Bacterial vaginosis – a disturbed bacterial flora and treatment enigma Review article IV
P. G. LARSSON1,2 and U. FORSUM1
Larsson PG, Forsum U. Bacterial vaginosis – a disturbed bacterial flora and treatment enigma. Review. APMIS 2005;113:305–16.

The syndrome bacterial vaginosis (BV) is characterized by a disturbed vaginal microflora in which the normally occurring lactobacilli yield quantitatively to an overgrowth of mainly anaerobic bacteria. As BV is a possible cause of obstetrics complications and gynaecological disease – as well as a nuisance to the affected women – there is a strong impetus to find a cure. In BV treatment studies, the diagnosis criteria for diagnosis of BV vary considerably and different methods are used for cure evaluation. The design of study protocols varies and there is no consensus respecting a suitable time for follow-up visits. For the purpose of this review, available data were recalculated for 4-week post treatment cure rates. For oral metronidazole the 4-week cure rate was found not to exceed 60–70%. Treatment regimens with topical clindamycin or topical metronidazole have the same cure rates. It can thus be said that no sound scientific basis exists for recommending any particular treatment. There is no evidence of beneficial effects on BV engendered by partner treatment, or by addition of probiotics or buffered gel. Long-term follow-up (longer than 4 weeks) shows a relapse rate of 70%. With a primary cure rate of 60–70%, and a similar relapse rate documented in the reviewed literature, clinicians simply do not have adequate data for determining treatment or designing clinical studies. This is unfortunate since – apart from the obvious patient benefits – clinical studies can often serve as a guide for more basic studies in the quest for underlying disease mechanisms. In the case of BV there is still a need for continued basic studies on the vaginal flora, local immunity to the flora and host-parasite interactions as an aid when designing informative clinical studies.

BV is characterized by a changed vaginal microflora in which the normally occurring lactobacilli yield to an overgrowth of a mixed anaerobic bacterial flora. As BV is a possible cause of obstetrics complications and gynaecological disease – as well as being socially unacceptable and disturbing for the affected women – there are good reasons for finding a cure. PubMed has published 122 English-language treatment studies of BV to date. A systematic evaluation would greatly facilitate a comparison of this bulky and diverse material. The diagnoses and the criteria for cure of BV are not the same throughout the PubMed material. One might assume that the same criteria that apply with respect to diagnosis would also apply with respect to a successful cure assessment, but this is not the case in the majority of the published studies (1).

When evaluating these studies it is thus important to keep in mind the generally held view that unblinded studies will give rise to an observation bias and that interobserver variation regarding criteria for cure assessment can be a cause for concern. Systematic bias is another critical factor. For instance, the examining physician might be paid per examination and not per patient, a circumstance that in cases where cure does not seem definite might sway a decision not to exclude the patient as a relapse but to schedule the patient for one more follow-up examination. Moreover, critical judgment might be influenced by a publication bias. Published studies in general show a higher cure rate than unpublished studies.

Differences in both inclusion criteria and exclusion criteria for diagnosis and cure assessment as applied in BV research are notoriously difficult to assess in published reports. As reviewed by us in an earlier publication many modifications of the Amsel criteria, the originally published gold standard in BV diagnostics, are used (2). Moreover, the Amsel criteria, which comprise the present gold standard, are subjective, and consequently the result might well differ from observer to observer.

Although numerous reviews on treatment of bacterial vaginosis have been published, none has dealt with the problem of the very low cure rates. Most reviews only discuss the 1-week cure rates (3–12). Our experience from clinical cases as well as treatment studies is that 1-week follow up is simply too short a time for meaningful interpretation of individual patient data (13). Therefore, studies that report cure after only 1 or 2 weeks are not included in the present review. This inadequate time lapse is not confined to older studies, but occurs even in recent studies (14–17).

MATERIAL AND METHODS Go to: ChooseTop of pageMATERIAL AND METHODS <<TREATMENT WITH ANTIBIOTIC...ALTERNATIVE MODELS FOR TR...BV TREATMENT DURING PREGN...CURE RATE AFTER PLACEBO T...FOLLOW UP LONGER THAN 4 W...RECURRENT BVDISCUSSIONREFERENCESThis article is cited by the following articles in Blackwell Synergy and CrossRef

This review is divided into six main themes: treatment with antibiotics, alternative models for treatment, BV treatment during pregnancy, natural history of BV and/or placebo treatments, follow-up longer than 4 weeks, and recurrent BV. The literature searches used these key words: Bacterial vaginosis (together with) treatment, treatment outcome, drug therapy, antibiotics, pregnancy, (MEDLINE) during 1983–2004; and also the key word bacterial vaginosis (Pubcrawler). Additional articles were located through references in the above-mentioned publications, or in papers recommended by colleagues.

The present compilation is an overview of documented cures still valid after 4 weeks. In most cases this will coincide with a point in time after the patient's next menstruation. Some studies report a cure after 1 week but with recurrence of BV after 4 weeks. We have included adjusted figures from these studies whenever recalculation is possible from data presented in the article. Cases reported as not being cured after 1 week are in this review compiled with cases not cured after 4 weeks. The report is a 10-year follow-up of a previous review of the field (1).

The Amsel criteria and scoring of Gram-stained smears of vaginal fluid are the most commonly used diagnostic principles for BV treatment in the reported studies (for review see (2)). The four Amsel criteria are usually regarded as the gold standard. If three of these four criteria are present, the patient has BV. However, these criteria are often modified, as typical homogenous discharge, the most subjective sign, is often not included, thus compromising a fair comparison of studies (Table 1). Other modifications include that at least 20% of epithelial cells in a given image area should be clue cells (Table 2). Nugent's Gram-staining criteria are supposedly more objective (2). In some studies patients have to fulfil both Amsel and Nugent criteria for diagnosis of BV to qualify as cured, and therefore these patients might represent a subgroup of BV. In this review we have endeavoured to compare the different studies despite the differences in diagnostic criteria. A table of officially recommended treatment regimens (Table 3) will assist comparison. In addition, the US Federal Drug Administration (FDA) has published recommendations as to how treatment studies for BV should be performed (Guidance for industry: Bacterial Vaginosis; Developing Antimicrobial Drugs for Treatment, 1998, www_fda.gov). According to these guidelines, a test to verify cure should be carried out on day 21–30 after the start of treatment and patients should have clinical resolution of Amsel criteria in combination with a Nugent score of less than 3.

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Oral metronidazole

The most established method of treating bacterial vaginosis is with oral metronidazole. It is employed in a number of different therapy regimens most commonly with 400 or 500 mg twice daily for 7 days. In open randomized studies, the compilation shows that cure is reported in 82% of all studies published. In Scandinavia, a common therapy model is 2 g on the first and third day. The historical background is an open-ended study that reported a 93% cure rate for this model as opposed to a cure rate of 89% following a regimen of 2 g on the first and second days (18). This difference is not significant, but the latter therapy model has had a considerable impact despite its weak scientific underpinnings.

Two studies are available that compare the results of treatment with oral metronidazole and treatment with placebo; one is a 7-day regimen (19) and one a 10-day regimen (20). Other placebo-controlled studies compare oral metronidazole with various other medications that counteract BV. Taken together, the anticipated average cure rate in the placebo-controlled studies is 66%. Compared to the cure rate reported in published blinded and open-ended studies, the difference is significant (p<0.001) (1).

Clindamycin cream

Ten published studies, all placebo-controlled, describe a regimen of clindamycin cream for treating BV (see Table 1). All 10 use somewhat different diagnostic criteria. Diagnosis and cure verification is based on three of the Amsel criteria (pH>4.5, positive whiff test and clue cells in microscopic examination). BV is judged to be improved if one of the three criteria is scored upon follow up, but cure is pronounced only when none of the criteria is present. With a follow-up period of 4 weeks, 73.4% of the cases are considered improved and 53.4% completely cured.

Clindamycin suppositories

Two studies are available: one reports 63% improved cases (31) (based on use of pH and whiff to verify cure) and the other reports 54% cured cases (29).

Peroral clindamycin

One 1988 study is available and it only reports cures after 1 week (94% cure), thus the 4-week cure rate is not known (32). This regimen was used to treat BV in early pregnancy to reduce late miscarriage and preterm delivery (33). A clinical cure rate of 90% at 2 weeks and 85% at 4 weeks was noted among pregnant women (33).

Metronidazole vaginal treatment

There are at present six published studies of treatment with metronidazole gel, all of which show a cure rate of 65% after a follow-up time of 4 weeks (Table 2). In the first of these studies, treatment is given twice daily. These studies are not fully comparable with the clindamycin therapy studies since the cure criteria in the two treatments differ. The cure benchmark for the metronidazole gel studies is that among the observed epithelial cells <20% should be clue cells together with only one of the Amsel criteria still present. The assumption is that the cure results for metronidazole studies are likely to be comparable with the improved cases in the clindamycin studies. Another study comprising 58 women treated with metronidazole gel versus placebo uses a slightly different definition of cure; with normalization of all three clinical criteria, pH, whiff test, and microscopy showed only 36% cure in the active group versus 11% in the placebo group (39).

In a single blind study where metronidazole ovules 500 mg combined with nystatin were compared with metronidazole gel, the cure rate was after 6 weeks 83% for the metronidazole ovules versus 62% for metronidazole gel (40). The discussion in the article centred on whether it is the dose of metronidazole, formula, or addition of nystatin that leads to the improved cure rate. Interestingly it was noticed that among women no longer infected with BV at the first follow-up, subsequent intercourse without condoms independently predicted subsequent recurrence (p<0.01) Metronidazole ovules alone has earlier been tested in an open study with 79% cure rate (41); however, this treatment regimen has not become common clinical practice. Addition of miconazole nitrate to metronidazole ovules showed an 86% cure in an open study with slightly different criteria for the diagnosis of BV, but it should be noted that women with mixed infections (both candida and BV) were treated. (42). A therapy of bioadhesive single dose vaginal tablets containing different doses of metronidazole was in one study tested against placebo (43). A cure rate of 65% was observed (49/76 patients) versus 29% (7/24 patients) in women treated with placebo. The BV diagnosis was based on presence of clue cells combined with two of the other three Amsel criteria. Since the evaluation of cure was done already after 1–2 weeks, it is difficult to draw any conclusions from this study (43). All in all, there are too many differing variables in the metronidazole vaginal treatment studies published to date to enable a well-founded recommendation to be made about local metronidazole treatment.

Clindamycin versus metronidazole

There are two comparative studies concerning metronidazole vaginal gel and clindamycin. The first study reports only 1–2 weeks' follow-up, where oral metronidazole accounts for 84%, metronidazole gel for 75%, and clindamycin vaginal cream for 86% cure. None of the observed differences is significant; the study comprised 101 women (44). A comparison between metronidazole vaginal gel and clindamycin ovules that employs an open randomized design in treatment of 115 women with a follow-up time of 35–45 days after start of treatment reports a resolution of BV (<2 Amsel criteria) of only 49% versus 48% (45).

A common observation among clinicians performing microscopy of vaginal fluid as part of their practice is that in patients treated with metronidazole, which in vitro has no effect on the lactobacilli, the observable vaginal flora reverts after a few days to a normal flora dominated by lactobacilli. It would seem plausible that it takes somewhat longer to reinstate normal flora after clindamycin treatment than after metronidazole since clindamycin is in vitro effective against many bacterial species observed in BV but also against lactobacilli. Cure statistics for metronidazole and clindamycin are, however, the same in published reports (see Tables 1 & 2). Any mechanisms of recolonization of the vagina with a flora dominated by lactobacilli are, meanwhile, not known, nor whether it is accomplished by endogenous or exogenous (intestinal?) lactobacilli. Treatment with clindamycin is associated with marked evidence of in vitro antimicrobial resistance among vaginal anaerobic bacteria compared to metronidazole treatment and thus clindamycin treatment is questionable from a bacterial ecology point of view (45).

Treatment of sexual partners

Five studies have evaluated the results of therapy prescribed for a patient's sexual partner, but none indicates improved cure rate for the patient when also the partner has ingested metronidazole. A study of the effects when oral clindamycin is prescribed for the partner showed a 10% improvement in the cure rate of the women being treated (46). This was a small study comprising only 84 evaluated patients and the improvement was not significant. Potter has, in addition, compiled an excellent comparison of all available studies (47).There is at present no support for treatment of the male partner. Whether female partners could benefit from treatment is not known (48).

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In alternative models for treating BV, few are placebo-controlled and a superior cure rate is not demonstrated for any of these.

Treatment with lactobacilli

Introduction of bacteria with supposed health-giving properties, probiotic therapy, is subject to intensive research (49). However, no breakthrough has been reported and there is still a serious lack of knowledge. The rise of research in this area does not mean that old-fashioned remedies have acquired legitimacy. Introducing yoghurt into the vagina is not a functional therapy. The introduction of pure lactobacilli has not proved efficacious. A double-blinded, placebo-controlled study of vaginal suppositories containing Lactobacillus acidophilus, a lactobacillus believed to be of bovine origin, had an initial cure rate after 1 week of 57%, but examination 4 weeks later showed only a resolution of BV in 18% of the cases (50). Reid et al. have reported in a placebo-controlled study of 64 women that oral ingestion of L. rhamnosus and L. fermentum for 60 days resulted in a cure rate of 37% (51).

Lactobacilli as an adjuvant to antibiotics which are effective in vitro against bacteria comprising BV flora is a hypothesis which has been put forward. Cure ought to be enhanced by decimating the anaerobic flora and then introducing a new lactobacillus. A study by our group using this method has been conducted: initial treatment with clindamycin suppositories for 3 days was followed by 5 days' treatment with lactobacilli-prepared tampons during the next menstruation. These tampons are impregnated with three different freeze-dried lactobacillus strains: L. fermentum, L. casei-rhamnosus, and L. gasseri. Follow-up showed no significant difference in cure, with a 56% cure in the lactobacillus group as compared to 62% in the placebo-controlled group. Several objections can be raised; among them that the therapy period was too brief when lactobacilli were introduced in a single menstrual cycle, but the fact remains that the study does not indicate that this treatment is successful (52). A report from the United States indicates that L. crispatus is able to colonize a healthy vagina (53). A study on the treatment of BV patients who received first metronidazole orally and thereafter suppositories with the same strain of L. crispatus indicated no enhancement of cure in the lactobacilli group as compared to the placebo-controlled group (Hillier, personal communication 2003). In a study of oestriol treatment, a restoration of the lactobacilli-dominated flora was claimed to be successful, but only 19 out of 360 patients initially had BV (54) and it is thus too limited for any conclusions to be drawn. The treatment studies using lactobacilli are disheartening. It may be that the right lactobacilli have not been found or that optimal delivery procedure is not achieved.

Buffered gel with lactate

Vaginal gel containing lactate in a buffer that does not contain any living lactobacilli has been formulated and administered for 7 days (55). The brand name of this preparation is LactalgelTM or GeliofilTM depending on the market area. A critical reading of two published studies does not indicate any effect. In the first study the cure process was examined 7 days after therapy was begun, i.e. the day after therapy was concluded. The patients were pronounced cured if a single one of the four Amsel criteria was absent, i.e. a low pH (55). In a follow-up study, an initial dose of buffered lactate gel was supplemented by a monthly dose of buffered lactate gel or placebo for 6 months. After 3 months of treatment there was no cure among the 20 patients who received one dose of buffered lactate gel followed by placebo (56). A report from Bulgaria indicates that lactate given as a vaginal tablet is effective as an adjuvant to vaginal metronidazole in a small-scale pilot study. The cure rate in the metronidazole group was 71% as opposed as 94% for metronidazole+lactate tablets (57).

In another study of 56 patients, the results of treatment with clindamycin for 7 days were compared to tinidazole+buffered lactate gel for 3 weeks (58). Resolution of BV was after 4 weeks 77% in the clindamycin group and 94% in the tinidazole+buffered lactate gel group; this difference is, however, not significant. It is doubtful if the two groups are comparable since the medication in one group was administered for 3 weeks and evaluated after 4 weeks. From the USA there is a pilot study of 10 women treated with buffered gel with disappointing results (59). Buffered gel is thus not to be recommended as treatment for BV.

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Generally speaking it seems that treatment for BV is more effective during pregnancy. Pregnant women do not menstruate and it appears that BV tends to recur during a menstrual period. Spontaneous cure among pregnant women has been noted. In studies where the follow-up period was 12 weeks, BV disappeared in 42% (60) and 47%, respectively (61), and a Danish study showed a 20% reduction of BV (62). In two recently published treatment studies, 13% and 31% had resolution of BV after placebo treatment at 4 weeks (33, 63), 22% after 10 weeks (63), and 43% after 20 weeks (33), respectively. In the final study of 231 placebo-treated women only 69 were followed until the 36th gestational week. Regarding spontaneous resolution among non-pregnant women, see below. Many studies document the use of antibiotics during pregnancy; most of these do not report a clinical cure but they do report an incidence of premature delivery (48). In these studies it is difficult to clearly establish the anticipated cure since a variety of antibiotics were used, and there are differences in the follow-up time and the design of the study. Table 2 displays some of the most pertinent of these studies and the cure rate achieved.

Some treatment studies report a significant difference in the cure rate, from a lowest of 33% (64) to a highest of 85% (33). These big differences in cure rates mostly concern prevention of preterm delivery and could to some extent explain the contradictory results achieved.

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Compiled results of all cures effected by means of oral placebo treatment of BV patients indicate a 10% cure rate (17 of 173) after 1 week, and a 5% cure rate (2 of 38) after 4 weeks (19, 20). Many more patients, however, received vaginal therapy. The cure rate after 1 week of vaginal therapy is 15% (22 of 143) and after 4 weeks 21% (21 of 102). The vaginal placebo treatments have a significantly (p<0.05) higher cure rate than the oral placebo treatment. The composition of the vaginal placebo gel is only reported in some studies, but in all those studies buffered to pH 5.0–5.5. The vaginal treatment could have a therapeutic effect of its own, but the numbers of oral placebo treatments are too small to draw any definitive conclusions. These results are the calculated spontaneous cure when placebo treatment is administered to a patient infected with BV. It is debatable whether this is a true spontaneous cure or whether it should be interpreted as being due to variation in BV diagnostics as discussed in our second review (2).

Bump et al. have done a 6-month follow up study of untreated BV and report a 78% spontaneous resolution of BV among 49 women (65). Spontaneous recovery from BV at such a high rate has not been noted by any other study and the diagnosis of BV is not very accurate. Vaginal discharge was defined as abnormal and considered suggestive of BV if it met one of the criteria: excessive volume, abnormal consistency, or characteristic fishy odour. The findings of this study should be approached with a great deal of caution.

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Few studies report a follow-up time longer than 1 month. The follow-up is of patients who have been diagnosed as cured after the first treatment. All in all, 452 patients were followed up and 66% of these retained a healthy status after an average of 3 months (66–73).

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No documentation is available to advise us how to cope with recurrent BV, which has been defined as four or more appearances of the infection in one year (74). Available data indicate that when BV reappears, it is more likely to be a state that is reactivated rather than a new infection (74–77). The literature records several anecdotal treatments for recurrent BV, such as avoiding use of a vaginal sponge for contraceptive purposes (78), use of oral clindamycin (40, 41, 79, 80), supplement of hydrogen peroxide (81–83), lactobacillus recolonization with yogurt or capsules (84), or vaccination with lyophilized Lactobacillus acidophilus (85). Treatment failure is sometimes ascribed to nontreated partners (86), Netherton's syndrome, (87), or carcinoma of the cervix (88). Repeated treatments of the type commonly applied to severe candida infections – albeit not well founded through controlled trials – find some support in published recommendations by Wilson and Alfonsi et al. (74, 89) that involve suppression with metronidazole vaginal gel for 10 days followed by twice weekly administration for 6 months or initial treatment with clindamycin vaginal cream followed by metronidazole vaginal gel after the next two menstruations.

A long-term follow-up study after successful treatment with oral metronidazole showed that 50% remain BV-free after 5 years. Most relapses occurred within the first year and – as observed in one study – if the patient remained free from infection after 1 year, the chances were good that she would continue to do so (73).

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Most studies of BV treatment differ in their definition of BV and of the follow-up time, which makes it very difficult to evaluate the data. The FDA has published recommendations regarding how treatment studies for BV should be performed (Guidance for industry: Bacterial Vaginosis; Developing Antimicrobial Drugs for Treatment, 1998 (http://www.fda.gov/). These guidelines recommend that a test of cure should be done at day 21–30 after the start of treatment, and patients should have clinical resolution of Amsel criteria combined with a Nugent score of less than 3. Almost none of the published studies fulfils the recommended definition of cure, i.e. cure according to both Amsel and Nugent scores. As we have discussed in our earlier review (2), these two diagnostic tests are not the same and thus this recommendation is questionable.

The present review indicates that the expected cure rate after treatment of BV following various therapy regimens does not exceed 60–70% after 4 weeks. This is a much lower cure rate than has been published previously as most reviews discuss only the cure rate after 1 week and report figures as high as 80–90%. It might be that the test of cure at 1 week only reflects an alteration in the vaginal microflora that is perceived by the patient as a cure while a 4-week cure rate is more relevant. This will normally be after the next regular menstruation for most women. One supposedly evidence-based review reported a 4-week cure rate of 78% after using oral metronidazole, 71% after using vaginal metronidazole gel, and 82% after clindamycin cream treatments (90), figures that are quite different from ours, and which we do not recognize from the original studies. The guidelines from the Centers for Disease Control and Prevention (CDC) state: "The recommended metronidazole regimens are equally efficacious. The vaginal clindamycin cream appears less efficacious than the metronidazole regimens" (91), statements that do not agree with our review of published data and recently published studies with cure rates below 50% (39, 45). The treatment recommended by the WHO – use of single-dose metronidazole – showed in an open study that 39% of the 31 women who came back for a follow-up visit already after 1–3 weeks needed new treatment for BV (92). The question arises whether the true cure rate is even lower than this.

Studies are now needed not to find new treatments that resemble those already in use, but to ascertain how to deal with the low cure rate of BV treatment. It must be difficult to find significant results regarding whether treatment of BV could lower risks of postoperative infections or whether treatment of asymptomatic women could give relief of symptoms as in Schwebke's analysis (39) when antibiotic treatment gives a cure rate not much better than after placebo treatment. A whole new approach to BV treatment must be sought when designing new treatment strategies and treatment regimens. This is the most important issue to be resolved before we can ascertain how hazardous BV is for women's health.


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1. Larsson PG. Treatment of bacterial vaginosis. Int J STD AIDS 1992;3: 239–47.

2. Forsum U, Hallen A, Larsson PG. Bacterial vaginosis – a laboratory and clinical diagnostics enigma. Review II. APMIS 2005;113: 153–61.

3. Lossick JG. Treatment of sexually transmitted vaginosis/vaginitis. Rev Infect Dis 1990;12 Suppl 6: S665–81.

4. Lugo-Miro VI, Green M, Mazur L. Comparison of different metronidazole therapeutic regimens for bacterial vaginosis. A meta-analysis. JAMA 1992;268: 92–5.

5. Berrebi A. [Antibiotics and bacterial vaginosis]. Rev Fr Gynecol Obstet 1993;88: 215–7.

6. Sweet RL. New approaches for the treatment of bacterial vaginosis. Am J Obstet Gynecol 1993;169: 479–82.

7. Ledger WJ. Historical review of the treatment of bacterial vaginosis. Am J Obstet Gynecol 1993;169: 474–8.

8. Neri A, Rabinerson D, Kaplan B. Bacterial vaginosis: drugs versus alternative treatment. Obstet Gynecol Surv 1994;49: 809–13.

9. Schlicht JR. Treatment of bacterial vaginosis. Ann Pharmacother 1994;28: 483–7.

10. Joesoef MR, Schmid GP. Bacterial vaginosis: review of treatment options and potential clinical indications for therapy. Clin Infect Dis 1995 20;Suppl 1: S72–9.

11. Carr PL, Felsenstein D, Friedman RH. Evaluation and management of vaginitis. J Gen Intern Med 1998;13: 335–46.

12. Joesoef MR, Schmid GP, Hillier SL. Bacterial vaginosis: review of treatment options and potential clinical indications for therapy. Clin Infect Dis 1999;28 Suppl 1: S57–65.

13. Larsson PG. Bacterial vaginosis treatment evaluation before one month is not accurate. Am J Obstet Gynecol 1995;172: 1638–9.

14. Chaithongwongwatthana S, Limpongsanurak S, Sitthi-Amorn C Single hydrogen peroxide vaginal douching versus single-dose oral metronidazole for the treatment of bacterial vaginosis: a randomized controlled trial. J Med Assoc Thai 2003;86 Suppl 2: S379–84.

15. Baloglu E, Ozyazici M, Baloglu A, Ova L. A randomized controlled trial of a new ovule formulation of ornidazole for the treatment of bacterial vaginosis. J Clin Pharm Ther 2003;28: 131–6.

16. Ballagh SA, Baker JM, Henry DM, Archer DF. Safety of single daily use for one week of C31G HEC gel in women. Contraception 2002;66: 369–75.

17. Wewalka G, Stary A, Bosse B, Duerr HE, Reimer K. Efficacy of povidone-iodine vaginal suppositories in the treatment of bacterial vaginosis. Dermatology 2002 204;Suppl 1: 79–85.

18. Jerve F, Berdal TB, Bohman P, Cappelen SC, Evjen OK, Gjönnaess H. Metronidazole in the treatment of non-specific vaginitis (NSV). Br J Vener Dis 1984;60: 171–4.

19. Blackwell AL, Fox AR, Phillips I, Barlow D. Anaerobic vaginosis (non-specific vaginitis): clinical, microbiological, and therapeutic findings. Lancet 1983;ii: 1379–82.

20. Larsson PG, Bergman B, Forsum U, Pahlson C. Treatment of bacterial vaginosis in women with vaginal bleeding complications or discharge and harboring Mobiluncus. Gynecol Obstet Invest 1990;29: 296–300.

21. Livengood CH 3rd, Thomason JL, Hill GB. Bacterial vaginosis: treatment with topical intravaginal clindamycin phosphate. Obstet Gynecol 1990;76: 118–23.

22. Hillier S, Krohn MA, Watts DH, Wolner-Hanssen P, Eschenbach D. Microbiologic efficacy of intravaginal clindamycin cream for the treatment of bacterial vaginosis. Obstet Gynecol 1990;76: 407–13.

23. Schmitt C, Sobel JD, Meriwether C. Bacterial vaginosis: treatment with clindamycin cream versus oral metronidazole. Obstet Gynecol 1992;79: 1020–3.

24. Andres FJ, Parker R, Hosein I, Benrubi GI. Clindamycin vaginal cream versus oral metronidazole in the treatment of bacterial vaginosis: a prospective double-blind clinical trial. South Med J 1992;85: 1077–80.

25. Stein GE, Christensen SL, Mummaw NL, Soper DE. Placebo-controlled trial of intravaginal clindamycin 2% cream for the treatment of bacterial vaginosis. Ann Pharmacother 1993;27: 1343–5.

26. Fischbach F, Petersen EE, Weissenbacher ER, Martius J, Hosmann J, Mayer H. Efficacy of clindamycin vaginal cream versus oral metronidazole in the treatment of bacterial vaginosis. Obstet Gynecol 1993;82: 405–10.

27. Dhar J, Arya OP, Timmins DJ, Moss S, Mukembo S, Alawattegama AB, et al. Treatment of bacterial vaginosis with a three day course of 2% clindamycin vaginal cream: a pilot study. Genitourin Med 1994;70: 121–3.

28. Ahmed-Jushuf IH, Shahmanesh M, Arya OP. The treatment of bacterial vaginosis with a 3 day course of 2% clindamycin cream: results of a multicentre, double blind, placebo controlled trial. B V Investigators Group. Genitourin Med 1995;71: 254–6.

29. Sobel J, Peipert JF, McGregor JA, Livengood C, Martin M, Robbins J, et al. Efficacy of clindamycin vaginal ovule (3-day treatment) vs. clindamycin vaginal cream (7-day treatment) in bacterial vaginosis. Infect Dis Obstet Gynecol 2001;9: 9–15.

30. McCormack WM, Covino JM, Thomason JL, Eschenbach DA, Mou S, Kapernick P, et al. Comparison of clindamycin phosphate vaginal cream with triple sulfonamide vaginal cream in the treatment of bacterial vaginosis. Sex Transm Dis 2001;28: 569–75.

31. Paavonen J, Mangioni C, Martin MA, Wajszczuk CP. Vaginal clindamycin and oral metronidazole for bacterial vaginosis: a randomized trial. Obstet Gynecol 2000;96: 256–60.

32. Greaves WL, Chungafung J, Morris B, Haile A, Townsend JL. Clindamycin versus metronidazole in the treatment of bacterial vaginosis. Obstet Gynecol 1988;72: 799–802.

33. Ugwumadu A, Reid F, Hay P, Manyonda I. Natural history of bacterial vaginosis and intermediate flora in pregnancy and effect of oral clindamycin. Obstet Gynecol 2004;104: 114–9.

34. Hillier SL, Lipinski C, Briselden AM, Eschenbach DA. Efficacy of intravaginal 0.75% metronidazole gel for the treatment of bacterial vaginosis. Obstet Gynecol 1993;81: 963–7.

35. Livengood CH 3rd, McGregor JA, Soper DE, Newton E, Thomason JL. Bacterial vaginosis: efficacy and safety of intravaginal metronidazole treatment. Am J Obstet Gynecol 1994;170: 759–64.

36. Soper DE, Livengood C, Sheehan KL, Fenner DE, Martens MG, Nelson AL, et al. Safety and efficacy comparison of two dosing regimens of MetroGel-Vaginal(R) in the treatment of bacterial vaginosis: a multicenter, randomized, single-blind, parallel comparison. Prim Care Update Ob Gyns 1998;5: 150.

37. Livengood CH 3rd, Soper DE, Sheehan KL, Fenner DE, Martens MG, Nelson AL, et al. Comparison of once-daily and twice-daily dosing of 0.75% metronidazole gel in the treatment of bacterial vaginosis. Sex Transm Dis 1999;26: 137–42.

38. Hanson JM, McGregor JA, Hillier SL, Eschenbach DA, Kreutner AK, Galask RP, et al. Metronidazole for bacterial vaginosis. A comparison of vaginal gel vs. oral therapy. J Reprod Med 2000;45: 889–96.

39. Schwebke JR. Asymptomatic bacterial vaginosis: response to therapy. Am J Obstet Gynecol 2000;183: 1434–9.

40. Sanchez S, Garcia PJ, Thomas KK, Catlin M, Holmes KK. Intravaginal metronidazole gel versus metronidazole plus nystatin ovules for bacterial vaginosis: a randomized controlled trial. Am J Obstet Gynecol 2004;191: 1898–906.

41. Bistoletti P, Fredricsson B, Hagstrom B, Nord CE. Comparison of oral and vaginal metronidazole therapy for nonspecific bacterial vaginosis. Gynecol Obstet Invest 1986;21: 144–9.

42. Ozyurt E, Toykuliyeva MB, Danilyans IL, Morton O, Baktir G. Efficacy of 7-day treatment with metronidazole+miconazole (Neo-Penotran) – a triple-active pessary for the treatment of single and mixed vaginal infections. Int J Gynaecol Obstet 2001;74: 35–43.

43. Voorspoels J, Casteels M, Remon JP, Temmerman M. Local treatment of bacterial vaginosis with a bioadhesive metronidazole tablet. Eur J Obstet Gynecol Reprod Biol 2002;105: 64–6.

44. Ferris DG, Litaker MS, Woodward L, Mathis D, Hendrich J. Treatment of bacterial vaginosis: a comparison of oral metronidazole, metronidazole vaginal gel, and clindamycin vaginal cream. J Fam Pract 1995;41: 443–9.

45. Beigi RH, Austin MN, Meyn LA, Krohn MA, Hillier SL. Antimicrobial resistance associated with the treatment of bacterial vaginosis. Am J Obstet Gynecol 2004;191: 1124–9.

46. Colli E, Landoni M, Parazzini F. Treatment of male partners and recurrence of bacterial vaginosis: a randomised trial. Genitourin Med 1997;73: 267–70.

47. Potter J. Should sexual partners of women with bacterial vaginosis receive treatment? Br J Gen Pract 1999;49: 913–8.

48. Larsson PG, Bergström M, Forsum U, Jacobsson B, Strand A, Wölner-Hanssen P. Bacterial vaginosis. Transmission, role in genital tract infection and pregnancy outcome: an enigma. Review III. APMIS 2005;113: 233–45.

49. Barbes C, Boris S. Potential role of lactobacilli as prophylactic agents against genital pathogens. AIDS Patient Care STDS 1999;13: 747–51.

50. Hallen A, Jarstrand C, Pahlson C. Treatment of bacterial vaginosis with lactobacilli. Sex Transm Dis 1992;19: 146–8.

51. Reid G, Charbonneau D, Erb J, Kochanowski B, Beuerman D, Poehner R, et al. Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum RC-14 significantly alters vaginal flora: randomized, placebo-controlled trial in 64 healthy women. FEMS Immunol Med Microbiol 2003;35: 131–4.

52. Eriksson K, Carlsson B, Forsum U, Larsson PG. A double blind treatment study of bacterial vaginosis with normal vaginal lactobacilli after an open treatment with vaginal clindamycin ovules. Acta Derm Venereol 2005;85: 42–6.

53. Antonio MA, Hillier SL. DNA fingerprinting of Lactobacillus crispatus strain CTV-05 by repetitive element sequence-based PCR analysis in a pilot study of vaginal colonization. J Clin Microbiol 2003;41: 1881–7.

54. Ozkinay E, Terek MC, Yayci M, Kaiser R, Grob P, Tuncay G. The effectiveness of live lactobacilli in combination with low dose oestriol (Gynoflor) to restore the vaginal flora after treatment of vaginal infections. BJOG 2005;112: 234–40.

55. Andersch B, Forssman L, Lincoln K, Torstensson P. Treatment of bacterial vaginosis with an acid cream: a comparison between the effect of lactate-gel and metronidazole. Gynecol Obstet Invest 1986;21: 19–25.

56. Andersch B, Lindell D, Dahlen I, Brandberg A. Bacterial vaginosis and the effect of intermittent prophylactic treatment with an acid lactate gel. Gynecol Obstet Invest 1990;30: 114–9.

57. Andreeva P, Slavchev B, Kovachev S, Nacheva A, Vacheva R. [Treatment of bacterial vaginosis with high dosage metronidazole and lactic acid]. Akush Ginekol (Sofiia) 2002;41: 36–9.

58. Milani M, Barcellona E, Agnello A. Efficacy of the combination of 2 g oral tinidazole and acidic buffering vaginal gel in comparison with vaginal clindamycin alone in bacterial vaginosis: a randomized, investigator-blinded, controlled trial. Eur J Obstet Gynecol Reprod Biol 2003;109: 67–71.

59. Harwell JI, Moench T, Mayer KH, Chapman S, Rodriguez I, Cu-Uvin S. A pilot study of treatment of bacterial vaginosis with a buffering vaginal microbicide. J Womens Health (Larchmt) 2003;12: 255–9.

60. Platz-Christensen JJ, Pernevi P, Hagmar B, Andersson E, Brandberg A, Wiqvist N. A longitudinal follow-up of bacterial vaginosis during pregnancy. Acta Obstet Gynecol Scand 1993;72: 99–102.

61. Hay PE, Morgan DJ, Ison CA, Bhide SA, Romney M, McKenzie P, et al. A longitudinal study of bacterial vaginosis during pregnancy. Br J Obstet Gynaecol 1994;101: 1048–53.

62. Boris J, Henriksen TH, Davidsen U, Secher NJ. Evaluation of specific symptoms of bacerial vaginosis among pregnant women. J Infect Dis Obstet Gynecol 1997;5: 361–5.

63. Klebanoff MA, Hauth JC, Macpherson CA, Carey JC, Heine RP, Wapner RJ, et al. Time course of the regression of asymptomatic bacterial vaginosis in pregnancy with and without treatment. Am J Obstet Gynecol 2004;190: 363–70.

64. Kurkinen-Raty M, Vuopala S, Koskela M, Kekki M, Kurki T, Paavonen J, et al. A randomised controlled trial of vaginal clindamycin for early pregnancy bacterial vaginosis. Bjog 2000;107: 1427–32.

65. Bump RC, Zuspan FP, Buesching WJ 3rd, Ayers LW, Stephens TJ. The prevalence, six-month persistence, and predictive values of laboratory indicators of bacterial vaginosis (nonspecific vaginitis) in asymptomatic women. Am J Obstet Gynecol 1984;150: 917–24.

66. Mengel MB, Berg AO, Weaver CH, Herman DJ, Herman SJ, Hughes VL, Koepsell TD. The effectiveness of single-dose metronidazole therapy for patients and their partners with bacterial vaginosis. J Fam Pract 1989;28: 163–71.

67. Heikkinen J, Vuopala S. Anaerobic vaginosis: treatment with tinidazole vaginal tablets. Gynecol Obstet Invest 1989;28: 98–100.

68. Nygaard OG, Csángó PA, Jagars G. Treatment in general practice of bacterial vaginosis associated with Mobiluncus species (English abstract). Tidsskr Nor Lægeforen 1991;111: 845–7.

69. Moi H, Erkkola R, Jerve F, Nelleman G, Bymose B, Alaksen K, et al. Should male consorts of women with bacterial vaginosis be treated? Genitourin Med 1989;65: 263–8.

70. Sobel JD, Schmitt C, Meriwether C. Long-term follow-up of patients with bacterial vaginosis treated with oral metronidazole and topical clindamycin [letter]. J Infect Dis 1993;167: 783–4.

71. Wathne B, Holst E, Hovelius B, Mardh PA. Erythromycin versus metronidazole in the treatment of bacterial vaginosis. Acta Obstet Gynecol Scand 1993;72: 470–4.

72. Friedman M, Talmon R, Itskovitz-Eldor J. Bacterial vaginoisis: assessment of short and long-term results of treatment by clindamycin versus metronidazole. Cervix Lower Genital Tract Infect 1994;11: 157–60.

73. Boris J, Pahlson C, Larsson PG. Six years observation after successful treatment of bacterial vaginosis. J Infect Dis Obstet Gynecol 1997;5: 297–302.

74. Wilson J. Managing recurrent bacterial vaginosis. Sex Transm Infect 2004;80: 8–11.

75. Cook RL, Redondo-Lopez V, Schmitt C, Meriwether C, Sobel JD. Clinical, microbiological, and biochemical factors in recurrent bacterial vaginosis. J Clin Microbiol 1992;30: 870–7.

76. Hay PE. Recurrent bacterial vaginosis. Dermatol Clin 1998;16: 769–73, xii-xiii.

77. Hay P. Recurrent Bacterial Vaginosis. Curr Infect Dis Rep 2000;2: 506–12.

78. Mengel MB, Davis AB. Recurrent bacterial vaginosis: association with vaginal sponge use. Fam Pract Res J 1992;12: 283–8.

79. Tepper RS, Ives TJ, Kebede M. Recurrent bacterial vaginosis unresponsive to metronidazole: successful treatment with oral clindamycin. J Am Board Fam Pract 1994;7: 431–2.

80. Bannatyne RM, Smith AM. Recurrent bacterial vaginosis and metronidazole resistance in Gardnerella vaginalis. Sex Transm Infect 1998;74: 455–6.

81. Winceslaus SJ, Calver G. Recurrent bacterial vaginosis–an old approach to a new problem. Int J STD AIDS 1996;7: 284–7.

82. Cardone A, Zarcone R, Borrelli A, Di Cunzolo A, Russo A, Tartaglia E. Utilisation of hydrogen peroxide in the treatment of recurrent bacterial vaginosis. Minerva Ginecol 2003;55: 483–92.

83. Papanikolaou EG, Tsanadis G, Dalkalitsis N, Lolis D. Recurrent bacterial vaginosis in a virgin adolescent: a new method of treatment. Infection 2002;30: 403–4.

84. Van Kessel K, Assefi N, Marrazzo J, Eckert L. Common complementary and alternative therapies for yeast vaginitis and bacterial vaginosis: a systematic review. Obstet Gynecol Surv 2003;58: 351–8.

85. Pattman RS, Sankar KN, Watson PG, Wardropper AG. An audit of Gynatren (a Lactobacillus acidophilus lyophilisate) vaccination in women with recurrent bacterial vaginosis. Int J STD AIDS 1994;5: 299.

86. Plourd DM. Practical Guide to Diagnosing and Treating Vaginitis. Medscape Women's Health 1997;2: 2.

87. Nicholls S, Patel HC, Jones M. Recurrent bacterial vaginosis and Netherton's syndrome. Int J STD AIDS 1999;10: 202–3.

88. Hudson MM, Tidy JA, McCulloch TA, Rogstad KE. When is bacterial vaginosis not bacterial vaginosis?–a case of cervical carcinoma presenting as recurrent vaginal anaerobic infection. Genitourin Med 1997;73: 306–7.

89. Alfonsi GA, Shlay JC, Parker S. What is the best approach for managing recurrent bacterial vaginosis? J Fam Pract 2004;53: 650–2; discussion 2.

90. Kane KY, Pierce R. What are the most effective treatments for bacterial vaginosis in nonpregnant women? J Fam Pract 2001;50: 399–400.

91. Treatment of BV. Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention. MMWR 2002;51: 43.

92. Andreeva PM, Omar HA. Effectiveness of current therapy of bacterial vaginosis. Int J Adolesc Med Health 2002;14: 145–8.

93. Koumans EH, Markowitz LE, Hogan V. Indications for therapy and treatment recommendations for bacterial vaginosis in nonpregnant and pregnant women: a synthesis of data. Clin Infect Dis 2002;35: S152–72.

94. National guideline for the management of bacterial vaginosis. Clinical Effectiveness Group (Association of Genitourinary Medicine and the Medical Society for the Study of Venereal Diseases). Sex Transm Infect 1999;75 Suppl 1: S16–8.

95. McDonald HM, O'Loughlin JA, Vigneswaran R, Jolley PT, McDonald PJ. Bacterial vaginosis in pregnancy and efficacy of short-course oral metronidazole treatment: a randomized controlled trial. Obstet Gynecol 1994;84: 343–8.

96. Hauth JC, Goldenberg RL, Andrews WW, DuBard MB, Copper RL. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med 1995;333: 1732–6.

97. McGregor JA, French JI, Parker R, Draper D, Patterson E, Jones W, et al. Prevention of premature birth by screening and treatment for common genital tract infections: results of a prospective controlled evaluation. Am J Obstet Gynecol 1995;173: 157–67.

98. Joesoef MR, Hillier SL, Wiknjosastro G, Sumampouw H, Linnan M, Norojono W, et al. Intravaginal clindamycin treatment for bacterial vaginosis: effects on preterm delivery and low birth weight. Am J Obstet Gynecol 1995;173: 1527–31.

99. McDonald HM, O'Loughlin JA, Vigneswaran R, Jolley PT, Harvey JA, Bof A, et al. Impact of metronidazole therapy on preterm birth in women with bacterial vaginosis flora (Gardnerella vaginalis): a randomised, placebo controlled trial. Br J Obstet Gynaecol 1997;104: 1391–7.

100. Yudin MH, Landers DV, Meyn L, Hillier SL. Clinical and cervical cytokine response to treatment with oral or vaginal metronidazole for bacterial vaginosis during pregnancy: a randomized trial. Obstet Gynecol 2003;102: 527–34.


 

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