Clostridium Difficile, Cdiff

Table I.

High risk	Medium risk	Low risk
Clindamycin	Quinolones	aminoglycosides
2nd- and 3rd-generation cephalosporins	1s- generation cephalosporins	vancomycin
ampicillin, amoxicillin	penicillin	metronidazole
	carbapenems	bacitracin
	piperacillin, ticarcillin
	tetracyclines
	macrolides
	trimethoprim/sulfa

Other risk factors for development of Cdiff-associated disease include longer hospital stay, use of antineoplastic agents, severe underlying disease, infection at another site, bedridden status, renal failure, hematologic malignancy, transplantation, burns, gastrointestinal disease, use of drugs that alter gastrointestinal motility, use of proton pump inhibitors, gastrointestinal surgery, tube feeding, and use of medical devices.

The past several years have seen increased rates of Cdiff with more severe disease and increased mortality that have been attributed to the emergence of the hypervirulent, epidemic NAP1/027/BI strains. Higher relapse rates have also been associated with NAP1/027/BI strains. While mechanisms such as toxin production and more efficient sporulation have been proposed as reasons for the hypervirulence of NAP1/027/BI, this remains controversial.

The Cdiff bacteria produces two protein exotoxins, Toxin A and Toxin B. These appear to act synergistically to cause disease by killing cells and inciting proinflammatory processes. Some strains have only Toxin B. Others release a third toxin, the binary toxin, which has been associated with more severe disease and increased rates of recurrence. The proportion of binary toxin positive strains in cases of Cdiff infection has increased over the past few years, independent of increased prevalence of NAP1/027/BI strains. The roles of toxins C, D and E remain unclear.

Clinical features of the condition

Only 1/3 of adults colonized with Cdiff will develop symptoms. Symptoms can occur within one day or as long as 6 weeks after antibiotic exposure, and can result from as little as one dose. The usual time course is 4-9 days after antibiotics.

The diarrhea of Cdiff is often distinctly characteristic. It can be watery or mucoid, and is often greenish. It can contain blood.

For treatment purposes, Cdiff-associated diarrhea can be categorized as mild to moderate, severe, and severe complicated. Severe disease is characterized by a white blood cell count greater than 15,000 cells per microliter, or creatinine 1.5 times or greater above the premorbid level. Severe complicated disease includes hypotension or shock, ileus or megacolon.

Although colonoscopy is generally not indicated for the diagnosis of Cdiff, pseudomembranes seen on colonoscopy are highly suggestive of Cdiff infection.

Pseudomembranes appear as yellow or whitish plaques that may be scattered or confluent. The intervening colonic mucosa may appear relatively normal or edematous, erythematous and friable. The absence of pseudomembranes does not rule out the presence of Cdiff infection.

Particularly in critically ill patients, Cdiff may occur without diarrhea. This can occur because the patient has a pre-existing ileus or because ileus develops as a result of Cdiff, because of constipation distal to the colitis, or because of predominantly right-sided involvement of the infection. Cdiff should always be suspected in patients with marked leukocytosis and abdominal pain.

Severe disease can be associated with full-blown sepsis. With severe colitis, ileus and even toxic megacolon can ensue with intestinal perforation and death.

Key management points

1. Supportive care including hydration, hemodynamic support, pain control, and, if necessary, surgical intervention to remove the infected portion of the colon

2. Discontinue the inciting antibiotic

3. Appropriate anti-Clostridial therapy

4. Imaging in the sicker patient to assess the extent of the disease and evaluate for development of megacolon, and/or need for surgery

5. Contact precautions and strict hand hygiene to prevent the spread of Cdiff to other patients

2. Emergency Management

For the patient with severe complicated Cdiff (hypotension or shock, ileus or megacolon) or peritoneal signs, volume repletion and hemodynamic support are paramount, followed by immediate surgical consultation for consideration of colectomy.

3. Diagnosis

Diagnostic tests

Most laboratories do not have the capability to perform the gold standard test, which is tissue culture cytotoxic assay for Toxin B, but there are several other options for diagnostic testing. The Cdiff PCR test is about 92% sensitive and 94% specific. That the PCR test detects the toxin gene and does not detect toxin in the stool raises concerns about false positives in asymptomatic carriers. PCR is also limited in its ability to diagnose recurrent Cdiff infection since up to 56% of patients will be positive by PCR at 1-4 weeks after completing treatment.

Where more sensitive and specific tests are not available, a reasonable option is the cytotoxin enzyme immunoassay. The results are available within hours. The specificity is 92-98% but sensitivity is low, around 70%. This low sensitivity is what has led to the common practice of sending two or three samples to rule out Cdiff when it is suspected.

Detection of glutamate dehydrogenase (GDH), an antigen expressed by all Cdiff strains, is another available diagnostic test. Though there is considerable sensitivity, the specificity is low. GDH assays are not specific to toxigenic strains and require a second test to evaluate for toxin production.

A newer diagnostic tool is detection of the toxin gene by loop-mediated isothermal amplification (LAMP), which is cheaper and faster than PCR with similar sensitivity and specificity. Availability of this test is still limited, and it shares the same concerns as PCR testing.

Normal lab values

Patients with Cdiff infection will typically have leukocytosis. Very high white blood cell counts are often characteristic, and should make Cdiff come to mind even in the absence of diarrhea.

Establishing the diagnosis

The diagnosis of Cdiff can be relatively difficult to make, especially if the Cdiff toxin assay is negative but the clinical scenario is strongly suggestive.

Leukocytosis is common, often with band forms present. Cdiff should come to mind any time a patient has a very high white blood cell count. Fecal leukocytes are strongly suggestive of Cdiff in an ICU patient.

CT often shows thickened colonic mucosa, which can be right-sided, left-sided, or throughout the colon. When severe enough, these changes are visible on plain x-ray.

On endoscopy, mucosa can be normal or demonstrate minimal erythema, but when pseudomembranes are seen the diagnosis of Cdiff is strongly suggested. Endoscopy can be dangerous in patients with colonic dilatation and severe disease.

Differential diagnosis

Cdiff colitis can be difficult to distinguish from antibiotic-associated diarrhea. While both generally occur during or soon after administration of a course of antibiotics, antibiotic-associated diarrhea is not caused by any specific organism but rather is believed to be due to a change in short-chain fatty acid and carbohydrate metabolism as a result of the disruption of bowel flora.

Many drugs are known to cause diarrhea in the intensive care unit. Laxatives, acid blockers, mineral supplements, especially magnesium, oral contrast and others are common offenders. Tube feeds are also commonly given to critically ill patients and contribute to diarrhea.

There are no pathognomonic findings on history or physical examination in Cdiff, and even pseudomembranes seen on colonoscopy, while indicative of Cdiff in the vast majority of cases, can rarely be seen with other conditions such as early ischemia, E coli 0157:H7 and certain medications (gold, NSAIDS and chlorpropamide).

4. Specific Treatment

In 25% of patients with mild disease, infection resolves with discontinuation of the inciting antibiotic alone.

Patients with a positive toxin assay in the absence of symptoms should be considered “carriers” and do not require treatment.

In patients with more significant disease, empiric therapy begun before toxin assay results return can result in better outcomes.

Antiperistaltic drugs like loperamide or narcotics should be avoided since they predispose to toxic megacolon.

According to the Infectious Diseases Society of America guidelines, the first-line agent for the treatment of mild to moderate Cdiff is oral metronidazole.

Oral vancomycin should be used instead of metronidazole in cases of pregnancy, lactation, metronidazole intolerance, failure to respond to metronidazole after 3-5 days of treatment, and severe disease.

Severe disease is defined by the Infectious Diseases Society of America guidelines as white blood cell count of 15,000 cells/microliter or greater, or creatinine greater than or equal to 1.5 times the premorbid level. Severe complicated disease includes hypotension or shock, ileus or toxic megacolon. Severe complicated Cdiff warrants high-dose vancomycin by mouth or nasogastric tube, along with the addition of adjunctive intravenous metronidazole. If complete ileus is present, vancomycin should be given by rectal tube.

While many studies have shown comparable efficacy between oral metronidazole and oral vancomycin, recent reports strongly suggest an increased failure rate with metronidazole, which is poorly understood but not thought to be explained by resistance.

Despite its being in the guidelines and recommended by experts, oral vancomycin was never FDA approved for Cdiff, and in fact oral metronidazole is the only FDA-approved medication for Cdiff.

In 2011, fidaxomicin was approved for the treatment of Cdiff. In two large multicenter clinical trials fidaxomicin was found to be non-inferior to oral vancomycin for clinical response at the end of treatment, and superior to oral vancomycin for sustained clinical response at the end of the follow-up period. This difference in sustained clinical response was due to a lower Cdiff recurrence rate in the subjects who received fidaxomicin. A meta-analysis of these two trials as well as a number of subsequent studies in different patient populations had similar findings supporting the use of fidaxomicin.

Other antibiotics have been studied for Cdiff and some have shown promising data but none have met criteria for FDA approval or inclusion in national guidelines.

Patients with peritoneal signs, systemic toxicity, toxic megacolon, colonic perforation, multiorgan failure, or progression of symptoms despite adequate therapy should be considered for surgical intervention. Generally, total colectomy with end ileostomy is performed, although for select cases right hemicolectomy should suffice, so long as intra-operative colonoscopy confirms absence of disease in the left colon.

Drugs and dosages

Duration of therapy is generally 10 days, unless the patient remains on an antibiotic for another reason, in which case anti-Clostridial therapy should be continued for one week past the date of discontinuation of that antibiotic. Longer courses, pulsed or tapered courses are used for Cdiff that has recurred more than once.

— Metronidazole 500 mg enterally every 8 hours

— Vancomycin 125 mg enterally every 6 hours for severe disease or other indications as above

— Vancomycin 500 mg enterally every 6 hours for severe complicated disease

— Vancomycin rectal instillation, dose not well established, generally 500 mg in normal saline (reports range from 100 ml to 1000 ml total volume) instilled every 6 hours. Some clamp the rectal tube to allow a “dwell time”. Other reports describe the use of a rectal decompression tube and continuous perfusion of vancomycin up to a total dose of 2 g per day.

— Metronidazole 500 mg IV every 8 hours added to enteral vancomycin in severe disease and/or in the presence of ileus or toxic megacolon

— Fidaxomicin 200 mg enterally every 12 hours

Refractory cases

Patients who do not respond to oral metronidazole in the first 4-5 days should be switched to oral vancomycin.

A major difficulty in treating Cdiff is the frequency with which it recurs. Experts recommend that the first relapse be treated with an additional 10-day course of oral metronidazole. The second relapse should be treated with oral vancomycin. For patients with more than two relapses, a number of approaches can be tried, including long courses of oral metronidazole or oral vancomycin, addition of oral rifampin to oral vancomycin, pulsed or tapered vancomycin regimens, and fidaxomicin. Metronidazole should never be used long term because of the risk of cumulative neurotoxicity.

A number of probiotic strains have been shown to be effective in decreasing the chance of relapse in patients with recurrent Cdiff infection and in preventing Cdiff in patients who receive antibiotics. Lactobacillus rhamnosus strain GG, Sacharomyces boulardii, and combination probiotics are the strains that have been most commonly studied.

A 2013 Cochrane Systematic Review found moderate evidence in favor of the safety and efficacy of probiotics for the prevention of Cdiff in adults and children. There are also some data suggesting that passive immunotherapy with IVIG can be helpful for patients with relapsing or refractory Cdiff.

Finally, an increasing number of reports suggest excellent results with the use of a procedure called “fecal microbiota transplantation (FMT)”. In this procedure, stool from a healthy family member or healthy anonymous donor is screened for safety and is introduced into the patient’s GI tract via NG tube, enema, or colonoscopy in an attempt to normalize the fecal flora. Results have been seen as early as 24-48 hours later.

Rates of clinical resolution have been as high as 90%, though this varies by route of administration. Greater success has been observed with delivery into the lower GI tract. Adverse events are rare and have not been directly attributable to FMT.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

On therapy, fever should decrease in 24 hours and diarrhea should mostly resolve in 4 to 5 days. If the patient is not responding, one must consider an alternate diagnosis, or that the orally administered drug may not be getting to the site of infection, as in the case of ileus or toxic megacolon. If poor delivery to the colon is suspected, the response should not be to change oral therapy to intravenous, since intravenous therapy is not thought to be efficacious for this disease. Rather, rectal instillation of vancomycin should be initiated.

Incorrect diagnosis

It can be hard to know whether failure of Cdiff therapy is due to the presence of an alternative diagnosis or simply progression of disease in the face of therapy, which is not uncommon. CT of the abdomen should be performed in sick patients not responding to Cdiff therapy to rule out other intra-abdominal processes.

Follow-up

Patients successfully treated for Cdiff should have resolution of fever, leukocytosis, diarrhea, and abdominal pain. If a patient has persistence of any one of these findings, treatment failure should be considered, and alternate diagnoses should be pursued. Cdiff toxin assay of stool should not be performed as test of cure, since it can remain positive even in the absence of disease.

Pathophysiology

Normal intestinal flora consists of 10¹⁰ to 10¹² bacteria per gram of feces, with over 100 distinct, primarily anaerobic, species, together exerting a protective effect known as colonization resistance against Cdiff by depleting the carbon sources necessary for its growth, preventing access to sites of adherence on the colonic mucosa, and producing antibacterial substances. With the disruption by antibiotics of this normal balance, Cdiff may overgrow, leading to disease in some patients, depending on host factors.

Cdiff is a large (2-17 micron) gram-positive anaerobic spore-forming bacillus. It produces two heat-labile protein exotoxins, Toxins A and B. Purified toxins alone are capable of causing the full spectrum of disease. Some strains produce only Toxin B but are just as pathogenic as those that produce both. The toxins appear to act synergistically, with Toxin A acting as an enterotoxin and toxin B as a cytotoxin. The result is disaggregation of actin, opening of tight junctions, and consequently cell rounding and death. The toxins are also proinflammatory. Cdiff produces tissue-degradation enzymes as well.

Epidemiology

In 1978, Cdiff was identified as a causative agent of antibiotic-associated diarrhea and colitis. Since 2003, the frequency and severity of Cdiff infections has been increasing, with Cdiff sufferers being more likely to relapse, undergo colectomy or die from their disease. The NAP1/BI/027 strain has been found to be responsible for this phenomenon. Since 2005, ribotype 078 has become more and more common. Ribotype 078 causes disease that can be community-acquired, and affects younger patients.

Between 20 and 50% of patients in hospitals and long-term care facilities are colonized with Cdiff. Cdiff is acquired by fecal oral transmission and can be carried on the hands of health care workers from patient to patient or room to room. Even asymptomatic carriers can shed Cdiff, which can be transmitted to other patients in an institution.

As such, it is integral to implement contact precautions for patients with known or suspected Cdiff. These patients should be placed in private rooms or cohorted if private rooms are not available. Gowns and gloves should be used when entering patient’s rooms and during patient care. Shared medical equipment should be dedicated or cleaned before and after patient care. These precautions should remain in place at least until diarrhea ceases.

Cdiff is readily transmitted by fomites, so cleaning of surfaces is an important measure to control its spread. Because Cdiff exists in the environment in spore form, it is resistant to many disinfectants, and to ethanol-based hand sanitizer. Rooms must be cleaned with bleach to rid them of Cdiff spores.

Prognosis

Proper management of Cdiff in the ICU is key, because mortality in critically ill patients may be as high as 24%. Among those who require colectomy, mortality climbs to between 38 and 80%. In one study of patients who required colectomy for Cdiff, the need for preoperative vasopressor support predicted postoperative mortality.

Cdiff-associated diarrhea relapses in 20-25% of cases. Relapse generally occurs 3-21 days after completion of therapy and is generally thought to be due to recurrence rather than reinfection. Patients who have had two or more relapses have a 65% chance of developing further relapse, and 3-5% of patients will have six or more relapses.

Special considerations for nursing and allied health professionals.

In keeping with the recommendations to reduce the spread of Cdiff within a healthcare institution, strict contact precautions should be initiated as soon as this infection is suspected, even before a specimen is sent for testing. Some institutions mandate the use of soap and water for hand disinfection rather than alcohol-based hand sanitizer after the care of a patient with Cdiff.

However, neither product kills Cdiff nor eradicates the spores. Consistent glove use remains the cornerstone for preventing Cdiff transmission via the hands of healthcare workers. Any theoretical benefits expected with soap and water hand hygiene may be negated by the decreased compliance often associated with this less convenient hand hygiene option.

What's the evidence?

Drees, M, Gorbach, SL, Cunha, BA. “Clostridium difficile-associated diarrhea and colitis”. Infectious Diseases in Critical Care Medicine. 2007. (This textbook provides a general overview of Cdiff infection, including microbiology, clinical presentation, diagnosis, and treatment.)

Hurley, BW, Nguyen, CC. “The spectrum of pseudomembranous colitis and antibiotic associated diarrhea”. Archives of Internal Medicine. vol. 162. 2002. pp. 2177-2184. (Description of the spectrum of disease associated with pseudomembranous colitis, pertinent risk factors, treatment options, and prevention measures.)

Bartlett, JG. “Antibiotic associated diarrhea”. New England Journal of Medicine. vol. 346. 2002. pp. 334-339. (Clinical vignette followed by a discussion of the causes of antibiotic-associated diarrhea, including, but not limited to Cdiff.)

Mylonakis, E, Ryan, ET, Calderwood, SB. “Clostridium difficile-associated diarrhea: a review”. Archives of Internal Medicine. vol. 161. 2001. pp. 525-533. (Review of the epidemiology, risk factors, clinical presentation, diagnostic tests, treaments, and prevention of Cdiff infection.)

Hunt, JJ, Ballard, JD. “Variations in Virulence and Molecular Biology among Emerging Strains of Clostridium difficile”. Microbiol Mol Biol Rev. vol. 77. 2013. pp. 567(Overview of Cdiff infection, diagnosis, and treatment; a review of important Cdiff virulence factors; and a description of the NAP1/027/BI strain.)

Gerding, DN, Johnson, S, Rupnik, M, Aktories, K. “Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance”. Gut Microbes. vol. 5. 2014. pp. 15-27. (Description of the Cdiff binary toxin CDT including genetics, molecular structure, cellular mechanism of action, epidemiology of Cdiff toxins, and roles in possible pathogenesis.)

Cohen, SH. “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)”. Infection Control and Hospital Epidemiology. vol. 31. 2010. pp. 431-455. (The most recent evidence-based clinical practice guidelines regarding epidemiology, diagnosis, treatment, and infection control and environmental management pertinent to Cdiff infection in adults.)

Goldenberg, SD, Cliff, PR, French, GL. “Laboratory diagnosis of Clostridium difficile infection”. Journal of Clinical Microbiology. vol. 48. 2010. pp. 3048-9. (Commentary on available diagnostic testing for Cdiff infection and performance characteristics of a two-step algorithm including glutamate dehydrogenase antigen testing and confirmation by Cdiff PCR.)

Bobo, LD, Dubberke, ER. “Recognition and prevention of hospital-associated enteric infections in the intensive care unit”. Critical Care Medicine. vol. 38. 2010. pp. S324-334. (Literature review that focuses on hospital-associated enteric infections in the ICU with a description of the epidemiology, microbial characteristics, diagnosis, and prevention, with particular emphasis on Cdiff.)

Oldfield, EC, Oldfield, EC, Johnson, DA. “Clinical update for the diagnosis and treatment of Clostridium difficile infection”. World J Gastrointest Pharmacol Tesr. vol. 5. 2014. pp. 1-26. (An updated literature review describing the epidemiology, risk factors, clinical presentation, diagnostic modalities, medical and procedural treatment options, prevention measures, and possible future treatment options for Cdiff.)

Cohen, SH. “Clinical practice guidelines for Clostridium difficile infectionin adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA)”. Infection Control and Hospital Epidemiology. vol. 31. 2010. pp. 431-455. (The most recent evidence-based clinical practice guidelines regarding epidemiology, diagnosis, treatment, and infection control and environmental management pertinent to Cdiff infection in adults.)

Pillai, A, Nelson, R. “Probiotics for treatment of Clostridium difficile-associated colitis in adults”. Cochrane Database of Systematic Reviews. vol. 1. 2009. (Systematic review of four small studies on the use of probiotics in the treatment of Cdiff infection that found insufficient evidence to support the use of probiotics as a therapeutic adjunct to antibiotic therapy and no evidence to support the use of probiotics alone for treatment of Cdiff.)

Nelson, R. “Antibiotic treatment for Clostridium difficile-associated diarrhea in adults”. Cochrane Database of Systematic Reviews. vol. 1. 2007. Systematic review of twelve studies with the conclusion that there is uncertainty regarding whether or not mild Cdiff-associated diarrhea needs to be treated with antibiotics and that if an antibiotic is used, it should be one that brings both symptomatic cure and bacteriologic cure.

Louie, TJ, Miller, MA, Mullane, KM. “Fidaxomicin versus vancomycin for Clostridium difficile infection”. New England Journal of Medicine. vol. 364. 2011. pp. 422-31. (The first randomized controlled trial comparing fidaxomicin and vancomycin for Cdiff infection which found that fidaxomcin was both non-inferior to vancomycin and associated with lower recurrence rate.)

Scott, L. “Fidaxomicin: A Review of Its Use in Patients with Clostridium difficile Infection”. Drugs. vol. 73. (2013). pp. 1733-1747. (Review of Fidaxomicin for treatment of Cdiff, including mechanism of action, pharmacodynamics and pharmacokinetics, potential mechanisms of resistance, review of pertinent clinical trials, therapeutic efficacy, and economic considerations.)

Cornely, OA. “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. vol. 12. 2012. pp. 281-89. (A multicenter, international, randomized controlled trial demonstrating fidaxomicin's non-inferiority compared to vancomycin for the treatment of Cdiff infection.)

Crook, DW. “Fidaxomicin Versus Vancomycin for Clostridium difficile Infection: Meta-analysis of Pivotal Randomized Controlled Trials”. (A meta-analysis which combined the two randomized controlled trials that previously demonstrated fidaxomicin's non-inferiority to vancomycin.)

Cornely, OA. “Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin”. Clin Infect Dis. vol. 55. 2012. pp. S154-61 . (A subgroup analysis of the 128 subjects from the two randomized controlled trials comparing fidaxomicin and vancomycin. These were the study subjects who experienced recurrent Cdiff disease, and the analysis demonstrated similar clinical response and lower rates of recurrence among those receiving fidaxomicin.)

Mullane, KM. “Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections”. Clin Infect Dis. vol. 53. 2011. pp. 440-7. (Clinical trial demonstrating that fidaxomcin was significantly more effective than vancomycin in achieving clinical cure in the presence of concurrent antibiotics and in preventing Cdiff recurrence regardless of concurrent antibiotic use.)

Mullane, KM. “Renal Impairment and clinical outcomes of Clostridium difficile infection in two randomized trials”. Am J Nephrol. vol. 38. 2013. pp. 1-11. (A post-hoc analysis of the two randomized controlled trials comparing fidaxomcin and vancomycin which compared endpoints by treatment received and renal function and noted that progressive CKD is associated with increased time to resolution of diarrhea, lower cure rates, and higher recurrence, and that the rate of recurrence following vancomycin was higher regardless of renal function.)

Goldenberg, JZ. “Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children”. Cochrane Database of Systematic Reviews. 2013. (An updated systematic review and meta-analysis of 23 randomized controlled trials including 4213 patients that found moderate quality evidence to suggest that probiotics are both safe and effective for preventing Clostridium difficile-associated diarrhea.)

Kassam, Z, Lee, CH, Yuan, Y, Hunt, RH. “Fecal Microbiota Transplantation for Clostridium difficile Infection: Systematic Review and Meta-Analysis”. Am J Gastroenerol. vol. 108. 2013. pp. 500-508. (A systematic review and meta-analysis of eleven studies with a total of 273 Cdiff patients treated with fecal microbiota transplantation showing high rates of clinical resolution, no reported adverse events, and suggesting the need for randomized controlled trials and long-term follow-up.)

Gough, E, Shaikh, H, Manges, AR. “Systematic Review of Intestinal Microbiota Transplantation (Fecal Bacteriotherapy) for Recurrent Clostridium difficile Infection”. Clin Infect Dis. vol. 53. 2011. pp. 994-1002. (A systematic review of 317 patients from 27 case series and reports of intestinal microbiota transplantation for recurrent Cdiff showing high rates of clinical resolution and low rates of adverse events.)

Mylonakis, E, Ryan, ET, Calderwood, SB. “Clostridium difficile-associated diarrhea: a review”. Archives of Internal Medicine. vol. 161. 2001. pp. 525-533. (Review of the epidemiology, risk factors, clinical presentation, diagnostic tests, treaments, and prevention of Cdiff infection.)

Rupnick, M. “Clostridium difficile infection: new developments in epidemiology and pathogenesis”. Nature Reviews: Microbiology. vol. 7. 2009. pp. 526-537. (A review summarizing the changing epidemiology of Cdiff, including its emergence as a community-acquired infection, new virulence factors, and treatment and prevention options.)

Bobo, LD, Dubberke, ER. “Recognition and prevention of hospital-associated enteric infections in the intensive care unit”. Critical Care Medicine. vol. 38. 2010. pp. S324-334. (Literature review that focuses on hospital-associated enteric infections in the ICU with a description of the epidemiology, microbial characteristics, diagnosis and prevention, with particular emphasis on Cdiff.)

Freeman, J. “The changing epidemiology of Clostridium difficile infections”. Clinical Microbiology Reviews. vol. 23. pp. 529-549. (A review of the evidence for the changing epidemiology, clinical virulence, and outcome of treatment of CDI, and the similarities and differences between data from various countries and continents.)

Rupnick, M. “Clostridium difficile infection: new developments in epidemiology and pathogenesis”. Nature Reviews: Microbiology. vol. 7. 2009. pp. 526-537. (A review summarizing the changing epidemiology of Cdiff, including its emergence as a community-acquired infection, new virulence factors, and treatment and prevention options.)

Cohen, SH. “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)”. Infection Control and Hospital Epidemiology. vol. 31. 2010. pp. 431-455. (The most recent evidence-based clinical practice guidelines regarding epidemiology, diagnosis, treatment, and infection control and environmental management pertinent to Cdiff infection in adults.)

Boyce, JM, Havill, NL, Moore, BA. “Terminal decontamination of patient rooms using an automated mobile UV light unit”. Infect Control Hosp Epidemiol. vol. 32. 2011. pp. 737-42. (A small study demonstrating significant reductions in aerobic bacterial colony counts and C. difficile spores on contaminated surfaces in patient rooms following the use of a mobile UV light unit for decontamination.)

Sitzlar, B. “Environmental decontamination with ultraviolet radiation to prevent recurrent Clostridium difficile infection in 2 roommates in a long-term care facility”. Infect Control Hosp Epidemiol. vol. 33. 2012. pp. 534-6. (A letter to the editor describing the use of UV radiation to prevent further episodes of Cdiff in 2 roommates in a long term care facility with 2 coincident Cdiff recurrences.)

Levin, J. “The effect of portable pulsed xenon ultraviolet light after terminal cleaning on hospital-associated Clostridium difficile infection in a community hospital”. Am J Infect Control. vol. 41. 2013. pp. 746-8. (A single center study at a private community hospital demonstrating a significant decrease in the rate of Cdiff, as well as in the number of both Cdiff-related deaths and Cdiff-related colectomies after hospital-wide implementation of portable pulsed xenon UV (PPX-UV).)

Anderson, DJ. “Decontamination of targeted pathogens from patient rooms using an automated ultraviolet-C-emitting device”. Infect Control Hosp Epidemiol. vol. 34. 2013. pp. 466-71. (A prospective cohort study at two tertiary care hospitals demonstrating significant reductions in the environmental bioburden by decreased total colony forming units of Cdiff, vancomycin-resistant Enterococci, and Acinetobacter spp.)

Nerandzic, MM, Cadnum, JL, Pultz, MJ, Donskey, CJ. “Evaluation of an automated ultraviolet radiation device for decontamination of Clostridium difficile and other healthcare-associated pathogens in hospital rooms”. BMC Infec Dis. vol. 10. 2010. pp. 197(A study showing that the Tru-D Rapid Room Disinfection device, a novel, automated UV radiation technology, significantly reduces Cdiff, VRE, and MRSA contamination on commonly touched hospital surfaces.)

Haas, JP, Menz, J, Dusza, S, Montecalvo, MA. “Implementation and impact of ultraviolet environmental disinfection in an acute care setting”. Am J Infect Control. vol. 42. 2014. pp. 586-90. (A retrospective study of the implementation of ultraviolet environmental disinfection following discharge cleaning of contact precautions rooms and other high-risk areas at a tertiary care hospital that showed significant reductions in hospital-acquired multi-drug resistant organisms and Cdiff infections.)

Aldeyab, MA. “An evaluation of the impact of antibiotic stewardship on reducing the use of high-risk antibiotics and its effect on the incidence of Clostridium difficle infection in hospital settings”. J Antimicrob Chemother. vol. 67. 2012. pp. 2988-2996. (An interventional, retrospective, ecological investigation in a medium-sized hospital over 6.5 years with restriction of high-risk antibiotics that demonstrated a significant change in the use of high-risk antibiotic and an associated reduction in Cdiff infection.)

Piacenti, FJ, Leuthner, KD. “Antimicrobial Stewardship and Clostridium difficile-Associated Diarrhea”. J Pharm Pract. vol. 26. 2013 Oct. pp. 506-13. (A literature review on various antimicrobial stewardship techniques, including audit with feedback, antibiotic restriction, hospital-wide guidelines, staff education, enforcement of infection-control policies, and the use of an electronic medical record to monitor antibiotic use, and their impact on Cdiff rates.)

Drees , M, Gorbach, SL, Cunha, BA. “Clostridium difficile-associated diarrhea and colitis”. Infectious Diseases in Critical Care Medicine. 2007. (This textbook provides a general overview of Cdiff infection, including microbiology, clinical presentation, diagnosis, and treatment.)

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