See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/23276276

Antibiotic-associated diarrhea: Epidemiology, trends and treatment

Article  in  Future Microbiology · November 2008

DOI: 10.2217/17460913.3.5.563 · Source: PubMed

CITATIONS READS
154 1,640

1 author:

Lynne Mcfarland
U.S. Department of Veterans Affairs
176 PUBLICATIONS   12,165 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Working on clinical efficacy of various probiotics, Epidemiology of C. difficile infections View project

All content following this page was uploaded by Lynne Mcfarland on 13 August 2014.

The user has requested enhancement of the downloaded file.

For reprint orders, please contact: REVIEW
reprints@futuremedicine.com

Antibiotic-associated diarrhea: epidemiology,

trends and treatment
Lynne V McFarland
Department of Health
Services Research &
Development, Puget Sound
Veterans Administration,
Healthcare System,
S-152, 1100 Olive Way,
#1400 Seattle, WA 98101,
USA
Tel.: +1 206 277 1095;
Fax: +1 206 764 2935;
lynne.mcfarland@va.gov
A common complication of antibiotic use is the development of gastrointestinal disease.
This complication ranges from mild diarrhea to pseudomembranous colitis. Outbreaks of
antibiotic-associated diarrhea (AAD) may also occur in healthcare settings, usually caused
by Clostridium difficile. AAD typically occurs in 5–35% of patients taking antibiotics and
varies depending upon the specific type of antibiotic, the health of the host and exposure to
pathogens. The pathogenesis of AAD may be mediated through the disruption of the
normal microbiota resulting in pathogen overgrowth or metabolic imbalances. The key to
addressing AAD is prompt diagnosis followed by effective treatment and institution of control
measures. Areas of active research include the search for other etiologies and more
effective treatments.

Antibiotics are an effective available treatment History

Keywords: antibiotic-
associated diarrhea,
antibiotic complications,
Clostridium difficile, colitis,
diarrhea, epidemiology,
probiotics, risk factors
part of
for numerous infectious diseases, but their use is
not without clinical complications. Concerns
include the overuse or inappropriate use of anti-
biotics, the emergence of antibiotic-resistant
strains of pathogens, poor compliance and the
increasing rates of disease related to antibiotic use
[1–4]. The most common intestinal complication
of antibiotic use arises when antibiotics disrupt
the ecology of the normal intestinal microbiota,
resulting in antibiotic-associated diarrhea
(AAD). AAD is a broad disease designation that
has historically lacked a standard definition in
the literature, but generally encompasses people
exposed to antibiotics who develop diarrhea
within 8 weeks. For nearly two-thirds of the
AAD cases, the etiology is not known, but
Clostridium difficile accounts for nearly one-third
of all cases. Unless otherwise designated in this
review, the term ‘AAD’ will refer to studies where
the etiologic agent was unknown or not diag-
nosed. The term ‘C. difficile AAD’ will refer to
studies focused specifically on this etiology only.
AAD has been reported in a wide variety of
populations including outpatients, hospitalized
patients and residents of long-term care facilities
[5]. The clinical presentation of AAD may range
from mild, uncomplicated diarrhea to more severe
colitis, and may result in toxic megacolon or
death [6,7]. Consequences of AAD may result in
extended hospital stays, increased medical care
costs and increased diagnostic procedures [8–12].
The objective of this review is to summarize the
current state-of-the-art on the epidemiology and
risk factors for AAD and suggest recommendations
for treatment and control.
AAD became a recognized clinical concern in the
1950s when the use of broad-spectrum antibiot-
ics (tetracycline and chloramphenicol) increased.
However, little attention was given to this seem-
ingly benign complication until the frequency of
a relatively rare but serious disease, pseudo-
membranous colitis (PMC), was reported in
10% of patients receiving clindamycin [13].
Attempts to uncover the etiologic agent
remained elusive until 1977/1978 when the link
between AAD and an opportunistic anaerobe,
C. difficile, was discovered [14].
In the 1980s, much of the attention centered on
nosocomial outbreaks that were due to C. difficile,
even though C. difficile was only implicated in
about one-quarter of the outbreaks [15,16].
Research during the 1990s was focused on
unraveling the pathogenesis, risk factors and
transmission of C. difficile disease [17–19].
The 21st century has brought greater under-
standing of the risk factors for AAD, mecha-
nisms, other possible etiologies, diagnostic assays,
treatment strategies and methods of control.
Although much has been discovered about AAD,
it continues to persist, especially with the devel-
opment of newer broad-spectrum antibiotics.
The search for other etiologies of AAD has been
expanded, although C. difficile remains the lead-
ing known cause of AAD. AAD has been shown
to be a risk for the individual (in whom AAD may
lead to serious complications), but also a risk for
the medical community (reflected by the
increased frequency of hospital outbreaks). As cur-
rent treatment regimes are not always successful,
AAD will be a continuing medical concern.

10.2217/17460913.3.5.563 © 2008 Future Medicine Ltd ISSN 1746-0913 Future Microbiol. (2008) 3(5), 563–578 563
REVIEW – McFarland

Incidence of AAD commonly contaminate hospital environments.

The reported incidence of AAD ranges from 12
per 100,000 person-years to 34 per 100 out-
patient visits (Table 1), depending upon the type of
antibiotic, host factors (age, health status, and so
on), etiology, hospitalization status and presence
of a nosocomial outbreak [20–34]. Rates of AAD are
similar in pediatric and adult populations (Table 1).
The highest frequency of AAD is found during
healthcare-associated outbreaks, when susceptible
patients are clustered by time, exposure and prox-
imity. Healthcare-associated (in hospitals, long-
term care facilities, nursing homes, and so on)
outbreaks of AAD are to be expected because
inciting agents (antibiotics), infectious agents and
a susceptible patient population are intermixed.
Historically, most cases of AAD were reported in
hospitalized patients [5]. More recently, although
AAD still occurs in hospital settings, high rates
have been reported in outpatient pediatric popu-
lations (6–33 out of 100 admissions) [21,22] and
lower rates (12 out of 100,000 person-years to 14
out of 100 persons) in nonhospitalized adults
[23,30]. Lower rates observed in outpatients may be
due to their generally higher health status com-
pared to hospitalized patients and also to the lack
of exposure to nosocomial pathogens that
Higher incidences are still found in healthcare-
associated pediatric and adult patients (ranging
from 5–34 out of 100 patients) [20,24–26,29].
Secular trends of AAD are only available for
C. difficile AAD, and data from several sources
show that these types of infections are increasing
over time. The National Nosocomial Infections
Surveillance reports increasing rates of C. difficile
AAD from 1987 to 2000 in US hospitals (from
2.7 out of 10,000 up to 5.5 out of 10,000 dis-
charges) and other reports reflect this increasing
trend in Canada and the UK [35–37]. Incidence of
C. difficile AAD from a large Veterans Adminis-
tration Healthcare System in Seattle, WA, USA
shows a trend for increasing rates (Figure 1), which
reflects the national experience in other Veterans
Administration centers [33,201].
Clinical presentation
AAD has a spectrum of severity including
uncomplicated diarrhea, colitis and PMC.
Epidemiologic studies are limited to the clinical
description of non-C. difficile-associated cases,
but C. difficile AAD has also been well described.
In the general healthcare-associated population,
most of the cases of C. difficile AAD are

Table 1. Incidence of antibiotic-associated diarrhea by population.

Population Age/group Country No. studied Frequency of Ref.
AAD
Population studies of AAD
Inpatient >12 years Sweden 2462 4.9% [20]

Outpatient 1 month–15 years France 650 11% [21]

Outpatient 4 months–14.5 years Thailand 225 6.2% [22]

Ambulatory Adults USA 358,389 12/100,000 py [23]

Clinical trials (placebo group rates) of AAD

Inpatient >50 years UK 56 33.9% [24]

Inpatient 1–36 months Poland 36 33.3% [25]

Inpatient 6–36 months Brazil 77 31% [26]

Inpatient >18 years USA 134 29.9% [27]

In and 6 months–14 years Poland 127 23% [28]

outpatient
Inpatient Children Japan 455 22.6% [29]

Outpatient >1 year UK 120 14% [30]

Clostridium difficile AAD

Inpatient Adults France 38 18.5% [31]

Inpatient Adults Ireland 60 21/1000 pd [32]

Inpatient veteran Adults USA 60,590 29.2/10,000 pd [33]

Inpatient Oregon residents USA 381,721 3.5/10,000 [34]

AAD: Antibiotic-associated diarrhea; pd: Person-days; py: Person-years.

564 Future Microbiol. (2008) 3(5) future science group

 Antibiotic-associated diarrhea: epidemiology, trends & treatment – REVIEW
Figure 1. Secular trend for Clostridium difficile infections at Puget Sound Veterans Administration Health
Care System, Seattle, WA, USA, from 1998–2006.
500
Incidence of CDAD/100,000 admissions
400
300
200
100
0
1998 1999 2000 2001 2002
CDAD: Clostridium difficile-associated disease.
uncomplicated diarrhea (10–30 out of
100 patients), while colitis is less frequent (5–10
out of 100 patients) and PMC is infrequent
(0.1–1 out of 100 patients) [5].
Incubation time
The incubation time (defined as the time
between antibiotic initiation and the onset of
diarrhea) falls into two groups: early onset,
occurring during antibiotic treatment and
delayed onset, which may occur from
2–8 weeks after the antibiotics have been dis-
continued [5,20]. In 225 outpatient children
given antibiotics, the mean onset after anti-
biotics was 2.3 ± 1.1 days and all cases of AAD
occurred while the children were taking the
antibiotics [22]. Of 157 inpatient children (aged
6–36 months), the mean onset was
4.0 ± 4.3 days and most cases occurred during
antibiotic exposure (92%), while only 8%
occurred within 15 days of discontinuing the
antibiotics [26]. The time of onset is similar for
outpatients (ranging from 2.3 to 7 days)
[21,22,38] and for inpatients (ranging from 4 to
19 days) [20,26,39]. The incubation time for
severe disease is also similar for milder forms of
AAD. Most patients with AAD and PMC
become symptomatic within 1 week following
antibiotic exposure, but symptoms may be
delayed in as many as 40% of patients with
PMC for 2–8 weeks after antibiotics have been
discontinued [24].
future science group www.futuremedicine.com
2003 2004 2005 2006
Antibiotic-associated diarrhea
Diarrhea is defined as a change in the normal stool
frequency with at least three loose or watery stools
per day for several days [40–42,202]. The duration of
AAD typically ranges from 1 to 7 days in both
pediatric and adult populations [21,22,38,43]. Of
225 outpatient children on a variety of different
types of antibiotics, the mean duration of AAD was
found to be 2.6 ± 1.1 days [22]. Hsu et al. reported
a longer mean duration of AAD in 42 hospitalized
elderly patients (26.2 ± 56.1 days) [43].
Antibiotic-associated colitis
If colitis develops, the diarrhea is usually more
severe and is associated with abdominal
pain/cramping, fever that exceeds 40°C,
hypoalbuminemia and leukocytosis [19,44]. Coli-
tis can be diagnosed by colonoscopy when
inflammatory changes (erythema, friability or
edema) are noted by biopsy, but no pseudomem-
branes are present. Histologic examination for
C. difficile colitis may reveal ‘summit lesions’ or
‘volcano lesions’ where inflammatory cells and
debris are ejected into the colonic lumen.
Sigmoidoscopy of patients with Klebsiella oxytoca
usually reveals diffuse or segmental left colitis.
Severe AAD
At the extreme end of the spectrum of severity is
PMC, which is almost always associated with
C. difficile. PMC may have a prolonged duration
(>1–3 weeks) [45,46]. The symptoms of PMC
565
REVIEW – McFarland
include watery diarrhea (90–95%), abdominal
cramping (80–90%), fever (80%), leukocytosis
(80%) and, rarely, vomiting [47]. Lee et al. deter-
mined that patients over 70 years of age and
patients with lengthy hospitalizations (>20 days)
had significantly increased risk of developing
PMC compared with AAD (adjusted odds ratio
[aOR]: 2.7; 95% confidence interval [CI]:
1.2–6.1 and aOR: 5.1; 95% CI: 2.1–12.2, respec-
tively) [48]. Complications of PMC may include
hypokalamia (37%), renal failure (27%) and
hypoproteinema (50%). Less frequently, compli-
cations of PMC may include toxic megacolon,
perforation of the colon and shock [49].
Recurrent AAD
In approximately 15–60% of the patients who
develop C. difficile AAD, a recurrent form of the
disease may develop, despite repeated antibiotic
treatments [37,50,51]. The clinical disease may be
more severe in patients with recurrent C. difficile
AAD compared to patients with an initial epi-
sode. Fekety compared 60 patients with recur-
rent C. difficile AAD with 64 nonrecurrent
disease and found more patients reported fever
(43 and 13%, respectively), abdominal cramping
(83 and 32%, respectively) and colitis (60 and
40%, respectively) [19]. This recurrent form of
AAD leads to increased use and cost of antibiot-
ics, especially vancomycin, additional hospitali-
zations and medical complications [50]. Patients
with recurrent episodes of C. difficile AAD do
not show an increase in the severity of disease as
the number of episodes progress [5].
Diagnosis of AAD
AAD should be suspected in persons exhibiting
continuing diarrhea and who have had a recent
exposure to either antibiotics or recent hospitali-
zation (within 8 weeks) (Table 2). If a specific
pathogen is not detected, the diagnosis may have
to rest on the exposure to antibiotics and the
exclusion of other causes of diarrhea (other med-
ications, chronic intestinal conditions, such as
inflammatory bowel disease or irritable bowel
syndrome, and food intolerances). If the patient
has had a recent hospitalization, C. difficile
should be suspected and appropriate assays per-
formed. The diagnosis of C. difficile disease must
fulfill all of the following criteria: a positive
C. difficile assay (culture, toxin A or toxin B),
presence of diarrhea associated with antibiotic
use and exclusion of other causes of diarrhea
[33,41]. Diagnosis must rely on the combination
of laboratory assays and the clinical presentation
566 Future Microbiol. (2008) 3(5)
of the patient owing to the multiplicity of etiolo-
gies of diarrhea and the high frequency of
asymptomatic carriers of C. difficile in hospital-
ized patients. Although enzyme immunoassays
(EIAs) are more frequently used in healthcare
facilities due to the rapid availability of results
and low cost, tissue cell-culture with neutraliza-
tion is considered the ‘gold standard’ for the
detection of C. difficile toxin B as it is very sensi-
tive to even low levels of stool toxin B [52]. How-
ever, a negative stool toxin B test should not be
relied upon to rule out C. difficile. EIAs for
C. difficile toxins A and B have been shown to
have 48–99% sensitivity and 75–100% specifi-
city [52–54]. Although few local microbiology lab-
oratories perform cultures for C. difficile, up to
32–35% of cases may be missed if cultures are
not done [33,53]. Examination of the stools for
leukocytes may not be sufficiently specific to
diagnose C. difficile infections by itself, but may
be clinically useful to identify inflammatory
diarrhea. Newer technologies including real-time
PCR assays have acceptable sensitivity and
specificity (86 and 97%, respectively) [52].
Endoscopic examination should be reserved for
patients who are seriously ill or whose diagnosis is
in doubt due to negative cultures, or when other
possible intestinal conditions are suspected. PMC
is diagnosed when sigmoidoscopic examination
reveals multiple yellow-tan or green raised plaques
(pseudomembranes) that can be dislodged from
the mucosa during biopsy. These pseudomem-
branes may range in size from small (1–2 mm)
distinct nodules to a confluent layer of pseudo-
membrane overlying the mucosa. Procto-
sigmoidoscopy may be completely negative and
some clinicians recommend colonoscopy. Histo-
logically, each plaque consists of mucous, inflam-
matory cells and fibrin excavate typically overlaying
normal appearing mucosa. Computerized tomog-
raphy may be useful to detect fulminant C. difficile
AAD, or infrequent cases of right-sided colitis or
acute abdomen syndrome [41,52].
The differential diagnosis of AAD includes
acute or chronic diarrhea caused by enteric
pathogens not associated with antibiotic expo-
sure (Giardia, Vibrio, Staphylococcal food poi-
soning and Shigella), chronic gastrointestinal
conditions (inflammatory bowel disease, irritable
bowel syndrome, ischemic colitis, collagenous
colitis and colon cancer), side effects of nonanti-
biotic medications (laxatives, cancer chemother-
apeutic agents, antiviral therapy, antacids and
nonsteroidal anti-inflammatory drugs), or other
infections (intra-abdominal sepsis).
future science group
 Antibiotic-associated diarrhea: epidemiology, trends & treatment – REVIEW

Table 2. Diagnosis of antibiotic-associated diarrhea and Clostridium difficile antibiotic-associated diarrhea.

General Check for
Medical history History of recent antibiotics (<2 months)
History of recent hospitalization
Defined diarrhea Change in normal bowel habits with at least three loose, watery
stools for at least 2 days
Exclude other diarrhea causes Medications resulting in diarrhea
Chronic intestinal conditions (inflammatory bowel disease,
Crohn’s, ischemic colitis, short bowel syndrome)
Food intolerances
Exclude nonantibiotic enteric pathogens Salmonella, Shigella, Campylobacter,
Aeromonas, Yersinia, Escherichia coli O157:H7
Test for specific known etiologies Clostridium difficile cell cytotoxin B assay or EIA kits for toxin A
and B or PCR
Clostridium perfringens cytotoxin test
Staphylococcus aureus
Klebsiella oxytoca
If diarrhea persists or serious symptoms develop Repeat Clostridium difficile assay
Consider sigmoidoscopy or colonoscopy with histologic
biopsy (colitis)
Consider computerized tomography scan
EIA: Enzyme immunoassay.

Consequences AAD, which may be due to two factors: the spec-

Consequences of AAD may include extended
hospital stays and increased medical costs [12,33].
Longer durations of hospitalizations for patients
with C. difficile AAD were noted in three studies
ranging from 3 to 24 days of non-C. difficile
AAD patients [9,11,33]. Estimates for costs for
medical care of patients with AAD and
C. difficile AAD have ranged from US$3500 to
US$77,483 (in surgery patients) [11,12,55]. Signif-
icantly increased rates of mortality have been
associated with outbreaks of the hypervirulent
BI/NAP1/027 strain of C. difficile [9,56].
Mechanisms of AAD pathogenesis
The pathogenesis of AAD involves two major
mechanisms that are initiated by the disruption of
normal intestinal microbiota: overgrowth by
opportunistic pathogens or alterations of meta-
bolic functions. Colonization resistance, or the
ability of the normal microbiota to resist over-
growth by pathogenic organisms, has been well
documented [57,58]. Colonization resistance oper-
ates on several levels within the intestinal lumen:
normal microbiota competes for microbial nutri-
ents, produces bacteriocins or toxin-degrading
proteases and shelters pathogen attachment sites
or toxin receptor sites. Colonization resistance is a
result of complex interactions of numerous bacte-
rial species, which can be disrupted by antibiotics.
Different types of antibiotics have varying rates of
trum of activity against the normal microbiota
and the degree of absorption from the intestinal
tract. Narrow spectrum antibiotics have low rates
of AAD and broad-spectrum antibiotics, espe-
cially those effecting anaerobic normal microbi-
ota, are associated with higher rates of AAD. The
degree of absorption may influence the rates of
AAD. Antibiotics that are poorly absorbed from
the colon or are secreted in bile (such as clindamy-
cin, cefixime, ceftriaxone or cefoperatzone) are
associated with high rates of AAD. Antibiotics
with high absorption, such as doxycycline and
cefaclor, have lower rates of AAD [59]. Once coloni-
zation resistance has been disrupted, overgrowth by
opportunistic pathogens may occur. Several patho-
gens have been studied that may be capable of this
opportunistic overgrowth and the supporting
evidence for their role in AAD is given below.
Overgrowth by pathogens:
Clostridium difficile
The majority of studies involving AAD have
focused on C. difficile-associated AAD, as this
pathogen came to the attention of the medical
community when the frequency of nosocomial
outbreaks began to increase. Approximately
25–33% of AAD cases and nearly all (95–99%)
cases of PMC can be attributed to C. difficile [52].
Gursoy et al. found that in 65 outpatients who
developed AAD, 27.7% were positive for

future science group www.futuremedicine.com 567

REVIEW – McFarland
C. difficile [60]. In another study, during an out-
break of AAD, 52% of the cases were due to
C. difficile [61]. Of 217 hospitalized patients with
AAD, 52 (24%) had a positive stool toxin for
C. difficile [42]. In a mixed population of
inpatients and outpatients with AAD, 13 out of
91 (14.3%) were due to C. difficile [62]. Another
study of hospitalized patients with AAD in Tai-
wan found only 12.5% of the AAD cases were
positive for C. difficile [43].
The effect of overgrowth by C. difficile results in
toxin-mediated pathogenesis mostly due to two
large heat-labile enterotoxic and cytotoxic toxins
called toxin A and toxin B, although up to
six types of toxins have been described [63]. Some
isolates, including the hypervirulent strain
BI/NAP1/027, which caused large outbreaks in
Canada, produce another type of toxin called
binary toxin, but the role of this toxin in the
pathology of C. difficile disease is uncertain [64].
tcdA has been found a potent stimuli of human
neutrophil IL-8 production and toxin A may also
stimulate neutrophils to increase adherence to
fibrinogen-coated surfaces. The effects of these
two toxins on enterocytes is to disrupt (via glyco-
sylation of Rho protein) the cytoskeleton of the
cell, disrupting F-actin, distorting the cellular
shape and broadening tight junction space
between the cells. Local production of hydrolytic
enzymes causes connective tissue damage, fluid
production and diarrhea results. In addition to the
physical disruption of enterocytes, toxins A and B
attract polymorphonuclear leukocytes and other
inflammatory cells to the site, which can be
observed at endoscopic or histologic examination.
The largest epidemic of C. difficile AAD occured
in Quebec, Canada between 2004 and 2005.
Increased rates (>15 out of 10,000 patient-days)
were reported in over 30 hospitals, which were
over four-times higher than expected rates and
cases had five-times the expected mortality rates. A
hypervirulent strain (BI/NAP1/027) of C. difficile
was associated with this increase and this strain was
also found to produce more toxin A and B than
other C. difficile strains owing to a mutation in a
toxin downregulator gene [3,9]. Although
C. difficile appears to cause approximately one-
third of all cases of AAD and has been the most
thoroughly studied, other possible etiologies need
to be examined to further understand AAD.
Clostridium perfringens
The association between Clostridium perfringens
and AAD has been reported in a few small stud-
ies. In 89 inpatients with AAD, only five (6%)
568 Future Microbiol. (2008) 3(5)
were positive for C. perfringens [60]. In 52 fecal
samples in hospitalized patients with diarrhea,
11% were positive for C. perfringens only, 44%
were positive for C. difficile only and 31% were
positive for both bacteria. [65]. Another study of
4659 consecutive inpatients from June 2001 to
April 2002, of which 94% had diarrhea and
85% had taken antibiotics within the past
28 days, a positive etiologic agent was only
found in 16.2% of the cases [8]. C. difficile cyto-
toxin was found in 591 patients (12.7%),
C. perfringens enterotoxin was found in 155
(3.3%) and methicillin-resistant Staphylococcus
aureus was found in 10 (0.2%). Usually, only
one etiologic agent was found in a patient at the
same time, but 21 (2.9%) were co-infected with
two agents (usually both C. difficile and C. perf-
ringens). Although C. perfringens is less fre-
quently isolated in patients with AAD, it appears
to contribute as an etiologic agent.
Klebsiella oxytoca
Another potential candidate that has been inves-
tigated is K. oxytoca, which produces a cytotoxin
and has been studied in rabbit intestinal loop
models. A recent case report of amoxicillin-asso-
ciated hemorrhagic colitis was caused by
K. oxytoca [66]. Högenauer et al. reported cyto-
toxic K. oxytoca was more frequently isolated in
patients with antibiotic-associated hemorrhagic
colitis (22.7% of 22 cases) compared with
healthy controls (6 out of 385, 1.6%, p <0.05)
[67]. Futher investigation is needed to determine
if Klebsiella has a causative role in AAD.
Staphyloccocus aureus
Historically, this bacteria was once implicated as
the major etiologic agent of AAD, but subse-
quent studies on AAD caused by clindamycin
(an effective antistaphylococcal antibiotic) dis-
counted this theory. The discovery of C. difficile
as an etiologic agent for AAD turned the atten-
tion away from this organism. Antibiotics pri-
marily associated with a positive stool for
S. aureus are tetracyclines, chloramphenicol and
neomycin and the pathology is evident in the
small bowel, which is atypical for AAD or
C. difficile-associated disease. Flemming et al.
cultured 2727 cases of nosocomial diarrhea and
only found that 198 (7.3%) were associated with
S. aureus [68]. Gravet et al. cultured stools from
inpatients in a 2-year prospective study (98%
with AAD) and found 60 cases of S. aureus [69].
Of 1033 diarrheal stools assayed at a 500-bed
teaching hospital, 22% were methicillin-resistant
future science group
 Antibiotic-associated diarrhea: epidemiology, trends & treatment – REVIEW
S. aureus-positive [70]. Thus, S. aureus may be an
infrequent etiology of AAD, but more research
is needed.
Candida albicans
The role of Candida albicans in AAD has been
investigated since 1955 with differing conclu-
sions. Firm conclusions have been clouded by
the presence of C. albicans in normal healthy
populations and the lack of biopsy evidence of
pathogenesis. Possible mechanisms of
C. albicans diarrhea may involve the impair-
ment of sodium and water absorption due to
this yeast or the ability of C. albicans strains to
produce high levels of β-lactamases.
Krause et al. found no significant difference in
the frequency of C. albicans from AAD patients
(77 out of 98, 78.6%) compared to patients
with antibiotic exposure but no diarrhea (75
out of 93, 80.6%) [71].
Other investigations for AAD etiologies
The above etiologies can account for approxi-
mately 40% of AAD, but the etiologies of the
remaining cases of AAD are still undetermined.
In a study by Vaishnavi and Kaur, hospitalized
patients taking antibiotics were cultured and
Campylobacter jejuni was found in 12 out of
138 (8.7%), but no controls were used [72].
Investigation of viral etiologies of AAD have
not been productive.
Metabolic alterations
The other major effect of disturbing the normal
microbiota is altered colonic digestion and fer-
mentation of ingested carbohydrates. Reduced
fermentation by disrupted normal microbiota
leads to accumulation of large osmotically
active saccharides in the colon. In the undis-
turbed intestine, fermented short chain fatty
acids (SCFAs) such as acetate, butyrate and
propionate acids are found in the lumen where
they stimulate sodium and water absorption
and maintain the integrity of colonic epithelial
cells [73]. When antibiotics disrupt normal
microbiota, patients may develop osmotic
diarrhea due to unfermented carbohydrates and
the lack of SCFAs. Broad-spectrum antibiotics
(associated with higher rates of AAD) disrupt a
greater range of normal microbiota and are
associated with a significant decrease in SCFA.
By contrast, narrow spectrum antibiotics
(which have lower rates of AAD) have less
impact on the normal microbiota and do not
affect SCFA concentrations [5].
future science group www.futuremedicine.com
Enteric nervous system
Antibiotics may affect the enteric nervous system
(ENS), which is involved in normal intestinal
transit and physiology. The ENS modulates
interactions between intestinal mucosa and
pathogenic bacteria and altered ENS activity has
been reported when the normal microbiota has
been disrupted by antibiotics [74]. C. difficile
toxin A increases myoelectric activity and affects
capsaicin-sensitive sensory afferent neurons and
mast cells in the intestine [5]. Further investigation
on the role of the ENS and AAD are needed.
Risk factors
Several types of risk factor are associated with
AAD (Figure 2), which can be broadly separated
into several major areas: the type of inciting anti-
biotic or medication, factors relating to the host,
exposure to pathogenic agents and procedures
that disrupt normal colonic microbiota.
Antibiotic type
The strongest predictor of AAD is the type of
antibiotic itself, although virtually all types of
antibiotics have been associated with AAD.
Even short courses of preoperative oral antibiot-
ics are associated with AAD [75]. Higher rates of
AAD are typically associated with broad-spec-
trum antibiotics [6,76]. The three most common
types of antibiotics with higher rates of AAD
include: ampicillin/amoxicillin, cephalosporins
and clindamycin [76]. Turck et al. reported that
the highest rates of AAD in 650 pediatric cases
were associated with amoxicillin/clavulanate
(23%), penicillin A or M (11%) and erythro-
mycin (16%) [21]. Wistrom et al. reported that
patients given a single antibiotic, broad-spectrum
penicillin or cephalosporin had low rates of
AAD (6.7 and 6.1%, respectively), but patients
receiving multiple antibiotics had significantly
higher rates of AAD (11%) [20]. The risk of AAD
doubled if the antibiotics were given for over
3 days (relative risk [RR]: 2.3; 95% CI: 1.2–4.2)
[20]. Asha et al. compared 503 patients with
C. difficile AAD and 132 with C. perfringens
AAD to 254 age- and sex-matched asympto-
matic controls and determined that there were
different risk factors for each etiology of AAD [8].
Risk factors for C. difficile AAD included: use of
cephalosporins (OR: 2.76; 95% CI: 1.88–3.64),
use of macrolides (OR: 3.56; 95% CI:
2.81–4.32), increasing length of hospitalization
(OR: 1.03; 95% CI: 1.01–1.04), cytotoxic drugs
(OR: 8.07; 95% CI: 6.4–9.8) and nasogastric
tube feeding (OR: 5.63; 95% CI: 4.52–6.41).
569
REVIEW – McFarland

Figure 2. Risk factors for antibiotic-associated diarrhea and Clostridium difficile

antibiotic-associated diarrhea.

Risk factors for AAD

Medications Host factors Pathogen exposure Procedures

• Antibiotics • Age >65 years • Prolonged hospitalization • Surgery
• Chemotherapy • Female • Infected roommate • Nasogastric tube
• Antacids? • Co-morbidity • Type of institution • Enemas?
• Reduced immune response • Prior admissions • Diagnostic endoscopy?
• Prior AAD history • Colonization pressure

AAD: Antibiotic-associated diarrhea.

Use of penicillin V or G was significantly protec-
tive against C. difficile AAD (OR: 0.13; 95% CI:
0.07–0.18). By contrast, only one risk factor for
C. perfringens AAD was found: antacid use
(OR: 2.79; 95% CI: 2.03–3.55). Use of broad-
spectrum pencillins was significantly protective
against C. perfringens AAD (OR: 0.26; 95% CI:
0.16–0.31). Hsu et al. did not find any significant
differences in risk factors between C. difficile AAD
and non-C. difficile AAD [43].
Proton pump inhibitors
Other medications that can alter colonic micro-
biota may also increase or decrease the risk of
AAD or C. difficile AAD. One area that is hotly
debated is whether proton pump inhibitors
(PPIs) increase the risk of C. difficile AAD. Some
studies have found a significant effect, while oth-
ers have not [33,44,77,78]. The role of PPIs in
C. difficile AAD has yet to be resolved.
Host factors
The frequency of AAD shows a distinctive curve
with increased frequencies found in children
under 6 years, a nadir in frequency for ages 7–50
and an increase in adults aged over 50 years [5]. In
hospitalized adults, the mean age of patients with
AAD was significantly older (mean: 70.2 ± 14.6)
than patients with no AAD (mean: 58.5 ± 21.0)
[15]. Higher rates of C. difficile AAD are typically
reported for patients over 65 years old [6,76].
There is no evidence that comorbidity plays a
role in non-C. difficile AAD. By contrast, co-
morbidity has been significantly associated with
C. difficile AAD in several studies [6,76,79]. The
risk of comorbidity may be due, in part, to addi-
tional antibiotic exposure used to treat the con-
current infection. However, the risk is significant
even for illnesses not treated with additional anti-
biotics and thus the comorbidity may be an
indictor of a patient in poor health who cannot
mount an effective immune response to challenge
by bacterial overgrowth.
There may be an immune component to the
pathogenesis of AAD, but this role needs further
investigation. Depressed immune response has
been associated with an increased risk of
C. difficile AAD. Munoz et al. found the rate of
C. difficile AAD was significantly higher in
141 hypogammaglobulinemic heart transplant
patients (29 cases, 20.6%) compared with 6 out
of 94 (6.4%) heart transplant patients treated
with γ-globulin [80]. In addition, symptomatic
C. difficile AAD patients have been found to have
lower IgG antitoxin A levels than healthy controls
or asymptomatic carriers of C. difficile [81].
Pathogen exposure
Being susceptible owing to antibiotic exposure is
not sufficient to cause AAD – exposure to a
pathogen is also involved. To date, most of the
etiologic agents are not culturable, but as hospi-
talized patients have higher rates of AAD, it may
be assumed that the pathogens are present in the
healthcare setting. The best example of this is
C. difficile AAD. Nonhospitalized adults and out-
patients have lower rates of AAD, even when
exposed to similar types of broad-spectrum

570 Future Microbiol. (2008) 3(5) future science group

 Antibiotic-associated diarrhea: epidemiology, trends & treatment – REVIEW
antibiotics. The lower rates are probably associ-
ated with a lower risk of exposure to pathogens
able to cause AAD. For inpatients, the length of
hospitalization before AAD develops has been
found to be a significant risk factor. Asha et al.
compared 503 C. difficile AAD cases to 254 age-
and gender-matched controls and determined
that the risk of C. difficile AAD increases by
each day of hospitalization (aOR: 1.03; 95% CI:
1.01–1.04) [8]. Admittedly, this factor may be
confounded by multiple in-hospital exposures
that increase the risk of AAD, such as exposure to
other infected patients, additional antibiotic expo-
sures, medical procedures, and so on. Coloniza-
tion pressure, or proximity to a C. difficile AAD
case, increases the risk of acquiring C. difficile
AAD in patients who are nearby [11,82].
Procedures
Healthcare-associated procedures, such as intes-
tinal surgery or endoscopy, can also disrupt
colonic microbiota and have been found to
increase the risk of AAD [5,73]. Asha et al. found
the use of nasogastric tubes increased the risk of
C. difficile AAD (aOR: 5.63; 95% CI:
4.52–6.41) even after adjusting for age, gender,
length of stay and antibiotic use [8].
Multivariate risk factor analyses
Many of the above risk factors are closely corre-
lated and the individual risk estimates of AAD
attributable to each factor are thus difficult to
quantitate. Multivariate models allow the
assessment of the risk for each factor, while
simultaneously adjusting for the influences of
the other risk factors in the model. Unfortu-
nately, the majority of studies utilizing multi-
variate modeling have focused on just one
etiology of AAD (C. difficile), so the risk factors
for other etiologies of AAD need to be studied
using this method of analysis. Multivariate
analyses indicate that antibiotics and exposures
that perturb colonic microbiota are consistently
predictive of C. difficile AAD. Most multi-
variate models for C. difficile AAD have found
age over 65 years, exposure to antibiotics,
comorbidities and length of hospitalization to
be common risk factors for this type of AAD
[33,64,78,79,83,84].
Treatments for AAD
Discontinuation of inciting antibiotic
For uncomplicated cases of AAD, the most pru-
dent measure is to discontinue or change the
inciting antibiotic if possible, as shown in Figure 3
future science group www.futuremedicine.com
[8,37,85].
However, for more serious cases of AAD
and C. difficile AAD, more active treatment
is required.
Antibiotic treatment
In instances where the etiologic agent for AAD is
known, specific antibiotics targeted against these
pathogens is recommended. For C. difficile, two
antibiotics are recommended: oral vancomycin
and metronidazole [3,85]. Vancomycin has been
shown to be more effective in reducing the time
until diarrhea is cured and the patient has less
than three loose stools per day (a mean of 3 days)
compared with metronidazole (a mean of 5 days)
[3,85]. Currently, however, oral vancomycin is not
given as a first-line treatment for patients with
initial C. difficile AAD owing to its expense and
the possibility of increased rates of vancomycin-
resistant enterococci. Vancomycin should be
used in patients whose use of metronidazole is
contraindicated (previously failed on metro-
nidazole, allergic or pregnant) or who have severe
C. difficile disease or toxic megacolon, or when
the AAD is caused by S. aureus [85,86]. If symp-
toms persist, if vancomycin cannot be given
orally, or if ileus is present, vancomycin may be
given via nasogastric tube or by enema. In simi-
lar cases, metronidazole may be delivered intra-
venously [85]. Intravenous immunoglobulin as an
adjunct to vancomycin has been helpful in a few
cases, but controlled randomized trials are lack-
ing. The higher rate of metronidazole treatment
failures associated with the BI/NAP1/027
C. difficile strain raises the concern that the two
most replied upon antibiotics may not be effec-
tive in the future. Other antibiotics under inves-
tigation for C. difficile AAD include
nitrazoxanide, tiacumicin B and rifampin [87–89],
but other treatments for non-C. difficile AAD
are urgently needed.
Another difficult treatment problem is recur-
rent C. difficile AAD. This form of C. difficile-
associated AAD has been noted in 20% of
patients after their initial episode of C. difficile
AAD has been treated, and recurrent episodes
may persist for up to 4 years, despite multiple
treatments with antibiotics [49,90]. Strategies of
antibiotic treatment for recurrent C. difficile
AAD include a repeat course of antibiotic using a
prolonged, tapering dose schedule or a pulsed
(every other day) scheme [90]. The need to find
an effective treatment that would not further
perturb the colon microbiota (as with an addi-
tional course of antibiotics) has generated inter-
est in nonantibiotic-dependent treatments. The
571
REVIEW – McFarland

Figure 3. Treatment algorithm for antibiotic-associated diarrhea and Clostridium difficile

antibiotic-associated diarrhea.

AAD diagnosed

No known etiology Clostridium difficile-positive Other etiology found

• Stop inciting antibiotic •Toxin or culture-positive • Appropriate antibiotic or antifungal
• Switch to lower-risk antibiotic • Rule out other etiologies for diarrhea

Asymptomatic carrier Primary episode of C. difficile AAD

• No treatment • Stop inciting antibiotic if possible
• Treat with oral metronidazole (500 mg t.i.d., 10–15 days)
• Treat with oral vancomycin (125–250 mg q.i.d., 10 days)

Initial resolution of symptoms

Persistence of symptoms or
development of serious colitis
• Intravenous metronidazole or
First recurrence of C. difficile AAD vancomycin enema
• Retreat with metronidazole or vancomycin • Intravenous immunoglobulin
• Last resort: colectomy

Repeated C. difficile recurrences

• Pulsed or tapering course of vancomycin If no response, consider investigational
• Adjunctive treatment with probiotics therapies
• Fecal replacement therapy • Intravenous immunoglobulin
• Toxin-binding polymers
• Investigational antibiotics

AAD: Antibiotic-associated diarrhea; q.i.d.: Four-times daily; t.i.d.: Three-times daily.

rationale is to find a treatment strategy that
would allow the re-establishment of normal
microbiota (and colonization resistance) or
decrease bowel motility while limiting the use
of additional antibiotics. One tactic has been to
use toxin-binders instead of targeting the patho-
gen directly with antibiotics. One investigational
drug, tolevamer, is a good example of using a
toxin binder and Phase III trials are ongoing [91].
Probiotic therapy
Use of living organisms as a treatment or prophy-
laxis for AAD has been tried using several species,
and probiotics are widely used in Europe for
diarrhea therapy [6,92]. Probiotics are defined as
‘living microorganisms, which administered in
adequate amounts, confer health benefits to the
host’ [93]. Although the evidence is strong for
some bacterial and yeast strains as probiotics for
the prevention of AAD, the evidence for
C. difficile AAD is weaker. The advantages of
using living microbes is that they are effective
while minimizing the impact on normal intestinal
microbiota and, unlike antibiotic treatments, have
not been associated with serious adverse effects.
Other types of treatments
As it has been shown in several studies that patients
with recurrent C. difficile AAD may be immuno-
suppressed, use of pooled immunoglobulin as a
treatment strategy has been reported in several case
reports and series, but there are no controlled trials
to date [94,95]. Other types of treatments under
investigation include colonization with nontoxi-
genic strains of C. difficile and fecal replacement
therapy using donor stool infusions [85].

572 Future Microbiol. (2008) 3(5) future science group

 Antibiotic-associated diarrhea: epidemiology, trends & treatment – REVIEW
Surgery should be considered the last resort
for some patients with severe or fulminant cases
of C. difficile AAD and intractable PMC.
Although the rate of colectomy has ranged from
3.4 out of 1000 to 23% in C. difficile AAD
patients [55,96], the rate of mortality is high in
these patients (44–47%) [55,97]. Patients with
severe disease treated with emergency colectomies
(soon after C. difficile AAD diagnosis) have a sig-
nificantly lower mortality rate (34%) than patients
treated with metronidazole or vancomycin before
surgery was performed (58%) [55].
Prevention
Because AAD is a direct effect of the use of anti-
biotics, simultaneous use of a probiotic which is
not sensitive to the prescribed antibiotic (such
as a yeast probiotic) may be an effective prophy-
lactic strategy. Another recommendation is to
limit the abuse and overuse of antibiotics. Anti-
biotics are overprescribed for viral respiratory
infections and bronchitis and the overuse of
antibiotics has been shown to be associated with
an increase in antibiotic-associated complica-
tions, such as AAD and antibiotic resistance
[1,98]. Kardas et al. analyzed data from
46 studies and found that the mean compliance
with a course of antibiotic was only 62%, part
of which may be due to the development of
AAD [2]. Rational use of antibiotics may well be
the best preventive in our arsenal.
There are several lines of evidence that probi-
otics may be effective for preventing AAD. Beau-
soleil et al. conducted a double-blind
randomized study of hospitalized patients for the
prevention of AAD using fermented milk with a
mixture of two lactobacilli strains
(Lactobacillus casei and Lactobacillus acidophilus
CI1285) compared with placebo milk [99]. Of
89 enrolled patients, AAD occurred in 7 out of
44 (15.9%) of the probiotic milk group, and sig-
nificantly more (16 out of 45, 35.6%) of the pla-
cebo group developed AAD. There were no
adverse effects of either treatment in this study.
Wenus et al. also found a significant protection
of probiotic fermented milk in their study of
87 adult inpatients receiving antibiotics [100].
Patients were randomized to either a probiotic
fermented milk (Lactobacillus rhamnosus GG,
Lactobacillus acidophilus La-5 and Bifidobacte-
rium bifidus Bb-12) or a control group with
heat-killed bacteria. Significantly fewer patients
(2 out of 46, 5.9%) given the probiotic milk
developed AAD compared with the patients
receiving the control milk (8 out of 41, 27.6%).
future science group www.futuremedicine.com
A meta-analysis of 25 randomized controlled
trials (involving 2810 patients) found that probi-
otics have an overall protective efficacy for AAD
(pooled RR: 0.43, 95% CI: 0.31–0.58) [101].
Another meta-analysis limited the trials to those
done with children and pooled results from six
randomized, controlled trials (involving
766 children) and found a protective effect
(pooled RR: 0.44; 95% CI: 0.25–0.77) [102]. The
efficacy was most pronounced for L. rhamnosus
GG, Saccharomyces cerevisiae variant boulardii
and a mixture of Bifidobacterium lactis and Strep-
tococcus thermophilus. In another study,
Szajewska et al. limited their meta-analysis to
randomized, controlled trials of one type of pro-
biotic (S. cerevisiae boulardii) [103]. Pooling the
results from five trials (involving 1076 subjects), a
significantly protective effect was found (pooled
RR: 0.43; 95% CI: 0.23–0.78). However, most
of the protective effect was due to two studies
with S. cerevisiae boulardii. Although these results
show promise, more clinical trials testing differ-
ent types of probiotics are needed for C. difficile
AAD and other types of AAD. In addition, it is
important to note that the therapeutic effect is
specific to the probiotic strain, so clinical efficacy
found for one strain does not guarantee efficacy
for another type of probiotic.
Prebiotics are ‘nondigestible food ingredients
that benefically affect the host by selectively stim-
ulating the growth and/or activity of one or a lim-
ited number of bacteria in the intestine’ [104].
Lewis et al. randomized 435 elderly inpatients
(>65 years old) taking broad spectrum antibiotics
to either a prebiotic (oligofructose, 12 g/d) or
placebo [105]. Patients were treated during the
duration of the antibiotics and for an additional
7 days. Patients given the prebiotic developed
AAD at a similar rate (36 out of 215, 17%) to the
control patients (37 out of 220, 16.8%).
Control of AAD
The prevention of AAD and C. difficile AAD that
is associated with healthcare facilities has been
easier to control than trying to reduce inappro-
priate antibiotic use. Several studies have shown
positive results when focused efforts have been
taken on several levels. The first step is to
promptly diagnosis and treat cases (when appro-
priate), which limits the spread of the organism
into the hospital environment. The second step is
to limit the transmission of pathogens through
increased enteric precautions, use of disposable
gloves and thermometers, increased room disin-
fection and increased educational programs for
573
REVIEW – McFarland

hospital personnel [3]. Hospital wide restriction Conclusion

of high-risk antibiotics (clindamycin and second
or third-generation cephalosporins) and control-
ling inappropriate antibiotic prophylaxis has
been shown to be effective in reducing nosoco-
mial rates of C. difficile AAD [3,98]. Integrated,
multidisciplinary multilevel infection control pro-
grams have been shown to be effective in reducing
outbreaks of C. difficile AAD and may well be
effective even in cases where the etiology is not
known, but is amenable to the same infection
control practices as C. difficile AAD [32,106].
AAD continues to become more frequent due to
the increase in broad spectrum antibiotics, the
aging of the population and the increasing fre-
quency of healthcare-associated outbreaks. Four
major factors increase the risk of AAD and
C. difficile AAD: host characteristics (age, co-
morbidity), exposure to fomites (shared hospital
rooms, prolonged hospital stays), medications
(antibiotics, chemotherapy, motility altering
drugs, antacids) and medical procedures (sur-
gery, enemas). AAD may result in increased costs

Executive summary
Incidence

• A lower incidence of antibiotic-associated diarrhea (AAD) is found in outpatients and

community populations.
• Higher incidences of AAD are found in healthcare-associated settings.
• Secular trends show a continued increase in incidence over time.

Clinical presentation

• AAD ranges from mild diarrhea to inflammatory colitis to pseudomembranous colitis (PMC).
• AAD may occur while taking antibiotics, or develop as much as 8 weeks afterwards.
• Duration of AAD ranges from 1 day to several months.
• Colitis and PMC are associated with fever, leukocytosis and abdominal cramping.

Consequences

• AAD may cause extended hospital stays and increased healthcare costs.
• Recurrent AAD may occur in 20–50% of patients.
• Mortality is increased in severe cases of AAD.

Pathogenesis

• Disruption of normal intestinal microbiota is the key step that causes susceptibility.
• Overgrowth of opportunistic pathogens or altered fermentation results in the development
of symptoms.
• Etiologic agents for AAD include Clostridium difficile, Clostridium perfringens, Klebsiella oxytoca and
Staphylococcus aureus.

Risk factors

• High-risk antibiotics (especially clindamycin, cephalosporins and penicillins).

• Low-risk antibiotics (fluoroquinolones and macrolides).
• Host factors (advanced age, immunosuppression and co-morbidities).
• Exposure to pathogens (hospitalization, shared rooms and outbreaks).
• Procedures (nasogastric tube feeding and surgery).

Treatment

• Discontinue inciting antibiotic or switch to a lower risk antibiotic if possible.

• If C. difficile AAD, treat with metronidazole or vancomycin.
• Consider probiotics for recurrent C. difficile AAD or to prevent AAD.
• Colectomy for nonresponsive cases.

Prevention

• Rational use of antibiotics.

• Prompt diagnosis and treatment.
• Infection control programs for inpatients.

574 Future Microbiol. (2008) 3(5) future science group

 Antibiotic-associated diarrhea: epidemiology, trends & treatment – REVIEW

of medical care and has infrequent, but serious
complications, especially if the etiology is
C. difficile. Further research into treatments and
preventive measures are required.
Limitations in the literature on AAD include a
lack of standardized definitions for AAD. Studies
often report different etiologies or do not fully
diagnose them, have a variety of incubation
period definitions, follow patients for varying
times and use different diagnostic procedures. In
addition, treatment or prevention clinical trials are
needed with consistant inclusion and exclusion
criteria, using standardized study drug doses and
durations and intention to treat analyses.
Future perspective
As C. difficile AAD continues to plague health-
care settings and rates continue to increase, effec-
tive control programs and newer treatments will
be the focus of future research. The development
of technologically advanced molecular probes are
beginning to characterize new, previously uncul-
turable species of intestinal microbes. A greater
understanding of the complexity of the inter-
actions between intestinal bacteria and the dis-
covery of the identity of more etiologies of AAD
is just around the corner. With these insights,
rational infection control programs should be
able to limit healthcare-associated outbreaks of
AAD and lessen the impact on the healthcare
community at large.
Veterans administration disclaimer
The views expressed in this article are those of the author and do
not represent the views of the Department of Veterans Affairs.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involve-
ment with any organization or entity with a financial inter-
est in or financial conflict with the subject matter or
materials discussed in the manuscript. This includes employ-
ment, consultancies, honoraria, stock ownership or options,
expert testimony, grants or patents received or pending,
or royalties.
No writing assistance was utilized in the production of
this manuscript.

Bibliography
Papers of special note have been highlighted as
either of interest (•) or of considerable interest (••)
to readers.
1. Mettler J, Simcock M, Sendi P et al.: Empirical
use of antibiotics and adjustment of empirical
antibiotic therapies in a university hospital: a
prospective observational study. BMC Infect.
Dis. 7, 21 (2007).
2. Kardas P, Devine S, Golembesky A,
Roberts C: A systematic review and meta-
analysis of misuse of antibiotic therapies in
the community. Int. J. Antimicrob. Agents
26(2), 106–113 (2005).
3. McFarland LV, Beneda HW, Clarridge JE,
Raugi GJ: Implications of the changing face
of C. difficile disease for health care
practitioners. Am. J. Infect. Control 35(4),
237–253 (2007).
4. Spellberg B, Guidos R, Gilbert D et al.:
Infectious Diseases Society of America. The
epidemic of antibiotic-resistant infections: a
call to action for the medical community from
the Infectious Diseases Society of America.
Clin. Infect. Dis. 46(2), 155–164 (2008).
5. McFarland LV: Epidemiology, risk factors
and treatments for antibiotic-associated
diarrhea. Dig. Dis. 16, 292–307 (1998).
6. McFarland LV: Updates on the changing
epidemiology of Clostridium difficile-
associated disease. Nat. Clin. Pract.
Gastroenterology Hepatol. 5(1), 40–48
(2008).
7. Walbrown MA, Aspinall SL, Mayliss NK
et al.: Evaluation of Clostridium difficile-
associated diarrhea with a drug formulatry
change in preferred fluoroquinolones.
J. Manag. Care Pharm. 14, 34–40 (2008).
8. Asha NJ, Tompkins D, Wilcox MH:
Comparative analysis of prevalence, risk
factors, and molecular epidemiology of
antibiotic-associated diarrhea due to
Clostridium difficile, Clostridium perfringens,
and Staphylococcus aureus. J. Clin. Microbiol.
44, 2785–2791 (2006).
• Excellent epidemiologic investigation of
three potential etiologies of antibiotic-
associated diarrhea (AAD). Different risk
factors were found for Clostridium difficile
AAD and Clostridium perfringens AAD.
9. Pepin J, Valiquette L, Cossette B: Mortality
attributable to nosocomial Clostridium
difficile-associated disease during an
epidemic caused by a hypervirulent strain in
Quebec. CMAJ 173(9), 1037–1042 (2005).
• Seminal paper describing the impact of an
emergent hypervirulent strain of C. difficile
in Canada. Outbreaks had higher than
expected incidence rates and higher
mortality rates.
10. Deshpande A, Pant C, Jain A, Fraser TG,
Rolston DD: Do fluoroquinolones
predispose patients to Clostridium difficile
associated disease? A review of the evidence.
Curr. Med. Res. Opin. 24(2), 329–333
(2008).
11. Lawrence SJ, Puzniak LA, Shadel BN,
Gillespie KN, Kollef MH, Mundy LM:
Clostridium difficile in the intensive care
unit: epidemiology, costs, and colonization
pressure. Infect. Control Hosp. Epidemiol.
28(2), 123–130 (2007).
12. Dubberke ER, Reske KA, Olsen MA,
McDonald LC, Fraser VJ: Short- and long-
term attributable costs of Clostridium difficile-
associated disease in nonsurgical inpatients.
Clin. Infect. Dis. 46(4), 497–504 (2008).
13. Tedesco FJ, Barton RW, Alpers DH:
Clindamycin-associated colitis. Ann. Intern.
Med. 81, 429–433 (1974).
14. Bartlett JG, Moon N, Chang TW, Taylor N,
Onderdonk AB: Role of Clostridium difficile
in antibiotic associated PMC.
Gastroenterology 75, 778–782 (1978).
15. McFarland LV, Mulligan ME, Kwok RYY,
Stamm WE: Nosocomial acquisition of
Clostridium difficile infection. N. Engl. J.
Med. 320, 204–210 (1989).
16. Aronsson B, Mollby R, Nord CD:
Antimicrobial agents and Clostridium
difficile in acute enteric disease:
epidemiological data from Sweden,
1980–82. J. Infect. Dis. 151, 476–481
(1985).
17. Brown E, Talbot GH, Axelrod P,
Provencher M, Hoegg C: Risk factors for
Clostridium difficile toxin-associated
diarrhea. Infect. Control Hosp. Epidemiol..
11, 283–290 (1990).

future science group www.futuremedicine.com 575

REVIEW – McFarland
18. McFarland LV, Surawicz CM, Stamm WE:
Risk factors for Clostridium difficile carriage
and C. difficile-associated diarrhea in a
cohort of hospitalized patients. J. Infect.
Dis. 162, 678–684 (1990).
19. Fekety R: Guidelines for the diagnosis and
management of Clostridium difficile-
associated diarrhea and colitis. Am. J.
Gastroenterology 92, 739–750 (1997).
20. Wiström J, Norrby SR, Myhre EB et al.:
Frequency of antibiotic-associated diarrhoea
in 2462 antibiotic-treated hospitalized
patients: a prospective study. J. Antimicrob.
Chemother. 47(1), 43–50 (2001).
• Large study of 2462 patients in Swedish
hospitals found a low rate of AAD (4.9%),
but rates differed by type of medical
service. Excellent data on the effect of
antibiotic duration and interactions
between antibiotic types.
21. Turck D, Bernet JP, Marx J et al.: Incidence
and risk factors of oral antibiotic-associated
diarrhea in an outpatient pediatric
population. J. Pediatr. Gastroenterology Nutr.
37(1), 22–26 (2003).
• Robust description of AAD in the pediatric
population. Higher incidences of AAD were
found in children under 2 years old, but risk
factors were similar to those found in adults.
22. Damrongmanee A, Ukarapol N: Incidence
of antibiotic-associated diarrhea in a
pediatric ambulatory care setting. J. Med.
Assoc. Thai. 90(3), 513–517 (2007).
23. Levy DG, Stergachis A, McFarland LV et al.:
Antibiotics and Clostridium difficile diarrhea
in the ambulatory care setting. Clin. Ther.
22, 91–102 (2000).
24. Hickson M, D’Souza AL, Muthu N et al.:
Use of probiotic Lactobacillus preparation to
prevent diarrhoea associated with
antibiotics: randomised double blind
placebo controlled trial. BMJ 335(7610),
80–85 (2007).
25. Szajewska H, Mrukowicz JZ: Probiotics in
the treatment and prevention of acute
infectious diarrhea in infants and children: a
systematic review of published randomized,
double-blinded, placebo-controlled trials.
J. Pediatr. Gastroenterology Nutr. 33,
S17–S25 (2001).
26. Corrêa NB, Péret Filho LA, Penna FJ,
Lima FM, Nicoli JR: A randomized formula
controlled trial of Bifidobacterium lactis and
Streptococcus thermophilus for prevention of
antibiotic-associated diarrhea in infants.
J. Clin. Gastroenterology 39(5), 385–389
(2005).
27. Thomas MR, Litin SC, Osmon DR,
Corr AP, Weaver AL, Lohse CM: Lack of
effect of Lactobacillus GG on antibiotic-
576
associated diarrhea: a randomized, placebo-
controlled trial. Mayo Clin. Proc. 76,
883–889 (2001).
28. Kotowska M, Albrecht P, Szajewska H:
Saccharomyces boulardii in the prevention of
antibiotic-associated diarrhoea in children:
a randomized double-blind placebo-
controlled trial. Aliment Pharmacol.
Ther. 21(5), 583–590 (2005).
29. Sugita R, Yamanaka N, Kudo F et al.:
Efficacy and safety of potassium
clavulanate/amoxicillin (CLAVAMOX) dry
syrup in children with otitismedia. Jpn. J.
Antibiot. 60(4), 221–241 (2007).
30. Conway S, Hart A, Clark A, Harvey I:
Does eating yogurt prevent antibiotic-
associated diarrhoea? A placebo-controlled
randomised controlled trial in general
practice. Br. J. Gen. Pract. 57(545), 953–959
(2007).
31. Blot E, Escande MC, Besson D et al.:
Outbreak of Clostridium difficile-related
diarrhoea in an adult oncology unit: risk
factors and microbiological characteristics.
J. Hosp. Infect. 53, 187–192 (2003).
32. Drudy D, Harnedy N, Fanning S,
Hannan M, Kyne L: Emergence and control
of fluoroquinolone-resistant, toxin A-
negative, toxin B-positive Clostridium
difficile. Infect. Control Hosp. Epidemiol.
28(8), 932–940 (2007).
33. McFarland LV, Clarridge JE, Beneda HW,
Raugi GR: Fluoroquinolone use and risk
factors for Clostridium difficile disease within
a Veterans Administration Health Care
System. Clin. Infect. Dis. 45(9), 1141–1151
(2007).
34. Chandler RE, Hedberg K, Cieslak PR:
Clostridium difficile-associated disease in
Oregon: increasing incidence and hospital-
level risk factors. ICHE 28(2), 116–122
(2007).
35. Archibald LK, Banerjee SN, Jarvis WR:
Secular trends in hospital-acquired
Clostridium difficile disease in the United
States, 1987–2001. J. Infect. Dis. 189,
1585–1589 (2004).
36. Mooney H: Annual incidence of MRSA falls
in England, but C. difficile continues to rise.
BMJ 335(7627), 958 (2007).
37. Monaghan T, Boswell T, Mahida YR: Recent
advances in Clostridium difficile-associated
disease. Gut 57(6), 850–860 (2008).
38. Yapar N, Sener A, Karaca B et al.: Antibiotic-
associated diarrhea in a Turkish outpatient
population: investigation of 288 cases.
J. Chemother. 17(1), 77–81 (2005).
39. Crabtree TD, Pelletier SJ, Gleason TG,
Pruett TL, Sawyer RG: Clinical
characteristics and antibiotic utilization in
Future Microbiol. (2008) 3(5)
surgical patients with Clostridium difficile-
associated diarrhea. Am. Surg. 65(6),
507–511 (1999).
40. Kutty PK, Benoit SR, Woods CW et al.:
Assessment of Clostridium difficile-associated
disease surveillance definitions, North
Carolina, 2005. Infect. Control Hosp.
Epidemiol. 29(3), 197–202 (2008).
41. McDonald LC, Coignard B, Dubberke E
et al.: Ad hoc surveillance of Clostridium
difficile-associated disease. Infect. Control
Hosp. Epidemiol. 28(2), 140–145 (2007).
42. Peled N, Pitlik S, Samra Z, Kazakov A, Bloch
Y, Bishara J: Predicting Clostridium difficile
toxin in hospitalized patients with antibiotic-
associated diarrhea. Infect. Control Hosp.
Epidemiol. 28(4), 377–381 (2007).
43. Hsu MS, Wang JT, Huang WK, Liu YC,
Chang SC: Prevalence and clinical features
of Clostridium difficile-associated diarrhea in
a tertiary hospital in northern Taiwan. J.
Microbiol. Immunol. Infect. 39(3), 242–248
(2006).
44. Sunenshine RH, McDonald LC:
Clostridium difficile-associated disease: new
challenges from an established pathogen.
Cleve. Clin. J. Med. 73, 187–197 (2006).
45. Dial S, Alrasadi K, Manoukian C, Huang A,
Menzies D: Risk of Clostridium difficile
diarrhea among hospital inpatients prescribed
proton pump inhibitors: cohort and case-
control studies. CMAJ 171(1), 33–38 (2004).
46. Pepin J, Valiquette L, Alary ME et al.:
Clostridium difficile-associated diarrhea in a
region of Québec from 1991 to 2003: a
changing pattern of disease severity. CMAJ
171, 466–472 (2004).
47. Surawicz CM, McFarland LV:
Pseudomembranous colitis: causes and
cures. Digestion 60(2), 91–100 (1999).
48. Lee KS, Shin WG, Jang MK et al.: Who are
susceptible to pseudomembranous colitis
among patients with presumed antibiotic-
associated diarrhea? Dis. Colon Rectum
49(10), 1552–1558 (2006).
49. Berman L, Carling T, Fitzgerald TN
et al.: Defining surgical therapy for
pseudomembranous colitis with toxic
megacolon. J. Clin. Gastroenterology
(2008) (Epub ahead of print).
50. McFarland LV, Surawicz CM, Rubin M,
Fekety R, Elmer GW, Greenberg RN:
Recurrent Clostridium difficile disease:
epidemiology and clinical characteristics.
Infect. Control Hosp. Epidemiol. 20, 3–50
(1999).
51. Do AN, Fridkin SK, Yechouron A et al.:
Risk factors for early recurrent Clostridium
difficile-associated diarrhea. Clin. Infect. Dis.
26(4), 954–959 (1998).
future science group
 Antibiotic-associated diarrhea: epidemiology, trends & treatment – REVIEW
52. Sloan LM, Duresko BJ, Gustafson DR,
Rosenblatt JE: Comparison of real-time
PCR for detection of the tcdC gene with
four toxin immunoassays and culture in
diagnosis of Clostridium difficile. Infection
J. Clin. Microbiol. 46(6), 1996–2001
(2008).
53. Starr JM, Martin H, McCoubrey J,
Gibson G, Poxton IR: Risk factors for
Clostridium difficile colonisation and toxin
production. Age Ageing 32, 657–660
(2003).
54. Novak-Weekley SM, Hollingsworth MH:
A study comparing the premier
toxins A & B and C. difficile TOX A/B II
assays for diagnosis of Clostridium difficile.
Infection Clin. Vaccine Immunol. 15(3),
575–578 (2008).
55. Zerey M, Paton BL, Lincourt AE,
Gersin KS, Kercher KW, Heniford BT: The
burden of Clostridium difficile in surgical
patients in the United States. Surg. Infect.
(Larchmt) 8(6), 557–566 (2007).
56. Lamontagne F, Labbé AC, Haeck O et al.:
Impact of emergency colectomy on survival
of patients with fulminant Clostridium
difficile colitis during an epidemic caused by
a hypervirulent strain. Ann. Surg. 245(2),
267–272 (2007).
57. Isolauri E, Salminen S: Probiotics, gut
inflammation and barrier function.
Gastroenterology Clin. North Am. 34(3),
437–450 (2005).
58. McFarland LV: Normal flora: diversity and
functions. Microb. Ecol. Health Dis. 12(4),
193–207 (2000).
59. Thompson JW, Jacobs RF: Adverse effects of
newer cephalosporins. An update. Drug Saf.
9(2), 132–142 (1993).
60. Gursoy S, Guven K, Arikan T et al.:
Clostridium difficile infection frequency in
patients with nosocomial infections or using
antibiotics. Hepatogastroenterology 54(78),
1720–1724 (2007).
61. Ackermann G, Thomalla S, Ackermann F,
Schaumann R, Rodloff AC, Ruf BR:
Prevalence and characteristics of bacteria
and host factors in an outbreak situation of
antibiotic-associated diarrhoea. J. Med.
Microbiol. 54, 149–153 (2005).
62. Altindi M, Usluer S, Ciftçi H, Tunç N,
Cetinkaya Z, Aktepe OCZ: Investigation of
the presence of Clostridium difficile in
antibiotic-associated diarrhea patients by
culture and toxin detection methods.
Mikrobiyol. Bul. 41, 29–37 (2007).
63. Rupnik M, Dupuy B, Fairweather NF
et al.: Revised nomenclature of Clostridium
difficile toxins and associated genes. J. Med.
Microbiol. 54(Pt 2), 113–117 (1995).
future science group
64. Loo VG, Poirier L, Miller MA et al.:
A predominantly clonal multi-institutional
outbreak of Clostridium difficile-associated
diarrhea with high morbidity and mortality.
N. Engl. J. Med. 353, 2442–2449 (2005).
65. Pituch H, Obuch-Woszczatyski P,
Wultaska D, van Belkum A,
Meisel-Mikoajczyk F, Uczak M: Laboratory
diagnosis of antibiotic-associated diarrhea:
a Polish pilot study into the clinical
relevance of Clostridium difficile and
Clostridium perfringens toxins. Diagn.
Microbiol. Infect. Dis. 58(1), 71–75 (2007).
66. Philbrick AM, Ernst ME: Amoxicillin-
associated hemorrhagic colitis in the presence
of Klebsiella oxytoca. Pharmacotherapy 27(11),
1603–1607 (2007).
67. Högenauer C, Langner C, Beubler E et al.:
Klebsiella oxytoca as a causative organism of
antibiotic-associated hemorrhagic colitis.
N. Engl. J. Med. 355(23), 2418–2426
(2006).
68. Flemming K, Ackermann G: Prevalence of
enterotoxin producing Staphylococcus aureus
in stools of patients with nosocomial
diarrhea. Infection 35(5), 356–358 (2007).
69. Gravet A, Rondeau M, Harf-Monteil C
et al.: Predominant Staphylococcus aureus
isolated from antibiotic-associated diarrhea
is clinically relevant and produces
enterotoxin A and the bicomponent toxin
LukE–LukD. J. Clin. Microbiol. 37(12),
4012–4019 (1999).
70. Boyce JM, Havill NL, Kohan C,
Dumigan DG, Ligi CE: Do infection control
measures work for methicillin-resistant
Staphylococcus aureus? Infect. Control Hosp.
Epidemiol.. 25(5), 395–401 (2004).
71. Krause R, Schwab E, Bachhiesl D et al.:
Role of Candida in antibiotic-associated
diarrhea. J. Infect. Dis. 184(8), 1065–1069
(2001).
72. Vaishnavi C, Kaur S: Is Campylobacter
involved in antibiotic associated diarrhoea?
Indian J. Pathol. Microbiol. 48(4), 526–529
(2005).
73. McFarland LV: Risk factors for AAD: facteurs
derisqué dela diarrhee associee aux
antibiotiques. Uner evuedela litterature. Ann.
Med. Interne (Paris) 149, 261–266 (1998).
74. Schreiber KL, Price LD, Brown DR:
Evidence for neuromodulation of
enteropathogen invasion in the intestinal
mucosa. J. Neuroimmune Pharmacol. 2(4),
329–337 (2007).
75. Wren SM, Ahmed N, Jamal A, Safadi BY:
Preoperative oral antibiotics in colorectal
surgery increase the rate of Clostridium
difficile colitis. Arch. Surg. 140(8), 752–756
(2005).
www.futuremedicine.com
76. Owens RC Jr, Donskey CJ, Gaynes RP,
Loo VG, Muto CA: Antimicrobial-
associated risk factors for Clostridium
difficile infection. Clin. Infect. Dis.
46(Suppl. 1), S19–S31 (2008).
77. Jayatilaka S, Shakov R, Eddi R, Bakaj G,
Baddoura WJ, DeBari VA: Clostridium
difficile infection in an urban medical
center: five-year analysis of infection rates
among adult admissions and association
with the use of proton pump inhibitors.
Ann. Clin. Lab. Sci. 37(3), 241–247
(2007).
• This well-done study found a twofold
increase in the incidence of C. difficile
AAD over a 5-year period, which was
highly correlated with the increase in
proton pump inhibitor use. A nested
case–control study found a significant risk
for proton pump inhibitors (odds
ratio: 2.7; 95% confidence interval:
1.7–4.5).
78. Dubberke EF, Reske KA, Yan Y, Olsen MA,
McDonald LC, Fraser VJ: Clostridium
difficile-associated disease in a setting of
endemicity: identification of novel risk
factors. Clin. Infect. Dis. 45, 1543–1549
(2007).
79. Vesta KS, Wells PG, Gentry CA, Stipek WJ:
Specific risk factors for Clostridium difficile-
associated diarrhea:
a prospective, multicenter, case–control
evaluation. Am. J. Infect. Control 33,
469–472 (2005).
80. Muñoz P, Giannella M, Alcalá L et al.:
Clostridium difficile-associated diarrhea
in heart transplant recipients: is
hypogammaglobulinemia the answer?
J. Heart Lung Transplant. 26(9), 907–914
(2007).
81. Maroo S, Lamont JT: Recurrent
Clostridium difficile. Gastroenterology 130(4),
1311–1316 (2006).
82. Dubberke ER, Reske KA, Olsen MA
et al.: Evaluation of Clostridium difficile-
associated disease pressure as a risk factor
for C. difficile-associated disease. Arch. Intern.
Med. 167(10), 1092–1097 (2007).
83. Modena S, Bearelly D, Swartz K,
Friedenberg FK: Clostridium difficile among
hospitalized patients receiving antibiotics:
a case–control study. Infect. Control Hosp.
Epidemiol. 26, 685–690 (2007).
84. Muto CA, Pokrywka M, Shutt K et al.:
A large outbreak of Clostridium difficile-
associated disease with an unexpected
proportion of deaths and colectomies
at a teaching hospital following increased
fluoroquinolone use. Infect. Control Hosp.
Epidemiol. 26, 273–280 (2005).
577
REVIEW – McFarland
85. Gerding DN, Muto CA, Owens RC Jr:
Treatment of Clostridium difficile infection.
Clin. Infect. Dis. 46(Suppl. 1), S32–S42
(2008).
86. Stepan C, Surawicz CM: Treatment
strategies for C. difficile associated diarrhea.
Acta Gastroenterology Latino Am. 37(3),
183–191 (2007).
87. Musher DM, Logan N, Mehendiratta V
et al.: Clostridium difficile colitis that fails
conventional metronidazole therapy:
response to nitazoxanide. J. Antimicrob.
Chemother. 59, 705–710 (2007).
88. Louie TJ, Miller M, Donskey C et al.:
A clinical and laboratory evaluation of
PAR-101 in patients with Clostridium
difficile-associated diarrhea. Presented at:
The 16th European Congress of Clinical
Microbiology and Infectious Diseases
(ECCMID). Nice, France, April 2006.
89. Lagrotteria D, Holmes S, Smiega M,
Smaill F, Lee C: Prospective, randomized
inpatient study of oral metronidazole versus
oral metronidazole and rifampin for
treatment of primary episode of Clostridium
difficile-associated diarrhea. Clin. Infect. Dis.
43, 547–552 (2006).
90. McFarland LV, Elmer GW, Surawicz CM:
Breaking the cycle: treatment strategies for
163 cases of recurrent Clostridium difficile
disease. Am. J. Gastroenterology 97,
1769–1775 (2002).
91. Louie TJ, Peppe J, Watt CK et al.:
Tolevamer, a novel nonantibiotic polymer,
compared with vancomycin in the treatment
of mild to moderately severe Clostridium
difficile associated diarrhea. Clin. Infect. Dis.
43, 411–420 (2006).
92. Elmer GW, McFarland LV, McFarland M:
Antibiotics-associated diarrhea and colitis
(Chapter 4). In: The Power of Probiotics:
Improving Your Health with Beneficial
Microbes. Haworth Press, Binghamton,
NY, USA (2007).
• Comprehensive and patient-friendly guide
on important aspects of probiotics and
therapy. Describes how to choose an
effective probiotic and provides detailed
evidence-based data on clinical trials from a
wide variety of diseases.
93. Reid G: Food and Agricultural Organization
of the United Nation and the WHO.
578
View publication stats
The importance of guidelines in the
development and application of probiotics.
Curr. Pharm. Des. 11(1), 11–16 (2005).
94. McPherson S, Rees CJ, Ellis R, Soo S,
Panter SJ: Intravenous immunoglobulin
for the treatment of severe, refractory, and
recurrent Clostridium difficile diarrhea.
Dis. Colon Rectum 49, 640–645
(2006).
95. Wilcox MH: Descriptive study of
intravenous immunoglobulin for the
treatment of recurrent Clostridium difficile
diarrhoea. J. Antimicrob. Chemother. 53,
882–884 (2004).
96. Ricciardi R, Rothenberger DA, Madoff RD,
Baxter NN: Increasing prevalence and
severity of Clostridium difficile colitis in
hospitalized patients in the United States.
Arch. Surg. 142(7), 624–631 (2007).
97. Ali SO, Welch JP, Dring RJ: Early
surgical intervention for fulminant
pseudomembranous colitis. Am. Surg.
74, 20–26 (2008).
98. Rice LB: The Maxwell Finland Lecture:
For the duration – rational antibiotic
administration in an era of antimicrobial
resistance and Clostridium difficile. Clin.
Infect. Dis. 46(4), 491–496 (2008).
99. Beausoleil M, Fortier N, Guénette S et al.:
Effect of a fermented milk combining
Lactobacillus acidophilus Cl1285 and
Lactobacillus casei in the prevention of
antibiotic-associated diarrhea: a randomized,
double-blind, placebo-controlled trial.
Can. J. Gastroenterology 11, 732–736
(2007).
100. Wenus C, Goll R, Loken EB, Biong AS,
Halvorsen DS, Florholmen J: Prevention of
antibiotic-associated diarrhoea by a
fermented probiotic milk drink. Eur. J. Clin.
Nutr. 62(2), 299–301 (2008).
101. McFarland LV: Meta-analysis of probiotics
for prevention of antibiotic associated
diarrhea and treatment of Clostridium
difficile disease. Am. J. Gastroenterology 101,
812–822 (2006).
• Largest meta-analysis of probiotics and
AAD/C. difficile AAD to date, reviewing
25 randomized controlled trials on AAD
and five on C. difficile AAD. Overall,
probiotics showed a significant protective
effect for both diseases.
Future Microbiol. (2008) 3(5)
102. Szajewska H, Ruszczynki M,
Radzikowski A: Probiotics in the prevention
of antibiotic-associated diarrhea in children:
a meta-analysis of randomized controlled
trials. J. Pediatr. 149, 367–372 (2006).
103. Szajewska H, Mrukowicz J: Meta-analysis:
non-pathogenic yeast Saccharomyces
boulardii in the prevention of antibiotic-
associated diarrhoea. Aliment. Pharmacol.
Ther. 22(5), 365–372 (2005).
104. Roberfroid MB: Prebiotics: preferential
substrates for specific germs? Am. J. Clin.
Nutr. 73(Suppl. 2), 406S–409S
(2001).
105. Lewis S, Burmeister S, Cohen S, Brazier J,
Awasthi A: Failure of dietary oligofructose to
prevent antibiotic-associated diarrhoea.
Aliment. Pharmacol. Ther. 21(4), 469–477
(2005).
106. Cherifi S, Delmee M, Van Broeck J, Beyer I,
Byl B, Mascart G: Management of an
outbreak of Clostridium difficile-associated
disease among geriatric patients. Infect.
Control Hosp. Epidemiol. 27(11),
1200–1205 (2006).
Websites
201. Perlin JB: Undersecretary for Health’s
Information Letter. Clostridium difficile.
9–8 (2005).
www.va.gov/vhapulbications/view
Publication.asp?pub_ID=1305
202. World Health Organization.
Diarrhoea (2008).
www.who.int/topics/diarrhoea/en/
Affiliation
• Lynne V McFarland, PhD
Department of Health Services Research &
Development, Puget Sound Veterans
Administration, Healthcare System,
S-152, 1100 Olive Way, #1400 Seattle,
WA 98101, USA
Tel.: +1 206 277 1095;
Fax: +1 206 764 2935;
lynne.mcfarland@va.gov
and,
Department of Medicinal Chemistry,
Box 357610, School of Pharmacy,
University of Washington, Seattle,
WA 98101, USA
future science group