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Digestive Diseases and Sciences, Vol. 48, No. 10 (October 2003), pp. 2077–2082 (°
C 2003)

A Randomized Trial of Yogurt for Prevention

of Antibiotic-Associated Diarrhea
RIPUDAMAN S. BENIWAL, MD,* VINCENT C. ARENA, PhD,† LENO THOMAS, MD,‡ SUDHIR NARLA,
MD,§ THOMAS F. IMPERIALE, MD,* RAUF A. CHAUDHRY, MD,‡ and USMAN A. AHMAD, MD‡

Antibiotic-associated diarrhea (AAD) is the most common adverse effect of antibiotic therapy. Our
aim was to determine the effectiveness of a dietary supplement of yogurt for prevention of AAD.
Two hundred two hospitalized patients receiving oral or intravenous antibiotics were randomized to
receive or not receive a dietary yogurt supplement, consisting of 227 grams of commercial yogurt,
and followed for 8 days. Mean age of the study group was 70 years and 43% were male. Compliance
and 8-day follow-up were 85% and 91%, respectively. Patients receiving yogurt reported less fre-
quent diarrhea (12% vs 24%; P = 0.04), and significantly less total diarrheal days (23 vs 60). The
cumulative proportions of patients without diarrhea were significantly different (P = 0.02) between
patients receiving and not receiving yogurt. For conclusion, dietary supplementation with yogurt is
a simple, effective, and safe treatment that decreases the incidence and duration of AAD.

KEY WORDS: effectiveness; yogurt; dietary intervention; biotherapeutics; prophylaxis; antibiotic-associated diarrhea.

Antibiotic-associated diarrhea (AAD) is the most com-
mon adverse effect of antimicrobial therapy, occurring in
5–39% of patients (1–3). AAD ranges in severity from
a mild increase in stool frequency to debilitating, life-
threatening diarrhea. Two major forms of AAD have been
identified. One form is enigmatic as no pathogen is identi-
fied. Typical clinical features include onset during antibi-
otic exposure, stool frequency that is dose-related, resolu-
tion upon discontinuation of the implicated drug, absence
of local or systemic inflammation, and a usually benign
course. Pathogenesis may be related to altered short-chain
fatty acids in the intestine, functional disturbance of car-
bohydrate and bile acid metabolism due to alteration of the
Manuscript received July 9, 2002; accepted January 16, 2003.
From the *Division of Gastroenterology and Hepatology, Department
of Medicine, Indiana University School of Medicine and Roudebush
VA Medical Center, Indianapolis, Indiana; †Department of Biostatistics,
Graduate School of Public Health, University of Pittsburgh, Pittsburgh,
Pennsylvania; and ‡Department of Medicine and §Division of Gas-
troenterology, Department of Medicine, UPMC-McKeesport Hospital,
McKeesport, Pennsylvania, USA.
Address for reprint requests: Dr. Ripudaman S. Beniwal, Health
Services Research and Development Roudebush VA Medical Center
(11H) 1481 W. 10th Street Indianapolis, Indiana 46202, USA; e-mail:
rbeniwal@iupui.edu
microflora, or toxic effects on the intestinal mucosa, and
pharmacological effect on motility. The second form is
Clostridium difficile-associated diarrhea, which accounts
for 10–20% of AAD. Symptoms may persist for months,
and endoscopic findings range from normal mucosa to
severe colitis, with the most characteristic lesion being
pseudomembranous colitis. Occasionally other bacteria
may be implicated. Pathogenesis of AAD may be related
to loss of the resistance provided by normal colonic flora,
as the antibiotics suppress the intestinal microflora that
hold proliferation of C. difficile in check (4, 5).
In a study from the United Kingdom, the economic im-
pact of AAD in a community hospital was $638,880 with
2100 lost bed days per year (6). AAD was associated with
a fivefold increased risk of other nosocomial infections
and a threefold increase in mortality (7).
Until recently, biotherapeutics has been a neglected
modality in the treatment and prevention of selected in-
testinal infections. Placebo-controlled studies have shown
that biotherapeutic agents have been used successfully to
prevent AAD (8). However, none of these studies eval-
uated the effectiveness of commercially available yogurt
with live active cultures for the prevention of AAD.

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Prompted by the limited work found in the literature and
anecdotal evidence found in both the medical and lay com-
munity that yogurt might be efficacious, we investigated
whether yogurt would reduce or prevent AAD in patients
receiving antibiotics. We conducted a randomized con-
trolled trail using vanilla flavored yogurt containing live
active cultures in a hospital setting to test its effectiveness
in preventing AAD.
MATERIALS AND METHODS
The study protocol was reviewed and approved by the
McKeesport Hospital Institutional Review Board (IRB) and pre-
sentation was made to the pharmacy, infectious disease, nursing,
and nutritional staff in order to facilitate its implementation and
standardization. Potential patients were identified from the gen-
eral medicine teaching floors, cardiac care unit (CCU), medical
intensive care unit (ICU), and skilled nursing facility (SNF) of
McKeesport Hospital during the time period of September 1998
through May 1999. Patients were eligible for study if oral or
intravenous antibiotics were started during hospital admission.
Individuals were excluded from consideration if any of the fol-
lowing conditions were present: diarrhea or a diagnosis or history
of a condition with diarrhea as a main symptom (such as inflam-
matory bowel disease); allergy to yogurt or any component of
yogurt; lactose intolerance; more than 12 hr from the first dose
of antibiotic; noncompliance with other medical interventions
such as diagnostic tests and treatment; inability to take yogurt
per orum; and the presence of a feeding tube (nasogastric, oro-
gastric, gastronomy, or jejunostomy), ileostomy, or colostomy.
Eligible subjects were approached by the principal investi-
gator or one of the coinvestigators within 12 hr of initiation of
antibiotics and asked if they were interested in participating in
the study. Patients affirming their interest were asked to sign
a statement of informed consent. All study subjects were told
prior to randomization about the association between antibiotics
and diarrhea, and that the purpose of the study was to determine
whether or not yogurt had any effect on this symptom. Subjects
were randomized to receive either yogurt or usual care without
yogurt supplementation. A block randomized design was used
for all treatment assignments. Within each block, six subjects
were randomized to one of two groups to ensure a balance in the
number of subjects assigned to receive yogurt and no treatment.
Randomization was stratified according to whether patients were
receiving C. difficile-treating antibiotics (eg, metronidazole or
vancomycin) or non-C. difficile-treating antibiotics. Treatment
assignment was not revealed to the patient until they agreed to
enrollment into the study.
The control group received no yogurt with their hospital
meals. The intervention group was given vanilla flavored yogurt,
227 g (8-oz container) twice daily for 8 days. Subjects discharged
prior to day 8, were given a supply of yogurt to take at home to
complete the full supplement of yogurt. Nutritional data, as pub-
lished by the manufacturer, indicates that vanilla-flavored yogurt
product contains 106 cultures/g of L. acidophilus, L. bulgaricus,
and S. thermophilus combined.
Each subject was followed for 8 days. While in the hospi-
tal, subjects were seen daily by a nutritionist and, with a stan-
dardized protocol, were asked about symptoms of abdominal
cramps, bloating, multiple bowel movements, or diarrhea. The
2078
BENIWAL ET AL
nutritionists assigned to respective medical floors conducted the
follow-up and recorded data. Patient reporting of diarrhea was
confirmed by the study team when possible by interviewing the
nurse assigned to the patient, except when patients were dis-
charged prior to hospital day 8, in which case follow-up was
done by telephone. The registered nurses assigned to each pa-
tient also assessed whether the yogurt as provided as consumed.
Subjects were considered compliant if at least half of each dose
of yogurt was consumed.
The primary outcome measure of the study was the occur-
rence of new onset of diarrhea, the definition of which was more
than two, less than formed bowel movements per day and which
represented a change from the patient’s prior bowel pattern, as
reported by the subject. A secondary outcome measure was the
occurrence of bloating and frequency of bowel movements (de-
fined as more than two well-formed stools per day). We did not
include testing for C. difficile. Based on sample size calculations,
200 subjects were required for adequate statistical power. From
the literature we expected diarrhea to occur in 22% of untreated
subjects. A study by Surawicz et al showed a decrease in AAD
from 22% to 9.5% in the treatment group with Saccharomyces
boulardii (22). Recruiting 200 subjects provided 82% power to
detect a decrease in the proportion of patients with diarrhea from
22.5% to 7.5% (a 67% relative risk reduction) assuming a two-
sided test with an alpha level of 0.05. The magnitude of this
reduction was based on a literature search (8, 22) and was con-
sidered to be clinically meaningful.
A database of the study information was maintained in
Microsoft Excel. All analyses were performed using Minitab (9)
and StatXact (10). Descriptive summaries and cross-tabulations
were examined for all patient characteristics and study outcomes
(ie, diarrhea, bloating, and frequency of bowel movements per
day). The proportions of subjects with diarrhea, bloating, and
frequency of bowel movements were compared between the two
groups with Fisher’s exact test. All treatment comparisons were
based on intention-to-treat analyses. Comparison of the num-
ber of days with diarrhea, bloating, and frequency of bowel
movements between the treatment groups was performed us-
ing the Mann-Whitney U test. Comparison of the mean duration
of a symptom (eg, diarrhea, bloating, and frequency of bowel
movements) among symptomatic patients between the treatment
groups was evaluated using Student’s t test. Kaplan-Meier plots
were constructed to examine the cumulative proportion of pa-
tients who were diarrhea-free over the course of 8 days. The
log rank test was used to compare the two curves, indicating a
diarrhea-free state, between the treatment and control group.
RESULTS
Patient Population. During a 9-month period, 210 sub-
jects were recruited into the trial. Eight subjects who
initially agreed to participate in the study subsequently
refused the administration of treatment and were not fol-
lowed further. Table 1 compares the baseline distribution
of demographic and clinical factors between the treatment
and the control groups. No clinically important differences
were identified. Table 2 summarizes the different classes
of antibiotics received by the subjects. The only differ-
ences were noted for the macrolide (prescribed 8% more
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YOGURT FOR DIARRHEA PREVENTION

TABLE 1. BASELINE CHARACTERISTICS bowel movements and bloating were no different between
Yogurt group Control group the two groups. Among subjects reporting diarrhea, the
duration was 31% shorter (P = 0.08) among subjects re-
Subjects [N (%)] 105 (52) 97 (48) ceiving yogurt (mean 1.8 ± 1.2 days) compared to con-
Male gender [N (%)] 51 (48.6) 36 (37.1)
Caucasian [N (%)] 91 (86.5) 82 (84.5) trols (mean 2.6 ± 1.6 days).
Mean age (yr, range) 69.5 (20–94) 70.5 (19–92) Figure 1 is a Kaplan-Meier plot of subjects who re-
Route of drug mained diarrhea-free according to treatment group. The
administration N (%)
Intravenous 70 (66.7) 64 (66.0) difference between the two curves is statistically signifi-
Per orum 27 (25.7) 24 (24.7) cant (P = 0.02). Eight-day diarrhea-free cumulative pro-
Intravenous and per orum [N (%)] 8 (7.6) 9 (9.3) portions were 0.74 (95% confidence interval 0.65–0.83)
Antibiotics [N (%)]
One 88 (83.8) 78 (80.4) for the control group and 0.87 (95% confidence interval
Two 17 (16.2) 19 (19.6) 0.80–0.94) for the intervention group.
Patient location [N (%)] Additional analyses were performed after classifying
General medicine floor 93 (88.6) 87 (89.7)
Critical care unit 12 (11.4) 10 (10.3) subjects into various subgroups. For diarrhea as the out-
come, subgroup analysis by gender, number of antibiotics
prescribed, route of antibiotic administration (intravenous,
often in the control group) and fluoroquinolones (pre- oral, or both), antibiotic class, and patient location (critical
scribed 12% less often in the control group). This pattern care versus general medicine floors) revealed no signifi-
was not the result of the intervention assignment, since the cant differences.
choice of antibiotic was made prior to enrollment into the
study. DISCUSSION
Effectiveness of Yogurt in Prevention of Antibiotic-
Associated Diarrhea. Compliance with active treatment There are anecdotal reports of favorable effects of
and follow-up among all subjects was 85% and 89%, re- commercially available yogurt with live active cultures
spectively. The mean follow-up was 7.5 days in the treat- on antibiotic-associated diarrhea (11, 12). However, a
ment group and 7.4 days in the control group. Subjects prospective randomized trial quantifying the preventive
were not followed beyond 8 days for subsequent occur- effects in acute care settings had not previously been done.
rence of diarrhea. The mean number of days of yogurt This randomized clinical trial of yogurt for the pre-
intake was 6.6 days. Subjects receiving yogurt did not re- vention of AAD in hospitalized patients receiving oral or
port any side effects or discomfort associated with the food intravenous antibiotics demonstrates that yogurt supple-
product. mentation effectively decreases the incidence and dura-
Table 3 summarizes the major end points of the study tion of antibiotic-associated diarrhea. Patients who were
by treatment group. Among subjects receiving yogurt, started on antibiotics after hospital admission and who did
13 (12.4%) of 105 developed diarrhea compared with 23 not have diarrhea, lactose intolerance, or a feeding tube,
(23.7%) of 97 subjects in the control group (P = 0.04). ileostomy, or colostomy at baseline were randomized to
Subjects in the control group reported having diarrhea for receive either usual care or usual care plus a supplement
a total of 60 days as compared to 23 days for the yogurt of 227 g of vanilla yogurt twice a day for 8 days. We
group. The incidence and days of increased frequency of used a single commercially available brand and flavor of
yogurt because the bioavailability of Lactobacillus may
vary among various brands (12). Yogurt decreased the risk
TABLE 2. ANTIBIOTIC CLASS RECEIVED
of developing AAD by nearly 50% (P = 0.04). The to-
N (%) tal number of diarrheal days was 60 in the control group
Antibiotic class Yogurt group Control group and 23 in the yogurt group. The incidence of AAD in
the control arm was 23.7%, which is in agreement with
Cephalosporin 39 (37.1) 43 (44.3)
Piperacillin/tazobactam 18 (17.1) 17 (17.5)
other reports of frequency of AAD (8). Based on our re-
and ampicillin/sulbactam sults, the absolute risk reduction implies that nine patients
Trimethoprim/sulfamethoxisole 2 (1.9) 1 (1.0) (95% confidence interval 4.1–132.6) need to be treated
Macrolide 11 (10.5) 18 (18.6)
Fluoroquinolones 45 (42.9) 30 (30.9)
with yogurt to prevent one case of antibiotic associated
Aminoglycosides 4 (3.8) 2 (2.1) diarrhea.
Tetracycline/doxycycline 2 (1.9) 0 Most of the study subjects were elderly (mean age
Metronidazole 0 1 (1.0)
Vancomycin 0 2 (2.1)
70 years), and since the incidence of AAD is higher
in the elderly, preventive therapy in this age group is

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BENIWAL ET AL

TABLE 3. SYMPTOM OUTCOMES

Yogurt group Control group P

Diarrhea: >2 loose bowel movements per day

Patients affected [N (%)] 13 (12.4) 23 (23.7) 0.04
Total number of days of diarrhea 23 60
Symptom duration (mean ± SD) among symptomatic patients 1.8 (±1.2) 2.6 (± 1.6) 0.08
Increased frequency of bowel movements (>2 well-formed stools per day):
Patients affected [N (%)] 2 (1.9) 5 (5.2) 0.26
Total number of days of frequent bowel movements 4 10
Symptom duration (mean ± SD) among symptomatic patients 2.0 (±1.4) 2.0 (±1.7) 1.0
Bloating:
Patients affected [N (%)] 6 (5.7) 8 (8.2) 0.58
Total number of days with bloating 8 18
Symptom duration (mean ± SD) among symptomatic patients 1.3 (±0.8) 2.2 (±1.0) 0.09

important. An added benefit of preventing AAD is in-
creased acceptability and compliance with antibiotic ther-
apy due to a decrease in one of the treatment’s major side
effects.
Our study was a logical extension of previously con-
ducted studies. Previous studies have reported the pre-
vention of AAD with the use of probiotics. A random-
ized trial of Bifidobacterium longum (BA) yogurt given
to healthy volunteers receiving oral erythromycin signif-
icantly decreased fecal weight, stool frequency, and ab-
dominal complaints as compared to subjects who received
erythromycin alone. BA yogurt also decreased the stool
clostridial spore count (13). In another trial Lactobacillus
acidophillus and L. bulgaricus together decreased the in-
cidence of diarrhea in patients receiving ampicillin. This
study showed that treating all patients on antibiotics would
not be cost-effective and suggested that yogurt might be
effective (11, 12).
Lactobacillus GG (LGG) has been used successfully to
prevent AAD in children (14). In a randomized, double-
blind clinical trial, 188 children between the ages of
6 months and 10 years on oral antibiotics were given
LGG (2 × 1010 colony-forming units) per day or placebo.
By the tenth day of treatment, the group receiving
LGG had significantly less diarrhea, lower stool fre-
quency, and improved stool consistency. Supplementation
of LGG has been shown to reduce the antibiotic-associated
gastrointestinal side-effects during Helicobacter pylori
eradication therapy and significantly improve treatment
tolerability (15)

Fig 1. Kaplan-Meier plot of the cumulative proportion of patients diarrhea-free through day 8.

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YOGURT FOR DIARRHEA PREVENTION
How might yogurt work to decrease the risk of AAD?
Although the exact mechanism is not clear, one possi-
ble explanation is that yogurt may maintain the normal
intestinal microflora that is otherwise reduced by antibi-
otics. Lidbeck et. al measured the impact of Lactobacil-
lus acidophilus on the normal intestinal microflora after
suppression with two antimicrobial agents in 20 healthy
volunteers and demonstrated partial restoration of intesti-
nal microflora due to reestablishment of Lactobacillus,
enterococci, and bacteroides. Another possible mecha-
nism may be through enhancement of the host immune
response. Lactobacillus strains have been shown to in-
crease the secretion of IgA and certain antiinflammatory
cytokines and to promote the gut immunological barrier
in animal models (16, 17).
Clinical trials have also indicated the potential effect of
probiotic bacteria in chronic inflammatory bowel disease
(18–20). Whether commercial yogurt or another probiotic
preparation might have a salutary role in other settings,
such as the treatment of acute or chronic inflammatory
bowel disease, requires further study (21).
A nonpathogenic yeast, Saccharomyces boulardii, has
been shown to prevent AAD in hospitalized patients in
a randomized, double-blind trial, in which 22% of pa-
tients receiving placebo reported diarrhea as compared
with 9.5% of patients receiving S. boulardii (P = 0.038)
(22). The mechanism of this prophylactic effect is not
known. The role of C. difficile in AAD has been previ-
ously evaluated and no significant association was found
between the presence of C. difficile or cytotoxin and AAD.
Approximately 33% of patients without diarrhea had one
or more C. difficile-positive stools and nearly 50% of these
patients had detectable cytotoxin (22). In a limited num-
ber of patients with diarrhea (N = 25), 33% had one or
more C. difficile-positive stool and 37% of these patients
had detectable cytotoxin.
In addition to the prevention of AAD, probiotics, in-
cluding LGG have been used successfully to treat more
severe forms of AAD such as recurrent C. difficile colitis
in children (23) and adults (24). Early results from a ran-
domized placebo-controlled trial of LGG in combination
with standard antibiotics for the treatment of C. difficile
infection suggest that LGG is effective in reducing the
3-week recurrence rate of C. difficile diarrhea and in pro-
ducing symptomatic improvement (25).
The limitations of this trial deserve comment. This study
was not double-blinded; due to the nature of the inter-
vention. However, patient responses were elicited in a
standardized fashion by certified dieticians, which may
mitigate the effect of the lack of blinding. Ideally, incor-
porating a treatment arm consisting of yogurt without ac-
tive culture would have strengthened the study. Due to
Digestive Diseases and Sciences, Vol. 48, No. 10 (October 2003)
financial and logistical constraints, this was not possible.
However, in a systematic review of 130 trials (26, 27),
primarily looking at the clinical effects of a placebo as a
treatment, no significant effects of placebo were observed
with the exception of subjective continuous outcomes and
for treatment of pain. Surprisingly, the clinical effects of
placebo were unrelated to blinding and no association
was found between measures of trial quality and placebo
effect.
Testing of stools for C. difficile (toxin or culture) was
not performed, as the main objective of the study was to
determine the effectiveness of yogurt in the prevention of
AAD, and C. difficile infection accounts for only 10–20%
of the cases of AAD (27). In other studies, no association
has been found between AAD and C. difficile (toxin or cul-
tures) in the stool (22). Further studies are required to de-
termine whether yogurt can prevent C. difficile-associated
diarrhea.
During the course of antibiotic therapy, supplementa-
tion with commercially available yogurt that contains ac-
tive cultures is a simple, safe, and cost-effective method
of reducing the occurrence and severity of AAD. Further
study of this preventive treatment is required to delineate
the beneficial effects in more detail, particularly in antibi-
otic and patient subgroups, and to elucidate the mechanism
of yogurt’s protective effects.
ACKNOWLEDGMENTS
We are grateful to and thank Jackie Catapano, MEd,
RD; Karen Stervick, RD; Kim Cenci, RD; and Patrick
Krydick, DTR, for their assistance in data collection. We
sincerely appreciate the support of the nursing, infectious
disease and pharmacy staff, UPMC-McKeesport Hospital.
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