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Home , Clindamycin, Endometritis, Infertility, Strawberry cervix, Terconazole, Vaginitis

UPDATE & TREATMENT PEARLS SANDY SULIK MD MEDICAL DIRECTOR PRIMARY CARE SERVICES – ST JOSEPH’S HEALTH ST JOSEPH’S FAMILY MEDICINE RESIDENCY PROFESSOR, UPSTATE MEDICAL CENTER I HAVE NO DISCLOSURES OBJECTIVES

• Review the most common causes of vaginitis and treatments for each • Discuss emerging causes of vaginitis including genitalium and desquamative vaginitis • Discuss treatment strategies for recurrent vaginal VAGINITIS

• One of the most frequent reasons to visit the OB/GYN office, services, student health and primary care offices • ACCOUNTS FOR UP TO 10 MILLION OFFICE VISITS PER YEAR • Many women never get a clear diagnosis and often have recurrent symptoms • Causes discomfort and pain, days lost from work/school, discomfort with sexual functioning and issues with self image • Often associated with other STI’s, HIV, and other infections of the female genital tract VAGINITIS

• Defined as a spectrum of conditions that cause vulvovaginal symptoms: • Itching • Burning • • Abnormal Discharge • Odor • Redness • Swelling • 3 Most Common etiologies of vaginitis: Trichomonas, , vulvovaginal VAGINITIS – CLINICAL PRESENTATION

• Inflammatory • presence of poly-morphonuclear (PMNS) on • with physical findings of erythema and edema • Trichomonas, candidiasis, , Mucosal erosive diseases, desquamative inflammatory vaginitis • Non-inflammatory • absence of PMNS • no erythema, no swelling with vaginal complaints of odor or abnormal discharge • Bacterial vaginosis most common, mixed VVC/BV BACTERIAL VAGINOSIS

• Vulvovaginal caused by a pathogenic shift of the with a polymicrobial overgrowth of facultative and anaerobic organisms • Most common cause of vaginal complaints • Most common in women of reproductive age • More prevalent in African-American and/or American-Hispanic women than white women • Even adjusting for age, education, poverty – 3 x more common • Other risk factors: douching, recent course of therapy, , smoking, IUD use • Decreased risk with -containing contraceptives and consistent use IMPLICATIONS OF BV INFECTION

• Associated with obstetrical complications: • Preterm labor, PPROM, low birth weight, post partum , spontaneous • Associated with surgical complications • Post-abortal endometritis, vaginal cuff or after hysterectomy, PID • Increased risk of acquiring other infections • HIV, HSV2, Neisseria , trachomatis, , UTI’s SEXUAL TRANSMISSION?

• Has been implicated in recurrent BV • Epidemiological studies are mixed • Multiple studies show up to 60% increased risk for BV in women with multiple sexual partners • Protective effect from both incident and recurrent BV with condom use SYMPTOMS AND FINDINGS

• Typical presentation includes foul smelling or fishy • Complaint of malodor is highly associated with BV (LR 3.2 [95% CI 2.1-4.7]) • Lack of perceived odor makes BV unlikely LR 0.07 (95% CI 0.01-0.51) • May be exacerbated by conditions that elevate the vaginal pH • with deposition • Presence of blood • Itching and burning unlikely (if present consider mixed infection with or other inflammatory process), doesn’t usually cause • Examination findings: thin gray-white discharge, should not see erythema, fissuring or bleeding DIAGNOSTIC TESTING

• Clinical diagnosis made by microscopic examination and measurement of vaginal pH • Classically 3 of 4 of Amsel’s criteria must be met • Thin homogenous gray-white discharge • An increased pH >4.5 • Release of an amine odor upon application of potassium hydroxide (+ Whiff test) • >20% clue cells on saline microscopy LAB TESTING

• Saline wet mount • A wet smear that shows more than 20% of the epithelial cells are clue cells COMMERCIAL TESTS/NAAT

AFFIRM VP III OSOM BVBLUE

DNA probe testing that identifies Chromogenic test based on sialidase produced by Gardnerella vs Trichomonas and Candida Gardnerella, , etc on DNA concentrations Sensitivity 90% Specificity is 68% Sensitivity 88-98% and Specificity 95-97% compared to Gram stain TREATMENT OF BV

• First line: 7 day course of oral 500 mg BID • 7 day course of intravaginal cream or 5 day course of intravaginal metronidazole • Clindamycin 300 mg orally for 7 days • Secnidazole (Secondax®/Solosec®) approved in 2018 for treatment of incident BV • Has a longer half life than metronidazole • Single dose regimen of 2 Gm • Intravaginal Clindamycin ovules x 3 days • 1 Gm daily for 5 days or 2 gm daily for 2 days • ALL regimens equally effective may respond to a second course of same therapy if first ineffective RECURRENT BV

• Greater than 50% of women will have a repeat episode of BV within 1 year of treatment • Recurrent BV defined as 3 or more symptomatic episodes within 1 year • Failure of symptom resolution during appropriate antibiotic treatment should raise suspicion for mixed infection and need for further evaluation • Risk factors: prior history of BV, having a regular sex partner, having female sex partner, presence of both G vaginalis and A vaginae • Mechanisms: reinfection by sexual activity, failure to re-establish normal predominant flora, formation of biofilms TREATMENT OF RECURRENT BV

• CDC recommendations 3 options after completion of a standard regimen: • Metronidazole vaginal gel 0.75% one full applicator twice weekly for 6 months • With the initiation of a standard treatment regimen start a 21 day course of vaginal boric acid capsules 600 mg once daily at bedtime. At completion of the boric acid treatment, start metronidazole vaginal gel 0.75% twice weekly for 6 months • After completion of standard regimen start oral metronidazole 2g and 150 mg once every month RECURRENT BV TREATMENT

• Other regimens that have been used: • Intravaginal metronidazole daily for 10 days followed by twice weekly for 4-6 months • Oral or intravaginal metronidazole for 3 days at the onset of menses for 3-6 months with therapy if history of candidiasis • In Canada a vaginal ovule with metronidazole 500 mg with 10,000 IU is available and can be used monthly to prevent recurrence TREATMENT OF PARTNERS

• Not recommended • Studies to date are flawed and inconclusive • For women who have sex with women the rate of BV concordance among partners is high • If partner is symptomatic – reasonable to treat both • Small studies have shown male circumcision may reduce the risk of BV in female partners OTHER TREATMENTS

• Vaginal administration of to help restore the acidic pH of the is thought to be helpful • Number of products available: Luvena, Gynofit gel • Oral Lactobacillus to improve the vaginal microbiome • Number of small studies have inconclusive evidence for or against in treatment of BV USE OF POLICARBOPHIL-CARBOPOL ACIDIC VAGINAL GEL

• A persistent high vaginal pH(>4.7) is a common alteration in women with recurrent BV • Use of a polycarbophil has been shown to be effective in reducing the vaginal pH • Polycarbophil is a weak polyacid large molecule that is neither absorbed nor immunogenic • It adheres to the vaginal epithelial cells until they turn over (3-5 days), buffers vaginal secretions near physiologic ph (4.3) POLICARBOPHIL-CARBOPOL ACIDIC GEL

• Several small studies have shown use has effectively treated recurrent BV • No RCT’s have been done to date • One study used daily treatment of 2.5g of gel for one week followed by twice weekly for 6 weeks • 2nd study used 2.5 g biweekly for 6 weeks • Both showed improvement in BV and decreased recurrence compared to placbo or acidic USE OF VAGINAL TABLETS

• Several small studies have shown efficacy with Vitamin C Vaginal tablets • 250 mg silicon-coated vaginal tablets daily for 6 days • Studies showed statistically significant improvement in BV in the Vitamin C treated groups IUDS AND BV

• The relationship between IUD use and BV is unclear – insufficient evidence to conclude one way or other • Thought to be related to the increase of unscheduled bleeding leading to a higher vaginal pH EFFECT OF DIET AND BV

• One study looked at diet and occurrence of BV • Increased dietary fat (saturated fats) was associated with an increase in BV and severe BV • Significant inverse association of BV with diets high in , calcium and Vitamin E TRICHOMONAS

• Trichomonas vaginalis: flagellated motile anaerobic protozoan organism which colonizes the vagina, urethra, par-urethral and Skene glands • Transmission is primarily sexual, can transmit via fomites, hot tubs, pools • Affects 3.7 million persons in the US annually • Prevalence in women 40 years and older is 11% overall and more common in women diagnosed with other STI’s including HIV • African-American women are disproportionally affected with a prevalence of 15% compared with 1.8% of white women IMPLICATIONS

• Obstetric • , PROM, low birth weight • Gynecologic • Often coexists with other STI’s, HPV, and BV • PID and tubal • Endometritis after delivery, abortion, or surgery • Facilitates acquisition and transmission of HIV RISK FACTORS

• Change in sexual partners • Frequent sexual intercourse • Having 3 or more sexual partners in a month • Coexistent sexually transmitted infections (HIV) • Illicit drug use, smoking • Lack of barrier contraception • Low socio-economic status SYMPTOMS AND FINDINGS

• Discharge, irritation, itching, burning, soreness, dyspareunia • and lower abdominal pain common • Copious yellow or green frothy vaginal discharge • and erythema of vestibule and vagina “strawberry ” and vaginal mucosa (punctate hemorrhages) • Vaginal pH >5 DIAGNOSTIC TESTING

• Vaginal pH usually >4.5 • Saline microscopy shows many PMNS and motile trichomonads • Sensitivity is only 51-65% NUCLEIC ACID AMPLIFICATION TESTS/NAAT

• Considered the gold standard test • Detect 3-5 times more trichomonal infections than wet mount • Sensitivity and specificity of 95-100% • 100% concordance with urine and vaginal samples COMMERCIAL TESTS AVAILABLE

• Affirm VP III Sensitivity 63%, specificity 99.9% • OSOM Trichomonas Rapid Test (10 min assay) Sensitivity 82-95%, specificity 97-100% • APTIMA T. vaginalis assay vaginal swab or urine Sensitivity 95-100%, specificity 95-100% • Culture (vaginal swab) Sensitivity 75-96%, specificity 100% TREATMENT

• Must treat all partners, must treat orally to address all reservoirs, until treatment complete • Metronidazole 2 gm orally single dose • Tinidazole 2 gm orally single dose • Metronidazole 500 mg orally bid for 7 days (recent RCT showed superior to single dose therapy) • Tinidazole is slightly more effective (higher serum levels, fewer GI side effects, longer half life) but considerably more expensive (cure rates 92-100%) as compared to metronidazole cure rates of 84-98% • Treat pregnant women if symptomatic • RETEST 3 months after treatment TREATMENT OF PERSISTENT TRICHOMONAS

• Most are reinfections and not persistent trich • Treatment failures due to patient non-compliance, reinfection, multiple sex partners, lack of condom use • Oral tinidazole 1000 mg daily for 7 days • Oral metronidazole 500 mg bid for 7 days • If persistent: Oral tinidazole or metronidazole 2 gm orally for 7 days REPEATED TREATMENT FAILURES

• Test for resistance after 3-4 courses (done with CDC) • Metronidazole resistance 4-10% • Tinidazole resistance 1% • Consider testing organism for resistance • Contact CDC http://www.cdc.gov/std • Treatment for nitroimidazole-resistant infections: Tinidazole 1 gm orally bid or tid x 14 days plus intravaginal tinidazole 500 mg/d x 14 days ALLERGIC TO METRONIDAZOLE

• Oral or parenteral desensitization to metronidazole followed by treatment is highly effective TRICHOMONAS AND HIV

• Up to 53% of HIV + women have trichomonas • screen at entry to care and at least annually thereafter • Treatment of trichomonas if HIV + decreases viral load and viral shedding, decreases PID • Treat with metronidazole 500 mg bid x 7 days NOT single dose therapy • Treat HIV + pregnant women with trichomonas to reduce vertical transmission of HIV • Retest HIV + women with trichomonas 3 months after treatment with NAAT testing VULVOVAGINAL CANDIDIASIS

• 75% women will have at least one episode of vulvovaginal candidiasis • 40-45% will have 2 or more • Changes in the host vaginal environment precipitate and induce pathologic effects of the organisms • Recurrent: 3 or more proven cases in 12 months at least one by culture OR at least 3 episodes unrelated to within 1 year • 8-10% have recurrent episodes • Chronic: a proven episode of candidiasis that does not respond to conventional antifungal therapy within 2 weeks RISK FACTORS

• Vaginal or systemic antibiotic use • Diet high in refined sugars • Uncontrolled • Topical or systemic corticosteroid use or other immunosuppression • Postmenopausal vaginal estrogen use • Frequent coitus, orogenital sex • OCP and IUD use, contraceptive sponge, diaphragm with spermicide • NO CLEAR RISK FACTORS in 50% of women with recurrent infections DEFINITIONS

• Uncomplicated – 80-90% of infections • Sporadic or infrequent vulvovaginal candidiasis • Mild to moderate symptoms or findings • Likely to be • Non-pregnant, non-diabetic woman • Complicated • 4 or more recurrences per year • Severe symptoms or findings • Suspected or proven non-albicans infection • Impaired host (diabetes, , immunosuppression, other vulvovaginal conditions)

• Vaginal discharge thick white cheesy • Pruritus • Vaginal soreness and burning • Dyspareunia • On exam: redness, swelling , fissures, or excoriations with vaginal signs of erythema or a tick curdy discharge IMPLICATIONS

• Obstetric: • Candida during pregnancy may be associated with PROM, preterm birth, , congenital cutaneous candidiasis • No evidence that one is more effective than another • Treatment of choice in pregnancy or cream vaginally x 7 days • First trimester use of a single dose of 150 mg fluconazole has not been associated with an increased risk of birth defects DIAGNOSTIC TESTING

• Vaginal pH 4.0-4.5 • Microscopic evaluation of vaginal secretions with 10% potassium hydroxide solution • Sensitivity 65-85% • Vaginal culture should be considered in recurrently symptomatic women with negative microscopy and normal pH • NAAT testing can be used MICROBIOLOGY OF VVC

• C Albican is responsible for most symptomatic episodes of VVC • Accounts for approx. 80% of infections • C Glabrata is the most common non-albicans type (15%) • Others: C Parapsilosis 6%, C tropicalis 8%, C krusei, C lusitaniae and Saccharomyces cerevisiae TREATMENT OF VVC

• Uncomplicated: • medications are mainstay • All oral and vaginal are equally effective for treatment with 90% cure rate • Topical creams may cause local burning • Clotrimazole cream and , Miconzaole cream and suppository, Butoconzaole cream, cream • Fluconazole 150 mg orally single dose • cream or suppository • 200 mg bid x 1 day or 200 mg orally x 3 days • Persistent symptoms mandate a re-evaluation which should include a culture ORAL THERAPY CONSIDERATIONS

• Fluconazole has drug-drug interactions: • Behavioral health medications: Alprazolam, citalopram, fluoxetine, sertraline, trazadone, clonazepam, escitalopram, venlafaxine, amitriptyline OK with duloxetine, lamictal, , lorazepam • Proton pump inhibitors and GERD medications: , cimetidine • Statins and cardiac medications: , atorvastatin, verapamil, OK with pravastatin • Sulfonylureas: glimepiride • Warfarin, , Rifampin, Cyclosporine, Methadone TREATMENT

• Severe vulvovaginal candidiasis • In most studies severity is not a predictor of outcomes, however, may be less likely to respond to standard therapy • Several small studies have shown that a two dose regimen (every 3 days) of oral therapy is more effective with higher cure rates • If using topical therapy treat for 7-14 days RECURRENT VVC

• Most are still positive for C albicans • Most effective treatment is maintenance antifungal therapy • Fluconazole 150 mg once weekly for 6 months • Clotrimazole 500 mg weekly for 6 months • Both preferred over 100 mg daily due to toxicity • Boric acid 600 mg capsules or suppositories vaginally 2 x per week for 6 months • 30-50% will recur after suppression, may continue longer than 6 months if needed TREATMENT FOR NON-ALBICANS CANDIDA SPECIES

• Resistant to all currently available • Boric acid 600 mg capsules vaginally x 14 days cures 70% of c. glabrata • Topical 15.5% compounded in hydrophilic cream base, insert 5 gms vaginally nightly for 14 days for c. glabrata & c. tropicalis • Gentian violet 0.25% or 0.5% aqueous solution in office once a week for 4-6 weeks. (may irritate, blister or erode vaginal walls, permanent purple stain on clothing) Fungicidal • Fluconazole 200 mg twice week x 1 month for c. parapsilosi • Amphoterocin B 50 mg vaginal suppositories x 14 days (irritation, blistering) • Casopfungin vaginal cream 100 mcg/4gm in sodium carboxy gel 5 Gm nightly x 14 days FLUCONAZOLE RESISTANT YEAST TREATMENT

• Itraconazole (Sporonax) 100 mg orally bid x 14 days (ck LFTs before and after) • Amphoterocin B 3% cream, 4 gm vaginally nightly x 7-14 days • (Noxafil) 300 mg bid x 2 doses to load then 300 mg orally x 7-14 days (ck EKG prior – prolongs QT) DESQUAMATIVE INFLAMMATORY VAGINITIS

• Newly recognized clinical syndrome • Persistent purulent vaginal discharge with vaginal erythema, and submucosal cervicovaginal petechiae • Inflammation is the cardinal feature • Exact cause unknown • Incidence 0.8-4.3% DIV

• Exact cause unknown but thought to be a dysbiosis of the normal vaginal microbiome associated with inflammation • Microflora different from BV • Vagina is colonized with facultative • E coli, staph aureus, grp B , faecalis • May represent a systemic inflammatory syndrome producing vaginal inflammation that causes the abnormal vaginal flora SIGNS AND SYMPTOMS

• Purulent vaginal discharge homogeneous and yellowish in color • No odor • Vulvar and vaginal mucosal erythema with ecchymotic lesions or erosions • Dyspareunia • Symptoms may last for a long time or fluctuate IMPLICATIONS

• Obstetrical • Has been linked to preterm birth, PROM, chorioamnionitis, • Might increase the risk of neonatal group B Streptococcal infection • Gynecological • May be associated with upper genital tract infections DIAGNOSTIC TESTING

• Vaginal pH increased • Microscopy with increased PMNs • Dx also requires an increase in parabasal epithelial cells • Diagnosis requires exclusion of infectious and estrogen-related causes • Diagnosis of exclusion TREATMENT

• Metronidazole is NOT effective • Treatment failures in women diagnosed with BV may suggest DIV • Clindamycin treats facultative bacteria and has an anti-inflammatory effect • Clindamycin 2% cream vaginally for 1-3 weeks, consider maintenance therapy once or twice a week for 2-6 months • One observational study suggested that clindamycin cream with 10% hydrocortisone (25 mg suppository nightly) is useful for severe DIV

• First identified in the early 1980’s • Recognized as a cause of male • 15-20% nongonococcal urethritis • 20-25% nonchlamydial NGU • Seen in 30% of persistent or recurrent urethritis • Co-infection with C trachomatis not uncommon • Unknown if causes or other male anogenital tract disease symptoms MYCOPLASMA GENITALIUM

• Pathogenic role is less definitive in women • Women are commonly asymptomatic • Detected in 10-30% of women with clinical • M. genitalium is found in the cervix and/or of women with PID more often than in women without PID • A few seroepidemologic studies have found that women with are more likely to have antibodies to M. genitalium than fertile women - more research needed IMPLICATIONS

• Obstetric • Tubal factor infertility • • Preterm delivery • Gynecologic • Mucopurulent cervicitis • PID DIAGNOSTIC TESTING

• Slow growing organism on culture • Preferred method is NAAT • Urine APTIMA® - patient should not have urinated within 1 hour of test collection • 3-4 day turn around • Cost 110.00 per test TREATMENT

• M. genitalium lacks a cell wall • antibiotics targeting cell-wall biosynthesis (e.g., beta-lactams including and cephalosporins) are ineffective against this organism • largely ineffective in treating • preferred treatment • 1 Gm single dose • Emerging resistance developing • Can use 500 mg followed by 250 mg for 4 days (marginally more effective) • If don’t respond to 1 Gm dose, longer treatment usually not effective TREATMENT

• (400 mg daily x 7, 10 or 14 days) has been successfully used to treat M. genitalium in men and women with previous treatment failures • Need further studies • Some resistance already being seen in some places PID

• Recommended PID treatment regimens are based on antibiotics that are not effective against M. genitalium. • Consider M. genitalium in cases that do not respond to therapy within 7–10 days. • If M. genitalium is detected, a regimen of moxifloxacin 400 mg/day for 14 days has been effective in eradicating the organism • No data to support testing all for the organism, significance is still not established IN SUMMARY…..

• Metronidazole and clindamycin are equally effective for eradicating BV (A) • Metronidazole and Tinidazole given orally in a single dose or over longer periods result in cure of in 90% of cases (A) • Oral and vaginal are equally effective in treating uncomplicated vulvovaginal candidiasis (A) • Desquamative Inflammatory vaginitis is a diagnosis of exclusion treatment with clindamycin is effective (C) • Testing for Mycoplasma Genitaliam should be considered in persistent cervicitis, urethritis, PID (C) REFERENCES

• Neggars et al. Dietary intake of selected nutrients affects bacterial vaginosis in women. J Nutr. 2007 Sep; 137(9) 2128-2133 • Paavonen et al. Bacterial vaginosis and desquamative inflammatory vaginitis. NEJM 2018:379:2246-54. • Neal et al. Noncandidal vaginitis: a comprehensive approach to diagnosis and management. Amer J Ob Gyn 2019, Sep 9: 1-7. • Hainer et al. Vaginitis: diagnosis and treatment. AAFP 2001 April; 83(7):807-815 • Nyirjesy . Vulvovaginal Candidiasis and Bacterial Vaginosis. Infect Dis Clin N Am 2008; 22: 637-652 • Sobel et al. Prognosis and treatment of desquamative inflammatory vaginitis. Obstet Gynecol 2011;117:850-5 • Vaginitis in Nonpregnant patients. ACOG Practice Bulletin Number 215 Obstet Gynecol 2020;135(1): e1-17. • Deese et al. Contraceptive use and the risk of sexually transmitted infections: systematic review and current perspectives. J Contracept. 2018 Nov 12;9:91-112. REFERENCES

• Fiorilli, A et al. Successful treatment of bacterial vaginosis with a policarbophil-carbopol acidic vaginal get: results from a randomized double-blind, placebo-controlled trial. European J Obstet Gynecol Reprod Biol. 2005 Jun 1; 120(2): 202-5. • Milani, M. et al. Effect on Vginal pH of a Polycarbophil Vaginal Gel Compared with an Acidic Douche in Women with Suspected Bacterial Vaginosis: A Randomized Controlled Study. Current Therapeutic Research Vol 61, No 11, October 2000. • Petersen, EE et al. Efficacy and safety of vitamin D vaginal tablets in the treatment on non-specific vaginitis. A randomized, double blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol; 2004 Nov 10:117(1): 70-5. • Peterson EE et al. Efficacy of vitamin C vaginal tablets in the treatment of bacterial vaginosis: a randomized, double blind, placebo controlled . Arzneimitteiforschung. 2001; 61(4): 260-5.