Topical Clindamycin Or Metronidazole for Treatment of Bacterial Vaginosis: Microbiologic-Clinical Study
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Egyptian Journal of Medical Microbiology, October 2007 Vol. 16, No 4 Topical Clindamycin or Metronidazole for Treatment of Bacterial Vaginosis: Microbiologic-Clinical Study Amal A. Wafy, M.D.; Ahmed T. Soliman, M.D. * and Safaa K. Marei, M.D. * Departments of Microbiology& Immunology and Obstetrics & Gynecology *, Faculty of Medicine, Tanta University BACKGROUND: Aim: To compare the frequencies, concentrations, and antimicrobial susceptibilities of vaginal microbes isolated from women with bacterial vaginosis (BV) before and after therapy with intra-vaginal clindamycin or metronidazole. DESIGN: Prospective randomized controlled study. PATIENTS & METHODS: 119 non-pregnant women aged 20 - 45 with clinical and Gram stain evidence of BV were randomized to receive intra-vaginal clindamycin or metronidazole. Vaginal swabs were collected at baseline and 7 to 12 days, 35 to 45 days, and 70 to 90 days following therapy for quantitative vaginal culture. For the 99 women completing all four visits, statistical analyses were performed comparing differences in vaginal microflora between the two treatment arms and between visits in the same treatment group. Antimicrobial susceptibility testing using the agar dilution method was performed for anaerobic gram-negative rods. RESULTS: Although both therapies resulted in decreased colonization by Gardnerella vaginalis and Mycoplasma hominis, only metronidazole treatment resulted in a significant decrease in the frequency and concentration of Prevotella bivia and black-pigmented Prevotella species. Of the 865 anaerobic gram-negative rods evaluated for susceptibility, only 3 (0.3%) were resistant to metronidazole, whereas clindamycin resistance increased significantly for P. bivia and black-pigmented anaerobic gram-negative rods persisting following clindamycin therapy. Clindamycin-resistant subpopulations of P. bivia and black-pigmented Prevotella species emerged 7 to 12 days after therapy even among women colonized initially by clindamycin- susceptible strains. These resistant subpopulations persisted at high frequencies (42 to 50%) 70 to 90 days following therapy. CONCLUSION: The two topical agents for treatment of BV have differing microbiologic effects on the vaginal microflora. The emergence of clindamycin-resistant anaerobic gram-negative rods following therapy is of concern. INTRODUCTION for the diagnosis of bacterial vaginosis have included culture for G. vaginalis 7, 8, direct Gram Bacterial vaginosis (BV) is a common stain of vaginal secretions 9, biochemical tests for lower genital tract syndrome affecting women of metabolic by-products of vaginal bacteria (gas reproductive age. Microbes associated with BV are chromatography) 10, and more recently, the proline part of the endogenous flora of the vagina, and the aminopeptidase test 11. acquisition of BV results when there are changes The treatments recommended by the of the normal flora of the vagina, causing an Centers for Disease Control (CDC) for BV are increased prevalence of Gardnerella vaginalis, either metronidazole or clindamycin administered Mycoplasma hominis, and anaerobic organisms orally or intravaginally 12. Metronidazole is a and a decreased prevalence of the dominant nitroimidazole with activity against anaerobic Lactobacillus species. Acquisition of BV is organisms, while clindamycin, a macrolide, has a associated with adverse outcomes among non- broad spectrum of activity against a variety of pregnant and pregnant women. Previous studies microbes including aerobic and anaerobic have shown that the alteration of the normal flora organisms. could increase the risk of acquiring BV, human Despite treatment with either immunodeficiency virus type 1, or sexually metronidazole or clindamycin, similar percentages transmitted diseases 1, 2 . Furthermore, BV has of women (approximately 10 to 15%) fail therapy been found to be associated with preterm labor, after 1 month 13. The proportion of women who preterm delivery, low birth weight, post-cesarean relapse also increases over time. The recurrence endometritis, and post-abortion pelvic rate of BV is approximately 30% at 3 months and inflammatory disease 3-5 . approximately 50 to 80% at 1 year following Because bacterial vaginosis is a clinical therapy with either drug 14-16. Current therapy for syndrome which has been associated with a group managing recurrent BV is repeated treatment with of genital microorganisms rather than a single antibiotics. An obvious problem and important etiologic agent, it has been defined primarily by health issue associated with repeated exposure to the following clinical signs: vaginal pH >4.5, the the same antibiotic is resistance of those microbes presence of adherent white discharge, detection of targeted by the drug, which can result in an "clue cells," and the presence of an amine odor alteration of flora and possible persistence of BV- after the addition of KOH 6. Laboratory methods associated pathogens. Resistance to metronidazole, 673 Egyptian Journal of Medical Microbiology, October 2007 Vol. 16, No 4 despite its use for over 3 decades, is rare 17, 18. days after finishing the last dose of medication and Recent studies have shown an emergence of 35 to 45 days and 70 to 90 days after treatment. If clindamycin-resistant genital organisms among women were diagnosed with BV at a follow-up clinically relevant bacteria, including group B visit, they were retreated with the same therapy streptococci 19, 20. they initially received. Although no comparative studies have Clinical evaluation evaluated the microbiologic responses, separate A clinical cure was defined as the absence of clue placebo-controlled trials suggest that there may be cells on wet mount in addition to the absence of different microbiological responses following two or more clinical signs (no homogenous therapy with metronidazole and clindamycin 13. discharge, pH less than 4.7, no amine odor upon The objectives of the present study were addition of potassium hydroxide). Only the subset to compare the frequencies and median of 99 women completing all four visits and having concentrations of major constituents of the vaginal valuable culture results from those visits was microflora before and after treatment to assess for included in the present analysis. metronidazole and clindamycin resistance among Specimen collection anaerobic components of the microflora before and Vaginal swabs were obtained at baseline after therapy and to evaluate whether (pretreatment) and at the three consecutive follow- antimicrobial susceptibility accounts for the up visits following treatment. Vaginal swabs were persistence of anaerobic gram-negative rods obtained by placing a non-lubricated speculum following therapy. into the vagina and swabbing the lateral wall discharge with a Dacron polyester fiber-tipped MATERIALS AND METHODS swab (Fisher Scientific, Pittsburgh, PA). The swabs were transported to the laboratory, where Patient population. A total of 119 non-pregnant they were processed within 24 hours of collection. women aged 20 to 45 years with a clinical and Gram stain diagnosis of BV were recruited from Microbiological evaluation the outpatient clinic of Tanta University Hospital. Isolation and identification. Quantitative vaginal Written informed consent of the protocol was culturing was performed. The Lactobacillus spp. obtained from all patients prior to enrollment. isolated were identified by Gram stain showing Exclusion criteria gram-positive rods, characteristic ground glass <20 years of age • colony morphology, and negative catalase • pregnancy reaction. Hydrogen peroxide (H2O2) detection of • known allergy to metronidazole or clindamycin the Lactobacillus spp. isolated was performed by a • concurrent antibiotic use, qualitative method in which isolates are inoculated • menstruation, onto a brucella agar base supplemented with • presence of an intrauterine device, 3,3',5,5'-tetramethylbenzidine and horseradish • known active infection due to Chlamydia, peroxidase. Anaerobic incubation at 37°C for 48 Gonorrhea, or Trichomonas, or clinically to 72 h followed by exposure to air for 30 min apparent herpes simplex infection. results in a blue pigment if there is H2O2 Clinical diagnosis of BV was determined using production and no pigment if H2O2 production is Amsel's criteria 6. Three or more of these criteria absent 22. The Gardnerella vaginalis isolates were must be present to ensure the clinical diagnosis: identified by their characteristic colony 1. Homogenous vaginal discharge, morphology, beta hemolysis on human bilayer 2. >20% clue cells on wet mount preparation, agar with Tween (Becton Dickinson, Rockville, 3. Elevated pH of vaginal discharge ( 4.7), MD), Gram stain showing gram-variable 4. Release of a fishy amine odor upon addition of pleomorphic rods, and negative catalase reaction. 10% potassium hydroxide solution to vaginal The Mycoplasma hominis and Ureaplasma fluid. urealyticum isolates were identified by their A Gram stain score of 4 based on the criteria for characteristic colony morphology on A-8 agar. BV assessment developed by Nugent et al. was The Escherichia coli isolates were identified by required for Gram stain diagnosis 21 . their colony morphology, Gram stain showing Treatment: Upon enrollment, women were gram-negative rods, and positive indole (Sigma, randomized using a computer-generated list to St. Louis, MO) test. The anaerobic gram-negative receive one of two treatments, clindamycin vaginal bacteria isolated were identified by Gram stain, a cream (Dalacin