Continuing Education

Community-Acquired Clostridium Difficile Infection:Awareness and Clinical ImplicationsCheryl Juneau, DrPH, FNP-BC, Elnora (Nonie) P. Mendias, PhD, FNP-BC, Nihas Wagal, BS,Michael Loeffelholz, PhD, Tor Savidge, PhD, Sharon Croisant, PhD, and Sara M. Dann, PhD

ABSTRACTThe epidemiology of Clostridium difficile infection (CDI) is changing. CDI, usually depicted as a nosocomial infection in the elderly, is now occurring in community-dwelling persons who are younger and otherwise dissimilar. A more virulent isolate, North American Pulsed Field type 1, associated withincreased morbidity and mortality, has been identified. In 2005, similar strainswere associated with severe disease in community-dwelling patients at a rateof 7.6/100,000. Screening patients with potential CDI symptoms and imple-menting preventive measures, including judicious use of antibiotics, canreduce disease burden.

Keywords: Clostridium difficile infection, community-acquired Clostridium difficile,North American pulsed-field type 1, PCR ribotype 027© 2013 Elsevier, Inc. All rights reserved.

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All authors are employed at the University of Texas Medical Branch in Galveston, except where indicated. Cheryl Juneau,DrPH, RN, FNP-BC, is an assistant professor in the School of Nursing and can be reached at cajuneau@utmb.edu.Elnora (Nonie) P. Mendias, PhD, RN, APRN, FNP-BC, is the Jesse and Alicia Dunn Professor of Nursing andDistinguished Teaching Professor in the School of Nursing. Nihas Wagal, BS, is a graduate student. Michael Loeffelholz, PhD,is an associate professor in the department of pathology. Tor Savidge, PhD, is an associate professor in the Baylor College ofMedicine. Sharon Croisant, PhD, is an associate professor in the department of preventive medicine and community health, andSara Dann, PhD, is an assistant professor in internal medicine-infectious diseases. In compliance with national ethical guide-lines, the authors report no relationships with business or industry that would pose a conflict of interest.

This CE learning activity is designed to augment the knowledge, skills, and attitudes of nurse practitioners and assist in their understanding of community-acquired Clostridium difficile and itstreatment.. At the conclusion of this activity, the participant will be able to:A. Describe how changing C. difficile epidemiology affects community healthB. Compare risk factors for community-acquired vs. hospital-acquired C. difficileC. Evaluate symptoms, diagnosis, treatment recommendations, and educational needs of patients with CA C. difficileThe authors, reviewers, editors, nurse planners, and pilot testers all report no financial relationships that would pose a conflict of interest.The authors do not present any off-label or non-FDA-approved recommendations for treatment.There is no implied endorsement by NPA or ANCC of any commercial products mentioned in the article.

Readers may receive the 1.0 CE credit free by reading the article and answering each question online at www.npjournal.org, or they may mail the test answers and evaluation, along with aprocessing fee check for $10 made out to Elsevier, to PO Box 540, Ellicott City, MD 21041-0540. Required minimum passing score is 70%. This activity has been awarded 1 contact hour for nurses and advanced practice nurses and 0.5 hour of pharmacology credit. The activity is valid for CE credit until February 1, 2015.

This educational activity is provided by Nurse Practitioner Alternatives™.

NPA™ is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. Accreditation does not imply endorsement byNPA, JNP, Elsevier, or ANCC of recommendations or any commercial products displayed or discussed in conjunction with the educational activity.

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Clostridium difficile (C. difficile) is typicallydefined as a nosocomial infection occur-ring in the elderly. Although about

500,000 Americans acquire a C. difficile infection(CDI) in institutions each year, an estimated 15,000to 180,000 cases occur in community settings.1

In 2000, a more severe strain, North AmericanPulsed Field type 1 (NAP1), was identified, leadingto increased morbidity and mortality.2 This strainappears more virulent because of increased sporegermination, secretion of potentially hypervirulentforms of toxins A and B, and production of an addi-tional virulence factor, binary toxin.2 In 2005, suchstrains were associated with severe disease in patientsin the community (7.6/100,000 people).3

Compared to patients with hospital-acquiredCDI (HA-CDI), patients with community-acquired CDI (CA-CDI) have lower mortality andshortened hospitalizations,4 but some may havepoorer prognosis. A large study funded by theCenters for Disease Control and Prevention(CDC) assessed rates of colectomy from CDI in 5tertiary care hospitals between 2000 and 2006.While 75 of 8,569 cases identified with CDIrequired a colectomy from disease severity, ratesfor patients with HA-CDI were lower than thosewith CA-CDI (4.3/1,000 vs 16.5/1,000 cases5).Appropriate screening and treatment of patientspresenting with potential CDI symptoms mayavoid such severe consequences.

Recent interest also has focused on differentiatingCA-CDI from another diagnosis, community-onsethospital-associated CDI (CO-HA-CDI). CDI sur-veillance recommendations indicate that symptomsbeginning within 4 weeks after discharge from hospi-tal/institutional settings are defined as CO-HA-CDI,while those beginning � 12 weeks after dischargeare considered CA-CDI.6 However, controversy stillexists in definitions, and failure to distinguish maycontribute to confusion in study findings.

CLINICAL VIGNETTEA 25-year-old woman presented to the clinic witha chief complaint of diarrhea for 7 days. Symptomsbegan with 4-5 loose stools daily and mild abdom-inal cramps but worsened, and she reported 5-10

watery stools daily, abdominal cramps and tender-ness, and a low-grade temperature since yesterday.She tried nonprescription medication (loperamidehydrochloride) without relief. Her medical historyis significant for recent sinusitis treated withciprofloxacin for 14 days. She denies known foodor drug allergies, recent travel out of the country,or eating salads, uncooked vegetables, meats, orexotic foods.

Differential Diagnosis and DiscussionDifferential diagnosis for infectious diarrhea includesviruses, bacteria, and protozoa. Viral agents are usuallyself-limiting; infected patients present with vomiting,nausea, occasional headache, fever, watery diarrhea,and generalized or periumbilical abdominal cramp-ing.7,8 Symptoms of protozoal agents commonlyinclude weight loss, loose stools, meteorism, hyper-peristalisis, perianal itching, wheezing, and rectal pro-lapsed,8 while symptoms of bacterial agents consist offever, blood and/or mucous in the stool, small-vol-ume stools, and suprapubic pain.8

Since this patient has not traveled, agents associ-ated with “traveler’s diarrhea” are unlikely. Nor hasshe eaten foods commonly associated with shiga-like toxins, such as Escherichia coli 0157H7. Otherdiagnoses, such as Giardia, might be considered, butGiardia is more commonly associated with daycarestay, travel, or immunocompetence.8 Although thispatient is young and has not been hospitalizedrecently, the primary differential diagnosis for con-sideration is CDI, especially given her recent use ofciprofloxacin.

PATHOPHYSIOLOGY C. difficile, a gram-positive, anaerobic spore-formingbacillus,2,9 is present in approximately 70% of healthyinfants. In the 1970s, C. difficile was first deemed patho-genic because of association with antibiotic use anddevelopment of pseudomembraneous colitis.9

C. difficile spores are noninfectious until ingestedand germination occurs. Ingested spores remaindormant in the colon until normal bowel floraare disrupted, at which time spores germinateinto the pathogenic bacteria, releasing 2 toxins (A and B) responsible for C. difficile colitis orpseudomembraneous colitis.2,9,10

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EPIDEMIOLOGYC. difficile is often found in the environment andcan survive for long periods as spores.10 It is trans-mitted via the fecal-oral route, usually after con-tact with contaminated surface areas (eg, bathtubs,rectal thermometer probes) or frequently aftercontact with contaminated hands of health careworkers.2 CDI symptoms typically present aswatery diarrhea, fever, anorexia, abdominal pain ortenderness, and nausea. CDI risk factors includeuse of antibiotics or proton pump inhibitors,increased age, gastrointestinal surgery, immuno-competence, complicated chronic illness, or pro-longed stays in health care settings.2,10,11

CLINICAL IMPACTHistorically, CDI was regarded as a nosocomialinfection occurring among the elderly, with its fre-quent occurrence attributed to immunocompe-tence.2,10,11 Reported HA-CDI incidence in 2005was 84/100,000.12 However, more recent evidencesuggests that CA-CDI occurs in younger patientswithout comorbidity, with estimates ranging from3.2-16.2 cases/100,000.13,14 Additionally, accordingto 2010 Emerging Infections Program data, 94% ofCDI cases occurred in persons receiving healthcare; 75% had symptoms that presented outsidehospital settings.9,15

While CDI risk factors appear to be changing,few studies have compared HA-CDI and CA-CDIrisk factors. Khanna et al examined CA-CDI andHA-CDI in Olmsted County, Minnesota, from1991-2005.16 Persons with CA-CDI were younger(median age 50 vs. 72), female (76% vs 60%), hadfewer comorbidities, and less likely to have severe

infection (20% vs 31%) or exposure to antibiotics(78% vs 94%) than patients with HA-CDI.16

Kuntz et al examined CA-CDI in a population-based, retrospective, nested, case-control study.Incidence rates for CA-CDI were lower than HA-CDI (11.16 vs 12.1/100,000 person-years). CA-CDI cases were more likely than controls to receiveantibiotics drugs (adjusted OR 6.09, 95% CI 4.59-8.08) and gastric acid suppressants (adjusted OR2.30, 95% CI 1.56-3.39) within 6 months beforediagnosis.17 CA-CDI in this article was termed ascommunity-associated CDI but defined as no his-tory of hospital discharge before diagnosis.

The economic burden associated with CDI issignificant. An estimated 178,000-246,139 CDIcases occur annually, with an average attributablecost of $2,848 to $3,791 per case.18,19 Based onthese assumptions, CDI cost estimates are from $433to $797 million annually.20

DIAGNOSTICSCDI diagnosis is based on symptom presentationand diagnostic confirmation. Patients with 3 ormore watery stools for more than 2 days, low-gradetemperature elevation, nausea, anorexia, and abdom-inal pain and tenderness should have diagnostic test-ing for toxigenic C. difficile.2,10

Costs, sensitivity, and specificity of molecular diag-nostic tests vary (Table 1). Stool culture of C. difficile isthe most sensitive test but is labor intensive, results maybe delayed 48-96 hours, and it can yield false-positivesfrom the presence of non-toxigenic strains.2 The mostcommon method in the United States is enzymeimmunoassay (EIA), which detects toxins A and B butlacks good sensitivity and specificity.11,21,26,27 Glutamate

Table 1. Diagnostic Performance and Cost of C. Difficile Detection Assays21-25

Performance Characteristics (%)a

Assay Sensitivity Specificity Costb

Toxin A, B IA 60-85.4 90.9-99.7 �$6

Cytotoxin assay 86.4 99.2 �$25

GDH 87.6-96.2 76.4-94.3 -

GDH/toxin 2-step algorithm 82.9-100 99.7-100 �$8-$14

NAAT 88.5-100 95.4-100 �$25-$48

IA � immunoassay; GDH � glutamate dehydrogenase; NAAT � nucleic acid amplification testa Compared with toxigenic culture.b Materials and labor.

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dehydrogenase (GDH) assay, a 2-step method, is rec-ommended. GDH, an antigen associated with C. diffi-cile, is present in both toxigenic and non-toxigenicstrains but largely absent for other bacteria. A GDH-negative specimen is reportedas negative for C. difficile with ahigh level of confidence. Apositive GDH result requiresadditional testing for C. difficiletoxin,11 using a polymerasechain reaction (PCR).11,28

Sensitive assays eliminatenecessity for more than 1stool specimen for confirma-tion. Repeat testing within 7 days is not beneficialunless patient health deteriorates.29-31

The stool specimen of the clinical vignette patienttested positive for C. difficile toxin. Though she com-pleted metronidazole 500 mg TID PO for 10 days,diarrhea recurred 3 weeks later. She still had not trav-eled nor eaten out lately and was very concerned.

TREATMENTTreatment of CDI differs according to disease sever-ity. Discontinuing an offending antibiotic may beeffective in very mild cases.10 However, in most cases,an antibiotic is needed. The Society for HealthcareEpidemiology of America (SHEA) and the InfectiousDiseases Society of America (IDSA) recommend ini-tial episodes of mild to moderate cases of CDI(leukocytosis with white blood cell count [WBC] of15,000 cell/ul or less) be treated with metronidazole500 mg TID PO for 10-14 days. Severe cases of CDI(leukocytosis with WBC � 15,000 cells/ul or ele-vated serum creatinine � 1.5 times premorbid levels)should be treated with vancomycin 125 mg QID POfor 10-14 days.11

Approximately 20% of patients with CDIdevelop a recurrent episode of C.difficile colitis, typi-cally within 3-10 days after completing antibiotics.10

The etiology of recurrent episodes of CDI is notwell understood, but it may be related to incom-plete eradication of C. difficile by prescribed antibi-otics or inadequate production of antibodies tobacterial toxins.10 CA-CDI versus HA-CDI rates ofrecurrence are not well documented, and furtherresearch is needed.

Treatment for a first recurrent case may includethe medication prescribed initially, depending ondisease severity.11 Metronidazole should not be usedafter the first recurrence because of drug-associated

neurotoxic effects.32 Secondrecurrences should be treatedwith pulsed or tapered dosesof vancomycin.11 Othertreatment options includetherapies such as nitazoxam-ide33 or intravenousimmunoglobulins.34-37

Further recurrent or severecases should be referred to

an infectious disease consultant. Use of antimotilitydrugs, such as loperamide, has been discouraged inpatients with CDI but supporting evidence is lim-ited,38 and more research is indicated.

NEW TREATMENT STRATEGIESHigh CDI recurrence rates demonstrate need fornew treatment strategies. Antibiotic developmentand testing has produced several new drugs cur-rently in Phase III clinical trials.39 The newestantibiotic approved in the US and Europe isfidaxomicin, a novel macrocyclic antibioticthought to inhibit bacterial RNA synthesis.Equally effective to vancomycin in treating activeinfection, fidaxomicin is superior in reducing ratesof recurrence.40 Its cost may limit use in clinicalpractice, but it should be considered for patients atincreased risk for recurrence.

Also in Phase III clinical trials are a number ofnonantibiotic treatments, including monoclonalantibodies and probiotics.39 Fecal transplants haveproved to be highly effective in treating recurrentinfections, through re-establishing balanced intes-tinal microbiota.41 A C. difficile toxoid vaccine(ACAM-CDIFF) designed to prevent CDI recur-rence has recently completed Phase II clinicaltrials,39 but study results have not yet been posted.SHEA and IDSA do not recommend probioticsbecause of potential risk of septicemia.11

CDI CONTROL MEASURES The most effective control measure is prevention.Preventive measures include effective hand hygiene

Repeat testing within 7 days is not beneficialunless patient health

deteriorates.

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and cleansing of patients’ rooms, exam rooms, bath-rooms, or other environments with antimicrobialdisinfectant. Exam tables should be cleaned with asporicidal agent registered with the EnvironmentalProtection Agency.2

Hand-washing with soap and water is recom-mended for health care workers in hospital set-tings with outbreaks2,42 and caregivers incommunity settings. Although research hasdemonstrated no actual decrease in CDI with useof soap and water vs alcohol-based products,SHEA and IDSA recommend use of soap andwater in settings with outbreaks.2,42

Given the association between use of antibi-otics and development of severe CDI illness orcomplications, clinicians are encouraged to pre-scribe antibiotics judiciously to prevent diseasedevelopment. Clinicians who follow IDSA guide-lines for optimal antibiotics for targeted bacteria,drug doses, and treatment duration also minimizedrug resistance.43

Other useful clinical advice includes teachingpatients about disease pathophysiology, diagnosis,course, various treatments, and outcomes. Clini -cians should advise patients to complete antibi-otics as prescribed and not to take medicationsbelonging to others.

CONCLUSIONMuch remains unknown about CDI and its effec-tive treatment. More research is indicated todetermine its epidemiology, risk factors, controlmeasures, and effective treatment strategies.Clinicians must be alert to patients presentingwith CDI symptoms and to screen, treat appro-priately, and implement preventive measures.

References

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AcknowledgmentsThis manuscript was supported in part by the Institute ofTranslational Sciences at The University of Texas MedicalBranch, Clinical and Translational Science AwardUL1TR000071 from the National Center for ResearchResources, now at the National Center for AdvancingTranslational Sciences, National Institutes of Health, inaddition to the support from Tor Savidge, PhD, andfunded grant RO1 NIAID AI10094001. Sara Dann issupported by Award Number KL2TR000072 from theNational Center for Advancing Translational Sciences. Thecontent is solely the responsibility of the authors and doesnot necessarily represent the official views of the NationalCenter for Advancing Translational Sciences or theNational Institutes of Health.

1555-4155/$ see front matter© 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.nurpra.2012.10.007