Bacterial vaginosis (BV) affects one third of all women at any given time [ALLSWORTH 2007, MACPHEE 2010] and causes significant gynaecological and obstetric morbidity such as pelvic inflammatory disease, infections following gynaecological surgery, increased risk of sexually transmitted infections including HIV infection and pre-term birth [MACPHEE 2010, FALAGAS 2007, REID 2009]. It is often asymptomatic and when symptoms/signs do occur, the most common are malodorous discharge and vaginal pH above 4.5 [KLEBANOFF 2004]. While BV may have significant consequences in terms of discomfort and pain, days lost from school or work, sexual functioning and self-image, it is also the source of considerable distress. This very prevalent condition is associated with a sizeable socioeconomic cost, including costs resulting from sick leave and medical costs. Distress and costs are further raised by the frequent relapses [VERSTRAELEN 2008].
Bacterial vaginosis is the clinical term describing an alteration in the composition of the vaginal microbiota from flora dominated by the Lactobacillus species to flora severely depleted of protective Lactobacilli with a massive overgrowth of a mixed, anaerobic flora with a 100- to 1000-fold increase in bacterial numbers (Gardnerella vaginalis, gram-positive anaerobic rods – Prevotella, Bacteroides, and Porphyromonas species – Mycoplasma hominis, Mobiluncus species, Atopobium vaginae). While anaerobic overgrowth is the most apparent feature, bacterial vaginosis further encompasses profound physico-chemical and immunological changes in vaginal environment. Thus, BV represents an almost complete breakdown of the normal vaginal antimicrobial defence with the loss of lactobacilli-driven colonization resistance [VERSTRAELEN 2008, WITKIN 2007].
Although the aetiology of BV remains obscure, risk factors for its development include: douching, use of an intrauterine contraceptive device, new or multiple sexual partners, smoking, and chronic stress. BV is also predominant in the black ethnicity. More recently, gene polymorphisms of the innate immune system have been added to this list. Conversely, hormonal contraceptive use has emerged as a protective factor [VERSTRAELEN 2008, WITKIN 2007, WILSON 2004].
The recommended treatment regimens for BV are oral or vaginal metronidazole or vaginal clindamycin [ACOG 2006]. Although these treatment options yield a reasonable cure rate immediately following treatment, recurrences are common within weeks and months and side effects including drug resistance are also common [BRADSHAW 2006, ODUYEBO 2009]. Recurrence rates are estimated to be as high as 30% at 3 months, reaching up to 80% at 9 months and necessitating repeated administration of antibiotics. Such repeated antibiotic exposure increases the risk of the emergence of resistant strains, alteration of microbiota, and possible persistence of BV-associated pathogens [SOBEL 2006, SENOK 2009].
These clinically observed cure rates with metronidazole are in contrast with in vitro data reported by Beigi et al. who determined metronidazole susceptibility of vaginal cultures up to 3 months following BV treatment, and found that less than 1% of all anaerobic isolates demonstrated metronidazole resistance [BEIGI 2004].
The limits of an antibiotic treatment
Two key elements in the pathogenesis of BV that are likely to explain the metronidazole paradox in the treatment of bacterial vaginosis have recently emerged:
- Several studies have recently identified Atopobium vaginae (a gram-positive anaerobe) as a key organism highly specific to BV, often metronidazole-resistant, and the strongest bacterial indicator known of resistant and relapsing BV [FERRIS 2004, BRADSHAW 2006]. Further data suggest that A. vaginae may elicit a pivotal role in the progression to BV. The concurrent presence of A. vaginae and G. vaginalis is highly specific for BV. It appears as if A. vaginae is dependent on G. vaginalis for colonisation of the vaginal epithelium, while conversely in the progression to BV A. vaginae appears to ultimately superimpose on G. vaginalis at an advanced stage of the disease [VERSTRAELEN 2008].
- The presence of a dense, adherent biofilm has been documented as a pathognomonic finding in BV. It could be shown that in women without BV the vaginal mucosa was mostly covered with Lactobacillus spp. displaying planktonic growth, whereas women with BV almost consistently elicited a dense biofilm with G. vaginalis constituting 60 to 95% and A. vaginae 1 to 40% of the overall biofilm mass [SWIDSINSKI 2005]. In a very recent intervention study, the in vivo resistance of the bacterial vaginosis biofilm to metronidazole was illustratively demonstrated [SWIDSINSKI 2008]. The resurgence with treatment cessation of a dense and active bacterial biofilm on the vaginal mucosa, primarily consisting of Gardnerella vaginalis and Atopobium vaginae, was consistently observed. Thus, the discovery of this bacterial vaginosis biofilm generally largely resisting conventional antibiotic therapy seems to explain poor long-term cure rates with standard treatment.
Allsworth JE, Peipert JF. Prevalence of bacterial vaginosis. Obstet Gynecol 2007; 109 (1): 114-20.
MacPhee RA, Hummelen R, Bisanz JE, Miller WN, Reid G. Probiotic strategy for the treatment and prevention of bacterial vaginosis. Expert Opin Pharmacother 2010; 11 (18): 2985-95.
Falagas ME, Betsi GI, Athanasiou S. Probiotics for the treatment of women with bacterial vaginosis. Clin Microbiol Infect 2007; 13 (7): 657-64.
Reid G, Dols J, Miller W. Targeting the vaginal microbiota with probiotics as a means to counteract infections. Curr Opin Clin Nutr Met Care 2009; 12: 583-7.
Klebanoff MA, Schwebke JR, Zhang, J, Nansel TR, Yu KF, Andrews WW. Vulvovaginal symptoms in women with bacterial vaginosis. Obstet Gynecol 2004; 104 (2): 267-72.
Verstraelen H. Cutting edge: the vaginal microflora and bacterial vaginosis. Verh K Acad Geneeskd Belg 2008;70 (3):147-74.
Witkin SS, Linhares IN, Giraldo P, Ledger WJ. An altered immunity hypothesis for the development of symptomatic bacterial vaginosis. Clin Infect Dis 2007; 44 (4): 554-7.
Wilson J. Managing recurrent bacterial vaginosis. Sex Transm Infect 2004; 80: 8-11.
ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists, Number 72, May 2006, Vaginitis. Obstet Gynecol 2006; 107 (5):1195-1206.
Bradshaw CS, Morton AN, Hocking J, Garland SM, Morris MB, Moss LM, Horvath LB, Kuzevska I, Fairley CK. 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: 1478-86.
Oduyebo OO, Anorlu RI, Ogunsola FT. The effects of antimicrobial therapy on bacterial vaginosis in non-pregnant women. Cochrane Database Syst Rev 2009; 3: CD006055.
Sobel JD, Ferris D, Schwebke J, Nyirjesy P, Wiesenfeld HC, Peipert J, Soper D, Ohmit SE, Hillier SL. Suppressive antibacterial therapy with 0,75 % metronidazole vaginal gel to prevent recurrent bacterial vaginosis. Am J Obstet Gynecol 2006; 194 (5):1283-9.
Senok AC, Verstraelen H, Temmerman M, Botta GA. Probiotiocs for the treatment of bacterial vaginosis (review) Cochrane Database Syst Rev. 2009 Oct 7; (4): CD006289.
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.
Ferris MJ, Masztal A, Alrlridge 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.
Bradshaw CS, Tabrizi SN, Fairley CK, Morton AN, Rudland E, Garland SM. The association of Atopobium vaginae and Gardnerella vaginalis with bacterial vaginosis and recurrence after oral metronidazole therapy. J Infect Dis 2006; 194:828-36.
Swidsinski A, Mendling W, Loening-Baucke V, Ladhoff A, Swidsinski S, Hale LP, Lochs H. Adherent biofilms in bacterial vaginosis. Obstet Gynecol 2005; 106 (5 Pt 1): 1013-23.
Swidsinski A e.a. An adherent Gardnerella vagina/is biofilm persists on the vaginal epithelium after standard therapy with oral metronidazole. Am J Obstet Gynecol 2008; 198 (1): 97. e1-6.