ARTICLE IN PRESS

Phytomedicine 15 (2008) 1025–1031

www.elsevier.de/phymed

A comparative study of the therapeutic effects of the Zataria multiflora

vaginal cream and metronidazole vaginal gel on bacterial vaginosis
M. Simbara,, Z. Azarbadb, F. Mojabc, H. Alavi Majdd
a
School of Midwifery, Shahid Beheshti Medical Science University, Tehran, Iran
b
Deputy of Research, Kashan Medical Science University, Kashan, Iran
c
School of Pharmacy and Pharmaceutical Sciences Research Center (PSRC), Shahid Beheshti Medical Science University,
Tehran, Iran
d
School of Paramedical, Shahid Beheshti Medical Science University, Tehran, Iran

Abstract
Bacterial vaginosis (BV) is one of most prevalent complications among reproductive-aged women. Metromidazole
prescription, which is considered as the first-line treatment of BV, is usually followed by a few side effects. Besides,
there is a growing tendency toward herbal medicines for the treatment of vaginitis. Antibacterial and antifungal effects
of Zataria multiflora (Z. multiflora) have been demonstrated in vitro and in vivo. This study aimed to compare the
therapeutic effects of the Z. multiflora vaginal cream and metronidazole vaginal gel on bacterial vaginosis.
This was a randomized clinical trial on 90 married women aged 18–40 affected by BV who attended for treatment to
the gynecology clinic of Shabih-Khani Hospital. They randomly divided to two groups of 45 participants. Diagnostic
criteria were Amsel’s criteria and Gram stain. Z. multiflora vaginal cream or metronidazole vaginal gel for five-night
usage were prescribed to each group, and after 2–7 days therapeutic effects on participants’ complications and their
Amsel criteria were assessed. Data analysis was performed by McNemar and Fisher exact tests.
Patients’ complication and their Amsel’s criteria were significantly decreased after treatment with Z. multiflora or
metronidazole (po0.05). Relative risk for unresponsiveness to treatment with Z. multiflora, to unresponsiveness to
metronidazole was 1.5, which was not significant. Therapeutic effects of Z. multiflora vaginal cream are similar
to metronidazole vaginal gel on BV. Therefore it could be an appropriate choice to BV treatment for those interested
in herbal medicines or those affected by side effects of metronidazole.
r 2008 Elsevier GmbH. All rights reserved.

Keywords: Bacterial vaginosis; Zataria multiflora; Metronidazole

Introduction anaerobic bacteria and a reduction in lactobacillary

Bacterial vaginosis (BV) results from an imbalance
of the normal vaginal flora, with an overgrowth of
Corresponding author. Tel.: +98 21 8888 3133;
fax: +98 21 4400 8378.
E-mail addresses: msimbar@sbmu.ac.ir, msimbar@yahoo.com
(M. Simbar).
flora (Weir, 2004). Its prevalence was reported to be
27%, with 28% in sexually experienced and 18% in
non-sexually experienced women (Yen et al., 2003). BV
is associated with adverse pregnancy outcomes,
upper genital tract infections such as pelvic inflamma-
tory disease, endometritis, post-gynecologic-surgery
infections, cervicitis, urinary tract infections, cervical
intraepithelial neoplasia, and increased risk of sexual

0944-7113/$ - see front matter r 2008 Elsevier GmbH. All rights reserved.
doi:10.1016/j.phymed.2008.08.004
 ARTICLE IN PRESS
1026 M. Simbar et al. / Phytomedicine 15 (2008) 1025–1031
acquisition of human immunodeficiency virus infection
(Cauci et al., 2002). Studies have shown that sponta-
neous abortion, preterm labor, premature birth, preterm
rupture of the membranes, amniotic fluid infection,
postpartum endometritis, and post-cesarean wound
infections are increased because of infection with BV
during pregnancy (McGregor and French, 2000). It is
the most common vaginal infection among women of
child-bearing age and in up to 25% of women attending
gynecologic clinics (Sweet, 2000). Although metronida-
zole has been known as an effective management of BV,
its efficacy must be weighed against its possible side
effects (Pheifer et al., 1978). The most frequently
reported side effects of metronidazole are vaginal
discharge, symptomatic candidiasis, and vulvovaginal
irritation; following oral metronidazole therapy, the side
effects are gastrointestinal disorders, nausea, and
metallic taste (Wain, 1998). The other option of
management is clindamycin, which may cause dry skin,
redness or irritation, peeling, oiliness, and itching or
burning (Medlineplus, Clindamycine, 2007). The emer-
gence of clindamycin-resistant anaerobic gram-negative
rods following therapy is of concern (Beigi et al., 2004;
Austin et al., 2005).
The use of herbal therapies is on the rise (Klepser and
Klepser, 1999) and more than 80% of people in
developing countries are using traditional medicines
including herbal medicine (WHO, 2002). These medi-
cines can be used safely if they are prescribed by
educated health personnel with appropriate dose and
special caution in pregnancy (Medlineplus, Herbal
Medicine, 2008). The most commonly used alternative
therapies for yeast vaginitis and BV are Lactobacillus
recolonization by yogurt or capsules, boric acid douch-
ing, tea tree oil, and garlic (Kessel et al., 2003).
Thyme is a herbal remedy with antibacterial proper-
ties including gram-positive and -negative bacteria
(Agnihotri and Vaidya, 1996). Its extract has been
used to treat gastrointestinal disturbances, respiratory
disorders, coughs due to colds, bronchitis and pertussis,
laryngitis and tonsillitis, minor wounds, the common
cold, disorders of the oral cavity, and as an antibacterial
agent in oral hygiene (WHO, 1999).
Zataria multiflora is a thyme-like plant that grows
wild in central and southern Iran, Afghanistan, and
Pakistan. It is a member of the Labiatae family to which
mint, rosemary, and several other medically useful
plants also belong. The generic name derived from
the Arabisc word ‘‘Za, atar’’ means Thyme. It can be
recognized by the orbicular, densely gland-dotted, ovate
leaves and the densely white hairy round buds in the leaf
axils. It is an aromatic shrub with up to 60–89 cm in
height. Mature branches are woody and leafless,
whereas young branches are white with a dense
glandular, spreading, pilose indumentums. Leaves
(5–10  5–10 mm) are orbicular ovate to orbicular.
Flowering stems are usually unbranched or sometimes
have short lateral branches. Flowers are sub-sessile, very
small, and often male sterile (Saleem, 2000). In Iran,
Z. multiflora, called Shirazian thyme, is used as a
traditional remedy for its antiseptic, analgesic, and
carminative properties. It is also successfully used in the
treatment of recurrent aphthous stomatitis (Jafari et al.,
2003; Mansouri et al., 2002) and denture stomatitis
(Amanlou et al., 2006).
The composition of the essential oil of Z. multiflora
Boiss was studied by gas liquid chromatography (GLC),
column chromatography (CC), NMR, and GLC/MS
(Shafiee and Javidnia, 1997). The main constituents of
the dry Z. multiflora are carvacrol (61.3%) and thymol
(25.1%), while the main constituents of the fresh plant
are thymol (48.4%), carvacrol (12.6%), P-cymene
(13.5%), linalool (5.2%), and g-terpinene (3.9%)
(Shafiee and Javidnia, 1997; Saleem et al., 2000, 2004).
The essential oils reported from Z. multiflora are
tricyclene, a-pinene, b-pinene, camphene, a-terpineol,
r-cymene, myrecene, 1,8-cineol, g-terpinene, terpino-
lene, terpinen-4-ol, a-thujene, carvone, cavacrol, thymol,
thymol acetate, methyl carvacrol, carvacrol acetate,
aromadendrene, valencene, 9-aristolen-1-a-ol, and
guaiol, a-himachalene (Saleem, 2000).
Its essential oil was found to contain a significant
amount of thymol and carvacrol, both of which are
antimicrobial and antifungal (Shafiee and Javidnia,
1997; Saleem et al., 2004). The essential oil of
Z. multiflora was also effective in impeding trichomonas
in in vitro condition (Azadbakht et al., 2003). It has also
demonstrated that Z. multiflora vaginal cream was as
effective as clotrimazole vaginal cream in the treatment
of candida vaginitis (Islami et al., 2004).
This study aimed to compare the therapeutic effects of
Z. multiflora (Loucorexs) vaginal cream with metroni-
dazole vaginal gel on bacterial vaginosis, which seemed
to be important with regard to the high prevalence of
bacterial vaginosis and the general tendency towards
herbal medicine.
Material and methods
This was a randomized clinical trial study, to compare
the therapeutic effects of Z. multiflora vaginal cream
(Loucorexs) with metronidazole vaginal gel on bacte-
rial vaginosis. Ninety married women, affected by
bacterial vaginosis, aged 18–40, participated in the
study. They were randomly divided into two groups of
45 participants. The study was performed in the
gynecology clinic of Shabih-Khani Hospital related to
Kashan Medical Sciences University. These women were
not pregnant; not breast feeding; not taking alcohol
or were anti-coagulant, or were immunosuppressive- or
IUD-users; and had no medical recognized disease.
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M. Simbar et al. / Phytomedicine 15 (2008) 1025–1031 1027

They were the only partner of their husbands. They were Data were analyzed using SPSS and using tests such
not using vaginal drugs during the last 14 days. They as Student’s T test, Chi Square, Fisher exact test, and
had no candidia or trichmonas vaginitis, or cervicitis McNemar. McNemar was used to compare signs of
based on direct smears. Written consent was taken bacterial vaginosis and Amsel’s criteria, before and after
from each participant before the commencement of the treatment, and Fisher’s exact test was also used to
study. Ethical committee of Shahid Beheshti Medical compare results following treatment between groups.
University confirms the study. The confidence interval for the tests was 95%.
Loucorexs was produced by Barij Essence Company
(serial no. 1632). It was prepared as a cream in a 50 g
tube, containing 0.315–0.385 mg thymol of Z. multiflora. Results
Metronidazole was made by Pars Darou Company, as
in a 0.75%g vaginal gel (serial no. 2625). Ninety women affected by bacterial vaginosis were
After history taking, the women were vaginally divided into two groups of 45. One woman from the
observed and examined using a speculum, to find out metronidazole treatment group was excluded from the
any signs of vaginitis and abnormal discharge. Samples study because of incompatibility of Gram stain with
of vaginal secretion specimen were collected using a Amsel’s criteria. Two women from the Z. multiflora
sterile swab from the upper-lateral side of the vaginal group were also excluded from the study because they
wall. It was applied onto three slides. The first specimen did not attend the follow-up visits. Therefore full
was added by normal saline to observe the possible acceptance of the treatment was related to 88 women
presence of clue cells and trichomonas vaginalis. The out of the 90 (97.8%) participants.
second specimen was added by one drop of 10% KOH Treatment groups had no significant differences
solution to carry out the Whiff test and to assess the regarding their demographic and reproductive charac-
possible presence of candidia microscopically (  40 teristics as well as their age, weight, years after marriage,
magnification, USA Leica Company). The third speci- education, age of first pregnancy, and number of
men was dried out at room temperature and was fixed pregnancy, abortion, or caesarian section (Student’s
by methanol to be used for Gram stain and diagnosis T test, p40.05, Table 1).Two groups were not signi-
of bacterial vaginosis by Nugent scoring. The sample ficantly different regarding their occupation (Fisher’s
pH was assessed using pH-meter paper (Nagel- exact test, p40.05). There were also no significant
Germany-Machery Co.). All the laboratory procedures differences between two groups regarding their contra-
were performed in the laboratory of Shabih-Khani ceptive method and health condition (Fisher’s exact test,
Hospital. Women were excluded if there were tricho- p40.05, Table 2). The two groups were also not
monas or candidia in their samples. significantly different regarding the history of menstrual
Criteria for diagnosis of BV were based on the disorders or using wet underwear (Fisher’s exact test,
presence of three Amsel’s criteria of the following four p40.05).
criteria: a vaginal pH higher than 4.5; the presence of
clue (vaginal epithelial) cells in the vaginal fluid; a thin,
grey or white homogenous discharge; or a positive KOH Table 1. Demographic and fertility characteristics of women
‘‘whiff’’ test (the release of an amine [fishy] odor upon with bacterial in two treatment groups of Zataria multiflora
the addition of 10% potassium hydroxide to the vaginal and metronidazole in Shabih-Khani Hospital of Kashan
Medical University
fluid). Also, Gram stain diagnosis of bacterial vaginosis
was based on score 7–10 by Nugent criteria. Characteristics Groups
The treatment group of Z. multiflora used an
application of the cream nightly for five nights. The Z. multiflora Metronidazole
treatment group of metronidazole used the gel vaginally (mean7SD) (mean7SD)
for five nights. Some notes for personal health were also Age (years) 32.2375.82 32.776.51
explained in a piece of paper for patients. A form for Weight (kg) 66.3579.82 68710.37
self-report was also given to all participants to assess Education (years) 9.0574.37 9.4374.46
their correct use of the medicines. The women were told Education of husband 10.0973.75 9.5273.61
to fill up the forms nightly, after the gel or the cream (years)
application. They were also asked to attend clinic 2–7 Marital duration (years) 12.0275.95 12.3076.45
days following the treatment period. They were asked First pregnancy age 19.7774.59 19.3272.88
about drug complications. In this follow-up visit, (years)
whole diagnosis procedures were repeated again and Number of pregnancies 2.0771.12 2.2571.45
successful treatment was demonstrated by the presence Number of caesarian 0.3570.65 0.3670.57
sections
of one or no Amsel’s criteria, and negative result of
Number of abortions 0.1270.32 0.2370.52
Gram stain.
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1028 M. Simbar et al. / Phytomedicine 15 (2008) 1025–1031

Table 2. Contraceptive use and health condition of women 86

with bacterial vaginosis in two treatment groups of Zataria
multiflora and metronidazole Shabih-Khani Hospital of 74
Kashan Medical University 72 71 90

Contraceptive and Groups 80

health condition
70
Zataria multiflora Metronidazole
no. (%) no. (%) 60
19 30
Contraceptive 27 50
Combined oral 4 (9.3) 4 (9.3) 14 7 25
contraceptives 23 40
ge 23 5 20
DMPA 1 (2.3) 0 (0) char
a g in al Dis dor
5 2 21 30
V O
Condom 4 (9.3) 3 (6.8) Amin onia 16
ar 07 0
Withdrawal 26 (60.5) 28 (63.8) Dysp pain 20
g a s tric 16 0 11
Tubectomey 3 (7) 3 (6.8) hyp s
coitu 2 2 10
Vasectomy 1 (2.3) 1 (2.3) dorin
malo r ia 5
Condom and 4 (9.3) 5 (11.4) dysu 0 0
in g
withdrawal itch After
Before
ol
Before After Zataria az ol metronidaz
Use Me tro nid
Zataria use e use
e use
General health
Pool-swimming 8 (18.6) 10 (22.7) Before Zataria use After Zataria Use
Public bath use 1 (2.3) 3 (6.8) After Metronidazole use Before metronidazole use
None 34 (79.1) 31 (70.5) Fig. 1. Complications of women with bacterial vaginosis in
Menstrual health two treatment groups of Zataria multiflora and metronidazole.
Pad-use 35 (81.4) 37 (84.1)
Mattress-use 5 (11.6) 3 (6.8) 100 100
98
Cotton-use 2 (4.7) 1 (2.3) 93 100
91
88 90
Total 82
81 80
No. (%) 43 (100) 44 (100)
70
60
50
40 41
The complications were significantly decreased in 40
both groups of women. Except for itching, signs and 919 30
symptoms were significantly decreased after the applica- 09 20
Grey Hemogenn Discharge
tion of Z. multiflora cream (McNemar test, po0.05). Clue cells in wet expansion 9 7 10
The frequency of itching was decreased from 16.3% to pH>4.5 0
Positive Anin Test After Before
4.7%, but this decrease was not significant. All signs Before Zataria After Metronidazolemetronidazole
Zataria Use use
and symptoms were significantly decreased after use use

metronidazole use (McNemar’s test, po0.01). There
were no significant differences between the two
groups regarding the frequency of complications
(Fisher’s exact test, po0.01). Therefore, both treatment
groups were effective in relieving patient’s complications
(Fig. 1).
There were significant differences between Amsel’s
criteria before and after Z. multiflora use (McNemar’s
test, po0.01). There were also significant differences
between Amsel’s criteria before and after metronidazole
use (McNemar’s test, po0.01). After treatment, Amsel’s
criteria were not significantly different between the two
groups (Fisher’s exact test po0.001). Therefore, both
treatments had similar effects in improving Amsel’s
criteria after treatment (Fig. 2).
The relative risk for the failure of Z. multiflora to the
failure of metronidazole in the treatment of BV was 1.53
(CI: 95%, 0.27–8.97). The relative risk was not
Before Zataria use After Zataria Use
After Metronidazole use Before metronidazole use
Fig. 2. Amsel’s criteria before and after treatment in women
with bacterial vaginosis in the two treatment groups of Z.
multiflora and metronidazole.
significant and therefore both treatments have similar
effects in the treatment of bacterial vaginosis (Table 3).
The complications of two treatment methods were
assessed and demonstrated that Z. multiflora causes
vaginal burning in 14% of users, although it does not
cause metallic taste or vertigo (Table 4).
Discussion
For the first time, this study demonstrated similar
treatment effects of Z. multiflora cream and metronidazole
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M. Simbar et al. / Phytomedicine 15 (2008) 1025–1031 1029

Table 3. Responses to the treatments of women with vaginalis demonstrated that Z. multiflora can reduce the
bacterial vaginosis in two treatment groups of Z. multiflora frequency of vaginal discharge, itching, urine burning,
and metronidazol and dyparonia, which was similar to the results of
this study (Islami et al., 2004; Fouladi, 2003). The
Treatment Groups
Z. multiflora vaginal cream was not effective in relieving
Zataria multiflora Metronidazole itching in our study. However, there were only a few
no. (%) no. (%) cases of itching before treatment that made statistical
analysis impossible. So it cannot be concluded that
Success 40 (93) 42 (95.5) Z. multiflora vaginal cream is not effective in improving
Failure 3 (7) 2 (4.5)
the itching problem.
Total 43 (100) 44 (100)
For the first time, this study showed that Z. Multiflora
vaginal cream is effective in reliving bacterial vaginosis
based on Amsel’s criteria. The frequency of Amsel’s
Table 4. Side effects of Zataria multiflora vaginal cream and criteria in BV patients of this study was similar to the
metronidazole vaginal gel in women with bacterial vaginosis frequency of other studies (Baloglu, 2003).
Metallic taste and vertigo was not caused by
Treatment Groups
metronidazole; however, the frequency of nausea
Zataria multiflora Metronidazole and vaginal dryness following the application of
no. (%) no. (%) Z. multiflora was similar to after metronidazole use
and burning vagina was even more frequent. Therefore,
Burning vagina 6 (14) 2 (4.5) although Z. multiflora is usually reported without
Vaginal dryness 1 (2.3) 1 (2.3) complication, thymol causes skin and mucosal irrita-
Vertigo 0 (0) 2 (6.8)
tion, and although there is no evidence for its
Nausea 1 (2.3) 2 (4.5)
Metallic taste 0 (0) 2 (4.5) teratogenic effects during pregnancy, its safety is not
Total 43 (100) 44 (100) proved and its use is prohibited during pregnancy and
breast feeding (Agnihotri and Vaidya, 1996).
One subject of the study in the metronidazole
treatment group was excluded from the study because
gel on bacterial vaginosis. Similar treatment effects of the of incompatibility of Gram stain with Amsel’s criteria.
essence of Z. multiflora and clotrimazole cream on Two subjects were also excluded from the Z. Multiflora
improving signs and symptoms of candida vaginitis were group because of their non-attendance in their follow-up
demonstrated in previous studies (Islami et al., 2004; visits. Therefore, accept abilities of the two treatment
Fouladi, 2003). Z. multiflora is a thyme-like plant. Thyme methods were 96% and 100% in the Z. multiflora and
is demonstrated to be as effective as clotrimazole in metronidazole groups, respectively.
destroying the pathogen of Trichomonas vaginalis in vitro Relative risk of failure in treatment was not sig-
(Azadbakht et al., 2003). Thyme is one of World Health nificant, which means Z. Multiflora vaginal cream is as
Organization-selected herbs with antibacterial and anti- effective as metronidazole in the treatment of bacterial
fungal effects (Agnihotri and Vaidya, 1996; Cowan, 1999). vaginosis. Bacterial vaginosis is the most prevalent cause
Essential oil of thyme was demonstrated to have of women attending gynecology clinics and besides it
antifungal and anti-gram-positive and anti-gram-negative may cause critical complications. Therefore its treat-
bacterial effects (López et al., 2007) such as some Bacillus ment is important and metronidazole is the first
species (Ozcan et al., 2006) Staphylococcus aureus, treatment of choice and the most effective method of
Bacillus subtilis, Escherichia coli (Fan and Chen, 2001) treatment of this condition. But metronidazole can
and Bacillus cerus (Akhound-Zadeh Basti et al., 2005). cause a few side effects. Therefore, introducing a few
The antibacterial effect of the herb is related to phenolic alternative medicines may be useful. Essential oil of
components of thymol and carvacrol (Jafari et al., 2003). Z. multiflora is very effective on nonaerobic bacteria
Carvacrol and thymol can alternate membrane fatty acid in vitro. Since Lactobacillus sp., which is a useful flora of
constituents of microbial cells (DiPasqua et al., 2006; vagina, is resistant to Z. multiflora, metronidazole is an
Kelemba and Kunicka, 2003). appropriate alternative medicine for bacterial vaginosis.
This study demonstrated that Z. multiflora vaginal In conclusion, herbal medicine and their healthy
cream has similar effects on improving the signs and production can make a wider range of treatment options
symptoms of bacterial vaginosis and Amsel’s criteria. for patients and practitioners. Herbal medicines
The frequency of women with vaginal discharge, have limited complications and can be appropriate
malodor, and itching was similar to a previous study alternatives for chemical medicines. With regard to the
(Gutman et al., 2005). A comparison between effects of long history of herbal medicine in Iran, women’s
Z. multiflora cream and clotrimazole cream for Candidia acceptability of these medicines is high and standard
 ARTICLE IN PRESS
1030 M. Simbar et al. / Phytomedicine 15 (2008) 1025–1031
production of these drugs can make their prescription
by health personnel easier. Obstetrician and midwives
can offer Z. multiflora as an appropriate alternative
medicine for women who like to use herbal medicines, or
who suffer metronidazole side effects in the treatment of
bacterial vaginosis.
Acknowledgement
We appreciate the research department of Shahid
Beheshti Medical University, which found the study and
Gynecology clinic as well as laboratory personnel of
Shabih-Khany Hospital for their friendly cooperation
with the researchers of the study.
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