January 13, 2009 Eaton Hotel Hongkong Updates and Controversies in the Management of Common Vulvovaginal Infections January 13, 2009 Eaton Hotel Hongkong Ditas D. Decena, MD, FPOGS, MPH

Ditas D. Decena, MD, FPOGS, MPH PHYSIOLOGICAL and THERAPEUTIC APROACH TO VAGINAL INFECTIONS UPDATES AND CONTROVERSIES Ditas D. Decena, MD, FPOGS, MPH Professor in the Royal and Pontifical University,Faculty of Medicine & Surgery, University of Santo Tomas, Manila Philippines Masters in Public Health, University of the Philippines Trained in Endoscopic Surgery in India and Maternal Nutrition at the University of California, Davis Member, Committee on Residency Training Program, University of Santo Tomas Hospital Inc. Department of Obstetrics and Gynecology Author of the study “Metronidazole with Lactacyd vaginal gel in Bacterial Vaginosis” published in the Journal of Obstetrics and Gyecology Research 2006

Points of Discussion Determinants of infectious disease Common vaginal infections Bacterial vaginosis Trichomoniasis Candidiasis Treatment modalities Specific pharmacotherapy Lactic acid, lactoserum wash, douche and gel

Infectious Disease Result of interactions of microorganisms with host (number of organism X virulence of organism ) host defenses Smith

Determinants of Infectious Disease Host’s defenses Properties of microorganisms

1. Categories of Host Defenses Anatomical barriers Nonspecific cellular and humoral defenses Immunologically specific cellular and humoral defenses Local immunity Larsen B. Microbiology 2nd ed CREOG 1998

Anatomical Barriers Performed by intact tissues (skin and mucosa) Normal vaginal flora Endocervical mucus (biochemical impediment) Larsen B. Microbiology 2nd ed CREOG 1998

Skin Barrier Homeostasis Acid mantle (ph 4.5 – 5.9) Lactic acid and amino acid (sweat) Free fatty acids (sebum) Carboxylic and urocranic acid Rippke F. et al. Stratum Corneum pH in Atopic Dermatitis. Am J. Clin Dermatol 2004; 5 (4): 217-223

Skin pH (4.5 – 5.9) Varies in different body areas Depends on skin moisture content (higher moisture; higher pH) Changes in pH → “contact & atopic dermatitis” Rippke F. et al. Stratum Corneum pH in Atopic Dermatitis. Am J. Clin Dermatol 2004; 5 (4): 217-223

Vulvar Skin Stratified squamous epithelium Contains hair follicles, sebaceous, sweat and apocrine glands Has a high moisture content Subject to both primary and secondary infections Sensitive to hormonal, metabolic and allergic influences

Vaginal Ecosystem estrogen glycogen lactobacilli lactic acid Promotes growth of lactobacilli, inhibits growth of pathogenic bacteria Oral contraceptives may cause an increase in the glycogen and sugar substrate content of the vaginal epithelium eventually leading to decrease in vaginal pH. This will promote yeast proliferation which thrive in a very low pH. lactic acid pH 3.8 – 4.5

Endogenous vaginal flora of asymptomatic healthy women Lactobacillus sp. Corynebacterium Diphtheroids Streptococcus sp. Staphylococcus epidermidis Enterococcus faecalis Escherichia coli Klebsiella pneumoniae Proteus vulgaris Prevotella bivia P. melaninogenica Bacteroides fragilis Fusobacterium nucleatum Fusobacterium necrophorum Hillier SL. Normal vaginal flora. In: Holmes KK et al., eds. Sexually Transmitted Diseases. 1999:191-204.

HEALTHY VAGINAL ECOSYSTEM Dominated by certain species of Lactobacillus that control and suppress the growth of other endogenous bacteria through different mechanisms: - Lactic acid - Hydrogen peroxide (H2O2) Bacteriocins

2. Properties of Microorganisms Virulence Adhesiveness Invasiveness Adaptation Proliferation Growth inhibited at acid pH of 5 Maximal growth at neutral pH Optimum pH (3.8 – 4.5) growth of Lactobacilli Staphylococcus Larsen B. Microbiology 2nd ed CREOG 1998 Rippke F. et al. Stratum Corneum pH in Atopic Dermatitis. Am J. Clin Dermatol 2004; 5 (4): 217-223

LACTOBACILLUS Lactic Acid As lactobacilli grow, the production of lactic acid increases (~2.5 mg/mL) The production of lactic acid maintains the vaginal pH < 4.5 (creating an inhospitable environment for the growth of most endogenous pathogenic bacteria) Low pH is a primary mechanism for maintaining the equilibrium of a healthy vaginal ecosystem: as the pH of the vagina increases, bacteriocin loses its effectiveness, hydrogen peroxide is degraded, and lactobacilli cannot compete with the other bacteria

Vulvar vs. Vaginal Infection Anatomic distribution of symptoms occasionally creates a semantic misinterpretation of the clinical reality First symptom: vulvar pruritus First sign: erythema and edema of vulvar skin

Semantic Compromise Excessive vaginal fluid is not appreciated until fluid flows from vagina to vulva Vaginal infections Vulvovaginitis

Common Vaginal Infections Candidiasis Trichomoniasis BV Predominant symptom pruritus Profuse discharge Foul odor Characteristic discharge Curd like Frothy Thin grayish white pH 4 5 6 Gram stain Pseudo hyphae (-) Gram (-) rods NSS mount Flagellated protozoa Clue cells 10% KOH Hyphae on microscopy + amine odor

Trichomonas Vaginalis Bubbly discharge Pap’s smear showing resemblance of WBCs to nonmotile parasites

Vulvovaginal Candidiasis

Bacterial Vaginosis Characteristic milky vaginal discharge of BV Clue cells consistent with BV

Therapeutic Approach to Vaginal Infections

Standard Treatment of BV Metronidazole 500 mg twice daily for 7 days Metronidazole gel 0.75%, 5 g intravaginally once daily for 5 days Clindamycin cream 5%, 5 g intravaginally hs for 7 days Alternative Regimen Clindamycin 300 mg twice daily for 7 days Clindamycin ovules 100 g intravaginally hs for 3 days

Candidiasis Treatment Uncomplicated Oral: Fluconazole 150 mg p. o. single dose Intravaginal Butoconazole 2% cream 5g intravaginal X 3 days Butoconazole 2% cream 5g (sustained release) single intravaginal application CDC 2006

Candidiasis Treatment Intravaginal Clotrimazole 1% cream 5 g intravaginal X 7 – 14 days Clotrimazole 100 mg tablet X 7 days Clotrimazole 100 mg tablet – 2 tablets X 3 days Clotrimazole 500 mg vaginal tablet – 1 tablet in a single application Miconazole 2% cream 5 g intravaginal X 7 days Miconazole 100 mg vaginal suppository X 7 days CDC 2006

Candidiasis Treatment Miconazole 200 mg vaginal suppository – 1 supp. X 3 days Nystatin 100,000 units vaginal tablet – 1 tablet X 14 days Terconazole 0.4% cream 5 g intavaginal X 7 days Terconazole 80 mg vaginal suppository X 3 days CDC 2006

Trichomonas Treatment Metronidazole 2g p o single dose Tinidazole 2g p o single dose Alternative Metronidazole 500mg BID X 7 days CDC 2006

Physiological Approaches to Infections Feminine wash Douche Vaginal gel

Why prescribe feminine wash? Hygiene Relieve vulvar irritation Postpartum care: cleaning episiotomy wound Prevention and /or treatment of vulvovaginitis

Acidic Wash vs. Soap Soap Acid wash Cross-over Koring et al.1995 pH Evolution of the propiobacterium counts per square centimeters (1), and of the mean pH value (2) on the subjects foreheads during repeat applications of alkaline soap and acidic syndet in the frame of a comparative crossover trial - = soap first 4 weeks, then syndet for 4 weeks - = syndet first 4 weeks, the soap 4 for weeks. 10.25 10.00 1 2 3 10 17 24 31 38 45 52 59 9.50 9.75 9.25 9.00 8.75 8.50 8.25 8.00 7.75 7.50 7.25 Days Propionibacteria/cm2 (log) Cross-over 4.00 4.25 4.50 4.75 5.00 5.25 5.50 pH Koring et al.1995 Soap Acid wash

Lactic acid for external hygiene Provides relief of itching and reduces inflammation Reacidifies the environment alkalinized by pathogens Fights infections

Lactoserum and Lactic Acid on External Genitalia in Thai Women Number and percentage of women on rating the product according to the evaluation criteria Evaluation criteria Total number Number and percentage of satisfaction P-value Fragrance free (%) N = 100 Sweet flora (%) Spring fresh (%) Ease of use Ability to refresh Scent Cleansing ability Overall assessment 300 100 (100) 99 (99) 93 (93) 98 (98) 97 (97) 96 (96) 1.000 0.482 0.331 High percentage of satisfaction and tolerability 2005 Tansupasiri et. Al. 2005

Assessment of the effectiveness and tolerability of Lactacyd FH when used as adjunctive external vaginal wash to standard treatment of Bacterial vaginosis Nguyen Thi Ngoc Phuong et al. Vietnam Gyne-OB Association Journal, 2005

The improvement of functional symptoms Experience of malodor relief * * * 88 82.1 84.2 * 77.1 * 65 69.8 71 63.5 59.7 28.9 40.2 N=96 n=103 8 18.6 4.8 D1 D2 D3 D4 D5 D6 D7 (*) p< 0.05 Lactacyd FH use (n=96) Non-Lactacyd FH use (n=103) Nguyen Thi Ngoc Phuong et al. Vietnam OB Gyne Association 2005

The improvement of functional symptoms Experience of pruritus relief * * * 100 * 98.6 98.6 98.6 * 91.7 90.3 91.2 89.7 89.7 88.2 89.7 66.7 75.0 57.4 D1 D2 D3 D4 D5 D6 D7 (*) p < 0.05 Lactacyd FH use (n=96) Non-Lactacyd FH use (n=103) Nguyen Thi Ngoc Phuong et al. Vietnam OB Gyne Association 2005

The improvement of functional symptoms 3b. Experience of tenderness relief 100 98.4 100 100 96.8 92.1 98.2 * 94.6 94.6 94.6 92.9 79 80.7 62.5 D1 D2 D3 D4 D5 D6 D7 (*) p< 0.05 Lactacyd FH use (n=96) Non-Lactacyd FH use (n=103) Nguyen Thi Ngoc Phuong et al. Vietnam OB Gyne Association 2005

Nguyen Thi Ngoc Phuong et al. Vietnam OB Gyne Association 2005 Conclusion Adding Lactacyd FH as external vaginal wash to standard regimen (Metronidazole) in Bacterial vaginosis is useful in relieving symptoms. Nguyen Thi Ngoc Phuong et al. Vietnam OB Gyne Association 2005

Types of Douching Solution Plain water Water with acetic acid (acidic solution) Betel Povidone iodine Lactic acid; lactoserum

Meta-analysis of studies on vaginal douching and risk of pelvic inflammatory disease 1.0 0.6 0.4 0.2 2 3 4 5 6 7 8 9 Internal Recent Douching 1-2 times/month  3 times/month Control Random ≥ 3 times/month ≥ 4 times/month ODDS RATIO Wolner-Hanssen Scholes Pooled RR Zhang et. Al 1997 

Possible factors for douching and PID Pressure douching Timing of douching during menstrual cycle Frequency Zhang, Thomas 1997

Meta-analysis of studies on vaginal douching and risk of ectopic pregnancy Chow Occasional  Weekly Daling Overall Once every few months 1/month Weekly Chow Ever douched Zhang et. Al 1997 Current douching Phillips Current douching Kendrick Current douching > 10 years Pooled RR Current douching 0.2 0.4 0.6 1.0 2 3 4 5 6 7 8 9 ODDS RATIO

Metronidazole with Lactacyd Vaginal gel in BV Open-labeled, randomized, 3-arm comparative study

Effect of Treatment on Lactobacilli Colony Count* *Repeated Measures ANOVA: p<0.001 across visits; p=0.0045 at day 8 between lactic acid gel group and metronidazole group; p=0.0002 at day 14 between combination arm and metronidazole arm and between LVG arm and metronidazole arm. Decena, Sison, Manalastas, Padolina, Palaypayon, Co, Dancel, Lelis, J.Obstet.Gynaecol.Res Vol 32, No. 2:243-251, April, 2006

Effect of Treatment on Vaginal pH* Figure 2: Frequency of patients with Vaginal pH <4.7 across time *Cochran’s Q test: p <0.001 across visits; 2 test: p>0.05 across treatment groups Decena, Sison, Manalastas, Padolina, Palaypayon, Co, Dancel, Lelis, J.Obstet.Gynaecol.Res Vol 32, No. 2:243-251, April, 2006

Recurrence of Foul-Smelling Vaginal Discharge at Day 56 Frequency of Recurrent* Foul-smelling Vaginal Discharge 4/28 (14.3%) Decena et. Al 2005 2/30 (6.7%) No. of Patients 1/28 (3.6%) *Fisher’s exact test: p=0.4965 across treatment groups.

Study Conclusion Lactacyd vaginal gel (LVG) is safe and as efficacious as metronidazole in the treatment of bacterial vaginosis. There is evidence that Lactacyd vaginal gel (LVG), when combined with metronidazole, is superior to metronidazole alone in promoting lactobacilli colonization Lactacyd vaginal gel (LVG) as an adjunct to metronidazole appears to result to a better long-term treatment effect on BV.

Lactic acid for internal hygiene Adjunct treatment in bacterial vaginosis Promotes the growth of Lactobacilli

Physiological Therapeutic Approaches in Vaginal Infections Summary Anatomical barriers as the acid mantle in the skin and normal vaginal flora are important host’s defenses Lactic acid wash in combination with standard regimen is effective in relieving symptoms of Bacterial vaginosis Lactic acid vaginal gel (LVG) is safe and as efficacious as metronidazole in the treatment of bacterial vaginosis. Specific pharmacotherapy for vaginal infections is still the mainstay of treatment

Take home messages Vaginal Health Prevention The vaginal microflora does not consist of a static population but, rather, a dynamic one (types and concentrations continuously fluctuate in accordance with the changing environment). Prevention Lactic acid wash and gel has been shown to be tolerated and efficacious in prevention and treatment of vulvovaginal infections.

Thank you!