Conventional oral and secondary high dose vaginal metronidazole therapy for recurrent bacterial vaginosis: clinical outcomes, impacts of sex and menses

Jack D Sobel, Navkiranjot Kaur, Nicole A Woznicki, Dina Boikov, Tina Aguin, Gurveer Gill, Robert A Akins, Jack D Sobel, Navkiranjot Kaur, Nicole A Woznicki, Dina Boikov, Tina Aguin, Gurveer Gill, Robert A Akins

Abstract

Purpose: Oral metronidazole therapy is the standard of care for bacterial vaginosis (BV), yet it has alarming rates of recurrence and refractory responses among recurrent BV (RBV) patients. This study addresses whether high dose vaginal metronidazole therapy (HDM) is beneficial in RBV patients who fail after standard of care (SOC) therapy, whether diagnostic test scores proximal to the HDM predict clinical outcome, and whether menses, coitus, or race influences therapy outcome.

Patients and methods: A total of 90 patients with RBV were given SOC and tracked 74 for up to 9 months. Refractory or recurrent patients (57) with symptomatic BV were given HDM and followed for up to 8 months. Patients were evaluated by Amsel criteria, Nugent score, and a qPCR assay that assesses the Lactobacillus content.

Results: HDM achieved at least short-term remission in 68% of the patients who were refractory to or recurred after SOC and provided a 10-day increase in the mean duration of remission among patients who eventually recurred (p=0.027). Patients with prolonged dysbiosis (pH >5 or Amsel 4) before symptomatic recurrence were more likely to recur after subsequent HDM. Most recurrence happened within 10 days of menses, but sex in this cohort was not associated with clinical outcome. Mean diagnostic BV scores of African American patients in remission were inferior to scores of a small cohort of Caucasian patients in remission.

Conclusion: Encouraging results obtained with HDM justify a prospective, randomized study to determine if follow-up HDM is beneficial among a broader cohort of women failing conventional oral metronidazole therapy.

Keywords: LbRC; amsel criteria; nugent score; prognosis of bacterial vaginosis.

Conflict of interest statement

Drs. Sobel and Akins are co-inventors of the LbRC technology, Patent 14/782,449 to Wayne State University, Detroit, MI, USA. Dr Akins reports grants from NIAID, during the conduct of the study. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Flow diagram of enrollment and responses to therapy. SOC oral metronidazole therapy results (italics) were reported previously. Copyright ©American Society for Microbiology, J. Clin, Microbiol. 57(5):pii:e00227-19. doi:10.128/JCM.0227-19. Remission patients were those who remained in clinical remission (Amsel 0–2, asymptomatic) for at least 3 months. Recurrent patients were those that achieved clinical remission for at least one month before recurring, defined here as Amsel 3–4 with symptoms warranting treatment. Refractory patients were those who did not achieve clinical remission after therapy. Percentages were calculated based on the subtotals in the upstream boxes. Percentages in red are calculated from the entire tracked HDM cohort. Abbreviations: SOC, standard of care; HDM, high dose vaginal metronidazole therapy.
Figure 2
Figure 2
Kaplan–Meier analysis of recurrence rates of BV patients who recurred after SOC versus HDM therapy. Recurrence in this analysis was defined as Amsel 3–4 and symptoms requiring treatment. Dotted lines denote 95% confidence intervals. Abbreviations: SOC, standard of care; BV, bacterial vaginosis; HDM, high dose vaginal metronidazole therapy.
Figure 3
Figure 3
Association of BV diagnostic test scores at the visit preceding recurrence and HDM therapy, with clinical outcome after HDM therapy. Notes: Ref: refractory after HDM, Rec: recurrent after HDM, Rem: remission after HDM. P-values were calculated from ANOVA; the comparisons driving low p-values for pH and Amsel were refractory versus remission groups. Abbreviations: BV, bacterial vaginosis; HDM, high dose vaginal metronidazole therapy.
Figure 4
Figure 4
Time to recurrence from menses. Number of patients who recurred with symptomatic bacterial vaginosis (sBV) in the weeks following the last incidence of vaginal blood were plotted next to numbers expected if recurrence was randomly associated with menses. This number was the total number of recurrences distributed equally over 4 weeks. Observed was significantly different than expected from the null hypothesis that menses and recurrence were not associated, Chi-sq p=0.010.

References

    1. Bradshaw CS, Morton AN, Hocking J, et al. High recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence. J Infect Dis. 2006;193(11):1478–1486. doi:10.1086/503780
    1. Hay P. Recurrent bacterial vaginosis. Curr Opin Infect Dis. 2009;22(1):82–86. doi:10.1097/QCO.0b013e32832180c6
    1. Knupp de Souza DM, Diniz CG, Filho DS, et al. Antimicrobial susceptibility and vaginolysin in Gardnerella vaginalis from healthy and bacterial vaginosis diagnosed women. J Infect Dev Ctries. 2016;10(9):913–919. doi:10.3855/jidc.7161
    1. Gottschick C, Szafranski SP, Kunze B, et al. Screening of compounds against Gardnerella vaginalis biofilms. PLoS One. 2016;11(4):e0154086. doi:10.1371/journal.pone.0154086
    1. De Backer E, Verhelst R, Verstraelen H, et al. Antibiotic susceptibility of Atopobium vaginae. BMC Infect Dis. 2006;6:51. doi:10.1186/1471-2334-6-51
    1. Ferris MJ, Masztal A, Aldridge KE, Fortenberry JD, Fidel PL Jr., Martin DH. Association of Atopobium vaginae, a recently described metronidazole resistant anaerobe, with bacterial vaginosis. BMC Infect Dis. 2004;4:5. doi:10.1186/1471-2334-4-5
    1. Muzny CA, Schwebke JR. Suspected heterosexual transmission of bacterial vaginosis without seminal fluid exposure. Sex Trans Dis. 2014;41(1):58–60. doi:10.1097/OLQ.0000000000000057
    1. Muzny CA, Schwebke JR. Pathogenesis of bacterial vaginosis: discussion of current hypotheses. J Infect Dis. 2016;214(Suppl 1):S1–S5. doi:10.1093/infdis/jiw121
    1. Zabor EC, Klebanoff M, Yu K, et al. Association between periodontal disease, bacterial vaginosis, and sexual risk behaviours. J Clin Periodontol. 2010;37(10):888–893. doi:10.1111/j.1600-051X.2010.01593.x
    1. Vodstrcil LA, Walker SM, Hocking JS, et al. Incident bacterial vaginosis (BV) in women who have sex with women is associated with behaviors that suggest sexual transmission of BV. Clin Infect Dis. 2015;60(7):1042–1053. doi:10.1093/cid/ciu1130
    1. Zozaya M, Ferris MJ, Siren JD, et al. Bacterial communities in penile skin, male urethra, and vaginas of heterosexual couples with and without bacterial vaginosis. Microbiome. 2016;4:16. doi:10.1186/s40168-016-0161-6
    1. Genc MR, Vardhana S, Delaney ML, Witkin SS, Onderdonk AB. TNFA-308G>A polymorphism influences the TNF-alpha response to altered vaginal flora. Eur J Obstet Gynecol Reprod Biol. 2007;134(2):188–191. doi:10.1016/j.ejogrb.2006.10.018
    1. Peixoto F, Camargos A, Duarte G, Linhares I, Bahamondes L, Petracco A. Efficacy and tolerance of metronidazole and miconazole nitrate in treatment of vaginitis. Intl J Gynecol Obstet. 2008;102(3):287–292. doi:10.1016/j.ijgo.2008.04.014
    1. 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(6):1898–1906. doi:10.1016/j.ajog.2004.06.089
    1. 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. Intl J Gynecol Obstet. 2001;74(1):35–43. doi:10.1016/S0020-7292(01)00388-5
    1. Aguin T, Akins RA, Sobel JD. High-dose vaginal maintenance metronidazole for recurrent bacterial vaginosis: a pilot study. Sex Trans Dis. 2014;41(5):290–291. doi:10.1097/OLQ.0000000000000123
    1. Aguin TJ, Akins RA, Sobel JD. High-dose vaginal metronidazole for recurrent bacterial vaginosis-a pilot study. J Lower Genital Tract Dis. 2014;18(2):156–61. doi:10.1097/LGT.0b013e31829a5558
    1. Algburi A, Volski A, Chikindas ML. Natural antimicrobials subtilosin and lauramide arginine ethyl ester synergize with conventional antibiotics clindamycin and metronidazole against biofilms of Gardnerella vaginalis but not against biofilms of healthy vaginal lactobacilli. Pathogens Dis. 2015;73(5)
    1. Cavera VL, Volski A, Chikindas ML. The natural antimicrobial subtilosin a synergizes with Lauramide Arginine Ethyl Ester (LAE), epsilon-Poly-L-lysine (Polylysine), clindamycin phosphate and metronidazole, against the vaginal pathogen Gardnerella vaginalis. Probiotics Antimicrob Prot. 2015;7(2):164–171. doi:10.1007/s12602-014-9183-1
    1. Masoudi M, Miraj S, Rafieian-Kopaei M. Comparison of the effects of Myrtus Communis L, Berberis Vulgaris and metronidazole vaginal gel alone for the treatment of bacterial vaginosis. J Clin Diag Res. 2016;10(3):Qc04–Qc07.
    1. Reichman O, Akins R, Sobel JD. Boric acid addition to suppressive antimicrobial therapy for recurrent bacterial vaginosis. Sex Trans Dis. 2009;36(11):732–734. doi:10.1097/OLQ.0b013e3181b08456
    1. Petersen EE, Genet M, Caserini M, Palmieri R. Efficacy of vitamin C vaginal tablets in the treatment of bacterial vaginosis: a randomised, double blind, placebo controlled clinical trial. Arzneimittelforschung. 2011;61(4):260–265. doi:10.1055/s-0031-1296197
    1. Verstraelen H, Vervaet C, Remon JP. Rationale and safety assessment of a novel intravaginal drug-delivery system with sustained DL-lactic acid release, intended for long-term protection of the vaginal microbiome. PLoS One. 2016;11(4):e0153441. doi:10.1371/journal.pone.0153441
    1. Otsuki K, Imai N. Effects of lactoferrin in 6 patients with refractory bacterial vaginosis. Biochem Cell Biol. 2017;95(1):31–33. doi:10.1139/bcb-2016-0051
    1. Russo R, Edu A, De Seta F. Study on the effects of an oral lactobacilli and lactoferrin complex in women with intermediate vaginal microbiota. Arch Gynecol Obstet. 2018;298(1):139–145. doi:10.1007/s00404-018-4771-z
    1. Russo R, Karadja E, De Seta F. Evidence-based mixture containing Lactobacillus strains and lactoferrin to prevent recurrent bacterial vaginosis: a double blind, placebo controlled, randomised clinical trial. Benef Microbes. 2019;10(1):19–26. doi:10.3920/BM2018.0075
    1. Collins SL, McMillan A, Seney S, et al. Promising prebiotic candidate established by evaluation of lactitol, lactulose, raffinose, and oligofructose for maintenance of a lactobacillus-dominated vaginal microbiota. Appl Environ Microbiol. 2018;84:5. doi:10.1046/j.1365-2672.1997.00313.x
    1. Hakimi S, Farhan F, Farshbaf-Khalili A, et al. The effect of prebiotic vaginal gel with adjuvant oral metronidazole tablets on treatment and recurrence of bacterial vaginosis: a triple-blind randomized controlled study. Arch Gynecol Obstet. 2018;297(1):109–116. doi:10.1007/s00404-017-4555-x
    1. Balkus JE, Srinivasan S, Anzala O, et al. Impact of periodic presumptive treatment for bacterial vaginosis on the vaginal microbiome among women participating in the preventing vaginal infections trial. J Infect Dis. 2017;215(5):723–731. doi:10.1093/infdis/jiw622
    1. Sobel JD, Kaur N, Woznicki NA, et al. Prognostic indicators of recurrence of bacterial vaginosis. J Clin Microbiol. 2019. doi:10.1128/JCM.00227-19
    1. Amsel R, Totten PA, Spiegel CA, Chen KC, Eschenbach D, Holmes KK. Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations. Am J Med. 1983;74(1):14–22.
    1. Bossuyt PM, Cohen JF, Gatsonis CA, Korevaar DA, group S. STARD 2015: updated reporting guidelines for all diagnostic accuracy studies. Ann Transl Med. 2016;4(4):85. doi:10.21037/atm.2016.04.05
    1. Nagaraja P. Antibiotic resistance of Gardnerella vaginalis in recurrent bacterial vaginosis. Indian J Med Microbiol. 2008;26(2):155–157.
    1. Schuyler JA, Mordechai E, Adelson ME, Sobel JD, Gygax SE, Hilbert DW. Identification of intrinsically metronidazole-resistant clades of Gardnerella vaginalis. Diagn Microbiol Infect Dis. 2016;84(1):1–3. doi:10.1016/j.diagmicrobio.2015.10.006
    1. Deng ZL, Gottschick C, Bhuju S, Masur C, Abels C, Wagner-Dobler I. Metatranscriptome analysis of the vaginal microbiota reveals potential mechanisms for protection against metronidazole in bacterial vaginosis. mSphere. 2018;3:3. doi:10.1128/mSphereDirect.00262-18
    1. Austin MN, Meyn LA, Hillier SL. Susceptibility of vaginal bacteria to metronidazole and tinidazole. Anaerobe. 2006;12(5–6):227–230. doi:10.1016/j.anaerobe.2006.06.002
    1. Demirbilek M, Can F, Gulec AT, Kuscu E, Kayhan Z, Haberal M. Incidence of bacterial vaginosis in renal transplant recipients. Transplant Proc. 2003;35(7):2696–2697.
    1. Genc MR, Onderdonk A. Endogenous bacterial flora in pregnant women and the influence of maternal genetic variation. BJOG. 2011;118(2):154–163. doi:10.1111/j.1471-0528.2010.02772.x
    1. Mitchell C, Marrazzo J. Bacterial vaginosis and the cervicovaginal immune response. Am J Reprod Immunol. 2014;71(6):555–563. doi:10.1111/aji.12264
    1. Cherpes TL, Hillier SL, Meyn LA, Busch JL, Krohn MA. A delicate balance: risk factors for acquisition of bacterial vaginosis include sexual activity, absence of hydrogen peroxide-producing lactobacilli, black race, and positive herpes simplex virus type 2 serology. Sex Trans Dis. 2008;35(1):78–83. doi:10.1097/OLQ.0b013e318156a5d0
    1. Swidsinski A, Mendling W, Loening-Baucke V, et al. Adherent biofilms in bacterial vaginosis. Obstet Gynecol. 2005;106(5 Pt 1):1013–1023. doi:10.1097/01.AOG.0000183594.45524.d2
    1. Swidsinski A, Mendling W, Loening-Baucke V, et al. An adherent Gardnerella vaginalis biofilm persists on the vaginal epithelium after standard therapy with oral metronidazole. Am J Obstet Gynecol. 2008;198(1):97.e91–97.e96. doi:10.1016/j.ajog.2007.06.039
    1. Patterson JL, Girerd PH, Karjane NW, Jefferson KK. Effect of biofilm phenotype on resistance of Gardnerella vaginalis to hydrogen peroxide and lactic acid. Am J Obstet Gynecol. 2007;197(2):170.e171–170.e177. doi:10.1016/j.ajog.2007.02.027
    1. Bradshaw CS, Pirotta M, De Guingand D, et al. Efficacy of oral metronidazole with vaginal clindamycin or vaginal probiotic for bacterial vaginosis: randomised placebo-controlled double-blind trial. PLoS One. 2012;7(4):e34540. doi:10.1371/journal.pone.0034540
    1. Lugo-Miro VI, Green M, Mazur L. Comparison of different metronidazole therapeutic regimens for bacterial vaginosis. A meta-analysis. JAMA. 1992;268(1):92–95.
    1. Krasnopolsky VN, Prilepskaya VN, Polatti F, et al. Efficacy of vitamin C vaginal tablets as prophylaxis for recurrent bacterial vaginosis: a randomised, double-blind, placebo-controlled clinical trial. J Clin Med Res. 2013;5(4):309–315. doi:10.4021/jocmr1489w
    1. Huang H, Song L, Zhao W. Effects of probiotics for the treatment of bacterial vaginosis in adult women: a meta-analysis of randomized clinical trials. Arch Gynecol Obstet. 2014;289(6):1225–1234. doi:10.1007/s00404-013-3117-0
    1. Buggio L, Somigliana E, Borghi A, Vercellini P. Probiotics and vaginal microecology: fact or fancy? BMC Women’s Health. 2019;19(1):25. doi:10.1186/s12905-019-0723-4
    1. Tan H, Fu Y, Yang C, Ma J. Effects of metronidazole combined probiotics over metronidazole alone for the treatment of bacterial vaginosis: a meta-analysis of randomized clinical trials. Arch Gynecol Obstet. 2017;295(6):1331–1339. doi:10.1007/s00404-017-4366-0
    1. Bohbot JM, Darai E, Bretelle F, Brami G, Daniel C, Cardot JM. Efficacy and safety of vaginally administered lyophilized Lactobacillus crispatus IP 174178 in the prevention of bacterial vaginosis recurrence. J Gynecol Obstet Human Reprod. 2018;47(2):81–86. doi:10.1016/j.jogoh.2017.11.005
    1. Laue C, Papazova E, Liesegang A, et al. Effect of a yoghurt drink containing Lactobacillus strains on bacterial vaginosis in women - a double-blind, randomised, controlled clinical pilot trial. Benef Microbes. 2018;9(1):35–50. doi:10.3920/BM2017.0018
    1. Lambert JA, John S, Sobel JD, Akins RA. Longitudinal analysis of vaginal microbiome dynamics in women with recurrent bacterial vaginosis: recognition of the conversion process. PLoS One. 2013;8(12):e82599. doi:10.1371/journal.pone.0082599
    1. Srinivasan S, Liu C, Mitchell CM, et al. Temporal variability of human vaginal bacteria and relationship with bacterial vaginosis. PLoS One. 2010;5(4):e10197. doi:10.1371/journal.pone.0010197
    1. Fredricks DN. Molecular methods to describe the spectrum and dynamics of the vaginal microbiota. Anaerobe. 2011;17(4):191–195. doi:10.1016/j.anaerobe.2011.01.001
    1. Bradshaw CS, Vodstrcil LA, Hocking JS, et al. Recurrence of bacterial vaginosis is significantly associated with posttreatment sexual activities and hormonal contraceptive use. Clin Infect Dis. 2013;56(6):777–786. doi:10.1093/cid/cis1030
    1. Riggs M, Klebanoff M, Nansel T, Zhang J, Schwebke J, Andrews W. Longitudinal association between hormonal contraceptives and bacterial vaginosis in women of reproductive age. Sex Transm Dis. 2007;34(12):954–959.
    1. van de Wijgert JH, Verwijs MC, Turner AN, Morrison CS. Hormonal contraception decreases bacterial vaginosis but oral contraception may increase candidiasis: implications for HIV transmission. AIDS. 2013;27(13):2141–2153. doi:10.1097/QAD.0b013e32836290b6
    1. Vodstrcil LA, Hocking JS, Law M, et al. Hormonal contraception is associated with a reduced risk of bacterial vaginosis: a systematic review and meta-analysis. PLoS One. 2013;8(9):e73055. doi:10.1371/journal.pone.0073055
    1. Fethers KA, Fairley CK, Hocking JS, Gurrin LC, Bradshaw CS. Sexual risk factors and bacterial vaginosis: a systematic review and meta-analysis. Clin Infect Dis. 2008;47(11):1426–1435. doi:10.1086/592974
    1. Muzny CA, Lensing SY, Aaron KJ, Schwebke JR. Incubation period and risk factors support sexual transmission of bacterial vaginosis in women who have sex with women. Sex Trans Infect. 2019. doi:10.1136/sextrans-2018-053824
    1. Ignacio MAO, Andrade J, Freitas APF, Pinto G, Silva MGD, Duarte MTC. Prevalence of bacterial vaginosis and factors associated among women who have sex with women. Rev Lat Am Enfermagem. 2018;26:e3077. doi:10.1590/1518-8345.2491.3077
    1. Norris Turner A, Carr Reese P, Snead MC, et al. Recent biomarker-confirmed unprotected vaginal sex, but not self-reported unprotected sex, is associated with recurrent bacterial vaginosis. Sex Trans Dis. 2016;43(3):172–176. doi:10.1097/OLQ.0000000000000414
    1. Kenyon CR, Buyze J, Klebanoff M, Brotman RM. Association between bacterial vaginosis and partner concurrency: a longitudinal study. Sex Trans Infect. 2018;94(1):75–77. doi:10.1136/sextrans-2016-052652
    1. Bradshaw CS, Walker J, Fairley CK, et al. Prevalent and incident bacterial vaginosis are associated with sexual and contraceptive behaviours in young Australian women. PLoS One. 2013;8(3):e57688. doi:10.1371/journal.pone.0057688
    1. Elsner P, Hartmann AA. Gardnerella vaginalis in the male upper genital tract: a possible source of reinfection of the female partner. Sex Trans Dis. 1987;14(2):122–123. doi:10.1097/00007435-198704000-00015
    1. Gottschick C, Deng ZL, Vital M, et al. The urinary microbiota of men and women and its changes in women during bacterial vaginosis and antibiotic treatment. Microbiome. 2017;5(1):99. doi:10.1186/s40168-017-0305-3
    1. Liu CM, Hungate BA, Tobian AA, et al. Penile microbiota and female partner bacterial vaginosis in Rakai, Uganda. mBio. 2015;6(3):e00589. doi:10.1128/mBio.00589-15
    1. Price LB, Liu CM, Johnson KE, et al. The effects of circumcision on the penis microbiome. PLoS One. 2010;5(1):e8422. doi:10.1371/journal.pone.0008422

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj