Comparison of three current Clostridioides difficile infection guidelines: IDSA/SHEA, ESCMID, and ACG guidelines

Abstract

Purpose
Clostridioides difficile infection (CDI) is a widely recognized condition associated with comorbidity and decreased patient quality of life. Certain professional medical organizations develop clinical practice guidelines for major diseases. This is done in an effort to streamline the universal clinical practice and ensure that a more accurate diagnosis and better treatments are offered to respective patients for optimal outcomes. However, as new data evolve, constant update of these guidelines becomes essential. While these guidelines provide up-to-date recommendations, they are not published around the same time; thus, their recommendations may vary depending on evidence available prior to guidelines preparation and publication.

Methods
Recommendations and corresponding justifications from three major CDI guidelines between 2013 and 2017 were pooled and compared, and notable differences were highlighted while providing an insight and a final recommendation from a clinical standpoint.

Results
Most recommendations were consistent among all three guidelines. One notable difference was in the specification of candidates for CDI diagnosis, where it would be recommended to mainly test patients with three or more diarrheal episodes over 24 h, if they had no other clear reason for the diarrhea. Another conflicting point was regarding the treatment of non-severe CDI where vancomycin can be considered for older or sicker patients; however, metronidazole still remains a reasonable option based on recent data, some of which were not cited in the most recent guidelines of IDSA/SHEA.

Conclusion
Overall, it is prudent to follow these guidelines with critical appraisal to fulfill the goal of achieving optimum patient outcomes.

Full text

Vol.:(0123456789)
1 3
Infection
https://doi.org/10.1007/s15010-019-01348-9
REVIEW
Comparison ofthree current Clostridioides difficile infection guidelines:
IDSA/SHEA, ESCMID, andACG guidelines
AbrarK.Thabit1 · MawadahH.Alsolami1· NojoudA.Baghlaf1,2· RaghadM.Alsharekh1· HadeelA.Almazmumi1·
AfrahS.Alselami1· FatmahA.Alsubhi1
Received: 18 January 2019 / Accepted: 10 August 2019
© Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract
Purpose Clostridioides difficile infection (CDI) is a widely recognized condition associated with comorbidity and decreased
patient quality of life. Certain professional medical organizations develop clinical practice guidelines for major diseases. This
is done in an effort to streamline the universal clinical practice and ensure that a more accurate diagnosis and better treatments
are offered to respective patients for optimal outcomes. However, as new data evolve, constant update of these guidelines
becomes essential. While these guidelines provide up-to-date recommendations, they are not published around the same
time; thus, their recommendations may vary depending on evidence available prior to guidelines preparation and publication.
Methods Recommendations and corresponding justifications from three major CDI guidelines between 2013 and 2017 were
pooled and compared, and notable differences were highlighted while providing an insight and a final recommendation from
a clinical standpoint.
Results Most recommendations were consistent among all three guidelines. One notable difference wasin the specifica-
tion of candidates for CDI diagnosis, where it would be recommended to mainly test patients with three or more diarrheal
episodes over 24h, if they had no other clear reason for the diarrhea. Another conflicting point was regarding the treatment
of non-severe CDI where vancomycin can be considered for older or sicker patients; however, metronidazole still remains a
reasonable option based on recent data, some of which were not cited in the most recent guidelines of IDSA/SHEA.
Conclusion Overall, it is prudent to follow these guidelines with critical appraisal to fulfill the goal of achieving optimum
patient outcomes.
Keywords Clostridioides difficile· Guidelines· IDSA· ESCMID· ACG · Vancomycin
Introduction
Clostridioides difficile infection (CDI) has been associated
with increased morbidity and decreased patients’ quality of
life. While mortality rates due to CDI remain low, it has
been associated with hospital outbreaks and an economic
burden. Appropriate management starts with appropriate
diagnosis, followed by antimicrobial therapy tailored to
the severity of the disease. As treating CDI is crucial, pre-
venting its recurrence in the individual patient, as well as
preventing and controlling its spread to other patients, is of
utmost importance.
Medical guidelines provide summary of recommenda-
tions or suggestions on the diagnosis, treatment, or preven-
tion of the diseases while evaluating the quality of evidence
with each statement of recommendation or suggestion [1].
These guidelines are developed by a panel of experts in
the field who incorporate results from the published stud-
ies along with their experience to generate the final clinical
judgment [1].
Due to the serious nature of CDI, several medical socie-
ties or organizations have published guidelines to help clini-
cians to appropriately manage the disease and control it. CDI
guidelines generally share the same outline which includes
diagnosis, classification based on CDI severity, treatment
(which is further divided into treatment of initial episode
and treatment of recurrence), and infection control and
* Abrar K. Thabit
akthabit@kau.edu.sa
1 Pharmacy Practice Department, Faculty ofPharmacy, King
Abdulaziz University, 7027 Abdullah Al-Sulaiman Rd,
Jeddah22254-2265, SaudiArabia
2 Jeddah Clinic Hospital, Jeddah, SaudiArabia

A.K.Thabit et al.
1 3
prevention. Some guidelines also added an additional section
on the role of prophylaxis against CDI in high-risk patients.
More than one CDI guidelines have been published in
the medical literature. Therefore, to simplify the task of the
health-care provider, this review aimed to combine the rec-
ommendations of three major CDI guidelines in each of the
aforementioned sections of the outline, summarize them, as
well as compare and contrast each recommendation backed
up with studies from the literature that were either cited or
not cited in the respective guidelines. The three guidelines
discussed in this review include those published by the
Society for Healthcare Epidemiology of America (SHEA)/
Infectious Diseases Society of America (IDSA) of 2017, the
American College of Gastroenterology (ACG) of 2013, and
the European Society of Clinical Microbiology and Infec-
tious Diseases (ESCMID) of 2014. Since a similar com-
parison of older CDI guidelines was previously published
[2], this review provides an updated comparison of the most
recently published guidelines.
Diagnosis ofCDI
Individual recommendations for diagnosis from the three
guidelines are summarized in Table1.
Candidates forCDI diagnosis
IDSA/SHEA and ACG guidelines specified that only
patients presenting with unexplained diarrhea (defined per
the World Health Organization as three or more unformed
stools within 24-h duration or more frequently than is nor-
mal for the individual) should be tested for CDI [3–5]. ESC-
MID guidelines also included the same definition for diar-
rhea, though it was not stated in the context of defining CDI
diagnosis candidates [6]. Notably, the recommendation of
ACG in this regard was rated strong, whereas that of IDSA/
SHEA was rated weak. This is possibly because the latter
guidelines reported that the number of diarrheal episodes
used to define clinical diarrhea has changed over the years
and that clinicians should look for other conditions to which
diarrhea can be attributed, such as inflammatory bowel dis-
ease (IBD), cancer chemotherapy, or use of laxatives within
the past 48h [4]. Conversely, since the ACG guidelines
were developed by a panel of gastroenterology experts, the
list of CDI diagnosis candidates was extended to include
patients with certain gastrointestinal problems, including
IBD (Table1) [3]. From a clinical standpoint, a patient with
diarrhea should be typically assessed for the presence of CDI
risk factors, namely the use of antimicrobial agents (which
is also emphasized in the extended list of candidates pro-
vided by ACG), potential transmission from another CDI
patient, as well as other factors listed in both guidelines.
However, a recent study found no difference in the rate of
CDI occurrence between patients with and patients with-
out underlying gastrointestinal conditions [7]. As a result, it
would be more prudent to follow IDSA/SHEA guidelines to
test patients with diarrhea that is clearly not linked to causes
other than a potential infection with C. difficile.
Although guidelines recommend CDI testing of only
unformed/loose stools (types 5–7 on Bristol stool chart) and
recommend against testing of formed stools (types 1–3 on
Bristol stool chart), no specific recommendation was made
regarding testing of semiformed stools (type 4 on Bristol
stool chart). In this regard, one study that quantified C. dif-
ficile in stool samples with varying degrees of consistency
according to Bristol stool chart found absence of direct cor-
relation between C. difficile quantity and the degree of stool
consistency [8]. As such, the authors concluded that semi-
formed stools should be sought for CDI testing in patients
presenting with the clinical picture of the disease.
Laboratory testing ofCDI
Both ACG and IDSA recommend using nucleic acid ampli-
fication tests (NAATs) as the single standard diagnostic
test [3, 4]. Alternatively, a multistep algorithm using glu-
tamate dehydrogenase (GDH) (for screening) followed by
toxin enzyme immunoassay (EIA) can be performed [3, 4].
In this regard, ESCMID elaborated on its recommendation
about the multistep algorithm testing where a positive first
test should be confirmed with one or two confirmatory tests
(GDH, Toxin A and B, or NAAT) [6]. CDI testing in patients
receiving laxative was addressed only in IDSA guidelines,
where they recommend using a stool toxin test as part of a
multistep algorithm [4].
All three guidelines recommend againstthe repeatof CDI
testing if the first result returned negative [3, 4, 6]. While
ACG also discourages testing for cure, IDSA recommends
against testing stool from asymptomatic patients [3, 4].
Severity classication ofCDI
The degree of CDI severity should be determined for initial
CDI episodes to tailor the treatment accordingly. Table2
provides a comprehensive summary on how each guideline
classified CDI patients according to disease severity.
Treatment ofCDI
The recommendations provided by each of the three guide-
lines for the treatment of initial and recurrent episodes of
CDI are listed in Table3. Stopping unnecessary (potentially
inciting) antibiotics is a universal recommendation made by
all three guidelines [3, 4, 6].

Comparison ofthree current Clostridioides difficile infection guidelines: IDSA/SHEA,…
1 3
Table 1 Recommendations for diagnosis of Clostridioides difficile infection by the three guidelines
IDSA/SHEA 2017 ESCMID 2014 ACG 2013
Candidate patients for CDI testing Patients with unexplained and new-onset ≥ 3
unformed stools in 24h. (Weak recommen-
dation, very low-quality evidence)
Not specified Only stools from patients with diarrhea. (Strong
recommendation, high-quality evidence)
The following comorbid situations are recom-
mended to have CDI testing
All patients with IBD hospitalized with a
disease flare. (strong recommendation, high-
quality evidence)
Ambulatory patients with IBD who develop
diarrhea in the setting of previously quiescent
disease or in the presence of risk factors such
as recent hospitalization or antibiotic use.
(sStrong recommendation, moderate quality
evidence)
Patients with IBD who have a surgically cre-
ated pouch after colectomy if they have CDI
symptoms. (Strong recommendation, moder-
ate quality evidence)
Patients with underlying immunosuppression
(including malignancy, chemotherapy, corti-
costeroid therapy, organ transplantation,and
cirrhosis) if they have a diarrheal illness.
(Strong recommendation, moderate quality
evidence)
Any diarrheal illness in women who are preg-
nant or periparturient. (Conditional recom-
mendation, low-quality evidence)
Laboratory testing of CDI NAAT alone or a multistep algorithm:
GDH EIA + toxin EIA (may or may not be
arbitrated by NAAT) or NAAT + toxin EIA
rather than a toxin test alone when there are
pre-agreed institutional criteria for patient
stool submission. (Weak recommendation,
low quality evidence)
Two- or three-stage algorithm, in which a
positive first test is confirmed with one or
two confirmatory tests or a reference method
such as GDH, toxins A and B, or NAAT
detecting Toxin B (TcdB)
NAAT is superior to toxins A + B EIA. (Strong
recommendation, moderate quality evidence)
Alternatively, two- or three-step algorithm:
GDH EIA followed by a confirmatory test.
(Strong recommendation, moderate quality
evidence).
Rectal swabs can be used for PCR and thus,
may be useful in timely diagnosis of patients
with ileusa
Diarrheal specimen from patients receiving
laxatives Use a stool toxin test as part of a multistep
algorithm: GDH EIA + toxin EIA (may
or may not be arbitrated by NAAT) or
NAAT + toxin EIA rather than a NAAT
when there are no pre-agreed institutional
criteria for patient stool submission. (Weak
recommendation, low quality evidence)
Not specified Not specified

A.K.Thabit et al.
1 3
Initial CDI episode
Similar to the older IDSA/SHEA guidelines of 2010 [9],
both ESCMID and ACG guidelines agreed on recommend-
ing metronidazole for patients with mild-to-moderate CDI as
the first-line treatment. This recommendation was based on
two old randomized control trials (RCTs) with a total of 213
patients comparing metronidazole with vancomycin. Both
studies concluded that the difference between metronidazole
and vancomycin was not significantly different and that met-
ronidazole was more economical [10, 11]. Moreover, both
metronidazole and vancomycin adversely promote the over-
growth of vancomycin-resistant Enterococci (VRE) [12].
On the other hand, the new IDSA/SHEA guidelines favored
vancomycin over metronidazole for the treatment of non-
severe CDI based on a new evidence from two RCTs that
demonstrated the superiority of vancomycin to metronida-
zole in terms of clinical cure [13, 14]. While the guidelines
cite the study by Zar etal. under this recommendation, the
study showed the superiority only in severe CDI, whereas
similar findings were seen in mild CDI [13]. Similarly, a
large retrospective study of 47,147 patients by Stevens and
colleagues demonstrated lack of difference in CDI recur-
rence and 30-day mortality between the metronidazole and
vancomycin groups in those who initially experienced mild-
to-moderate CDI [15]. However, significantly lower 30-day
mortality was observed in the vancomycin group in patients
with initial severe episode of the disease [15]. Interestingly,
while the new IDSA/SHEA guidelines were ready to be pub-
lished in late 2017, Crowell etal. published a study in the
same year showed that appropriate adherence to the older
IDSA/SHEA guidelines of 2010 (that recommended met-
ronidazole prior to vancomycin as first-line for non-severe
CDI) was significantly associated with lower mortality and
shorter length of stay [16]. Due to the conflicting evidence
in this area, the use of metronidazole for non-severe cases
may continue to remain a reasonable option, particularly in
less endemic areas, as well as for younger, less sick patients
(e.g., non-immunocompromised).
Both ESCMID and ACG included a recommendation on
the use of fidaxomicin but only for severe cases of CDI,
whereas IDSA/SHEA guidelines included this recommen-
dation as an alternative to vancomycin and preferable over
metronidazole for non-severe CDI episodes. IDSA/SHEA
justified this recommendation based on two studies that
compared vancomycin with fidaxomicin showing non-
inferiority results [17, 18]. Furthermore, four more studies
showed potential benefits associated with the use of fidax-
omicin over vancomycin. The first study by Housman etal.
assessed the microbiological effect of either agent on C.
difficile colony counts using quantitative culturing of stool
samples collected at different time points before, during,
and after completion of therapy from CDI patients given
Table 1 (continued)
IDSA/SHEA 2017 ESCMID 2014 ACG 2013
Role of repeat testing including symptomatic,
asymptomatic patients and cure test No repeat testing (within 7days) during the
same episode of diarrhea and no stool test-
ing from asymptomatic patients, except for
epidemiological studies. (Strong recommen-
dation, moderate quality evidence)
Samples with the first negative test result
can be reported as negative (i.e., no repeat
testing)
Repeat testing and testing for cure should be
discouraged. (Strong recommendation, mod-
erate quality evidence)
CDI, Clostridioides difficile infection; EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; NAAT, nucleic acid amplification test; PCR, polymerase chain reaction
a No specification of recommendation strength

Comparison ofthree current Clostridioides difficile infection guidelines: IDSA/SHEA,…
1 3
the antibiotics [19]. The study found no significant differ-
ence between the colony counts of vegetative C. difficile
in samples from patients who received fidaxomicin or van-
comycin. Nonetheless, fidaxomicin resulted in a significant
reduction in spore counts by ≥ 2 log10 CFU/g compared with
vancomycin at the 9–19days follow-up visit (P = 0.02). The
second study was a pilot study comparing C. difficile toxin
concentrations between patients who received vancomycin
vs. fidaxomicin, where only the latter was associated with
sustained levels of both toxins for up to 30days post-therapy
[20]. The third study by Gallagher and colleagues showed
the economic advantage of fidaxomicin, where a signifi-
cantly lower number of patients who received the agent were
readmitted to the hospital with CDI within 90days com-
pared with those who received vancomycin (P = 0.03) [21].
Moreover, those who received fidaxomicin also experienced
a shorter total length of hospital stay vs. the vancomycin
group (87 vs. 183days) on the basis of actual total costs of
$196,200 and $454,800 in the fidaxomicin and vancomycin
groups, respectively. Similar results with fidaxomicin were
demonstrated in the fourth study by Goldenberg etal., where
implementing the use of fidaxomicin resulted in significantly
lower rate of CDI recurrence and 28-day mortality compared
with the period prior to fidaxomicin use (P < 0.05 for both
comparisons) [22]. It is presumed that such effects of fidax-
omicin can help mitigate CDI symptoms, as demonstrated by
the decrease in toxin concentrations which might have been
translated into the shortened length of stay seen in the two
latter studies. Additionally, fidaxomicin is also presumed to
be linked to decreased probability of CDI recurrence within
the same patient or transmission between patients given its
effects on spore reduction, which showed reduced rates of
readmission in the two latter studies. All four studies were
published in or after 2015, though none was cited in the
IDSA/SHEA guidelines of 2017 to support recommending
fidaxomicin, perhaps over vancomycin. Overall, fidaxomicin
seems to be a very attractive option for clinicians given its
clinical, microbiological, and economical value in CDI
treatment. Hence, it was presented as a favorable option in
IDSA/SHEA guidelines and is presumed to receive an equal
level of favorability in the upcoming ESCMID and ACG
guidelines.
Table 2 Severity classification of Clostridioides difficile infection according to the three guidelines
√Factors indicating severe CDI
*Additional criteria for increased risk of severe CDI: serious comorbidity, immunodeficiency, and age≥65years
a Factors indicating complicated (or fulminant) CDI
IDSA/SHEA 2017 ESCMID 2014aACG 2013
Physical examination
Fever ≥ 38.5°C √ *
Rigors √
Abdominal tenderness √
Abdominal distention *
Ileus * √ *
Signs and symptoms of peritonitis √
Hemodynamic instability * √ *
Respiratory failure √ *
Mental status change *
Intensive care unit admission √ *
Laboratory alterations
Leukocyte count ≥ 15,000 cells/mm3> 15,000 cells/mm3 (band neutro-
phils > 20% of leukocytes) ≥ 15,000 cells/mm3
(≥ 35,000 or < 2000
cells/mm3)*
Creatinine > 1.5mg/dL > 50% above the baseline or ≥ 133μM Renal failure*
Albumin < 30g/L < 30g/L
Lactate ≥ 5mM > 2.2mmol/L*
Colonoscopy and imaging
Pseudomembranous colitis √
Megacolon/large intestine distension * √
Colonic wall thickening √
Pericolonic fat stranding √
Unexplained ascites √

A.K.Thabit et al.
1 3
Table 3 Pharmacological treatment recommendations for Clostridioides difficile infection of the three guidelines
IDSA/SHEA 2017 ESCMID 2014 ACG 2013
Initial episode, non-severe (mild-to-moderate) Vancomycin 125mg PO every 6h or fidax-
omicin 200mg PO every 12h for 10days.
(Strong recommendation, high-quality
evidence)
If above agents are unavailable, metronidazole
500mg PO every 8h for 10days. (Weak
recommendation, high-quality evidence)
Metronidazole 500mg PO every 8h for
10days. (Strong recommendation, high-
quality evidence)
Vancomycin 125mg PO every 6h or fidax-
omicin 200mg PO every 12h for 10days.
(Moderate recommendation, high-quality
evidence)
Vancomycin 500mg PO every 6h for
10days. (Weak recommendation, high-
quality evidence)
Stop inducing antibiotics and observe for
48h. (Weak recommendation, moderate
quality evidence)
Metronidazole 500mg PO every 8h for
10days. (Strong recommendation, high-
quality evidence)
Failure to respond to metronidazole within
5–7days should prompt consideration of a
change to vancomycin 125mg every 6h for
10days. (Strong recommendation, moderate
quality evidence)
Patients in whom oral antibiotics cannot reach
a segment of the colon (i.e., ileus), vanco-
mycin enema should be added as 500mg
in 100–500mL of normal saline every 6h.
(Conditional recommendation, low quality
evidence).
Initial episode, severe Vancomycin 125mg PO every 6h or fidax-
omicin 200mg PO every 12h for 10days.
(Strong recommendation, high-quality
evidence)
Vancomycin 125mg PO every 6h for
10days. (Strong recommendation, high-
quality evidence)
Vancomycin 500mg PO every 6h for
10days. (Moderate recommendation, mod-
erate quality evidence)
Fidaxomicin 200mg PO every 12h for
10days. (Moderate recommendation, high-
quality evidence)
Vancomycin 125mg PO every 6h for 10days.
(Conditional recommendation, moderate
quality evidence)
Patients in whom oral antibiotics cannot reach
a segment of the colon (i.e., ileus), vanco-
mycin enema should be added as 500mg
in 100–500mL of normal saline every 6h.
(Conditional recommendation, low quality
evidence)

Comparison ofthree current Clostridioides difficile infection guidelines: IDSA/SHEA,…
1 3
Table 3 (continued)
IDSA/SHEA 2017 ESCMID 2014 ACG 2013
Initial episode, fulminant (severe complicated) Vancomycin 500mg PO or NG every 6h.
(Strong recommendation, moderate quality
evidence)
If ileus, consider adding vancomycin 500mg
in 100mL of normal saline PR every
6h. (Weak recommendation, low quality
evidence) + IV metronidazole 500mg every
8h. (Strong recommendation, moderate
quality evidence)
Surgery if failed antibiotic therapy with sys-
temic toxicity, peritonitis, or toxic colonic
dilatation and bowel perforationa
If no significant abdominal distention, vanco-
mycin 125mg PO every 6h + metronidazole
500mg IV every 8h. (Strong recommenda-
tion, low-quality evidence)
If ileus or toxic colitis and/or significant
abdominal distention, vancomycin 500mg
PO every 6h + 500mg PR in 500mL normal
saline every 6h + metronidazole 500mg IV
every 8h. (Strong recommendation, low-
quality evidence)
Surgical therapy should be considered in
patients with any one of the following condi-
tions attributed to CDI
Hypotension requiring vasopressor therapy
Clinical signs of sepsis
Organ dysfunction
Mental status changes
WBC count ≥ 50,000 cells/mm3
Lactate ≥ 5mmol/L
Complicated CDI with failure to improve on
medical therapy after 5days
(Strong recommendation, moderate quality
evidence)
First recurrence If a standard regimen was used for the initial
episode, vancomycin PO tapered and
pulsed regimen (125mg PO every 6h for
10–14days, every 12h for a week, once per
day for a week, and then every 2 or 3days
for 2–8weeks). (Weak recommendation, low
quality evidence)
If vancomycin was used for the initial episode,
fidaxomicin 200mg PO every 12h for
10days. (Weak recommendation, moderate
quality evidence)
If metronidazole was used for the primary
episode, vancomycin 125mg PO every 6h
for 10days rather than a second course of
metronidazole. (Weak recommendation, low
quality evidence)
Vancomycin 125mg PO every 6h or fidax-
omicin 200mg PO every 12h for 10days.
(Moderate recommendation, high-quality
evidence)
Metronidazole 500mg PO every 8h for
10days. (Weak recommendation, high-
quality evidence)
Vancomycin 500mg PO every 6h for
10days. (Weak recommendation, low qual-
ity evidence)
Same as initial episode. (Conditional recom-
mendation, low quality evidence)

A.K.Thabit et al.
1 3
Table 3 (continued)
IDSA/SHEA 2017 ESCMID 2014 ACG 2013
Second recurrence Vancomycin PO tapered and pulsed regi-
men. (Weak recommendation, low quality
evidence)
Vancomycin 125mg PO every 6h for 10days
followed by rifaximin 400mg PO every 8h
for 20days. (Weak recommendation, low
quality evidence)
Fidaxomicin 200mg PO every 12h for
10days. (Weak recommendation, low quality
evidence)
Vancomycin 125mg PO every 6h for 10days
followed by pulsed regimen (125–500mg
per day every 2–3days for at least 3weeks,
vancomycin orally 125mg PO every 6h for
10days followed by taper regimen (gradu-
ally decreasing the dose to 125mg per day),
or fidaxomicin 200mg PO every 12h for
10days. (Moderate recommendation, mod-
erate quality evidence)
Vancomycin 500mg PO every 6h for
10days. (Weak recommendation, moderate
quality evidence)
Pulsed vancomycin regimen (Conditional rec-
ommendation, low quality evidence)
Multiple (≥ 3 recurrences) who have failed
appropriate antibiotic treatments Fecal microbiota transplantation. (Strong rec-
ommendation, moderate quality evidence) Same as second recurrence
Fecal microbiota transplantation + van-
comycin 500mg PO every 6h for
4–14days + bowel lavage. (Strong recom-
mendation, high-quality evidence)
Fecal microbiota transplantation (Conditional
recommendation, moderate quality evidence).
CDI, Clostridioides difficile infection; IV, intravenous; NG, nasogastric; PO, by mouth; PR, per rectum
a No specification of recommendation strength

Comparison ofthree current Clostridioides difficile infection guidelines: IDSA/SHEA,…
1 3
The ACG guidelines rank vancomycin second to met-
ronidazole in case the latter did not result in satisfactory
response. This was based on an observational study of 207
patients who received 500mg of metronidazole every 8h
and continued to be symptomatic after completing 10days
of therapy [23]. The authors concluded that the lack of
response despite receiving the full course is an indica-
tion of a severe disease, warranting additional treatment
approaches. In patients where oral antibiotics cannot reach
a segment of the colon, ACG recommends that vancomy-
cin enema be added relying on data from two studies [24,
25]. In contrast, IDSA/SHEA suggests metronidazole only
if vancomycin and fidaxomicin are unavailable because of
the inferior results reported in four studies [14, 23, 26, 27].
For severe CDI, all three guidelines recommend vanco-
mycin for first-line treatment. In addition, IDSA/SHEA and
ESCMID guidelines also include fidaxomicin as an alterna-
tive to vancomycin, based on several clinical trials demon-
strating the superiority of both vancomycin and fidaxomicin
to metronidazole in severe CDI cases [13, 14, 28]. Rectal
administration of vancomycin is also recommended by ACG
in the presence of conditions halting delivery of oral antibi-
otics [3]. In addition, ESCMID moderately recommend (and
weekly recommend for mild-to-moderate CDI) a higher dose
of vancomycin at 500mg based on four studies [10, 11, 29,
30]. Nevertheless, one cited study reported equal response
with 125mg and 500mg of vancomycin [31]. Interestingly,
a study that assessed the correlation between fecal vanco-
mycin concentrations resulting from 125mg dose and clini-
cal outcomes did not find that higher concentrations were
associated with better outcomes [32].
ACG and IDSA/SHEA guidelines recommend adding
intravenous (IV) metronidazole and rectal vancomycin (in
case of ileus) to oral vancomycin in patients with fulminant
(severe complicated) CDI based on a study by Rokas etal.
that showed mortality advantage when IV metronidazole
was added to the regimen (P = 0.03) [33]. The only differ-
ence between the two guidelines is that ACG keeps the rec-
ommended vancomycin dose at 125mg, while IDSA/SHEA
recommend the 500mg dose. The high dose recommenda-
tion by IDSA/SHEA seems to stem from an expert opinion,
and a statement recommending monitoring trough concen-
trations of vancomycin has been added to the guidelines, as
such high doses were associated with prolonged exposure
and renal failure [4, 34].
Recurrent CDI
CDI recurrence is defined by the three guidelines as the
reappearance of documented CDI within 8weeks after the
onset of the previous episode, provided that symptoms have
resolved after completing therapy [3, 4, 6].
For the treatment of the first CDI recurrence, the three
guidelines did not have a consensus on the choice of antibi-
otics. Repeating the same regimen used in the initial episode
was the recommendation made by ACG [3]. ESCMID pro-
vided a recommendation similar to its recommendation for
the treatment of severe CDI (vancomycin or fidaxomicin)
[6]. IDSA/SHEA preferred tailoring the treatment accord-
ing to the choice made for treating the initial episode and
including a recommendation for the use of tapered and
pulsed regimen of vancomycin [4]. In this regard, a regimen
comprising tapered or pulsed dosing of vancomycin resulted
in a significantly lower recurrence rate compared with met-
ronidazole (P = 0.01 and 0.02 for tapered and pulsed regi-
mens, respectively) [35]. Moreover, the use of fidaxomicin
was associated with fewer secondary recurrences compared
with vancomycin after using it for the treatment of a first
CDI recurrence per a study by Cornely etal. (recurrence
rate = 35.5% vs. 19.7%; P = 0.0003) [36]. A recommendation
for the use of fidaxomicin for the first recurrence of CDI was
made by IDSA/SHEA and ESCMID [4, 6].
For the second recurrence of CDI, both IDSA/SHEA and
ESCMID guidelines agree on the use of either fidaxomicin
or tapered and pulsed vancomycin regimen [4, 6]. On the
other hand, ACG only recommended the latter approach
in this situation [3]. Of note, IDSA/SHEA guidelines also
included a new suggestion not included in its ESCMID and
ACG counterparts, that is, using oral rifaximin therapy fol-
lowing a 10-day course of standard oral vancomycin [4].
This novel suggestion was made on the basis of a rand-
omized, double-blind, placebo-controlled trial showing a
significantly reduced rate of recurrent diarrhea (despite of
the cause) in the rifaximin arm vs. the placebo arm (21% vs.
49%; P = 0.018); however, no significant difference between
the two groups was observed in terms of CDI-associated
diarrhea (15% vs. 31%; P = 0.11) [37].
For patients with multiple recurrences (defined as three or
more CDI episodes) who have failed appropriate antibiotic
treatment, all three guidelines recommend fecal microbiota
transplantation [3, 4, 6]. ESCMID recommends continuing
oral antibiotic therapy with this treatment approach [6].
With regard to probiotics, none of the guidelines recom-
mended their use for primary or secondary prevention of
CDI due to insufficient data or controversial results [3, 4, 6].
CDI prevention
The first step to be carried out to prevent the transmission
of infection is to isolate the CDI patient in a single pri-
vate room. Such recommendation is provided by all three
guidelines [3, 4, 6]. ACG extends this recommendation to
include patients with suspected infection [3]. In case of
limited room vacancy, ESCMID and IDSA suggest placing

A.K.Thabit et al.
1 3
infected patients in cohort [4, 6]. Moreover, health-care
workers and visitors are strongly recommended to use per-
sonnel protective equipment, such as gown and gloves,
prior to entering rooms of CDI patients followed by hand
washing with soap and water (to physically eliminate C.
difficile spores) along with hand sanitization with an anti-
septic after exiting the room as recommended by all three
guidelines [3, 4, 6].
After a CDI patient is discharged from the hospital room,
a disinfection procedure of the room surfaces and equipment
should be carried on as recommended by IDSA and ESC-
MID using chlorine-containing agent (of a concentration of
at least 1000ppm) or other sporicidal cleaning agents [4, 6].
ACG was more specific with regard to the disinfection agent
to be used: it should be an Environmental Protective Agency
(EPA) registered disinfectant with C. difficile sporicidal label
claim, or 5000ppm chlorine-containing cleaning agent [3].
Additional recommendations provided by the three guide-
lines to prevent the spread of CDI include use of dedicated
and disposable materials and dedicating medical devices to
a single patient or use of disposable caps as in the case of
rectal electronic thermometers [3, 4, 6].
While ESCMID limits the duration of precautions to 48h
after symptomatic CDI has resolved and bowel movements
have returned to normal, ACG and IDSA did not specify a
duration, but recommended maintaining contact precautions
for the duration of the diarrhea [3, 4, 6]. Following appro-
priate infection control and prevention measures in health-
care settings is crucial to limit the spread of the infection,
since exposure to health care was the major significant factor
associated with reinfection (rather than relapse) with new
C. difficile ribotype (over other factors, such as age, initial
infection with 027 strain, exposure to antibiotics or proton
pump inhibitors, or type of antibiotic used in initial CDI
therapy) [38].
Conclusion
Clinical practice guidelines get updated regularly as new evi-
dence arise in the medical literature which may influence the
change in recommendations compared with the older ver-
sion of the guidelines or older guidelines published by peer
organizations. The most prominent example observed here
was the significant change in treatment recommendation for
initial non-severe CDI episode in the 2017 guidelines by
IDSA/SHEA compared with ESCMID and ACG guidelines
of 2014 and 2013, respectively.
As guidelines are developed by a panel of experts in the
field to include only reliable evidence to draw recommenda-
tions, compliance with these guidelines in clinical practice
is deemed prudent.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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