Managing recurrent bacterial vaginosis

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  1. J Wilson
  1. Correspondence to:
 J Wilson
 Department of Genitourinary Medicine, The General Hospital at Leeds, Dandy George Street, Leeds, LS1 3 EX, UK; janet_d.wilson{at}leedsth.nhs.united kingdom of great britain and northern ireland

Abstruse

Bacterial vaginosis (BV) is the most frequently found status of the female genital tract. It increases a woman's risk of acquiring HIV, is associated with increased complications in pregnancy, and may be involved in the pathogenesis of pelvic inflammatory disease. Yet in that location are many unanswered questions about its aetiology, making management of recurrent infection difficult and often idiosyncratic. This paper discusses the current noesis and possible management of recurrent BV.

  • recurrent bacterial vaginosis
  • vaginal lactobacilli
  • vaginal pH
  • bacteriotherapy

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  • recurrent bacterial vaginosis
  • vaginal lactobacilli
  • vaginal pH
  • bacteriotherapy

Bacterial vaginosis is characterised by a sparse homogeneous white discharge, a vaginal pH of greater than 4.five, a positive amine test, and the presence of clue cells microscopically. At that place is also a alter in vaginal flora from the normal lactobacilli (LB) ascendant to flora with greatly reduced numbers of LB and an overgrowth of Gardnerella vaginalis, Mycoplasma hominis, and anaerobic bacteria such equally peptostretococci, Prevotella spp, and Mobiluncus spp. In that location is no universally accustomed definition of recurrent bacterial vaginosis, but in the few publications on the topic the definition used is three or more proved (clinically by Amsel's criteria or microscopically) episodes of BV in 12 months.1, two

A search was performed using Dialog DataStar for articles published betwixt 1966 and September 2003, using the keywords bacterial vaginosis, recurrent bacterial vaginosis, vaginal pH, vaginal lactobacilli, probiotics, and bacteriotherapy.

Frequency of recurrent BV

Handling trials study cure rates of 80–90% at one week, but recurrence rates of fifteen–30% within 3 months.3 In a study of long term follow up of women who had been successfully treated for BV, 48% remained BV free, and 52% had at least one further episode.four The mean follow up was six.9 years. Well-nigh relapses were during the first year and were significantly correlated with new sexual contacts.iv And then following successful treatment, half of women will stay cured for years.

Predisposing factors

Several factors are known to increase the risk of BV, including younger age,5 black ethnicity,half dozen douching,vii smoking,8 and the IUD as contraception.nine The studies on douching and IUD use were longitudinal studies of incidence, so women with recurrent BV may benefit from stopping douching, and changing their method of contraception if they have an IUD. Many papers have linked BV with sexual behaviour; a contempo alter of sexual partner,7 and multiple partners compared with 1 partner10 increasing the risk. The increase in BV in women with new sexual partners was independent of frequency of intercourse, suggesting exposure to a new partner is a more of import run a risk factor than the number of episodes of intercourse.vii, 10 These findings lead onto the next question virtually aetiology.

AETIOLOGY

Are frequent episodes of BV the result of re-infection or relapse? If it is re-infection what are the pathogens and is it related to behaviour of the women or her sexual partner? If it is relapse what triggers the disruption in the flora? The link with sexual behaviour suggests that BV is sexually transmitted and that further episodes are due to re-infection. Yet treatment of the sexual partner demonstrates no benefit in terms of recurrence rates in women. Five out of six trials, using oral metronidazole, tinidazole, or clindamycin to treat the male partner showed no benefit for the women.11 These findings practise not support the theory of sexual transmission and re-infection.

A study looking at risk factors for repeated episodes of BV suggests they are due to relapse. Cook et al studied 13 women with recurrent BV over a 9 month menses, and compared them with a control group of 31 women with no current, or history of, BV.1 There were 31 episodes of BV during the written report catamenia and each was treated with metronidazole 500 mg twice daily for 7 days. Complete clinical and microscopic cure occurred in but 23% of the episodes, in 61% in that location was an improvement, but in xvi% there was clinical failure. Following treatment, raised vaginal pH was nowadays in 65%, positive amine whiff test in xv%, and aberrant Gram stained flora in 24%. Anaerobic Gram negative rods were isolated from xix% of the women post-therapy compared with 3% of the command grouping. Women who developed early on recurrence tended to complain of an abnormal discharge at the finish of therapy. Some asymptomatic women considered themselves cured after treatment, but they continued to accept significant abnormalities of vaginal flora, the more severe the abnormality the earlier the recurrence. These findings back up the theory of relapse.

The exact machinery for the onset of BV remains a mystery. It is associated with a reduction in lactobacilli (LB) and hydrogen peroxide product, a rise in the vaginal pH, and the overgrowth of BV associated organisms (meet fig 1). But which of these happens first, and which is the most important? If we knew the answers to these questions, we could use this noesis to attempt to prevent further recurrences of BV.

Reduction in lactobacilli and hydrogen peroxide production

The main hydrogen peroxide producing strains of lactobacilli (LB+) are L crispatus and 50 jensenii.12 The presence of these has been positively associated with being white, aged over 20 years, using barrier contraception, and low frequency of BV and gonorrhoea.12 A accomplice study showed that lack of LB+ gave a twofold risk of acquiring BV and no LB gave a fourfold risk.7 Klebanoff et al showed in vitro that combining myeloperoxidases with hydrogen peroxide and a halide produced a strong oxidant, which was toxic to BV associated bacteria.13 Myeloperoxidase activity has been found in vaginal fluid and cervical fungus, and chloride is nowadays in cervical fungus in amounts in excess of that required for this system. In vitro testing showed LB+ in high concentration (just compatible with the levels found in the vagina) were toxic to G vaginalis and Prevotella bivia. This toxicity was inhibited by catalase indicating that hydrogen peroxide was the toxic amanuensis. When the concentration of LB+ was lowered then that growth of the bacteria was non inhibited the addition of myeloperoxidase and chloride reinstated the toxicity.thirteen The toxic event of this LB+/myeloperoxidase/chloride system was rapid, with reduction in numbers of Thou vaginalis at 15 minutes and consummate loss of viability at 60 minutes.

It is not known what causes the reduction in LB+ in BV. Pavlova et al suggest that as BV associated organisms are sensitive to lactic acid and hydrogen peroxide, suppression of LB must come earlier overgrowth of BV associated bacteria. Phage mediated lysis of LB may cause such a reduction. Phages from one woman can infect LB from a different woman so they could be the sexually transmitted amanuensis,14 which would explain the lack of benefit of treatment of the male partner with antibiotics.eleven

However, some studies suggest that LB may not totally protect against BV. A study in pregnant women revealed that 63% with BV had LB+ isolated from the vagina, all the same despite these they still had BV. Rosenstein et al propose that abnormal bacteria starting time to appear and increase before disappearance of LB+, and that BV may develop in some women despite the presence of hydrogen peroxide producing LB.15 This suggestion is supported by another study of women with BV where 33% had LB present at days 1–five of the menstrual cycle, rising to 54% at days 19–24.16 It is known that broad spectrum antibiotics reduce the numbers of LB.17 If reduction in LB was the initiating factor for BV, wide spectrum antibiotics should predispose to BV, and however this has not been described.

Change in pH

The low pH of the vagina is attributable to production of lactic acrid by LB metabolism, and by the conversion of glycogen to lactic acid by oestrogenised vaginal epithelial cells.

In vitro LB acidify their growth medium to a pH of three.2–4.8 (that is, similar to normal vaginal pH). At that pH a steady land of equilibrium develops where the acerbity becomes autoinhibitory. Anaerobes grow poorly at pH 4.v or less; the optimum pH for Prevotella spp and Yard vaginalis growth is six–seven. In vitro studies show that the concentrations of these bacteria increase with increasing pH, but both are susceptible to low pH.18 McClean and McGroarty found that lactic acid and low pH had a greater inhibitory effect on M vaginalis than hydrogen peroxide.19 The in vitro experiments past Klebanoff et al showed that the LB+/myeloperoxidase/chloride system had maximum toxicity at a pH of between 5 and 6, with inhibition falling as pH increased beyond 6. This suggests that pH has an additional result to the LB+/myeloperoxidase/chloride organization. At pH 4.5, the growth of G vaginalis was inhibited, and the add-on of LB+ produced no extra inhibition. The LB+/myeloperoxidase/chloride arrangement did have some additional inhibitory effect on growth, but less and then than at pH v–vi when in that location was a highly pregnant reduction in 1000 vaginalis.13 One interpretation of these findings is that at pH four.v or less the LB+/myeloperoxidase/chloride organisation is less of import equally the low pH produces an inhibitory consequence on bacterial growth. Yet, at times of a rise in vaginal pH, such as later on sex activity and during menstruation, when bacterial overgrowth could occur, the LB+/myeloperoxidase/chloride system rapidly kicks in to inhibit bacterial growth.

A low pH as well appears to be important for LB adherence to the epithelial cells. In vitro testing showed at pH of 4.4, a hateful of v.5 LB adhered per vaginal cell, compared with ane.4 at pH of half dozen.2.20

Overgrowth of BV associated organisms

The initial work by Gardner and Dukes showed that BV can be produced past inoculating BV associated bacteria into a healthy vagina. G vaginalis alone caused BV in just one of 13 women, but when vaginal secretions from women with BV were inoculated xi of fifteen women developed BV.21 This suggests that the inter-relation betwixt the different groups of bacteria is important for overgrowth. P bivia and G vaginalis have a symbiotic association. Growth of Chiliad vaginalis is enhanced by ammonia which is produced past P bivia. Amino acids are produced during Chiliad vaginalis growth, which are stimulatory to the growth of P bivia.22 Information technology is therefore possible that the symbiotic human relationship betwixt these leaner is because the byproducts of metabolism of one fuel the growth of the other.

A microbiological study throughout the menstrual cycle showed that in women with or without BV the rate of recovery of LB increased over the bike and the concentration of non-LB species was higher at menses, suggesting instability of the vaginal flora at that fourth dimension with the potential for bacterial overgrowth.16

THERAPEUTIC OPTIONS TO Foreclose BV RECURRENCES

What therapeutic options do we have to manage or try to foreclose further recurrences of BV?

Bacteriotherapy

Bacteriotherapy, using harmless bacteria to readapt pathogenic organisms is considered "natural" and without any side effects, but there is lack of efficacy data with few randomised controlled trials (RCT). The LB used need to be able to adhere to vaginal epithelial cells, and to produce hydrogen peroxide. If given orally the LB demand to laissez passer through the abdominal tract and ascend from the perianal surface area into the vagina.

In that location have been several publications of attempts to restore vaginal flora past recolonising with LB using both intravaginal and oral assistants. However, the LB used have not been vaginal strains. LB strains from yoghurt adhere less well to vaginal cells than clinical isolates. In a double blind RCT looking at LB as a handling for BV, vaginal pessaries containing L acidophilus were used for six days. With active therapy 57% of women cleared their infection compared with 0% of those given placebo, merely only three remained BV complimentary after menstruation.23 It was idea there was a problem with LB adherence. One grouping of researchers has published example reports and small case serial of vaginal and oral LB replacement. They written report successful vaginal colonisation following administration by both routes.24, 25 This group have recently published a RCT of oral capsules of L rhamnosus GR-1 and L fermentum RC-xiv for 60 days. Microscopy showed restoration to normal flora from asymptomatic BV in 37% women receiving LB treatment compared with 13% receiving placebo. This significant comeback in vaginal flora was also accompanied by a meaning increase in LB at day lx.26 These results are encouraging but nosotros do not know if the non-vaginal LB will remain in the vagina to protect against further episodes of BV. A RCT of oral Lactobacillus GG drinkable for the prevention of recurrent urinary tract infection (UTI) showed no reduction in UTIs over 12 months.27 The principles of UTI prevention by this method are like to that of BV prevention—that is, LB replacement to protect against bacterial overgrowth, so it is unlikely that oral Lactobacillus GG would be beneficial for BV prevention. In a study looking at mechanisms of LB blockage of uropathogen adherence to vaginal epithelial cells, Fifty crispatus showed greater chapters to block uropathogen adherence than other LB.28 A study looking at sustained vaginal colonisation of LB showed xl% of women remained colonised with 50 crispatus and L jensenii for over 8 months compared with 5% of women colonised with other LB spp indicating better ability to adhere to vaginal cells.17 There is currently a RCT using vaginal pessaries containing Fifty crispatis to endeavor to recolonise the vagina with LB (Due south Hillier, personal communication). This is the first study of replacement with ane of the chief vaginal hydrogen peroxide producing LB.

Maintaining vaginal pH at four.5

The main goal of therapy here is to continue the vaginal pH at 4.5 or less, in society to prevent overgrowth of pathogens until the normal LB are re-established and able to maintain the pH themselves. In a RCT of 42 women with recurrent BV using intravaginal lactate gel to endeavor to foreclose BV recurrences, 17 women used lactate gel for 3 days immediately afterwards menstruation for 6 months, the balance used placebo. The 6 months on-handling analysis showed that 88% were clear of BV with active handling compared with simply 10% with placebo. Intent to care for analysis at 6 months showed 71% were clear with treatment and 4.8% were clear with placebo.29 The treatment was well tolerated only there was a big dropout charge per unit, especially in the placebo arm because of malodour. The authors suggested more than intensive handling might accept improved this.

Preventing overgrowth of BV associated organisms

Although intermittent therapy, on an episodic or prophylactic footing, is oft used for recurrent BV, there are very few publications on this. Hay et al brash women with recurrent BV to nerveless daily vaginal specimens for between ane–12 months, to try to identify the times of recurrence. BV recurrences most often arose inside the first 7 days of the menstrual bike, and frequently followed candida infection.2 Consequently they brash oral or intravaginal metronidazole for 3 days at the onset of period for 3–6 months, and add antifungal treatment if there is a history of candidiasis.30

Amend treatments and/or combined treatments

Using oral or vaginal preparations of metronidazole and clindamycin, 80–ninety% of women will have an initial response to treatment simply 15–xxx% will get a recurrence within 3 months.3 In women with recurrent BV the initial response charge per unit appears to be lower.1 The heterogeneity of micro-organisms involved in BV may contribute to treatment failure and high recurrence rates. Clindamycin has better activeness against 1000 hominis, Mobiluncus spp, and G vaginalis than metronidazole, merely metronidazole has the advantage of not affecting LB. In trials comparing treatments, cure rates for metronidazole 400 mg or 500 mg twice daily for 7 days have been equivalent to clindamycin vaginal cream daily for 3–7 days, and to metronidazole vaginal gel one time or twice per mean solar day for 5 days.31 In the absenteeism of better treatments would women with recurrent BV benefit from longer courses of current treatment? This question remains unanswered.

In view of the clan betwixt lactobacilli, hydrogen peroxide production, vaginal pH, and overgrowth of BV associated bacteria, simply trying to suit one of these may assistance some women with recurrent BV, but information technology may not be enough to resolve all cases. Would a combined approach piece of work better? In that location are very few publications on this, but they do suggest that the answer might be yes. A pocket-sized report using single dose oral metronidazole followed by vaginal lactate tablets compared to no vaginal maintenance treatment reported an improved rate of normal vaginal flora of 94% compared to 71%.32 Another modest study compared tinidazole ii g unmarried oral dose followed by acidic vaginal gel for three weeks with ii% clindamycin vaginal cream 5 g per dark for 7 nights. At 4 weeks the clinical cure charge per unit was 94% versus 77%. The vaginal pH was <4.five in 78% and 38% respectively.33

CONCLUSIONS

In that location is an important inter-relation betwixt lactobacilli, hydrogen peroxide production, vaginal pH, and overgrowth of BV associated bacteria, merely the initiating factor for BV remains a mystery. From current prove it appears that a rise in vaginal pH assuasive the overgrowth of bacteria may exist more important than reduction of LB+. However long term colonisation with LB+ is necessary to help maintain an acidic pH and support the LB+/myeloperoxidase/chloride system. Therapies aimed at one aspect of this inter-relation may assistance some women with recurrent BV, but a combined arroyo might work meliorate. Probably the ideal way of managing recurrent BV would be to tackle all aspects of the inter-relation past replacing the lactobacilli, at the same time maintaining the vaginal pH at 4.v, and if necessary also adding in safety treatment to command overgrowth of bacteria (run into fig two). If the current RCT of vaginal LB+ replacement proves successful this arroyo may soon be possible.

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