Efficacy of single- versus multiple-dose clotrimazole therapy

in the management of vulvovaginal candidiasis

T. Lebherz, M.D., E. Guess, M.D., and N. Wolfson, M;D.
Los Angeles, California, and Metairie, Louisiana

Single-dose treatment of vulvovaginal candidiasis with a 500 mg clotrimazole vaginal tablet was compared
to 3-day treatment with two 100 mg vaginal tablets administered daily in 115 patients enrolled in a double-
blind trial, 101 of whom were evaluated for efficacy. Patients with clinically and mycologically active
disease were treated (visit 1) and examined at 5 to 10 days (visit 2) and again at least 27 days (visit 3)
post treatment. At visit 2, mycologic tests and clinical examinations were negative in 37 of 48 patients
receiving single-dose treatment (77%) and in 47 of 53 patients receiving 3-day treatment (89%).
Corresponding results for visit 3 were 65% and 74%, respectively. There were no significant differences in
treatment response between groups, and only three patients reported adverse reactions. These data show
that single-dose treatment with clotrimazole, 500 mg, is as safe and effective as the more complex 3-day
regimen. (AM J OasTET GVNECOL 1985;152:965.)

Key words: Vulvovaginal candidiasis, c1otrimazole therapy

Clotrimazole is a synthetic antifungal agent used in
the treatment of vulvovaginal candidiasis. The mech-
anism of action of c1otrimazole is believed to involve
the inhibition of fungal sterol synthesis, specifically the
inhibition of formation of ergosterol-an essential con-
stituent of the fungal cell membrane . The degree of
inhibition of ergosterol biosynthesis by c1otrimazole is
a function of drug concentration. At low concentra-
tions, only partial inhibition occurs, resulting in a fun-
gistatic effect. At higher concentrations, c1otrimazole
may completely block ergosterol synthesis, producing
a fungicidal effect.
The antimycotic properties of c1otrimazole facilitated
the shortening of treatment for vaginal mycoses from
approximately 14 days to 6 or 7 days when a 100 mg
vaginal tablet or 5 ml of a I % vaginal cream was used.
Increasing the dose was found to reduce the required
treatment period to only 3 days. This study is designed
to see the effect of a 500 mg vaginal suppository.
Efforts to shorten the treatment period even further
by developing a more concentrated form of the drug
have been complicated by the relatively low water sol-
ubility of c1otrimazole. Water solubility of the drug at
pH values of less than 4 was known to be four times
greater than its solubility at a neutral pH. Bioavailability
studies showed acid formulations of c1otrimazole to be
associated with an increased rate of drug release. Vag-
inal secretion concentrations of c1otrimazole in patients
using one 500 mg suppository were found to produce
a zone of inhibition at 24, 48, and 72 hours consistently
greater than that produced for secretions in patients
From the Department of Obstetrics and Gynecology, University of
California (Los Angeles) Center for Health Sciences, the University
of Southern California School of Medicine, and Lakeside Hospital.
using 100 or 200 mg applications nightly for the same
period. Consequently, lactic acid-sodium lactate was
used for acidification of the c1otrimazole formulation,
and a 500 mg vaginal tablet was developed.
Quantitative subculture tests showed this new for-
mulation to have a killing rate of greater than 99 .19%
for Candida albicans.
For determination of clinical efficacy of once-daily
administration of the 500 mg lactic-acid formulation of
c1otrimazole, a double-blind multicenter study com-
paring this regimen was conducted in patients with vul-
vovaginal candidiasis.
Material and methods
Women 18 years of age and older with clinically di-
agnosed and mycologically confirmed vulvovaginal can-
didiasis of recent onset were considered for enrollment
in this study. The clinical diagnosis was based on the
presence of six signs and symptoms: vulval irritation,
vaginal irritation, discharge, pruritis, burning, and dys-
pareunia. These disease manifestations were graded on
a scale of zero to three. A total score of at least three
was required for entry into the study. Microscopic ex-
amination (potassium hydroxide) and cultures were
used for mycologic confirmation of vulvovaginal can-
didiasis.
Patients having continued treatment with tetracycline
or erythromycin were excluded. Women who used con-
traceptive foams, creams, or jellies were not eligible,
although the use of an oral contraceptive drug, intra-
uterine device , or diaphragm alone was permitted. Pa-
tients in whom early pregnancy was suspected and pa-
tients pregnant less than 13 weeks were excluded from
the trial. Other exclusion factors included hypersen-
sitivity to the imidazoles; concomitant vaginal infection
965
966 Lebherz, Guess, and Wolfson August 1, 1985
Am J Obstet Gynecol

___ 1 Day 500 mg

Table I. Baseline patient characteristics of
_ 3 Days 200 mg daily
_ 6 Day. 100 mg daily patients evaluable for efficacy
50
Clotrimazole
Inhibition Zone 40
From Vaginal 500mg 200mg
Secretion. mm 30 (n = 48) (n = 53)

Age (yr)
20 Mean 29.1 29.2
Range 19.0-71.0 19.0-59.0
10 Weight (lb)
0 24 48 72 Mean 132.3 138.8
Hours After Last Application Range 104.0-186.0 99.0-212.0
Duration of disease (mo)
Fig. 1. Inhibition zones of vaginal secretions. 0-1 41 51
> 1, <6 7 2
Pregnancy status
with Trichomonas, Gardnerella vaginalis, or group B Strep- Pregnant (> 13 wk) 44 48
Nonpregnant 3 3
tococcus; a history of diabetes mellitus; and treatment No information I 2
with exogenous estrogens. Contraceptive use
Written informed consent was obtained from all Oral contraceptive 20 20
Intrauterine device 1 0
study participants, at which point patients were ran- Other 10 II
domly assigned to one of two treatment groups. None 17 21
Group 1 received one vaginal tablet containing 500 No information 0 1
Recent medication
mg of clotrimazole with appropriate placebo; the other Yes 2 2
group received two 100 mg clotrimazole vaginal tablets No 45 50
Jaily for 3 days. No information I 1
Concomitant therapy
At the initial visit a physical examination was con- Yes 0 2
ducted and vaginal specimens were obtained for mi- No 48 51
croscopic evaluation and culture. The investigator then Signs and symptoms
(mean score)
placed three tablets deep into the vagina. Women in Vulval irritation 2.11 2.19
group 1 received one 500 mg clotrimazole tablet and Vaginal irritation 2.06 2.13
two placebo tablets. Women assigned to group 2 had Discharge 2.25 2.26
Itching 2.40 2.48
two 100 mg clotrimazole tablets and one placebo tablet Burning 2.21 2.21
inserted into the vagina. Both groups then inserted two Dyspareunia 1.50 1.35
tablets into the vagina on days 2 and 3; in group 1 the
tablets were placebo, and in group 2 they were active
drug, 100 mg. Results
Patients were instructed to return 5 to 10 days later A total of 115 patients were admitted to the study.
for visit 2 and again after 27 to 31 days for visit 3. At Data from 14 patients were considered to be invalid
these visits the signs and symptoms of candidiasis were and were excluded from the analysis of efficacy. Con-
again graded and vaginal specimens were obtained for sequently the outcome of treatment was analyzed in
microscopic examination and culture. Adverse reac- 101 patients: 48 assigned to the single-dose 500 mg
tions were also recorded at each visit. clotrimazole group and 53 treated with 200 mg of clo-
At the final visit the overall outcome of treatment trimazole daily for 3 days. Data from all 115 patients
was evaluated. Successful treatment was defined as the enrolled in the study were included in the analysis of
absence of signs and symptoms of vulvovaginal can- safety.
didiasis, coupled with negative mycologic findings. The Baseline data, such as demographic characteristics,
persistence of signs and symptoms or positive myco- pregnancy status, contraceptive use, recent use of other
logic findings constituted treatment failure. medication, concomitant use of medication other than
Fisher's exact test for categorical data and Student's the study drugs, and disease duration, were comparable
t test for continuous data were used for analysis of the in the two treatment groups. The pretreatment severity
baseline demographic and clinical characteristics of the of the signs and symptoms of vulvovaginal candidiasis
two treatment groups. Pretreatment comparability of did not differ significantly between these two groups
signs and symptoms of vulvovaginal candidiasis was de- (Table I).
termined by using a non parametric Wilcoxon's rank Ultimately the number of patients actively enrolled
test. Fisher's exact test was used to compare treatment in the study for efficacy were 48 in the 500 mg group
efficacy. and 53 in the 200 mg group. Results of microscopic
Volume 152
Number 7, Part 2
Table II. Overall posttreatment response
5-10 days
500 mg
(n= 48)
Response No.
I % No.
Success 37 77 47
Failure 11 23 6 II
examination at the final visit were negative in 39 of 48
patients (81 %) treated with a single dose of 500 mg of
clotrimazole and in 45 of 53 patients (85%) receiving
clotrimazole for 3 days. Cultures at the final visit were
negative in 32 of 48 patients (67%) receiving 500 mg
of clotrimazole and in 40 of 53 patients (75%) receiving
200 mg of clotrimazole for 3 days. Both microscopic
evaluations and cultures were negative in 32 of 48 pa-
tients (67%) receiving 500 mg of clotrimazole versus 39
of 53 patients (74%) receiving clotrimazole over 3 days.
The results of mycologic tests did not differ signifi-
cantly between the two groups.
At the first follow-up visit 5 to 10 days after treat-
ment, success was achieved in 37 of 48 patients (77%)
treated with a single dose of clotrimazole and in 48 of
53 patients (89%) treated in a 3-day regimen. At the
final visit, at least 27 days after treatment, clotrimazole
therapy was considered to be successful in 31 of 48
patients (65%) treated with 500 mg and in 39 of 53
patients (74%) treated with 200 mg daily for 3 days.
The higher rate of success at the first follow-up visit
was attributed to the successful response initially noted
in six patients treated with a single dose of clotrimazole,
and results in eight patients given the drug for 3 days
did not differ significantly at either follow-up evalua-
tion (Table II).
Only three adverse reactions were noted during the
study. A vulvar lesion was noted in one patient treated
with a single dose of 500 mg of clotrimazole and in one
patient treated with 3-day therapy. In both cases, this
finding was considered to be remotely related to clo-
trimazole treatment. A perianal rash possibly related
to clotrimazole administration occurred in one patient
in the 200 mg treatment group.
Comment
The results of this study, in which administration of
a single vaginal tablet containing 500 mg of clotrimazole
was shown to be equivalent to treatment with two 100
mg tablets administered over 3 days, support the find-
ings of in vitro investigations with the lactic acid for-
mulation of the drug.
An earlier study compared the vaginal secretion
Management of vulvovaginal candidiasis 967
Clotrimazole
~27 days
200 mg 500 mg 200 mg
(n= 53) (n= 48) (n= 53)
I % No.
I % No.
I %
89 31 65 39 74
17 35 14 26
levels of clotrimazole in women undergoing treatment
for vulvovaginal candidiasis after administration of 100
mg for 6 days, 200 mg for 3 days, and 500 mg for I
day. Secretions were collected at 24, 48, and 72 hours
after the last dose of clotrimazole. The vaginal concen-
tration of the drug was determined by measuring the
diameter of the zone of inhibition that resulted after
introduction of the collected secretions on agar plates
inoculated with C. albicans. At all three time periods,
vaginal secretions from each treatment group markedly
inhibited yeast growth. The zone of inhibition pro-
duced by secretions from women treated with the 500
mg dose was consistently greater, however, than that
produced by the secretions from women treated with
the 100 or 200 mg dose (Fig. 1). These observations
demonstrate that levels of clotrimazole achieved after
treatment with a single dose of the lactic acid formula-
tion of the drug remain sufficient to inhibit the growth
of C. albicans for at least 3 days after administration.
Additionally, it appears that the 500 mg, one-dose ap-
plication can be used alternately in recurrent cases.
With the low water solubility of clotrimazole, tissue
penetration of neutral forms of the drug is poor. At a
pH of 3.5 to 3.8 in the lactic acid formulation, the
release rate of clotrimazole is increased, thereby per-
mitting increased tissue penetration. In addition, ani-
mal studies have suggested clotrimazole to be reversibly
bound to keratin of the vaginal skin, which may also
explain the persistence of high concentrations of the
drug several days after administration. Finally, the
adhesion of C. albicans to the vaginal epithelial cells is
markedly stronger and higher at a pH of 6 than at a
pH of 3 to 4. All of these features seem to be associated
with lactic acid formation and may contribute to the
efficacy of I-day treatment with high-dose clotrimazole.
REFERENCES
I. Plempel M. On the action of kinetics of clotrimazole. Che-
motherapy 1982;28(suppl 1):22-31.
2. Robertson WH, et al. Genital candidiasis: Topical manage-
ment with clotrimazole. Cutis 1976; 17 :760-2.
3. Robertson WHo Vulvovaginal candidiasis treated with clo-
trimazole cream in seven days compared with fourteen-day
treatment with miconazole cream. AM J Os STET GYNECOL
1978;132:321-3.
 Lebherz, Guess, and Wolfson August I, 1985
Am J Obstet Gynecol

4. Franklin R. Seven-day clotrimazole therapy for vulvovag-
inal candidiasis. South Med J 1978;71 (2): 141-3.
5. Masterton G, Napier IR, Henderson IN , Roberts JE.
Three-day clotrimazole treatment in candidal vulvovagi-
nitis. Br J Vener Dis 1977;53:126-8.
6. Robertson WH o A concentrated therapeutic regimen for
vulvovaginal candidiasis. JAMA 1980;244:L2549-50.
7. Granitzka S. Efficiency of various therapeutic concepts in
genital mycoses. Chemotherapy 1982;28(suppl 1):92-8.
8. Mendling W, Plempel M. Vaginal secretion levels after 6
days, 3 days and 1 day of treatment with 100, 200 and 500
mg vaginal tablets of clotrimazole and their therapeutic
efficacy. Chemotherapy 1982;28(suppl 1):43-7.

Therapeutic results obtained in vaginal mycoses after single-

dose treatment with 500 mg clotrimazole vaginal tablets
F. Fleury, M.D., D. Hughes, M.D., and R. Floyd, M.D.
Springfield, Illinois, Philadelphia, Pennsylvania, and Stanford, California

A multicenter, double-blind study of 103 patients with clinically and mycologically documented vulvovaginal
candidiasis compared single-dose treatment with a 500 mg clotrimazole vaginal tablet to 3-day treatment
with two 100 mg clotrimazole vaginal tablets administered daily. Patients were examined 5 to 10 days (visit
2) and at least 27 days (visit 3) post treatment. At visit 2, mycologic and clinical examinations were
negative in 43 of 48 efficacy-evaluable patients receiving clotrimazole, 500 mg (90%), versus 42 of 47
efficacy-evaluable patients receiving clotrimazole, 200 mg (89%). Similarly, at visit 3, 75% of patients
receiving clotrimazole, 500 mg, had treatment success versus 72% receiving clotrimazol~, 200 mg. There
were no significant intergroup treatment differences, indicating that single-dose treatment with clotrimazole,
500 mg, is equipotent to the multidose regimen. (AM J OaSTEl GVNECOL 1985;152:968.)

Key words: Vulvovaginal candidiasis, clotrimazole

Patient compliance is an important factor in the suc-
cessful management of vulvovaginal candidiasis. Few
women with this condition delay in consulting a phy-
sician for treatment of the clinical signs and symptoms
of vaginal mycoses. I Once these signs and symptoms
subside, however, patients often neglect to continue
treatment. 2
The introduction of the imidazole antifungal agent
clotrimazole has had a significant impact on patient
compliance. Before the availability of this drug, the
required duration of therapy in patients with vulvo-
vaginal candidiasis was at least 14 days. Because of the
potent antimycotic properties of clotrimazole, this drug
was effective when administered once daily for only 6
to 7 days.3.5
Subsequent investigations showed that the clotrim-
azole treatment regimen could be further simplified
by the use of higher doses of the drug. When a daily
dose of 200 mg was administered, the treatment period
could be shortened to only 3 days.6.s The use of this
dose level was found to be associated with a higher rate
of patient compliance. Rausch et al.I reported a 100%
compliance rate in patients treated with clotrimazole
for 3 days. In addition, 81 % of these patients returned
for a follow-up examination. When a 6-day clotrimazole
regimen was used, the compliance rate was 94%, and
79% of the patients returned for a follow-up exami-
nation . A 12-day clotrimazole regimen was associated
with a compliance rate of 83%. Only 66% of patients
assigned to this regimen returned for a follow-up ex-
amination.
These findings illustrate the relationship between pa-
tient compliance and the complexity of the treatment
regimen. In an effort to further increase compliance
in patients with vulvovaginal candidiasis, a more potent
clotrimazole preparation was developed. This formu-
lation contains 500 mg of the drug and is intended for
administration only once. A double-blind multicenter
trial was conducted to determine whether a single dose
of this new preparation was as effective and safe as two
100 mg clotrimazole tablets administered daily for 3
days.

Methods and material

From the Southern Illinois School of Medicine, the Department of To be eligible for participation in this study, patients
Obstetrics and Gynecology, Medical College of Pennsylvania, and
the Department of Obstetrics and Gynecology, Stanford University were required to be at least 18 years of age and to have
School of Medicine. clinically diagnosed and mycologically confirmed vul-

968