Clostridium difficile disease: Diagnosis, pathogenesis ... · C difﬁcile infections is imperative for optimal patient outcomes. National and international guidelines ... focused

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Clostridium difficile disease:Diagnosis, pathogenesis, andtreatment update
Lena M. Napolitano, MD, FACS, FCCP, MCCM,a andCharles E. Edmiston, Jr, PhD, CIC FIDSA, FSHEA, FAPIC,b Ann Arbor, MI, and Milwaukee, WI
Clostridium difficile infections are the leading cause of health care–associated infectious diarrhea,posing a significant risk for both medical and surgical patients. Because of the significant morbidity andmortality associated with C difficile infections, knowledge of the epidemiology of C difficile in com-bination with a high index of suspicion and susceptible patient populations (including surgical, post-colectomy, and inflammatory bowel disease patients) is warranted. C difficile infections present with awide spectrum of disease, ranging from mild diarrhea to fulminant colitis or small bowel enteritis andrecurrent C difficile infections. Early implementation of medical and operative treatment strategies forC difficile infections is imperative for optimal patient outcomes. National and international guidelinesrecommend early operative consultation and total abdominal colectomy with end ileostomy and preser-vation of rectum. Diverting loop ileostomy and colonic lavage followed by intravenous metronidazole andintracolonic vancomycin administered via the efferent limb of the ileostomy should be considered as analternative to total colectomy in selected patients. New and emerging strategies for C difficile infectiontreatment include monoclonal antibodies, vaccines, probiotics, biotherapeutics, and new antibiotics. Asuccessful C difficile prevention and eradication program requires a multidisciplinary approach thatincludes early disease recognition, implementation of guidelines for monitoring adherence to environ-mental control, judicious hand hygiene, evidence-based treatment and management strategies, and afocused antibiotic stewardship program. Surgeons are an important part of the clinical team in themanagement of C difficile infection prevention and treatment. (Surgery 2017;j:j-j.)

From the Department of Surgery,a University of Michigan Health System, Ann Arbor, Michigan; and theDepartment of Surgery,b Medical College of Wisconsin, Milwaukee, Wisconsin

A 64-YEAR-OLD MAN developed pneumonia afteremergency repair of an incarcerated inguinal her-nia (small bowel incarcerated, but no intestinalresection required). He was treated with broad-spectrum intravenous antibiotics for pneumonia.He then developed increasing abdominal disten-tion and increasing leukocytosis (maximum whiteblood cell count 80,000u/L) and obstipation.Abdominal radiographs confirmed evidence of in-testinal ileus and abdomen/pelvis computed to-mography (CT) imaging confirmed pancolitisand ascites (Fig 1). Laboratory testing confirmedClostridium difficile, and medical management was

d for publication January 25, 2017.

requests: Lena M. Napolitano, MD, FACS, FCCP,Acute Care Surgery and Trauma and Surgical Criticalniversity of Michigan Health System, Room 1C340-UH,ty Hospital, 1500 East Medical Drive, SPC 5033, AnnI 48109-5033. E-mail: [email protected].

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Elsevier Inc. All rights reserved.

x.doi.org/10.1016/j.surg.2017.01.018

initiated with intravenous metronidazole andenteral and rectal vancomycin. He failed toimprove with medical management and requiredloop ileostomy with antegrade vancomycin instilla-tion. He fully recovered and subsequently under-went closure of ileostomy without complication.

As in this patient case, C difficile infection (CDI)is a common problem in surgical patients and canpresent with ileus and obstipation or with diarrhea.We provide an update regarding diagnosis, epide-miology, pathogenesis, and clinical treatment inthis review.1,2

EPIDEMIOLOGY

It has been conservatively estimated that CDI isresponsible for over 500,000 enteric infections, themajority of which are hospital acquired.3 Over thepast decade, there has been a significant increasein both the incidence and economic burden asso-ciated with CDI. Estimates of the annual economicburden ranges from $436 million to $3 billion dol-lars in the United States.4-7 The morbidity associ-ated with this disease process is significant, with

SURGERY 1

Delta:1_given name

Delta:1_surname

mailto:[email protected]

http://dx.doi.org/10.1016/j.surg.2017.01.018

Fig 1. CT scan of abdomen/pelvis. Scout with colonic ileus (A). Marked diffuse colonic wall thickening (B, C, and D)compatible with infectious pancolitis. Asictes, moderate to large amount (C). No pneumatosis, no free intraperitonealgas. Patent central mesenteric vessels without portal venous gas. No intra-abdominal abscess.

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2 Napolitano and Edmiston

more than 9% of hospital admissions for CDI re-sulting in death.8

In the United States, C difficile is the mostfrequently reported health care–associated path-ogen, and CDI rates continue to rise.9,10

Community-associated CDI is also increasing, anddisease onset outside of the hospital setting hasincreased as well. Nursing home–onset CDI sawapproximately 113,000 infections in the UnitedStates in 2012, representing approximately one-quarter of all US CDI cases, and was associatedwith a 19% recurrence rate and 8% 30-day mortal-ity rate.11

Epidemiologic data document that CDI isincreasing in US surgical patients and is mostprevalent after emergency operations and intesti-nal resection.12 In 2006–2010, compared with theprior 5 years, the C difficile colitis rate increasedby 47%, and a 32% increase in the rate of colecto-mies for CDI was noted in the Nationwide Inpa-tient Sample.13

The spectrum of CDI ranges from mild diarrheato toxic megacolon, fulminant colitis, colonicperforation, multiple organ failure, and ultimatelydeath.14 Patients with severe CDI manifest a severesystemic inflammatory response, which differs

significantly from mild/moderate infection.15

The majority of all-cause gastroenteritis deathsare associated with CDI.16 Infection with C difficileis an independent predictor of increased intensivecare unit and hospital duration of stay, totalcharges, and mortality rate after operative careand represents a considerable burden to both pa-tients and hospitals.

There has also been a significant increase inmorbidity and mortality related to CDI, in partrelated to new hypervirulent strains (C difficile BI/NAP1/027 clones that produce binary toxin [Cdifficile transferase toxin] in addition to toxins Aand B), causing increased mortality and increaseduse of colectomy since CDI was refractory to med-ical management. The BI/NAP1/027 strain ischaracterized by high-level fluoroquinolone resis-tance, efficient sporulation, markedly high toxinproduction,17,18 and a mortality rate 3-fold higherthan less virulent strains, such as the 001 or 014 ri-botypes.19,20 Rates of CDI caused by BI/NAP1/027remain high in the United States, where 28.4% of2,057 recent C difficile isolates were NAP1.21 It isimportant to understand C difficile epidemiologyand transmission because it has a significantimpact on the clinical management of CDI.22

Table I. Risk factors for initial, recurrent, severe, and BI/NAP1/027 CDI

Initial CDI Recurrent CDI Severe CDI BI/NAP1/027 CDI

Antibiotic exposureIncreased patient agePrior hospitalizationSeverity of underlying illnessProton pump inhibitors and

H2 blocker useAbdominal operationNasogastric tubeLong duration of

hospitalizationLong-term care residencyIBDOrgan transplantationChemotherapyChronic kidney diseaseImmunodeficiency

Any prior episodes of CDIAdditional antibiotic useAdvanced ageProlonged or recent stay inhealth care facility

High severity of Horn Indexfor underlying illness

Proton pump inhibitor useInfection with NAP1/BI/027strain type

Absence of an antitoxin Aantibody response

Absence of an antitoxin Bantibody response

White blood cell count>15,000/mL

Serum creatinine levelgreater than 1.53 baseline

Low serum albumin levelIncreased C-reactive proteinlevel

Infection with NAP7-8-9/BK/078 and NAP1/BI/027 C difficile strains

Age >65 yearsFluoroquinoloneantibiotic exposure

Adapted from Gerding et al.148

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Napolitano and Edmiston 3

HISTORY

The first description of a C difficile–associateddisease (CDAD)-like process was recorded in a sur-gical patient at Johns Hopkins University in 1892.23

The patient was a 22-year-old woman who under-went operative care by Dr William Osler for resec-tion of a tumor in the gastric pylorus. Early in thepostoperative period, she developed severe diar-rhea and died on the 15th postoperative day. Thepostmortem revealed a pseudomembranous “diph-theritic membrane” in the small bowel which uponcytological examination presented with the key in-flammatory features of CDAD.

After the introduction of antibiotics in the late1940s and early 1950s, case reports of pseudo-membranous enterocolitis became much morenumerous with Staphylococcus aureus implicated asthe causative organism based up routine stool cul-tures.24,25 In 1974, clindamycin was linked to a se-ries of patients who developed fulminant diarrheawhile being treated for anaerobic infections.26 Ina subsequent prospective study, 21% of patientswho received clindamycin developed diarrheawith 50% of patients demonstrating pseudomem-branous lesions on endoscopy.27 The character-ization of the disease process and toxigenicnature of the pseudomembranous colitis was veri-fied by investigators at the University of Michiganand in the United Kingdom.28,29 Eventually,several investigators were able to isolate C difficilefrom the stool of patients with pseudomembra-nous colitis.30,31

RISK FACTORS FOR CDI

Clinicians must be aware of the risk factors forCDI (Table I), because this will assist them in hav-ing a high index of suspicion in making an earlydiagnosis. Antibiotic use is the most common riskfactor for initial and recurrent CDI.32 Althoughall antibiotics are associated with increased CDIrisk, clindamycin, fluoroquinolones, and second-generation and higher cephalosporins areassociated with the highest CDI risk. Protonpump inhibitors were identified as risk factors insome studies but not confirmed in others.32-35

Other risk factors include increased age, nasogas-tric tube, and kidney disease.36-38

Abdominal operations, specifically colorectaloperations, are a significant CDI risk factor. Arecent study examined risk factors and variationassociated with the development of nosocomialCDI among patients undergoing colorectal resec-tion in New York State from 2005–2013. Of 150,878colorectal resection patients, 3,323 (2.2%) devel-oped CDI. This study documented that colorectalsurgery patients are at high risk for CDI. There wasan approximately 5-fold difference in adjusted CDIrates across hospitals (0%–11.3% among surgeons;0%–6.8% among hospitals), confirming significantvariation unexplained by patient, surgeon, andhospital factors.39

Solid-organ transplant recipients are atincreased risk for hospital-onset CDI, 5-fold higherthan among general medicine patients (209 vs 40per 10,000 hospital discharges from the University



Health System Consortium 2012–2014).40 Furtherefforts to detect, prevent, and manage CDI amongtransplant recipients are needed.41

PATHOGENESIS

The gastrointestinal tract is a complexecosystem exposed to a constant flow of microbialpopulations, many of which transit through thelength of the bowel without establishing residencyor causing disease. This microbial population ofthe gastrointestinal tract represents great geneticand ecologic diversity with an estimated 15,000 to36,000 different species of bacteria residing withinthe lumen and on the mucosal surfaces.42

Clostridia are a heterogeneous group of organ-isms that exist in both the lumen of the bowel andon the epithelial brush-border surface of the largeintestines. C difficile colonizes the intestinal tract inapproximately 1% to 15% of healthy adults, and ithas been estimated that colonization in newbornscan approach 80%, but rarely does the organismcause disease in this population.43,44

In healthy adults, the intrinsic combination of acompetent (intact) normal intestinal flora and theproduction of antibodies to toxin A protect againstC difficile colonization and infection. Antitoxin IgGhas been found to be more common in asymptom-atic carriers than patients with active disease.45,46 Ithas been hypothesized that individuals who arecolonized early in life most likely develop an im-mune memory, which has a protective effectthrough adulthood but wanes in the sixth or sev-enth decade.

Microbial virulence. The principal virulencefactors (Table II) associated with CDAD are 2 largemolecular weight cytotoxins, toxin A and toxin B,which have enterotoxigenic and cytotoxic activity.Both toxins can cause significant colonic inflamma-tion and disruption of the epithelial mucosal sur-face. These toxins are coded in the region of thegenome called the pathogenicity locus (PaLoc).

The mechanistic action of toxin A (TcdA) and B(TcdB) most likely begins with the binding of thetoxin C-terminus to one or more target receptorspresent on the colonic epithelial cell surface.Upon binding to the receptor, the toxins are endo-cytosed, where the toxins are acidified prior totranslocation into the cell cytosol.47 Once insidethe cell, a host cytoplasmic inositol hexaphosphateinduces autocleavage of the toxin mediated by a Cdifficile asparate protease, resulting in a biologicallyactive toxin.48 Upon entry into the cell, the toxinstarget Rho GTPases, which play a central role in amultitude of cellular processes, including

organization of the actin cytoskeleton, controllingepithelial barrier function, and the signaling andmotility of host immune cells.49

The cumulative effect of this intoxication is theeventual loss of the intestinal barrier function. Thenormal tight junctions between individual epithe-lial cells are disrupted, allowing the migration ofcells, such as neutrophils, into the intestines,which play a role in the inflammatory responsethat is typically seen with colitis. The loss-of-barrierfunction leads to increased intestinal permeabilityand fluid accumulation followed by diarrhea.50

Two additional genes, which are not on thePaLoc, encode the binary toxin. Another potentialvirulence loci includes slpA, a gene that codes theS-layer proteins (adherence and inflammatorystimulation); genes that code for the extracellularmatrix-binding domain; a collagen protease gene;a gene for the surface anchor protein requiredfor covalent attachment to peptidoglycan; a pilusbiosynthesis locus involved in fimbrial biosynthesis;and a cluster of genes involved in extracellularpolysaccharide synthesis.51 The nontoxigenic Cdifficile strains lack the PaLoc gene locus.

In 2003, a severe outbreak of CDAD occurred inboth the United States and Canada, which wascaused by a clone that was designated as BI/NAP1/027. Studies have demonstrated that thisstrain (027) produces both toxins A and B fasterand in large quantity (hyperproduction). Theseclones are also capable of producing an actin-ADP-ribosylating toxin, called binary toxin (C difficiletransferase toxin), which is not encoded on thePaLoc and contributes to CDAD by cytotoxic activ-ity, inducing the formation of thin microtubuleson the outer surface of the epithelial cell (colono-cyte), leading to increased clostridial adherence.49

This strain also expresses resistance to the fluoro-quinolones, levofloxacin, and moxifloxacin. Inmany geographical areas of the United States,B1/NAP1/027 accounts for >50% all strains recov-ered from CDI.52,53

An interesting finding in a recent study foundthat isolates recovered from relapse cases show asignificantly higher germination rate compared toisolates recovered from single cases.54 Whether thishigher germination rate has an impact on diseaserecurrence is unknown. Although our primaryknowledge of the microbial virulence of C difficilehinges on deciphering the genetic components ofthe PaLoc and its toxigenic variations, other viru-lence factors, such as adherence and motility, arelikely to emerge as we further probe the biology ofthis significant health care pathogen.

Table II. Selective microbial virulence factors for Clostridium difficile

Virulence factor Target effect on host cells

Toxin A (PaLoc-TcdA gene) Cytotoxic loss of gastrointestinal cell barrier functionToxin B (PaLoc-TcdB gene) Synergistic interaction with toxin AVariant toxin A–/B+ Cardiotoxic-multiorgan failureBinary toxin Increases clostridial adherence to intestinal cell surface–fluoroquinolone resistanceS-layer protein Gene encoding cell surface adherence/stimulates inflammationS-anchor protein Mediates covalent attachment to cell wall peptidoglycanSporulation/germination Outer spore coat protein that induces inflammation

Adapted from Badger et al.2



DIAGNOSIS AND LABORATORY TESTING

The diagnosis of CDI requires rapid and accu-rate technologies for individual patient manage-ment and prevention of nosocomial transmission.Accurate diagnosis of CDI relies on a combinationof clinical history and laboratory tests.55 Anaerobicculture of C difficile from stool remains a sensitivemethod for diagnosis, but acquisition of C difficilealone does not diagnose CDI because 4% ofhealthy adults may carry this organism in theirnormal intestinal flora and 20% to 25% of C diffi-cile strains may be nontoxigenic. Toxigenic culturetesting from anaerobic culture remains the goldstandard for laboratory diagnosis owing to itshigh sensitivity (94%–100%) and high specificity(99%). While extremely sensitive and specific,the toxigenic culture test is time consuming andlaborious, taking 2 to 5 days.56

Enzyme immunoassays (EIAs) for toxins A and Bhave been a popular laboratory practice because thetests are simple to perform and results are availablewithin 2 to 6 hours. EIAs are relatively inexpensive,easy to perform, and can provide accurate, rapidresults. However, performance of EIAs can varywidely by product and can also be affected byprotocol deviations, improper technique, or spec-imen handling. EIA sensitivity is 63% to 99%, andfalse-negative results can occur.57-60 EIAs should notbe used as an indicator of response to therapy,because results remain positive for extended pe-riods in 25% of successfully treated patients.

A second EIA targets the C difficile common an-tigen, glutamate dehydrogenase (GDH), which issecreted by C difficile into the stool.61 GDH is anenzyme (present in most microbes) that convertsglutamate to a-ketoglutarate. GDH is not specificto C difficile, and its presence does not confirmthe presence of a strain of C difficile containingthe PaLoc locus. However, the absence of GDHfrom stool is strongly predictive of the absence ofC difficile, making it a potential screening assay.GDH-positive specimens are then confirmed using

an assay that specifically detects toxin or the toxingenes (polymerase chain reaction [PCR]).

Nucleic acid amplification (NAAT) is the newestcommercially available method for the diagnosis ofCDI. Current NAATs are formatted in PCR, DNAmicroarray, and loop-mediated isothermal amplifi-cation methods. A result (positive or negative) isreported within 2 hours. NAAT sensitivity rangesfrom 84% to 96% and specificity ranges from 94%to 99% depending on the gold standard used.62,63

The 2010 Society forHealthcareEpidemiology ofAmerica (SHEA) guidelines established specimencollection requirements and recommendations foroptimal C difficile testing based on existing evi-dence.64 The SHEA guidelines recommend that Cdifficile testing only be performed on diarrheal (un-formed) stool, unless ileus due to CDI is suspected.The proper stool specimens should be watery andtake the shape of the collection container. Althoughswab specimens are not considered acceptable,newer molecular probe technology is in develop-ment that will allow swab samples to be analyzed inthe future. Testing of formed stools and asymptom-atic patients is discouraged because a significantproportion of the hospitalized population will becolonized with C difficile.

A recent study has documented that exclusiverelianceonmolecular tests forCDIdiagnosis withouttests for toxin or host response is likely to result inoverdiagnosis, overtreatment, and increased healthcare costs.65When the current SHEAguidelineswerepublished, the optimal method with sufficientevidentiary support for C difficile testing was a 2-stepalgorithm combining GDH with toxin EIA testing.The addition of GDH as a screen increased the sensi-tivity for C difficile but alone was not specific enoughto sufficiently exclude nontoxigenic strains. This ledto the development of the 2-step algorithm whereinGDH-positive specimens are confirmedusing a toxinEIA or C difficile NAAT (Fig 2).

An additional challenge of selecting C difficiletesting is an increasing requirement for public

Fig 2. Recommended C difficile diagnostic testing. Reprinted with permission from Martin et al.22



reporting of C difficile rates. A potential downside ofpublic reporting is a lack of adjustment for case mixand testing methodology.66 Institutions that have im-plemented PCR screening forCdifficilehave reported2- to 3-fold increases in CDI positivity rates. If publicreporting does not allow for rate adjustments basedon testing methodology and population prevalence,

hospitals may be disadvantaged when performingthe most sensitive testing methodologies.

RADIOLOGIC DIAGNOSTIC IMAGING

Diagnostic imaging can assist in making an earlydiagnosis of CDI. Plain radiography of theabdomen can demonstrate polypoid mucosal

Fig 3. Radiologic diagnostic CT imaging findings in patients with CDI. (A) Accordion sign in 50-year-old woman with Cdifficile colitis. Marked submucosal edema is present in the right colon (“thumbprint” appearance on longitudinal axis,short arrows). Oral contrast material (arrowhead) is trapped within the lumen. Reprinted with permission from Macariet al.67 (B) Target sign in a 65-year-old woman with C difficile infection, with CT through the midabdomen showingdiffusely thickened colonic wall appearing as a “target sign” (concentric circles formed by the layers of bowel wall in in-flammatory disease) on axial imaging (arrow). Reprinted with permission from Ash et al.68 (C) Pneumatosis intestinalisin a 76 year old who underwent esophagectomy and splenectomy for adenocarcinoma and developed ileal C difficile en-teritis requiring small bowel resection, ultimately died. Reprinted with permission from Wee B et al.69



thickening, “thumbprinting” (wide transversebands associated with haustral fold thickening),or gaseous distention of the colon (ileus). CT scanimaging is most commonly used to evaluatepatients with CDI to determine the severity ofdisease. Common CT findings include wall thick-ening, low-attenuation mural thickening corre-sponding to mucosal and submucosal edema, the“accordion sign,” the “target sign” (“double halosign”), pericolonic stranding, and ascites (Fig 3).70

Pneumatosis intestinalis (affecting both the smalland large intestine) has also been reported in pa-tients with CDI.71-73 Familiarity with these imagingcharacteristics may allow early diagnosis and treat-ment and prevent progression to more seriouspathologic conditions.

CLINICAL PRESENTATION

Acquisition of C difficile, like most enteric patho-gens, results in a wide spectrum of clinical manifes-tations including intracolonic and extracolonic.The clinical features can vary from asymptomatic

presentation to fulminant colitis and peritonitisdue to perforation of the colon.

Intracolonic disease manifestations. Asymptom-atic carriers. Most individuals who are culture pos-itive for toxin producing C difficile areasymptomatic carriers. Asymptomatic carriage isvery common in hospitalized patients. Symptom-atic disease is less often seen in carriers despitethe observation that most C difficile isolates exhibittoxin production. Asymptomatic carriage can beinfluenced by certain clinical factors, such asrecent antibiotic exposure or previous occurrenceof CDAD.74,75

C difficile diarrhea. This manifests as mild tomoderate diarrhea, often associated with crampsand abdominal pain. Although patients will oftenexhibit malaise and fever, it is not a commoncomponent of disease presentation. Symptomsusually occur during or shortly after antibiotictherapy but sometimes may be delayed for severalweeks. C difficile toxins are normally detected instool samples even though endoscopic and



histologic features may be normal in patients withmild disease.76

C difficile colitis. This is the most commonclinical manifestation of CDI. This is generally amore serious illness, and patients present withmild to moderate abdominal pain, nausea,anorexia, and watery diarrhea. Dehydration, low-grade fever, and systemic polymorphonuclearleukocytosis may occur in selected patients. Anonspecific diffuse or patchy erythematous colitiswithout pseudomembranes may be seen withsigmoidoscopy.77

Pseudomembranous colitis. Symptoms of pseudo-membranous colitis are similar to C difficile colitisbut often more severe. Diarrhea is often profuse,and patients have intense abdominal pain (left orright lower quadrants). Endoscopy will often revealpseudomembranes that appear as raised yellowplaques, measuring about 2 to 10 mm in diameter,scattered over the colorectal mucosa. Most patientswith pseudomembranous colitis have involvementof the rectosigmoid colon, and many will alsohave involvement of the proximal large bowel.There is often marked leukocytosis (white bloodcell count >20,000), and hypoalbuminemia of3.0 g/dL or lower may be observed in severely illpatients.78

Fulminant colitis. Fulminant colitis (FC) is themost feared presentation of CDI and occurs in 2%to 3% of patients. FC accounts for most of theserious CDI complications, including ileus, mega-colon, colonic perforation, and death.79 In somecases, patients presenting with benign symptomswill suddenly and rapidly progress to shock.Contributory factors associated with diseaseseverity and patient death include age, immunestatus, patient comorbidities, microbial virulencefactors, and perhaps antimicrobial resistance.80

Patients with FC complain of severe lowerquadrant or diffuse abdominal pain, distensionand diarrhea, or ileus. Diarrhea is minimum inpatients with ileus, since secretions accumulate inthe dilated atonic colon. FC may lead to toxicmegacolon. The small bowel can also exhibitdilated segments with air-fluid levels simulatingintestinal obstruction or pseudo-obstruction. Thehigh morbidity and mortality associated with FCcan be mitigated by early aggressive diagnosis andtherapy.

Recurrent CDI. Recurrent CDI manifests as reap-pearance of diarrhea/ileus and abdominal symp-toms usually within a few weeks after completion oftreatment for CDI.81 The pathophysiology ofrecurrent CDI has not been well described, but itis likely related to a persistently altered fecal flora

in combination with C difficile sporulation and animpaired host immune response to C difficileand/or its toxin. Recurrent CDI develops inapproximately 5% to 20% of patients treated forCDI. In older patients, acute confusion or alteredmental state may be the first symptom of recurrentCDI. Other nonspecific signs of infection mayinclude weakness and lethargy, frequent falls,anorexia, and loss of physical functional capacity.5

Extracolonic disease manifestations. Extraco-lonic manifestation of CDI in a variety of organsystems includes small bowel infection, bacteremia,reactive arthritis, and other infectious processes(cellulitis, necrotizing fasciitis, and osteomyelitis).Small bowel CDI is often seen after a previousoperation and is associated with high mortality andis also observed in patients with inflammatorybowel disease (IBD) who have undergone totalcolectomy.

Impact of CDI in IBD. Current clinical andepidemiologic findings document a significantincrease in the burden of CDI in the IBD patientpopulation over the last decade. One study re-ported that the rate of CDI-IBD-associated CDI as aproportion of institutional burden increased from7% in 2005 to 16% in 2006 (P < .01). The majorityof patients contracted CDI as outpatients. Anti-biotic exposure in the CDI-IBD patients was foundto be 61%. Univariate and multivariate analysis re-vealed that maintenance immunomodulation andcolonic involvement were independent risk factorsfor CDI.4

In a retrospective study of CDI in IBD patientsover 7 years, there was a doubling of CDI inCrohn’s patients (9.5 to 22.3/1,000 admissions)and a tripling of CDI in ulcerative colitis patients(18.4 to 57.6/1,000 admissions).82 In a study of pa-tients who underwent colectomy for severe ulcera-tive colitis, many developed high-volume ileostomyoutput (clostridial toxin positive), fever, leukocy-tosis, and ileus in the postoperative period.83 Indata obtained from the US Healthcare Cost andUtilization Project Nationwide Inpatient Sample,hospitalized patients with concurrent CDI andIBD had a 4-fold or greater risk of mortality thanpatients admitted for either CDI or IBD alone.CDI-IBD patients also had longer hospital staysand a higher rate of gastrointestinal operationsand endoscopic evaluations than patients withCDI alone.6

IBD patients who acquire CDI share many of therisk factors (environmental acquisition, prior anti-biotic exposure, immunosuppressive therapy, andgastric acid suppressive therapy) associated withnon–IBD patient populations. An interesting



epidemiologic finding associated with CDI acqui-sition in IBD patients is that in the majority(>75%) of IBD patients, C difficile acquisition oc-curs in the community.84 This is in direct contrastto many of the CDIs that are acquired within thehospital environment. The reason for this findingis unknown.85

A recent study suggested that a subset of IBDpatients in remission has a higher carriage rate ofC difficile than healthy individuals, and that C diffi-cile carriage appears unrelated to antibiotic expo-sure or immunosuppressive therapy.86 The roleof immunomodulation may be a significant riskfactor in IBD patients because these drugs (azathi-oprine, 6-mercaptopurine, methotrexate, and in-fliximab) have all been associated with anincrease in CDI in IBD patients, with almost 50%of the patients taking 2 immunosuppressive agentsfor maintenance therapy.87

IBD patients may develop C difficile enteritis andC difficile pouchitis. C difficile small bowel enteritis israre but associated mortality is high (60%–83%).83,86 The clinical presentation includes diar-rhea followed by ileus with fluid-filled loops ofsmall bowel and sepsis. C difficile associated pouchi-tis is responsive to medical management.88,89 Po-tential treatment with inhibitory bile acids maybe a future nonantibiotic therapy for CDI pouchi-tis, as the restoration of secondary bile metabolismmay be the key mechanism underlying the successof fecal microbiota transplantation in treatingrecurrent CDI.90 Clinicians should have a high in-dex of suspicion of postoperative CDI in any pa-tient who has a history of IBD, particularly withhistory of CDI prior to colectomy. Most patientswill respond to rapid and aggressive therapy.

MEDICAL TREATMENT STRATEGIES

Initial management of CDI should always bediscontinuation of antimicrobial agents that mayhave led to CDI. Antibiotic treatment of CDI is themainstay of therapy, and specific antibiotic treat-ment guideline recommendations are based onthe severity of CDI disease. Although initial sys-tematic reviews documented that no antimicrobialagent was clearly superior for the initial cure ofCDI,91 additional analyses stratified by diseaseseverity identified that vancomycin providedimproved initial clinical and sustained cure ratesin patients with severe CDI compared with metro-nidazole.92 In a study of quantitative bacterial cul-tures of fecal samples, vancomycin treatmentconsistently reduced C difficile counts to the limitof detection, whereas metronidazole was associated

with C difficile counts 1.5 to 2 log higher at 10 daysof treatment.93 Based on these results, vancomycinis considered first-line therapy for severe andcomplicated CDI (Table III).94

Additional antimicrobials that have potentialefficacy for CDI treatment include rifaximin,tigecycline, ramoplanin, and nitazoxanide.95 Smalltrials of these agents have been encouraging, butadditional studies are warranted.

Fidaxomicin. Fidaxomicin is a member of anew class of antibacterials (macrocycles) and hasbeneficial properties, including in vitro activity 8times greater than vancomycin against clinical Cdifficile isolates,96 minimal systemic absorption,97

and limited activity against the normal gutflora.98 Based on data from 2 phase 3 trials(n = 1,164), clinical cure rates were similar for fi-daxomicin and vancomycin, but CDI recurrence(relative risk [RR] 0.47, 95% confidence interval[CI] 0.34–0.65) was significantly lower and sus-tained cure rates (RR 1.75, 95% CI 1.35–2.27)were significantly higher for fidaxomicin thanvancomycin.99-101 A significant limitation of fidax-omicin compared to other antibiotics for CDI isits high cost.

Intravenous immunoglobulin. Intravenousimmunoglobulin is another potential treatmentstrategy for CDI. Few case reports are available,and current guidelines state the following: “Intra-venous immunoglobulin may be helpful in pa-tients with hypogammaglobulinemia (strongrecommendation, low quality of evidence)”---seeAJG guideline, page 488, right column.102

Monoclonal antibodies. Antibody-based immu-notherapies for CDI are emerging.103 Monoclonalantibodies active against toxins A and B adminis-tered by intravenous (IV) infusion were superiorin reducing rates of recurrent CDI when adminis-tered with antibiotics compared to antibioticsalone (7% vs 25% recurrent CDI) in a phase 2 ran-domized controlled trial that enrolled 200 adultpatients with CDI.104 The mechanistic basis ofthe monoclonal antitoxin antibodies is throughdirect neutralization of the toxins and does notappear to involve host effector functions.105

Bezlotoxumab,106 a fully human monoclonalimmunoglobulin G1/kappa antibody that bindsto and neutralizes C difficile toxin B, was an effica-cious adjunctive therapy for the prevention ofrecurrent CDI. Two global, phase 3, double-blindstudies were conducted to evaluate bezlotoxumab,either alone or in combination with actoxumab (afully human monoclonal antibody against C difficiletoxin A), compared to placebo for the prevention

Table III. Medical treatment recommendations for CDI based on severity of illness

Severity Treatment

Mild/moderate CDI Mild/moderate CDI

Diagnosis of CDI andNone of the criteria in “severe” or “complicated” CDI

Metronidazole 500 mg PO TID for 10–14 days

In patients with metronidazole allergy, pregnant, nursing,

or on warfarin therapy:

Vancomycin 125 mg PO QID for 10–14 days

Severe CDI Severe CDI

WBC $15KCr $ 1.53baselineAge $65 yearsANC #500ALB #2.5 g/dLSOT/BMT <100 daysChronic GVHD (BMT)Treatment of rejection in the preceding 2 months (SOT)Small bowel CDI

Vancomycin 125 mg PO QID for 10–14 days

Complicated CDI Complicated CDI

Septic shock–sepsis with persistent hypotension, requiring

vasopressors to maintain MAP $65 mm Hg and serum

lactate level >2 mmol/L despite adequate fluid

resuscitation

Sepsis–life-threatening organ dysfunction caused by a

dysregulated host response to infection. Suspected or

documented infection and an acute increase of $2

SOFA points

Ileus or bowel obstruction

Toxic Megacolon

Peritonitis

Bowel perforation

Vancomycin 500 mg PO QID

Metronidazole 500 mg IV every 8 hours, and

Vancomycin enema 500 mg in 1,000 mL of normal saline

every 8 hours (in patients with ileus, bowel obstruction

or toxic megacolon).

Consult infectious diseases and surgery to assist in man-

agement including possible surgical intervention.

Operative management strategies for CDI may include

exploratory laparotomy, diverting loop ileostomy with

lavage, total or subtotal abdominal colectomy with end

ileostomy.

ANC, Absolute neutrophil count; ALB, albumin; BMT, bone marrow transplant; Cr, serum creatinine; GVHD, graft versus host disease; MAP, mean arterialpressure; SOFA, sequential organ failure assessment; SOT, solid organ transplant; WBC, white blood cell count.



of recurrent CDI in patients on standard of careantibiotics for a primary or recurrent CDI. TheMODIFY (monoclonal antibodies for C difficiletherapy) I study enrolled 1,452 patients (medianage 65 years) in 19 countries, and the MODIFY IIstudy enrolled 1,203 patients (median age 67 years)in 17 countries. The studies were conducted inboth hospital and outpatient settings, and the pri-mary end point for each study was evaluatedthrough 12 weeks after study drug administration.

In the MODIFY I study, patients receivingstandard-of-care antibiotics for C difficile were ran-domized to receive a single, 1-time infusion ofeither bezlotoxumab (10 mg/kg) (n = 403), actox-umab (10 mg/kg) (n = 242), the combination of

bezlotoxumab and actoxumab (10 mg/kg each)(n = 403), or placebo (n = 404). The actoxumabarm was stopped for efficacy and safety reasons af-ter an interim analysis. In the MODIFY II study, pa-tients receiving standard-of-care antibiotics for Cdifficile were randomized to receive a single, 1-time infusion of either bezlotoxumab (10 mg/kg) (n = 407), bezlotoxumab and actoxumab(10 mg/kg each) (n = 397), or placebo (n = 399).

In both MODIFY I and MODIFY II, the rate ofCDI recurrence through week 12, the primaryefficacy end point, was significantly lower in thebezlotoxumab arms (17.4%, P = .0003) and(15.7%; P = .0003) and the combination bezlotox-umab and actoxumab arms (15.9%, P < .0001) and



(14.9%, P < .0001) compared to the placebo arms(27.6%) and (25.7%), respectively. In both studies,the rate of CDI recurrence was lower in the bezlo-toxumab arms compared to the placebo arms inpatient subgroups known to be at high risk forCDI recurrence, including patients with any priorepisodes of CDI within the previous 6 months, pa-tients infected with the BI/NAP1/027 strain, pa-tients with severe CDI (Zar score $2), patients65 years of age or older, and patients with compro-mised immunity.

These subpopulation analyses were prespecifiedin the protocol for each study. Rates of seriousadverse reactions and deaths assessed through12 weeks after infusion were comparable across thetreatment arms. Treatment with the combination ofbezlotoxumabandactoxumabdidnotprovideaddedefficacy over bezlotoxumab alone. Furthermore,actoxumab alone provided no benefit in the preven-tion of CDI recurrence compared with placebo.

Clinical cure of the initial CDI episode, how-ever, was lower for both actoxumab/bezlotoxumab(74.7%; P = .0057) and bezlotoxumab (77.5%;P = .0622) compared with placebo (82.8%) inMODIFY I. In MODIFY II, clinical cure of theinitial CDI episode was numerically lower for ac-toxumab/bezlotoxumab (72.3%) compared withplacebo (77.8%). In contrast, clinical cure wasnumerically higher for bezlotoxumab (82.5%)compared with placebo. Neither of these compari-sons was statistically significant (P = .0801 andP = .0973, respectively).

Based on these results, bezlotoxumab (admin-istered IV as a single dose of 10 mg/kg over1 hour) was recently approved by the Food andDrug Administration (FDA) for the prevention ofCDI recurrence in patients aged 18 years or olderwho are receiving antibacterial drug treatment forCDI.107,108

Vaccines. Despite numerous scientific and oper-ational challenges, there are vaccine candidates inlate-stage clinical development for CDI, and 3 Cdifficile vaccines have progressed to phase 2/3 clin-ical trials.109 Some observations suggest that recur-rent CDI is associated with failure to develop anadequate immune response to C difficile toxins. Im-munization could therefore be beneficial in high-risk patients.

A phase 3 clinical trial with an estimatedprimary completion date of December 2017 isevaluating a vaccine (Cdiffense) that containstoxins A and B for induction of an immuneresponse against toxins A and B.110 The Cdiffensestudy is enrolling 2 patient cohorts: (1) those whohave had at least 2 hospital stays and received

systemic antibiotics in the 12 months prior toenrollment and (2) those scheduled for an inpa-tient hospitalization (>72 hours) for a plannedoperative procedure (kidney, bladder, urinary sys-tem, musculoskeletal system, respiratory system,circulatory system, central nervous system) within60 days of enrollment. Patients will be randomizedto the C difficile vaccine at days 0, 7, 30 or to normalsaline placebo.

TheEuropeanUnion is funding a 3-year initiativeto develop anoral (sublingual)Cdifficile vaccine; theintended strategy is to use harmless bacterial sporesthat carry the antigen and boost immunity by target-ing the protein needed for the infection to takehold.111 The candidate C difficile vaccine has beenwell tolerated by patients. To date, no C difficile–tar-geted vaccine has been approved by the FDA,although an agent is currently under clinical devel-opment by Pfizer Inc (PF-06425090).112,113

NEW AND EMERGING MEDICAL TREATMENTSTRATEGIES

New approaches to CDI prevention and treat-ment are needed (Fig 4). Antibiotics under devel-opment include cadazolid and ridinilazole.Surotomycin has had disappointing phase 3 re-sults. Multiple live biotherapeutics are being devel-oped, including freeze thawed and encapsulatedversions of fecal microbiota transplantation toimprove the practicality of treating patients withrecurrent CDI. Alternatives to fecal microbiotatransplantation that aim to improve safety,including a microbial suspension (RBX2660) anda complex spore formulation (SER-109), have pro-gressed to phase 2 studies. A nontoxigenic C diffi-cile strain has also shown promise to preventrecurrent CDI.114,115

OPERATIVE TREATMENT STRATEGIES

Operative consultation should be consideredearly in the course of severe and complicated CDI(Fig 5), as operative consultation may be benefi-cial.116,117 High mortality rates have been reportedwith operative treatment for CDI, likely related tosignificant delay in operative intervention,118 butoperative therapy for severe CDI can indeed belifesaving. A systematic review of 510 patients withfulminant C difficile colitis reported decreased mor-tality comparing operative treatment with medicaltherapy (RR 0.70, 95% CI 0.49–0.99).119

Subtotal colectomy, end ileostomy with preser-vation of rectum has been a standard recommen-ded operative treatment, particularly for fulminantcolitis. A systematic review of 31 studies (n = 1,442)

Fig 4. Emerging strategies for the prevention and treatment of primary and recurrent CDI. NTCD, Nontoxigenic Clos-tridium difficile. Reprinted with permission from Kociolek et al.114



of patients undergoing emergency operation forCDI documented that 1.1% of all patients withCDI and 29.9% with severe CDI underwent emer-gency operation. The most commonly performedoperation was total colectomy with end ileostomyin 89% of patients. In patients who underwent par-tial colectomy, reoperation to resect additional co-lon was required in 15.9% of patients. The 30-daymortality rate was high (41.3%), and the strongestpredictors of postoperative death were preopera-tive intubation, acute renal failure, multiple organfailure, and shock requiring vasopressors.120

A review of the Nationwide Inpatient Sample2001–2010 documented over 2.7 million dis-charges with a diagnosis of CDI in the UnitedStates over this decade, and colectomy was per-formed in 19,374 cases (0.7%), with an associatedmortality of 30.7%. Predictors of mortality aftercolectomy included coagulopathy, age >60 years,acute renal failure, respiratory failure, sepsis, pe-ripheral vascular disease, and congestive heartfailure. Importantly, operative treatment morethan 3 days after admission was associated withhigher mortality rates.13

Similarly, a review of the American College ofSurgeons National Surgical Quality ImprovementProgram database from 2005–2010 identified 335open colectomies for CDI with an overall mortalityrate of 33% and a median time to death of 8 days.Risk factors for postoperative mortality includedage >80 years, preoperative shock, preoperativedialysis dependence, chronic obstructive pulmo-nary disease, thrombocytopenia, coagulopathy,and renal insufficiency.121

Recent experience with a minimally invasive,colon-preserving approach as an alternative tototal colectomy has proven to be successful inselect patients. Diverting loop ileostomy andcolonic lavage followed by intravenous metronida-zole and vancomycin administered via the efferentlimb of the ileostomy (n = 42) is an accepted alter-native to total colectomy in the treatment of severecomplicated CDI with reduced mortality (19% vs50%) compared to a historical total colectomycohort (n = 42) in a single-institution (Universityof Pittsburgh) report.122

This strategy led to colon preservation in 39/42patients; 3 patients subsequently required total

Fig 5. Surgical consultation and treatment strategies for CDI. (From Brian S. Zuckerbraun MD, University of Pittsburgh.)



colectomy, either for abdominal compartment syn-dromeor for continued sepsis. The advantage of thisapproach is that it can be considered early if patientsare failingmedical management, and it can be donelaparoscopically in many patients. This approach,however, should not be considered in patients withabdominal compartment syndrome or concern forcolonic ischemia, necrosis, or perforation (Fig 6).

National and international guidelines recom-mend total abdominal colectomy with endileostomy and preservation of rectum. Diverting

loop ileostomy and colonic lavage followedby intravenous metronidazole and vancomycinadministered via the efferent limb of the ileos-tomy should be considered as an alternative tototal colectomy in selected patients (Table IV).The 2014 Eastern Association for the Surgery ofTrauma practice management guidelines foroperative treatment of CDAD strongly recom-mended that adult patients with CDI undergoearly operative care, before the development ofshock and need for vasopressors, and

Fig 6. Operative management strategy for CDI. (From Brian S. Zuckerbraun MD, University of Pittsburgh.)



conditionally recommended total or subtotal co-lectomy (versus partial colectomy or other opera-tion) as the procedure of choice.

If the diverting loop ileostomy and coloniclavage procedure are planned, it is important tohave an institutional protocol to facilitateprompt performance of this procedure becausethe supplies required may not be readilyavailable in the operating room. We have createda 1-page document that allows our operatingroom staff to obtain all supplies needed andprovides the steps of the operative intervention

in a clear, concise approach to achieve successwith this operative procedure (Fig 7).

SMALL BOWEL CDI

Small bowel involvement in CDI (enteritis) isuncommon; however, increasing case reports andseries have been published, some leading to fataloutcome. Small bowel CDI is more commonlyassociated with abdominal operations and particu-larly among patients with IBD and with totalabdominal colectomy.85 CT imaging features ofCDI of the small bowel include mesenteric or

Table IV. Guideline recommendations for operative management of CDI

Guideline Operative consultation recommended Operative treatment

SHEA/IDSA Guidelines 201066 “Severely ill patient” Subtotal colectomy, end ileostomywith preservation of rectum

American College ofGastroenterology (ACG)Guidelines 2013102

Surgical consultation should besolicited in all severe-complicatedCDI cases with 1 or more of thefollowing: hemodynamic instabilityrequiring vasopressors, clinicalsepsis with organ failure, changesin mental status, extremeleukocytosis ($50,000 cells/mL),elevated lactic acid ($5 mmol/L),or evidence of treatment failureafter 5 days of conservative therapy(strong recommendation,moderate quality evidence).

Subtotal colectomy, end ileostomywith preservation of rectum

Diverting loop ileostomy and coloniclavage followed by intravenousmetronidazole and vancomycinadministered via the efferent limbof the ileostomy; alternative to totalcolectomy in selected patients

European Society of ClinicalMicrobiology and InfectiousDiseases (ESCMID) 2014149

Patients with “systemic inflammationand deteriorating clinical conditiondespite maximal antibiotic therapy(with) toxic megacolon, acuteabdomen, and severe ileus”

Subtotal colectomy, end ileostomywith preservation of rectum.Diverting loop ileostomy andcolonic lavage followed byintravenous metronidazole andvancomycin administered via theefferent limb of the ileostomy;alternative to total colectomy inselected patients

EAST Practice ManagementGuidelines 2014150

No recommendation Subtotal colectomy, end ileostomywith preservation of rectum

WSES Guidelines for Management ofClostridium difficile infection insurgical patients 2015151

18) Patients with severe CDI whoprogress to systemic toxicity shouldundergo early surgical consultationand be evaluated for potentialsurgical intervention(Recommendation 1 C).

“patients with fulminant colitis”

19) Resection of the entire colonshould be considered to treatpatients with fulminant colitis (FC)(Recommendation 1 B).

20) Diverting loop ileostomy withcolonic lavage may be a usefulalternative to resection of entirecolon (Recommendation 2 C).

Practice parameters for themanagement of Clostridium difficileinfection. American Society ofColon and Rectal Surgeons,2015152

“There is no high-grade evidenceregarding the optimal

timing of surgical intervention, but itappears that

surgical consultation early in thecourse of disease may bebeneficial.”

Subtotal colectomy with ileostomy istypically the operative procedure ofchoice for C difficile colitis. Grade ofrecommendation: strongrecommendation based on low-quality evidence, 1C.

Diverting loop ileostomy with coloniclavage may be an alternative to totalabdominal colectomy for thetreatment of severe C difficile colitis.Grade of recommendation: weakrecommendation based on low-quality evidence, 2C.

Australasian Society for InfectiousDiseases (ASID) 2016153,154

Indications for surgery are toxicmegacolon, bowel perforation, orsevere deterioration in spite of first-and second-line medical therapy.

Subtotal colectomy, end ileostomywith preservation of rectum.Diverting loop ileostomy andcolonic lavage followed byintravenous metronidazole andvancomycin administered via theefferent limb of the ileostomy;alternative to total colectomy inselected patients



Fig 7. Checklist for preoperative and intraoperative preparation at University of Michigan



retroperitoneal fat stranding, ascites, small boweldistention and mural thickening with the terminalileum being the most affected, pneumatosis intesti-nalis (gas within the wall of the small bowel), andintrahepatic portal venous gas.69

The largest case series of ileal CDI (12 cases in5 years) also included a report of fatal ileal CDI ina 61-year-old man admitted for radical

prostatectomy with lymphadenectomy for prostateadenocarcinoma with no prior antibiotic use. Hewas discharged on postoperative day 4 but wasreadmitted with severe diarrhea; he received oraland intrarectal vancomycin and intravenousmetronidazole for treatment, but died 2 days laterof multiple organ failure. Autopsy confirmed Cdifficile enteritis in the ileum but not in the colon;



toxigenic C difficile was isolated from ileal tissue butnot colonic tissue. This case depicts the potentialrapid trajectory of disease in ileal CDI.123 A patientwith possible ileal CDI should be treated with oralvancomycin (not metronidazole) because it resultsin reliable therapeutic concentrations in the smallbowel.124

Recommendations for treatment for smallbowel CDI include IV metronidazole 500 mg IV18 hours, by mouth, orally (PO) vancomycin500 mg every 6 hours (q6h) if evidence of resolu-tion of ileus, and if ileostomy present initiate retro-grade vancomycin flushes (500 mg in 100–500 mLnormal saline q6h) via the ileostomy to reduceluminal toxin. If severe ileus is still present, consid-eration of retrograde polyethylene glycol lavage viathe ileostomy to flush out the intestinal luminaltoxin (similar to the strategy used for loop ileos-tomy and colonic lavage) may be helpful.

RECURRENT CDI TREATMENT

Recurrent CDI affects 15% to 35% of patientswith primary CDI, and additional patients go on todevelop chronic relapsing CDI. Prolonged vanco-mycin oral taper is the initial treatment strategy forrecurrent CDI. For the first recurrence, use ofthe same regimen used in the first episode isrecommended, unless the severity of disease dic-tates a switch from metronidazole to vancomycin.For the second recurrence and all subsequentrecurrences, vancomycin is typically recommendedin tapering and pulsed doses (eg, vancomycin125 mg 4 times a day for 14 days, 125 mg twice dailyfor 7 days, 125 mg daily for 7 days, 125 mg everyother day for 7 days, and 125 mg PO every third dayfor 2–8 weeks).2

Spores are only susceptible to killing by antibi-otics when they are in a fully vegetative form, andby pulsing vancomycin intermittently, spores areallowed to germinate, thus making them suscepti-ble to killing. The repetitive cycle of antibiotic-freeperiods also allows an opportunity for the normalcolonic flora to reestablish itself.

For patients with multiple CDI recurrences whobreak through a tapering/pulsed vancomycintreatment strategy, the use of a fidaxomicin“chaser” (200 mg PO twice a day for 10 days) hasbeen shown to be effective in some patients, butrandomized comparative data are not avail-able.125,126 Bezlotoxumab (administered IV as asingle dose of 10 mg/kg over 1 hour) wasapproved (October 2016) by the FDA for the pre-vention of CDI recurrence in patients aged 18 yearsor older who are receiving antibacterial drug treat-ment for CDI.

Fecal microbiota transplant. In patients withrecurrent CDI, fecal microbiota transplant (FMT)aims to restore the normal composition of the gutmicrobiome and is recommended when antibi-otics fail to resolve CDI. The efficacy of FMT inrecurrent CDI had previously been limited to caseseries and open-label trials.127 The first random-ized controlled double-blind clinical trialenrolled 46 patients who had 3 or more recur-rences of CDI and received a full course of vanco-mycin for their most recent acute episode in 2academic medical centers. FMT with donor orautologous stool was administered by colonos-copy with the primary end point of resolution ofdiarrhea without need for anti-CDI therapy dur-ing the 8-week follow-up. This study demon-strated that donor FMT was more efficacious(90.9% clinical cure) than autologous FMT(62.5% clinical cure) in prevention of additionalCDI episodes.128

Although FMT is a highly effective treatment forrecurrent or refractory CDI, 10% to 20% ofpatients fail to achieve a cure after a single FMT.Risk factors for FMT failure have been identifiedand include severe and severe-complicated indica-tion, inpatient status during FMT, and increasednumber of previous CDI-related hospitalizations. Aprediction model based on these risk factors hadgood discrimination for identification of patientsat high risk of failure after FMT therapy.129 FMT isassociated with primary and secondary cure ratesof 88% and 94% in patients with severe or compli-cated CDI, respectively.130

The National Institute of Allergy and InfectiousDiseases of the National Institutes of Health hasprovided funding to launch the American Gastro-enterological Association Fecal Microbiota Trans-plantation National Registry, the first nationalregistry to track short- and long-term outcomesin patients who have undergone the gut-micro-biome–based therapy. The American Gastroenter-ological Association plans to put a formalinfrastructure into place for physicians and pa-tients to report information that will standardizebest practices for FMT while offering insight intothe gut microbiome and its role in human healthand disease.131

Probiotics. The use of probiotics to restorebalance to colonic microbiota either in the treat-ment or prevention of CDI has been investigated.An updated Cochrane systematic review and meta-analysis of 23 randomized controlled trials,including 4,213 patients (moderate quality evi-dence), suggests that probiotics are both safe andeffective for preventing C difficile–associated

Table V. Prevention strategies for CDI

Handwashing

Contact precautions

Antibiotic stewardship

Chlorhexidine gluconate bathing

Hydrogen peroxide vapor for terminal room cleaning

Pulsed xenon ultraviolet light for terminal room

cleaning

Daily cleaning with hydrogen peroxide disposable wipes

Probiotics



diarrhea.132,133 The SHEA/Infectious Diseases So-ciety of America treatment guidelines do notrecommend probiotics for CDI treatment due tolimited data and potential risk for bloodstreaminfection.

Of the probiotics studied, Saccharomyces boulardiihas the most data as a potential adjunctive treat-ment agent in recurrent CDI in adult pa-tients.134,135 A recent cost-effectiveness analysisconducted in Canada evaluated the impact oforal probiotics on the incidence and cost ofCDAD among hospitalized adult patients. The pre-ventive intervention involved the administration ofone oral dose (capsule) in any formulation withthe course of antibiotics and continuing for5 days after the completion of therapy (the controlgroup received no probiotics). The study docu-mented a reduced risk of CDAD and a cost savingsof $518 per patient treated.120,136

In the operative patient population, a singledose of antibiotic prophylaxis is often sufficient tostimulate the development of CDAD. If we extrap-olate to a population undergoing an operativeprocedure that would most likely require a singleprophylactic antibiotic dose, conservatively esti-mating that number to be 25 million, the pro-jected saving to the US health care system forreducing the risk of CDAD using a probiotic agentwould approach $13 billion. Further studies arewarranted in selective surgical patient populationsto validate the cost-effective and risk-reductionbenefits associated with probiotic prophylaxis forCDI.

INFECTION CONTROL STRATEGIES ANDPREVENTION

The challenges posed by CDI represent one ofthe most difficult patient care issues confrontinghealth care workers and infection control

personnel. All efforts to prevent and control CDIshould be implemented (Table V). Early recogni-tion of patients who are suspected of having orwho are diagnosed with CDI is the primary stepin preventing the spread of this epidemiologicallysignificant organism.49 C difficile can spread bydirect or indirect contact with the patient or his/her environment. CDI patients should be placedin Contact Precautions as recommended by theHealthcare Infection Control Practices AdvisoryCommittee/Centers for Disease Control and Pre-vention guidelines for isolation precautions. Strictadherence to the components of Contact Precau-tions will help to break the chain of infection, mak-ing a significant impact on limiting the spread orcross-contamination of this organism.

The following infection control strategies havedocument efficacy when applied in an appropriatemanner.137-139

(I) Patient placement: Ideally, CDI patients should be

kept in a private room with a bathroom or

commode solely dedicated for their use.

(II) The use of personal protective equipment: Incorporating

effective and consistent barrier precautions is

deemed critical to preventing transmission of

spores from patient to health care providers and

subsequently to other patients. It is important

that personal protective equipment (gown and

gloves) be donned before entering the patient’s

room and discarded before leaving the patient

room. High-touch surfaces like bed railings, door-

knobs, and light switches are often highly contam-

inated with C difficile spores. Consequently, gloves

must be donned before contact with patients or

their environment and throughout the period of

direct or indirect patient care.

(III) Patient transport: Unless it is absolutely necessary,

transport of CDI patients from their rooms should

be limited as much as possible. Individual persons

involved in this transport should be aware of the

patients’ status and use appropriate personal pro-

tective equipment.

(IV) Patient care equipment, instruments, devices, and patient

care environment: C difficile spores will contaminate

patient care equipment and devices through fecal

shedding or through contaminated hands of the

patient or health care providers. C difficile spores

can persist for months within the health care envi-

ronment and be transmitted to patients over a long

period of time (months). Fecal contamination of

surfaces, devices, and materials, such as commodes,

thermometers, and blood pressure equipment may

provide a reservoir for C difficile spores to dissemi-

nate, leading to transmission throughout the



health care environment. Disinfectant products

with approved Environmental Protection Agency

registration should be used for daily routine clean-

ing in the health care setting and hypochlorite-

based disinfectants used for environmental surface

disinfection in those patient-care areas where sur-

veillance and epidemiology data indicate ongoing

transmission of C difficile. The Centers for Disease

Control and Prevention currently recommend

that hospital rooms be terminally cleaned with

bleach when patients are discharged or trans-

ferred. The use of selective spectrum ultraviolet

light and hydrogen peroxide vapor have demon-

strated in both laboratory and clinical trials to

reduce (or eliminate) C difficile (vegetative cells

and spores) from inert, contaminated surfaces.140

Hand hygiene. Health care providers’ hands areoften contaminated with C difficile after patient con-tact. After gloves are removed, health care providersshould wash their hands with soap and water rinse.Although alcohol hand gel products are effectiveagainst vegetative cells, they are ineffective againstclostridial spores.141 Numerous studies have docu-mented that judicious compliance with appropriatehand hygiene practice is an effective strategy forreducing the risk of dissemination and acquisitionof C difficile within the health care environment.142

Antibiotic stewardship. Judicious and appro-priate use of antibiotics under an antimicrobialstewardship program plays an important role inprevention strategies for C difficile.143 CDI canoften be linked to prior antibiotic use. Virtuallyall antibiotics produce disruption of the hostnormal colonic flora but differ in their capabilityto cause collateral damage to the patient’s gastro-intestinal flora. There are 2 key considerationswhen evaluating the risk for CDI: (1) the level ofrisk conferred by antibiotics, categorized as low, in-termediate, or high risk; and (2) the number ofdays the patient will be at risk for CDI.

A patient who receives a narrow-spectrum anti-biotic for less than 1 day will be considered to havea low risk and a short duration of risk. Alterna-tively, for a patient who receives operative prophy-laxis with an unnecessary broad-spectrumantibiotic, the level of risk for developing CDIwould move from low to high without any addi-tional clinical benefit from the inappropriatedrug.144

A recent case-controlled clinical trial found thatertapenem operative prophylaxis was significantlyassociated with postoperative CDI (P < .028).145

Furthermore, an analysis of morbidity and mortal-ity outcomes in postoperative CDI in Veterans

Affairs hospitals found that administration of 3or more classes of antibiotics in a 60-day preopera-tive period was one of several significant risk fac-tors.146 Implementation of an effectiveantimicrobial stewardship program would assist inthe development of institutional policies thataddress inappropriate antimicrobial use andlowering the potential for collateral damage.147

In conclusion, C difficile infections are the lead-ing cause of health care–associated infectious diar-rhea, posing a significant risk for both medical andsurgical patients. Because of the significantmorbidity and mortality associated with CDI,knowledge of the epidemiology of C difficile incombination with a high index of suspicion andsusceptible patient populations (including surgi-cal, postcolectomy, and IBD patients) is warranted.

CDI presents with a wide spectrum of disease,ranging from mild diarrhea to fulminant colitis orsmall bowel enteritis and recurrent CDI. Earlyimplementation of medical and operative treat-ment strategies of CDI is imperative for optimalpatient outcomes. National and internationalguidelines recommend early operative consulta-tion and total abdominal colectomy with endileostomy and preservation of rectum. Divertingloop ileostomy and colonic lavage followed byintravenous metronidazole and intracolonic van-comycin administered via the efferent limb of theileostomy should be considered as an alternative tototal colectomy in selected patients.

New and emerging strategies for CDI treatmentinclude monoclonal antibodies, vaccines, probiot-ics, biotherapeutics, and new antibiotics. A suc-cessful C difficile prevention and eradicationprogram requires a multidisciplinary approachthat includes early disease recognition, implemen-tation of guidelines for monitoring adherence toenvironmental control, judicious hand hygiene,evidence-based treatment and management strate-gies, and a focused antibiotic stewardship pro-gram. Surgeons are an important part of theclinical team in management of CDI preventionand treatment.

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