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Clinical Therapeutics/Volume 30, Number 3, 2008
March 2008 453
Accepted for publication January 8, 2008.
doi: 10.1016/j.clinthera.2008.03.013
0149-2918/$32.00
2008 Excerpta Medica Inc. All rights reserved.
ABSTRACT
Background: Lactobacilli are the dominant bacteria
of the vaginal flora and possess antimicrobial proper-
ties that regulate other urogenital microbiota. Incom-
plete cure and recurrence of genitourinary infections
lead to a shift in the local flora from a predomi-
nance of lactobacilli to coliform uropathogens. Use of
Lactobacillus-containing probiotics to restore commen-
sal vaginal flora has been proposed for the treatment
and prophylaxis of bacterial urogenital infections.
Objective: This review summarizes randomized
controlled trials that have assessed the therapeutic ef-
ficacy and tolerability of lactobacilli in bacterial vagi-
nosis (BV) and urinary tract infection (UTI).
Methods: Relevant randomized controlled trials pub-
lished in English were identified through a search of
MEDLINE (through November 2007), ClinicalTrials.gov,
and the Cochrane Database (second quarter 2007).
The search terms included probiotics, Lactobacillus,
lactobacilli, urinary, urogenic, bacterial vaginosis,
vaginal, colonization, bacteremia, sepsis, pathogenic,
taxonomy, diagnosis, and infections.
Results: Eleven randomized controlled trials were
identified that investigated the effects of lactobacilli in
the treatment and prophylaxis of bacterial urogenital
infections. In the 2 studies that reported a beneficial
effect for probiotics in the treatment of BV, cure rates
for lactobacilli at 30 days were 60% (P = 0.004) and
88% (P < 0.005), more than double the effect of con-
trols. One trial reported a 35% reduction in recurrent
episodes of BV compared with placebo (P = 0.004).
Among the 4 trials involving treatment of UTI, 1 re-
ported a 73% reduction in episodes of recurrent UTI
compared with the previous year (P = 0.001). Seven
studies found no therapeutic effect of lactobacilli in
the treatment or prophylaxis of BV or UTI. Only 2 of
the identified trials attempted to validate the probiotic
dosing strategy by obtaining quantitative evidence of
local colonization with lactobacilli and had sufficient
power to detect treatment effects, and only 1 trial ad-
dressed the stability of the probiotic product at the
end of the study.
Conclusions: Despite enhanced cure rates in some
studies, concerns about product stability and limited
documentation of strain-specific effects prevent rec-
ommendations for the use of Lactobacillus-containing
probiotics in the treatment of BV. The results of stud-
ies of lactobacilli for the prophylaxis of UTI remain
inconclusive as a result of small sample sizes and use
of unvalidated dosing strategies. (Clin Ther. 2008;
30:453468) 2008 Excerpta Medica Inc.
Key words: probiotics, Lactobacillus, bacterial
vaginosis, urinary tract infection, vaginal coloniza-
tion, vaginal flora.
INTRODUCTION
Probiotics have been defined as live microorganisms
which when administered in adequate amounts confer
a health benefit on the host.
1
The potential beneficial
effects of probiotics have been of interest since at least
the early part of the last century, when Ilya Mechnikov,
a Russian Nobel laureate, theorized that lactic acid
bacteria were responsible for the unusually long life
spans of Bulgarian peasants, who consumed large
quantities of yogurt.
2
Since that time, probiotics have
become a multibillion-dollar industry, helped by their
categorization as dietary supplements, which are
not subject to stringent evaluation by the US Food and
Drug Administration (FDA). The rationale for the use
of probiotics is based on the gastrointestinal and geni-
tourinary regulatory role played by the commensal
microflora and the need for restoration of this micro-
Use of Lactobacillus Probiotics for Bacterial Genitourinary
Infections in Women: A Review
Robert Barrons, PharmD, BCPS
1
; and Dan Tassone, PharmD
2
1
Wingate University School of Pharmacy, Wingate, North Carolina; and
2
Inova Fairfax Campus, Virginia
Commonwealth University School of Pharmacy, Falls Church, Virginia
454 Volume 30 Number 3
Clinical Therapeutics
adhesion to vaginal epithelial cells.
7
Vaginally inserted
capsules are an effective way of introducing or boost-
ing the local Lactobacillus content.
7
Oral formula-
tions of lactobacilli for genitourinary infections must
be capable of maintaining their structural integrity
during passage through the gut and delivery to the
rectal area for ascension and colonization of the vagi-
nal tract.
8
In vitro evidence indicates that lactobacilli
have varying degrees of adhesion to vaginal epithelial
cells, with the greatest adhesion among specific strains
of Lactobacillus gasseri, Lactobacillus brevis, and
Lactobacillus acidophilus.
7,9
Studies of vaginal colo-
nization by lactobacilli in humans have focused
largely on oral or intravaginal therapy with the com-
bination of Lactobacillus rhamnosus GR-1 and Lac-
tobacillus fermentum RC-14

(1.0 10
9
colony-
forming units [CFU]) dosed once daily.
1013
Use of
oral formulations of these strains has been associated
with normalization of vaginal lactobacilli within 28
to 60 days after the initiation of treatment.
10,11
Evi-
dence of fecal and vaginal colonization by these
strains was observed after 14 days of oral administra-
tion.
7
With vaginal formulations, local colonization
by these strains was noted after 3 days and continued
bial ecosystem after insult. Given a shift in thinking
about probiotics from dietary supplement to medical
therapy, examination of the properties and capabili-
ties of these substances has become essential. The FDA
now requires that manufacturers of probiotics in-
tended for the treatment or prevention of disease
submit an Investigational New Drug application.
3

Currently, no probiotics have been approved by the
FDA for therapeutic uses.
Health care providers who are interested in the
therapeutic potential of probiotics require evidence of
efficacy from randomized controlled trials, including
data on successful local colonization and strain-specific
outcomes, and information on product integrity and
stability. This article reviews available information on
the efficacy and tolerability of probiotics in the treat-
ment and prophylaxis of bacterial vaginosis (BV) and
the prophylaxis of urinary tract infection (UTI).
METHODS
Relevant randomized controlled trials published in
English were identified through searches of MEDLINE
(through November 2007), ClinicalTrials.gov, and the
Cochrane Database (second quarter 2007) using the
terms probiotics, Lactobacillus, lactobacilli, urinary,
urogenic, bacterial vaginosis, vaginal, colonization,
bacteremia, sepsis, pathogenic, taxonomy, diagnosis,
and infections.
RATIONALE FOR USING PROBIOTICS IN
GENITOURINARY INFECTIONS
Among women producing estrogen or receiving estro-
gen supplementation, the largest part of the vaginal
flora consists of lactobacilli, which possess antimicro-
bial properties that regulate other urogenital micro-
biota.
4
Genitourinary infections in women are often
characterized by an alteration in the local flora from
a predominance of lactobacilli to coliform uropatho-
gens as a result of hormone deficiency, sexual activity,
contraceptive measures, and other factors.
5
There are
>80 known species of lactobacilli in the intestines and
vagina; thus, in terms of probiotic effects, individual
species may differ in their ability to restore normal
flora and regulate the overgrowth of uropathogens.
4

Lactobacillus spp that have been studied for their
probiotic potential (based on their metabolic produc-
tion of lactic acid from sugars) are listed in Table I.
6
The ability of lactobacilli to colonize the vaginal
mucosa depends on the route of delivery and extent of
Table I. Classification of selected lactobacilli for
probiotic use, based on metabolic pro-
duction of lactic acid from sugars.
6
Obligately homofermentative
Lactobacillus delbreuckii group
Lactobacillus acidophilus
Lactobacillus crispatus
Lactobacillus gasseri
Lactobacillus johnsonii
Lactobacillus salivarius group
L salivarius
Facultatively heterofermentative
Lactobacillus casei group
L casei
Lactobacillus paracasei
Lactobacillus rhamnosus
Lactobacillus plantarum group
L plantarum
Obligately heterofermentative
Lactobacillus reuteri group
L reuteri
Lactobacillus fermentum
March 2008 455
R. Barrons and D. Tassone
trolled trials can establish the role of lactobacilli in the
treatment, augmentation of treatment, and prevention
of bacterial urogenital infections.
BACTERIAL VAGINOSIS
BV is a common condition in women of childbearing
age, occurring in 16% to 20% of pregnancies and ac-
counting for up to 25% of visits to gynecologic clin-
ics.
4
BV is characterized by a shift in the vaginal mi-
crobiota from a predominance of protective lactobacilli
to pathogenic bacteria, including G vaginalis and My-
coplasma hominis. Risk factors for the development
of BV include douching, use of an intrauterine contra-
ceptive device, new or multiple sexual partners, smok-
ing, and black ethnicity.
17
The preferred methods for establishing the diagno-
sis of BV are clinical assessment based on the Amsel
criteria and microscopic assessment using the Nugent
score.
18
There are 4 Amsel criteria: presence of a thin,
white homogeneous discharge; presence of clue cells
on microscopy; vaginal fluid pH >4.5; and release of
a fishy odor on addition of alkali (10% KOH). The
Nugent score is derived from microscopic assessment
of a gram-stained vaginal smear; the relative propor-
tions of bacterial morphotypes are estimated, yielding
a score between 0 and 10. A score <4 is considered
normal, a score of 4 to 6 is considered intermediate,
and a score >6 represents BV. The Centers for Disease
Control and Prevention (CDC) recommends basing
the diagnosis of BV on the presence of 3 Amsel crite-
ria and a Nugent score 7.
19
According to guidelines
from the FDA,
20
verification of BV cure should be
conducted between 21 and 30 days after the initiation
of therapy, with cure defined as an absence of Amsel
criteria and a Nugent score <3.
Cure rates of BV with conventional antibiotic treat-
ments have been disappointing. Larsson and Forsum
21

reviewed the literature on studies of BV treatment and
found that among placebo-controlled studies with at
least 21 days of follow-up that evaluated cure based
on an absence of Amsel criteria, metronidazole gel
and clindamycin cream were associated with overall
cure rates of 36% and 53%, respectively. Similarly,
oral metronidazole and clindamycin were associated
with overall cure rates of 66% and 85%, respectively.
BV recurs in up to 30% of women within 3 months
after initiation of antibiotic therapy and in up to 50%
of women at 6 months.
17
Whether recurrence is
caused by relapse or reinfection, high recurrence rates
to be evident at 12 days.
13,14
However, while these
studies determined the presence of the 2 strains, most
did not quantify the extent of colonization, which
may be an important component of the antibacterial
effects of lactobacilli.
15
For use as probiotics in the prevention and/or treat-
ment of genitourinary infections, lactobacilli must ex-
hibit adequate antibacterial activity. The most relevant
property in this context is the ability to maintain a
vaginal pH 4.5. This ability depends particularly on
the number of lactobacilli present to produce lactic
acids, re-emphasizing the importance of coloniza-
tion.
15
An acidic vaginal environment is conducive to
replication of lactobacilli and subsequent production
of additional antibacterial substances, including bacte-
riocin and hydrogen peroxide.
15
However, different
strains of lactobacilli produce varying amounts of these
substances. In an in vitro study, Aroutcheva et al
15
in-
vestigated defense factors against infection in 22 Lac-
tobacillus strains isolated from specimens provided by
women with healthy vaginal ecosystems. Moderate to
high production of hydrogen peroxide and bacteriocin
was found in 82% and 68% of strains, respectively,
with no production in the remaining strains.
In addition, lactobacilli may offer protection against
genitourinary infections through production of biosur-
factants. Biosurfactants discourage the growth of uro-
pathogens by inhibiting adhesion of microorganisms
along uroepithelial cells.
16
Velraeds et al
16
conducted
an in vitro study of 15 strains of lactobacilli, most of
which were considered normal inhabitants of the vagi-
nal flora. These lactobacilli produced varying amounts
of biosurfactants that provided up to 82% inhibition
of Enterococcus faecalis adhesion to a glass surface.
Finally, lactobacilli may co-aggregrate with uro-
pathogens to block adhesion and/or displace previ-
ously adherent uropathogens on vaginal epithelial
cells. It has been suggested that co-aggregation may
promote a microenvironment around the pathogen
in which the previously mentioned inhibitory sub-
stances may be concentrated.
9
Mastromarino et al
9

found varying degrees of co-aggregation with Candida
albicans and Gardnerella vaginalis among 10 strains
of lactobacilli that were being evaluated for use in
probiotic vaginal tablets.
The contribution of these individual antibacterial
properties to clinical efficacy is unclear, as the proper-
ties vary by Lactobacillus strain and by the susceptibil-
ity of specific uropathogens. Only randomized con-
456 Volume 30 Number 3
Clinical Therapeutics
tients who received probiotic yogurt had a 60% re-
duction in BV episodes, compared with a 25% reduc-
tion in those who received pasteurized yogurt (P =
0.004). The results were similar after 2 months of
therapy, although statistical analysis was not reported
and there was an unexplained attrition of >25% pa-
tients in both groups. Adverse events were not re-
ported, and product integrity was assessed only before
initiation of the study.
Neri et al
25
studied yogurt-containing probiotics
for the treatment of BV in 84 women who were in the
first trimester of pregnancy. BV was diagnosed based
on the presence of 3 Amsel criteria. Infection with
Trichomonas vaginalis, Neisseria gonorrhoeae, or
yeast was an exclusion criterion. Patients were ran-
domized either to administer 10 to 15 mL of a vaginal
douche containing L acidophilus dosed at >1.0 10
8

CFU/mL (n = 32), to insert a tampon containing 5%
acetic acid (n = 32), or to receive no treatment (n =
20). The active treatments were administered twice
daily for 7 days. At 4 weeks, BV was cured (absence
of Amsel criteria) in 88%, 38%, and 15% of patients
receiving intravaginal yogurt, acetic acid, and placebo,
respectively. The difference in cure rates was signifi-
cant between the yogurt and acetic acid groups (P =
0.04) and the yogurt and control groups (P < 0.005).
Data on discontinuations and adverse events were not
reported. Product integrity was not assessed.
Four randomized controlled trials found no benefi-
cial effect of probiotics in the treatment of BV (Table
II).
2629
In a double-blind, placebo-controlled trial,
Eriksson et al
26
examined the augmentative effects of
lactobacilli on BV cure rates in 187 women (median
age, 32 years) over 2 menstrual periods. BV was diag-
nosed based on the presence of 3 Amsel criteria and
a Nugent score 7. Women were excluded if they were
pregnant, had been exposed to antibiotics in the week
before the diagnosis of BV, or had a vaginal infection
involving yeast or Chlamydia trachomatis. All patients
received 3 days of open-label treatment with clindamy-
cin ovules 100 mg/d. They were then randomized to
insert at least 5 tampons impregnated with L gasseri,
L rhamnosus, and L fermentum (n = 91), each contain-
ing 1.0 10
8
CFU per tampon, or placebo tampons
(n = 96) during the next menstrual period. After the
second menstrual period, cure rates of BV (absence of
Amsel criteria) in the probiotic and placebo groups
were 56% and 62%, respectively (P = NS). The most
commonly recorded adverse event was Candida infec-
result in repeated exposure to antibiotics; this raises
concerns about the emergence of drug-resistant strains
and the potential for adverse reactions,
22
and suggests
a need for alternative therapeutic measures.
Clinical Trials of Lactobacilli in the Treatment or
Prevention of Bacterial Vaginosis
Three randomized controlled trials reported en-
hanced cure rates or a reduced recurrence of BV
among premenopausal women treated with lactoba-
cilli (Table II).
2325
Anukam et al
23
assessed the effi-
cacy of combining oral metronidazole with either
probiotics or placebo in 125 premenopausal Nigerian
women (age range, 1844 years). The diagnosis of BV
was based on a Nugent score 7 and a positive bacte-
rial sialidase test. Patients were excluded if they had
been exposed to antibiotics in the previous 14 days,
were pregnant, or had evidence of a sexually transmit-
ted disease (STD). All patients received oral metro-
nidazole 500 mg BID for 7 days, after which they
were randomized to receive twice-daily therapy with
an oral capsule containing either L rhamnosus GR-1
and Lactobacillus reuteri RC-14 dosed at 1.0 10
9
CFU
per capsule (n = 65) or placebo (n = 60) for a total
treatment duration of 30 days. At the end of this pe-
riod, BV was absent (Nugent score <3 and negative
sialidase test) in 88% and 40% of patients in the pro-
biotic and placebo groups, respectively (P < 0.001).
Rates of treatment discontinuation (25% in the probi-
otic group, 6% in the placebo group) were assumed to
be the result of improvement in the initial symptoms;
patients who discontinued the study were not includ-
ed in the final analysis. Adverse events were not re-
ported, and product integrity was not assessed.
Two trials evaluated the effectiveness of L acido-
philuscontaining yogurt in patients with BV.
24,25

Shalev et al
24
compared rates of BV recurrence with
probiotic yogurt and pasteurized yogurt in 46 pre-
menopausal women who had 4 episodes of BV and/
or vaginal candidiasis in the previous year. The diag-
nosis of BV was based on the presence of 3 Amsel
criteria. Patients were excluded if they were receiving
long-term antibiotic or immunosuppressive therapy,
or had consumed yogurt daily before the study (time
frame not reported). Patients were randomly assigned
to ingest 150 mL of L acidophiluscontaining yogurt
(>1.0 10
8
CFU/mL) (n = 23) or pasteurized yogurt
(n = 23) daily for 2 months, followed by 2 months
with no yogurt intake. After 1 month of therapy, pa-
March 2008 457
R. Barrons and D. Tassone
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460 Volume 30 Number 3
Clinical Therapeutics
after the initiation of therapy, cure rates had decreased
to 21% in the probiotic group and remained at 0% in
the placebo group (P = NS). The findings were com-
promised by unexplained attrition rates of 50% in the
probiotic group and 86% in the placebo group. Ad-
verse-event and compliance data were not reported,
and product integrity was not assessed.
An open-label trial by Fredricsson et al
29
compared
cure rates with 4 intravaginally administered products
in 61 women with BV. The diagnosis of BV was based
on the presence of 3 Amsel criteria, and cure was
defined as the presence of 1 Amsel criterion at 4 and
8 weeks. Women were excluded if culture indicated
the presence of C trachomatis or N gonorrhoeae. Pa-
tients were randomized to receive 7 days of twice-
daily treatment with 5 mL fermented milk containing
L acidophilus NCDO 1748 dosed at 5 10
8
to 2
10
9
CFU/mL (n = 13), 5 mL acetic acid jelly
(n = 15), 5 mL estrogen cream (n = 16), or metronida-
zole 500-mg vaginal tablets (n = 15). Four weeks after
the initiation of treatment, the probiotic group had a
BV cure rate of 7%, compared with rates of 18%, 6%,
and 93% for acetic acid jelly, estrogen cream, and
metronidazole, respectively (statistical comparisons
not reported). The findings remained unchanged at
8 weeks. Probiotic therapy had no significant effect on
clinical cure rates. However, dropouts and adverse
events were not reported, making it difficult to inter-
pret the results. Patient compliance and product integ-
rity were not assessed.
URINARY TRACT INFECTIONS
UTIs are among the most commonly occurring bacte-
rial infections, accounting for 8 million patient visits
annually.
3032
An estimated 1 in 3 women will have
had a UTI by the age of 24 years.
33
Twenty-five to
30% of adult women with a first episode of UTI will
have a recurrence.
34
Risk factors associated with an
increased likelihood of UTI in women include urinary
tract obstruction, urinary catheterization, neurologic
malfunction, pregnancy, and use of spermicides, a dia-
phragm, or anticholinergic agents.
34
UTIs are generally diagnosed based on the presence
of a microorganism with a count of 100,000 CFU/mL
in a clean-catch urine specimen.
35
Escherichia coli is the
predominant pathogen in UTIs; other common causa-
tive microorganisms are Staphylococcus saprophyticus,
E faecalis, and occasionally Klebsiella pneumoniae and
Proteus mirabilis.
30
Although not approved for these
tion, which occurred in 13 patients (14.3%) in the
probiotic group and 13 patients (13.5%) in the place-
bo group. Itching and burning were reported by
4 women receiving lactobacilli and 8 women receiving
placebo. No discontinuations were reported. At the
end of the trial, the number of viable bacteria per tam-
pon was reduced from 10
8
to 10
6
CFU.
Anukam et al
27
conducted a single-blind compari-
son of intravaginal probiotics and metronidazole gel
for the treatment of BV in 40 Nigerian women. Partici-
pants ranged in age from 18 to 50 years. The diagnosis
of BV was based on the presence of 3 Amsel criteria,
a Nugent score 7, and a positive sialidase test. Women
were excluded for yeast vaginitis, an STD, or HIV-
positive status. Patients were randomized to insert an
intravaginal capsule containing L rhamnosus GR-1
and L reuteri RC-14 dosed at 1.0 10
9
CFU per cap-
sule every night (n = 20) or to apply 0.75% metronida-
zole gel BID (n = 20) for 5 days. Cure of BV was based
on a Nugent score 3 at 30 days; only those patients
who returned for the 30-day evaluation were included
in the analysis. BV was absent in 55% of the probiotic
group and 33% of the metronidazole group (P = NS).
Three of 20 patients (15%) in the probiotic group and
2 of 20 patients (10%) in the metronidazole group
discontinued treatment prematurely; the reasons were
not specified. Adverse events were not described, but
the authors reported complete patient compliance
based on the return of empty vials on study days 6, 15,
and 30. Product integrity was not assessed.
In a double-blind trial, Halln et al
28
compared cure
rates of BV in 57 women (mean age, 24 years) treated
with a probiotic or placebo. BV was diagnosed based
on the presence of 3 Amsel criteria. Women were ex-
cluded from the study if they had an STD (N gonor-
rhoeae, Chlamydia, C albicans, or T vaginalis) or were
receiving any medications other than oral contracep-
tives at study entry. Patients were randomized to re-
ceive either a vaginal suppository containing L acido-
philus dosed at 1.0 10
89
CFU per suppository (n =
28) or placebo (n = 29) twice daily for 6 days. BV cure
was evaluated based on symptom resolution, which
was poorly defined. At initial follow-up (710 days
after the initiation of therapy), BV was absent in 57%
of the probiotic group and 0% of the placebo group
(P < 0.005). Three patients in the probiotic group and
19 in the placebo group had persistent symptoms re-
quiring treatment with metronidazole; these patients
were excluded from the final analysis. At 20 to 40 days
March 2008 461
R. Barrons and D. Tassone
dence rate ratio over 26 weeks was 1.41 (95% CI,
0.881.98). Colonization of lactobacilli, as assessed in
periurethral samples, did not differ significantly be-
tween patients with and without a UTI. Enterococci,
E coli, and undefined gram-positive cocci were the
most commonly isolated causative organisms in the
group treated with L rhamnosus, representing a re-
spective 16%, 24%, and 44% of identified pathogens.
There were no dropouts during treatment, and treat-
ment was generally well tolerated. Four patients allo-
cated to L casei reported messy discharge on the day
after suppository insertion, compared with 1 in the
placebo group. Patient compliance was evaluated
monthly, but the method of assessment and outcomes
were not reported. Product integrity was not assessed.
In a multicenter, randomized, active-controlled,
blinded study, Reid et al
38
evaluated rates of recurrent
UTI with a short course of antimicrobial therapy
followed by Lactobacillus vaginal suppositories in
41 premenopausal women. Exclusion criteria included
pregnancy; a history of diabetes, cancer, or urinary
tract obstruction; allergy to TMP/SMX; and current
use of any prescription medications. After positive
results on tests for bacteriuria (>1.0 10
5
CFU/mL) in
a fresh midstream urine specimen and sensitivity to
norfloxacin and TMP/SMX, participants received a
3-day supply of either oral norfloxacin 400 mg BID
(n = 20) or TMP/SMX 160/800 mg (n = 20) to be
taken once daily. On the final day of oral antimicro-
bial treatment, patients were allocated to insert either
vaginal suppositories containing freeze-dried L rham-
nosus GR-1 and L fermentum B-54 (1.6 10
9
CFU
per suppository) or active-control suppositories con-
taining sterilized skim-milk powder twice weekly for
2 weeks and once at the end of the next 2 months
(total duration of treatment, 2.5 months). Specimens
for urine culture were obtained during follow-up visits
at 48 hours, 2 weeks, 5 weeks, 3 months, and 6 months.
The sample size was calculated for preliminary exami-
nation of the tolerability and potential for use of
probiotic suppositories after antimicrobial therapy.
There was no significant difference in the rate of re-
currence of symptomatic lower UTI over 6 months in
the antimicrobial-plus-Lactobacillus group compared
with the antimicrobial-plus-placebo group (21% and
47%, respectively). E coli was the most commonly
isolated organism associated with recurrent UTI. After
3 days of treatment with norfloxacin or TMP/SMX,
there were no significant differences in rates of bacte-
indications, antimicrobial therapy with such agents as
trimethoprim/sulfamethoxazole (TMP/SMX), nitro-
furantoin, and fluoroquinolones has been effective in
the treatment of symptomatic infections and is pre-
scribed for prophylaxis.
34
Antibiotic prophylaxis has
been associated with a decrease in the rate of recur-
rence, from 2 to 3 cases per patient-year to 0.1 to
0.2 cases per patient-year, although use of these agents
has the potential to disrupt the normal flora of the
urinary tract and possibly to increase the development
of resistance in uropathogens.
34,36
Therefore, there is
a need for alternatives to long-term antimicrobial
prophylaxis.
Clinical Trials of Lactobacilli for the Prevention
of Recurrent UTI
Four randomized trials of lactobacilli for the pre-
vention of recurrent UTI were identified (Table
III).
3740
These studies used Infectious Diseases Society
of America definitions of bacterial cystitis or pyelone-
phritis.
30
Diagnostic criteria for UTI included the
presence of classic signs or symptoms, including dysu-
ria, increased urinary frequency and urgency, and evi-
dence of bacteriuria (>1.0 10
2
CFU/mL). Cure was
evaluated based on the resolution of clinical findings.
Baerheim et al
37
conducted a randomized, double-
blind, placebo-controlled study of Lactobacillus vagi-
nal suppositories for the prevention of recurrent UTI
in 47 women. Patients inserted vaginal suppositories
containing either live L rhamnosus (7.5 10
8
CFU
per suppository) or placebo twice weekly for 26 weeks.
Study participants were between the ages of 18 and
50 years (mean age, 37 years), had a history of 3 epi-
sodes of UTI symptoms (1 of these a medically con-
firmed UTI) over 12 months, and had been symptom
free and received no antibiotic treatment for 3 weeks
before initiation of the study. Participants were ex-
cluded if they were pregnant or became pregnant dur-
ing the study, used a diaphragm, or had diabetes,
cancer, urinary tract obstruction, or any other compli-
cating illness. Recurrence was defined as the presence
of all the following: urinary symptoms, leukocyturia,
bacteriuria (>1.0 10
4
CFU/mL or any quantity of
S saprophyticus). Recurrence was assessed at follow-
up visits 2 weeks after study inclusion and monthly
thereafter for 6 months. There was no significant dif-
ference in the monthly incidence of symptomatic
lower UTIs between the L casei group and the placebo
group (0.21 and 0.15, respectively); the observed inci-
462 Volume 30 Number 3
Clinical Therapeutics
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R. Barrons and D. Tassone
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464 Volume 30 Number 3
Clinical Therapeutics
other treatment (1). No adverse events were reported.
The bacteria-containing suppositories were assessed
for purity and potency each month during the study.
Although complete data were not provided, the count
of viable lactobacilli from vaginal swabs was report-
ed to be increased from baseline at each monthly
assessment.
In a randomized, open-label study, Kontiokari et al
40

compared a probiotic drink and cranberrylingonberry
juice in the prevention of recurrent UTI in 149 women
(mean age, 30 years) with a history of recurrent UTI,
as evidenced by bacterial counts of 1.0 10
5
CFU/mL
on urine culture. Participants were randomly assigned to
ingest 100 mL of a drink containing L rhamnosus GG
(4.0 10
10
CFU/100 mL) 5 days per week for 1 year
(n = 49), to drink 50 mL of cranberrylingonberry
juice (7.5 g cranberry concentrate, 1.7 g lingonberry
concentrate) daily for 6 months (n = 50), or to receive
no intervention (n = 50). The primary end point was
the first recurrence of UTI, diagnosed based on symp-
toms suggestive of UTI and a urine culture with bacte-
rial counts of 1.0 10
5
CFU/mL. At 6 months, more
patients in the Lactobacillus and control groups had
1 recurrence of UTI compared with the group that
received cranberrylingonberry juice (39%, 36%, and
8%, respectively). This represented a 20% absolute
risk reduction in the group receiving cranberry
lingonberry juice compared with the control group
(95% CI, 336; P = 0.023; number needed to treat =
5). At 12 months, more patients in the Lactobacillus
and control groups had 1 recurrence of UTI com-
pared with the group receiving cranberrylingonberry
juice (47%, 42%, and 26%; P = 0.048, cranberry
lingonberry juice vs probiotic). E coli was the most
commonly isolated organism (80%); the proportions
of episodes associated with this organism did not dif-
fer significantly between the intervention groups and
the control group. Other causative organisms were
found but not specified. Thirteen patients dropped out
of the study, 4 (8%) in the group receiving lactobacilli,
4 (8%) in the group receiving cranberrylingonberry
juice, and 5 (10%) in the control group, all because of
moving away. Treatment was well tolerated, with no
adverse events reported in any group. Fifty-three of
99 women (54%) receiving active treatment returned
a self-report concerning their consumption of the as-
signed doses. Women in the probiotic drink group re-
ported taking 88% of the prescribed doses, and
women in the cranberrylingonberry juice group re-
rial eradication (100% and 95%, respectively) or re-
currence (29% and 41%). Thirty-one of 41 patients
completed the study. One patient was removed from
the study because of an absence of bacteria in urine
culture 2 days after antibiotic treatment, 6 patients
did not use the suppositories because of a lack of UTI
symptoms, 3 dropped out for personal reasons, and
1 dropped out because of an unrelated case of pneu-
monia. No adverse events were reported during the
study. Thirty-one patients were reported to have good
compliance, but the method of assessing compliance
was not described. Product integrity was not assessed.
In another randomized, double-blind study, Reid et
al
39
compared the effect of lactobacilli and Lactoba-
cillus growth factor (LGF)which has been reported
to stimulate the growth of indigenous lactobacillion
the recurrence of UTI in 55 premenopausal women
(mean [SD] age, 34 [6] years). Eligible participants
had 4 UTIs in the past 12 months (each requiring
antimicrobial therapy) and 2 documented urine cul-
tures with 1.0 10
5
CFU/mL, or had been receiving
long-term (>3 months) low-dose antimicrobial thera-
py for recurrent UTI. Exclusions included a history of
urinary tract obstruction, abnormal renal function,
diabetes, neurogenic bladder, or use of prednisone or
immunosuppressive medications. Long-term prophy-
lactic antimicrobial therapy was discontinued 1 month
before initiation of the trial. Patients were randomized
to receive once-weekly vaginal suppositories contain-
ing either L rhamnosus GR-1 and L fermentum B-54
(1.0 10
9
CFU per suppository) or LGF for 12 months.
There was no significant difference in the number of
recurrent UTIs over 12 months between the group
receiving lactobacilli and the group receiving LGF; the
mean incidence of UTIs in the 2 groups was 1.6 and
1.3 per patient per year, respectively. However, both
rates were 73% lower than those in the year before
prophylaxis (6.0 per patient per year in both groups;
P = 0.001). Seventeen of 20 UTIs in the probiotic
group occurred during the first month of therapy,
compared with 5 of 20 UTIs in the LGF group. E coli
was the most commonly isolated causative organism
(57%) in both groups. Seventeen of 25 patients (68%)
in the Lactobacillus group and 21 of 24 patients
(88%) in the LGF group completed the study. Six pa-
tients in the Lactobacillus group were excluded within
2 weeks of study initiation due to poor compliance or
pregnancy; 11 other discontinuations were associated
with recurrence of UTI (4), moving (4), and receipt of
March 2008 465
R. Barrons and D. Tassone
from a probiotic strain was recovered in only 1 case.
Overall mortality among all Lactobacillus-associated
infections was ~30%, mainly attributable to polymi-
crobial sources or inadequate treatment. While L casei
and L rhamnosus were the most commonly isolated
organisms, no association was found between particu-
lar Lactobacillus spp and infection type or mortality.
However, overall resistance to vancomycin and cefa-
zolin among lactobacilli was 87% and 52%, respec-
tively. Such resistance rates may make a substantial
contribution to therapeutic failure and raise concerns
about potential transference of resistance to other patho-
gens, including Enterococcus spp and Staphylococcus
aureus. However, the vancomycin-resistance genes of
Lactobacillus spp are chromosomal and not easily trans-
ferable to other bacterial species or genera.
44
Nonethe-
less, based on susceptibility data from case reports, it
has been suggested that Lactobacillus strains for pro-
biotic use should be susceptible to at least 2 major
antibiotics and that vancomycin should not be used in
instances of documented Lactobacillus infection.
44
None of the reviewed trials of lactobacilli in BV or
UTI involved patients who were immunocompro-
mised or debilitated. Eight of the 11 trials enrolled
premenopausal women,
2226,28,3840
who are less likely
to be immunocompromised or debilitated than older
women. The remaining studies excluded patients with
underlying or complicated disease, although what
this included was poorly defined or not reported.
Overall, 5 of the 11 trials reported Lactobacillus
therapy to be well tolerated based on the absence of
treatment-related discontinuations and either an ab-
sence of adverse events or a similar number of adverse
events in the Lactobacillus and control groups.
26,3740

The remaining 6 studies provided no information on
adverse events.
DISCUSSION
The clinical trials included in this review examined the
use of lactobacilli for the treatment and prophylaxis
of BV and the prevention of recurrent UTI. In the
2 randomized controlled trials that reported a positive
effect for probiotics in the treatment of BV,
23,25
lacto-
bacilli were associated with cure rates of 60% and
88%, more than double the effect associated with
control. These rates were comparable to those re-
ported 4 weeks after the initiation of therapy with
oral metronidazole (66%) and clindamycin (85%) in
women with BV.
21
In the randomized controlled trial
ported taking 91% of the prescribed doses. Although
both products were commercially available at the time
of the study, product integrity was not assessed.
ADVERSE EVENTS
Lactobacillus is a ubiquitous bacterium of the mouth,
gastrointestinal tract, and female genitourinary tract,
and can be acquired through the intake of probiotics
or fermented foods (eg, cheese, yogurt, olives).
41
Infec-
tions caused by lactobacilli are extremely rare, esti-
mated to account for 0.05% to 0.4% of combined
cases of infective endocarditis and bacteremia. Most
cases occur in patients with chronic disease or debili-
tating conditions, and any association with exposure
to probiotic-containing foods or supplements has
been questioned.
41,42
L rhamnosus GG was intro-
duced into dairy products in Finland in 1990. In 1994,
the National Public Health Institute of Finland man-
dated national surveillance of all bloodstream infec-
tions, including infections with lactobacilli.
42
There was
a substantial increase in the consumption of L rhamno-
sus GGcontaining foods from 1995 to 2000 (from
1 to 6 L per person), but there was no evidence to sug-
gest an increase in Lactobacillus-associated bacteremia.
In a review of the literature, Boyle et al
43
identified
26 cases of probiotic-associated bacteremia or fungemia
that were confirmed by comparing DNA/RNA finger-
printing or biochemical analysis of cultures with pro-
biotic bacterial strains. Seven of these cases were as-
sociated with receipt of L rhamnosus GG for daily
supplementation, short-gut syndrome, or antibiotic-
induced diarrhea. However, no outcome data or ad-
ditional bacterial sources of infection were reported.
Based on these cases, the authors identified major and
minor risk factors for probiotic-associated sepsis. Ma-
jor risk factors were immunocompromise (including a
debilitated state or malignancy) and prematurity in
infants. Minor risk factors were the presence of a cen-
tral venous catheter, valvular heart disease, intestinal
inflammation, and administration of probiotics by je-
junostomy or concurrently with antibiotics to which
the probiotic is resistant. The authors recommended
avoiding use of probiotics in patients with 1 major
risk factor or >1 minor risk factor.
Cannon et al
44
reviewed 241 cases of Lactobacillus-
associated bacteremia, endocarditis, and localized in-
fections. Only 4 cases (1.7%) were considered possibly
linked to heavy consumption of dairy products. How-
ever, a Lactobacillus isolate that was indistinguishable
466 Volume 30 Number 3
Clinical Therapeutics
Among the 11 randomized controlled trials re-
viewed, 7 found no therapeutic effect of lactobacilli in
either the treatment of BV
2629
or the prophylaxis of
UTI.
37,38,40
Although the majority of these 7 studies
assessed patient compliance, only 1 trial reported com-
pliance outcomes.
40
Most of these trials employed ex-
clusions based on receipt of specific medications and
the presence of risk factors for recurrent UTI or BV.
However, the study outcomes may have been compro-
mised, as only 2 of the 7 studies had sufficient statistical
power to detect a treatment effect
29,38
and only 2 stud-
ies evaluated urogenital colonization after therapy.
29,38

In the remaining 5 trials,
23,26,28,37,40
the evidence for
local colonization was inconclusive, as the investigators
only tested for the presence of lactobacilli rather than
quantifying lactobacilli in vaginal, perianal, or urethral
cultures. The specific strains of Lactobacillus used were
reported in only 3 of the 7 trials,
29,38,40
and only 1 of
these trials
38
used a strain (L rhamnosus GR-1) that
was associated with efficacy in the trials that did find
beneficial effects.
23,39
In the trial that addressed the vi-
ability of the Lactobacillus dose,
26
the dose was found
to be reduced from 1.0 10
8
CFU per tampon at the
initiation of treatment to 1.0 10
6
CFU per tampon at
the completion of the study.
As probiotic use begins to shift from nutritional
supplement to medical therapy, product stability is a
source of concern. Although the FDA has recently
mandated that manufacturers of probiotics intended
for the treatment or prevention of disease provide evi-
dence of the products potency and stability,
45
the
majority of these products will not be evaluated in this
way. Consequently, health care providers and consum-
ers will have to rely on independent services to con-
firm product stability and dosage.
CONCLUSIONS
Among premenopausal women with BV, administra-
tion of lactobacilli alone or in combination with met-
ronidazole has been associated with significant differ-
ences in cure rates relative to placebo in some studies.
Based on the limited data, lactobacilli alone were as-
sociated with BV cure rates comparable to those with
standard antibiotic therapies. The combination of lac-
tobacilli and antibiotics was associated with some evi-
dence of enhanced BV cure rates relative to mono-
therapy with oral metronidazole. The evidence
supporting the use of Lactobacillus-containing yogurt
to reduce the recurrence of BV in premenopausal
of BV prophylaxis in women with a history of 4 BV
episodes per year,
24
consumption of Lactobacillus-
containing yogurt reduced the recurrence of BV by
35% relative to control. In the trials that found posi-
tive effects in BV, lactobacilli were administered as
intravaginal or oral monotherapy
24,25
or orally in
combination with metronidazole.
23

Lactobacillus doses were 1.0 10
8
CFU per solid
dosage formulation (oral capsule,
23
intravaginal
capsule,
27
vaginal suppository,
28,3739
or vaginal tam-
pon
26
); 1.0 10
8
CFU/mL milk
29
or yogurt
24,25
; and
4.0 10
10
CFU/100 mL cranberrylingonberry juice
40

administered for at least 5 days. Each trial involved at
least 28 days of follow-up, but none of them used
both the Amsel criteria and Nugent scores to assess
BV cure, as recommended by the CDC.
19
This sug-
gests that the cure rates in these studies may have been
higher than if they had been evaluated based on a
combination of clinical presentation and laboratory
results. In the study of BV prophylaxis,
24
the assess-
ment of outcomes was compromised by a high rate of
patient attrition (25%) at 1 month; the reasons for
discontinuation were not reported, and omission of
the dropouts from the final assessment may have en-
hanced the study findings. Although L acidophilus,
L rhamnosus, or L reuteri was used in all the trials of
BV treatment or prophylaxis, only 3 of 7 trials re-
ported the bacterial strains used (ie, L rhamnosus
GR-1 and L reuteri RC-14).
23,27,29
Human studies
have reported vaginal colonization with both of these
strains when given exogenously.
1013
Identification of
bacterial strains will be necessary for replication of
study findings and to ensure consistency of treatment
before specific Lactobacillus-containing probiotics
can be recommended.
Only 1 of the 4 studies of probiotics for the prophy-
laxis of UTI reported a significant reduction in recur-
rent episodes.
39
Compared with a mean of 6.0 UTIs
per patient in the previous year, intravaginal adminis-
tration of probiotics reduced the incidence to 1.3 UTIs
per patient over 12 months of treatment. However,
17 of 20 recurrent UTIs in the probiotic group oc-
curred during the first month of therapy, when the
vaginal presence of Lactobacillus was least detectable.
Increased vaginal colonization was observed on
monthly evaluation of the purity and potency of the
once-weekly probiotic product containing L rhamno-
sus GR-1 and L fermentum B-54 (1.0 10
9
CFU per
suppository).
March 2008 467
R. Barrons and D. Tassone
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Address correspondence to: Robert Barrons, PharmD, BCPS, Associate
Professor of Pharmacy, Wingate University School of Pharmacy, 316 North
Main Street, Wingate, NC 28174. E-mail: rbarrons@wingate.edu