Updates and Controversies in the Management of Common Vulvovaginal Infections

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

2. PHYSIOLOGICAL and THERAPEUTIC APROACH TO VAGINAL INFECTIONSUPDATES AND CONTROVERSIES • 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 Ditas D. Decena, MD, FPOGS, MPH

4. 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

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

6. Determinants of Infectious Disease • Host’s defenses • Properties of microorganisms

7. 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

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

9. 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

10. 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

11. 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

12. estrogen glycogen lactic acid Vaginal Ecosystem lactobacilli Promotes growth of lactobacilli, inhibits growth of pathogenic bacteria pH 3.8 – 4.5

13. 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.

14. HEALTHY VAGINALECOSYSTEM • 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

15. 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

16. 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

17. 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 Vulvar vs. Vaginal Infection

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

19. Common Vaginal Infections

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

21. Vulvovaginal Candidiasis

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

23. Therapeutic Approach to Vaginal Infections

24. 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

25. 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

26. 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

27. 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

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

29. Physiological Approaches to Infections • Feminine wash • Douche • Vaginal gel

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

31. Cross-over Cross-over 10.25 10.00 5.50 9.75 5.25 9.50 9.25 5.00 9.00 Propionibacteria/cm2 (log) 8.75 pH 4.75 8.50 8.25 4.50 8.00 7.75 4.25 7.50 7.25 4.00 10 1 2 17 24 31 38 45 52 59 3 1 2 3 10 17 38 45 52 24 31 59 Days Days Soap Acid wash 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. Koring et al.1995 Acidic Wash vs. Soap

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

33. Lactoserum and Lactic Acid on External Genitalia in Thai Women Number and percentage of women on rating the product according to the evaluation criteria High percentage of satisfaction and tolerability 2005 Tansupasiri et. Al. 2005

34. 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

35. The improvement of functional symptoms Experience of malodor relief * * 88 * 84.2 82.1 * 77.1 * 65 71 69.8 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

36. 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

37. 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

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

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

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

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

42. Metronidazole with Lactacyd Vaginal gel in BVOpen-labeled, randomized, 3-arm comparative study

43. 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

44. 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

45. Frequency of Recurrent* Foul-smelling Vaginal Discharge Recurrence of Foul-Smelling Vaginal Discharge at Day 56 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.

46. 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.

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

48. 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

50. Take home messages Vaginal Health 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.