Supplementation of standard antibiotic therapy with oral probiotics for bacterial vaginosis and aerobic vaginitis: a randomised, double-blind, placebo-controlled trial

Piotr B Heczko, Anna Tomusiak, Paweł Adamski, Artur J Jakimiuk, Grzegorz Stefański, Aleksandra Mikołajczyk-Cichońska, Magdalena Suda-Szczurek, Magdalena Strus, Piotr B Heczko, Anna Tomusiak, Paweł Adamski, Artur J Jakimiuk, Grzegorz Stefański, Aleksandra Mikołajczyk-Cichońska, Magdalena Suda-Szczurek, Magdalena Strus

Abstract

Background: This multicentre, randomised, double-blind, placebo-controlled trial was performed to determine whether the use of oral probiotic preparation (prOVag®) containing three Lactobacillus strains together with standard metronidazole treatment and also targeted antibiotic treatment (following the failure of metronidazole therapy) could reduce the recurrence rates of bacterial vaginosis (BV) and aerobic vaginitis (AV).

Methods: Patients at private gynaecological clinics in Poland with histories of recurrent BV/AV and current symptoms were randomly allocated to receive metronidazole and probiotic or placebo, and assessed monthly on visits II and III-V. The total number of study visits was 5-6 (I, II, II bis - if applicable, III, IV, V). One probiotic or placebo capsule was administered with metronidazole/targeted antibiotic twice daily for 10 days; during follow up, patients took one capsule daily for 10 days perimenstrually. Clinical examination and vaginal swabbing were performed at each visit. Primary outcomes were clinical or microbiological BV/AV recurrence and probiotic safety. Secondary outcomes were vaginal pH, Nugent score, and Lactobacillus counts in the vaginal microbiota. Safety analysis was performed in 578 (probiotic, n = 285; placebo, n = 293) 18-50-year-old women who were randomised.

Results: BV/AV was confirmed microbiologically in 241 (probiotic, n = 118; placebo, n = 123) participants, who continued the trial. Data from 154 (probiotic, n = 73; placebo, n = 81) participants who completed the study were analysed to determine the efficacy of prOVag. Additional analyses included 37 (probiotic, n = 22; placebo, n = 15) participants who received targeted antibiotics and probiotics or placebo. prOVag lengthened the time to clinical relapse of BV/AV symptoms up to 51 % (p < 0.05) compared with placebo; AV relapse was delayed by up to 76 % (p < 0.05). Probiotic use also reduced and maintained low vaginal pH and Nugent score, and increased vaginal Lactobacillus counts following standard treatment.

Conclusion: This study demonstrated that oral probiotics lengthened remission in patients with recurrent BV/AV and improved clinical and microbiological parameters.

Trial registration: NCT01993524 ; 20 November 2013.

Figures

Fig. 1
Fig. 1
Participant flow
Fig. 2
Fig. 2
Interval between end of treatment and appearance of clinical relapse in patients on standard therapy taking prOVag or placebo
Fig. 3
Fig. 3
Interval between end of treatment and clinical relapse in patients receiving targeted antibiotics and prOVag or placebo
Fig. 4
Fig. 4
Number of patients with microbiological relapse detected at consecutive visits
Fig. 5
Fig. 5
Interval between end of treatment and microbiological relapse in patients receiving antibiotics and taking prOVag or placebo
Fig. 6
Fig. 6
Effect of prOVag application on total numbers of vaginal lactobacilli during consecutive visits
Fig. 7
Fig. 7
Effect of placebo application on total numbers of vaginal lactobacilli during consecutive visits

References

    1. Allsworth JE, Peipert JF. Prevalence of bacterial vaginosis: 2001–2004 National Health and Nutrition Examination Survey data. Obstet Gynecol. 2007;109(1):114–120. doi: 10.1097/01.AOG.0000247627.84791.91.
    1. Li J, McCormick J, Bocking A, Reid G. Importance of vaginal microbes in reproductive health. Reprod Sci. 2012;19(3):235–242. doi: 10.1177/1933719111418379.
    1. Donders GG. Definition and classification of abnormal vaginal flora. Best Pract Res Clin Obstet Gynaecol. 2007;21(3):355–373. doi: 10.1016/j.bpobgyn.2007.01.002.
    1. 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(1):114–119. doi: 10.1097/01.AOG.0000130068.21566.4e.
    1. Leitich H, Kiss H. Asymptomatic bacterial vaginosis and intermediate flora as risk factors for adverse pregnancy outcome. Best Pract Res Clin Obstet Gynaecol. 2007;21(3):375–390. doi: 10.1016/j.bpobgyn.2006.12.005.
    1. Tempera G, Furneri PM. Management of aerobic vaginitis. Gynecol Obstet Invest. 2010;70(4):244–249. doi: 10.1159/000314013.
    1. Oduyebo OO, Anorlu RI, Oqunsola FT. The effects of antimicrobial therapy on bacterial vaginosis in non-pregnant women. Cochrane Database Syst Rev. 2009;3:CD006055.
    1. Bradshaw CS, Morton AN, Hocking J, Garland SM, Morris MB, Moss LM, 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. Han C, Wu W, Fan A, Wang Y, Zhang H, Chu Z, et al. Diagnostic and therapeutic advancements for aerobic vaginitis. Arch Gynecol Obstet. 2015;291(2):251–257. doi: 10.1007/s00404-014-3525-9.
    1. Larsson PG, Stray-Pedersen B, Ryttig KR, Larsen S. Human lactobacilli as supplementation of clindamycin to patients with bacterial vaginosis reduce the recurrence rate; a 6-month, double-blind, randomized, placebo-controlled study. BMC Womens Health. 2008;8:3. doi: 10.1186/1472-6874-8-3.
    1. Marcone V, Rocca G, Lichtner M, Calzolari E. Long-term vaginal administration of Lactobacillus rhamnosus as a complementary approach to management of bacterial vaginosis. Int J Gynaecol Obstet. 2010;110(3):223–226. doi: 10.1016/j.ijgo.2010.04.025.
    1. Ya W, Reifer C, Miller LE. Efficacy of vaginal probiotic capsules for recurrent bacterial vaginosis: a double-blind, randomized, placebo-controlled study. Am J Obstet Gynecol. 2010;203(2):120.e1-6.
    1. Delia A, Morgante G, Rago G, Musacchio MC, Petraglia F, De Leo V. Effectiveness of oral administration of Lactobacillus paracasei subsp. paracasei F19 in association with vaginal suppositories of Lactobacillus acidofilus in the treatment of vaginosis and in the prevention of recurrent vaginitis. Minerva Ginecol. 2006;58(3):227–231.
    1. Vujic G, Jajac Knez A, Despot Stefanovic V, Kuzmic Vrbanovic V: Efficacy of orally applied probiotic capsules for bacterial vaginosis and other vaginal infections: a double-blind, randomized, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol 2013, [Epub ahead of print]
    1. Reid G, Bruce AW, Fraser N, Heinemann C, Owen J, Henning B. Oral probiotics can resolve urogenital infections. FEMS Immunol Med Microbiol. 2001;30(1):49–52. doi: 10.1111/j.1574-695X.2001.tb01549.x.
    1. Strus M, Brzychczy-Włoch M, Kochan P, Heczko P. Hydrogen peroxide produced by Lactobacillus species as a regulatory molecule for vaginal microflora. Med Dosw Mikrobiol. 2004;56(1):67–77.
    1. Hay P. Recurrent bacterial vaginosis. Curr Opin Infect Dis. 2009;22(1):82–6. doi: 10.1097/QCO.0b013e32832180c6.
    1. Senok AC, Verstraelen H, Temmerman M, Botta GA. Probiotics for the treatment of bacterial vaginosis. Cochrane Database Syst Rev. 2009;4:CD006289.
    1. Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. 3. New York: Springer-Verlag, selected chapters; 1996.
    1. 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(4):870–877.
    1. Blackwell AL, Fox AR, Philips I, Barlow D. Anaerobic vaginosis (nonspecific vaginitis): clinical, microbiological and therapeutic findings. Lancet. 1986;2:1379–1382.
    1. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol. 1991;29(2):297–301.
    1. Srinivasan S, Morgan MT, Liu C, Matsen FA, Hoffman NG, Fiedler TL, et al. More than meets the eye: associations of vaginal bacteria with gram stain morphotypes using molecular phylogenetic analysis. PLoS One. 2013;8(10):e78633. doi: 10.1371/journal.pone.0078633.
    1. Leclercq R, Cantón R, Brown DF, Giske CG, Heisig P, MacGowan AP, et al. EUCAST expert rules in antimicrobial susceptibility testing. Clin Microbiol Infect. 2013;19(2):141–160. doi: 10.1111/j.1469-0691.2011.03703.x.
    1. van de Wijgert JH, Borgdorff H, Verhelst R, Crucitti T, Francis S, Verstraelen H, et al. The vaginal microbiota: what have we learned after a decade of molecular characterization? PLoS One. 2014;9(8):e105998. doi: 10.1371/journal.pone.0105998.
    1. Strus M, Chmielarczyk A, Kochan P, Adamski P, Chełmicki Z, Chełmicki A, et al. Studies on the effects of probiotic Lactobacillus mixture given orally on vaginal and rectal colonization and on parameters of vaginal health in women with intermediate vaginal flora. Eur J Obstet Gynecol Reprod Biol. 2012;163(2):210–215. doi: 10.1016/j.ejogrb.2012.05.001.
    1. Tomusiak A, Strus M, Heczko PB. Antibiotic resistance of Gardnerella vaginalis isolated from cases of bacterial vaginosis. Ginekol Pol. 2011;82(12):900–904.
    1. Austin MN, Beigi RH, Meyn LA, Hillier SL. Microbiologic response to treatment of bacterial vaginosis with topical clindamycin or metronidazole. J Clin Microbiol. 2005;43(9):4492–4497. doi: 10.1128/JCM.43.9.4492-4497.2005.
    1. Mayer BT, Srinivasan S, Fiedler TL, Marrazzo JM, Fredricks DN, Schiffer JT. Rapid and profound shifts in the vaginal microbiota following antibiotic treatment for bacterial vaginosis. J Infect Dis. 2015. jiv079.
    1. Aroutcheva A, Simoes JA, Shott S, Faro S. The inhibitory effect of clindamycin on Lactobacillus in vitro. Infect Dis Obstet Gynecol. 2001;9(4):239–44. doi: 10.1155/S1064744901000394.
    1. Eriksson K, Larsson PG, Nilsson M, Forsum U. Vaginal retention of locally administered clindamycin. APMIS. 2011;119(6):373–6. doi: 10.1111/j.1600-0463.2011.02742.x.
    1. Anukam K, Osazuwa E, Ahonkhai I, Ngwu M, Osemene G, Bruce AW, et al. Augmentation of antimicrobial metronidazole therapy of bacterial vaginosis with oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14: randomized, double-blind, placebo controlled trial. Microbes Infect. 2006;8(6):1450–4. doi: 10.1016/j.micinf.2006.01.003.
    1. Schulz KF, Altman DG, Moher D for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Ann Intern Med. 2010;152(11):726–732.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner