DIAGNOSIS AND TREATMENT OF VAGINITIS Stephanie N. Taylor, MD LSUHSC Department of Medicine Section of Infectious Diseases

DISCLOSURE I have no financial interests or other relationship with manufacturers of commercial products, suppliers of commercial services, or commercial supporters. My presentation will not include any discussion of the unlabeled use of a product or a product under investigational use.

VAGINITIS Inflammation of the vagina leading to vaginal irritation and discharge Both cervicitis and vaginitis can cause vaginal discharge and distinction can be difficult (Speculum Exam)

ETIOLOGY OF VAGINITIS YEAST (CANDIDA SP.) TRICHOMONAS VAGINALIS BACTERIAL VAGINOSIS ALLERGIC RXN, ESTROGEN DEF., etc.

VULVOVAGINAL CANDIDIASIS Candida albicans, Candida glabrata, etc. colonize vagina Proliferation or allergic reaction caused by known and unknown factors (Antibiotic use, diabetes, pregnancy, etc.) Estimated that >75% of women will have at least one episode during lifetime

VULVOVAGINAL CANDIDIASIS VVC causes 20-25% of vaginitis in STD clinics Not truly sexually transmitted - males can acquire the organism however (Candida balanitis or dermatitis)

VULVOVAGINAL CANDIDIASIS Symptoms Vulvar pruritis, burning or pain “External dysuria” - 20 to inflammed labia Complaint of discharge Physical Examination Vulvar erythema, edema, fissures, vulvar dermatitis with satellite lesions Clumped, white, adherent discharge - classic Occasionally scant, homogeneous, purulent

VULVOVAGINAL CANDIDIASIS Diagnosis KOH Prep - Pseudohyphae in ~80% Vaginal pH < 4.5, Negative amine odor, absent or scant PMNs Treatment Fluconazole 150-200 mg po (single dose) Any of several imidazole creams or suppositories administered 3-7 days Partner - imidazole cr. for dermatitis/balanitis

VAGINITIS

CANDIDA DERMATITIS

CANDIDA BALANITIS

TRICHOMONAS VAGINITIS Caused by the unicellular parasite Trichomonas vaginalis Causes 5-15% of vaginitis in STD clinics Sexually transmitted - (Older women - delayed diagnosis of chronic infection) Colonizes male urethra - mostly asymptomatic but can cause NGU

TRICHOMONAS VAGINITIS Symptoms Increased vaginal discharge, often profuse Sometimes malodor Vulvar irritation, pruritis Physical Examination Homogeneous discharge, yellow, copious Mucosal erythema, petechiael cervix (strawberry cervix), bubbles in vaginal fluid

TRICHOMONAS VAGINITIS Diagnosis Motile trichomonads and predominant PMNs on saline wet prep Vaginal pH > 5.0, Positive amine odor Treatment Metronidazole 2.0 gm (single dose) Metronidazole 500 mg po bid for 7 days if single dose fails Partner - Eval. and Metro. 2.0 gm po (single dose)

TRICHOMONAS VAGINITIS

TRICHOMONAS VAGINALIS

WHAT IS BACTERIAL VAGINOSIS? Most prevalent cause of vaginal symptoms in women of childbearing age Characterized by: Increased malodorous discharge Decrease or absence of Lactobacillus sp. (L. crispatus and L. jensenii most common) Overgrowth of Gardnerella vaginalis, Mycoplasma sp. and other anaerobic organisms Altered pattern of organic acids from these bacteria (e.g., putrescine, cadaverine, etc.) producing odor Lack of inflammation – vaginosis (not vaginitis)

HISTORY OF BACTERIAL VAGINOSIS 1892 – Doderlein described normal vaginal bacteria in pregnant women – Later became known as Lactobacillus 1899 – Menge and Kronig isolated facultative and strictly anaerobic bacteria, as well as the Doderlein bacillus from the vaginal bacteria of most women Early Studies – Established the normal flora of women – Lactobacillus sp. and a mixture of other organisms

HISTORY OF BACTERIAL VAGINOSIS Early 1900’s – “Leukorrhea” – white discharge from the vagina became focus of research Initially thought to have come from the uterus Treated by curettage of the endometrium 1913 – A. H. Curtis demonstrated the bacteria that later became known as Gardnerella 1913 – Curtis also demonstrated: a. The discharge was of vaginal origin, not endometrial b. Women with leukorrhea did not have many Dordelein bacilli c. Presence of anaerobic bacteria correlated with leukorrhea

HISTORY OF BACTERIAL VAGINOSIS 1920’s – R. Schroder reported 3 types of vaginal flora 1. Acid-producing rods – Doderlein’s bacilli – and the least pathogenic flora 2. Mixed flora with Doderlein bacilli in the minority 3. Mixed vaginal flora with no Doderlein bacilli and the most pathogenic flora 1950 – J.D. Weaver also noted the association of mixed flora with BV

HISTORY OF BACTERIAL VAGINOSIS 1955 – Gardner and Dukes demonstrated that Haemophilus vaginalis caused non-specific vaginitis (Later named Gardnerella vaginalis) 1955 – Gardner and Dukes erroneously failed to find association with mixed flora For 25 years research focused on Gardnerella vaginalis as the cause of BV and ignored the potential role of other organisms.

WHAT’S IN A NAME? Leukorrhea Non-specific vaginitis Haemophilus vaginalis vaginitis Gardnerella vaginitis Anaerobic vaginosis (but not just anaerobes) Bacterial vaginosis (since inflammation is not a feature of BV, the term vaginosis has replaced vaginitis)

EPIDEMIOLOGY Prevalence depends upon population studied Student Health Clinics – 4-10% Family Planning Clinics – 17-19% Pregnant women – 16-29% Infertility Clinics – 30% STD Clinics – 24-40%

EPIDEMIOLOGY Prevalence also depends on ethnicity Large U.S. Study of pregnant women 13,747 at 23-26 weeks gestation 16.3% of women had BV Asians – 6.1% Caucasians – 8.8% Hispanics – 15.9% African American – 22.7% 51% of 4,718 women in Ugandan study

EPIDEMIOLOGY BV is common in most populations More common in STD clinics than in family planning or prenatal clinics More common in women with discharge Related to ethnicity for unknown reasons Especially common in Sub-Saharan Africa

WHAT ABOUT SEXUAL TRANSMISSION? Conflicting and controversial area Women who use condoms have decreased prevalence of BV Yet multiple partner treatment trials have failed to demonstrate benefit to women with BV Evidence of sexual transmission of BV in women who have sex with women

WHAT ABOUT SEXUAL TRANSMISSION? Females with no sexual exposure have significantly lower prevalence of BV Some studies have found association with younger age of sexual debut In college women, Amsel demonstrated that 0 of 18 virgins versus 69 of 293 (24%) sexually experienced women had BV

WHAT ABOUT SEXUAL TRANSMISSION? Association with number of partners also seen Women with new or multiple sex partners also have higher prevalence of BV Evidence of NGU in male partners of patients with BV

WHAT ABOUT SEXUAL TRANSMISSION? Sexual transmission of Gardnerella vaginalis has been demonstrated Gardner and Pheifer detected G. vaginalis in the urethras of 79 and 86% of male sex partners of women with BV but not in controls Piot et al. developed a typing system and demonstrated that Gardnerella isolates in women with BV and from the urethras of their partners were the same Ison and Easmon recovered G. vaginalis and other anaerobes at 103 to 107 org/ml from semen in 16% of men attending an infertility clinic

PREDISPOSING/RISK FACTORS Douching IUD as contraceptive method Younger age New sex partner Multiple sex partners

PREDISPOSING/RISK FACTORS Decrease or absence of Lactobacillus sp. Non-white ethnicity Smoking in some studies Failure to use condoms Female sexual partners

ETIOLOGY BV represents a complex change in vaginal flora Reduction in H2O2-producing lactobacilli Increase prevalence and concentration of G. vaginalis, M. hominis, and anaerobes such as Prevotella, Bacteroides sp., Porphyromonas, Peptostreptococcus sp., etc. These organisms found in low levels in normal vagina – also argues against sexual transmission alone as cause

PATHOGENESIS Decreased Lactobacilli – decreased lactic acid causes increased pH Overgrowth of anaerobes associated with increased enzymes that breakdown vaginal peptides into amines that are malodorous Trimethylamine, cadaverine, putrescine, etc.

PATHOGENESIS Amines – increase vaginal transudation and squamous cell exfoliation causing the discharge At elevated pH – G. vaginalis adheres to squamous cells (“Clue cells”) Amines also provide substrate for growth of M. hominis

PATHOGENESIS Lactobacilli are essential for normal vaginal pH and inhibit growth of other bacteria Lactobacilli are also acidophilic and are attracted to an acid environment Anaerobic environment of BV is not conducive to growth of lactobacilli or dominance Remains unknown whether the loss of lactobacilli occurs first or follows the flora disturbance

LACTOBACILLUS INTERACTIONS Reduction in Lactobacilli – Decreased H2O2 Production Overgrowth of BV-associated bacteria Raised pH

CLINICAL MANIFESTATIONS “Fishy-smelling” discharge – More noticeable after intercourse (Addition of semen with alkaline pH is similar to addition of KOH) Discharge is gray or off-white, thin, homogeneous, and adherent to vaginal wall No erythema or inflammation Some patients report vaginal itching Cervix usually normal

CLINICAL MANIFESTATIONS

CLINICAL MANIFESTATIONS Bacterial vaginosis Trichomonas vaginitis

DIAGNOSIS Amsel’s Criteria (3 of 4 criteria for dx.) Adherent, homogeneous gray-white discharge Positive amine or whiff test with addition of 10% KOH Elevated vaginal pH of >4.5 Presence of “clue cells” – Squamous cells with adherent bacteria (>20% of cells on wet mount)

DIAGNOSIS – GRAM STAIN Points Scored per Morphotype* Bacterial Morphotype None 1+ 2+ 3+ 4+ Large Gram-Positive Rod 4 3 2 1 0 Small Gram-neg/var. Rod 0 1 2 3 4 Curved Gm-neg/var. Rod 0 1 2 3 4 *Score 0-3 points – Normal 4-6 points – Intermediate 7-10 points – Bacterial Vaginosis

CLUE CELLS

COMPLICATIONS OF BV IN PREGNANCY 7 studies have reported increased risk of pre-term birth in women with BV Relative risk from 2.0-6.9 directly attributable to BV ~40% elevated risk of pre-term, low birth weight delivery 16-29% of pregnant women with BV Large number of women at risk

COMPLICATIONS OF BV IN PREGNANCY Considerable reduction in pre-term births in high risk women treated for BV Screening and treatment is currently recommended in high-risk patients (previous pre-term delivery) Similar results have not been seen in low-risk patients with asymptomatic BV Therefore routine screening and treatment of BV in all asymptomatic pregnant women is not indicated

INFECTIOUS COMPLICATIONS OF BV Organisms found in the lower genital tract in women with BV are found in ~50% with positive cultures of amniotic fluid or placenta Greatly increased risk of postpartum endometritis and post-Ceasarian endometritis Increased rates of wound infections

INFECTIOUS COMPLICATIONS OF BV Vaginal cuff cellulitis after hysterectomy Post-abortion PID Pre-operative antibiotic prophylaxis that covers BV-associated flora can reduce these complications Since the 1970’s BV has also been associated with PID, especially in the absence of GC or CT

BV AND HIV ASSOCIATION Presence of BV or absence of lactobacilli associated with heterosexual transmission of HIV 2-fold increased prevalence of HIV in Thai and Ugandan women with BV Study of African pregnant and postnatal women in Malawi found that women with BV were more likely to seroconvert to HIV These data raise the question of whether BV should be treated more aggressively (In the past – asymptomatic BV was not treated)

TREATMENT OF BV Treatment Metronidazole 500 mg po bid for 7 d Metronidazole 2.0 gm no longer recommended Metro. 0.75% gel qd or bid for 5 d Clinda 2% Cr., 5 gm qd for 7 d Clinda 300 mg po bid for 7d (Active against Lactobacillus - interferes with re-establishment of normal flora Partner tx. - No treatment required New Drug - Tinidazole 500 bid po x 5 days – 95% efficacy/ Vaginally once daily – 80% eff.

SIDE EFFECTS OF TREATMENT Overall in about 15% of patients Nausea Metallic taste Headaches Gastrointestinal complaints Oral metronidazole assoc. with Disulfiram-like or “antabuse” reaction after consumption of alcohol – Patient education point 3-5% will stop therapy due to side-effects

RECURRENT BV 80-90% cure rates at 1 week 15-30% recur within 3 months Single Dose versus 7 day course – 73% vs. 82% Higher recurrence rates for single dose tx.

RECURRENT BV Several trials have demonstrated that partner treatment does not improve clinical outcome of BV or reduce recurrence Discrepancy between data suggesting sexual transmission and lack of benefit with treatment of male partners is puzzling Excellent opportunities for further research

RECURRENT BV – COMBINED OR ALTERNATIVE TREATMENTS Reduction in Lactobacilli – Decreased H2O2 Production Replace Lactobacilli Oral or vag Overgrowth of BV-associated bacteria Raised pH Maintain 4.5 pH – vag. gel Intermittent Tx.

RECURRENT BV – COMBINED OR ALTERNATIVE TREATMENTS Replacement or Restoration of Lactobacilli (LB)(Bacteriotherapy) Unfortunately lack of efficacy with few controlled trials LB used needs to be able to adhere and produce H2O2 If given orally, LB needs to survive pass through GI tract and ascend from the perianal area into the vaginal area Lactobacilli used have not been vaginal strains

RECURRENT BV – COMBINED OR ALTERNATIVE TREATMENTS Lactobacilli in yogurt strains do not bind to vaginal epithelial cells Only 1 of 14 women were cured after applying yogurt intravaginally twice daily for 7 days Little utility for therapies employing yogurt

RECURRENT BV – COMBINED OR ALTERNATIVE TREATMENTS Other types of capsules, powders, etc. in health food stores are also dairy derived In addition, 9 of 16 preparations were contaminated with other types of bacteria and 5 of 16 did not contain peroxide producing strains Placebo-controlled trial of purified Lactobacillus suppositories being studied by Sharon Hillier. ~50% of women improved during therapy Only 4 of 29 remained free of BV at 2nd visit

RECURRENT BV – COMBINED OR ALTERNATIVE TREATMENTS Disinfectants Chlorhexidine – 79% effective but 50% recurred at one month Povidone-iodine – bid for 2 wks – only 20 % efficacy Acidifiers Lactic Acid suppository – 20% efficacy Lactic acid gel x 7 days – 77% - 7 day follow-up – not repeated 5% acetic acid tampon – 38% efficacy Suppressive therapy – Currently being studied (Sobel) Metronidazole or Tinidazole twice a week Results pending

WHAT CAN WE OFFER PATIENTS WITH RECURRENT BV? Clearly explain bacterial vaginosis Carefully go through personal hygiene practices to remove douching, etc. that may disrupt normal flora Explain that course of therapy may relieve symptoms but it takes time for the bacterial imbalance normalize and recolonize with Lactobacilli Longer course of antibiotics or combination therapy for recurrences (2 weeks/ oral + vaginal therapy) ???Suppressive and alternative combination therapy in the future