment of C difficile.
A review of 10 clinical trials evaluating the treatment of an initial episode of CDI showed that nitazoxanide and teicoplanin did not demonstrate inferiority relative to vancomycin and metronidazole. [84] However, other antimicrobials, including rifampin, and the toxin-binding polymer tolevamer, did show inferiority compared with vancomycin and metronidazole. [84]
Intravenous immunoglobulin (IVIG), which contains C difficile antitoxin, has been reported as an effective adjunctive treatment for refractory and severe cases of C difficile colitis/diarrhea. In some individuals, a poor host immune response to C difficile may be a risk factor for the lack of clearance of C difficile and may be the reason for the benefit of IVIG.
A review of the literature and a retrospective review of 21 of 1230 patients with CDI who received IVIG showed that conventional treatments were used for an average of 8 days before IVIG was administered. [85] All of the patients reviewed had radiologic pancolitis or clinical ileus. Following treatment with IVIG, 9 (43%) of the patients survived with resolution of their colitis, whereas 12 (57%) of the patients died. Patients who survived showed resolution of their symptoms after an average of 10 days (range, 2-20 d). [85]
Cholestyramine binds toxins A and B of C difficile, but the clinical experience of different investigators has shown marked variation in results. Cholestyramine binds vancomycin and should not be used concurrently with vancomycin therapy. Although not as effective as primary therapy for C difficile, the advantage of anion-binding resins is that they do not alter the colonic flora.
Other investigational therapies include the following:
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Tolevamer: A toxin-binding polymer with no antimicrobial properties
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The antibiotics ramoplanin and OPT-80 (poor intestinal absorption)
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C difficile vaccination
Antibiotics, Other
Class Summary
The purpose of treatment is to eradicate C difficile infection (CDI) and/or promote restoration of the normal colonic flora.
Metronidazole (Flagyl)
Metronidazole is recommended as the treatment of choice for mild to moderate cases of CDI. This agent provides effective therapy, with reported response rates from 95-100%. Its in vitro activity is bactericidal and dose dependent. Standard dosing has been shown to promote fecal concentrations capable of a 99.99% reduction of C difficile.
Metronidazole is relatively inexpensive. Intravenous (IV) metronidazole may be administered to those patients who cannot tolerate oral (PO) medications because of its potential to accumulate in the inflamed colon. However, the IV route is not as effective as the PO route.
Bacitracin
Bacitracin inhibits the formation of major components of the bacterial cell wall and is bactericidal. This agent is used as an alternative therapy for CDI, but it is expensive and not as effective as metronidazole or vancomycin in clinical trials and is thus without sufficient data to warrant its use. Bacitracin is bitter and must be specially prepared in capsule form to prevent nausea. This agent is administered PO, and it is only negligibly absorbed from the gastrointestinal (GI) tract.
Glycopeptides
Class Summary
Oral vancomycin does not get absorbed and acts directly at the site of infection.
Vancomycin (Firvanq, Vancocin)
Vancomycin has excellent in vitro activity against C difficile. This agent kills the organism by inhibiting cell wall synthesis. Significant luminal levels after administration of PO vancomycin can be obtained because the drug is poorly absorbed from the GI tract. Its major disadvantage, however, is that it is relatively expensive.
Because of the cost and the concern over the emergence of vancomycin-resistant enterococci strains, this agent should be reserved for patients who cannot tolerate or do not respond to metronidazole, pregnant patients, and patients younger than 10 years.
Vancomycin is also preferred for severe cases and in patients who are high risk. Unlike IV metronidazole, IV vancomycin is not excreted into the GI lumen; therefore, it is difficult to deliver effective IV doses. Available orally as capsules or oral solution.
Macrolides
Class Summary
Fidaxomicin has a narrower antimicrobial spectrum and alters the gut microflora less compared with metronidazole and vancomycin.
Fidaxomicin (Dificid)
Fidaxomicin is a macrolide antibiotic indicated for C difficile–associated diarrhea in adults and children aged 6 months or older. This agent is bactericidal against C difficile in vitro and demonstrates a postantibiotic effect vs C difficile of 6-10 h. It inhibits RNA synthesis by binding to RNA polymerases.
Monoclonal Antibodies
Class Summary
Human monoclonal antibodies that bind to C difficile toxins may be considered with standard-of-care antibiotics to prevent recurrent infection.
Bezlotoxumab (Zinplava)
Bezlotoxumab is a human monoclonal antibody that binds to C difficile toxin B, thereby neutralizing its effects. It is administered as a single IV infusion in conjunction with standard-of-care antibiotics to reduce recurrence of C difficile infection (CDI) in patients aged 1 year and older who are at a high risk for recurrence.
Bile Acid Sequestrants
Class Summary
Bile acid sequestrants bind C difficile toxin and other proteins. Although not as effective as primary therapy for C difficile, the advantage of bile acid sequestrant therapy is that it does not alter the gut microflora.
Cholestyramine (Questran)
Cholestyramine is used to treat diarrhea associated with pseudomembranous colitis. This agent forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits the enterohepatic reuptake of intestinal bile salts.
Note that cholestyramine binds vancomycin, which precludes combination therapy. This agent is available as a powder that must be mixed with water prior to ingestion. The efficacy of cholestyramine is inferior to that of metronidazole or vancomycin, but the drug may have a role under certain circumstances (eg, in patients who continue to relapse). This agent is not absorbed from the GI tract.
Fecal Microbiota Transplantation
Class Summary
Microbiota-based live biotherapeutic provides a broad consortium of diverse microbes to the gut to reduce recurrent C difficile infection after antibiotic treatment.
Microbiota rectal (Rebyota)
Microbiota rectal product is indicated for prevention of recurrence of Clostridioides difficile infection (CDI) in adults, following antibiotic treatment for recurrent CD.
Microbiota oral (Vowst)
Orally administered microbiota is indicated to prevent C difficile recurrence in adults.
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Clostridioides (Clostridium) Difficile Colitis. Endoscopic visualization of pseudomembranous colitis, a characteristic manifestation of full-blown <i>C difficile</i> colitis. Classic pseudomembranes are visible as raised, yellow plaques ranging from 2 to 10 mm in diameter and scattered over the colorectal mucosa. Courtesy of Gregory Ginsberg, MD, University of Pennsylvania.
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Clostridioides (Clostridium) Difficile Colitis. Colonic pseudomembranes of pseudomembranous colitis. Photographs courtesy of Eric M Osgard, MD.
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Clostridioides (Clostridium) Difficile Colitis. Gross pathology specimen from a case of pseudomembranous colitis revealing the characteristic yellowish plaques.
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Clostridioides (Clostridium) Difficile Colitis. Gross pathology specimen from a case of pseudomembranous colitis, again demonstrating the characteristic yellowish plaques.
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Clostridioides (Clostridium) Difficile Colitis. Frontal abdominal radiograph in a patient with proven pseudomembranous colitis. Note the nodular haustral thickening, most pronounced in the transverse colon.
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Clostridioides (Clostridium) Difficile Colitis. Barium enema demonstrating the typical serrated appearance of the barium column (resulting from trapped barium between the edematous mucosal folds and the plaquelike membranes of pseudomembranous colitis).
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Clostridioides (Clostridium) Difficile Colitis. Axial computed tomography scan of pseudomembranous colitis.
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Clostridioides (Clostridium) Difficile Colitis. Computed tomography scan depicting pseudomembranous colitis.
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Clostridioides (Clostridium) Difficile Colitis. Ultrasonographic image of pseudomembranous colitis.
