Treatment of Bacterial Vaginosis What We
Treatment of Bacterial Vaginosis What We
Treatment of Bacterial Vaginosis What We
6. Treatment of BV in pregnancy
i) decent study layout, ii) proper statistics, iii) comparison group (placebo or
standard treatment) and iv) language English, French, Dutch or German.
7. Expert opinion
The following keywords were used: bacterial vaginosis and treatment or
management or therapy or prophylaxis or prevention. Results were grouped
in treatment categories and were discussed.
Expert opinion: Clindamycin and metronidazole are the standard drugs for
BV. As other antibiotic and acidifying treatments are progressively being
studied, like tinidazole, rifaximin, nitrofuran, dequalinium chloride, vitamin
C and lactic acid, more options have become available for switching therapy,
combining therapies and long-term prophylactic use to prevent recurrences.
For personal use only.
Further studies are needed. Also, adjuvant therapy with probiotics may have
a significant role in improving efficacy and in preventing recurrences.
However, it is unlikely that probiotics will replace antibiotherapy.
1. Introduction
and commercialized, but in most circumstances, microscopy to placebo showing that rifaximin 25 mg/day for 5 days is
and clinical examination suffice for a proper diagnosis [67-74]. the most effective treatment to be used in future pivotal stud-
ies for the treatment of BV [110]. Quantitative polymerase
4. Therapy chain reaction (PCR) demonstrated an increase of Lactobacil-
lus genus and a decrease of the BV-related bacterial groups
The cornerstone of the treatment is the use of local or sys- after the antibiotic treatment. PCR-denaturing gradient gel
temic antibiotics with activity against anaerobes. Besides electrophoresi (DGGE) profiles confirmed the capability of
these, antiseptic or probiotic preparations can be used, the rifaximin to modulate the composition of the vaginal micro-
latter more in an adjuvant or prophylactic setting (Table 1). bial communities and to reduce their complexity [111]. In a
study comparing women with BV using rifaximin versus
4.1 Antibiotics normal control women, it was demonstrated that a large num-
At present, three antibiotics are approved for treatment of BV: ber of human proteins were differentially expressed in women
metronidazole, tinidazole and clindamycin. These drugs have with BV in comparison with healthy women (n = 118) and in
a similar efficacy when given locally in the vagina or taken BV-affected women treated with rifaximin (n = 284) [112]. In
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by 193.191.9.110 on 02/28/14
orally and have cure rates of about 58 to 92% after 1 month both comparisons, approximately 20% of the dysregulated
in doses of 500 mg oral metronidazole twice daily for proteins were involved in the innate immune response. Of
5 days, 2% vaginal clindamycin cream once daily for 7 days, the 24 proteins, 21 increased in abundance in women with
oral clindamycin 300 mg twice daily for 7 days, metronida- BV versus healthy women and 31 of 59 proteins decreased
zole 0.75% vaginal gel once daily for 5 days or the stat regi- after rifaximin treatment, thus suggesting a general reduction
mens of 2 g of metronidazole or tinidazole in a single of the immune response resulting from the therapy. Major
dose [75-85]. None of the 5-nitro-imidazoles (tinidazole, met- changes in protein abundance were found following treatment
ronidazole, ornidazole, secnidazole) was superior to the other with 25 mg/day of rifaximin for 5 days.
(cure rates 57 -- 63%) after 1 month, but the combination of
vaginal plus oral use was somewhat superior: 80 -- 86% cure 4.2 Antiseptics
For personal use only.
rates vs 75 -- 86% [86-90]. Using a high stat dose of 2 g of met- Antiseptics have antibacterial actions against a wide range of
ronidazole vaginally proved as efficacious as 2 g orally, but it aerobic and anaerobic bacteria, by nonspecifically disrupting
produced few side effects [91]. In general, for both metronida- the bacterial cells membrane. Antiseptics like benzydamine,
zole and clindamycin, the local formulations showed equal chlorhexidine, dequalinium chloride, polyhexamethylene
efficacies than oral route (75 -- 86%), but few side effects biguanide, povidone iodine and hydrogen peroxide have
were noted [92,93]. been administered to women with BV as vaginal supposito-
Other antibiotics like ofloxacin, azithromycin or erythro- ries, bioadhesive gel formulations and occasionally loaded on
mycin should not be used to treat BV [94-96], although cefa- pessaries. There are only sporadic reports of antimicrobial
droxil had comparable cure rates to metronidazole in one resistance against antiseptics agents, and they are safe for
study [97]. Some data indicate that more aggressive BV treat- mucosal applications in appropriate concentrations and with-
ment with antibiotics (2% clindamycin vaginal cream out systemic exposure [113]. Stray-Pedersen et al. have shown
together with oral clindamycin 600 mg/day 7 days, followed that vaginal douching with 0.2% chlorhexidine during labor
with vaginal metronidazole gel for 5 days) combined with spe- can reduce both maternal and early neonatal infectious
cific Lactobacillus strain and partner treatment can provide morbidity, but the main target of this treatment was to reduce
long-lasting cure in some cases [98]. However, the doses used the transmission of Escherichia coli, Group B streptococci and
in this trial were non-conformistic and supratherapeutic and Staphylococcus aureus and to prevent early onset neonatal
cannot be advised for uncomplicated cases. sepsis [114]. Dequalinium chloride showed in vitro and
Side effects like nausea, pyrosis, stomach pains, intolerance in vivo similar antibacterial and antifungal properties than
for alcohol due to metronidazole [99] and the weakening effect povidone iodine [115,116] and its vaginal use was recently found
on the condoms [100,101] and the rare but severe complication to be as effective as clindamycin cream in a single-blind, ran-
of pseudomembranous colitis [102] due to clindamycin, war- domized trial in women with BV, and a nonsignificant reduc-
rant caution for excessive use of these drugs, as well as the tion of Candida infection was found in the dequalinium
increasing development of antibiotic resistance [103-108]. group [117]. Besides one study showing slightly better results
An innovative approach was to test a locally applied non- in 15 days after treatment of acute BV than when only vaginal
absorbable, non-imidazole antibiotic, rifaximin, in the vagina lactobacilli were applied [118], no studies show a benefit of
of women with BV. Rifaximin, a derivative of rifamycin, with povidone iodine. Nevertheless, the product is frequently
broad-spectrum antibacterial activity covering gram-positive, used by women with BV and other abnormal conditions of
gram-negative, aerobic, and anaerobic bacteria has been used the vagina, most likely because of the temporary relief of the
to treat gastrointestinal infections as an oral formulation symptoms because of the vaginal rinsing effect itself.
and, being negligibly absorbed, presents a good safety pro- Unknown allergy of iodium may cause severe allergic
file [109]. Four different regimens were tested and compared reactions in women.
Table 1. Overview of treatment modalities for bacterial vaginosis and the levels of evidence and activity of each
therapy.
Antibiotics
Metronidazole Per os 500 mg 2dd 5 days A ++ [177]
Per os 2 g stat, once A ++ [93]
Vag ovulae 500 mg 1dd 5 days A ++ [75,91]
Vag ovulae 2 g once B ++ [87]
Vag cream 0.75% 1dd 5 days A + [77,80,92]
Tinidazole Per os 1dd 1 g 5 days B + [85]
2 g stat, once B ++ [78,85-87]
Vag tablets 1dd 500 mg 14 days B + [88]
Ornidazole Vag tablets/sup 1dd 500 g 7 days C + [178]
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Grading of recommendation: A. High: further research is very unlikely to change our confidence in the estimate of effect, B. Good: further research is likely to
have an important impact on our confidence in the estimate of effect and may change the estimate (only one high-quality study or several studies with some
limitations), C. further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate and D.
any estimate of effect is very uncertain.
dd: Durante diam (per day); Vag: Vaginal application
In Eastern Europe, nifuratel vaginal tablets have increas- excellent in vitro activity against Gardnerella vaginalis,
ingly been studied and used as a possible alternative treat- Mobiluncus and Atopobium vaginae, whereas it is not active
ment for BV. Its mode of action, originally designed for against lactobacilli [119,120]. Recently, two randomized con-
prevention and treatment of urinary tract infection, shows trolled trials (RCTs) using vaginal nifuratel were presented
ronidazole and caused severe caustic side effects on the vaginal cilli inhibit the growth of bacteria causing BV by producing
epithelium [125]. In another study, 0.92% acetic acid-based gel H2O2, lactic acid, bacteriocins and inhibit the adherence of
applied twice daily for 7 days was not superior to a pla- G. vaginalis to the vaginal epithelium [137].
cebo [124]. Also, lactic acid suppositories were less effective In one placebo-controlled study, vaginal use of three probi-
than metronidazole and equivalent to placebo in women otic lactobacilli (Lactobacillus brevis, L. saliverus and L. gasseri)
with BV [126]. gave better cure rates than placebo in symptomatic women
Polycarbophil--Carbopol-based vaginal gel during a 5-week with BV [138].
treatment course, however, was found to be effective: after In head-to head comparison studies comparing the efficacy
6 and 12 weeks, respectively, 97 and 83% were cured accord- of probiotic therapy with antibiotic therapy in women with
ing to the definitions of these authors versus 5 and 8% in the acute BV, a 5-day regimen of vaginal lactobacilli GR-1/
placebo group [127]. In this study, however, cure was defined as RC-14 showed equal results after 1 -- 4 weeks than 75% met-
absence of abnormal vaginal discharge, low pH, negative odor ronidazole vaginal gel [139]. However, in this study the cure
and Nugent < 7, without considering presence or absence of rates of metronidazole were only 55% after 6 days, which is,
clue cells or the typical anaerobic type bacterial flora, as seen even with the strictest criteria, rather low. Further, 7 years
in women with asymptomatic, yet often recalcitrant and/or later, still no single study has been able to repeat these find-
recurrent, partial or full-blown BV [54]. ings, although the implications of confirmatory studies con-
Ascorbic acid is available as silicon-coated tablets contain- solidating these data would be enormous. In another study,
ing 250 mg vitamin C that ensure long-lasting reduction in women with abnormal vaginal flora, also including women
vaginal pH and does not produce irritation [128]. Bacteria with other flora types than BV, were randomized to receive
such as lactobacilli, capable of reproduction even at low either 12 days of lactobacilli with 0.03 mg of estriol or
pH are favored in growth, but undesirable anaerobes 500 mg metronidazole vaginally for 6 days [140]. One week
are severely inhibited by vitamin C-induced vaginal after treatment the failure results were equal, but after 4 weeks
acidification [129]. metronidazole was superior, indicating that in order to obtain
Peterson et al. [129,130] reported effective and safe use of long-term effects, repetitive application with lactobacilli may
vaginal vitamin C in a 6 days monotherapy regimen in the be indicated.
management of BV. Recently, its safety and pH-lowering Adjuvant therapy after antibiotic therapy with metronida-
capacity was confirmed in pregnant women’s abnormal zole or clindamycin with L. acidophilus [141], L. casei rhamno-
vaginal microflora: pH and microflora improved, both after sus (Lcr35) [142] or Lactobacillus rhamnosus GR-1 and L. reuteri
an induction dose of daily treatment during a week, as RC-14 (GR-1/RC-14) [143] after therapy was able to provide
after maintenance treatment with a three-times-a-week better cure rates of symptomatic BV and diminish the fre-
schedule [131]. quency of recurrences during 1 -- 6 months follow up [144].
Larsson et al., in a randomized, double--blind, placebo- postpartum endometritis, in women with abnormal vaginal
controlled study using L. rhamnosus and L. gasseri followed flora (AVF) or BV [34-51,148,150-152]. In follow up, the predom-
after 2% clindamycin vaginal cream, could not show inance of certain strains of lactobacilli, especially L. crispatus,
improvement of BV therapy during the first month, but seems to provide long-term protection against abnormal vag-
adjunct treatment with lactobacilli significantly increased the inal flora, more than the presence of L. gasseri and L. iners
time to relapse [145]. As other studies showed no improvement [153]. The latter even seems to be a destabilizing factor, increas-
of vaginal probiotic use in women with BV, we need further ing the risk of developing BV over time. Treatment studies of
RCTs with larger samples of symptomatic women, comparing BV have been less consistent, leading to numerous meta-anal-
lactobacilli with placebo and/or antibiotics [146]. yses, of which some claimed a reduced complication rate in
subgroups of patients at high risk for preterm delivery [47,154],
5. Prevention of recurrences of BV but most found no beneficial effect at all, especially in low-
risk women [155-163]. In one careful, large RCT treating
Women with frequent recurrences need extra attention to women with BV, metronidazole did not show any benefit in
minimize the burden that BV imposes on their quality of the prevention of preterm birth compared to placebo [164],
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by 193.191.9.110 on 02/28/14
life. In one placebo-controlled, randomized trial, weekly vag- while in two other RCTs the use of metronidazole was even
inal metronidazole was compared to placebo during 16 weeks, disadvantageous, causing an increased rather than a decreased
showing a significant difference in 70% of women being risk of preterm birth [165,166]. Further, in at least two meta-
symptom-free in the treatment group as against only 30% in analyses, metronidazole was found to increase the risk of
the placebo group [147]. However, even with metronidazole adverse pregnancy outcome [162,164]. On the other hand,
maintenance therapy, only 35% of patients and 20% of con- although older RCT studies with vaginal clindamycin did
trols were still without recurrences, at 12 weeks post therapy. not seem to influence the preterm birth rate [167-170], three
Further, patients having received vaginal metronidazole cream more recent RCTs using the broader spectrum antibiotic clin-
suffer from vulvovaginal candidosis more often than placebo damycin provided beneficial evidence of reduced preterm
users (p = 0.02). birth rates, either given orally or vaginally [171-174]. Timing
For personal use only.
In order to prevent taking antibiotics in repetitive courses, of medication -- as early in pregnancy as possible or at least
the adjuvant use of probiotics after an initial course of antibi- before 20 gestational weeks -- seems to be important according
otics has been tested in a number of RCTs. For the duration to one study [171]; however, in the most recent meta-analysis,
of 1 month after treatment with 1 g/day metronidazole for a screening for and treatment of BV in pregnancy does not
week, 125 premenopausal Nigerian women with BV were seem to lead to any reduction in preterm delivery [174]. Still,
treated with oral L. rhamnosus GR-1 and L. reuteri RC-14 or according to the same review and analysis, treatment did
placebo, leading to 88% complete cure rates in the lactobacil- reduce early pregnancy losses before 20 weeks, and treatment
lus group (LB) versus 40% in the placebo group (p < 0.001) of abnormal vaginal flora or intermediate flora (clindamycin)
and none of the LB-treated women had BV vs 30% in the pla- did reduce preterm birth by over 50%, indicating that in
cebo group [144]. Also in placebo-controlled, randomized tri- pregnancy other types of abnormal vaginal flora than BV,
als, vaginal application of probiotics following treatment of such as AV, probably play an important role.
BV or other forms of vaginitis were efficient in reducing the Non-antibiotic therapy has also sporadically been tested for
post-treatment cure rate [141] or in preventing recurrences of women with AVF or BV in pregnancy. In 1990, Holst and
BV over a 6 months period [145]. Brandburg reported a clear benefit of using acidifying cream
Recently, monthly vaginal application of vitamin C during for BV in a small group of women during pregnancy [175],
6 days after menses was able to reduce the BV recurrences for but this paper was never followed by larger series.
32 to 16% of patients over 6 months [149]. A Cochrane review of all randomized trial using probiotics
indicated a clear reduction of vaginal infection after the use
6. Treatment of BV in pregnancy of oral or vaginal L. acidophilus containing milk products or
yoghurt, but data on the outcome of pregnancy were
Till a decade ago, treatment of BV during pregnancy caused lacking [176].
concerns because of teratogenic risk of high doses of metroni-
dazole in animals. Progressively, however, this risk has never 7. Expert opinion
been confirmed in humans treated with physiological doses
of metronidazole or clindamycin, and hence they are no lon- The authors see three major challenges in BV treatment
ger ill-advised, although in some countries their use during research. One is to develop drugs with better cure rates than
the first trimester is still ill-advised. the current gold standards, metronidazole and clindamycin,
Most studies show a consistent increase in risk of pregnancy which neither achieve therapeutic cure rates > 65 to 70% after
complications, such as failed implantations after embryo 1 month and which allow recurrence rates of 50% after
transfer, increased spontaneous miscarriages, preterm rupture 6 months. Part of this challenge may only be resolved by
of the membranes, chorioamnionitis, preterm delivery and applying more stringent diagnostic techniques. Indeed, not
all women fitting the diagnosis of BV according to clinical (at replacement of classical antibiotherapy by alternative thera-
least three of the four Amsel features) and/or laboratory pies, such as vitamin C, probiotic lactobacilli or antiseptics,
(Nugent score > 7 on Gram-stained vaginal smears) display or an adjuvant therapy to precede antibiotherapy may be the
the same microbiological or metabolic characteristics of future management option of choice. Definitely more
the disease. Metagenomic and proteomic analyses of the research is needed, not only to test for disappearance of the
vaginal microflora have shown some types of BV to express targeted microorganisms due to treatment but also to test
A. vaginae, whereas others harbor L. iners, Veillonella sp., the changes in specific biomarkers such as proteins, metabolic
G. vaginalis or other bacteria as the main microorganism. As products and biofilm features.
the sensitivity of these microorganisms to antibiotics are vari- A third challenge, only briefly addressed in this contribu-
able, neither clindamycin nor metronidazole, and probably no tion, is the development of a treatment that not only decreases
other, will be able to cover all with sufficient efficacy to the signs and symptoms of BV, but rather its complications in
accomplish complete cure. Hence, we might need to individ- pregnancy. Till date, the best treatment and timing to prevent
ualize the treatment according to the subtype of the abnor- BV-associated complications in pregnancy are not known,
mal/BV flora, in order to determine the most adequate and several randomized, placebo-controlled studies, especially
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by 193.191.9.110 on 02/28/14
therapy to obtain optimal results. Also, a more complete diag- with metronidazole have given negative results. Although
nosis of the at-times complex abnormal findings may be war- studies are scarce, the authors’ best guess would be to combine
ranted, as a failure to detect a concomitant AV or Trichomonas repeated testing and retreatment with alternative (probiotic,
infection may lead to a suboptimal treatment choice. Antibi- acidification, etc.) maintenance therapy to prevent preterm
otics may have to be adapted to the breakdown of the biofilm labor and rupture of membranes.
structure and/or to the proteomic and metabolomic features
of certain subtypes of BV, in order to be effective and provide Declaration of interest
long-term cure and prevention of recurrences.
A second challenge is to adjust the therapy with the purpose The authors state no conflict of interest and have received no
of preventing recurrences. To achieve this goal, either the payment in preparation of this manuscript.
For personal use only.
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