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Dose-Response Efficacy of a Proprietary Probiotic Formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for Antibiotic-Associated Diarrhea and Clostridium difficile-Associated Diarrhea Prophylaxis in Adult Patients


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Standard therapies for antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) have limited efficacy. Probiotic prophylaxis is a promising alternative for reduction of AAD and CDAD incidence. In this single-center, randomized, double-blind, placebo-controlled dose-ranging study, we randomized 255 adult inpatients to one of three groups: two probiotic capsules per day (Pro-2, n=86), one probiotic capsule and one placebo capsule per day (Pro-1, n=85), or two placebo capsules per day (n=84). Each probiotic capsule contained 50 billion c.f.u. of live organisms (Lactobacillus acidophilus CL1285 +Lactobacillus casei LBC80R Bio-K+ CL1285). Probiotic prophylaxis began within 36 h of initial antibiotic administration, continued for 5 days after the last antibiotic dose, and patients were followed for an additional 21 days. Pro-2 (15.5%) had a lower AAD incidence vs. Pro-1 (28.2%). Each probiotic group had a lower AAD incidence vs. placebo (44.1%). In patients who acquired AAD, Pro-2 (2.8 days) and Pro-1 (4.1 days) had shorter symptom duration vs. placebo (6.4 days). Similarly, Pro-2 (1.2%) had a lower CDAD incidence vs. Pro-1 (9.4%). Each treatment group had a lower CDAD incidence vs. placebo (23.8%). Gastrointestinal symptoms were less common in the treatment groups vs. placebo and in Pro-2 vs. Pro-1. The proprietary probiotic blend used in this study was well tolerated and effective for reducing risk of AAD and, in particular, CDAD in hospitalized patients on antibiotics. A dose-ranging effect was shown with 100 billion c.f.u., yielding superior outcomes and fewer gastrointestinal events compared to 50 billion c.f.u. ( number NCT00958308).
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The American Journal of GASTROENTEROLOGY VOLUME 105 | JULY 2010
ORIGINAL CONTRIBUTIONS nature publishing group
Antibiotic-associated diarrhea (AAD) is a common complica-
tion that occurs in 5 25 % of adult patients, depending on the
type of antibiotic that is administered ( 1 ). Although mild cases
are o en treated with conservative measures, AAD may progress
in severity to result in colitis, dehydration, electrolyte distur-
bance, bowel perforation, and megacolon. A common cause of
AAD is infection with the bacterium Clostridium di cile . In fact,
most AAD cases that result in colitis are caused by C. di cile ( 2 ).
is condition, commonly referred to as C. di cile -associated
diarrhea (CDAD), has progressively increased in incidence and
severity over the last decade, largely due to the common use of
broad-spectrum antibiotics ( 3 ). CDAD is a major public health
concern and accounts for signi cant morbidity and mortality,
extended hospitalization, and greater health-care expenses, espe-
cially in patients with recurring episodes and in the elderly ( 4 7 ).
Current standard prevention treatments for AAD and CDAD
have limitations ( 8 ). Mild cases are typically treated with discontinu-
ation of the o ending antibiotic and with dietary changes. However,
severe cases o en require bed rest, intravenous  uids, and additional
Dose Response Effi cacy of a Proprietary Probiotic
Formula of Lactobacillus acidophilus CL1285 and
Lactobacillus casei LBC80R for Antibiotic-Associated
Diarrhea and Clostridium diffi cile -Associated Diarrhea
Prophylaxis in Adult Patients
Xing Wang Gao , MD
1 , Mohamed Mubasher , PhD
2 , Chong Yu Fang , MD
1 , Cheryl Reifer , PhD
2 and Larry E. Miller , PhD
OBJECTIVES: Standard therapies for antibiotic-associated diarrhea (AAD) and Clostridium diffi cile -associated
diarrhea (CDAD) have limited effi cacy. Probiotic prophylaxis is a promising alternative for reduction
of AAD and CDAD incidence.
METHODS: In this single-center, randomized, double-blind, placebo-controlled dose-ranging study, we randomized
255 adult inpatients to one of three groups: two probiotic capsules per day (Pro-2, n = 86), one
probiotic capsule and one placebo capsule per day (Pro-1, n = 85), or two placebo capsules per day
( n = 84). Each probiotic capsule contained 50 billion c.f.u. of live organisms ( Lactobacillus acidophilus
CL1285® + Lactobacillus casei LBC80R® Bio-K + CL1285). Probiotic prophylaxis began within 36 h
of initial antibiotic administration, continued for 5 days after the last antibiotic dose, and patients were
followed for an additional 21 days.
RESULTS: Pro-2 (15.5 % ) had a lower AAD incidence vs. Pro-1 (28.2 % ). Each probiotic group had a lower AAD
incidence vs. placebo (44.1 % ). In patients who acquired AAD, Pro-2 (2.8 days) and Pro-1 (4.1 days) had
shorter symptom duration vs. placebo (6.4 days). Similarly, Pro-2 (1.2 % ) had a lower CDAD incidence vs.
Pro-1 (9.4 % ). Each treatment group had a lower CDAD incidence vs. placebo (23.8 % ). Gastrointestinal
symptoms were less common in the treatment groups vs. placebo and in Pro-2 vs. Pro-1.
CONCLUSIONS: The proprietary probiotic blend used in this study was well tolerated and effective for reducing risk
of AAD and, in particular, CDAD in hospitalized patients on antibiotics. A dose-ranging effect was
shown with 100 billion c.f.u., yielding superior outcomes and fewer gastrointestinal events compared
to 50 billion c.f.u. ( number NCT00958308).
Am J Gastroenterol 2010; 105:1636–1641; doi: 10.1038/ajg.2010.11; published online 9 February 2010
1 Department of Gastroenterology, Xinhua / Yuyao Hospital , Shanghai , China ;
2 Sprim Advanced Life Sciences , San Francisco , California , USA . Correspondence: Larry E. Miller,
PhD , Sprim Advanced Life Sciences , 235 Pine Street, Suite 1175, San Francisco , California 94104 , USA . E-mail:
Received 25 September 2009; accepted 23 November 2009
© 2010 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
1637 Probiotics for AAD and CDAD
antibiotics such as metronidazole or vancomycin. Unfortunately,
almost one in four patients treated with antibiotics for CDAD will
relapse within 2 months and over half of patients with two or more
previous episodes will relapse ( 7 ). Furthermore, signi cant morbid-
ity and expense are associated with continued antibiotic use.  ere
is an obvious need for new AAD and CDAD prevention treatments
that are safer and more e ective than the current options.
Probiotics are a promising therapy that may prevent AAD and
CDAD as well as reduce mortality, morbidity, and health-care
costs ( 9 11 ). Probiotic bacteria enhance the host  ora by stimulat-
ing immune function and suppressing pathogenic bacteria colo-
nization ( 12 ). Several meta-analyses have concluded that various
strains of probiotics can decrease AAD and CDAD incidence
in adults ( 13 15 ). However, many of the trials on this topic are
plagued by methodological  aws such as lack of power, limited
sample size, and lack of dose-ranging outcomes.
e current randomized, double-blind, controlled study represents
the largest trial of probiotic therapy for AAD and CDAD prevention
to date. Furthermore, this is the  rst trial to examine dose-ranging
outcomes with this promising therapy. We tested two hypotheses in
this trial. First, would probiotic prophylaxis lower the incidence of
AAD and CDAD in hospitalized adults receiving antibiotic therapy?
Second, would this e ect occur in a dose-dependent manner?
is single center, three-arm, randomized, double-blind, pla-
cebo-controlled dose-ranging study was conducted at the
Xinhua / Yuyao Hospital (Shanghai, China), which is a liated
with Shanghai Jiao Tong University School of Medicine (Shanghai,
China). All research procedures performed in this trial were in
strict accordance with a prede ned protocol that was approved
by all researchers and the local ethics committee.  e ethics com-
mittee approved the study protocol on 8 October 2008 and par-
ticipants gave informed consent before participation.  is study
is registered under number NCT00958308.  e
CONSORT statement for randomized trials served as a template
for reporting this clinical study ( 16 ).
Eligible patients were hospitalized for various types of infections
and received antibiotic therapy with penicillin, cephalosporin, or
clindamycin. Inclusion criteria were age 50 to 70 years, hospitaliza-
tion of 5 or more days, and antibiotic therapy of at least 3 days but
no more than 14 days. Exclusion criteria were use of other probiotic
products, active diarrhea, noncontrolled intestinal disease, docu-
mented C. di cile infection within the 3 months before enrollment,
immunosuppressive therapy, antibiotic use within 30 days of enroll-
ment, or active participation in another clinical study.
Study products were made available, formulated, and produced by
Bio-K + International (Laval, Quebec, Canada). e product was
stored at 4 ° C in a secure area until dispensed and administered
by the assigned clinical sta . Patients were randomized into one
of the three study groups: two probiotic capsules per day (Pro-2,
n = 86), one probiotic capsule and one placebo capsule per day
(Pro-1, n = 85), or two placebo capsules per day ( n = 84). Each
commercially available probiotic capsule contained 50 billion
c.f.u. ( Lactobacillus acidophilus CL1285® + Lactobacillus casei
LBC80R® ).
Patients received the initial dose of the assigned intervention
within 36 h of their prescribed antibiotic therapy, and continued daily
usage of the product for 5 additional days a er completion of their
anti biotics. Patients were then followed for an additional 21 days a er
completion of the assigned intervention. Patients took their daily dose
2 h a er breakfast and antibiotic administration each day.
Standard baseline assessments included a complete physical
examination, medical history, blood pressure, and body mass
index. If diarrhea occurred while hospitalized, patients provided
a stool sample for C. di cile analysis of Toxin A and / or B. All epi-
sodes were recorded by a nurse or designated clinician on a case
report form using the seven-item Bristol Stool Form Scale ( 17 ). A
diarrhea episode was de ned as a bowel movement consisting of
watery stool with or without solids. Diagnosis of AAD was made
when a patient produced three or more liquid stools in a 24-h
period a er antibiotic treatment with no other obvious reason for
diarrhea. Duration of diarrhea was determined by number of con-
tinuous days of diarrhea. Average number of liquid stools per day
was determined by the sum of the number of liquid stools per day
in the AAD episode divided by the duration of diarrhea in days.
e stool from patients presenting with two or more liquid
stools was tested for C. di cile by a triage panel and the cytotoxin
cell culture assay, performed on all specimens tested by triage,
which were antigen positive and Toxin A negative. Furthermore,
all stools were tested for C. di cile for the second diarrhea episode
and considered C. di cile positive when it was antigen and Toxin
A and / or B positive.
Episodes of AAD and gastrointestinal disorders during hospi-
talization were recorded by patient interview and were con rmed
by review of patient diaries. Posthospitalization episodes were
recorded in patient diaries and con rmed by patient interview.
Sample size
e sample size of this trial ( n = 255, 85 per group) provided a
minimum statistical power of 86 % to detect a signi cant dose
response relationship and to allow for a maximum 12 % dropout
rate in each group.
e randomization sequence used in this trial was generated by a
computerized random-number generator (SAS, release 9.2; SAS
Institute, Cary, NC) using a permuted block design that rand-
omized among the three study groups while stratifying for age
(50 59 vs. 60 70 years) and number of days on antibiotics (3 8
and 9 14 days). Study products were delivered to the investigative
site in identical containers labeled only with the lot number and a
sequentially numbered patient identi cation code.
The American Journal of GASTROENTEROLOGY VOLUME 105 | JULY 2010
1638 Gao et al.
is study was conducted using triple-blinding procedures. First,
patients were blinded to the treatment received throughout the
trial. Each patient received two pills each day, which were identi-
cal in shape, size, taste, smell, and color regardless of the assigned
treatment group. Second, investigators and all involved clinicians
were blinded to the treatment allocation throughout the course
of the study. Finally, all study coordinators, clinical monitors, and
biostatisticians were blinded to treatment allocation throughout
the entire clinical study and until a er all analyses were completed.
is methodology is the most e ective and stringent design to
minimize study bias.
Statistical methods
All data were recorded on case report forms, double-entered,
veri ed, and independently monitored for accuracy by Sprim
Advanced Life Sciences (San Francisco, CA). All analyses were
performed according to the intention-to-treat principle, i.e., out-
come measures were based on the original denominator of 255
patients and each patient analyzed according to original treat-
ment assignment. Continuous variables, e.g. days with AAD, are
reported as mean ± s.d. Categorical variables, e.g. incidence of
AAD, are presented as n ( % ). Further group comparisons were
assessed with χ 2 -test or Fisher s exact test. No adjustments were
made for multiplicity. Statistical analyses were performed using
SAS / STAT so ware (release 9.2; SAS Institute).
Of the 1120 patients who were eligible to participate in the study,
865 were excluded from participation ( Figure 1 ). e remaining
255 patients were enrolled in the trial between January 2009 and
March 2009. Nineteen (7.5 % ) patients did not complete the study
(Pro-2, n = 4; Pro-1, n = 7; placebo, n = 8). All failures to com-
plete the study were due to personal reasons and not related to
the study.  ese patients still returned for regular follow-up visits
and none experienced an episode of AAD or CDAD.  ere was
full concordance with the study treatment by the remaining 236
patients. All patients were of Asian ethnicity. No major di erences
were observed in baseline characteristics among the three study
groups ( Table 1 ).
A distinct dose response relationship was observed as higher
probiotic dosage resulted in a lower incidence of AAD ( Figure 2 ).
Furthermore, both probiotic dosages were more e ective in reduc-
ing AAD vs. the placebo group. Similar relative bene ts were
observed across the three treatment groups regardless of age and
antibiotic time course strata ( Tabl e 2 ).
Patients treated with probiotics reported fewer ( P < 0.001) days
with continuous AAD vs. the placebo group ( Ta b l e 3 ). e dura-
tion of AAD symptoms in the Pro-2 group was 32 % shorter com-
pared to the Pro-1 group. Similar relative improvements were
observed across age and antibiotic time course strata.
A dose response relationship was also observed regarding the
incidence of CDAD, which lowered with higher probiotic dos-
ages ( Figure 3 ). In the placebo group, 23.8 % (20 / 84) of patients
were positive for CDAD. In comparison, only 9.4 % (8 / 85) of Pro-1
patients ( P = 0.03 vs. placebo) and 1.2 % (1 / 86) of Pro-2 patients
( P = 0.002 vs. placebo) were positive for CDAD. Furthermore,
fewer Pro-2 patients ( P = 0.04) were CDAD positive vs. Pro-1
patients. Similar relative bene ts were observed across the three
treatment groups regardless of age and antibiotic time course
strata ( Table 2 ).
Table 1 . Baseline patient characteristics
Characteristic Group
Placebo ( n = 84) Pro-1 ( n = 85) Pro-2 ( n = 86)
Age (years) 60 ± 6 60 ± 6 60 ± 6
Sex (no. ( % ))
Male 42 (50) 43 (51) 46 (54)
Female 42 (50) 42 (49) 40 (46)
Days on antibiotic
(mean ± s.d.)
8.4 ± 3.2 8.4 ± 3.3 8.2 ± 3.6
Comorbidities (no. ( % ))
COPD 23 (27) 18 (21) 14 (16)
Chronic bronchitis 12 (14) 13 (15) 14 (16)
Hypertension 5 (6) 14 (17) 10 (12)
Diabetes mellitus 6 (7) 8 (9) 12 (14)
Heart disease 6 (7) 12 (14) 7 (8)
Tracheitis 6 (7) 6 (7) 8 (9)
Digestive ulcer 1 (1) 4 (5) 1 (1)
Pneumonia 0 1 (1) 2 (2)
Gastritis 0 0 1 (1)
Type of administered antibiotic (no. ( % ))
Cephalosporins 35 (42) 35 (41) 28 (33)
Penicillins 26 (31) 19 (22) 30 (35)
Lyncomycin 23 (27) 31 (36) 28 (33)
COPD, chronic obstructive pulmonary disease.
All P values were > 0.05.
Figure 1 . CONSORT patient fl ow diagram. Pro-1, one capsule of probiotics;
Pro-2, two capsules of probiotics.
Assessed for eligibility
Excluded for inclusion/exclusion
violations (n=744)
Refused to participate (n=121)
Randomized (n=255)
Pro-2 (n=86)
Discontinued (n=4) Discontinued (n=7) Discontinued (n=8)
Analyzed (n=84)Analyzed (n=85)Analyzed (n=86)
Pro-1 (n=85) Placebo (n=84)
© 2010 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
1639 Probiotics for AAD and CDAD
e incidence of abdominal pain, abdominal distension, loose
stool, and constipation during the trial was lower ( P < 0.05) with
higher dosages of probiotic therapy. Speci cally, the incidences
in the placebo, Pro-1, and Pro-2 groups were 40.5 % , 24.7 % , and
12.8 % for abdominal pain; 35.7 % , 21.2 % , and 9.3 % for abdominal
distension; 58.3 % , 44.7 % , and 31.4 % for loose stool; and 14.3 % ,
11.8 % , and 8.1 % for constipation.
ree (1.2 % ) patients reported a nonserious adverse event dur-
ing the study. Two adverse events occurred in the placebo group
(fever and hematochezia) and one occurred in the Pro-2 group
(fever). None of the adverse events were deemed study related.
is randomized, double-blind, controlled dose-ranging study
showed a signi cantly lower incidence of AAD and, in particu-
lar, CDAD for both probiotic treatment groups compared to the
placebo group. Furthermore, a distinct dose response e ect was
observed with higher probiotic dosages resulting in greater e -
cacy, shorter time with continuous AAD, and fewer gastrointes-
tinal symptoms.
e results of this study compare favorably with similar
trials. Plummer et al. ( 18 ) reported that patients taking a probiotic
containing Lactobacillus and Bi dobacterium had a 2.9 % CDAD
incidence vs. 7.3 % in a placebo group. Hickson et al. ( 19 ) studied
135 patients randomized to either probiotics ( L. casei , L. bulgari-
cus , and Streptococcus thermophilus formula) or placebo. Patients
treated with probiotics had a lower incidence of AAD (12 % vs.
34 % ) and CDAD (0 % vs. 17 % ) and reported no side e ects.  is
study included patients who were prescribed with cephalosporin,
penicillin, and clindamycin, the so-called high-risk antibiotics,
which were excluded in the Hickson study.  erefore, this study
shows the e cacy of the Lactobacilli formula in the prevention of
CDAD even when the most o ending antibiotics are used. Fur-
thermore, neither the Plummer nor the Hickson trial reported out-
comes with multiple probiotic dosages.
Although meta-analytic techniques have suggested that higher
probiotic dosages may be associated with better outcomes ( 20 ),
this is the  rst clinical study to show this  nding. In light of the
dose response relationship shown in this study, we propose that
positive patient outcomes may be partly due to the high probiotic
dosage (50 100 billion c.f.u. per day) compared to other similar
trials (mean, 3 billion c.f.u. per day) ( 14 ). Although the mecha-
nism of action has not been fully elucidated, the probiotic load of
this quantity likely overwhelms the intestinal tract and repopulates
the gut with nonpathogenic  ora, as well as enhances immune
response to inhibit or destroy pathogenic bacteria ( 20 ).
Preventative probiotic therapy may be especially appealing for
older patients and for patients on prolonged antibiotic adminis-
tration. For example, 62 % of patients in the placebo group, in the
60 70 year stratum, and the 9 14 days antibiotic length stratum
acquired AAD. In comparison, Pro-2 patients in the same strata
had only a 24 % AAD incidence. Relative risk reductions of 62 68 %
were observed with Pro-2 vs. placebo across all strata. Given that 61
AAD cases occur per 100,000 population with greater incidence in
the elderly ( 21 ), we found that probiotic administration has poten-
tial to prevent approximately 4 million AAD cases worldwide each
year. It has also been suggested that probiotic administration may
reduce hospital costs associated with CDAD by 50 % vs. standard
therapies ( 18 ). With a 23 % lower absolute risk of CDAD with Pro-2,
the number needed to treat to prevent one case of CDAD is only
ve patients. Overall, probiotic therapy is a particularly appealing
therapy due to its e cacy, safety, and potential for cost savings. In
contrast, the current standard of care for CDAD antibiotic treat-
ment with metronidazole or vancomycin has distinct limitations.
Table 2 . AAD and CDAD incidence by age and antibiotic time course
Placebo ( n = 84) Pro-1 ( n = 85) Pro-2 ( n = 86)
Age (years) ; antibiotic
time course (days)
incidence ( % )
incidence ( % )
incidence ( % )
incidence ( % )
incidence ( % )
incidence ( % )
50 59; 3 8 28.6 19.1 23.8 9.5 9.1 0
50 – 59; 9 14 42.9 23.8 27.3 9.1 14.3 0
60 70; 3 – 8 42.9 23.8 28.6 9.5 13.6 0
60 70; 9 14 61.9
28.6 33.3 9.5 23.8 4.8
AAD, antibiotic-associated diarrhea; CDAD, Clostridium diffi cile -associated diarrhea; Pro-1, one capsule of probiotics; Pro-2, two capsules of probiotics.
Figure 2 . Antibiotic-associated diarrhea incidence by study group. AAD,
antibiotic-associated diarrhea; Pro-1, one capsule of probiotics; Pro-2, two
capsules of probiotics.
AAD incidence (%)
Placebo Pro-1 Pro-2
The American Journal of GASTROENTEROLOGY VOLUME 105 | JULY 2010
1640 Gao et al.
e evidence for probiotic prophylaxis in AAD and CDAD
has been hindered by trials with inconsistent study outcomes,
especially in adult patients, small sample sizes, and poor study
quality ( 13 – 15,20,26 ). is clinical study di ers from previous
trials of probiotic therapy on AAD and CDAD in several ways.
First, this study is the largest randomized controlled trial of pro-
biotic therapy for AAD and CDAD to date. Second, this study
is the  rst to report greater e cacy with higher probiotic dose.
Finally, this trial used very stringent data collection and data
analysis methods including triple blinding, double data entry
with veri cation, independent data monitoring, and an intent-
to-treat analysis. Overall, we believe that this study represents
the highest quality trial of probiotic prophylaxis for AAD and
CDAD in adults.
e proprietary probiotic blend of Lactobacillus acidophilus
CL1285® + Lactobacillus casei LBC80R® (Bio-K + CL1285) studied
in this clinical trial was e ective in reducing risk of AAD and,
in particular, CDAD and was well tolerated in hospitalized adult
patients on antibiotic therapy. A dose-ranging e ect was shown
with 100 billion c.f.u. yielding superior outcomes and fewer gas-
trointestinal conditions compared to 50 billion c.f.u.
We thank Charlie Zhang, MD, and Kelly Zhang, RN, of Sprim
Advanced Life Sciences for their help with study conduct and data
Guarantor of the article: Xing Wang Gao, MD.
Speci c author contributions: Planning study: Xing Wang Gao,
Mohamed Mubasher, Chong Yu Fang, and Cheryl Reifer;
conducting study: Xing Wang Gao, Chong Yu Fang, and Cheryl Reifer;
collecting data: Xing Wang Gao and Chong Yu Fang; interpreting
data: Xing Wang Gao, Mohamed Mubasher, and Larry E. Miller;
dra ing paper: Xing Wang Gao, Mohamed Mubasher, Cheryl Reifer,
and Larry E. Miller; approval of submitted  nal dra : Xing Wang Gao,
Mohamed Mubasher, Chong Yu Fang, Cheryl Reifer, and
Larry E. Miller.
Financial support: Bio-K + International (Laval, Quebec, Canada)
provided  nancial support for this clinical trial. Sprim Advanced
Life Sciences helped with study planning, conduct, and analysis and
with paper development.
Potential competing interests: N o n e .
Study Highlights
3 Antibiotic-associated diarrhea and Clostridium diffi cile -
associated diarrhea are common in hospitalized adults.
3 Current treatments have limited effectiveness.
3 Probiotic prophylaxis lowers risk for antibiotic-associated
diarrhea and, in particular, Clostridium diffi cile -associated
3 Probiotic effi cacy improves in a dose-dependent manner.
Metronidazole is inexpensive but has marginal e cacy whereas
vancomycin is more e ective but is very expensive ( 7,22 ). Further-
more, AAD and CDAD o en recur a er treatment with either of
these therapies and their continued use compounds the growing
worldwide problem of antibiotic resistance ( 23,24 ). Overall, there
is growing evidence to support the use of probiotics over antibiot-
ics for prevention of AAD and CDAD.
is study had several limitations worth mention. First, the
present results are speci c to the product studied and cannot be
generalized to other probiotic products ( 25 ). Second, although
AAD and CDAD o en begin between 4 and 9 days a er antibiotic
use is stopped, they can occur up to 8 weeks later.  erefore, it is
plausible that some late cases of AAD and CDAD were missed.
ird, we enrolled only patients aged 50 70 years in this study,
which may limit applicability to younger patients. However, we feel
that this is a minor limitation because AAD / CDAD is most com-
mon in older patients and because probiotics have been success-
fully used for these conditions in patients of all ages ( 14 ). Fourth,
the length of antibiotic therapy in this study was between 3 and 14
days.  erefore, the e ects of probiotic administration on AAD /
CDAD with prolonged antibiotic treatment are unknown. Finally,
patients in this study were solely of Asian descent.  erefore, cau-
tion must be exercised when applying these study outcomes to
patients of other ethnic origins.
Table 3 . Duration of AAD symptoms by age and antibiotic time course
Age (years) ; antibiotic
time course (days)
( n = 37 / 84)
( n = 24 / 85)
( n =13 / 86)
Total patients 6.4 ± 1.8 4.1 ± 1.5* 2.8 ± 0.8*
50 59; 3 8 4.3 ± 0.8 2.2 ± 0.8 1.5 ± 0.7
50 – 59; 9 14 5.2 ± 0.7 3.7 ± 0.5 2.7 ± 0.6
60 70; 3 8 6.1 ± 1.1 4.5 ± 1.1 2.7 ± 0.6
60 70; 9 14 8.2 ± 1.0 5.6 ± 1.0 3.4 ± 0.6
Mean ± s.d. calculated in patients diagnosed with antibiotic-associated diarrhea.
Pro-1, one capsule of probiotics; Pro-2, two capsules of probiotics.
* P < 0.001 vs. placebo;
P = 0.04 vs. Pro-1.
Figure 3 . Clostridium diffi cile -associated diarrhea incidence by study
group. CDAD, C. diffi cile -associated diarrhea; Pro-1, one capsule of
probiotics; Pro-2, two capsules of probiotics.
Placebo Pro-1 Pro-2
CDAD Incidence (%)
© 2010 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
1641 Probiotics for AAD and CDAD
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... A study done by McFarland [32] and Gao has revealed that Bio-K+ was also found to prevent CDI. In Gao's study [33] , 255 adult inpatients receiving antibiotics at a hospital took part in a randomized clinical trial. The probiotic capsules given contained 50 billion CFU of L. acidophilus CL1285 ® + L. casei LBC80R ® Bio-K+ CL1285). ...
... Its greatest efficacy on different patients' conditions as well as their safety and limitations are also essential to be studied in future research. [9] Antibiotic-associated diarrhea As a treatment: L. rhamnosus GG and S. boulardii CNCM I-745 [20] For prevention: Mixture of L. acidophilus CL1285, L. casei LBC80R and L. rhamnosus CLR [20] Traveler's diarrhea For prevention: S. boulardii CNCM I-745 [16,24] Acute infectious diarrhea As a treatment: L. rhamnosus GG, S. boulardii CNCM I-745 [20] Clostridioides difficile infection For prevention: Mixture containing L.acidophilus CL1285, L.casei LBC80R and L. rhamnosus CLR2 [32,33] Irritable bowel syndrome As a treatment: Bifidobacterium infantis 35624 [37] , E. coli (DSM 17252) [39,39] , L. plantarum 299v [40] Helicobacter pylori infection As a treatment: (higher successful rate of eradication with probiotics supplementation to the standard eradication regime): L. reuteri [40] , S. boulardii CNCM I-745 [47] ...
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Gastrointestinal (GI) health is important because a healthy gut can maintain our general health and protect our body from infection or illness. Apart from vitamins and minerals, probiotics, prebiotics, and synbiotics have become increasingly famous as a supplement in our daily diet. Previously, a large number of studies had been performed to study the efficacy of probiotics in the prevention or treatment of illnesses. The purpose of our review is to discuss recent data on the benefits of probiotics in human's GI health. Promising results on the effect of probiotics in the treatment of inflammatory bowel disease, particularly ulcerative colitis and pouchitis have been obtained from studies. Other reports also showed that a few probiotics can improve symptoms in irritable bowel syndrome. Saccharomyces boulardii was shown to prevent traveler's diarrhea but further studies are needed for firm conclusions. Lactobaccilus rhamnosus and S. boulardii are recommended in the treatment of acute infectious diarrhea. There are promising indications that probiotics could be useful in the prevention or treatment of antibiotic-associated diarrhea, and a Lactobacillus-containing combination has been shown to prevent diarrhea caused by Clostridioides difficile. Addition of probiotics to current Helicobacter pylori eradication regime can further increase the eradication rate.
... Bio-K Plus International Inc. (Bio-K +) is specialized in the development and manufacturing of a lactobacilli-based probiotic formulation, combining the Lactobacillus acidophilus CL1285, Lacticaseibacillus (Lactobacillus) casei LBC80R, and Lacticaseibacillus (Lactobacillus) rhamnosus CLR2 strains. This formulation has previously showed to significantly reduce the incidence of antibiotic-associated diarrhea and Clostridioides (Clostridium) difficile infections and improve the quality of life in people with diarrhea-predominant irritable bowel syndrome [32][33][34][35][36]. In this study, a Bio-K + proprietary collection of Lactobacillaceae has been screened using a multi-mechanism approach, targeting BSH and FAE activities, to select bacterial candidates with the potential to manage and reduce cholesterol levels in humans. ...
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Dyslipidemia, specifically abnormal levels of low-density lipoprotein cholesterol (LDL-C), is an important risk factor of cardiovascular disease. Evidence showing the promising abilities of probiotics to lower total cholesterol or LDL-C has, however, not yet convinced experts to recommend probiotic bacteria as treatment for blood lipid management. Therefore, there are opportunities for the development of new efficient cholesterol-lowering probiotics. Bile salt hydrolase (BSH) and feruloyl esterase (FAE) are bacterial enzymes proposed to explain the cholesterol-lowering capacity of some bacteria and have both been shown to be responsible for lipid reduction in vivo. Here, in order to select for cholesterol-lowering bacteria, 70 strains related to Lactobacillaceae were screened for BSH and FAE activities. Based on this two-way screening approach, two bacteria were selected and assessed for their capacity to assimilate cholesterol in vitro, another suggested mechanism. Lactobacillus acidophilus CL1285 showed BSH and FAE activity as well as capacity to assimilate cholesterol in vitro. Lactiplantibacillus plantarum CHOL-200 exhibited BSH activity and ability to assimilate cholesterol. These properties observed in vitro make both strains good probiotic candidates for the management of dyslipidemia. Further investigation is needed to assess their ability to reduce blood cholesterol in human trial.
... Probiotic blend effective in lowering CDAD incidence in patients treated with probiotics vs. placebo. (Gao et al. 2010;Beausoleil et al. 2007) Probiotic formulation composed of L. acidophilus CL1285, L. casei LBC80R, and L. rhamnosus CLR2 ...
Clostridioides difficile infection (CDI) is a life-threatening disease caused by the Gram-positive, opportunistic intestinal pathogen C. difficile. Despite the availability of antimicrobial drugs to treat CDI, such as vancomycin, metronidazole, and fidaxomicin, recurrence of infection remains a significant clinical challenge. The use of live commensal microorganisms, or probiotics, is one of the most investigated non-antibiotic therapeutic options to balance gastrointestinal (GI) microbiota and subsequently tackle dysbiosis. In this review, we will discuss major commensal probiotic strains that have the potential to prevent and/or treat CDI and its recurrence, reassess the efficacy of probiotics supplementation as a CDI intervention, delve into lessons learned from probiotic modulation of the immune system, explore avenues like genome-scale metabolic network reconstructions, genome sequencing, and multi-omics to identify novel strains and understand their functionality, and discuss the current regulatory framework, challenges, and future directions.
... Probiotics display a well-documented activity in the prevention of health problems, including digestive disorders such as constipation, infection-induced diarrhoea, antibioticinduced diarrhoea, irritable bowel syndrome, diarrhoea caused by Clostridioides difficile in adults and children, ulcerative colitis, Crohn's disease, colorectal cancer, as well as allergic disorders such as atopic dermatitis (eczema) or allergic rhinitis [20,36,38,42,51] (Table 3). Phase 3 of clinical research has proved the effectiveness of probiotics containing Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R strains in preventing and shortening the duration of antibiotic-induced diarrhoea and infection with C. difficile [52]. ...
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The proper functioning of the human organism is dependent on a number of factors. The health condition of the organism can be often enhanced through appropriate supplementation, as well as the application of certain biological agents. Probiotics, i.e., live microorganisms that exert a beneficial effect on the health of the host when administered in adequate amounts, are often used in commonly available dietary supplements or functional foods, such as yoghurts. Specific strains of microorganisms, administered in appropriate amounts, may find application in the treatment of conditions such as various types of diarrhoea (viral, antibiotic-related, caused by Clostridioides difficile), irritable bowel syndrome, ulcerative colitis, Crohn’s disease, or allergic disorders. In contrast, live microorganisms capable of exerting influence on the nervous system and mental health through interactions with the gut microbiome are referred to as psychobiotics. Live microbes are often used in combination with prebiotics to form synbiotics, which stimulate growth and/or activate the metabolism of the healthy gut microbiome. Prebiotics may serve as a substrate for the growth of probiotic strains or fermentation processes. Compared to prebiotic substances, probiotic microorganisms are more tolerant of environmental conditions, such as oxygenation, pH, or temperature in a given organism. It is also worth emphasizing that the health of the host may be influenced not only by live microorganisms, but also by their metabolites or cell components, which are referred to as postbiotics and paraprobiotics. This work presents the mechanisms of action employed by probiotics, prebiotics, synbiotics, postbiotics, paraprobiotics, and psychobiotics, together with the results of studies confirming their effectiveness and impact on consumer health.
... Many patients with COVID-19 who underwent treatment with antibiotic, indicated dysbiosis and GI symptoms such as diarrhea, vomiting, and stomachache, named as Antibiotic Associated Diarrhea (AAD) (29). Accordingly, AAD is a common complication of antibiotic therapy, occurring in approximately 50 to 75% of those patients who receive antibiotics (30). Additionally, in patients aged more than 65 years old infected with COVID-19, the incidence of GI symptoms is higher than those aged under 65 years old (31). ...
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Coronavirus Disease 2019 (COVID-19) is a pandemic disease caused by a new corona virus. COVID-19 affects different people in different ways. COVID-19 could affect the gastrointestinal system via gut microbiota impairment. Gut microbiota could affect lung health through a relationship between gut and lung microbiota, which is named gut-lung axis. Gut microbi-ota impairment plays a role in pathogenesis of various pulmonary disease states, so GI diseases were found to be associated with respiratory diseases. Moreover, most infected people will develop mild to moderate gastrointestinal (GI) symptoms such as diarrhea, vomiting, and stomachache, which is caused by impairment in gut microbiota. Therefore, the current study aimed to review potential role of gut microbiota in patients with COVID-19, its relation with lung axis, Central Nervous System (CNS) axis and improvement with probiotic therapy. Also, this review can be a guide for potential role of gut microbiota in patients with COVID-19.
Background Exposure to antimicrobials is a known risk factor for Clostridioides difficile infection (CDI). Antimicrobials cause collateral damage by disrupting the natural intestinal microbiota allowing for C. difficile to thrive and production of C. difficile toxins. Probiotics could modulate the onset and course of CDI. However, the data on probiotics for the prevention of CDI is conflicting. Objective To evaluate the rates of hospital-onset Clostridioides difficile infection (HO-CDI) among patients who received intravenous (IV) antibiotics plus probiotics versus IV antibiotics alone. Design Retrospective, single-center cohort study. Methods We included adult patients that received at least 1 dose of IV antibiotics and had a hospital length of stay of at least 3 days between August 2017 and July 2020. Patients were separated into 2 cohorts, either receipt of probiotics or non-receipt of probiotics. Patients with positive C. difficile toxin test prior to antibiotic therapy, or receipt of only C. difficile active treatment were excluded. The primary outcome was incidence of HO-CDI in patients who received IV antibiotics plus probiotics compared to those that received IV antibiotics alone. Logistic regression was performed to account for confounding variables. Results We identified 17 598 patients that received IV antibiotics alone and 2659 patients received IV antibiotics plus probiotics. HO-CDI occurred in 46 (0.26%) of those that received antibiotics alone compared to 5 (0.19%) of those that received probiotics with IV antibiotics (OR 0.72, 95% CI 0.28-1.81). ICU admission (OR 1.81, 95% CI 1.02-3.19) and history of CDI (OR 3.37, 95% CI 1.07-10.97) in the past 12 months were associated with a higher incidence of HO-CDI. Conclusion The addition of probiotics did not reduce the incidence of HO-CDI among inpatients receiving IV antibiotics.
The positive impact of probiotics and prebiotics on human health has been demonstrated by various preclinical and clinical experiments. Therefore, they are used as supplements in a wide range of food products, including packaged foods, drinks, pickles, etc. However, preserving their beneficial effects in functional foods during food processing and storage is a major challenge in the food industrial sector. So, an effective delivery system is needed to acquire and retain the therapeutic properties and control the release of pro- and prebiotics. The nanoemulsion-based system is a revolutionary approach for sustaining the beneficial potential of pro- and prebiotics in functional foods and also for the effective delivery of these bioactives. This chapter discusses pro- and prebiotics together with the emerging role of food-grade nanoemulsions as an effective delivery system into functional food products toward improving their stability, specific target approach, and prolonged bioactivity.
Clostridioides difficile is the predominant pathogen responsible for antimicrobial associated diarrhea (AAD) and health care facility-associated infectious diarrhea. The role of C. difficile in China and its impact on public health have gained attention in recent years. Most clinical C. difficile isolates in China belong to multilocus sequence type clade 1 with sequence types (STs) 3, 35 and 54 predominating. Of note, the proportion of C. difficile isolates from clade 4, especially ST37 (PCR ribotype 17), is much higher in China than in other areas. In China, the antimicrobial-resistance profile of C. difficile is similar to that of other countries, demonstrating a higher resistance rate to erythromycin, clindamycin, and fluoroquinolones (ciprofloxacin, levofloxacin, and moxifloxacin). In general, susceptibility to vancomycin and metronidazole of clinical C. difficile in China is high, however, some resistance to metronidazole have recently been reported. Preclinical research on C. difficile in animals in China is limited, and different studies have reported varied isolation rates and antimicrobial resistance profiles. The diverse molecular types of C. difficile in China merit further epidemiological, genomic and evolutionary investigation. While the use of probiotics in preventing C. difficile infection (CDI) have received both support and opposition, the discovery of new probiotics and new formulations are showing promising results in combating the threat posed by CDI.
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To critically appraise evidence on probiotic use for prevention and treatment of diarrhea in children and adults. Several randomized controlled trials and meta-analyses suggested that probiotics are effective in primary and secondary prevention of gastroenteritis and its treatment. Selected Lactobacillus strains had a modest, although significant effect in primary prevention. Saccharomyces boulardii was effective in antibiotic-associated and in Clostridium difficile diarrhea. There is evidence that it might prevent diarrhea in day-care centers. Lactobacillus rhamnosus GG was associated with reduced diarrheal duration and severity, more evident in case of childhood Rotavirus diarrhea. Similar, although weaker, evidence was obtained with S. boulardii. Both strains are included in evidence-based recommendations for gastroenteritis management in children. Data on other Lactobacillus strains are preliminary. Probiotic efficacy was related to cause, early administration and bacterial load, and their mechanisms were associated with antiinfectious action in the intestine or, indirectly, to modulation of innate and adaptive immunity. Probiotics have gained a role as adjunctive treatment of infantile gastroenteritis together with rehydration. Their efficacy is less convincing in adults, but promising in antibiotic-associated diarrhea. However, evidence of efficacy is limited to a few strains.
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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.
Clostridium difficile-associated diarrhea (CDAB) has become the most common cause of infectious diarrhea acquired in the hospital, with an estimated 3 million annual cases and an annual cost of $1 billion. Risk factors for CDAD include antibiotic use (especially ampicillin, clindamycin, and cephalosporins), advanced age, and gastrointestinal surgery. Specific diagnosis of CDAD is made with an enzyme immunoassay to detect toxins A and B. Metronidazole remains the initial treatment of choice, with a 95% success rate. Vancomycin is reserved for failures. Despite the high initial success rates, recurrence of CDAD remains a significant problem in 20% to 30% of cases, with increased cost and substantial morbidity. Efforts to prevent CDAD will need to be strengthened, including education and better compliance with isolation, use of gloves, and hand washing.
To comprehend the results of a randomized controlled trial (RCT), readers must understand its design, conduct, analysis, and interpretation. That goal can be achieved only through complete transparency from authors. Despite several decades of educational efforts, the reporting of RCTs needs improvement. Investigators and editors developed the original CONSORT (Consolidated Standards of Reporting Trials) statement to help authors improve reporting by using a checklist and flow diagram. The revised CONSORT statement presented in this article incorporates new evidence and addresses some criticisms of the original statement.The checklist items pertain to the content of the Title, Abstract, Introduction, Methods, Results, and Comment. The revised checklist includes 22 items selected because empirical evidence indicates that not reporting the information is associated with biased estimates of treatment effect or because the information is essential to judge the reliability or relevance of the findings. We intended the flow diagram to depict the passage of participants through an RCT. The revised flow diagram depicts information from 4 stages of a trial (enrollment, intervention allocation, follow-up, and analysis). The diagram explicitly includes the number of participants, according to each intervention group, included in the primary data analysis. Inclusion of these numbers allows the reader to judge whether the authors have performed an intention-to-treat analysis.In sum, the CONSORT statement is intended to improve the reporting of an RCT, enabling readers to understand a trial's conduct and to assess the validity of its results.
Antibiotic-associated diarrhea (AAD) occurs in approximately 25% of patients receiving antibiotics. Hospitalized patients with AAD are at increased risk for nosocomial infections and have a higher mortality. Probiotics are living microorganisms used to restore gut health by changing the intestinal microbiota. Several have been studied for the prevention of AAD. Five meta-analyses of trials of probiotics for the prevention of AAD have been performed. The results showed an overall reduction in the risk of AAD when probiotics were coadministered with antibiotics. McFarland conducted the largest meta-analysis to date analyzing 25 randomized controlled trials of probiotics for the prevention of AAD including 2810 subjects. More than half of the trials demonstrated efficacy of the probiotic. In particular, Lactobacillus GG, Saccharomyces boulardii, and the probiotic mixtures were effective. The Cochrane Database of Systematic Reviews published a review of the literature on the use of probiotics for the prevention of pediatric AAD, including 10 randomized trials testing 1986 children. The per protocol pooled analysis, but not the intent-to-treat analysis, showed that probiotics are effective for preventing AAD with the number needed to treat to prevent 1 case of diarrhea being 10. Lactobacillus GG, Bacillus coagulans, and S. boulardii appeared to be most effective. Probiotics are generally safe, however, they should be used with caution in patients who have compromise of either the immune system or the integrity of the intestinal mucosa, and in the presence of a central venous catheter.
The proportion and severity of Clostridium difficile-associated diarrhoea (CDAD) is increasing in health-care settings. Antibiotics remain the most important risk factor for CDAD, due to their limiting the ability of the gastrointestinal flora to inhibit C difficile colonisation. Probiotics have therefore been investigated for primary and secondary prophylaxis against CDAD, with varying success. This Review looks at the current literature for in-vitro and clinical evidence for probiotic use in the prevention of CDAD. Its aim is to examine the mechanisms through which probiotics interact with C difficile and its toxin, and the association of these mechanisms with the clinical evidence for probiotics in the prevention of this disease. The Review briefly describes the recent epidemiological changes in C difficile disease, and our current understanding of its pathophysiology. It looks at the safety profile of probiotics, highlighting patients groups in which their use is inappropriate, and attempts to synthesise guidance for clinicians interested in using probiotics to prevent CDAD within health-care institutions.
Antimicrobials are effective agents used to combat virulent bacterial, yeast, and fungal infections that may otherwise cause rampant disease leading to skyrocketing social/economic costs and possible epidemic morbidity and mortality rates. Antibiotics are designed to attack specific bacterial pathogens but, in the process, indiscreetly reduce the number of beneficial human microbiota that is part of the gut-associated lymphatic tissue. Broad-spectrum antibiotics can upset this uniquely balanced gut ratio, allowing pathogens to propagate in a largely unrestrained environment, which may result in antibiotic-induced diarrhea. Critical illness, age, immunosuppression, exposure to nosocomial microorganisms, and the length of hospitalization are additional factors that contribute to the overgrowth of opportunistic pathogens. In mild to moderate cases of diarrhea, absorptive impairment may occur, thereby reducing micro/macronutrient assimilation, resulting in malnutrition and growth issues in children. In severe cases, infectious diarrhea can have devastating complications. Of particular interest is the bacterium Clostridium difficile, which has the potential to cause a host of symptoms ranging from mild diarrhea to severe life-threatening conditions. C. difficile infection can increase mortality rates by 10%-30%. Probiotic supplementation may prevent and treat antibiotic-associated diarrhea. Specific probiotics may modulate the intestinal mucosa by antagonizing pathogens through the production of antimicrobial compounds and chemicals, thereby reducing the rate of nosocomial infection and recurrence of C. difficile.