IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read State-of-the-art interventions in acute large-vessel ischemic stroke; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit the post-test online at no charge at www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.

KEY POINTS

■ Incidence and prevalence rates of Clostridium difficile infection (CDI) are increasing, along with reports of community-acquired CDI. Hypervirulent C difficile strains are causing worldwide epidemics.

■ Diagnosis is confirmed by culture or the presence of C difficile toxins or toxin strains in the stool.

■ The first step in treatment is to discontinue the offending antibiotic, unless there are convincing contraindications to doing so.

■ Metronidazole is not as effective as vancomycin for severe disease or recurrent infection. FDA-approved medications to treat severe or recurrent CDI are lacking.

■ To control CDI, antibiotic stewardship and environmental infection controls are a must.

Clostridium difficile, a spore-forming, gram-positive, anaerobic bacillus, has reemerged to become the leading cause of nosocomial infectious diarrhea and a worldwide public health threat.1 Over the past decade, the changing epidemiology of C difficile infection (CDI) has been demonstrated by epidemic outbreaks of drug-resistant, toxin-producing, hypervirulent strains causing severe disease, disease recurrence, and death.2 CDI has placed a huge financial burden on the US health care system, with cost estimates of $3.2 billion annually.3 


Antibiotic use continues to be the leading risk factor for CDI. However, other factors implicated in this changing infection include host immunity, comorbid diseases, the use of gastric acid-altering medications, and the use of specific antibiotics, such as fluoroquinolones and clindamycin (Cleocin, generics).1,4 Increased incidences of CDI are being reported in the community and in persons without traditional risk factors.4,5 


Efficient and effective diagnosis remains a challenge; treatment options are limited; and currently, a vaccine does not exist. Preventing and controlling this disease through antibiotic stewardship, good hand hygiene, and environmental disinfection is imperative. This article provides current evidence about CDI that will enable physician assistants to serve as leaders in the prevention and intervention efforts required to curb the resurgence of this old infection. 


CHANGING EPIDEMIOLOGY AND RISK FACTORS


In the United States, an estimated 500,000 cases of CDI occur annually.6 Over the 7-year period of 1996 to 2003, the discharge diagnosis rate of CDI increased almost 100% from 31 per 100,000 to 61 per 100,000.7 Similar increases in incidence rates were seen in Europe and Canada, with epidemic proportions impacting the infirm and the elderly.1,8 As the rates of CDI increased, the severity and complications of the disease also increased, with more cases of prolonged hospitalization, disease recurrence, colectomy, toxic megacolon, and death.2,4 


The risk of developing CDI is directly related to the number of antibiotics to which a person is exposed, as well as the length of exposure and the spectrum of antibiotic coverage.4 Any antibiotic that disturbs colonic flora, including a single dose for surgical prophylaxis, is a risk factor for CDI.9 Several medications have been linked to CDI, including penicillins, cephalosporins, and lincosamides. In 1978, clindamycin phosphate, a lincosamide, was the first antibiotic associated with C difficile and pseudomembranous colitis (PMC)(Figure 1).10 More recently, widespread use of fluoroquinolones has been associated with a 3-fold increased risk of CDI.11 Fluoroquinolones are known to significantly decrease colonic flora, and this may be a factor in their high association with CDI. 


The use of gastric acid-altering medications, such as proton pump inhibitors (PPIs), has also increased in recent years; and although the evidence is not clear-cut, some patients taking PPIs have experienced increased rates of CDI.12 The decrease in gastric acid resulting from these medications is thought to facilitate colonization and transit of C difficile through the stomach to the bile-laden small bowel, promoting growth of the organism. 


Advanced age, antibiotic use, current or previous hospitalization, and comorbid disease remain traditional risk factors for CDI (Table 1). Host immunity and low production of antibody against C difficile toxins are associated with developing active disease versus asymptomatic colonization. Transplant recipients and others on immunosuppressant therapy or chemotherapeutic agents face an increased risk of CDI.4 Inflammatory bowel disease (IBD) has recently been identified as a risk factor for CDI, as rates of CDI infection are higher in patients with IBD and these patients may have a worse outcome.1,4C difficile-associated diarrhea (CDAD) and IBD may manifest very similarly. Clinicians should be judicious in their management of patients with IBD, so that they do not overlook a complicating CDI. 


GI surgery and procedures that manipulate the GI tract disrupt colonic function and are risk factors for CDI.9 Community-acquired C difficile infection (CA-CDI) rates are on the rise in the pediatric and young adult population and in pregnant women.4,5 Community sources of CDI include exposure to recently hospitalized patients, soil, pets, water, animals used for food, meats, and vegetables.2,6 


PATHOPHYSIOLOGY 


Pathogenesis As a spore-forming anaerobic bacterium, C difficile is difficult to isolate and grow in culture and deserving of the name "difficile." Colonization with C difficile occurs primarily in the colon and is rare in other parts of the body. The preference of C difficile for the colon is most likely related to the anaerobic colonic environment. Antibiotic treatment resulting in a lack of competing flora creates an environment that allows the anaerobic bacilli to grow and thrive.2 


The virulence of C difficile is related to the two toxins that it produces: endotoxin A (TxA) and cytotoxin B (TxB). Both toxins cause intestinal permeability and cytoskeletal reactions. The release of toxins in the colon triggers a cascade of increased fluid secretion, inflammation, and tissue necrosis that can form a pseudomembrane of immune cells. 


Epidemic strains Between 1989 and 1992, an epidemic of CDI associated with clindamycin use was reported in the United States.13 A follow-up study between 2000 and 2003 identified a virulent strain of C difficile that was highly resistant to fluoroquinolones.14 This strain, named BI/NAP1/027, was also found in Canada and Europe and produced 16 to 23 times more toxin, was highly infectious, and more virulent than earlier identified strains.2,6 Most recently noted in the literature as NAP1/BI/027, this epidemic strain has been linked to increased incidence, complications, morbidity, and mortality of CDI.9


TransmissionC difficile exists in vegetative and spore forms. The vegetative form is more common, sensitive to oxygen, and easily eradicated even with brief air exposure.15 In the spore form, C difficile is primarily transmitted person to person through the fecal-oral route and through fomite instrumentation.9C difficile spores can survive harsh environments because they are resistant to high heat, alcohol-based hand sanitizers, ultraviolet light, and many chemicals used for cleaning.2,6 Therefore, even with cleaning, spores contaminate and survive on the surfaces of health care facilities and on the hands of health care workers. 


CLINICAL MANIFESTATIONS AND DIAGNOSIS


Signs and symptoms The disease manifestations of CDI range from asymptomatic colonization to mild diarrhea, fulminant colitis, and death. Typically, CDI begins with watery diarrhea that may be associated with nausea, fever, and lower-abdominal cramping or pain. Mucus may be present in the stool, but frank blood or hematochezia are rare. Findings on the physical examination are usually unremarkable, except in cases of severe colitis, when the patient may present with abdominal pain and distention. 


Laboratory evaluation may reveal leukocytosis and hypoalbuminemia. In severe disease, CT may demonstrate colonic wall thickening, and inflammation and pseudomembranes may be visible on endoscopy as raised yellowish plaques. Sigmoidoscopy and colonoscopy are not recommended as diagnostic screening tests because only 50% of patients with CDI form visible colonic pseudomembranes.2 


CDI can progress rapidly; and if it does, it is associated with severe disease and poorer outcomes, as seen in fulminant and pseudomembranous colitis.1 These patients may exhibit high-volume, foul-smelling diarrhea (15-30 episodes a day), which may be bloody; marked leukocytosis; fever; hypoalbuminemia; hypotension; and rising creatinine levels.1,15 Patients with fulminant colitis and PMC may progress from initial diagnosis to colectomy in 5 days. In advanced disease, such as with PMC, 20% of patients may not present with watery diarrhea; instead they present with an ileus and marked abdominal distention and pain.1 This presentation is not characteristic of classic CDI and could lead to an incorrect diagnosis. 


Testing Accurate and timely diagnosis of CDI remains a challenge and should be based on the patient's history and findings on physical examination, associated risk factors, clinical presentation, laboratory results, and identification of C difficile or its toxin or toxigenic strain in unformed stool. 


The gold standard for diagnosing CDI is the cell culture cytotoxic assay. This test has high specificity and sensitivity but requires specialized laboratory techniques; it is both labor- and time-intensive.15 Most laboratories in the United States use enzyme immunoassays (EIAs) for diagnosing CDI by detecting C difficile toxins in stool samples. EIAs have a rapid turnaround time and are easy to perform, although they have a higher false-negative rate over the more sensitive cell culture cytotoxic assay.9 


Laboratories typically diagnose CDI using a two-step approach. Initially, stool is screened with an EIA that detects glutamate dehydrogenase, a C difficile antigen, and positive results are confirmed with an EIA toxin test. Real-time polymerase chain reaction (PCR) tests that detect C difficile toxins (sensitivity, 90-95%; specificity, 95-96%) are rapid, easy to perform, and becoming more commonly used.4,9 One such PCR test was approved by the FDA in 2011. It detects the presence of C difficile in the stool and determines whether the bacterium is the epidemic BI/NAP1/027 strain.16 Stool testing on asymptomatic patients and repeat stool tests of cure are not recommended.9 


CURRENT AND EVOLVING THERAPIES 


Treatment For 25 years, oral vancomycin (Vancocin), metronidazole (Flagyl, generics), or combinations of both medications have served as the primary treatment of CDI.4 Clinical guidelines to date have shown these medications to be equally effective.9,17 However, a recent study by Zar and colleagues showed decreased efficacy of metronidazole in patients with severe CDI: The cure rate was 76% for metronidazole and 97% for vancomycin.18 


The Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America (SHEA-IDSA) provide current guidelines for treating CDI (Table 2).9 The first step in treatment is to discontinue the offending antibiotics if at all possible. Empiric therapy should be administered if severe or complicated CDI is suspected. Intravenous vancomycin does not reach adequate concentration in the colonic lumen and is not recommended for the treatment of CDI. 


Many clinicians continue CDI therapy for at least 1 week after the offending antibiotic is discontinued. If clinicians choose to prolong CDI therapy, the guidelines recommend using vancomycin instead of metronidazole. SHEA-IDSA guidelines do not make recommendations for treating CDI when contraindications to stopping the offending antibiotic exist. In cases of fulminant colitis or toxic megacolon, colectomy may be a lifesaving intervention.


The changing epidemiology of CDI has seen an approximately 20% recurrence rate of infection in those patients treated with vancomycin and metronidazole.19 The first recurrence of CDI should be treated with the same medication as the initial infection. However, metronidazole should not be utilized in subsequent recurrences because of its associated neurotoxicity; instead tapered or alternative dosing of vancomycin should be instituted.9 Patients with CDI should not be treated with medications that decrease colonic peristalsis, such as antidiarrheals, as these agents may place patients at greater risk for complications.2 


In May 2011, fidaxomicin (Dificid) was approved by the FDA for the treatment of CDI.20 Fidaxomicin was found to be as effective as vancomycin. Patients receiving fidaxomicin had fewer recurrences of the nonvirulent strain of CDI.21 


Evolving therapies Rifaximin (Xifaxan) and teicoplanin are two other agents utilized in treating CDI. Both medications have reported efficacy rates comparable to that of vancomycin, and rifaximin has been efficacious in treating initial and recurrent CDI. However, questions arise regarding resistance to rifaximin, and teicoplanin is not approved for use in the United States.4 Stool infusion therapy, also known as fecal bacteriotherapy, is being utilized as a way to replenish gut flora and treat CDI. Donor stool flora is infused either through a nasogastric tube or rectally. Studies utilizing fecal therapy are showing great promise, with 90% patient success rates.22 Early treatment success has also been observed in patients who received monoclonal antibodies against C difficile along with either metronidazole or vancomycin.23 Additional emerging and investigational therapies include toxin-
binding agents, other probiotic agents, and IV immunoglobulin (IVIG).22 


PREVENTION AND CONTROL 


The single most modifiable risk factor associated with development of CDI is antibiotic therapy. The best prevention and intervention techniques must be targeted to decrease the use of antibiotics in the general population. Two recent studies showed 50% and 70% decreases in CDI incidence rates when prescribers complied with institutional prescribing policies.24,25


Providers and institutions should implement a systems-based practice approach that considers the indications of each medication, employs medication intervention only if necessary, and utilizes medications with the narrowest spectrum and for the shortest duration (antibiotic/medication stewardship). Antibiotic therapy should be based on local disease epidemiology, but limiting the routine use of cephalosporins and clindamycin may be beneficial. Whenever possible, utilize antibiotics that have the lowest risk associated with CDI. PAs practice the tenets of beneficence and nonmalfeasance and would not intentionally place patients at risk for CDI and the consequences of this infection. Therefore, utilizing a systems-based approach to practice will help to ensure that PAs are mindful in their efforts to prevent CDI.


Along with antibiotic stewardship, vigilant hand hygiene and infection control measures must be instituted in health care settings to decrease the spread of infection (Table 3). Because alcohol-based hand sanitizers are not effective at killing C difficile spores, soap and water should be used for hand washing.9 Hypochlorite (bleach)-based disinfectants and solutions have been shown to decrease rates of CDI contamination on high-use surfaces subject to contamination, such as control switches, bed rails, commodes, faucets, and doors.15,26 Use of disposable rectal thermometers will reduce CDI related to fomite instrumentation.9 


CONCLUSION


CDI has reemerged as a serious public health threat, with more virulent strains causing severe disease and infecting those in the community who are at low risk for the disease. Preventing and controlling this disease is a huge challenge. Diagnosing CDI remains problematic, as no single test is sensitive enough, specific enough, or fast enough; and treatment options remain limited. 


CDI is primarily a preventable disease. Therefore, even one death from this infection is unacceptable. Antibiotic stewardship and strict environmental infection control polices provide the best public health prevention and control strategies. PAs are well positioned to serve as leaders and educators within their practice settings to combat the reemerging public health threat of C difficile. JAAPA

Jacqueline Barnett is an assistant professor of health care sciences in the PA program at The George Washington University School of Medicine and Health Sciences in Washington, DC. The author has indicated no relationships to disclose relating to the content of this article.

IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read State-of-the-art interventions in acute large-vessel ischemic stroke; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit the post-test online at no charge at www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.

REFERENCES


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9. Cohen SH, Gerding DN, Johnson S, et al. 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.


10. Bartlett JG. Historical perspectives on studies of Clostridium difficile and C difficile infection. Clin Infect Dis. 2008;46(suppl 1):S4-S11.


11. Pépin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. 2005;41(9):1254-1260.


12. Surawicz C. The acid test: is proton pump inhibitor therapy an independent risk factor for Clostridium difficile-associated disease? Gastroenterology. 2007;133(1):355-357.


13. Johnson S, Samore MH, Farrow KA, et al. Epidemics of diarrhea caused by a clindamycin-resistant strain of Clostridium difficile in four hospitals. N Engl J Med. 1999;341(22):1645-1651.


14. McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant strain of Clostridium difficile.N Engl J Med. 2005;353(23):2433-2441.


15. McFee RB, Abdelsayed GG. Clostridium difficile. Dis Mon. 2009;55(7):439-470.


16. Food and Drug Administration. FDA news release. FDA clears test for bacteria that can cause serious intestinal disease. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm250498.htm. Published April 8, 2011. Accessed December 2, 2011.


17. Voelker R. Increased Clostridium difficile virulence demands new treatment approach. JAMA. 2010;303(20):2017-2019.


18. Zar FA, Bakkanagari SR, Moorthi KMLST, 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.


19. Johnson S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect. 2009;58(6):403-410.


20. Food and Drug Administration. FDA news release. FDA approves treatment for Clostridium difficile infection. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm257024.htm. Published May 27, 2011. Accessed December 2, 2011.


21. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.


22. Salkind AR. Clostridium difficile: an update for the primary care clinician. South Med J. 2010;
103(9):896-902.


23. Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med. 2010;362(3):197-205.


24. O'Connor KA, Kingston M, O'Donovan M, et al. Antibiotic prescribing policy and Clostridium difficile diarrhoea. QJM. 2004;97(7):423-429.


25. Wilcox MH, Freeman J, Fawley W, et al. Long-term surveillance of cefotaxime and piperacillin-tazobactam prescribing and incidence of Clostridium difficile diarrhoea. J Antimicrob Chemother. 2004;54(1):168-172.


26. Hacek DM, Ogle AM, Fisher A, et al. Significant impact of terminal room cleaning with bleach on reducing nosocomial Clostridium difficile. Am J Infect Control. 2010;38(5):350-353.



IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read State-of-the-art interventions in acute large-vessel ischemic stroke; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit the post-test online at no charge at www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.