Treatment of recurrent Clostridium difficile infection: a ......CLINICAL AND EPIDEMIOLOGICAL STUDY Treatment of recurrent Clostridium difficile infection: a systematic review J.

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CLINICAL AND EPIDEMIOLOGICAL STUDY

Treatment of recurrent Clostridium difficile infection: a systematicreview

J. C. O’Horo • K. Jindai • B. Kunzer •

N. Safdar

Received: 21 April 2013 / Accepted: 12 June 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract

Background Clostridium difficile infection (CDI) recurs

in nearly one-third of patients who develop an initial

infection. Recurrent CDI (RCDI) is associated with con-

siderable morbidity, mortality, and cost. Treatment for

RCDI has not been not well examined.

Methods A systematic review.

Results Sixty-four articles were identified evaluating

eight different treatment approaches: metronidazole, van-

comycin, fidaxomicin, nitazoxanide, rifampin, immuno-

globulins, probiotics, and fecal bacteriotherapy. The meta-

analysis found vancomycin to have a similar efficacy to

metronidazole, although studies used varying doses and

durations of therapy. Fidaxomicin was slightly more effi-

cacious than vancomycin, though the number of studies

was small. Good evidence for probiotics was limited. Fecal

bacteriotherapy was found to be highly efficacious in a

single randomized trial.

Conclusion Metronidazole and vancomycin have good

evidence for use in RCDI but heterogeneity in treatment

duration and dose precludes robust conclusions. Fidax-

omicin may have a role in treatment, but evidence is lim-

ited to subgroup analyses. Fecal bacteriotherapy was the

most efficacious. Saccharomyces boulardii may have a role

as adjunctive treatment.

Keywords Recurrent Clostridium difficile � Clostridium

difficile � Treatment � Antibiotic � Immunoglobulin �Fecal bacteriotherapy

Introduction

Clostridium difficile infection (CDI) is the leading cause of

healthcare-associated infectious diarrhea in hospitalized

patients and is on the rise in the outpatient setting [1].

Recent years have seen the emergence of a hyper-virulent

strain, BI/NAP/27 [2], associated with increased toxin

production and adverse clinical outcomes [1, 3–6].

Recurrent or relapsing CDI (RCDI) occurs in approxi-

mately 20–30 % of patients following initial CDI, and up

to 45 % of patients will have subsequent recurrences [7].

The economic costs associated with RCDI are estimated to

exceed $13,000 per relapse [8].

Current Infectious Diseases Society of America (IDSA)

guidelines [9] recommend discontinuation of the offending

antibiotic and treatment with metronidazole (or vancomy-

cin for severe CDI) for the first episode of CDI. The same

options are recommended for the first recurrence. Sub-

sequent episodes of RCDI are recommended to be treated

by tapering or pulse-dosed vancomycin.

Effective treatments for RCDI are urgently needed; yet,

few therapeutic options have been well studied. We

undertook a systematic review to critically evaluate the

efficacy of therapeutic interventions in RCDI.

Electronic supplementary material The online version of thisarticle (doi:10.1007/s15010-013-0496-x) contains supplementarymaterial, which is available to authorized users.

J. C. O’Horo

Section of Pulmonary and Critical Care Medicine, Department of

Medicine, Mayo Clinic, Rochester, MN, USA

K. Jindai � B. Kunzer � N. Safdar (&)

Section of Infectious Diseases, Department of Medicine,

University of Wisconsin School of Medicine and Public Health,

Madison, WI, USA

e-mail: [email protected]

N. Safdar

William S. Middleton VA Hospital, Madison, WI, USA

123

Infection

DOI 10.1007/s15010-013-0496-x

Page 2

Methods

Search strategy and data abstraction

With the aid of an expert librarian, MEDLINE, CINAHL,

EMBASE, and the Cochrane Review Database were searched

in September of 2012 for articles on RCDI treatment without

publication date restrictions. The full search strategy is

available in Supplemental Table 1. Inclusion criteria for the

review were human trials or reports that provided outcome

data on a specific intervention for RCDI. No language

restrictions were applied; abstracts and articles were trans-

lated as needed. The references of all relevant articles,

including reviews and editorials, were manually inspected for

potentially relevant studies. The search strategy was in

accordance with the Preferred Reporting Items for Systematic

Reviews and Meta-Analyses (PRISMA) statement [10].

Data abstracted from each study included the specifics of

the treatment regimen, the definition of RCDI used, con-

comitant or adjunctive therapies, study design, inclusion and

exclusion criteria, duration of surveillance, and study end-

point. Study endpoints that included clinical cure were con-

sidered stronger methodologically than those that used solely

surrogates, such as the clearance of toxin from stool. Out-

comes were measured as both clinical cure and recurrence.

Clinical cure was defined as an initial positive response to

therapy in a patient with RCDI. Recurrence was defined as a

patient who, after initial response to RCDI therapy, had a

subsequent relapse following clinical cure. When provided,

side effect data and mortality data were abstracted as well.

When appropriate, quantitative analysis was performed

with DerSimonian and Laird random effects modeling in

RevMan software [11].

Assessment of risk of bias

Two authors independently assessed the risk of study bias.

Because retrospective, prospective, and interventional studies

met the inclusion criteria, the risk of bias was assessed

according to the instrument developed by Downs and Black

[12]. This tool encompasses six sections which assess

reporting, external validity, internal validity/bias, internal

validity/confounding, and power. Inter-rater agreement was

excellent (Cohen’s j coefficient = 0.86). Disagreements

were resolved by a third author. Studies with scores C12

were considered to be high-quality studies.

Results

Literature review

A total of 4,242 articles were retrieved with the search

strategy described above. 173 additional studies were

identified via manual chart review. Of these, 105 studies

analyzing eight major treatments strategies for RCDI were

identified and included in this review (see PRISMA dia-

gram, Fig. 1).

Vancomycin

Ten studies evaluated the efficacy of vancomycin in RCDI,

with four case series [13–16] and six randomized con-

trolled trials (RCTs) [17–22] including 615 patients with

376 sustained responses to therapy (61 %). Initial cure

rates ranged from 20 to 100 %, with sustained cure rates

ranging between 49 and 100 %. Six studies were of high

quality. Study endpoints were histologic resolution of

pseudomembranous colitis (PMC) in one study [13],

Fig. 1 PRISMA diagram

J. C. O’Horo et al.

123

Page 3

resolution of toxin positive assay in one study [18], and

clinical resolution in the remaining studies.

One study was exclusively among inpatients [14]; the

remainder included both in- and outpatients. All studies

were among adults. Variable dosing and administration

methods were used; this is summarized in Table 1.

Examining high-quality trials using vancomycin, three

studied a metronidazole comparator [15–17] and two fi-

daxomicin [19, 20]. The metronidazole comparator studies

included 179 patients given metronidazole compared to

310 receiving vancomycin. Using sustained response (e.g.,

no recurrence), vancomycin was as efficacious as metro-

nidazole [relative risk (RR) 1.08, 95 % confidence interval

(CI) 0.85–1.35, I2 = 0 %, p = 0.53). Studies comparing

fidaxomicin to vancomycin, discussed further below,

included a total of 79 patients in each arm, and appeared

slightly more efficacious than vancomycin (RR 1.86, 95 %

CI 1.04–3.31, I2 = 0 %, p = 0.04) (Fig. 2).

Pulsing or tapering doses of vancomycin has demon-

strated efficacy in small studies and subgroups [13, 15],

and has been adopted as part of the current guidelines but

has not yet been evaluated in large RCTs [7, 23]. Tapering

vancomycin involves a prolonged regimen where the dose

is slowly reduced over several weeks. Pulsing involves a

dose of vancomycin every 3 days following the completion

of a full 10–14-day course for several weeks [24].

Evidence supporting the use of vancomycin is moderate.

There is considerable variability in dosing and duration for

RCDI, but it is currently the standard of care in treating

RCDI.

Metronidazole

Two case series [15, 16] and three RCTs [17, 25, 26]

evaluated metronidazole in RCDI. A total of 283 patients

were treated with metronidazole-containing regimens, with

a second recurrence in 86 patients (29 %). Rates of initial

response were between 77 and 100 %. One study con-

cluded that metronidazole was non-inferior to vancomycin

in a first relapse [16], while two favored vancomycin reg-

imens [15, 17]. Two studies used metronidazole plus pla-

cebo as part of a control group to evaluate either C. difficile

immune whey or probiotic regimens [25, 26], discussed

further below.

The dosing regimens and duration of metronidazole are

summarized in Table 2. The patient populations were

exclusively adults. All studies included both inpatients and

outpatients. Primary endpoints were resolution of symp-

toms without recurrence for 1 or 2 months [17, 26] or

1 year [15].

Current IDSA guidelines endorse one repeat course of

metronidazole as the standard of care for the first recur-

rence [9]. A temporal correlation of treatment failure has

been noted since the emergence of the BI/NAP1/027 strain

[7, 27]. It is not recommended beyond a first recurrence

because of the risk of accumulation of neurotoxic metab-

olites [9]. All of the identified studies were of high quality,

and found a fairly consistent efficacy, similar to vanco-

mycin (see Fig. 2).

Other antibiotics

Several other antibiotics have been examined, particularly

nitazoxanide [18, 28], rifaximin [29–35], and fidaxomicin

[19, 20]. Nitazoxanide is a thiazoline-class antibiotic

developed primarily as an anti-parasitic agent. Early stud-

ies in primary CDI indicated it to be relatively safe and

well tolerated, with a response rate similar to metronida-

zole [36]. Two prospective studies [18, 28] on 47 patients

found an initial response in 27 patients, with one second

recurrence (55 % sustained response). Both studies were in

adults, used a mix of in -and outpatients, and dosed the

nitazoxanide at 500 mg twice daily for 10 [21] or 14 days

[18]. One study used clinical resolution as an endpoint

[21], while the other used toxin assay negativity as the

endpoint [18]. In each study, the authors noted efficacy

rates that were similar to vancomycin in treating RCDI (see

Supplemental Table 1).

Seven publications report the use of rifaximin in treating

RCDI, including two case reports [29, 30], three case series

[31–34], and one prospective trial [35]. These total 49

patients, and report an aggregate of 12 failures. One study

used toxin clearance as the primary endpoint [35], while

the rest used clinical resolution. Three used rifaximin in

combination with vancomycin regimens [30, 31, 33] (see

Supplemental Table 2).

Fidaxomicin is a poorly absorbed, orally administered

narrow-spectrum macrolide [37]. Both studies of fidax-

omicin were prospective trials in a mixed inpatient–out-

patient population [19, 20], totaling 116 patients. Clinical

resolution was the endpoint of both studies. Initial response

rates were high at 93 %, with sustained response occurring

in 82 % of patients. One study indicated a clear reduction

in recurrence after treating primary CDI, and evaluated

RCDI as a subset. In that secondary analysis, fidaxomicin

was superior to vancomycin in preventing a second

recurrence in 28 days [19]. Fidaxomicin is the only drug

other than vancomycin approved by the U.S. Food and

Drug Administration (FDA) for CDI [38]. Both of the

existing studies on fidaxomicin compared the drug to

vancomycin and found non-inferiority [19, 20], with

pooled results showing the slight superiority of vancomy-

cin (see Fig. 2). However, it is worth noting that this

medication is considerably more expensive than oral van-

comycin, and may have decreased activity against the

NAP1-027 strain [19] (see Table 3).

Treatment of recurrent Clostridium difficile infection

123

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Treatment of recurrent Clostridium difficile infection

123

Page 6

Alternative antibiotic regimens deserve study, but lack

the records of vancomycin and metronidazole. Evidence

for fidaxomicin is moderate in light of two positive, high-

quality studies. The current evidence for nitazoxanide and

rifaximin is weak.

Immunoglobulins

Ten studies were found evaluating immunoglobulin treat-

ments, with one evaluating oral immunoglobulins [25], one

monoclonal antibodies [39], and the remainder polyclonal

IVIG [40–44]. These articles included 77 patients, and had

21 relapses (26 %). No study reported an initial response

rate lower than 80 %. One study used toxin clearance as

the primary endpoint [39], with the rest reporting clinical

resolution. Two studies were determined to have a low risk

of bias [25, 39], while the remainder had a high risk of bias

(see Table 4).

Depressed levels of IgG generally, and anti-C. difficile

toxin A deficiency specifically, have been demonstrated as

a risk factor for developing severe or recurrent CDI [45,

46]. In a previous systematic review, the greatest benefit

was observed in studies restricted to known hypogamma-

globulinemia patients [47], but the overall study quality

was low. A more recent, high-quality RCT evaluating a

monoclonal antibody against C. difficile toxins demon-

strated benefits in preventing recurrence in 29 patients with

active RCDI refractory to vancomycin and/or metronida-

zole [39].

The use of polyclonal IVIG in the treatment of recurrent

or severe CDI has equivocal evidence. Evidence for using

monoclonal IVIG is stronger, with a single RCT showing

benefit [39]. While oral immune globulin (OIG) appears

promising and has a good biological rationale for its effi-

cacy, the solitary high-quality study to date did not dem-

onstrate a benefit over metronidazole, which is

considerably more cost-effective than the expensive

immunoglobulin preparations.

Probiotics

Intestinal microbiota in a typical human outnumber host

cells by 10:1, and are involved in a plethora of metabolic

and biochemical interactions vital to immunologic function

[48]. The complexity and activity of the flora has been

likened to an organ [49], and recent advances have found a

limited number of ‘‘enterotypes’’, balanced microbiota,

which are consistent with a state of health [50]. Antibiotic-

associated diarrhea (AAD), a condition in which the mic-

robiota is severely disrupted, allows overgrowth by virulent

bacteria such as C. difficile. Probiotics attempt to remedy

this by providing normal host microbes to recolonize the

colon and prevent invasion by pathogens. The majority of

studies of probiotics in AAD have been preventive and

have indicated some benefit [51], while a growing number

of studies have evaluated its utility in the treatment of CDI.

Common probiotic formulations are derived from Lacto-

bacillus spp., Enterococcus faecium, Bifidobacteria spp.,

and Saccharomyces boulardii.

Eight studies evaluated probiotics in RCDI, four using S.

boulardii [17, 52–54], three Lactobacillus spp. [26, 55, 56],

and one a non-toxigenic strain of C. difficile [57] (see

Fig. 2 Forest plot of vancomycin versus metronidazole and fidaxomicin. Risk ratio of not having further relapses with vancomycin versus

comparators in listed studies

J. C. O’Horo et al.

123

Page 7

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29

9v

12

92

%6

6N

on

eN

/AN

/AH

igh

63

Pla

ceb

o9

77

%5

6N

RN

/AN

/AH

igh

Pep

inet

al.

[16]

Cas

e

seri

es

RC

DI

wit

hp

osi

tiv

e

tox

inas

say

or

clin

ical

dia

gn

osi

so

f

pse

udo

mem

bra

no

us

coli

tis

Po

siti

ve

cyto

toxin

assa

yo

ren

do

sco

pic

evid

ence

of

PM

C

2m

on

ths

NR

No

ne

11

5N

R7

9V

anco

NR

60

%H

igh

Mat

tila

etal

.

[25]a

RC

TA

du

ltp

atie

nts

wit

hat

leas

ttw

oep

iso

des

of

tox

in-p

osi

tiv

e

sym

pto

mat

icC

DI

wit

hin

3m

on

ths

Act

ive

dia

rrh

eaw

ith

po

siti

ve

toxin

assa

y

28

day

s6

6C

lost

rid

ium

dif

fici

le

imm

un

e

wh

ey

20

10

0%

60

CD

IW8

3%

61

%H

igh

NR

not

report

ed,

RC

Tra

nd

om

ized

con

troll

edtr

ial,

Va

nco

van

com

yci

n,

CD

IWC

lost

rid

ium

dif

fici

leim

mu

ne

wh

ey,

EIA

enzy

me

imm

un

oas

say

,P

MC

pse

udo

mem

bra

no

us

coli

tis

aH

igh

qu

alit

yin

dic

ates

aD

ow

ns

and

Bla

cksc

ore

gre

ater

than

or

equ

alto

12

bC

om

bin

edfo

rw

ith

adju

nct

ive

S.

bo

ula

rdii

and

wit

ho

ut

cF

rom

‘‘H

igh

do

sev

anco

my

cin’’

com

par

ato

rar

m

Treatment of recurrent Clostridium difficile infection

123

Page 8

Table 5). All studies used clinical symptoms as a primary

endpoint. Three were considered to be high-quality studies

[17, 26, 54].

In RCDI, S. boulardii has the strongest evidence, with

two placebo-controlled RCTs finding benefit [17, 52],

though the first did not control for prior antibiotic regi-

mens, and the second found benefit only when used as an

adjunct to high-dose vancomycin [58]. A third trial noted a

high relapse rate (66 %), though this study found higher

concentrations of S. boulardii in stool correlated with a

decreased risk of recurrence [53].

Lactobacillus spp. have not been well evaluated, with

two case series supporting the use of Lactobacillus GG and

one randomized underpowered trial failing to show sig-

nificant benefit from L. plantarum 299v [26]. Evidence for

the use of other organisms is limited to case reports.

Overall, the evidence for the adjunctive use of S. bou-

lardii in treating RCDI is moderate. Other probiotic for-

mulations need to be studied for efficacy.

Fecal bacteriotherapy

Fecal bacteriotherapy (FBT) delivers a complete comple-

ment of intestinal microbiota and its milieu to restore

normal ecology. FBT has been a reported treatment of

PMC since 1958 [59]. Since then, dozens of retrospective

studies have been published supporting its use. The major

adverse effects associated with FBT in the published

studies have been complications of the delivery mecha-

nism, e.g., gastrointestinal bleeding from nasogastric tube

placement [60].

There is variability among published protocols, but all

are largely consistent with a highly detailed FBT protocol

published by Bakken et al. [60]. Potential donors are

screened for bloodborne viruses and gastrointestinal ill-

ness. A stool sample from a donor is collected and mixed

with milk, water, or saline, filtered, and diluted to a target

volume which is delivered by nasogastric tube or enema,

rectal tube, or colonoscope [60]. Success rates appear to be

higher with lower gastrointestinal delivery, repeated

treatments, and greater volume of infusate [61], though a

recent meta-analysis found no difference in upper versus

lower gastrointestinal delivery [62].

Thirty-three publications addressing FBT for RCDI

were identified. There were two prospective trials [63, 64],

seven case reports [65–71], 23 case series [72–94], and one

RCT [22]. These included 609 patients and reported 63

failures (10.3 %). Except for one study using toxin clear-

ance as a primary endpoint [77], all used clinical criteria to

define success (see Table 6).

An RCT undertaken in the Netherlands, the FECAL

trial, demonstrated the superiority of fecal transplant

delivered into the duodenum over vancomycin (RR 3.05,Ta

ble

3F

idax

om

icin

inR

CD

I

Stu

dy

Des

ign

Incl

usi

on

crit

eria

Defi

nit

ion

of

recu

rren

ce

Du

rati

on

of

foll

ow

up

Mea

n

age

Ad

jun

ctiv

e/

pre

par

ato

ry

trea

tmen

ts

No

.tr

eate

d

wit

h

fid

axo

mic

in

Init

ial

resp

on

se

rate

(%)

Su

stai

ned

resp

on

se

rate

(%)

Co

mp

arat

or

Co

mp

arat

or

init

ial

resp

on

se

rate

(%)

Co

mp

arat

or

sust

ain

ed

resp

on

se

rate

(%)

Stu

dy

qu

alit

ya

Lo

uie

etal

.

[19

]

RC

TL

ack

of

resp

on

se

to met

ron

idaz

ole

Po

siti

ve

tox

inas

say

wit

hat

leas

t3

loo

sest

oo

lsin

pre

ced

ing

24

h

90

day

s6

3N

on

e4

89

58

8V

anco

95

72

Hig

h

Co

rnel

y

etal

.

[20

]

RC

TF

irst

tim

eR

CD

I

occ

urr

ing

wit

hin

90

day

s

of

ind

exca

se

Po

siti

ve

tox

inas

say

wit

hat

leas

t3

loo

sest

oo

lsin

pre

ced

ing

24

h

28

day

s6

5N

on

e6

69

28

0V

anco

92

65

Hig

h

RC

Tra

nd

om

ized

con

tro

lled

tria

l,va

nco

van

com

yci

na

Hig

hq

ual

ity

ind

icat

esa

Do

wn

san

dB

lack

sco

rem

ore

than

12

J. C. O’Horo et al.

123

Page 9

Ta

ble

4S

tud

ies

of

imm

un

og

lob

uli

nth

erap

y

Stu

dy

Des

ign

Incl

usi

on

crit

eria

Defi

nit

ion

of

CD

ID

ura

tion

of

foll

ow

up

Mea

n

age

Adju

nct

ive/

pre

par

atory

trea

tmen

ts

Tre

atm

ent

No.

trea

ted

Init

ial

resp

onse

rate

Sust

ained

resp

onse

rate

(%)

Com

par

ator

Com

par

ator

init

ial

resp

onse

rate

Com

par

ator

sust

ained

resp

onse

rate

Stu

dy

qual

ity

Leu

ng

etal

.

[40]

Cas

ese

ries

Hypogam

mag

lobuli

nem

iaA

ctiv

edia

rrhea

wit

h

posi

tive

toxin

assa

y

4–6

month

s2

None

IVIG

5100

%80

N/A

N/A

N/A

Low

Has

sett

etal

.

[103]

Cas

ere

port

Sel

ecti

ve

IgG

1an

tibody

defi

cien

cy

NR

24

month

s49

S.

boula

rdii

IVIG

1100

%100

N/A

N/A

N/A

Low

Sal

cedo

etal

.[4

1]

Cas

ese

ries

Lac

kof

resp

onse

to

met

ronid

azole

and

van

com

yci

n

Dia

rrhea

,ab

dom

inal

pai

n,

fever

,an

d

posi

tive

cyto

toxin

assa

y

1m

onth

64

None

IVIG

2100

%50

N/A

N/A

N/A

Low

Bea

les

[42]

Cas

ese

ries

CD

Ire

frac

tory

to

met

ronid

azole

/

van

com

yci

n

NR

5m

onth

s76

Tap

erin

g

van

com

yci

n

IVIG

4100

%100

N/A

N/A

N/A

Low

Wil

cox

[43]

Ret

rosp

ecti

ve

study

RC

DI

refr

acto

ryto

met

ronid

azole

/

van

com

yci

n

At

leas

t3

loose

stools

/day

for

2day

sw

ith

posi

tive

cyto

toxin

assa

y

3m

onth

s79

None

IVIG

580

%80

N/A

N/A

N/A

Low

McP

her

son

etal

.[4

4]

Ret

rosp

ecti

ve

study

Tw

oor

more

dis

cret

e

epis

odes

of

CD

Iocc

urr

ing

wit

hin

1m

onth

At

leas

t3

loose

stools

/day

for

2day

sw

ith

posi

tive

cyto

toxin

assa

y

1m

onth

76

None

IVIG

14

NR

64

N/A

N/A

N/A

Low

Murp

hy

etal

.

[104]

Cas

ere

port

6-m

onth

his

tory

of

RC

DI

refr

acto

ryto

met

ronid

azole

and

van

com

yci

n

Act

ive

dia

rrhea

wit

h

posi

tive

toxin

assa

y

4m

onth

s57

None

IVIG

1100

%100

N/A

N/A

N/A

Low

Has

soun

and

Ibra

hai

m

[105]

Cas

ere

port

Mer

kel

cell

carc

inom

aan

d

RC

DI

afte

rm

etro

nid

azole

and

van

com

yci

n

Act

ive

dia

rrhea

wit

h

posi

tive

toxin

assa

y

6w

eeks

72

None

IVIG

1100

%100

N/A

N/A

N/A

Low

Mat

tila

etal

.[ 2

5]

RC

TA

dult

pat

ients

wit

hat

leas

t

two

epis

odes

of

CD

I

wit

hin

3m

onth

san

d

toxin

-posi

tive

CD

I

Act

ive

dia

rrhea

wit

h

posi

tive

toxin

assa

y

28

day

s56

Met

ronid

azole

OIG

18

83

%61

Met

ronid

azole

100

%60

%H

igh

Low

yet

al.

[39]a

RC

TT

oxin

-confi

rmed

CD

Iw

ith

acti

ve

sym

pto

ms

atti

me

of

enro

llm

ent

At

leas

t3

loose

stools

in24

hw

ith

posi

tive

toxin

assa

y

84

day

s63

Met

ronid

azole

or

van

com

yci

n

IVIG

a101

NR

93

Pla

cebo

75

%H

igh

RC

Tra

ndom

ized

contr

oll

edtr

ial,

CD

IC

lost

ridiu

mdif

fici

lein

fect

ion,

IVIG

intr

aven

ous

imm

unoglo

buli

n,

OIG

ora

lim

mune

glo

buli

n,

NR

not

report

ed

aU

sed

am

onocl

onal

pre

par

atio

n

Treatment of recurrent Clostridium difficile infection

123

Page 10

Ta

ble

5S

tud

ies

of

pro

bio

tics

Stu

dy

Des

ign

Incl

usi

on

crit

eria

Defi

nit

ion

of

CD

I

Dura

tion

of

foll

ow

up

Mea

n

age

Adju

nct

ive/

pre

par

atory

trea

tmen

ts

Org

anis

ms

use

d

No.

trea

ted

wit

h

pro

bio

tics

Init

ial

resp

onse

rate

Sust

ained

resp

onse

rate

(%)

Com

par

ator

Com

par

ator

init

ial

resp

onse

rate

Com

par

ator

sust

ained

resp

onse

rate

Stu

dy

qual

ity

a

Gorb

ach

etal

.[5

5]

Cas

ese

ries

2–5

rela

pse

s

over

pre

cedin

g

10

month

s

Dia

rrhea

,

abdom

inal

pai

n,

wei

ght

loss

,an

d

posi

tive

cyto

toxin

assa

y

NR

NR

None

Lact

obaci

llus

GG

580

%80

N/A

N/A

N/A

Low

Sea

let

al.

[57

]

Cas

ese

ries

RC

DI

Act

ive

dia

rrhea

wit

hposi

tive

cyto

toxin

assa

y

45

day

s77

None

C.

dif

fici

le

(non-

toxig

enic

)

2100

%100

N/A

N/A

N/A

Low

Sura

wic

z

etal

.[5

4]

Pro

spec

tive

tria

l

Rec

urr

ent

PM

CS

ym

pto

mat

ic

RC

DI

30

day

s56

Van

com

yci

nS.

boula

rdii

13

85

%85

N/A

N/A

N/A

Low

McF

arla

nd

etal

.[5

2]

RC

TR

CD

Iw

ith

pri

or

trea

tmen

t

wit

h

van

com

yci

n

and

met

ronid

azole

Act

ive

dia

rrhea

wit

hla

bora

tory

confi

rmat

ion

8w

eeks

57

Van

com

yci

nor

met

ronid

azole

S.

boula

rdii

26

NR

77

Pla

cebo

NR

35

%H

igh

Elm

eret

al.

[53

]

RC

TA

dult

pat

ients

wit

hac

tive

RC

DI

Toxin

-confi

rmed

RC

DI

4W

eeks

NR

Van

com

yci

n,

met

ronid

azole

,

or

both

S.

boula

rdii

50

NR

33

Pla

cebo

NR

bN

Rb

Low

Bil

ler

etal

.

[56

]

Cas

ese

ries

Chil

dre

nw

ith

3–5

rela

pse

s

of

CD

I

Act

ive

dia

rrhea

wit

hposi

tive

toxin

assa

y

8m

onth

s3

Eit

her

met

ronid

azole

or

van

com

yci

n

Lact

obaci

llus

GG

5100

%60

N/A

N/A

N/A

Low

Sura

wic

z

etal

.[1

7]

RC

TT

oxin

-

confi

rmed

RC

DI

wit

h

index

case

in

last

yea

r

3or

more

loose

stools

/day

for

at

leas

t2

day

s

wit

hposi

tive

EIA

,cu

lture

,or

toxin

assa

y

8W

eeks

61

cH

igh-d

ose

van

com

yci

n

S.

boula

rdii

41

NR

83

Pla

cebo

NR

50

%H

igh

62

cL

ow

-dose

van

com

yci

n

S.

boula

rdii

27

NR

49

Pla

cebo

NR

55

%H

igh

66

cM

etro

nid

azole

S.

boula

rdii

11

NR

51

Pla

cebo

NR

50

%H

igh

Wull

tet

al.

[26

]

RC

TA

dult

sw

ith

RC

DI

3or

more

loose

stools

/day

for

at

leas

t2

day

s

wit

hposi

tive

EIA

70

day

s65

Met

ronid

azole

L.

pla

nta

rum

299v

11

72

%54

Pla

cebo

89

%67

%H

igh

RC

Tra

ndom

ized

contr

oll

edtr

ial,

NR

not

report

ed,

CD

IC

lost

ridiu

mdif

fici

lein

fect

ion

aH

igh

qual

ity

indic

ates

aD

ow

ns

and

Bla

cksc

ore

gre

ater

than

or

equal

to12

bS

tudy

endpoin

tw

asex

cret

ion

of

S.

boula

rdii

,not

clin

ical

cure

cM

ean

age

of

com

bin

edpla

cebo/S

.boula

rdii

arm

s

J. C. O’Horo et al.

123

Page 11

Ta

ble

6P

ub

lica

tio

ns

rep

ort

ing

on

the

effe

ctiv

enes

so

ffe

cal

bac

teri

oth

erap

y(F

BT

)

Stu

dy

Ty

pe

Stu

dy

po

pu

lati

on

Defi

nit

ion

of

recu

rren

ce/

foll

ow

up

inte

rval

Fo

llo

wu

p

inte

rval

Met

ho

do

f

del

iver

y

Ad

jun

ctiv

e/

pre

par

ato

ry

trea

tmen

ts

No

.

rece

ivin

g

trea

tmen

t

Su

cces

s

rate

Stu

dy

qu

alit

ya

Sch

wan

etal

.

[65

]

Cas

ere

po

rt6

5Y

OF

fail

ing

sev

eral

cou

rses

ora

lv

anco

my

cin

To

xin

-po

siti

ve

dia

rrh

ea2

yea

rsE

nem

aV

anco

my

cin

11

00

%L

ow

Tv

ede

and

Ras

k-M

adse

n

[72

]

Cas

ese

ries

Ch

ron

icre

lap

sin

gd

iarr

hea

To

xin

-po

siti

ve,

sym

pto

mat

icd

iarr

hea

2y

ears

En

ema

No

tre

po

rted

61

00

%L

ow

Flø

tter

ød

and

Ho

pen

[70

]

Cas

ere

po

rtP

atie

nt

wit

hse

ven

rela

pse

so

fC

DI

Sy

mp

tom

atic

recu

rren

ceN

RD

uo

den

altu

be

Bac

itra

cin

11

00

%L

ow

Pat

erso

net

al.

[73

]

Cas

ese

ries

Pat

ien

tsag

ed3

0–

80

yea

rsw

ith

mu

ltip

leco

mo

rbid

itie

san

dat

leas

to

ne

rela

pse

Dia

rrh

ea,ab

do

min

alp

ain

,

tox

in-p

osi

tiv

est

oo

ls

2–

4y

ears

En

ema

No

ne

rep

ort

ed7

10

0%

Lo

w

Har

ko

nen

[71

]C

ase

rep

ort

71

YO

wit

hR

CD

IS

ym

pto

mat

icre

curr

ence

8m

on

ths

Co

lon

osc

op

yN

on

ere

po

rted

11

00

%L

ow

Lu

nd

-Tø

nn

esen

etal

.[9

4]

Cas

ese

ries

Pat

ien

tsw

ith

RC

DI

Sy

mp

tom

atic

recu

rren

ce

wit

hto

xin

-po

siti

ve

sto

ol

NR

Co

lon

osc

op

y

(on

ev

ia

gas

tro

sto

my

)

No

ne

rep

ort

ed1

81

00

%L

ow

Per

sky

and

Bra

nd

t[6

6]

Cas

ere

po

rt6

0Y

OF

wit

hR

CD

Ire

frac

tory

to

met

ron

idaz

ole

Per

sist

ent

wat

ery

sto

ols

and

tox

inp

osi

tiv

ity

3y

ears

Co

lon

osc

op

yN

ot

rep

ort

ed1

10

0%

Lo

w

Fau

stet

al.

[74]

Cas

ese

ries

Pat

ien

tsag

e3

4–

74

yea

rsw

ith

2–

6

rela

pse

sre

frac

tory

toei

ther

met

ron

idaz

ole

or

van

com

yci

n

Sy

mp

tom

atic

recu

rren

ce

wit

hto

xin

-po

siti

ve

sto

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Treatment of recurrent Clostridium difficile infection

123

Page 12

Ta

ble

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J. C. O’Horo et al.

123

Page 13

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)

Treatment of recurrent Clostridium difficile infection

123

Page 14

95 % CI 1.09–290.05). Initial treatment cured 81 % of

RCDI patients, and subsequent retreatment reached 94 %

efficacy. However, it is worth noting that the treatment

failure rate for vancomycin is considerably higher in this

study than in any other study. This may be, in part, due to

the long follow up interval of 10 weeks capturing more

treatment failures. Although the total number in this trial

was small (n = 16 in FBT treatment group), and the study

excluded both critically ill and immunocompromised

patients, this represents the strongest evidence to date in

support of this practice [22].

Discussion

The treatment options of RCDI are limited; yet, the impact

on patients and healthcare costs is considerable [7–9]. In

our systematic review, we found that most therapeutic

options currently available for treatment of RCDI have, at

best, moderate evidence to support their use.

We found moderate-strength evidence that treatment with

either oral vancomycin or oral metronidazole has consistent

efficacy for clinical cure. One is not clearly more efficacious

than the other. There is insufficient data regarding optimal

dosing regimens, especially in critically ill patients. Pulsing

or tapering doses of oral vancomycin have weak evidence, as

does intracolonic vancomycin. No study evaluated intrave-

nous metronidazole therapy for RCDI.

Among novel antibiotic approaches, fidaxomicin has

been the most rigorously examined, mainly in primary CDI

to evaluate recurrence. It is an option for RCDI, but

parameters should be developed in order to guide appro-

priate use. Few studies have evaluated nitazoxanide, and

evidence supporting the use of either is of low quality.

Non-antimicrobial options for the treatment of RCDI

should be examined further. We found only one high-

quality study suggesting that S. boulardii could be useful as

an adjunctive therapy with high-dose vancomycin.

Evidence for polyclonal intravenous immunoglobulins

is weak in RCDI, though novel approaches with mono-

clonal immunoglobulins and oral immunoglobulins appear

promising, and merit further study in the RCDI population.

FBT has a large body of non-comparative literature

supporting its use, but, to date, has only been studied in one

RCT. However, this does appear to be a promising option,

and a recent review of 27 papers found an 89 % overall

success rate, similar to our findings [61].

The available data would suggest that a reasonable

clinical approach for a patient with RCDI would be the

removal, if possible, of triggering antibiotics, followed by:

(1) second treatment with either metronidazole or vanco-

mycin with consideration of adjuvant probiotics, (2) con-

sideration of either fidaxomicin or alternative dosing

regimens of vancomycin (pulse or taper) depending on cost

factors, and then (3) FBT. Data supporting each measure in

this algorithm become sequentially weaker, but all of these

measures have reasonable evidence for efficacy, and could

be attempted in a patient with RCDI.

Our analyses have several limitations, most stemming

from the design of the included studies. Except for sub-

groups, we were not able to perform a rigorous meta-

analysis of the efficacy of therapeutic options for RCDI

because of the non-comparative nature of the studies and

the clinical heterogeneity. Each treatment approach had a

very limited number of studies, thus, even after pooling,

the study populations remained quite small. Also, publi-

cation bias is a concern for interventions where case series

predominate, as positive results are more likely to be

published. Finally, we did not examine all possible repor-

ted interventions for RCDI treatment, mainly because of

the very limited data. For example, two other interventions,

colonic irrigation [95] and tigecycline [96] have been

reported as being successful in single-case series, but there

are inadequate data to evaluate these interventions. Other

interventions that have shown some success in primary

CDI, like tolevamer [97] and cholestyramine [98], have not

been evaluated specifically in RCDI.

The lack of data for the effective treatment of RCDI

underscores the importance of prevention of primary CDI.

Antimicrobial stewardship programs are important for the

prevention of CDI [99, 100] and prompt discontinuation of

offending antibiotics when CDI is detected may hasten

recovery and reduce the risk of RCDI [101, 102]. Future

studies should examine therapies specifically for RCDI

using multisite, adequately powered, methodologically

rigorous study designs.

Acknowledgments The authors would like to thank librarian Mona

K. Stevermer for her assistance with the literature search.

Conflict of interest None of the authors have any relevant conflicts

of interest to disclose.

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