Managing Clostridium difficile Infection on the Verge of the Postantibiotic Era

Clostridium difficile infection (CDI) is one of the most common nosocomial infections and a frequent cause of morbidity and mortality among elderly persons residing in long-term care facilities. Treatment for CDI is complex because infection is often caused and resolved by antibiotics. Over the past few years, there has been nationwide reporting of greater frequency and severity of CDI due to the emergence of so-called hypervirulent strains. In 2013, the Centers for Disease Control and Prevention (CDC) described the imminent threat of a postantibiotic era, a time in which certain infectious diseases will become unresponsive to antibiotic treatment. In its report, the CDC attributed more than 250,000 cases of CDI and 14,000 deaths from CDI to antibiotic use and resistance.¹

The medical community is rising up to meet this challenge by investigating the use of novel therapies for CDI and developing protocols for prudent prescribing of antibiotics. To gain insight on the complex, multifaceted treatment of CDI in the long-term care setting, Annals of Long-Term Care: Clinical Care and Aging^® (ALTC) spoke with Teena Chopra, MD, MPH, and Amar Krishna, MD. Chopra is an assistant professor of medicine, division of infectious diseases, Wayne State University, and director, Infection Prevention, Epidemiology, and Antibiotic Stewardship, Kindred Hospital and University Health Center, Detroit, MI. Krishna is an internal medicine physician, UPMC McKeesport Hospital, McKeesport, PA. The responses below represent their collective answers.

ALTC: Please start by explaining the urgency of C difficile associated with the emergence of the hypervirulent strains of C difficile, now collectively referred to as NAP1/BI/027. What makes these strains uniquely challenging in how they are detected and treated?

Between the years of 2003 and 2006, CDI was noted to be more frequent, severe, refractory to therapy, and more likely to relapse. This was mainly seen in North America and Europe and was attributed to a new strain of C difficile, designated BI, NAP1, or ribotype O27. These designations are based on different methods of strain typing; pulsed-field gel electrophoresis (NAP1), restriction endonuclease analysis (BI), and polymerase chain reaction (027).     

The NAP1 strain was noted to be distinct from other C difficile strains in producing larger quantities of toxin A and B and noted to be resistant to fluoroquinolones in vitro. NAP1/BI/O27 was also noted to be more severe, associated with low cure rates, high recurrence rates, and higher mortality rates.Treatment of CDI due to NAP1/BI/O27 strains is similar to CDI caused by other strains. Although there is some data indicating superiority of vancomycin over metronidazole for CDI caused by NAP1/BI/O27 strain, current guidelines recommend no change in therapy based on the virulence of the strain.²

What’s the first step for treating patients with suspected CDI?

An important initial step in managing CDI is stopping the inciting antibiotics as soon as possible, whenever feasible. It is also important that patients with suspected CDI be placed on contact precautions, and that healthcare workers and visitors wash their hands, ideally with soap and water, before and after contact with patients.

Therapy for suspected CDI can be started empirically if clinical suspicion is high, pending the results of diagnostic testing. Patients with typical manifestations of CDI, including diarrhea, abdominal pain, nausea, vomiting, and a positive diagnostic assay, should receive antibiotics for treatment of CDI. Initial therapy for CDI depends on severity of CDI. Mild CDI is treated with metronidazole. In patients with severe C difficile, current guidelines recommend using oral vancomycin because it is associated with significantly higher cure rates than therapy with metronidazole.

Fidaxomicin can be given as an alternative to vancomycin especially when there is higher risk of recurrence.³ A recent study suggests that healthcare providers use a model for recurrence prediction.⁴ According to this study, there are four independent risk factors for determining whether to use fidaxomicin over vancomycin to treat recurrent CDI: 75 years of age or older, 10 or more episodes of loose stools during the previous 24 hours, serum creatinine level at or above 1.2 mg/dL, and if there was a previous episode of CDI.⁴ However, further studies need to be done to validate this prediction model.

How should providers distinguish between severe versus non-severe CDI?  

There is no consensus definition for severe CDI. The current recommendations are based on expert opinion. Various studies consider the following factors to be markers of severe infection: 10 or more bowel movements per day, age older than 60 years, temperature less than 38.3ºC, serum albumin less than 2.5 mg/dL, elevated leucocyte count (>15,000 cell/ųL vs >20,000 cells/ųL), creatinine level greater than 1.5 times the premorbid level, and severe abdominal pain. However, the current Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (IDSA) guidelines recommend the following as markers of severe CDI: leukocytosis with a white blood cell count of 15,000 cells/mL or higher or a serum creatinine level equal to or greater than 1.5 times the premorbid level. Presence of shock, hypotension, toxic megacolon, or ileus are considered markers of complicated, severe C difficile.

How does treatment differ for severe versus non-severe CDI?

The recommended therapy for a non-severe episode of CDI is oral metronidazole given at a dosage of 500 mg three times daily or 250 mg four times daily for 10 to 14 days. Intravenous metronidazole at a dosage of 500 mg every 8 hours can be used in patients who cannot tolerate oral therapy. Oral vancomycin is the preferred antibiotic for patients with severe CDI at a dosage of 125 mg four times a day for 10 to 14 days. This recommendation is based on data from randomized trials that show vancomycin is associated with higher cure rates when compared with metronidazole in patients with severe CDI. In severely ill patients with ileus, where passage of oral antibiotics from stomach to colon is delayed, adding intravenous metronidazole to oral vancomycin can be considered, as studies have shown similar fecal concentrations of metronidazole with oral and intravenous administration. Fidaxomicin (200 mg orally twice daily) might be another option for patients with severe CDI.⁵

When does route of administration become an important consideration in treating CDI with antibiotics?

Routinely, metronidazole and/or vancomycin for treatment of CDI are usually given orally. When patients are unable to tolerate antibiotics orally or when patients have ileus secondary to CDI and the antibiotic passage to the colon is delayed, then other routes of administration need to be considered.

Metronidazole can be given intravenously or orally. Studies have shown similar fecal concentrations when metronidazole is administered intravenously or orally. Vancomycin can be given orally or can be given via colonic administration. Oral vancomycin is not absorbed through the gastrointestinal tract and it achieves high levels in the colon. The dosage of vancomycin during intracolonic administration is not established; the current recommendation is to give 500 mg in 100 mL of normal saline every 6 hours. Intracolonic vancomycin carries risk of colonic perforation and therefore should be administered by personnel trained in administering enemas. Intravenous vancomycin is not recommended since vancomycin is not excreted into the colon.

How is recurrent CDI defined?

Recurrent CDI is defined by the presence of diarrhea (ie, passage of three or more unformed stools in 24 or fewer consecutive hours) and a stool test result positive for the presence of toxigenic C difficile or its toxins within more than 2 weeks and 8 weeks or fewer of the initial positive test result.⁶ It also requires complete abatement of symptoms following therapy for the initial episode followed by subsequent reappearance of diarrhea or other symptoms after treatment has been stopped. Recurrence can be due to reinfection from a different strain or relapse from the same strain. Fifty percent of the recurrences are due to reinfection from a different strain. Recurrences usually occur 1 to 3 weeks after discontinuing antibiotic therapy.

How is refractory CDI defined?

There is no consensus on definition of refractory CDI. One randomized study comparing the efficacy of oral vancomycin and metronidazole for mild and severe CDI defined refractory CDI as persistence of diarrhea and/or a positive result of a C difficile toxin A assay despite antibiotic therapy for 6 days, need for colectomy, or death after 5 days of therapy.⁷ As per guidelines from the American College of Gastroenterology, refractory CDI is defined as mild to moderate CDI not responding to 1 week of monotherapy with metronidazole.⁸ They recommend switching over to vancomycin in these cases.

There is growing evidence for the use of probiotics in preventing and treating CDI-associated diarrhea. Can you briefly explain the mechanism of action of probiotics and their potential role in treating CDI?

Probiotics are nonpathogenic bacteria or fungi that are capable of colonizing the colonic mucosa. Patients with C difficile have markedly diminished bacterial diversity in the colon when compared with controls. Probiotics colonize the gut temporarily, producing bacterial acids and peptides, and promote competition among microbes by competing for nutrients and epithelial adhesion, reducing favorability of the environment for C difficile. Acids produced by these bacteria lower the pH of the local gut environment, inhibiting the growth of other bacteria. They also afford intestinal barrier protection, which may be capable of interfering with binding of C difficile toxins A and B to intestinal epithelial cells. Other proposed mechanisms of action include modulation of the innate and adaptive immune systems, upregulating cytokine production, and enhancing phagocytic activity.

When the IDSA released its guidelines on CDI in 2010, there was not enough evidence to recommend the use of probiotics for primary prevention of CDI, although a randomized trial did show that ingestion of a specific brand of yogurt drink did reduce risk of CDI in patients who were on antibiotics.^9,10 However, the conclusion of this trial was based on a small number of highly selected patients who were not receiving high-risk antibiotics. They also did not find compelling evidence that probiotics are useful to prevent or treat recurrent CDI.

Since that trial, there have been two systematic reviews, and one multicenter randomized, double-blind placebo-controlled trial to evaluate the efficacy of probiotics for CDI. The randomized study identified no evidence that a multistrain preparation of Lactobacilli and Bifidobacteria was effective in preventing CDI.^11-13

While adding probiotics to prevent CDI, risks and benefits of therapy should be considered as there have been case reports of bacteremia and fungemia attributed to probiotic use in patients with significant comorbidities, on immunosuppressive medication, recent surgical intervention, or prolonged hospitalization.

What are some of the other therapies for CDI besides antibiotics?

Some of the non-antibiotic therapies for CDI include fecal bacteriotherapy (also called fecal microbiota transplantation), intravenous immunoglobulins, anion binding resins, and surgery. The use of artificially produced bacterial mixtures in place of fecal samples is under investigation.

What is the evidence, or general consensus, on using some of these non-antibiotic therapies for CDI in elderly persons?          

Fecal microbiota transplantation can be considered in elderly long-term care residents with recurrent or severe CDI that has failed antibiotic therapy; however, both donors and recipients should be screened for common viral and bacterial organisms and parasites before transplantation. In a recent systematic review and meta-analysis that identified 11 studies with a total of 273 CDI patients treated with fecal microbiota transplantation, 8 of these studies reported a mean or median patient age over 65 years; the authors of the review concluded that fecal microbiota transplantation is a promising therapy for recurrent CDI, but that well-designed randomized controlled trials and long-term follow-up registries are needed to determine patient selection, efficacy, and safety before widespread advocacy can occur.¹⁴ One randomized trial on fecal bacteriotherapy, which showed infusion of donor feces to be more effective for treatment of recurrent C difficile than the use of vancomycin, mainly involved elderly patients.¹⁵

Although many popular diets advise high fiber for good digestive health, currently there are no data recommending a high-fiber diet for prevention or treatment of CDI. Additionally, providers should be careful of high-fiber diets in elderly persons, as an excessive intake (more than 50-60 g per day) may worsen intestinal discomfort and interfere with the body’s ability to properly absorb vitamins and minerals.¹⁶

The efficacy of the other therapies needs further study. Intravenous immunoglobulins for treating relapsing or severe C difficile has mainly been demonstrated in case reports. Anion-binding resins, such as cholestyramine and colestipol, have treated some patients with CDI and has been shown to be efficacious as adjuvant therapy with antibiotics in patients with frequent relapses, but further studies are warranted to assess optimal indications.¹⁷

What does the literature say about the two surgical interventions for managing CDI: subtotal colectomy and diverting loop ileostomy with colonic lavage? Who is considered candidate for either of these two surgical interventions?

The optimal timing of surgery remains uncertain. Most favor early surgery since delay increases perioperative mortality. Indications for surgery in patients with CDI include severe ileus, toxic megacolon, colon perforation or impending perforation, necrotizing colitis, or septic shock with multiorgan failure.

With the emergence of hypervirulent strains, there is rapid progression to death within 48 hours of admission in the intensive care unit. In these patients, colectomy is most beneficial in patients older than 65 years of age with a white blood cell count of 20,000 cells per ųL or greater and/or a plasma lactate level between 19.8 and 44 mg/dL. One study showed that perioperative mortality of colectomy was 75% or above in CDI patients with lactate level of 45 mg/dL or greater.¹⁸

A study that compared patients who underwent loop ileostomy, intraoperative colonic lavage with polyethylene glycol solution followed by antegrade instillation of vancomycin, with historical patients who had underwent colectomy found that diverting loop ileostomy was associated with lower mortality.¹⁹ The mean age of these patients was around 60 years, and there was no significant difference between study groups, which indicates that diverting ileostomy might be better tolerated by elderly patients. More studies are required to validate the benefit of this procedure.

Are there any other points you would like to stress to healthcare professionals about CDI?

The changing epidemiology of CDI reflects the increasing incidence of the disease beyond acute healthcare settings. Given the higher number of older adults residing in long-term care facilities and the frequent interfacility transfers, infection prevention guidelines should be judiciously applied to all healthcare settings. This will not only help in decreasing the burden of primary CDI but also of recurrent CDI.

References

1. Centers for Disease Control and Prevention. Antibiotic Resistance in the United States, 2013. www.cdc.gov/drugresistance/threat-report-2013. Published 2013. Accessed July 22, 2014.
2. Al-Nassir WN, Sethi AK, Riggs MM, Bobulsky GS, Jump RLP, Donskey CJ. Comparison of clinical and microbiologic response to treatment of Clostridium difficile-associated disease with metronidazole and vancomycin. Clin Infect Dis. 2008;47(1):56-62.
3. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.
4. D'Agostino RB Sr, Collins SH, Pencina KM, Kean Y, Gorbach S. Risk estimation for recurrent Clostridium difficile infection based on clinical factors. Clin Infect Dis. 2014;58(10):1386-1393.
5. Cornely OA, Crook DW, Esposito R, el al; OPT-80-004 Clinical Study Group. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012;12(4):281-289.
6. Gould C, McDonald C. Clostridium difficile (CDI) infections toolkit. www.cdc.gov/hai/pdfs/toolkits/CDItoolkit2-29-12.pdf. Accessed July 11, 2014.
7. Zar FA, Bakkanagari SR, Moorthi, KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45(3):302-307.
8. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478-498.
9. Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;335(7610):80.
10. Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455.
11. Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157(12):878-888.
12. Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013;5:CD006095.
13. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 382(9900):1249-1257.
14. Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(4):500-508.
15. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415.
16. Bersamin A, Hathaway C, Zidenberg-Cherr S. Nutrition and health info-sheet: some facts about fiber. Davis, CA: University of California, 2004. Accessed July 22, 2014.
17. Poutanen SM, Simor AE. Treating C. difficile. CMAJ. 2005;172(4):448-448a.
18. Pepin J, Vo T T, Boutros M. et al. Risk factors for mortality following emergency colectomy for fulminant Clostridium difficile infection. Dis Colon Rectum. 2009;52(3):400-405.
19. Neal MD, Alverdy JC, Hall DE, Simmons RL, Zuckerbraun BS. Diverting loop ileostomy and colonic lavage: an alterntaive to total abdominal colectomy for the treatment of severe, complicated Clostridium difficile associated disease. Ann Surg. 2011;254(3):423-427.