The guidelines were endorsed by the American Society for Health Systems

Pharmacists, the Society of Infectious Diseases Pharmacists, and the

Pediatric Infectious Diseases Society

Clostridium
difficile

Key Points

Epidemiology

Diagnosis

 Infection Prevention and Control

 Treatment

GuidelineCentral.com
 Key Points

•  C. difficile remains the most important cause of healthcare-associated

diarrhea and has become the most commonly identified cause of
healthcare-associated infection in adults in the United States. Moreover,
C. difficile has established itself as an important community pathogen.

•  C. difficile infection (CDI) is defined by the presence of symptoms

(usually diarrhea) and either a stool test positive for toxins or detection
of toxigenic C. difficile or colonoscopic or histopathologic findings
revealing pseudomembranous colitis.

•  Recent estimates suggest the U.S. burden of CDI is close to 500,000

infections annually although the exact magnitude of burden is highly
dependent upon the type of diagnostic tests used.

•  Diagnosis of CDI recommendations are dependent upon institutional

policy on which patients to test. See Diagnosis section.

•  Treatment recommendations no longer include metronidazole as first-

line treatment for CDI of any severity. See Treatment section.

Epidemiology

Adult
➤➤ To increase comparability between clinical settings, use available
standardized case definitions for surveillance of healthcare facility-
onset (HO) CDI; community-onset healthcare facility-associated
(CO-HCFA); and community-associated (CA) CDI (GP).

➤➤ At a minimum, conduct surveillance for healthcare facility-onset

C. difficile infection (HO-CDI) in all inpatient healthcare facilities to
detect elevated rates or outbreaks of CDI within the facility (W-L).

➤➤ Express the rate of HO-CDI as the number of cases per 10,000 patient-
days. Express the CO-HCFA prevalence rate as the number of cases per
1,000 patient admissions (GP).

➤➤ Stratify data by patient location in order to target control measures

when CDI incidence is above national and/or facility reduction goals
or if an outbreak is noted (W-L).

Pediatric
➤➤ Use the same standardized case definitions (HO, CO-HCFA, CA) and
rate expression (cases per 10,000 patient-days for HO, cases per 1,000
patient admissions for CO-HCFA) in pediatric patients as for adults (GP).

➤➤ Conduct surveillance for HO-CDI for inpatient pediatric facilities but

do not include cases <2 years of age (W-L).

➤➤ Consider surveillance for CA-CDI to detect trends in the community (W-L).

2
 Diagnosis

Adult
➤➤ Patients with unexplained and new onset ≥3 unformed stools in 24 h
are the preferred target population for testing for CDI (W-VL).

➤➤ Use a stool toxin test as part of a multiple step algorithm (i.e.,

glutamate dehydrogenase [GDH] plus toxin; GDH plus toxin, arbitrated
by nucleic acid amplification test [NAAT]; or NAAT plus toxin) rather
than a NAAT alone for all specimens received in the clinical laboratory
when there are no pre-agreed institutional criteria for patient stool
submission (see Figure 1) (W-L).

➤➤ Use a NAAT alone or multiple step algorithm for testing (i.e., GDH plus
toxin; GDH plus toxin, arbitrated by NAAT; or NAAT plus toxin) rather
than a toxin test alone when there are pre-agreed institutional criteria
for patient stool submission (see Figure 1) (W-L).

➤➤ Do not perform repeat testing (within 7 days) during the same episode
of diarrhea and do not test stool from asymptomatic patients, except
for epidemiological studies (S-M).

➤➤ There are insufficient data to recommend use of biologic markers as an

adjunct to diagnosis (NR).

Pediatric
➤➤ Because of the high prevalence of asymptomatic carriage of toxigenic
C. difficile in infants, testing for CDI should never be routinely
recommended for neonates or infants ≤12 months of age with
diarrhea (S-M).

➤➤ C. difficile testing should not be routinely performed in children with

diarrhea who are 1–2 years of age unless other infectious or non-
infectious causes have been excluded (W-L).

➤➤ In children 2 years and older, C. difficile testing is recommended for

patients with prolonged or worsening diarrhea and risk factors (such
as underlying inflammatory bowel disease or immunocompromising
conditions) or relevant exposures (such as contact with the healthcare
system or recent antibiotics) (W-M).

S, strong; W, weak; H, high; M, moderate; L, low; VL, very low quality of evidence;
GP, good practice; NR, no recommendation
3
 Diagnosis

Figure 1. CDI Laboratory Test Recommendations Based on

Pre-Agreed Institutional Criteria for Patient Stool Submission

Stool toxin testa as

part of a multiple step
algorithm (i.e., GDH plus
toxin; GDH plus toxin,
arbitrated by NAAT;
NO or NAAT plus toxin)
rather than a nucleic
Clinicians and laboratory acid amplification test
personnel agree at the (NAAT) alone.
institutional level not to
submit stool specimens
from patients receiving
laxatives and to submit
stool specimens only from
patients with unexplained
and new onset ≥3 unformed
stools in 24 h for testing
for CDI. NAAT alone OR stool
toxin testa as part of a
YES multiple step algorithm
(i.e. GDH plus toxin;
GDH plus toxin,
arbitrated by NAAT; or
NAAT plus toxin) rather
than a toxin test alone.

a
Approved stool enzyme immunoassay (EIA) toxin tests vary widely in sensitivity.
Laboratories should choose a toxin test with sensitivity in the upper range of
sensitivity as reported in the literature.

4
Table 1. Summary of Available Tests for CDI in Decreasing
Order of Sensitivity
Substance
Test Sensitivity Specificity Detected

Toxigenic culture (TC) High Lowa C. difficile vegetative

cells or spores
Nucleic acid High Low/moderate C. difficile toxin
amplification tests genes
(NAAT)
Glutamate High Lowa C. difficile common
dehydrogenase (GDH) antigen
Cell culture cytotoxicity High High Free toxins
neutralization assay
(CCNA)
Toxin A, B enzyme Low Moderate Free toxins
immunoassays
a
Must be combined with a toxin test.

5
 Infection Prevention and Control

➤➤ Accommodate patients with CDI in a private room with a dedicated

toilet to decrease transmission to other patients. If there is a
limited number of private single rooms, prioritize patients with stool
incontinence for placement in private rooms (S-M).

➤➤ If cohorting is required, it is recommended to cohort patients infected

or colonized with the same organism(s) — i.e., do not cohort patients
with CDI who are discordant for other multidrug resistant organisms
such as methicillin resistant Staphylococcus aureus (MRSA) or
vancomycin resistant enterococcus (S-M).

➤➤ Healthcare personnel must use gloves (S-H) and gowns (S-M) on entry
to a room of a patient with CDI and while caring for patients with CDI.

➤➤ Patients with suspected CDI should be placed on pre-emptive contact

precautions pending the C. difficile test results if test results cannot
be obtained on the same day (S-M).

➤➤ Continue contact precautions for at least 48 hours after diarrhea has

resolved (W-L).

➤➤ Prolong contact precautions until discharge if CDI rates remain high

despite implementation of standard infection control measures
against CDI (W-L).

➤➤ In routine or endemic settings, perform hand hygiene before and after

contact with a patient with CDI and after removing gloves with either
soap and water or an alcohol-based hand hygiene product (S-M).

➤➤ In CDI outbreaks or hyper-endemic (sustained high rates) settings,

perform hand hygiene with soap and water preferentially instead of
alcohol-based hand hygiene products before and after caring for a
patient with CDI, given the increased efficacy of spore removal with
soap and water (W-L).

➤➤ Handwashing with soap and water is preferred if there is direct

contact with feces or an area where fecal contamination is likely,
e.g., the perineal region (GP).

➤➤ Encourage patients to wash hands and shower to reduce the burden

of spores on the skin (GP).

➤➤ Use disposable patient equipment when possible and ensure

that reusable equipment is thoroughly cleaned and disinfected,
preferentially with a sporicidal disinfectant that is equipment
compatible (S-M).

6
➤➤ Terminal room cleaning with a sporicidal agent should be considered
in conjunction with other measures to prevent CDI during endemic
high rates or outbreaks or if there is evidence of repeated cases of
CDI in the same room (W-L).

➤➤ Incorporate measures of cleaning effectiveness to ensure quality of

environmental cleaning (GP).

➤➤ There are limited data at this time to recommend use of automated,

terminal disinfection using a sporicidal method for CDI prevention
(NR).

➤➤ Daily cleaning with a sporicidal agent should be considered in

conjunction with other measures to prevent CDI during outbreaks
or in hyperendemic (sustained high rates) settings, or if there is
evidence of repeated cases of CDI in the same room (W-L).

➤➤ There are insufficient data to recommend screening for asymptomatic

carriage and placing asymptomatic carriers on contact precautions
(NR).

➤➤ Minimize the frequency and duration of high-risk antibiotic therapy

and the number of antibiotic agents prescribed, to reduce CDI risk
(S-M).

➤➤ Implement an antibiotic stewardship program (GP).

➤➤ Antibiotics to be targeted should be based on the local epidemiology

and the C. difficile strains present. Restriction of fluoroquinolones,
clindamycin and cephalosporins (except for surgical antibiotic
prophylaxis) should be considered (S-M).

➤➤ Although there is an epidemiologic association between proton pump

inhibitors (PPIs) use and CDI, and unnecessary PPIs should always
be discontinued, there is insufficient evidence for discontinuation of
PPIs as a measure for preventing CDI (NR).

➤➤ There are insufficient data at this time to recommend administration

of probiotics for primary prevention of CDI outside of clinical trials
(NR).

S, strong; W, weak; H, high; M, moderate; L, low; VL, very low quality of evidence;
GP, good practice; NR, no recommendation
7
 Treatment

Adult
➤➤ Discontinue therapy with the inciting antibiotic agent(s) as soon as
possible, since this may influence the risk of CDI recurrence (S-M).

➤➤ Antibiotic therapy for CDI should be started empirically for situations

where a substantial delay in laboratory confirmation is expected, or for
fulminant CDI* (W-L).
* Fulminant CDI, previously referred to as severe, complicated CDI, may be
characterized by hypotension or shock, ileus, or megacolon.
➤➤ Either vancomycin or fidaxomicin is recommended over metronidazole
for an initial episode of CDI.
Note: The dosage is: vancomycin 125 mg orally 4 times per day or fidaxomicin
200 mg twice daily for 10 days (S-H).
➤➤ In settings where access to vancomycin or fidaxomicin is limited, we
suggest using metronidazole for an initial episode of non-severe CDI*
only (W-H). The suggested dosage is metronidazole 500 mg orally 3
times per day for 10 days. Avoid repeated or prolonged courses due to
risk of cumulative and potentially irreversible neurotoxicity (S-M).
* See Table 3 for definition of CDI severity.
➤➤ For fulminant CDI,* vancomycin administered orally is the regimen of
choice (S-M). If ileus is present vancomycin can also be administered
per rectum (W-L). The vancomycin dosage is 500 mg orally 4 times per
day and 500 mg in approximately 100 mL normal saline per rectum
every 6 hours as a retention enema. Intravenously administered
metronidazole should be administered together with oral or rectal
vancomycin particularly if ileus is present (S-M).
Notes: The metronidazole dosage is 500 mg intravenously every 8 hours.
* Fulminant CDI is described above.
➤➤ If surgical management is necessary for severely ill patients, perform
subtotal colectomy with preservation of the rectum (S-M). Diverting
loop ileostomy with colonic lavage followed by antegrade vancomycin
flushes is an alternative approach that may lead to improved outcomes
(W-L).

➤➤ Treat a first recurrence of CDI with oral vancomycin as a tapered

and pulse regimen rather than a second standard 10-day course of
vancomycin (W-L), OR;

➤➤ Treat a first recurrence of CDI with a 10-day course of fidaxomicin

rather than a standard 10-day course of vancomycin (W-M), OR;

➤➤ Treat a first recurrence of CDI with a standard 10-day course

of vancomycin rather than a second course of metronidazole if
metronidazole was used for the primary episode (W-L).

8
➤➤ Antibiotic treatment options for patients with more than one recurrence
of CDI include (W-L):
•  oral vancomycin therapy using a tapered and pulse regimen,
•  a standard course of oral vancomycin followed by rifaximin, or
•  fidaxomicin.
➤➤ Fecal microbiota transplantation (FMT) is recommended for patients
with multiple recurrences of CDI who have failed appropriate antibiotic
treatments (S-M).

➤➤ There are insufficient data at this time to recommend extending

the length of anti-C. difficile treatment beyond the recommended
treatment course or re-starting an anti-C. difficile agent empirically
for patients who require continued antibiotic therapy directed against
the underlying infection or who require re-treatment with antibiotics
shortly after completion of CDI treatment, respectively (NR).

Pediatric
➤➤ Either metronidazole or vancomycin is recommended for the
treatment of children with an initial episode or first recurrence of
non-severe CDI (see Table 4 for dosing) (W-L).

➤➤ For children with an initial episode of severe CDI, oral vancomycin is

recommended over metronidazole (S-M).

➤➤ For children with a second or greater episode of recurrent CDI, oral

vancomycin is recommended over metronidazole (W-L).

➤➤ Consider fecal microbiota transplantation (FMT) for pediatric patients

with multiple recurrences of CDI following standard antibiotic
treatments (W-VL).

S, strong; W, weak; H, high; M, moderate; L, low; VL, very low quality of evidence;
GP, good practice; NR, no recommendation
9
 Treatment

Table 2. Potential Treatment Agents for Treatment of the

Primary C. difficile Infection (CDI) Episode
Initial
Treatment Recurrence
a
Agent Adult Dose Cost Response Risk

Proven Efficacy
Vancomycin 125 mg PO qid × $$$$ +++ ++
10 days $ (Liq)
Fidaxomicin 200 mg PO bid × $$$$ +++ +
10 days
Metronidazole 500 mg PO tid × $ ++ ++
10 days

Probable Efficacy
Nitazoxanide 500 mg PO bid × $$ +++ ++
10 days

Fusidic acid 250 mg PO tid × N/A in ++ ++

10 days USA

Inadequate Data To Support Efficacy

Rifaximin 400 mg PO tid × $$$ ++ +?
10 days

Tigecycline 50 mg IV every bid $$$$ ++? ?

× 10 days
Bacitracin 25,000 units PO $$ + +?
qid × 10 days
a
All prices are estimated in US dollars as quoted from Red Book Online Search, Micromedex
Solutions, last accessed on March 10, 2015 or approximated hospital pharmacy pricing (tigecycline,
bacitracin).
$: $0–100; $$: $101–500; $$$: $501–1000; $$$$: >$1000

10
Resistance in Clinical
Isolates Adverse Events Evidence Supporting Efficacy

Not reported Minimally absorbed Multiple RCTs; U.S. FDA-Approved

One clinical isolate with Minimally absorbed Two Phase III RCT comparisons to
increased MIC vancomcyin; U.S. FDA-Approved
Increased MIC reported Neuropathy, Nausea Multiple RCTs
in some studies; Hetero-
resistance also reported

Not reported GI symptoms •  Small RCT comparison to

vancomycin and a modest
sized RCT comparison to
metronidazole
Reported to develop in GI symptoms •  Modest-sized RCT comparison to
vivo resistance metronidazole and a small RCT
comparison to vancomycin

Potential for Minimally absorbed •  1 small RCT comparison to

development of high- vancomycin for primary treatment
level resistance •  Case series and 1 RCT pilot study
show promise for use as a post-
vancomycin ‘chaser’ strategy in
management of recurrent CDI
Not reported GI symptoms Case reports and small case series

Increasing resistance Minimally Two small RCT comparisons to

noted absorbed, poor taste vancomycin

11
 Treatment

Table 3. Recommendations for the Treatment of C. difficile

Infection (CDI) in Adults
Clinical Supportive Strength-
Definition Clinical Data Recommended Treatmenta Quality

Initial episode, Leukocytosis with Vancomycin 125 mg given qid S-H

non-severe a white blood cell for 10 days, OR
count of <15,000
cells/mL and a
serum creatinine Fidaxomicin 200 mg given S-H
level <1.5 mg/dL bid for 10 days
Alternate if above agents are W-H
unavailable: Metronidazole,
500 mg tid PO for 10 days

Initial episode, Leukocytosis with Vancomycin, 125 mg qid PO S-H

severeb a white blood cell for 10 days, OR
count of ≥15,000
cells/mL or a
serum creatinine Fidaxomicin 200 mg given S-H
level >1.5 mg/dL bid for 10 days

Initial episode, Hypotension Vancomycin, 500 mg qid PO S-M

fulminant or shock, ileus, or by nasogastric tube. If (oral vanco)
megacolon ileus, consider adding rectal W-L
instillation of vancomycin. (rectal vanco)
Intravenously administered S-M
metronidazole (500 mg q8h) (intravenous
should be administered metro)
together with oral or rectal
vancomycin particularly if
ileus is present.

12
 Table 3. Recommendations for the Treatment of C. difficile
Infection (CDI) in Adults (cont'd)
Clinical Supportive Strength-
Definition Clinical Data Recommended Treatmenta Quality

First … Vancomycin 125 mg given qid W-L

recurrence for 10 days if metronidazole
was used for the initial
episode, OR
Use a prolonged tapered and W-L
pulsed vancomycin regimen if
a standard regimen was used
for the initial episode (e.g.,
125 mg qid for 10–14 days,
bid for a week, qd for a week,
and then q2–3d for 2–8
weeks), OR
Fidaxomicin 200 mg given W-M
bid for 10 days if vancomycin
was used for the initial
episode
Second or … Vancomycin in a tapered and W-L
subsequent pulsed regimen, OR
recurrence
Vancomycin, 125 mg qid PO W-L
for 10 days followed by
rifaximin 400 mg tid for 20
days, OR
Fidaxomicin 200 mg given W-L
bid for 10 days, OR
Fecal microbiota S-M
transplantationc
a
All randomized trials have compared 10 day treatment courses, but some patients (particularly
those treated with metronidazole) may have delayed response to treatment, and clinicians should
consider extending treatment duration to 14 days in those circumstances.
b
The criteria proposed for defining severe or fulminant CDI are based on expert opinion. These may
need to be reviewed in the future upon publication of prospectively validated severity scores for
patients with CDI.
c
The opinion of the panel is that appropriate antibiotic treatments for at least 2 recurrences;
(i.e., 3 CDI episodes) should be tried prior to offering FMT.

S, strong; W, weak; H, high; M, moderate; L, low; VL, very low quality of evidence;
GP, good practice; NR, no recommendation
13
 Treatment

Table 4. Recommendations for the Treatment of C. difficile

Infection (CDI) in Children
Clinical Recommended Maximum Strength,
Definition Treatment Pediatric Dose Dose Quality

Initial •  Metronidazole •  7.5 mg/kg/dose •  500 mg tid W-L

episode, × 10 days (PO), tid or qid or qid
non-severe OR
•  Vancomycin × •  10 mg/kg/dose •  125 mg qid W-L
10 days (PO) qid

Initial •  Vancomycin × •  10 mg/kg/dose •  500 mg qid S-M

episode, 10 days qid
severe/ (PO or PR),
fulminant WITH OR
WITHOUT
•  Metronidazole •  10 mg/kg/dose •  500 mg tid W-L
× 10 days (IV)a tid
First •  Metronidazole •  7.5 mg/kg/dose •  500 mg tid W-L
recurrence, × 10 days (PO), tid or qid or qid
non-severe OR
•  Vancomycin × •  10 mg/kg/dose •  125 mg qid
10 days (PO) qid

Second or •  Vancomycin •  10 mg/kg/dose •  125 mg qid W-L

subsequent in a tapered qid
recurrence and pulsed
b
regimen ,
OR
•  Vancomycin for •  Vancomycin: •  Vancomycin: W-L
10 days followed 10 mg/kg/dose 500 mg qid;
by rifaximinc for qid; Rifaximin: Rifaximin:
20 days, no pediatric 400 mg tid
OR dosing
•  Fecal microbiota •  — •  — W-VL
transplantation
a
In cases of severe or fulminant CDI associated with critical illness, consider addition of intravenous
metronidazole to oral vancomycin.
b
Tapered and pulsed regimen as described in Table 2: Vancomycin 10 mg/kg with max of 125 mg
qid for 10–14 days, then 10 mg/kg with max of 125 mg bid for a week, then 10 mg/kg with max of
125 mg qd for a week, and then 10 mg/kg with max of 125 mg q2–3d for 2–8 weeks.
c
No pediatric dosing for rifaximin. Not approved by the US FDA for use in children <12 years
of age.

14
 Recommendation Grading

1. 2. 3.
Establish initial Consider lowering or raising Final level of
level of confidence level of confidence confidence
rating
1. Rating the quality

Study Design Initial Reasons for considering

of the evidence

confidence lowering or raising confidence Confidence

in an in an estimate
$ Lower if # Higher if
estimate of effect
of effect Risk of Bias Large effect across those
Inconsistency Dose response considerations
Randomized High
trials ª confidence Indirectness All plausible H = High
Imprecision confounding
& bias M = Moderate
Publication
• would reduce a L = Low
Observational Low bias
demonstrated
studies ª confidence
effect, or VL = Very Low
• would suggest
a spurious
effect if no
effect was
observed

Certainty that the desirable • Population: Most people in

consequences exceed the this situation would want the
undesirable consequences after
considering all of the following: recommended course of action and
only a small proportion would not
S = Strong

• Health care workers: Most people

should receive the recommended
Balance course of action
2. Determinants of the strength

Quality
3. Implication of the strength

between • Policy makers: The recommendation

(certainty) benefits, harm
of evidence can be adapted as a policy in most
of recommendation

of recommendation

& burden
situations

• Population: The majority of people

Patients'
values & Resources in this situation would want the
preferences and cost recommended course of action, but
many would not
• Health care workers: Be prepared to
W = Weak

help people to make a decision that

is consistent with their own values/
decsion aids and shared decision
making
• Policy makers: There is a need for
substantial debate and involvement
of stakeholders

15
Abbreviations
CA, community-associated; CO-HCFA, community-onset healthcare facility-associated;
CXR, chest radiograph; EIA, enzyme immunoassays; GDH, glutamate dehydrogenase;
HIV, human immunodeficiency virus; HO-CDI, healthcare facility-onset C. difficile
infection; HPLC, high-performance liquid chromatography; IGRA, interferon-γ
release assay; IV, intravenous; LTBI, latent tuberculosis infection; Mtb, Mycobacterium
tuberculosis; NAAT, nucleic acid amplification test; PO, by mouth; PPI, proton pump
inhibitors; PR, per rectum; RCT, randomized clinical trial; RR, relative risk; TB,
tuberculosis; TST, tuberculin skin test

The guidelines provide evidence-based recommendations that have been developed

using GRADE (Grading of Recommendations, Assessment, Development, and
Evaluation) methodology. GRADE involves structured literature review, systematic
reviews and meta-analyses of combined data, and expert discussion to assess the
certainty in the evidence and determine the strength of each recommendation.

Source
McDonald LC et al. Clinical Practice Guidelines for Clostridium difficile Infection in
Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA)
and Society for Healthcare Epidemiology of America (SHEA).

The guidelines were endorsed by the American Society for Health Systems Pharmacists
(ASHP), the Society of Infectious Diseases Pharmacists (SIDP), and the Pediatric
Infectious Diseases Society (PIDS)

Disclaimer
This Guideline attempts to define principles of practice that should produce high-quality patient
care. It is applicable to specialists, primary care, and providers at all levels. This Guideline
should not be considered exclusive of other methods of care reasonably directed at obtaining the
same results. The ultimate judgment concerning the propriety of any course of conduct must be
made by the clinician after consideration of each individual patient situation.
Neither IGC, the medical associations, nor the authors endorse any product or service associated
with the distributor of this clinical reference tool.

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