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GASTROENTEROLOGY 2009;136:1899–1912

reatment of Clostridium difficile-Associated Disease

Daniel A. Leffler J. Thomas Lamont

ivision of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

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lostridium difficile infection is an increasing burdeno the health care system, totaling more than $1 bil-ion/year in the United States. Treatment of patientsith C difficile infection with metronidazole or vanco-ycin reduces morbidity and mortality, although the

umber of patients that do not respond to metroni-azole is increasing. Despite initial response rates ofreater than 90%, 15%–30% of patients have a relapsen symptoms after successful initial therapy, usuallyn the first few weeks after treatment is discontinued.ailure to develop specific antibody response has re-ently been identified as a critical factor in recur-ence. The review discusses the different managementtrategies for initial and recurrent symptomatic Cifficile infections.

lostridium difficile is an anaerobic, gram-positive,spore-forming, toxin-producing bacillus transmit-

ed between human beings by the fecal– oral route. Thisathogen infects �20% of hospitalized patients takingntibiotics1 and is an increasing burden to the healthare system. Nosocomial C difficile infection has beenstimated to more than quadruple the cost of otherwiseatched hospitalizations,2 totaling �$1 billion/year in

he United States.3,4 The most important control mea-ures are proper hand hygiene with the use of soap, water,nd disposable gloves; isolation of infected patients; andimitation of unnecessary antibiotic use.

Specific treatment of C difficile infection with metronida-ole or vancomycin reduces morbidity and mortality. Ineneral, metronidazole’s high level of efficacy and low costake it the initial treatment choice for nonpregnant adults.

ancomycin is reserved for individuals with severe infectionnd those who have failed or cannot take metronidazoleherapy. C difficile is highly sensitive to both antibiotics initro, but treatment failures with metronidazole appear toe increasing. Despite initial response rates of �90%, 15%–0% of patients will experience a relapse in symptoms after

uccessful initial therapy, usually in the first few weeks after

reatment is discontinued. Recurrence may involve reinfec-ion with the initial strain or a new strain. Failure to developpecific antibody response has recently been identified as aritical factor in recurrence. Management strategies for ini-ial and recurrent symptomatic C difficile infection are de-cribed in detail below.

Epidemiology and PathogenesisInfection occurs when a susceptible host ingests C

ifficile spores, which then colonize the large bowel (Fig-re 1) and release 2 protein exotoxins that cause colitisnd diarrhea. Healthy adults are protected from C difficileolonization and disease by normal bacterial flora and byntibody to toxin A.1 Antibiotic therapy, bowel surgery,nd rarely cancer chemotherapy change the indigenousolonic microflora, allowing C difficile to colonize in someatients. C difficile infection is most common in elderlyospitalized adults receiving either antibiotics or cancerhemotherapy. C difficile also colonizes 60%–70% ofealthy newborns and infants up to 12–18 months of ageho lack the adult microflora.5,6 However, infants rarelyevelop colitis even with large amounts of toxins in theirtool. The infantile carrier state disappears at 18 –24

onths of age, at about the same time that the normaldult flora becomes established. The lack of clinical re-ponse to toxin A in newborn animals was attributed tohe lack of toxin-binding receptors.7 The actual incidencef clinical C difficile infection in hospitalized patientsaries widely with time and between locations; one recenttudy estimated an incidence of 1.5% in adults receivingerioperative antibiotic prophylaxis from 2003 to 2005.8

In the external environment, C difficile survives as heat-,cid-, and antibiotic-resistant spores. After ingestion and

Abbreviations used in this paper: Ig, immunoglobulin; IVIG, intrave-ous immunoglobulin; MIC, minimal inhibitory concentration; VRE,ancomycin-resistant enterococci.

© 2009 by the AGA Institute0016-5085/09/$36.00

doi:10.1053/j.gastro.2008.12.070

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1900 LEFFLER AND LAMONT GASTROENTEROLOGY Vol. 136, No. 6

olonization, spores convert to vegetative forms in thearge intestine which divide and produce toxins. Sporesemain viable for months or longer in the hospital wherehey can be detected on bedding, hospital furniture, andquipment and on the skin, fingernails, and rings ofatients and their caregivers.

Risk FactorsThe most important risk factor for the develop-

ent of C difficile infection is antibiotic use. Ampicillin ormoxicillin, cephalosporins, clindamycin, and fluoro-uinolones are most frequently associated with disease,ut almost all antibiotics, including metronidazole, haveeen associated with infection, although many show at

east some in vitro activity against C difficile (Table 1).ospitalization or residence in nursing homes or reha-

ilitation facilities are also main predisposing factors,9

robably because of the increased concentration ofpores from caregivers and infected patients. Advancedge also predisposes to risk of acquisition as well aseverity of infection.8 In one study individuals older than5 years had a 10-fold higher risk of contracting C difficileuring an outbreak than did younger patients.10 The

ncreasing incidence of hospital-acquired infection haseen accompanied by increased reports of community-cquired infection.11,12 The role of acid suppression in Cifficile infection is unclear. In theory, reduction of gastric

Figure 1. Pathogenesis of C difficile infection.

cid should allow more viable spores to reach the colon; N

owever, because spores are generally acid resistant, themportance of this is unclear. Although some studiesave shown an increased risk of C difficile infection withcid suppression,13,14 others have not confirmed thisnding.9,15 It has been suggested that acid suppression isssociated with infection only as a marker of increasedomorbidity.16 Other important emerging risk factors for

difficile infection include white race17 and inflammatoryowel disease in which C difficile is the most commonuperimposed infection.18 –21

Clinical Spectrum of C difficileInfectionTwo factors appear to influence clinical expres-

ion of disease: virulence of the infecting strain and theost immune response. In particular, infection with theighly virulent NAP1/027 strain characterized by fluoro-uinolone resistance and higher levels of toxin produc-ion than conventional strains causes a 3-fold higher

ortality rate than matched controls infected with lessirulent strains.10,22,23 Outbreaks with this and other ep-demic strains in North America, Europe, and Asia areccompanied by dramatic increases in incidence and se-erity of infection. This has public health implications,ecause surveillance for epidemic strains may allow con-rol measures to limit the spread and morbidity associ-ted with these outbreaks. Although all strains showdequate in vitro sensitivity to metronidazole and van-omycin, reduced clinical response to metronidazole ismerging,24 –27 perhaps relating to increasing minimalnhibitory concentration (MIC).

The host immune response appears to develop in in-ancy. Infants that are asymptomatic carriers of toxigenic

difficile develop a lasting serum immune response tooxins A and B6 (Figure 2). Moreover, mice infected with

able 1. Susceptibility of C difficile Isolates to VariousAntibiotics

AgentMedian MIC90

(�g/mL) Range (�g/mL) % Resistant

etronidazole 0.5 �0.06–1 0ancomycin 1 �0.5–4 0acitracin �128 �128 NAusidic acid 2 �0.06–64 1.2ifampin �0.06 �0.06 0efotaxime �128 64 to �128 100eftriaxone �128 16 to �128 82.6eropenem 4 0.5–8 0iperacillin-tazobactam

8 4 to �128 0.4

larithromycin �128 0.125 to �128 85.3lindamycin �128 0.125 to �128 14.7iprofloxacin �128 16 to �128 100evofloxacin �32 �32 100atifloxacin 128 2 to �128 82.2

OTE. Data from reference 27.

A, not applicable.

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difficile or vaccinated against the toxins are protectedgainst subsequent infection.28 In adult human beings,igher titers of serum immunoglobulin (Ig) G againstoxin A appear to protect against C difficile–induced diar-hea and promote the development of the asymptomaticarrier state.1 Conversely, low levels of toxin A antibody,pecifically, antitoxin A IgM and posttreatment antitoxin

IgG2 and IgG3, increase the risk of symptomatic Cifficile recurrence.29 –31

Overview of TherapyPermanent cure of C difficile requires restoration of

ormal colonic microflora, resulting in the elimination ofdifficile. Therefore, patients with mild symptoms can

ccasionally be managed conservatively by stopping ad-inistration of the inciting antibiotic and following

hem to confirm clinical improvement. In one early studyf clindamycin-associated colitis, which in retrospect wasrobably C difficile colitis, all patients recovered afteressation of clindamycin administration, followed byupportive care.32 Antibiotic treatment of C difficile aimso ameliorate symptoms while allowing gradual restora-ion of the normal gut flora (Table 2).

It is also important to note that symptoms of C difficilenfection are not specific and that confirmation of theiagnosis should be made with the use of assays for fecaloxin before specific therapy. Nonspecific antibiotic-asso-iated diarrhea, postinfectious irritable bowel syndrome,ew onset celiac disease or inflammatory bowel disease,r other infections, including Klebsiella oxytoca, Clostridiumerfringens, and Staphylococcus aureus33 all may be confusedith C difficile–associated disease.34 The reported sensitiv-

ty and specificity of C difficile toxin assays varies from.83 to 0.95 and from 0.93 to 1.00, respectively.35 Incutely ill patients with probable C difficile infection,reatment should be initiated while test results are pend-ng and, in select cases, continued despite negative toxinssays. Sigmoidoscopy or colonoscopy may be helpful

igure 2. Age-related prevalence of antibody to C difficile toxin A and. Modified from Viscidi et al.6

hen another cause such as inflammatory bowel disease p

s suspected. However, they are not recommended foriagnosis because perforation may occur, and pseudo-embranes may occur in only half of infected patients.36

olonoscopy is recommended because pseudomem-ranes may be limited to the right colon only.37

Antibiotic Treatment of Initial C difficileInfectionMost patients with acute C difficile–associated dis-

ase require antibiotic therapy and, whenever possible,iscontinuation of the predisposing antibiotics. It is vitalo assess disease severity based on clinical and demo-raphic information, to determine the most appropriatereatment for each individual. Markers of severity includeevere diarrhea, pseudomembranous colitis, ileus, feverecause of C difficile, age older than 60 years, and acuteenal failure (Table 2).

In younger patients with mild symptoms, a reasonablepproach is to stop the predisposing antibiotic and pro-ide supportive care with hydration and close monitoringor deterioration. This approach is supported by datahowing faster elimination of spores in carriers not givenntibiotics, a finding that could have important conse-uences in limiting spread and recurrence.38

For individuals with comorbidities and those withoderate-to-severe infection, specific antibiotic therapy

imed at C difficile is warranted. Although toxin-bindingesins and probiotics are currently being studied, the onlyherapies confirmed to be effective are antibiotics andolectomy for patients with fulminant disease not re-ponding to antibiotic therapy.

Primarily because of its low cost, metronidazole isurrently recommended as first-line therapy. The value ofimiting vancomycin use to slow the emergence of van-omycin-resistant enterococci (VRE) is unclear becauseetronidazole has also been shown to select for VRE,39,40

nd VRE colonization rates appear similar in patientsreated with vancomycin and metronidazole.41 The stan-ard initial therapy is 500 mg orally (7.5–15 mg/kg inhildren) 3 times daily for 14 days, which successfullyesolves symptoms in �90% of patients within 1eek.42,43 Oral vancomycin is preferred if metronidazoleas failed or is contraindicated. This approach is sup-orted by professional society guidelines44 and a recentochrane review.45 However, metronidazole’s apparentecreasing efficacy46,47 (Figure 3) and slower response,ompared with vancomycin,43 has led to controversybout this recommendation. Moreover, recent data sup-ort the use of vancomycin as a first-line treatment in

ndividuals with severe C difficile infection.48,49 Althoughata are lacking, antidiarrheal agents and narcoticshould be avoided in patients with symptomatic C difficilenfection because of concerns about toxin retention and

ossible precipitation of toxic megacolon.

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MetronidazoleMetronidazole is generally recommended as the

rst-line treatment of C difficile. Parenteral, oral, or rectaldministration can be used in patients unable to takeral doses and leads to similar systemic and colonicissue drug levels.

Metronidazole, a nitroimidazole-class antibiotic andntiprotozoal, is administered and taken up in an inac-ive state by anaerobic organisms then reduced to its

able 2. Classification and Treatment of Initial C difficile Infe

Severity Clinical manifestations

arrier ● No discernible clinical symptoms or sigild to moderate ● Mild diarrhea � 12 stools/day

● Afebrile● Mild-to-moderate abdominal discomfort

tenderness● Nausea with rare or absent vomiting● With or with hospitalization● Not in intensive care unit● Dehydration● Leukocytosis �20,000● BUN or creatinine above baseline

evere ● Severe or bloody diarrhea � 12 stools/● Pseudomembranous colitis● Severe abdominal pain● Nausea or vomiting● Ileus● Temperature �38.9°C● Age � 60 years● in intensive care unit● Leukocytosis � 20,000● Albumin � 2.5mg/dL● Renal failure

ulminant ● Toxic megacolon● Peritonitis● Albumin � 2.5mg/dL● Renal failure● Respiratory distress● Hemodynamic instability

UN, blood urea nitrogen.

ctive form. It induces microbial cell death by DNAisruption and subsequent inhibition of nucleic acidynthesis. Metronidazole is most effective in anaerobicites such as the human colonic lumen. In addition to itsntimicrobial properties, metronidazole also appears toave anti-inflammatory, antioxidant, and immunomodu-

atory effects.50,51

Oral absorption of metronidazole is highly efficient,ith a serum half-life of 8 hours and bioavailability of

Figure 3. Recent increase in re-ported treatment failures for met-ronidazole. Modified from Aslamet al.46

Treatment

● No treatment is indicated● Discontinuation of predisposing antibiotics● Hydration● Monitor clinical status● Isolation● Consider probiotics● Oral metronidazole 500 mg 3 times daily or intravenous

metronidazole 500 mg 3 times daily if not toleratingoral intake

● Oral vancomycin 125 mg 4 times daily if intolerant ofmetronidazole

● As above plus:● Oral vancomycin 125 mg 4 times daily● Consider addition of intravenous metronidazole 500 mg

3 times daily

● As above plus:● Surgical consultation● Oral vancomycin 125 mg 3 times daily and intravenous

metronidazole 500 mg 3 times daily● Consider IVIG

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90%. Food may slow the rate, but not the overall extent,f absorption. Intravenous and oral administration re-ults in distribution to all tissues and fluids, includinghe placenta and breast milk. Sixty to eighty percent of

etronidazole is metabolized by the liver and subse-uently cleared by the kidneys; the remaining unmetabo-

ized metronidazole is excreted in feces, with similarmounts reaching the colon after oral and parenteraldministration. Metronidazole preferentially diffusesrom the serum and interstitial compartment of the in-amed colon into the lumen, a property that can increase

ts efficacy against C difficile.52 Impaired renal functionoes not alter metronidazole pharmacokinetics, al-hough the dose should be reduced in patients withevere liver disease.

Side effects and toxicity. The most common sideffects of metronidazole are metallic taste, headache, nau-ea, and a disulfiram-like effect with alcohol, although theseymptoms rarely require cessation of treatment. The neuro-oxic effects of metronidazole include peripheral neuropa-hy, vertigo, and, rarely, ataxia or encephalopathy. Fortu-ately, neuropathy is seldom observed in patients whoeceive �2 weeks of therapy, and most cases have occurredfter exposure to standard doses for �1 month.53–55 Treat-ent with metronidazole should be immediately discontin-

ed if there is concern about neurotoxicity, which may note reversible. Metronidazole is rated pregnancy class B, but

t should not be given in the first trimester, because ofoncerns of teratogenicity based on animal data.

Activity. Metronidazole is highly active againstost strains of pathogenic C difficile with only rare re-

orts of antibiotic resistance.56 –58 Although MIC washown to differ between strains, MIC remains below inivo therapeutic levels in nearly all isolates.26,59,60 Increas-ng evidence suggests, that prolonged exposure to met-onidazole can lead to resistance61 and that susceptibilityecreases over time.48,62,63 For this reason, surveillance ofntibiotic resistance in C difficile is ongoing and resistanceould limit the use of this antibiotic in the future.

VancomycinVancomycin, a tricyclic glycopeptide that inhibits

acterial cell wall synthesis,64 has broad activity againstram-positive bacteria, but it essentially has no effect onram-negative bacteria or fungi. Vancomycin is orallydministered in its active form and, because o f its largeolecular weight, is not absorbed and reaches the colon

ntact, an advantage for the treatment of C difficile. Con-ersely, parenteral vancomycin is not excreted into theolonic lumen and, for this reason, is not effective forreatment of C difficile. However, ileus may result in un-redictable delivery of vancomycin to the colon. In theseatients the drug may be delivered by rectal or colonicube or by enemas. Although the initially recommended

ose used to treat C difficile was 500 mg 4 times daily, 125 o

g 4 times daily also results in concentrations in theolon well above the MIC for C difficile, with identicallinical outcomes (Figure 4).42

Side effects and toxicity. Because vancomycin isot absorbed systemically from the gastrointestinal tract,eported side effects observed during parenteral admin-stration, including ototoxicity, nephrotoxicity, and Red-

an syndrome, are avoided.64 Mild upset stomach andausea are the most common side effects of oral vanco-ycin and rarely limit treatment. Although systemic van-

omycin is classified as pregnancy class C, oral vancomy-in is the agent of choice for C difficile infection duringregnancy.

Activity. Vancomycin is highly active against alltrains of pathogenic C difficile, and resistance has beeneported in only a single study65 (Table 1). Vancomycin isecommended as first-line therapy in pregnant women, inhildren younger than 10 years of age, and for severenfections.

Regimen. Initial treatment and treatment of arst recurrence should be for 10 –14 days. Although thereoes not appear to be any benefit of vancomycin com-ared with metronidazole in treating mild-to-moderate Cifficile infection, some evidence suggests that outcomesre improved with the use of vancomycin for severeisease48 (Figure 5). Vancomycin enemas can be givenhen oral administration is not possible; colonoscopicecompression with vancomycin lavage was described in

igure 4. Equivalent response of low and high dose vancomycin.Modified with permission from Fekety et al.42)

ne report.66

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1904 LEFFLER AND LAMONT GASTROENTEROLOGY Vol. 136, No. 6

Other TreatmentsAlthough metronidazole and vancomycin are the

ainstays of therapy for symptomatic infection, severalther agents (Table 4) are used or under investigation for

difficile, either as stand-alone treatments or as adjunc-ive agents.

Alternative AntibioticsRifaximin is a nonabsorbed antibiotic similar to

ifampin that inhibits bacterial RNA synthesis. The lackf systemic absorption gives rifaximin a favorable safetyrofile, especially in cases requiring prolonged treatment.nimal data67 and human studies68 –71 suggest efficacy inoth initial and recurrent C difficile infection, but wide-pread use of this agent for C difficile is likely to be limitedy the appearance of resistant strains.68,72 Rifaximin isesignated pregnancy class C.Nitazoxanide is a synthetic antiparasitic and antibiotic

hat appears to interfere with enzyme-dependent electronransfer and has activity against many anaerobic and

icroaerophilic bacteria. Side effects are mild and areimilar to placebo. Studies have shown in vitro and clin-cal efficacy of nitazoxanide against C difficile,25,73–76 andecent studies have reported non-inferiority comparedith both metronidazole74 and vancomycin.77 Nitazox-nide is currently approved only for use in Giardia intes-inalis and cryptosporidium infection in children. Nita-oxanide is designated pregnancy class B.

Bacitracin is an inhibitor of cell wall synthesis derivedrom Bacillus subtilis. In general, this agent is less effectivehan vancomycin, and clearance of viable spores from thetool occurs in a significantly lower percentage of indi-iduals treated with bacitracin.78 – 81 Bacitracin is morexpensive than metronidazole and currently only avail-ble in topical formulations; it is not recommended forreatment of C difficile infections.

Ramoplanin is a novel glycolipodepsipeptide antibioticith broad activity against C difficile, S. aureus, and van-

omycin-resistant enterococci, by inhibiting peptidogly-an synthesis. A phase 2 study reported similar efficacy to

Figure 5. Vancomycin is more effective than metronidazole for

ancomycin in patients with mild-to-moderate C difficile b

nfection.82 Ramoplanin is currently being tested inhase 3 trials for VRE, and further studies are plannedor C difficile.

Teicoplanin is similar to vancomycin in structure,ode of action, and antibacterial activity. Small studies

f teicoplanin report a benefit compared with vancomy-in,45 although it is not yet approved for use in thenited States. Oritavancin is another vancomycin analog

urrently under review by the Food and Drug Adminis-ration. Early data suggest that, unlike vancomycin, ori-avancin has activity against C difficile spores, a trait which

ay be important in preventing relapse.83

Rifampin has also been studied for treatment of Cifficile infection either alone or with metronidazole. Usef rifampin has fallen from favor after a recent studyeported increased mortality in patients treated with met-onidazole and rifampin compared with metronidazolelone.84

Treatment of Acute Fulminant InfectionDespite the efficacy of antibiotic treatment, acute

difficile infection remains a disease that has a high ratef morbidity with an estimated case–fatality rate of2%.85 Severe C difficile colitis tends to occur during the

nitial infection or first recurrence. Patients with riskactors such as advanced age, significant comorbidities,igh peak white blood cell count, and lactate acidemiare at increased risk of death and should be followedlosely. Importantly, diarrhea may be absent in cases ofevere C difficile infection with toxic megacolon, and aigh index of suspicion must be kept in these situationso prevent delay in therapy. Hemodynamic instability isonsistently associated with high rates of mortality.86,87

nfortunately, the interval between presentation and he-odynamic collapse can be short and unpredictable,ith a mean of 9 days in one study88 but a range of 0 to30 days.Patients with fulminant disease should be treated with

oth oral vancomycin and intravenous metronidazoleespite a lack of evidence from clinical trials about com-

e C difficile infection. Modified with permission from Zar et al.48

ination therapy. If oral administration of medications is

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ot possible because of ileus, parenteral metronidazolean be supplemented with vancomycin enemas. Closeonitoring of clinical status is vital, and, for patientsho fail to respond to antibiotics or who have deterio-

ating hemodynamics, respiratory status or renal func-ion, urgent surgical intervention may be required. Pa-ients who are not good candidates for surgery can beiven doses of pooled human immunoglobulin (200 –500g/kg/day) until they improve, although evidence to

upport efficacy of this therapy is anecdotal.For patients with fulminant disease and severe ileus,

oxic megacolon, or localizing peritoneal signs, emergentubtotal colectomy and ileostomy is generally required;ostoperative mortality rates range from 35% to 80%.andomized trials evaluating the timing or type of sur-ical procedure for severe C difficile infection are unavail-ble; however, observational studies suggest that survivals improved with prompt surgical intervention in pa-ients with severe or fulminant infection.86,87,89 –93 Subto-al colectomy is the procedure of choice because reportsf hemicolectomy suggest increased mortality.91

Treatment of Recurrent C difficileInfectionAfter successful initial therapy, approximately 15%–

0% of patients experience a symptomatic recurrence afteriscontinuation of antibiotics.30,94–100 Older patients andhose with a history of prior C difficile recurrence are at anven higher risk (�50%) for recurrent disease.47,101 Mostecurrences happen within 2 weeks of stopping therapy, butelayed recurrences have been documented.95,100 Approxi-ately half of recurrent C difficile infections are caused by

epeated ingestion of bacteria (reinfection) before the nor-al intestinal flora recovers, and half are attributed to

ncomplete eradication of the original strain during antibi-tic treatment (relapse).101–104 The first recurrence can bereated with the same antibiotic, for example a 14-dayourse of metronidazole (if tolerated) or with supportiveare alone, if symptoms are mild. Unfortunately, a signifi-ant rate of further episodes follows a first recurrence�65%, in one study96). Management strategies for recur-ent C difficile infection include repeat courses of metroni-azole or vancomycin, tapered and pulsed dosing of vanco-ycin, toxin-binding agents such as cholestyramine,

robiotics such as Saccharomyces boulardii, and immunother-py, but none are supported by randomized large clinicalrials4,34,95,96,100,105–115 (Tables 3 and 4).

For patients who experience �2 recurrences of symp-omatic C difficile infection, a change in strategy is war-anted. Before starting antibiotic therapy, the diagnosisf recurrent C difficile infection should be confirmed bytool assay, because other causes, including postinfec-ious irritable bowel syndrome, have similar presenta-ions. For confirmed recurrent C difficile infection, weecommend a 6-week pulsed-tapered course of oral van-

omycin therapy (Table 3). During continuous antibiotic n

herapy C difficile persists in the bowel lumen as antibi-tic-resistant spores.106,107 Pulsed doses of antibioticsay allow spores to germinate into antibiotic-sensitive

egetative forms, which are then killed on the next day ofntibiotic therapy. Pulsing may also allow restoration oformal colonic flora while conferring adequate protec-ion against C difficile. Metronidazole is generally notecommended for long-term therapy, because of the riskf peripheral neuropathy, particularly in older patients.robiotics or toxin-binding resins107 may provide addi-ional benefit when added in the later weeks of thentibiotic taper and continued for 4 – 6 weeks after anti-iotic therapy is stopped. A more recent strategy reportedor treatment of multiply-recurrent C difficile infections ishe addition of a 2-week course of rifaximin (400 – 800

g daily) in 2 or 3 divided doses for 2 weeks, immediatelyfter 10 –14 days of vancomycin therapy while the patients still in clinical remission.68 Seven of 8 patients with a

inimum of 4 prior recurrent episodes treated in thisanner had no further recurrences.Despite these treatment strategies, some patients still

ave repeat bouts of C difficile infection, after multiplettempts at eradication. For infirm or elderly patients, weometimes recommend chronic vancomycin therapy athe lowest effective dose, usually 125 mg daily or everyther day for an indefinite period. Immunotherapy orecal bacteriotherapy, described below, are other optionsn younger patients or if recurrences are particularlyevere.

Toxin-Binding ResinsC difficile toxins in the colonic lumen lead to clin-

cal disease, but the bacteria itself is not invasive and does

able 3. Treatment of Recurrent C difficile Infection

Initial recurrence● 14-day course of oral metronidazole or vancomycin● Consider probiotics

Second Recurrence● Tapered pulse dose oral vancomycin

� 125 mg 4 times daily for 1 week� 125 mg twice daily for 1 week� 125 mg daily for 1 week� 125 mg every other day for 1 week� 125 mg every third day for 2 weeks

● Consider 1-month course of probiotics starting in the final 2weeks of antibiotic therapy

Third or subsequent recurrence● Tapered pulse dose oral vancomycin (see above)

Followed by● 14-day course of rifaximin, nitazoxanide, or toxin-binding resins● Consider 1-month course of probiotics starting in the final 2

weeks of antibiotic therapy● Consider intravenous immunoglobulin or fecal bacteriotherapy● Consider chronic low-dose suppressive therapy with oral

vancomycin for elderly patients and those with multiplecomorbidities

ot cause tissue damage. This observation prompted

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1906 LEFFLER AND LAMONT GASTROENTEROLOGY Vol. 136, No. 6

esearch into the efficacy of compounds that bind andequester C difficile toxin but do not alter the intestinalora or lead to antibiotic resistance. Unfortunately, ini-ial studies with the bile acid– binding resins colestipolnd cholestyramine were disappointing, with responseates in patients with acute infection of 36% and 68%,espectively.116 –118 These findings largely relegated these of binding resins to adjunct therapy of patients who

ail to respond to antibiotics or those with mild diseasehat do not tolerate or need antibiotics. Later studiesetermined that the binding affinity of cholestyramine to

difficile toxin was substantially greater than that ofolestipol119; these findings suggest that higher affinityinding agents might be more effective.

Tolevamer, a nonabsorbed anionic polymer, was devel-ped specifically as a high-affinity binder of C difficileoxins. Studies in animals showed that tolevamer wasuperior to metronidazole in reducing acute C difficilenfection.120 A phase 2 study reported efficacy in patientsith mild-to-moderate C difficile infections that was sim-

lar to that of vancomycin with a trend toward lower ratesf recurrence in the group given tolevamer.121 However a

arger phase 3 study suggested that tolevamer was infe-ior to vancomycin.49 Investigations into other formula-ions of tolevamer are underway.122

ImmunotherapyThe association between low serum levels of IgG

ntitoxin A and increased disease severity1,30,31 suggestshat bolstering the immune response to C difficile toxins

ight prevent or ameliorate disease in patients. Animalodels support this concept; passive immunization has

een shown to substantially improve outcome123,124 ando reduce C difficile colonization rates.125 Currently intra-enous immunoglobulin (IVIG) is the only available ther-peutic option.

Randomized clinical trials are not available, but case

able 4. Treatment Options for C difficile Infection

Treatment Regimen

etronidazole 250–500 mg 3 times daily orby mouth or intravenously

ancomycin 125–500 mg 3 times daily orby mouth

ifaximin 400–800 mg twice daily or 3 tmouth

inding resins; cholestyraminepreferred over colestipol

4 g 3 times daily or 4 times d

itazoxanide 500 mg twice daily by mouthmmunoglobulin 300–500 mg/kg daily until res

maximum of 6 dosesrobiotics Variable oral dosing

urgery Subtotal colectomy with ileost

eports suggest efficacy of IVIG in patients with either a

ecurrent or severe acute disease.113–115 Two small studieseported IVIG treatment for recurrent C difficile infectionith response rates of 100% in children114 and 60% indults.115 In the typical regimen, patients were given00 –500 mg IVIG/kg/day (1 and 5 total doses); a clinicalesponse occurred in most patients within 1 week. Innother small series, IVIG provided no benefit in acuteisease.126 In addition to issues of expense and availabil-

ty, side effects of IVIG are common and include infusioneactions, hemolytic anemia, neutropenia, anaphylaxis,enal toxicity, and aseptic meningitis. We reserve the usef IVIG for patients with multiple moderate-to-severeecurrences of C difficile who have failed vancomycin taperherapy at least twice, in combination with probioticsnd toxin-binding resins or rifaximin.

Active vaccination of animals against C difficile toxinsas been successful in preventing infection and death

rom C difficile.127,128 Phase 1 trials have shown that in-ramuscular injection of C difficile toxoid vaccine is safend immunogenic in healthy volunteers, inducing robusterum IgG antitoxin and fecal IgA antitoxin produc-ion.129,130 A small case series suggested efficacy of ther-peutic vaccination in adults with multiply recurrentisease.131

Microbiologic TherapyThe critical factor in C difficile pathogenesis is

ntibiotic-induced reduction of colonization resistance,rovided by the normal colonic microflora, which allows

difficile to have a selective advantage. For this reason,ctive reconstitution of the normal colonic flora is theo-etically attractive for prevention and treatment. Severaleports have documented the efficacy of stool trans-lants, delivered by enema or gastric tube, from a healthyonor to patients with recurrent132,133 or acute134 C diffi-

ile infection. Inadvertent spread of pathogenic microor-anisms from donor to host as well as distaste by patients

Comments

es daily First-line therapy or in combination with vancomycinin severe disease

es daily First-line therapy for severe disease

daily by Adjunctive in recurrent C difficile infection

Adjunctive with antibiotics; must be taken �2hours apart from vancomycin

Adjunctive in recurrent C difficile infectionon or Adjunctive with antibiotics in severe refractory or

recurrent C difficile infectionAdjunctive with antibiotics for treatment or

prevention of recurrent C difficile infectionEarly surgical consultation recommended in severe

disease

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May 2009 TREATMENT OF CLOSTRIDIUM DIFFICILE INFECTION 1907

ral administration of nontoxigenic strains of C difficileo compete with and limit the growth of toxin-producingtrains was reported to lead to remission of recurrent Cifficile infection in 2 patients,135 and studies are under-ay to characterize a strain that is suitable for larger

rials.136

Probiotic TherapyProbiotics are commonly used for prevention and

reatment of infectious diarrhea.137,138 Organisms stud-ed in C difficile include Saccharomyces boulardii, Lactobacil-us rhamnosus GG, Lactobacillus plantarum, Lactobacillus aci-ophilus, and Bifidobacterium bifidum. Most studies to dateave focused on the prevention of antibiotic-associatediarrhea and C difficile infection. A recent meta-analysiseviewed 31 studies of various probiotics for C difficileiarrhea (25 studied prevention of disease).139 This anal-sis found that prophylactic probiotics significantly re-uced the subsequent incidence of acute C difficile diar-hea (relative risk [RR], 0.43; P � .001).

A smaller number of studies have evaluated the efficacyf probiotics for treatment of C difficile diarrhea andrevention of recurrence. Although no individual studyeduced recurrence, in aggregate, a significant therapeuticenefit of probiotics was reported (RR, 0.59; P � .005).139

n contrast, a recent Cochrane Review found only 4tudies of sufficient quality for inclusion and suggested a

odest benefit of Saccharomyces boulardii in both preven-ion of recurrence and cessation of diarrhea as an adjuncto antibiotics. Lactobacillus rhamnosus GG and Lactobacilluslantarum did not appear to provide any benefit. Thisochrane Review concluded that evidence is insufficient

o recommend probiotic therapy as an adjunct to antibi-tic therapy and that no evidence supports the use ofrobiotics alone in the treatment of C difficile diarrhea.140

ther studies not included in this meta-analysis haveeen published,141,142 with some studies reporting bene-t, while others found no difference. Despite these dis-repant results, probiotics remain a safe and reasonableption for prevention of initial infections and possiblyor treatment of recurrent infections. Animal studies arenderway to optimize the type and dose of organismsnd to explore the mechanisms of action.136,143–148

PreventionAs with any disease, C difficile is better managed by

revention than by cure (Table 5). Appropriate use ofntibiotics, especially broad-spectrum agents and thosehown to have a particular predisposition to cause Cifficile infections, will continue to be the cornerstone ofisease control for the foreseeable future. Several studiesave shown that antibiotic prescription guidelines reducedifficile infection rates by approximately 50%.149 –152

Although community-acquired C difficile infection has

een increasingly reported,11,153 the main nidus of C

ifficile remains hospitals and nursing facilities.34,154 –160

iable C difficile spores are widespread in the hospitalnvironment155,156,161–163 and are spread by asymptom-tic carriers and hospital personnel, giving rise to hospi-al outbreaks and geographic clustering in specificards.155,156,161 The use of alcohol wipes or solutions to

lean hands and equipment after patient contact is inef-ective against C difficile spores. Only the use of disposableloves, gowns, and hand washing with chlorhexidine glu-onate– containing soap have been documented to reducehe spread of C difficile by health care workers.164,165 De-ontamination of rooms and equipment with the use ofporicidal agents such as sodium hypochlorite, ethylenexide, and alkaline glutaraldehyde is recommended.34

reatment of known carriers with vancomycin is notffective.38 Combination of tactics that include educa-ion, increased case finding, expanded infection-control

easures, a C difficile infection management team, andtringent antimicrobial guidelines has been shown toeduce the spread of C difficile and to improve out-omes.166

ConclusionsC difficile prevention requires avoidance of inap-

ropriate antibiotic use, combined with proper handygiene by medical staff and surveillance and prompt

solation of new cases of C difficile infection.For infected individuals, treatment should be individ-

alized and based on severity of symptoms and whetherymptomatic disease is primary or recurrent. For mostatients with active symptoms, metronidazole is thereatment of choice for initial infection and first or sec-nd recurrence, because of cost concerns. For patientsith severe disease or multiple recurrences, vancomycin

s recommended. Surgical consultation is warranted earlyn the course of suspected fulminant disease. The roles ofther antibiotics, probiotics, binding resins, and vaccina-ion hold great promise for future management.

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Individual patient● Limit antibiotics

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Received October 21, 2008. Accepted December 22, 2008.

eprint requestsAddress requests for reprints to: Daniel A. Leffler, MD, Beth Israel

eaconess Medical Center, 330 Brookline Avenue, Boston, MA2215. e-mail: dleffler@caregroup.harvard.edu; fax: (617) 667-2767.

onflicts of interest

The authors disclose no conflicts.