Best Strategies in Recurrent or Persistent Clostridium difficile Infection

Abstract

Background:

Clostridium difficile infection (CDI) is the primary cause of antibiotic-associated colitis and 15–25% of nosocomial antibiotic-associated diarrhea. Its clinical manifestations can range from mild diarrhea to toxic megacolon, bowel perforation, septic shock, and death. Over the past decade, more virulent strains have become increasingly common causes, and the incidence of CDI has risen, especially in elderly patients. These developments have led to an increase in recurrent CDI, which is more difficult to treat. This review focuses on recurrent CDI and its treatment.

Methods:

MEDLINE review using search terms Clostridium difficile, Clostridium difficile infection, recurrent Clostridium difficile infection.

Results:

A first recurrence may be treated with the same regimen as the first episode. Metronidazole 500 mg q 8 h for 10–14 days is the drug of choice for moderate infection, and vancomycin 125 mg q 6 h for 10–14 days is the drug of choice for severe CDI. Metronidazole should not be used for treatment of subsequent recurrences because of potential neurotoxicity and hepatic toxicity. Second recurrences should be treated with an oral vancomycin course and taper: 125 mg q 6 h × 10–14 days, 125 mg q 12 h × 7 days, 125 mg q 24 h × 7 days, 125 mg q 48–72 h × 2–8 weeks. Alternative agents are fecal bacteriotherapy, a “rifaximin chaser,” nitazoxanide, probiotics, and intravenous immunoglobulin. Fidaxomicin has been approved recently. Monoclonal antibodies against C. difficile toxin remain investigational.

Conclusion:

Treatment of recurrent CDI remains challenging. Because of the lack of high-quality studies, recommendations for treatment are based on expert opinion. Metronidazole and vancomycin are the mainstays of treatment for both the initial infection and the first recurrence. For second recurrences, a vancomycin course plus taper is recommended. For subsequent recurrences, treatment options are many, with no one approach being entirely satisfactory. New drugs (fidaximicin) and treatments (monoclonal antibodies against the causative toxin) appear promising.

C lostridium difficile is a gram-positive, spore-forming, toxin-producing bacillus that was first described as a component of intestinal flora in healthy newborn infants in 1935 [1]. It was not until 1977 that it was identified as the causative agent of pseudomembranous colitis shortly after clindamycin was introduced [2]. Clostridium difficile infection (CDI) is the primary cause of antibiotic-associated colitis and 15%–25% of nosocomial antibiotic-associated diarrhea [3]. Its incidence is increasing. Clostridium difficile is transmitted via the fecal–oral route through contact with a contaminated environment or hands of healthcare workers.

The clinical manifestations of CDI can range from mild or substantial diarrhea accompanied by abdominal pain and systemic symptoms; to life-threatening pseudomembranous colitis, toxic megacolon, bowel perforation, and septic shock, resulting in death. Infection occurs through the ingestion of spores, which resist stomach acidity and pass into the small intestine, where they germinate into a vegetative form. When exposure to antibiotics or chemotherapeutic agents disrupts the commensal colon flora, C. difficile flourishes. Disease results from its production of toxins.

Before 2000, more than $1.1 billion was spent per year in the U.S. for CDI treatment. There was an average of $3,600 excess cost per case of CDI, and patients spent an average of 3.6 additional days in the hospital [4]. The disease had a low attributable mortality rate. However, from 2000 to 2003, CDI increased dramatically, from 0.27% to 0.51% of all hospital discharges [5]. The incidence of severe disease also increased. For example, Pittsburgh saw an increase in the rate of life-threatening CDI from 1.6% to 3.2% [2], and in 2004, Québec reported a 30-day attributable mortality rate of 6.9% and a 12-mo attributable mortality rate of 16.7% [6]. Overall, there was a jump in the number of deaths from 5.7 per million in 1999 to 23.7 per million in 2004 [7]. The increase in both incidence and severity was a result of the appearance of several highly virulent strains. The most prevalent is B1/NAP1/027, which is characterized by greater toxin production. Infection with this strain results in severe diarrhea and a higher mortality rate, and many isolates are fluoroquinolone-resistant [8].

Approximately 20% of patients develop recurrent CDI after a first episode; however, the incidence of recurrent disease increases after the appearance of a hypervirulent strain. The Québec strain had a 33% recurrence rate, and 11% of these patients had severe CDI [9]. Recurrence after a second episode was even more common at 45% [10]. Of 93 patients with recurrent CDI, 61% had a single recurrence, 27% had two recurrences, and 12% had three or more [11].

Recurrent CDI is attributable either to relapse, in which there is endogenous persistence of the same strain of C. difficile, or to reinfection, in which there is acquisition of a new strain from an exogenous source. The mean time to relapse is 14.5 days, whereas the mean time to reinfection is 42.5 days [12]. Recurrent CDI can be attributed to a new strain anywhere from 33%–75% of the time [11 –14].

Twenty to fifty percent of hospitalized patients may be colonized with C. difficile [15 –17]. Colonization correlates with the length of the hospital stay [18]. Broad-spectrum antimicrobial agents that have a propensity for killing colonic bacteria create the greatest risk. Clindamycin, cephalosporins, and fluoroquinolones are the most frequently implicated, as well as chemotherapeutic agents [19]. Proton pump inhibitors are being recognized increasingly as risk factors for CDI [20 –22].

Advanced age is one of the greatest risk factors for recurrent CDI [23]. Disruption of the normal colonic flora and decreased colonization resistance appears to place patients at risk. Organisms of the phyla Bacteroides (mostly commensal anaerobic bacteria) and Firmicutes (a widely diverse group of gram-positive organisms that includes Clostridium) predominate in the normal colon. Patients with only an initial episode of CDI and control patients have a predominance of Bacteroides and Firmicutes, whereas patients who develop recurrent CDI have significantly less diversity [24]. Because anaerobic bacteria are believed to be the most important determinant of colonization resistance, the use of metronidazole and vancomycin may precipitate recurrent CDI. An inadequate immune response may play a role also. Patients with relapsing disease had lower concentrations of toxin A-specific immunoglobulin (Ig) G [25]. Asymptomatic carriers of C. difficile had an anamnestic response with high concentrations of toxin A-specific IgG, which increased rapidly after colonization [26]. Patients with a single episode of CDI had higher concentrations of IgM antibodies to toxin A on day three and of IgA antibodies on day 12 than did patients with recurrent CDI [26]. Independent predictors of recurrent CDI are age >65 years, acquisition of CDI during the hospital stay, a long hospital stay, and a lower quality-of-life score [27,28]. In a meta-analysis of 12 studies, Garey et al. found that in addition to older age, continued use of non-C. difficile-specific antibiotics after diagnosis of CDI and concomitant receipt of antacid medication were independent predictors of recurrent CDI [29].

Recommendations to reduce CDI outbreaks, and thus recurrent CDI, include restriction of antimicrobial use, reducing exposure to C. difficile, interrupting C. difficile transmission by using contact isolation and good handwashing techniques, and early identification of recurrence with use of appropriate treatments [30].

Therapeutic Approach

Metronidazole is the first-line treatment of CDI. It can be administered orally, parenterally, or rectally. Its concentration is significantly greater in diarrhea (9.3 mcg/g) than in formed stool (1.2 mcg/g) [31]. Recurrent CDI does not appear to be a result of resistance. There have been only rare reports of resistance and in other reports only after prolonged exposure [31,32]. Vancomycin is the only agent with a U.S. Food and Drug Administration (FDA) indication for CDI. Its use decreased after the 1995 recommendation by the U.S. Centers for Disease Control and Prevention that vancomycin use be reduced to decrease the selection pressure for vancomycin-resistant Enterococcus [34]. In order to reach the colon, the drug must be given orally. In patients with ileus, delivery to the colon is precluded, a problem that can be circumvented by rectal administration. Because it is not absorbed, vancomycin has minimal systemic side effects. It also is the first line of therapy in pregnant patients with CDI and in children younger than ten years of age.

The risk of recurrent CDI is similar with either metronidazole or vancomycin. Metronidazole is associated with a 14%–27% recurrence rate and vancomycin a 7%–23% recurrence rate [35,36].

The initial treatment of CDI depends on the severity of presentation. For patients with only mild symptoms, the inciting antibiotic should be stopped; the patient should then be given supportive hydration and be monitored. No antibiotics are required in otherwise healthy adults. In fact, there is faster elimination of spores in carriers not given antibiotics. For patients with moderate symptoms or co-morbidities, treatment is similar to that for mild symptoms with the addition of C. difficile-specific antibiotic therapy: Metronidazole 500 mg orally (PO) or parenterally q 8 h for 10–14 days. In more than 90% of patients, symptoms resolve within 1 week. Vancomycin, 125 mg PO q 6 h for 10–14 days, may be given instead if the patient is intolerant of or allergic to metronidazole.

In severe CDI, vancomycin is the drug of choice; however, the dose is increased to 500 mg po q 6 h when severe CDI is complicated by shock, ileus, or megacolon. If the patient has ileus, vancomycin 500 mg in physiologic saline 100 mL is given q 6 h as a retention enema. Metronidazole may also be added as 500 mg intravenously (IV) q 8 h [37].

In some patients, colectomy is indicated. The procedure usually is performed in patients with toxic megacolon, perforation, an acute abdomen, or, increasingly, septic shock. For patients with a serum lactate concentration >5 mmol/L and a white blood cell count 50,000/mm³, the post-operative mortality rate has been reported to exceed 75%, suggesting that colectomy should have been considered earlier [38]. For patients with severe, complicated CDI who are over the age of 64 years, immunocompromised, a white blood cell count >20,000/mm³ and a serum lactate concentration 2.2–4.9 mmol/L, colectomy should be considered.

A first recurrence of CDI usually is treated with the same regimen as the initial episode, taking disease severity into consideration. However, a second recurrence should not be treated with metronidazole because of its potential neurotoxicity with prolonged use. The drug can cause peripheral neuropathy, characterized by numbness and paresthesias of the extremities [39].

Although there are no data from randomized, controlled trials supporting any particular strategy for the treatment of multiple recurrent CDI, vancomycin treatment with taper dosing is the most widely used (Fig. 1). The efficacy of this treatment regimen was described by McFarland et al. after retrospectively analyzing data from two placebo-controlled trials of Saccharomyces boulardii in combination with either metronidazole or vancomycin [10]. A vancomycin taper regimen keeps C. difficile vegetative forms in check while allowing restoration of normal flora. A taper regimen alone had a 31% recurrence rate, and the addition of pulsed doses dropped the recurrence to 14.3%. Shorter courses of pulsed doses resulted in a higher recurrence rate.

FIG. 1.

Suggested approach to recurrent Clostridium difficile infection.

Because there are no well-defined strategies for the treatment of multiple recurrent CDI, other options have been sought. Currently available agents include rifaximin, which is a poorly absorbed rifamycin derivative. When this drug was given orally as a “rifaximin chaser” in an uncontrolled clinical trial, seven of eight patients with four to eight prior CDI episodes were treated successfully, whereas the eighth patient required a second course of rifaximin [40]. Rifaximin is given as 400 mg q 12 h for 14 days after completion of the vancomycin treatment but before recurrence of symptoms. Resistance to rifaximin may be a limiting factor in its use, particularly against the more virulent B1/NAP1/027 strain [41,42].

Nitazoxanide is another alternative agent that interferes with the anaerobic metabolism of protozoa and bacteria. It is usually used to treat cryptosporidiosis and Giardia infection. Given as 500 mg PO q 12 h for 10 days, it was non-inferior to metronidazole in CDI and may be as effective as vancomycin [43 –45].

Fidaxomicin is a promising macrocyclic antibiotic that is active against gram-positive aerobic and anaerobic bacteria, especially C. difficile. It has poor activity against gram-negative obligate anaerobes, allowing it to preserve the normal colonic flora. In Phase II trials, it was well tolerated with rapid symptom control and a clinical cure rate of 91% with only a 5% recurrence rate at 1 mo [46]. In Phase III trials, fidaxomicin 200 mg q 12 h had a higher global cure rate than vancomycin (p = 0.006) and a recurrence rate less than that of vancomycin (p = 0.004)[47]. Fidaxomicin was approved recently by the FDA.

Toxin binders have been proposed as adjuncts in the treatment of CDI. Anion-exchange resins such as cholestyramine are to be avoided, as they have some affinity for vancomycin and limited clinical efficacy. Tolevamer, a novel non-antibiotic toxin binder, was inferior to vancomycin and metronidazole for treatment of CDI, but the recurrence rate was lower in those who responded [36].

Another approach to the treatment of recurrent CDI is through the restoration of the colonic ecosystem. Various bacteria are able to suppress C. difficile growth through competition for nutrients, lowered pH, and production of inhibitory metabolites. Prebiotics are non-digestible food ingredients that stimulate growth and activity of beneficial bacteria in the colon selectively. They have the advantage of not being foreign organisms. A pilot study from the United Kingdom found that oligofructose increased fecal Bifidobacteria concentrations, but it did not reduce the frequency of antibiotic-associated diarrhea and CDI [48]. Probiotics such as Saccharomyces boulardii or Lactobacillus spp. are beneficial micro-organisms that modulate mucosal and systemic immunity and contribute to the microbial equilibrium. They are being proposed as adjuncts to the antibiotic treatment of CDI. McFarland reviewed various formulations of probiotics and summarized their efficacy in the treatment of CDI [49]. A meta-analysis of six randomized controlled trials of different probiotics showed that in general, probiotics significantly helped in preventing recurrences of CDI [49]. In a study using antibiotics with Saccharomyces boulardii for primary CDI, patients receiving S. boulardii had a lower relative risk of recurrent CDI [50]. The use of probiotics does pose the risk of fungemia (S. boulardii) or bacteremia (Lactobacillus) in immunocompromised patients.

Fecal bacteriotherapy restores colon homeostasis by reintroducing normal bacterial flora harvested from stool from a healthy donor or cultures. It is a low-technology procedure that can be performed in most hospitals. It breaks the cycle of repeated antimicrobial use. It prevents the emergence of resistant strains of C. difficile, avoids the possibility of allergic reactions, and reduces drug-related treatment costs. Cure rates in small case series range from 94%–100% [51 –53]. Although promising, the data remain sparse, and the safety of the method, especially the risk of pathogen transmission, remains unclear.

Immunotherapy has been tried as an adjunct. A C. difficile vaccine has been tested in patients with recurrent CDI. A toxoid preparation for both toxins A and B was given to three patients while they were receiving vancomycin. None of the three had recurrent CDI, and two formed neutralizing serum antibodies [54].

Because asymptomatic carriers of C. difficile have serum IgG antitoxin A concentrations three-fold higher than those in patients with CDI, and because patients with high IgG antitoxin A titers during an initial episode of CDI are 48 times less likely to develop recurrent CDI, passive immunization with intravenous immunoglobulin has been suggested for those patients in whom other options are not effective. A recent Phase II study of human monoclonal antibodies to toxins A and B, given as a single infusion to patients receiving either metronidazole or vancomycin, was associated with an overall recurrence rate of 7% vs. 25% in the control group. The rate of recurrent CDI decreased from 38% to 7% with addition of the monoclonal antibody [55].

Treatment of recurrent CDI remains challenging. Metronidazole and vancomycin are the mainstays of treatment for both the initial infection and the first recurrence. For second recurrences, vancomycin course plus taper is recommended. For subsequent recurrences, the treatment options are many, with no one treatment being satisfactory. Fecal bacteriotherapy is gaining adherents. New drugs (fidaximicin) and treatments (monoclonal antibodies to toxin) appear promising.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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