clostridium difficile in adults treatment 2013

7/28/2019 Clostridium Difficile in Adults Treatment 2013

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Clostridium difficile in adults: TreatmentAuthorsCiarn P Kelly, MDJ Thomas LaMont, MDSection EditorStephen B Calderwood, MD

Deputy EditorElinor L Baron, MD, DTMHDisclosures

All topics are updated as new evidence becomes available and ourpeer review process iscomplete.Literature review current through: Mar 2013. | This topic last updated: mar 26, 2013.

INTRODUCTION Clostridium difficile infection (CDI) is one of the most common hospital-

acquired (nosocomial) infections, and is an increasingly frequent cause of morbidity and

mortality among elderly hospitalized patients [1]. C. difficile colonizes the human intestinal tract

after the normal gut flora has been altered by antibiotic therapy and is the causative organism of

antibiotic-associated pseudomembranous colitis.

The treatment of CDI, including initial management, management of relapse, and management

of severe disease, will be reviewed here [2]. The pathophysiology, epidemiology, clinical

manifestations, and diagnosis are discussed separately. (See"Clostridium difficile in adults:

Epidemiology, microbiology, and pathophysiology" and"Clostridium difficile in adults: Clinical

manifestations and diagnosis".)

GENERAL MANAGEMENT PRINCIPLES An important initial step in the treatment of C.

difficile infection (CDI) is cessation of the inciting antibiotic as soon as possible. Treatment with

concomitant antibiotics (ie, antibiotics other than those given to treat C. difficile infection) is

associated both with significant prolongation of diarrhea and with increased risk of recurrent C.

difficile infection [3,4]. If ongoing antibiotics are essential for treatment of the primary infection, it

may be prudent, if possible, to select antibiotic therapy that is less frequently implicated in

antibiotic-associated CDI, such as parenteral aminoglycosides, sulfonamides,

macrolides, vancomycin, ortetracycline.

Management must also include implementation of infection control policies. Patients with

suspected or proven C. difficile infection should be placed on contact precautions, and

healthcare workers should wash hands before and after patient contact. Hand hygiene with

soap and water may be more effective than alcohol-based hand sanitizers in removing C.

difficile spores, since C. difficile spores are resistant to killing by alcohol. Therefore, use of soap

and water is favored over alcohol-based hand sanitization in the setting of a CDI outbreak,

although thus far no studies have demonstrated superiority of soap and water in non-outbreak

settings [1]. (See "Prevention and control of Clostridium difficile in hospital and institutionalsettings".)

In addition, antimotility agents such as loperamideand opiates have traditionally been avoided

in CDI, but the evidence that they cause harm is equivocal [5,6]. Supportive care with attention

to correction of fluid losses and electrolyte imbalances is also important. Patients may have

regular diet as tolerated, unless surgery or other procedure is planned.

INDICATIONS FOR TREATMENT Patients with typical manifestations of C. difficile (eg,

diarrhea, abdominal pain, or nausea and vomiting) and a positive diagnostic assay should

receive antibiotics for treatment for C. difficile [7,8]. Empiric therapy is appropriate pending

results of diagnostic testing if the clinical suspicion is high. Treatment of C. difficile is not

indicated in patients who have a positive toxin assay but are asymptomatic. (See"Clostridiumdifficile in adults: Clinical manifestations and diagnosis".)
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NON SEVERE DISEASE

Initial therapy Therapy for non-severe C. difficile infection (CDI) consists of

oralmetronidazoleor oralvancomycin(table 1) [1,9]. Several randomized trials have

demonstrated equivalent efficacy of metronidazole and vancomycin for the treatment of non-

severe CDI [10-12]. In one prospective, randomized double-blind trial including 81 patients with

mild or moderately severe CDI, metronidazole and vancomycin produced similar rates of clinical

cure (90 versus 98 percent) [10].

Guidelines published in the 1990s advocated metronidazole overvancomycinas first-line

therapy [13-16]. Reasons included the lower cost of metronidazole relative to vancomycin and

the comparable clinical effectiveness in non-severe disease. In addition, use of metronidazole

has been favored over vancomycin to limit the spread of vancomycin-resistant enterococci

(VRE), although subsequent data have suggested that the risk of bowel VRE colonization is

equivalent with these drugs [17,18].

Observational study of C. difficile disease in Canada from 1991 to 2003 preliminarily suggested

that patients treated with metronidazole for an initial episode of CDI may be at increased risk for

relapse [19,20]. However, review of the data through 2006 demonstrated a similar trend in the

frequency of recurrences for both metronidazole and vancomycin, suggesting that the rise in

recurrence rate during 2003 to 2004 for patients treated with either drug may have

corresponded to reinfection during a period when in-hospital exposure to C. difficile spores was

very high [21,22].

Limitations ofmetronidazole include dose-dependent peripheral neuropathy and side effects of

nausea and metallic taste. Although the above studies are limited because of their observational

methodologies, the findings raise the possibility that metronidazole may be less effective than

oralvancomycin[23].

The treatment of severe disease is discussed below. (See 'Treatment'below.)Antibiotic dosing Metronidazole can be used for initial treatment of non-severe CDI. The

recommended regimen is 500 mg three times daily or 250 mg four times daily for 10 to 14 days.

As discussed below, intravenous metronidazole at a dose of 500 mg every eight hours may also

be used for treatment of CDI in patients in whom oral therapy is not feasible. Fecal

concentrations in the therapeutic range are achievable with this regimen because of the drug's

biliary excretion and increased exudation across the intestinal mucosa during CDI [ 24-26].

If oral vancomycin is used, the recommended dose is 125 mg four times daily. Oral vancomycin

is not absorbed systemically and achieves predictably high levels in the colon. Dosing regimens

of 125 mg four times daily and 500 mg four times daily are equally effective for the treatment of

non-severe CDI (figure 1) [27]. Intravenous vancomycin has no effect on C. difficile colitis sincethe antibiotic is not excreted appreciably into the colon.

Duration of therapy The recommended duration of initial antibiotic therapy for non-severe

C. difficile diarrhea is 10 to 14 days [1]. Patients with an underlying infection requiring prolonged

duration of antibiotics should continue CDI treatment throughout the antibiotic course plus an

additional week after its completion [4].

Repeat stool assays are NOT warranted during or following treatment in patients who are

recovering or are symptom free. Up to 50 percent of patients have positive stool assays for as

long as six weeks after the completion of therapy [27,28].

Recurrent disease Recurrence is defined by complete abatement of CDI symptoms while on

appropriate therapy, followed by subsequent reappearance of diarrhea and other symptoms

after treatment has been stopped. Recurrence should be distinguished from persistent diarrhea
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without resolution during initial therapy, which should prompt an evaluation for other causes. In

the absence of an alternative diagnosis, such patients should be considered to have refractory

illness.

Recurrent CDI often results from reinfection with the same or a different strain of C. difficile [29-

31]. Studies using molecular methods have shown that up to one-half of recurrent episodes are

reinfections rather than relapses of infection with the original strain [ 32,33].

Recurrence occurs in approximately 25 percent of cases treated

with metronidazoleorvancomycin, and patients may experience several episodes of recurrent

colitis [11,16,34-37]. Most recurrences present within one to three weeks after discontinuing

antibiotic therapy, although recurrences rarely can occur as late as two to three months.

Recurrences may be mild or severe and may result from an impaired host immune response to

C. difficile. (See "Clostridium difficile in adults: Epidemiology, microbiology, and

pathophysiology".)

Risk factors for recurrence include age >65 years, severe underlying medical disorders, and the

need for ongoing therapy with concomitant antibiotics during treatment for CDI [3,35,38,39].

Patients with at least one episode of recurrent C. difficile have a 45 to 65 percent chance of

additional episodes [40].

Pathophysiology The mechanism of CDI recurrence following initial infection is not fully

understood. It may be due to persistent spores from the initial infection. C. difficile spores in

colonic diverticula, for example, may escape mechanical clearance by peristalsis [35].

Impairment of the host immune response to C. difficile toxins may also be an important

mechanism for recurrence. Asymptomatic carriers of C. difficile tend to have high serum

antibody levels against C. difficile toxins [41], while patients with recurrent CDI tend to have

lower anti-toxin antibody levels than patients with a single, brief episode of diarrhea [38,42-44].

Antibiotic resistance does not appear to be a factor in recurrence. However, treatmentwith metronidazoleorvancomycin for an initial episode of CDI may alter the colonic

microenvironment (with regard to flora or other factors), potentially increasing susceptibility to

reinfection and recurrence. (See 'Metronidazole failure'below.)

Management of initial recurrence The signs and symptoms of recurrence are similar to

those in the initial episode, usually without progression in severity [45]. Because a positive stool

toxin assay does not exclude asymptomatic carriage, other causes for diarrhea should be

considered, including other infections, inflammatory bowel disease, or irritable bowel syndrome.

Colonoscopy should be considered in atypical cases to evaluate for evidence of CDI and to

exclude other etiologies.

For treatment of an initial episode of CDI, fidaxomicin has been associated with a lower

incidence of recurrent CDI than vancomycin (15 versus 25 percent) [46]. For treatment of initial

recurrence of CDI, the initial response to therapy with fidaxomicin and vancomycin has been

observed to be comparable, although the likelihood of recurrence four weeks later is lower with

fidaxomicin than vancomycin (20 versus 36 percent) [47].

Patients with mild symptoms of recurrence who are otherwise well may be managed

conservatively, without further antibiotic therapy. Non-severe initial recurrence following therapy

for CDI can be treated withmetronidazole. The decision to administervancomycin as treatment

for a first recurrence should be based upon the presence of markers of severe disease at the

time of first recurrence, rather than on previous drug exposure.

Fidaxomicinis an alternative agent for treatment of an initial recurrence of CDI (table 1). In one

study including 128 patients with a first CDI recurrence, the recurrence rate was lower among
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patients treated with fidaxomicin than among patients treated with vancomycin (19 versus 35

percent) (95% CI 30-0.3%; p = 0.045) [47]. (See'Fidaxomicin' below.)

Management of subsequent recurrences Patients with one recurrence have a substantial

risk of subsequent CDI episodes after the second course of antibiotic therapy is discontinued. In

one study, for example, patients with one or more previous recurrences had a subsequent

recurrence rate of 65 percent following standard therapy with metronidazole orvancomycin[37].

Antibiotic therapy There are no rigorous studies of management for multiple recurrences of

CDI. Patients with multiple recurrences may benefit fromvancomycin(administered in a pulse

tapered fashion),fidaxomicin orrifaximin, with or without the use of probiotics (table 1).

Vancomycin Administration ofvancomycin in a pulse tapered fashion may be effective for

management of recurrent C. difficile infection (table 1). The use of intermittent antibiotic therapy

is based upon a theory that relapse may be due to the presence of persistent spores that

survive antibiotic therapy. Intermittent therapy may allow the spores to germinate on the days

when no antibiotics are administered. Once the spores have converted to the fully functional

vegetative, toxin-producing forms, they are susceptible to killing when the antibiotics are

readministered.

A tapered oral vancomycinregimen consists of a stepwise decrease in dose over a period of

time. Intermittent (or pulsed) vancomycin therapy consists of administering the drug every few

days. Prolonged antibiotic therapy, with or without tapered or intermittent dosing, may also be

important for definitive treatment.

Intermittent and tapered vancomycin regimens have been evaluated in observational studies

[28,35]. In one study of 163 CDI cases, for example, 29 patients were treated with a vancomycin

tapered regimen and 7 were treated with a vancomycin pulsed regimen; recurrence rates were

31 and 14 percent, respectively, compared with a recurrence rate of 45 percent for other

regimens [28].Rifaximin Small case series have suggested that sequential therapy

with vancomycinfollowed byrifaximinmay be effective for the treatment of recurrent CDI [48,49].

In one series, eight women with recurrent CDI received a two-week course of rifaximin when

they were asymptomatic, immediately after completing their last course of vancomycin. Seven

patients had no further recurrence of infection [48].

Exposure to rifamycins prior the development of CDI is a risk factor forrifampin resistant C.

difficile infection. In such cases, the use ofrifaximin for treatment of CDI may be limited [50].

Fidaxomicin Fidaxomicinis a macrocyclic antibiotic that is bactericidal against C. difficile (in

contrast tometronidazoleandvancomycin, which are bacteriostatic) [51]. It has a narrower

antimicrobial spectrum than metronidazole or vancomycin, leading to less disruption of the

normal colonic anaerobic microflora [52-56].

In a phase 3 randomized trial including 629 patients with non-severe C. difficile infection, clinical

cure rates withfidaxomicin (200 mg orally twice daily) and vancomycin(125 mg orally four times

daily) were similar, but recurrence of C. difficile infection occurred significantly less often with

fidaxomicin than with vancomycin among patients with non-NAP1 strains (10 versus 28 percent

in the modified intention-to-treat population) [46]. Lower recurrence rates were not seen among

patients with the NAP1 strain (See "Clostridium difficile in adults: Epidemiology, microbiology,

and pathophysiology", section on 'Hypervirulent strain: NAP1/BI/027'.)

Fidaxomicinmay be an appropriate therapy in patients with recurrent CDI or perhaps as initial

therapy in patients at high risk of developing recurrent disease, although parameters for its most

appropriate use are still being defined.
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Probiotic therapy Studies of probiotics are inconclusive regarding treatment benefit. This

issue is discussed further separately. (See "Clostridium difficile and probiotics"and"Probiotics

for gastrointestinal diseases", section on 'Antibiotic-associated diarrhea'.)

Fecal bacteriotherapy Fecal bacteriotherapy may be useful for treatment of patients with

recurrent CDI. This issue is discussed further separately. (See "Fecal microbiota transplantation

in the treatment of recurrent Clostridium difficile infection".)

Monoclonal antibodies Adjunctive use of monoclonal antibodies against C. difficile toxins A

and B (in addition to antibiotic therapy) appears to reduce the recurrence rate of C. difficile

infection; they are not yet available for routine clinical use. In a study of 200 patients with C.

difficile treated with antibiotics (metronidazoleorvancomycin) in addition to monoclonal

antibodies or placebo, recurrence rates were 7 versus 25 percent, respectively [57]. Studies are

needed to confirm these results for recurrent disease, as well as to determine whether

monoclonal antibodies are useful in the management of severe disease or whether there is a

role for prophylactic passive immunization for patients at highest risk.

SEVERE DISEASE

Definition Patients with acute C. difficile infection (CDI) may develop signs of systemic

toxicity with or without profuse diarrhea warranting admission to an intensive care unit or

emergency surgery.

There is no consensus definition for severe CDI, nor is there agreement as to the most

important clinical indicators that should be used to differentiate severity [10,20,58]. The following

illustrate some definitions that have been described in the literature:

Guideline parameters for severe CDI include white blood cell count of

>15,000 cells/microL or a serum creatinine level 1.5 times the premorbid level [1].

Clinicians in the setting of the Quebec outbreak identified a white blood cell count

>20,000 cells/microLand an elevated serum creatinine as potential indicators ofcomplicated disease [20]. Significantly elevated white blood cell counts in the absence

of any other evident cause should raise suspicion for C. difficile infection.

As part of a randomized trial comparingmetronidazolewithvancomycin, a scoring

system was devised to identify patients with severe infection [10]. One point each was

given for age >60 years, temperature >38.3C, serum albumin 15,000 cells/microLwithin 48 hours of enrollment.

Two points were given for endoscopic evidence of pseudomembranous colitis or

treatment in the intensive care unit. Patients with two or more points were considered to

have severe disease.

In a phase 3 trial of tolevamer versus vancomycin and metronidazole, severe disease

was defined as 10 bowel movements per day, a peripheral white blood cell count

20,000 cells/microL, or severe abdominal pain [59].

For the purposes of the treatment decisions in the following discussion, determination of

disease severity is left to clinician judgment and may include any or all of the criteria mentioned

above.

Incidence Data on the incidence of severe CDI are limited, especially given the lack of a

consensus definition. The risk of complications during first CDI recurrence in the Quebec

outbreak caused by the hypervirulent North American Pulsed Field type 1 (NAP1) strain was 11

percent [39]. Complications included shock, need for colectomy, megacolon, perforation, or

death within 30 days. Older age, high leukocyte count, and acute renal failure were strongly
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associated with a complicated course. (See "Clostridium difficile in adults: Epidemiology,

microbiology, and pathophysiology".)

Treatment Patients with severe CDI (by clinician judgment) should receive antibiotic therapy,

supportive care, and close monitoring. Surgery should be considered if the patient's clinical

status fails to improve and the serum lactate is above 2.2 [60]. Toxic megacolon should be

suspected if the patient develops abdominal distention with diminution of diarrhea; this may

reflect paralytic ileus resulting from loss of colonic muscular tone [34]. (See"Toxic

megacolon"and 'Surgery' below.)

Antibiotics Guidelines issued in 2010 by the Society for Healthcare Epidemiology of

America (SHEA) and the Infectious Disease Society of America (IDSA) recommend

oralvancomycinas first-line therapy for severe CDI [1]. This is in contrast to previous guidelines

published in the 1990s which recommended oralmetronidazoleas initial therapy for both mild

and severe C. difficile-associated diarrhea (CDAD) [13-16]. This change reflects reports of

frequent metronidazole failures in CDI and studies showing the superiority of oral vancomycin in

severe disease [10-12,20,59].

The major pharmacologic advantage ofvancomycin overmetronidazole is that vancomycin is

not absorbed, so maximal concentrations of the drug can act intracolonically at the site of

infection. The major advantage of metronidazole over vancomycin is that the cost of

metronidazole is substantially lower. With respect to in vitro activity, risk of relapse, and

potential for emergence of vancomycin resistant enterococci, the drugs appear to be relatively

similar[17,22,52,61,62].

Oral vancomycin is the preferred therapy for severe or refractory cases [1,10,39,59,63]. This

issue was directly addressed in a prospective, randomized double-blind trial that included 69

patients with severe CDI as defined above [10]. The cure rate was significantly higher with

vancomycin (97 versus 76 percent with metronidazole). (See 'Definition' above.)

Although the data are limited, clinical practice is shifting toward using oral vancomycin as initial

therapy for severe CDI [64]. Many have endorsed vancomycin as the preferred therapy for

moderate or severe disease caused by the epidemic strain, and most favor its use for all

patients with severe and/or complicated disease [1,22,61,65].

Intracolonic administration ofvancomycin via enema (given in combination with

intravenousmetronidazole) is an option for patients who do not tolerate oral medication, but

there is risk of colonic perforation. Therefore, use of intracolonic vancomycin should be

restricted to patients who are unresponsive to standard therapies, and the procedure should be

performed by personnel with expertise in administering enemas. (See 'Intracolonic

antibiotics'below.)

Oral antibiotics Oral vancomycin (125 mg four times daily) should be initiated promptly for

severely ill patients. Some data suggest that levels achieved with higher dosing of vancomycin

(500 mg four times daily) may be equivalent to levels with standard dosing [ 27]. Nevertheless,

many clinicians favor higher dosing for severe disease although there is no supportive evidence

[1].

For patients with severe disease who do not demonstrate clinical improvement with

oralvancomycin, administration of therapy with fidaxomicin is reasonable. Additional data are

needed on the efficacy of fidaxomicin in the setting of severe disease.

(See 'Fidaxomicin' above.)
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For circumstances in which neithervancomycin norfidaxomicin is available,

oralmetronidazole(500 mg three times daily or 250 mg four times daily for 14 days) may be

administered, although it is less effective than vancomycin [10].

Intravenous antibiotics Severely ill patients with ileus may have markedly delayed passage

of oral antibiotics from the stomach to the colon. These individuals may benefit from the addition

of intravenousmetronidazole at a dose of 500 mg every eight hours. Fecal concentrations in the

therapeutic range can be achieved with this regimen because of biliary and intestinal excretion

of the drug [24-26]. However, it is uncertain whether intravenous therapy alone is as effective as

oral therapy, so oral therapy should be administered whenever feasible [66].

Intravenous vancomycin has no effect on C. difficile colitis since vancomycin is not excreted into

the colon.

Intravenous tigecycline has been used in a small number of patients with severe CDI that was

refractory to standard therapy [67].

Intracolonic antibiotics Intracolonic vancomycin (vancomycin enema) may be an effective

adjunctive therapy for patients who cannot tolerate the oral preparation, or patients who havemegacolon or ileus which would prevent oral vancomycin from reaching the colon [68-70]. In a

case series of nine patients with refractory symptoms, toxic megacolon, or fulminant colitis,

rectal vancomycin was administered in addition to standard antibiotics [68]. Eight patients had

complete resolution of symptoms and one patient died from multisystem organ failure.

Intracolonic vancomycin may be useful in the setting of profound ileus that impairs the distal

delivery of orally administered drugs. Although the optimal dosing and volume has not been

established by clinical trials and case descriptions vary widely, rectal vancomycin is often given

as a retention enema containing 500 mg in 100 mL of normal saline every 6 hours [1,68,69,71-

75]. One report suggests that patients with megacolon may benefit from colonoscopic

decompression and placement of a tube in the right colon which can be perfused with a1 mg/mLsolution of vancomycin in normal saline to deliver a total dose of 1 to 2 g per day [ 69];

however, this requires further confirmation. Dose adjustments may be required depending on

individual circumstances including extent of colonic disease and patient weight. It is important to

note that vancomycin can be absorbed through inflamed colonic mucosa and cause toxicity if it

accumulates in patients with renal failure. (See"Vancomycin dosing and serum concentration

monitoring in adults".)

Antibiotic recommendations We recommend that patients with severe disease be treated

with oralvancomycin (125 mg four times daily). For patients with severe disease who do not

demonstrate clinical improvement, we suggest increasing the dose of oral vancomycin to 500

mg four times daily.Fidaxomicin may be considered in patients who cannot tolerate

vancomycin, although more data are needed. In the setting of ileus, addition ofintravenousmetronidazole(500 mg every eight hours) is appropriate. Intracolonic vancomycin

may be considered in patients with profound ileus.

The standard duration of antibiotic therapy for C. difficile diarrhea is 10 to 14 days; the antibiotic

course should be tailored to clinical circumstances for patients with severe disease. Those with

an underlying infection requiring prolonged duration of antibiotics should continue CDI treatment

throughout the antibiotic course plus one additional week after its completion.

Surgery Some severely ill patients with CDI require surgical intervention as a result of toxic

megacolon, perforation or impending perforation, necrotizing colitis or rapidly

progressive and/or refractory disease with systemic inflammatory response syndrome leading to

multiorgan system failure [76,77]. The optimal timing of surgery remains uncertain.
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Timing Literature written prior to the emergence of the hypervirulent strain suggested

surgery for CDI patients with severe disease unresponsive to medical therapy within 48 hours,

bowel perforation, or multiorgan system failure [78]. However, in the setting of CDI due to the

hypervirulent strain, some patients progressed from severe disease to death in less than 48

hours. Furthermore, some patients with severe disease cannot receive enteral therapy due to

ileus or severe nausea and vomiting.

Data from the Canadian outbreak with the hypervirulent strain have been used to try to

standardize criteria for surgical intervention. In a retrospective review, colectomy was most

beneficial for immunocompetent patients aged 65 years with a white blood cell count

20,000 cells/microL and/or a plasma lactate between 2.2 and 4.9meq/L [60].

We favor early surgery for patients with the above criteria. In addition, surgical intervention is

advisable in the setting of peritoneal signs, severe ileus, or toxic megacolon.

Procedure Two surgical approaches for management of CDI have been described: subtotal

colectomy (removal of the entire colon with ileostomy, without removal of the rectum), and

diverting loop ileostomy with colonic lavage.

Subtotal colectomy Subtotal colectomy is the procedure for which there is greatest

experience in the setting of emergency surgical intervention for CDI [60,79-81]. In a

retrospective review of 14 patients who underwent surgery for severe CDI, nine patients

survived, of whom eight had subtotal colectomy and one had a right hemicolectomy [79]. Four of

the five patients who died had undergone left hemicolectomy.

Primary anastomosis is not feasible acutely due to the pancolitis associated with severe

disease. However, after colonic inflammation has subsided, closure of the ileostomy and

ileorectal anastomosis can be created.

Diverting loop ileostomy and colonic lavage Diverting loop ileostomy and colonic lavage

may be a potential alternative procedure to colectomy in the treatment of severe, complicatedCDI. In one study including 42 patients with severe CDI, reduced mortality was observed among

patients who underwent loop ileostomy and colonic lavage, compared with the historical controls

who underwent colectomy (19 versus 50 percent; odds ratio, 0.24; P = 0.006) [ 82]. The surgical

approach involved creation of a loop ileostomy, intraoperative colonic lavage with warmed

polyethylene glycol solution via the ileostomy, and postoperative antegrade instillation

ofvancomycin flushes via the ileostomy. Preservation of the colon was achieved in 93 percent

of patients. This surgical approach is potentially promising, but further data from prospective,

randomized controlled trials are needed to validate this preliminary study.

METRONIDAZOLE FAILURE The reasons formetronidazole failure are poorly understood

[83]. Stool metronidazole concentrations in patients receiving the drug orally are higher inwatery stools at the beginning of C. difficile infection (CDI) treatment than in semiformed stools

a few days later[24]. Thus, stool metronidazole levels decrease as colonic inflammation

subsides. In contrast, oral vancomycin maintains high stool concentrations (1000 to

3000 mcg/mL throughout the course of therapy) [24,84].

Given these observations, even a modest increase in an organism's minimum inhibitory

concentration formetronidazolemight lead to insufficient stool levels after a few days of

treatment. Although some metronidazole resistance in C. difficile has been described [ 85-89],

resistance rates are low and do not appear to be increasing in the setting of the rising rates of

treatment failure [36,90-92].

Risk factors associated with metronidazole failure include recent cephalosporin use, C. difficileon admission and transfer from another hospital [93].
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ALTERNATIVE THERAPIES Other therapeutic options for C. difficile infection (CDI) are

being developed, and drugs used for other infections are being studied as alternatives

to metronidazole and vancomycin [94].

Probiotics Studies of probiotics are inconclusive regarding benefit. The data are presented

separately. (See"Clostridium difficile and probiotics".)

Fecal bacteriotherapy Fecal bacteriotherapy may be useful for treatment of patients with

recurrent CDI. This issue is discussed further separately. (See "Fecal microbiota transplantation

in the treatment of recurrent Clostridium difficile infection".)

Alternative antibiotics A meta-analysis of 12 studies including 1157 participants evaluated

eight different antibiotics for the treatment of CDI: vancomycin,metronidazole,fusidic

acid,nitazoxanide, teicoplanin, rifampin,rifaximin, and bacitracin [7]. In paired comparisons, no

single antibiotic was clearly superior to others. Combination therapy has been tried without

success [95].

Nitazoxanide may be as effective as vancomycin (as suggested by a randomized trial of 50 CDI

patients), although the small sample precluded conclusions about noninferiority of nitazoxanideto vancomycin [96].

Teicoplanin may be at least as effective as vancomycin ormetronidazole, although it is costly

and is not available in the United States [11,97].

Fidaxomicinwas approved by the United States Food and Drug Administration (FDA) in 2011.

(See 'Fidaxomicin'above.)

Anion-binding resins The importance of toxin production in the pathophysiology of C.

difficile diarrhea has prompted consideration of anion-binding resins as a possible alternative to

antimicrobial therapy [98]. An advantage of resin therapy is that the bowel flora is not altered, as

occurs with vancomycin ormetronidazole. This may allow more rapid reconstitution of thenormal colonic flora.

The anion-binding resinscolestipol andcholestyramine are not effective as primary therapy for

C. difficile colitis [99,100], although they may be beneficial as adjunctive therapy for relapsing

infection [101]. In a series of 11 patients with relapsing CDI, the administration of colestipol with

tapered vancomycin led to sustained resolution in all patients [101].

Anion-exchange resins bind vancomycin as well as toxins; thus, the resin must be taken at least

two or three hours apart from the vancomycin [98]. Suggested regimens are colestipol (5 g

every 12 hours) orcholestyramine(4 g three or four times daily) for one to two weeks, usually

with vancomycin.

Tolevamer is a C. difficile toxin binding resin developed specifically for CDI [59,102]. Preliminary

studies with tolevamer showed promising results. However, two large multicenter trials found

that it was inferior to bothvancomycin and metronidazole as primary therapy for CDI [59].

Intravenous immunoglobulin Intravenous immunoglobulin (IVIG) contains C. difficile

antitoxin and has been used in some patients with relapsing or severe C. difficile colitis.

Although there are case reports suggesting IVIG may be a useful addition to antibiotic therapy

for refractory CDI [42,103,104], a retrospective review of 18 patients who received IVIG

demonstrated no significant difference in clinical outcomes compared with 18 matched control

cases [105].

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials,

The Basics and Beyond the Basics. The Basics patient education pieces are written in plain

language, at the 5th to 6th grade reading level, and they answer the four or five key questions a
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