© 1990 S. Karger AG, Basel 0378-7346/90/0294-0296$2.75/0

Gynecol Obstet Invest 1990;29:296-300

Treatment of Bacterial Vaginosis in Women with Vaginal Bleeding Complications or Discharge and Harboring Mobiluncus P.G. Larssona, B. Bergmana, U. Forsumb, C. Pahlsonb a Department of Obstetrics and Gynecology, Central Hospital, Skovde, and bDepartment of Clinical Bacteriology, Huddinge Hospital, Karolinska Institute, Stockholm, Sweden

Key Words. Mobiluncus • Vaginal bleeding • Discharge • Bacterial vaginosis

Introduction The syndrome bacterial vaginosis (BV) has been ac­ cepted by many authors as a condition affecting women of childbearing age with abnormal malodorous dis­ charge as the main symptom. In order to make the clin­ ical composite diagnosis of BV three out of the following criteria must be fulfilled: typical homogeneous dis­ charge, vaginal pH >4.5, sniff test positive and pres­ ence of clue cells [1], The presence of motile rods in wet smear preparations and/or isolation of the rod Mobilun­ cus is found in 15-60% of all cases of BV, depending on the population studied. Mobiluncus is rarely found in other conditions though it can occur in extragenital infections [2-4] and may be identified in women pre­ senting with vaginal bleeding irregularities [5], The vari­ able and low isolation rates of Mobiluncus in different

studies may be due to difficulties in transporting and culturing the bacteria. Some treatment studies of BV have been published [6-8] with a cure rate of 70-99%. However, in the most frequently quoted study, by Pheifer et al. [9], the evalu­ ation of patients in the treatment part of the study is not based on wet smear examinations. Spiegel [10] assumed that, because some strains of Mobiluncus have a higher MIC value for metronidazole, the varying prevalence of a particular Mobiluncus species would explain the differ­ ent results of treatment and relapses of BV. We deliberately designed this treatment study of BV to include only those patients presenting with bleeding irregularities and/or discharge, fulfilling the criteria for BV and harboring motile rods in wet smears. In this way the study included a fairly unselected patient group. However by setting the criterion, the presence of motile

Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:24:35 AM

Abstract. A double-blind study of treatment for bacterial vaginosis (BV), using metronidazole tablets 500 mg 3 times daily for 10 days versus placebo in the same regimen, was performed on 42 outpatients with irregular bleeding episodes or discharge attending a gynecological clinic. All patients had motile rods in wet smears in addition to fulfilling the criteria for BV. Treatment gave a cure rate of 76% versus 5% in the placebo group. Mobiluncus sp. was identified in 81 % of these cases before treatment, in 8 % of the cured patients and in 50% of those not initially cured at follow-up. Repeated treatments, once or twice, resulted in a 100% cure rate. A 6-month follow-up was carried out on 39 of the 42 patients. There were 7 relapses after 6 months giving a cure rate of 82 %. After successful treatment all bleeding disturbances disappeared. We conclude that it is important to treat BV in patients with symptoms other than malodorous discharge.

Mobiluncus and Treatment

rods, a stricter, although more restrictive, bacteriological definition was used. A double-blind study was designed using metronidazole tablets 500 mg 3 times daily for 10 days versus placebo to investigate the cure rate in the patient group selected.

297

Samples were possible to take from the urethra of 11 male part­ ners for culturing of Mobiluncus. A one-tail z test was used for statistical evaluation; p values over 0.05 were considered not significant. The metronidazole tablets and identical placebo tablets were supplied by Dumex Ltd., Copenha­ gen, Denmark. The study was approved by the local Ethical Com­ mittee and National Board of Health and Welfare. Department of Drugs in Sweden.

Material and Methods

Microbiological Procedures A sample was taken from the cervix and the urethra and ana­ lyzed using Clamydiazyme (Abbott Scandinavia) for Chlamydia tra­ chomatis. A cotton tip swab sample from the posterior fornix was mailed in Steward’s transport medium (SBL, Stockholm, Sweden) to the department of Clinical Bacteriology, Uppsala University for cul­ turing of Mobiluncus. Transportation time did not exceed 1 day. An air-dried preparation from the vagina was taken for monoclonal antibody analysis [ 12]. Division of Mobiluncus into species and sub­ species was not considered necessary for this clinical study because of the ambiguity of subdivision of Mobiluncus. Serum for analysis of antibodies against Mobiluncus was drawn and stored at -2 0 °C. An indirect immunofluorescence assay was used for this analysis as described earlier [13]. Culturing for Neisseria gonorrhoea was not performed because of its low prevalence in our community. Culturing of Gardnerella vaginalis was not performed.

Results Forty-eight patients were enrolled in the study. Six women were excluded, 4 due to positive C. trachomatis tests, 1 whose treatment was interrupted and 1 who did not attend the follow-up. Twenty-one of the remaining women were given metronidazole tablets 500 mg 3 times daily for 10 days, and 21 were given placebo. Some of the women had both discharge and bleeding disturbances as their symptoms. Discharge was one of the symptoms in 67% in the treatment group and 90% in the placebo group. Bleeding disturbances was one of the symptoms in 71% of the metronidazole group and in 52% of the placebo group. The difference in symptoms between the groups was not statistically significant. The double-blind study showed a cure rate of 76% in the metronidazoletreated group and of 5% (1 patient) in the placebo group, with p < 0.001 (table 1). None of the patients who did not fulfill the criteria for BV on the follow-up harbored motile rods in the wet smear preparation. No major adverse side effects were reported. The bleeding disturbances disappeared in all patients that were treated with the active drug and were regarded as cured according to our criteria (11 out of 11 ). How­ ever, 5 of the 6 patients that did not respond to active treatment had also had bleeding disturbances as their main symptom. In 2 women the bleeding disturbances disappeared even though they were regarded as not

.

Table 1 Cure rate after 1 month in a double-blind trial of metronidazole tablets 500 mg 3 times daily for 10 days versus pla­ cebo for the treatment of patients with bleeding complications or discharge and harboring Mobiluncus as part of BV syndrome

Metronidazole Placebo

Patients

Cured

Not cured

21 21

16(76.2) 1 (5)

5 (23.8)* 20 (95.2)

Figures in parentheses are percentages. * p < 0.001 versus placebo.

Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:24:35 AM

Forty-eight consecutive nonpregnant patients, 18-45 years old, attending the outpatient clinic at the Gynecological Department, Skovde, because of discharge or irregular bleeding episodes were enrolled in a double-blind study. The bleeding disturbances were defined as small intermenstruational bleeding episodes, spottings, or increased menstrual bleedings, menorrhagia. Patients with me­ trorrhagia were not included, as this is often a sign of hormonal disturbances. The patients also fulfilled the criteria for BV and har­ bored motile rods, or Mobiluncus, with the typical movements in wet smear preparations described by Thomason et al. [11]. Women treated with antibiotics for any reason within 1 month or during the study were excluded. None of the patients had any signs of other genital infection such as Candida colpitis, Trichomonas colpitis or cervicitis. After verbal informed consent to participate the patients were given either metronidazole tablets 500 mg 3 times daily for 10 days or placebo tablets in a double-blind manner, together with a written description to avoid alcoholic beverages, but no recommen­ dations about sexual intercourse were given. Follow-up was per­ formed after 4-8 weeks in order to allow for at least one normal menstruation after treatment. Treatment was regarded successful if the criteria for BV were not fulfilled and no motile rods were present in wet smears. Those patients not cured at the follow-up received further treat­ ment with metronidazole 500 mg 3 times daily for 10 days and were again followed up 1-2 months later. Only 2 patients were still not cured. These 2 received the same treatment again until they were finally cured. Patients were interviewed by telephone and offered a follow-up, 6 months after successful treatment. A few patients who regarded themselves as cured and did not wish to attend the 6month follow-up were considered cured. Partners of the women with relapses received metronidazole treatment on the same regi­ men as the patients.

Larsson/Bergman/Forsum/Pâhlson

298

Table 2. Antibody titers against Mobiluncus in 3 women with intramenstrual bleedings and presence of Mobiluncus in the va­ gina Patient

0 month

1 month

3 months

6 months

M.E. M.R. I.L.

10 20 20

80 80 160

80 40 80

_ 20 80

The first patient was treated with metronidazole tablets 500 mg 3 times daily for 10 days and became free of her intermenstruational bleedings. The other 2 were initially given the placebo, and their intermenstruational bleedings stopped, although they still had BV and had Mobiluncus present in wet smears.

Table 3. Identification of Mobiluncus or motile rods in relation to the cure rate in patients treated with metronidazole tablets 500 mg 3 times daily for 10 days in the double-blind study

Motile rods in wet smears Culture Monoclonal antibodies Culturing or monoclonal antibodies

Second visit cured1 n - 36

not cured n=6

42/42 (100) 26/42 (62) 20/36 (56)

0/36 2/32 (6) 2/25(7)

3/6 (50) 1/6 (17) 3/4 (75)

34/42 (81)

3/36(8)

3/6 (50)

Figures in parentheses are percentages. 1 Includes patients that received placebo on the first visit and were then treated with metronidazole tablets.

cured after treatment. Bleeding disturbances disap­ peared also in half of the cases (5 of 11 ) in the placebo group within the first follow-up after 1-2 months with­ out active treatment, even though they were not cured as they still had Mobiluncus and fulfilled the criteria for BV in wet smears. After that they were treated with metro­ nidazole, and, followed up after another 1-2 months, all bleeding disturbances had disappeared. The serological study of antibody titers against Mobi­ luncus sp. showed a significant increase in 3 patients (ta­ ble 2), all with intermenstruational bleeding distur­ bances. One patient was treated with the active drug and the other 2 initially received placebo. Bleeding distur­ bances in the 2 who received placebo disappeared within the observation period of 1 month. One of these patients

Discussion BV has mostly been associated with vaginal dis­ charge. In this study almost half of the women had bleed­ ing disturbances or spottings as their main complaint. However, there is a bias in this study population, since if a woman calls our department of gynecology complain­ ing of vaginal discharge she will be recommended to see her general practitioner, but if she has bleeding distur­ bances she will get an appointment. Women with bleed­ ing disturbances are a major clinical problem and ac­ count for many consultations at our gynecological de­ partment. Because the risk for malignancy we deliber­ ately chose only women under 45 years of age to be enrolled in our double-blind study and had our follow-up after 1-2 months. To leave a woman untreated with bleeding disturbances longer we thought to be unethi­ cal. Five of our placebo-treated patients with bleeding dis­ turbances were normalized under this observation peri­ od, even though they still had Mobiluncus in the wet smear. Two of these patients had a significant rise in antibody titers against Mobiluncus spp. This could possi­ bly signify a deeper infection in the endometrium caused by Mobiluncus. Bleeding disturbances associated with C. trachomatis infection on the basis of plasma cell endometritis are documented [14], but this study does not provide unequivocal proof that bleedings are nor­ malized by the given treatment. The etiology of bleeding

Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:24:35 AM

First visit n = 42

also had a significant fall in antibody titer. She relapsed after 12 months. The 6-month follow-up was conducted in 39 women: 30 by physical examination and 9 by telephone inter­ view. Seven of the cured patients had relapsed in the 6 months (18 %). Three of the 7 relapses were patients that had not been cured after the first active treatment. We could not find any differences in the clinical signs of patients who had relapsed, but the patients that did relapse were more likely to have had Candida in their wet smears on the follow-up. The Candida infections were mild and did not always require treatment. Table 3 data show identification of Mobiluncus in patients at the first and second visits. We were able to identify Mobiluncus in 3 patients that were regarded as cured. They all relapsed, not within the 6-month follow­ up period, as one could have suspected, but a year after successful treatment.

299

Mobiluncus and Treatment

clone, according to enzyme and cell wall analyses of Mobilurtcus, from the urethra of the male partner of 1 patient who had a history of BV and had relapsed twice within a 12-month period (data not shown). Our study has shown that patients with BV, associ­ ated with the presence of motile rods or Mobilurtcus, may present with clinical problems other than malodor­ ous discharge. BV can be successfully treated in these women and the diagnosis of the bleeding disturbances can wait till after treatment, but the importance of a fol­ low-up must be stressed. Further studies of the preva­ lence of BV among the patients with bleeding distur­ bances is required.

Acknowledgments Thanks are due to Olga Svensson for her skills in culturing the Mobilurtcus and to Dr. Jan Leyon for kind support in finding patients for the study. Financial support was given by the Svenska Lakarsâlskapets Forskningsfond.

References 1 Eschenbach D, Bekassy S, Blackwell A, Ekgren J, Hallén A, Wathne B: The diagnosis of bacterial vaginosis; in Mârdh PA, Taylor-Robinson S (eds): Bacterial Vaginosis. Stockholm, Almqwist & Wiksell International, 1984, pp 260-261. 2 Glupczynski Y, Labbe M, Crokaert F, Pepersack F, Van Der Auwera, Yourassowsky E: Isolation of Mobiluncus in four cases of extragenital infections in adult women. Eur J Clin Microbiol 1984;3:433-435. 3 Weinbren MJ, Perinpanayagam RM, Malnick FI, Ormerod F: Mobiluncus spp: Pathogenic role in non-puerperal breast abscess (letter). J Clin Pathol 1988;39:342-343. 4 Sturm AW, Sikkenk PJH: Anaerobic curved rods in breast abscess. Lancet 1984;ii: 1216. 5 Larsson PG, Bergman B: Is there a causal connection between motile curved rods, Mobiluncus species, and bleeding complica­ tions? Am J Obstet Gynecol 1986;154:107-108. 6 Blackwell AL, Fox AR, Phillips I, Barlow D: Anaerobic vaginosis (non-specific vaginitis): Clinical, microbiological and thera­ peutic findings. Lancet 1983;ii: 1379—1382. 7 Balsdon M, Taylor G, Pead L, Maskell R: Corynebacterium va­ ginale and vaginitis: A controlled trial of treatment. Lancet 1980;ii:501—504. 8 Eschenbach DA, Critchlow CW, Watkins H, Smith K, Spiegel CA, Chen KCS, Holms KK: A dose-duration study of metroni­ dazole for the treatment of nonspecific vaginosis. Scand J Infect Dis Suppl 1983;40:73-80. 9 Pheifer TA, Forsyth PA, Durfee MA, Pollock H, Holms KK: Nonspecific vaginitis: Role of Haemophilus vaginalis and treat­ ment of metronidazole. N Engl J Med 1978;298:1429-1434. 10 Spiegel CA: Susceptibility of Mobiluncus species to 23 antimi-

Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:24:35 AM

disturbances in our patients was not further studied, since it was not the aim of the investigation to study the multiple etiologies of bleeding disturbances that in some cases will not be obvious until after many years. This is the first study to be published on the treat­ ment of BV where all patients harbour Mobiluncus spp. or motile rods in wet smears. In previous treatment studies of BV with metronidazole tablets 500 mg twice daily for 7 days [6-8], a cure rate of 70-98% was achieved. In a pilot study of 55 patients (data not shown) we only had a cure rate of 44% when using the same treatment schedule. This difference can be ex­ plained by the selection of patients, as we included only patients with Mobilurtcus and by the fact that the criteria for BV in previous studies were not the same as used today [6, 9]. Also, the follow-up time in the other studies is mostly 1-2 weeks. Our follow-up was done 1-2 months after treatment. To be considered effective by the patient the cure should last longer than 1 week, and thus a follow-up time of 1-2 weeks is too short. We therefore considered that if the woman is not cured at follow-up at 1-2 months it is not due to a relapse but inadequate treatment. In addition our results suggest that a longer treatment, with metronidazole 500 mg 3 times daily for 10 days, of patients with BV and harbor­ ing Mobilurtcus is more effective. Patients that do not respond to initial treatment can be given the same regimen again. We have not seen any patients so far that do not respond to treatment. Other authors have excluded patients that did not respond to the first treatment [6-9], However, in clinical reality, these patients have to be treated. By repeating the treat­ ment all patients were cured and followed up for at least 6 months. Twenty-five of the patients who had been included in the study visited the clinic for different reasons, other than discharge, 1-2 years after: controlling cytological atypia, myoma controls, abortion, sterilization and post­ operative checkup. Twelve of these had been given treat­ ment for relapses during this time. Four were patients that had relapsed once before. Five of the 6 patients who were not cured at the second visit after active treatment had relapsed. It seems that it is the same patients that do not respond to treatment. This may be because we have not dealt with the underlying reason for the disease. The primary habitat of Mobilurtcus is not yet known, but it may be in the rectum [15]. Whether Mobilurtcus is part of the etiology of BV and whether the presence of Mobiluncus is related to sexual transmission are still open questions. We were able to isolate the same strain and

Larsson/Bergman/Forsum/Pâhlson

300

12

13

14

15 Hallén A, Pâhlson C, Forsum U: Rectal occurrence o f Mobiluncus species. Genitourin Med 1988;64:273-275.

Received: June 8, 1989 Accepted: November 15, 1989 Dr. P.G. Larsson Kvinnokliniken Central Hospital S—541 85 Skovde(Sweden)

Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:24:35 AM

11

crobial agents and 15 other compounds. Antimicrob Agents Chemother 1987;31:249-252. Thomason JL, Schrechenberger PC, Spellacy WN, Riff LJ, LeBeau L: Clinical and microbiological characterization of patients with nonspecific vaginosis associated with motile, curved anaer­ obic rods. J Infect Dis 1984;149:801-803. Pâhlson C, Hallén A, Forsum U: Curved rods related to Mobiluncus phenotypes as defined by monoclonal antibodies. Acta Pathol Microbiol Scand (B) 1986;94:117-125. Larsson PG, Pâhlson C, Bergman B, Forsum U, Gottardsson L: Mobiluncus-speciüc antibodies in a postoperative infection. Am J Obstet Gynecol 1986; 154:1167-1168. Paavonen J, Kiviat N, Brunham R, Stevens C, Cho-Cho Kou PA, Stamm W, et al: Prevalence and manifestations of endome­ tritis among women with cervicitis. Am J Obstet Gynecol 1985; 152:280-286.

Treatment of bacterial vaginosis in women with vaginal bleeding complications or discharge and harboring Mobiluncus.

A double-blind study of treatment for bacterial vaginosis (BV), using metronidazole tablets 500 mg 3 times daily for 10 days versus placebo in the sam...
642KB Sizes 0 Downloads 0 Views