Special Report – Treating Candidal Vaginitis and Mixed Vaginal Infections in Primary Care

Special Report

Treating Candidal Vaginitis and Mixed Vaginal Infections in Primary Care Vulvovaginal Candidiasis The Big Three Considerations in the Diagnosis of Vaginal Discharge A Guide to the Management of Vaginal Discharge Managing Recurrent Infection, Hard to Treat Infection, and Infection in Special Circumstances

Published by Global Business Media

Soft Gel Pessary combination: How comforting

Canesten® Soft Gel Pessary Combi has a teardrop shape, designed to be soft and comfortable to insert.

Together with the 2% w/w cream, it works to clear the internal infection and soothe the external symtoms.

Oral & Cream O

Combi

Pessary & Cream eam e Clotrimazole

Canesten® Combi 500mg Soft Gel Pessary & 2% Cream (clotrimazole 500mg soft gel pessary and clotrimazole 2% w/w cream). Indications: Treatment of candidal vaginitis and mixed vaginal infections where Trichomonas is present or suspected, and candidal vulvitis. Not recommended as sole treatment for pure Trichomoniasis except when systemic therapy is contra-indicated. It can also be used for treatment of the sexual partner’s penis to prevent reinfection. Dosage and Administration: Adults: The soft gel pessary should be inserted into the vagina at night using the applicator. Treatment should be finished before the onset of menstruation. The cream should be applied to the vulva and surrounding area two or three times daily and rubbed in gently. Treatment with the cream should be continued until symptoms of the infection disappear. However, if after concomitant treatment of the vaginitis, the symptoms do not improve within seven days, the patient should consult a physician. For treatment of the sexual partner’s penis, the cream should be applied two or three times daily for up to two weeks. Children: Not recommended in children under 16 as the product is used with an applicator. Contraindications: Hypersensitivity to clotrimazole or any other ingredients in the medicine e.g. cetostearyl alcohol. Warnings and Precautions: Patients should be advised to consult their physician if the symptoms have not been relieved within one week of using Canesten 500mg Soft Gel Pessary. Canesten 500mg Soft Gel Pessary can be used again if the candidal infection returns after 7 days. However, if the candidal infection recurs more than twice within six months, patients should be advised to consult their physician. This product may damage latex contraceptives therefore patients should use alternative precautions for at least five days after using the product. Side-effects: Allergic reaction, genital peeling/exfoliation, blisters, pruritis, rash, oedema, discomfort/ pain, stinging/burning, irritation, pelvic pain, abdominal pain. Use in Pregnancy: Only when considered necessary by a physician. During pregnancy the pessary should be inserted without using an applicator.

Cost: £12.00 (Excl. VAT). MA Number: PL 00010/0636. MA Holder: Bayer plc, Consumer Care Division, Newbury, Berkshire RG14 1JA, UK. Legal Category: POM. Date of Preparation: February 2012.

Canesten® Combi 500mg Pessary & 2% Cream (clotrimazole 500mg pessary and clotrimazole 2% w/w cream). Indications: Treatment of candidal vaginitis and mixed vaginal infections where Trichomonas is present or suspected, and candidal vulvitis. Not recommended as sole treatment for pure Trichomoniasis except when systemic therapy is contra-indicated. It can also be used for treatment of the sexual partner’s penis to prevent re-infection. Dosage and Administration: Adults: The pessary should be inserted into the vagina using the applicator. The cream should be applied to the vulva and surrounding area two or three times daily and rubbed in gently. If the cream is being used for treatment of the sexual

www.canesten.co.uk

Soft Gel Pessary Combi

500mg Soft Gel Pessary & 2% w/w Cream Clotrimazole

partner’s penis it should be applied two or three times daily for up to two weeks. Children: Paediatric use is not recommended. Contraindications: Hypersensitivity to clotrimazole or any other ingredients in the medicine e.g. cetostearyl alcohol. Warnings and Precautions: Creams contain cetostearyl alcohol which may cause local skin reactions (e.g. contact dermatitis). Do not use during menstrual period. Known hypersensitivity to imidazoles or other vaginal antifungal products. These products may damage latex contraceptives and therefore patients should use alternative precautions for at least five days after using them. Side-effects: Rarely, local mild burning or irritation immediately after use. Allergic reaction, pelvic pain, pruritis and rash. Blisters, discomfort/pain, oedema, irritation, genital peeling/exfoliation and burning/stinging. Use in Pregnancy: Only when considered necessary by a physician. During pregnancy the pessary should be inserted without using an applicator. Cost: Cost: £11.20 (Excl.

VAT). MA Numbers: PL 00010/0258 & PL 00010/0077. MA Holder: Bayer plc, Consumer Care Division, Newbury, Berkshire RG14 1JA, UK. Legal Category: POM. Date of Preparation: February 2012.

Canesten® Oral & Cream Duo (fluconazole 150mg capsule, plus 10g tube of clotrimazole 2% w/w cream). Indications: The capsule is for treatment of candidal vaginitis, acute or recurrent. Also for treatment of partners with associated candidal balanitis. The cream is for the treatment of candidal vulvitis. Dosage and Administration: Adults (16 – 60 years): Swallow one capsule whole. Apply cream to vulva and surrounding area two or three times daily and rub in gently. Treatment with the cream should be continued until symptoms of the infection disappear. If after concomitant treatment of vaginitis, symptoms do not improve within seven days, the patient should consult a physician. For treatment of sexual partner’s penis, cream should be applied two or three times daily for two weeks. Children: Paediatric usage is not recommended (in under 16).

Contraindications: Hypersensitivity to fluconazole, clotrimazole, related azole compounds or any of the excipients e.g. cetostearyl alcohol; coadministration with terfenadine, cisapride or ergot-derivatives. Warnings and Precautions: Adequate contraception necessary. A physician should be consulted if the patient or partner have had exposure to sexually transmitted disease, or if the patient: has had more than two infections of thrush in the last six months; is experiencing thrush for the first time; has known hypersensitivity to other vaginal antifungal products; is taking any medicine other than the Pill; has any disease or illness affecting the liver or kidneys or has had unexplained jaundice; suffers from any other chronic disease or illness; is uncertain of the cause of symptoms. Or if the patient has any of the following symptoms: abnormal or irregular vaginal bleeding or a blood-stained discharge; vulval or vaginal sores, ulcers or blisters; lower abdominal pain or dysuria; any adverse events such as redness, irritation or swelling associated with the treatment; fever or

Duo®

Fluconazole & F C Clotrimazole

chills; nausea or vomiting; diarrhoea; foul smelling vaginal discharge. In men, medical advice should be sought if they have penile sores, ulcers or blisters, there is abnormal penile discharge, the penis has started to smell, they have dysuria, or their sexual partner does not have thrush. Patients should consult their doctor if symptoms have not been relieved within one week of treatment. Fluconazole has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. Fluconazole must be taken with particular care in patients with congenital or acquired QT prolongation and torsades de pointes or a history thereof, known cardiomyopathy, sinus bradycardia, cardiac arrhythmia, or are treated with a co-medication potentially leading to QT prolongation. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this capsule. The cream contains cetostearyl alcohol, which may cause local skin reactions (e.g. contact dermatitis). The cream may damage latex contraceptives so patients should be advised to use alternative precautions for at least five days after using the product. Side-effects: Oral capsule may cause nausea, diarrhoea, vomiting, gastrointestinal and abdominal pains, abdominal distension and flatulence. Leukopenia, neutropenia, agranulocytosis and thrombocytopenia. Torsades de pointes/QT prolongation. Mild transient elevations in transaminases, hepatitis (non infective), jaundice, cholestatis and acute hepatic failure, including fatalities. Allergic reaction, anaphylactic reaction, anaphylactic shock. Hypersensitivity reactions including rash, urticaria, oedema, pruritus, cardio-respiratory distress.

Electrocardiogram QT prolonged, electrocardiogram QT corrected interval prolonged, hypercholesterolaemia, hypertriglyceridaemia and hypokalaemia. Seizures, dizziness, headache, dysgeusia. Rash, pruritis, alopecia, exfoliative skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis. Cream may cause allergic reactions, blisters, discomfort/pain, oedema, irritation, peeling/exfoliation, pruritus, rash, stinging/burning. Use in pregnancy: Do not use during pregnancy, suspected pregnancy and breast-feeding. Cost: £11.20 (Excl. VAT).

MA Number: PL 00010/0282 & PL 00010/0077. MA Holder: Bayer plc, Consumer Care Division, Newbury, Berkshire RG14 1JA, UK. Legal Category: P. Date of Preparation: February 2012.

Adverse events should be reported. Reporting forms and information can be found at ‘www.mhra.gov.uk/yellowcard’. Adverse events should also be reported to Bayer plc, Consumer Care Division. ® = Registered trademark of Bayer AG.

Item code: CGY349 Date of preparation: May 2013

SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

SPECIAL REPORT

Treating Candidal Vaginitis and Mixed Vaginal Infections in Primary Care Vulvovaginal Candidiasis The Big Three

Contents

Considerations in the Diagnosis of Vaginal Discharge A Guide to the Management of Vaginal Discharge Managing Recurrent Infection, Hard to Treat Infection, and Infection in Special Circumstances

Foreword

2

Dr Robert Sykes, Editor

Vulvovaginal Candidiasis

3

Vulvovaginal Candidiasis (Thrush) Diagnosis: Complicated or Uncomplicated Vulvoaginal Candidiasis Published by Global Business Media

Treatment Options Conclusions

Published by Global Business Media Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom

The Big Three

7

Switchboard: +44 (0)1737 850 939 Fax: +44 (0)1737 851 952 Email: info@globalbusinessmedia.org Website: www.globalbusinessmedia.org

Bacterial Vaginosis Trichomoniasis Candidiasis Mixed Infections

Publisher Kevin Bell

Considerations in the Diagnosis of Vaginal Discharge 10

Business Development Director Marie-Anne Brooks Editor Dr Robert Sykes Senior Project Manager Steve Banks Advertising Executives Michael McCarthy Abigail Coombes Production Manager Paul Davies For further information visit: www.globalbusinessmedia.org The opinions and views expressed in the editorial content in this publication are those of the authors alone and do not necessarily represent the views of any organisation with which they may be associated.

Material in advertisements and promotional features may be considered to represent the views of the advertisers and promoters. The views and opinions expressed in this publication do not necessarily express the views of the Publishers or the Editor. While every care has been taken in the preparation of this publication, neither the Publishers nor the Editor are responsible for such opinions and views or for any inaccuracies in the articles.

A Note on Physiological Discharge History, Examination, and Investigation Key Clues from the History and Examination Diagnosis

A Guide to the Management of Vaginal Discharge

14

Management Pointers Recommended Regimes for BV and TV Recommended Regimens for VVC Self-Treatment Summary

Managing Recurrent Infection, Hard to Treat Infection, and Infection in Special Circumstances 18 Recurrent and Hard to Treat Infections Special Circumstances

Š 2013. The entire contents of this publication are protected by copyright. Full details are available from the Publishers. All rights reserved.

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SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

Foreword W

hen asked to put together this report

The subsequent three articles then break down the

on vulvovaginal candidiasis (VVC) and

diagnosis and management of BV, TV and VVC into

mixed infections, I recognised that VVC needs

manageable chunks. However, rather than focusing

to be considered in the wider context of vaginal

specifically on the minutiae, they seek to provide

discharge and vaginitis. Vaginitis is usually

pointers from the available guidelines, and to stimulate

characterized by a vaginal discharge and/ or vulval

further reading where appropriate.

itching and irritation that is sometimes associated with malodour.

Much of the report is taken from several key sources: the 2011 European (IUSTI/WHO) Guidelines on

Three diseases are commonly cited in the literature

the Management of Vaginal Discharge; the 2006

as being associated with vaginal discharge: bacterial

“Sexually Transmitted Diseases Guidelines: Diseases

vaginosis (BV), which occurs due to replacement of

Characterized by Vaginal Discharge” from the centers

the normal vaginal flora by an overgrowth of anaerobic

for disease control and prevention; and the 2006

microorganisms, myco-plasmas, and Gardnerella

document “Sexually Transmitted Infections in Primary

vaginalis; trichomoniasis (TV) also T. vaginalis – a

Care” produced in collaboration between the Royal

sexually transmitted infection; and candidiasis, which

College of General Practitioners’ Sex, Drugs and HIV

is usually caused by Candida albicans. Although

Task Group, and the British Association for Sexual

cervicitis can sometimes cause a vaginal discharge,

Health and HIV (BAASH). Additional guidelines are

and is associated with chlamydia and gonorrhoea,

also available at the BAASH website on a host of

these infections were considered beyond the limited

related topics, and I would recommend that you visit

scope of this report.

their site If you wish to read the guidelines directly.

The report focuses on vaginal discharge in general, and the “big three” specifically: BV, TV and VVC. We open with a refresher article designed to remind the reader about the aetiology of these, and provide a brief outline as to what is meant by “mixed infection”.

Robert Sykes Editor

Dr Robert Sykes qualified with a degree in medicine (MBChB Honours) in 2004 from the University of Liverpool where he was awarded the George Holt Medal for high academic achievement, along with commendations for a number of his clinical reviews. As a postgraduate he entered into a GP vocational training scheme before opting to work in a portfolio career, and in 2008, he set up Northern Editing (www.docrob.co.uk/nothernediting) for medical writing and editing. Currently, he is also the Executive Editor for the UK’s only peer support organisation for doctors with mental illness, the Doctors’ Support Network (registered charity 1103741; www.dsn.org.uk).

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SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

Vulvovaginal Candidiasis V

aginitis is the most common gynecological problem that women seek treatment for 1,2 , and is the most common gynecologic diagnosis in the primary care setting3. It causes disruptive symptoms including itching, irritation, pain during intercourse, and discharge that all result in physical discomfort, and can cause psychological distress when chronic, untreated, or recurrent. Additionally, vaginitis may influence sexual behaviors and disrupt an individual’s sex life4,5.

Four types of infectious vaginitis are commonly found in women – candidiasis (thrush), trichomoniasis, bacterial vaginosis, and gonococcal infections6,7. In these conditions, the vaginal flora is altered by either the introduction of a pathogen or by changes in the local environment that allow pathogens or normal saprophytes to proliferate3. Among the infectious agents, Trichomonas vaginalis is the most common non-viral sexually-transmitted infection, and candidiasis is the second most common vaginal infection overall2,8. Seventyfive percent of women suffer from vulvovaginal candidiasis at least once during their lives, with almost 45% of women experiencing the disease twice or more annually8,9. Approximately 5% of women are diagnosed with chronic and recurrent infections8,9.

Although vuvlovaginal candidiasis is a significant problem, mixed infections are observed very frequently too10. Bacterial vaginosis has become an increasing problem in recent years6,11,12 but since it is frequently asymptomatic, its true prevalence is difficult to estimate11,12. In most cases of bacterial vaginosis, it is the loss of normal vaginal flora that leads to it (eg lactobacilli) as might occur following the menopause or the use of antibiotics for other infections13. The organisms that most commonly cause bacterial vaginosis are Gardenerella vaginalis, Mycoplasma hominus and Ureaplasma urealyticum, together with anaerobes like Prevotella, Mobiluncus, Bacteroides, and Peptostreptococcus6,11,12,13.

Vulvovaginal Candidiasis (Thrush) Thrush is caused by the opportunistic overgrowth of the normally harmless candida yeasts that inhabit the gastrointestinal tract, skin and vagina.

When host defenses fail for some reason, candida

species cause the symptoms of thrush. In 80% to 90% of cases9, candida albicans is the pathogen most commonly found to be causative. However, the aetiology of vulvovaginal candidiasis varies, with other species coming to prominence over recent years. Candida glabrata is the second most common cause of candidal disease and is found in 5%-15% of cases14. When candidal infection is sustained by candidal species other than candida albicans, such as Candida glabrata and Candida tropicalis, it is often resistant to treatment8,14,15.

Under normal circumstances, host defenses act locally in the vagina to combat infection and to keep levels of candida under control.

‘Protective’ vaginal bacteria, like the lactobacilli mentioned above, produce lactic acid which create an acidic vaginal environment that is hostile to micro-organisms such as candida albicans.

However, various triggers and lifestyle factors (see table 1) may alter the vaginal pH balance, destroying the ‘protective’ bacteria and increasing the risk of infection in the process. The use of antibiotics, oral contraceptives, corticosteroids, and immunosuppressive drugs all increase the risk of contracting vulvovaginal candidiasis, while pregnancy and diabetes in combination with normal changes in the vaginal flora are also major risk factors for the disease2,16.

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Table 1: The main triggers of thrush include: • Intake of medicines such as antibiotics • Trauma of sexual activity • Stress • Perfumed soap, shower gels and bubble baths • Periods and menstruation • Wearing of tight clothing • Pregnancy

Diagnosis: Complicated or Uncomplicated Vulvoaginal Candidiasis Whilst thrush is an infection that starts internally, women may only experience the external symptoms of vaginal itching and irritation, and this itch is typically the major presenting feature17. Thrush also presents with symptoms that include a thick white vaginal discharge, redness, soreness and swelling of the vulva and vaginal walls, burning or stinging of the vulva

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SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

Four types of infectious vaginitis are commonly found in women— candidiasis (thrush), trichomoniasis, bacterial vaginosis, and gonococcal infections

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when passing urine, and pain during sexual intercourse, all due to the local inflammation.

Examination frequently reveals erythema and swelling of the labia and vulva, often with separate pustulopapular peripheral lesions. If a discharge is present, it is typically described as whitish, thick and curd-like. The cervix is normal, and mucosal erythema is present together with the pathognomonic appearance of an adherent whitish discharge17.

Vulvovaginal candidiasis can affect any woman at any age. However, those women who have suffered recurrent bouts will usually opt for self-treatment, meaning that doctors are left to manage first-time presenters, patients with recurrent or persistent symptoms, or those with associated risk factors such as pregnancy, poorly controlled diabetes, or compromised immunity.

It is useful to classify vulvovaginal candidiasis as uncomplicated or complicated when assessing the patient.

Uncomplicated vulvovaginal candidiasis is:18 • Sporadic or infrequent • Mild to moderate • Likely to be due to Candida albicans •N OT associated with risk factors such as pregnancy, poorly controlled diabetes, compromised immunity, or debilitation.

Complicated vulvovaginal candidiasis includes:18 •R ecurrent infection – four or more documented episodes in 1 year, with at least partial resolution of symptoms between episodes.

•S evere infection — extensive vulval erythema, oedema, excoriation, and fissure formation.

• I nfection with yeasts other than Candida albicans.

• Infection during pregnancy.

• I nfection in immunocompromised women – with debilitating medical conditions such as uncontrolled diabetes mellitus, or who are taking systemic corticosteroid treatment.

Investigation is very much dictated by the above findings, and is only indicated in complicated cases. A full blood count and random blood glucose are typically required in recurrent vulvovaginal candidiasis. Microscopy and fungal

culture of vaginal secretions is recommended only when the diagnosis is uncertain, there is treatment failure or the candidiasis is severe and/or recurrent. Examination of a smear from the vaginal wall will reveal spores and mycelia, and a positive culture should only be considered significant if the patient is symptomatic. As part of the diagnostic process, Trichomonas and bacterial vaginosis should be excluded in women with itch and discharge.

Treatment Options When making a treatment decision, it is important to clear both the internal infection and to relieve the external symptoms. Therefore, it may be necessary to co-prescribe both topical and systemic therapy. This could involve prescribing a pessary and external cream or an oral capsule and external cream for example. Several antifungal agents exist for vulvovaginal candidiasis, and include nystatin and any pharmaceutical agent containing an azole product.

Antifungals Antifungals can be divided into the Imidazoles (e.g. clotrimazole, ketoconazole, miconazole, tolnaftate) and the triazoles (e.g. fluconazole).

These work by inhibiting the synthesis of ergosterol, an essential component of fungal cell membranes. By inhibiting the enzyme 14-alphadimethylase, the cell is unable to build up demethyl-lanosterol out of lanosterol, and therefore also unable to build up ergosterol. When this is missing, the cell membrane is damaged, and the cell contents leak causing destruction of the fungus. Antifungal agents are often classed as fungistatic because they inhibit the growth of the fungus.

These agents are all available in several formats, with the imidazoles in particular being available in the convenient forms of suppositories, creams, and vaginal pills for VC19. However, their use can cause local irritation or stimulation, and once the presenting symptoms settle, women may not complete the full course of treatment before the infection is fully eradicated9. Fluconazole (150mg) has the same effect as vaginally administered products following a single dose and has the

SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

Table 2: Self-help tips for patients • Wear loose clothing and cotton underwear – avoid synthetic underwear and nylon tights • Shower, wash or bathe immediately after exercising and cool off as quickly as possible •U se non-fragranced soaps and shower gels.

•A void friction in the vaginal area as this can cause candida to thrive. This can happen in situations such as:

o Scrubbing the genital area hard with sponges or flannels

o Trauma of sexual intercourse, often due to vaginal dryness. Suggest the customer uses a lubricant

o Inserting a tampon • Try to avoid stressful situations – stress can cause a thrush attack.

advantage of being able to treat mycosis in the gastrointestinal tract, although this is at the cost of potential systemic side effects19. Whatever method is used, it is essential that women be educated on the need to continue the full course of treatment, even after symptoms have abated.

Clotrimazole is typically the first-line treatment for vulvovaginal candidiasis, with fluconazole being reserved for cases with no response to clotrimazole treatment9. Clotrimazole, is a broad spectrum imidazole derivative that penetrates the skin in high concentrations, resulting in it being a highly effective treatment. Since the active ingredient reaches the blood stream in only minute quantities, general side-effects due to a treatment with clotrimazole are rare, and primary or secondary resistance of fungi against clotrimazole is unlikely. In addition to its antifungal properties, clotrimazole also has recognised antibacterial properties. Mixed infections can be effectively treated by a topical azole antifungal medication such as clotrimazole, especially when given in combination with oral drugs like metronidazole and tinidazole8,10,18.

Alternative treatment options Some researchers have suggested that vulvovaginal candidiasis leads to destruction of the vaginal flora and that that there may be a role for probiotics20 (for example, lactobacillus and Bifidobacterium) in preventing vaginal

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infections21,22. Lactobacilli administered within the genital tract may act prophylactically by improving the genital micro-flora and defending against bacterial infections23. However, the effects are as yet unproven and remain controversial16,24. Finally, there remains a role for self-care, both with overthe-counter medications, and also with basic selfhelp tips (see table 1).

Conclusions Most vaginal infections usually respond to pathogen-specific treatments6,9 but, in absence of a single drug that can treat the most frequent infections, treatment efficacy largely depends on the ability of health care providers to make the correct diagnosis8,25. Additionally, many women with vaginal complaints may selftreat incorrectly with over-the-counter drugs without consulting health care providers26. These treatments can weaken the natural defenses against infections and favor the emergence of resistant strains of microorganisms, the development of mixed infections, or incomplete treatment26. As a result, hard to treat vaginal infections with recurrences of vaginal candidiasis or trichomoniasis are frequently observed27.

Proper treatment with effective first line agents, for sufficient duration, and with proper education is key to improving the efficacy of therapy and to reducing the morbidity associated with vuvlovaginal candidiasis.

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SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

References: 1

Ryan KJ, Berkowitz RS, Barbieri RL, Dunaif A. Kistner’s Gynecology and Women’s Health. 7th edition. England, UK: Mosby; 1999.

2

Berek JS, Novak E. Berek and Novak’s Gynecology. Lippincott Williams & Wilkins; 2007.

3

Egan ME, Lipsky MS. Diagnosis of vaginitis. Am Fam Physician 2000; 62: 1095-1104.

4

Martinez RCR, Franceschini SA, Patta MC, et al. Improved treatment of vulvovaginal candidiasis with fluconazole plus probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14. Letters in Applied Microbiology. 2009;48(3):269–274.

5

Akbarzadeh M, Bonyadpoure B, Pacshir K, Mohagheghzadeh A. Causes and clinical symptoms of vaginal candidiasis in patients referring to selective clinics of Shiraz University of Medical Sciences. Arak University of Medical Sciences Journal. 2009;13(3):12–20.

6

Owen MK, Clenney TL. Management of vaginitis. Am Fam Physician 2004; 70: 2125-2132.

7

Gibbs RS, Danforth DN, Karlan BY, Haney AF. Danforth’s Obstetrics and Gynecology. Lippincott Williams & Wilkins; 2008.

8

CDC. Center for Disease Control and Prevention. Sexually-transmitted diseases treatment guidelines 2006. Recomm Rep 2006; 55: 1-95. Available online from: www.cdc.gov.

9

Sobel JD. Vulvovaginal candidosis. Lancet 2007; 369: 1961-1971

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Soper DE. Taking the guesswork out of diagnosis and managing vaginitis. Contemporary OB/GYN 2005; 50: 32-39.

Klebanoff MA, Schwebke JR, Zhang J, Nansel TR, Yu KF, Andrews WW. Vulvovaginal symptoms in women with bacterial vaginosis. Obstet Gynecol 2004; 104: 267-272.

12

Weir E. Bacterial vaginosis: more questions than answers. Can Med Assoc J 2004; 171: 448-501.

13

Ness RB,Hillier SL, Kip KE, Soper DE, Stamm CA, McGregor JA, Sweet RL, Rice P, Richter HE. Bacterial vaginosis and risk of pelvic inflammatory disease. Obstet Gynecol 2004; 104: 761-769.

14

Ullah A, Lopes MI, Brul S, Smits GJ. Intracellular pH homeostasis of Candida glabrata in infection associated conditions. Microbiology. 2013 Feb 1.

[Epub ahead of print]

15

Lockhart SR,et al. Comparison of in vitro susceptibility characteristics of Candida species from cases of invasive candidiasis in solid organ and stem cell transplant recipients: Transplant-Associated Infections Surveillance Network (TRANSNET), 2001 to 2006. J Clin Microbiol. 2011 Jul;49(7):2404-10.

16

Falagas ME, Betsi GI, Athanasiou S. Probiotics for prevention of recurrent vulvovaginal candidiasis: a review. Journal of Antimicrobial Chemotherapy. 2006;58(2):266–272.

17

Candidiasis. Page 105 in: Kumar and Clark. Clinical Medicine, 4th Edition. W.B Saunders. Hardcourt publishers Ltd 1999.

18

CDC (2006) Diseases characterized by vaginal discharge. Sexually transmitted diseases treatment guidelines 2006. MMWR Morbidity and Mortality Weekly Report 55(RR-11), 49-56.

19

BNF section 7.2.2 Vaginal and vulval infections > Fungal infections.

Accessed at: http://www.medicinescomplete.com/mc/bnf/current/PHP4832-preparations-for-vaginal-and-vulval-candidiasis.htm

20

Ehrström S, Daroczy K, Rylander E, et al. Lactic acid bacteria colonization and clinical outcome after probiotic supplementation in conventionally treated bacterial vaginosis and vulvovaginal candidiasis. Microbes and Infection. 2010;12(10):691–699.

21

Fernández MF, Boris S, Barbés C. Probiotic properties of human lactobacilli strains to be used in the gastrointestinal tract. Journal of Applied Microbiology. 2003;94(3):449–455.

22

Shi Y, Chen L, Tong J, Xu C. Preliminary characterization of vaginal microbiota in healthy Chinese women using cultivation-independent methods.

Journal of Obstetrics and Gynaecology Research. 2009;35(3):525–532.

23

Rönnqvist D, Forsgren-Brusk U, Husmark U, Grahn-Håkansson E. Lactobacillus fermentum Ess-1 with unique growth inhibition of vulvo-vaginal candidiasis pathogens. Journal of Medical Microbiology. 2007;56(11):1500–1504.

24

Pirotta M, Gunn J, Chondros P, et al. Effect of lactobacillus in preventing post-antibiotic vulvovaginal candidiasis: a randomised controlled trial.

British Medical Journal. 2004;329(7465):548–551.

25

Landers DV, Wiesenfel HC, Heine RP, Krohn MA, Hillier SL. Predictive value of the clinical diagnosis of lower genital tract infection in women.

Am J Obstet Gynecol 2004; 190: 1004-1010.

26

Ferris DG, Nyirjesy P, Sobel JD, Soper D, Pavletic A, Litaker MS. Over-the-counter antifungal drug misuse associated with patient-diagnosed vulvovaginal candidiasis. Obstet Gynecol 2002; 99: 419-425.

27

Say PJ, Jacyntho C. Difficult-to-manage vaginitis. Clin Obstet Gynecol 2005; 48: 753-768.

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SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

The Big Three V

ulvovaginal complaints are one of the most common reasons why women visit their doctors. A common condition under this heading, vaginitis is defined as “a spectrum of conditions that cause vaginal and sometimes vulvar symptoms, such as itching, burning, irritation, odour, and vaginal discharge1”. The most common infectious causes of vaginitis are bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and trichomoniasis (TV); the big three. This article seeks to provide a brief recap of the aetiology of each of these conditions, before we move on to look at how they are diagnosed and managed in subsequent articles.

Bacterial Vaginosis In terms of the causes of vaginal discharge, BV is typically the most frequently occurring. It tends to be prevalent in woman of childbearing age, but can also be a problem in menopausal women, and very occasionally in children2,3,4. In the UK, prevalence rates of between 12% and 30% have been reported5,6,7. BV is highly prevalent in African and American blacks (45-55%), less so in Asian women (20-30%) and the least in whites (5-15%). The precise reasons for this are not known.

The vaginal ecology in BV: Lactobacilli are the dominant bacteria in the healthy vagina, and through them, the vaginal pH is maintained at a pH below 4.5. This results in low levels of other bacteria; BV however, is characterised by an elevation of this pH above 4.5, to around 6.0. In the majority of cases, this is caused by an overgrowth of anaerobic organisms, typically Gardnerella vaginalis, Prevotella spp., Mycoplasma hominis, and/or Mobiluncus spp., which replace the lactobacilli and cause the pH of the vaginal secretions to increase. More recently, techniques have been able to identify previously unknown bacteria, including bacterial vaginosis associated bacterium (BVAB; 1, 2, and 3) as well as Atopobium species, Leptotrichia spp., and Sneathia spp8. Since these bacteria are difficult to culture, their susceptibility to antibiotics is not known, and they may be a cause for treatment failure and recurrence. In some women aerobic micro-flora derived from the gut, including Escherichia coli, group B streptococci, and

Staphylococcus aureus predominate. This is termed aerobic vaginitis (AV), and is frequently associated with mixed infections4,9.

It is not known for certain whether BV is merely an imbalance in vaginal ecology, or if is initiated as a sexually transmitted infection (STI)9. Risk factors include vaginal douching, receptive cunnilingus, black race, recent change of sex partner, smoking, and the presence of an STI (e.g. chlamydia or herpes)9. BV can arise and remit spontaneously. The prevailing theories argue that infection is due to one of two reasons4.

One argument is that lactobacilli disappear due to environmental factors such as vaginal douching, or frequent pH insults due to sexual intercourse.

The other argument is that some lactobacilli are attacked by viruses and are unable to recolonize the vagina, thus facilitating anaerobic overgrowth.

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BV – not a benign infection: The symptoms and signs of BV can be seen in Figure 1a. Although it is not sexually transmitted, there are associations between BV, STIs and other genital infections, including HIV, and the recurrence rate of infections such as gonorrhoea and chlamydia10,11,12. BV is also associated with late miscarriage, preterm birth, preterm premature rupture of membranes, and postpartum endometritis13,14.

Trichomoniasis Trichomonas vaginalis (TV) is an almost universally sexually transmitted flagellated protozoon that is present as a parasite in the urogenital tracts (the vagina, urethra and paraurethral glands) of infected women4. Due to site specificity, infection can only follow intra-vaginal or intra-urethral inoculation of the organism15. Although the urinary tract is the sole site of infection in less than 5% of cases, urethral infection is present in over 90% of episodes. Systemic therapy is therefore usually needed to ensure that both vulvovaginal and urethral infection is cleared. The most obvious host response to infection is a local increase in polymorphonuclear leukocytes. Figure 1b lists the most common signs and symptoms associated with TV infection.

TV is increasingly associated with complications: There is increasing evidence that T. vaginalis infection can have a detrimental outcome on

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SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

Both co-infection and mixed vaginitis appear to be understudied in the research literature, and represent challenging clinical conditions

Figure 1a: Clinical Features of BV Signs • Thin, white, homogeneous discharge, coating the walls of the vagina and vestibule.

• BV is not usually associated with signs of inflammation.

Symptoms • Offensive fishy smelling vaginal discharge • Not associated with soreness, itching, or irritation • Many women (approximately 50%) are asymptomatic

Figure 1b: Clinical Features of TV Signs • Vaginal discharge in up to 70%. The classic discharge of frothy yellow occurs in only 10-30% of women.

• Vulvitis and vaginitis.

• Colposcopy may reveal a strawberry cervix.

• As many as 1 in 6 women will have no abnormalities on examination.

Symptoms • 10 - 50% are asymptomatic.

• Vaginal discharge, • Vulval itching, • Dysuria, • Offensive odour.

• Occasionally low abdominal discomfort.

Figure 1c: Clinical Features of VVC Signs • Erythema • Fissuring • Discharge, typically curdy but may be thin, and Non-offensive • Oedema • Satellite lesions • Excoriation

pregnancy and is associated with preterm delivery and low birth weight16,17,18 although it is not known if the association is causal, and trials have found that treatment of TV infection in pregnancy does not improve pregnancy outcome, and may be harmful16,17. Screening of asymptomatic individuals for T. vaginalis infection is therefore not currently recommended15.

Candidiasis Vulvovaginal candidiasis (VVC) is covered extensively elsewhere in this report. It is caused by an overgrowth of Candida albicans in upwards of 90% of women, with the remainder being due to species such as C. glabrata, C. tropicalis, C. krusei, C. parapsilosis, and Saccharomyces cerevisiae. Three quarters of women can expect to experience at least one episode during their lifetime, and around one in five, to one in ten women are asymptomatic vaginal carriers4,19.

The symptoms and signs of VVC can be seen in Figure 1c. None of these are however either sensitive or specific for VVC, and laboratory testing is essential to confirm the diagnosis. It is important to note that many women may have other conditions that they are incorrectly treating 8 | www.primarycarereports.co.uk

Symptoms • Vulval itch • Vulval soreness • Vaginal discharge • Superficial dyspareunia • External dysuria

as thrush (e.g. dermatitis, allergic reactions, and lichen sclerosus)20.

Mixed Infections There are a wide range of conditions that fall into this category, including aerobic vaginitis (AV), bacterial vaginosis (BV), and indeed any coinfection with the three major vaginal pathogens21.

Mixed vaginitis is rare (<5% of cases), but can reasonably be defined as “infection due to at least two different vaginal pathogens, where both contribute to the abnormal symptoms and signs of vaginitis22”. However, it can be difficult to separate out micro-flora that are simply “present” from those that are causing symptoms; just because a pathogen is present, doesn’t mean that it is pathogenic. Co-infection occurs much more frequently than true mixed infection in women with vaginitis. For example, approximately 20 %-30 % of women with bacterial vaginosis (BV) are co-infected with Candida species, while BV pathogens and T. vaginalis are seen in as many as 60% to 80% of cases22. Both co-infection and mixed vaginitis appear to be understudied in the research literature, and represent challenging clinical conditions.

SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

References: 1

Hainer B. Gibson, M. Vaginitis: Diagnosis and Treatment. Am Fam Physician. 2011 Apr 1;83(7):807-815.

2

Bhalla P, Chawla R, Garg S, Singh MM, Raina U, Bhalla R et al. Prevalence of bacterial vaginosis among women in Delhi, India.

Indian J Med Res 2007; 125(2):167-172.

3

Koumans EH, et al. The prevalence of bacterial vaginosis in the United States, 2001-2004; associations with symptoms, sexual behaviors, and reproductive health. Sex Transm Dis 2007; 34(11):864-869.

4

Sherrard J, et al. 2011 European (IUSTI/WHO) Guideline on the Management of Vaginal Discharge.

5

Blackwell AL, et al. Health gains from screening for infection of the lower genital tract in women attending for termination of pregnancy.

Lancet 1993 July 24;342(8865):206-10.

6

Hay PE, et al. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage.

Br Med J 1994 January 29;308(6924):295-8.

7

Akinbiyi AA, Watson R, Feyi-Waboso P. Prevalence of Candida albicans and bacterial vaginosis in asymptomatic pregnant women in South Yorkshire, United Kingdom. Outcome of a prospective study. Arch Gynecol Obstet 2008; 278(5):463-466.

8

Fredricks DN, Fiedler TL, Marrazzo JM. Molecular identification of bacteria associated with bacterial vaginosis. N Engl J Med 2005 November 3;353(18):1899-911.

9

Phillip et al. UK National Guideline for the management of Bacterial Vaginosis 2012. Clinical Effectiveness Group.

British Association for Sexual Health and HIV

10

Ness RB, et al. Bacterial Vaginosis and Risk of Pelvic Inflammatory Disease. Obstet Gynecol Surv 2005 February;60:99-100.

11

Schwebke JR, Desmond R. A randomized trial of metronidazole in asymptomatic bacterial vaginosis to prevent the acquisition of sexually transmitted diseases. Am J Obstet Gynecol 2007 June;196(6):517-6.

12

Taha TE, Hoover DR, Dallabetta GA, Kumwenda NI, Mtimavalye LA, Yang LP et al. Bacterial vaginosis and disturbances of vaginal flora: association with increased acquisition of HIV. AIDS 1998 September 10;12(13):1699706.

13

Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 2000 May 18;342(20):1500-7.

14

McGregor JA, et al. Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: results of a controlled trial of topical clindamycin cream. Am J Obstet Gynecol 1994 April; 170(4):1048-59.

15

Sherrard, J. United Kingdom National Guideline on the Management of Trichomonas vaginalis (2007). Clinical Effectiveness Group, British Association of Sexual Health and HIV.

16

Cotch MF, et al. Trichomonas vaginalis associated with low birth weight and preterm delivery. Sex Trans Dis 1997;24:353-360

17

Andrews et al. Randomised controlled trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal firbronectin-positive women. Obstet Gynecol 2003; 101: 847-55.

18

Klebanoff MA, et al. Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Eng J Med 2001; 345: 487-93.

19

White, D. Robertson, C. Guideline on the Management of Vulvovaginal Candidiasis (2007). Clinical Effectiveness Group.

British Association of Sexual Health and HIV.

20

Ferris DG, Dekle C, Litaker MS. Womenâ&#x20AC;&#x2122;s use of over-the-counter antifungal medications for gynecologic symptoms. Journal of Family Practice 1996; 42(6):595-600.

21

Fan A, Yue Y, Geng N, Zhang H, Wang Y, Xue F. Aerobic vaginitis and mixed infections: comparison of clinical and laboratory findings.

Arch Gynecol Obstet. 2013 Feb;287(2):329-35. doi: 10.1007/s00404-012-2571-4. Epub 2012 Sep 27.

22

Sobel JD, Subramanian C, Foxman B, Fairfax M, Gygax SE. Mixed Vaginitis-More Than Coinfection and With Therapeutic Implications.

Curr Infect Dis Rep. 2013 Jan 27. [Epub ahead of print]. Abstract

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SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

Considerations in the Diagnosis of Vaginal Discharge

The commonest cause of non-pruritic, non-malodorous vaginal discharge is physiological. It is typically hormonally dependent and changes over time in both quality and quantity

V

aginal discharge is a very common symptom that is seen at all levels of medicine from primary care to genitourinary medicine and family planning clinics.

Although some women present in the belief that they have a sexually transmitted infection (STD), it can be extremely difficult based on the presenting complaints to determine the cause1. Indeed, the Royal college of General Practitioners (RCGP) document “sexually transmitted infections in primary care,” produced in collaboration with the British Association of Sexual Health and HIV (BAASH) in 2006, confirms this2.

Although vaginal discharge can be separated into either infectious or noninfectious causes, the rates are very different at 90% and 10%, respectively3. The most common cause of discharge in women with an infective aetiology is bacterial vaginosis (40%-50% of cases), followed by vulvovaginal candidiasis (20%-25%), and then trichomoniasis (15%20%) 3 . However, the RCGP document simplifies this data into the aide memoire that around 1/3 of cases are due to bacterial vaginosis, 1/3 are due to candida, and 1/3 are due to either STIs or physiological causes2.

Therefore, although a women may present with the fear of an STI, such as gonorrhea or chlamydia, these are often much lower in the differential diagnosis. In this article we will review some of the key aspects of the history and examination of a woman with discharge.

A Note on Physiological Discharge The commonest cause of non-pruritic, nonmalodorous vaginal discharge is physiological.

It is typically hormonally dependent and changes over time in both quality and quantity.

Every woman will have her own sense of normality, and what is acceptable or excessive for her 1. Factors that affect physiological discharge include1: a woman’s age, i.e., whether they are pre-pubertal, reproductive or post10 | www.primarycarereports.co.uk

menopausal; local factors such as the woman’s personal hygiene habits, semen, menstruation malignancy; or hormonal effects, such as cyclical hormonal contraception, cyclical changes, and pregnancy. Although rarer, foreign bodies and malignancy can cause vaginal discharge2.

It is particularly important to be vigilant for changes in vaginal discharge in the post-menopausal woman, as this may indicate cancer.

History, Examination, and Investigation It is essential to clarify the nature of the discharge4: its onset, duration, amount, colour, consistency, odour and whether there is any blood staining.

Equally, you should check for the presence of associated symptoms such as: itching, soreness, dysuria, intermenstrual or post-coital bleeding, lower abdominal pain, pelvic pain, previous episodes, and dyspareunia (superficial and deep). Also, the RCGP /BAASH guidelines2 offer useful additional pointers: History: •C heck for consistency and whether it is itchy, malodourous, or cyclical?

• I f it sounds physiological, reassure, but examine if necessary • I f it sounds like Candida, you can treat pragmatically; consider giving treatment immediately if suspected, but review and re-examine if symptoms persist.

• I f the patient is known to have BV, treat recurrent malodorous discharge pragmatically if it is recognised by the patient as being an uncomplicated recurrence. Reexamining and testing is not necessary in the first instance.

Examination: • I f there is evidence of cervicitis, endometritis, or salpingitis, swabs MUST be taken.

• I f there is a retained foreign body, it should be removed and metronidazole started according to symptoms, but especially if there is malodour.

SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

Figure 2a: Clues

VVC

BV TV

No

No

Usually

Not a single organism but an over growth of anaerobic bacteria that are normally present

A Protozoan

Background Information Sexually transmitted

Causative organism Candida albicans

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Symptoms Discharge White (typically curd-like) White/grey homogenous

Yellow green frothy is classical

Smell

Nil (yeasty)

Malodorous

Prunitis

Yes Occasionally Yes

Fishy or oniony

Clinical findings Vulvitis Possibly No

Possibly

Vaginitis Yes

Yes

No

Cervicitis Occasionally No

Yes

PH

< 4.5

Raised

Raised

WBC / Candida

Clue cells / altered flora

WBC / TV

No

No

Laboratory findings Microscopy

Culture Yes

•D o a vaginal examination if there is abdominal pain (Treat early if you suspect pelvic inflammatory disease [PID]) Investigation: •p H – should be taken by endocervical rather than high vaginal swab – (take a swab, rub it along the lateral wall, collecting some discharge, then rub it onto pH paper) The normal vaginal pH is 4.5 or less. A raised pH can point to pathogenic infection.

•H igh Vaginal Swabs – (HVS) or Endocervical swabs: HVSs have a poor evidence base in vaginal discharge and their use should be reserved for cases of suspected cervicitis, endometritis, or salpingitis i.e., PID. •M icroscopy should be requested for chlamydia, gonorrhea, candida, BV, and TV according to the clinical picture.

Key Clues from the History and Examination The most likely infective causes are vaginal candidiasis5, bacterial vaginosis6, and vaginal trichomoniasis7. Although diagnosis can be difficult, an excellent 2004 literature review looked at the likelihood ratios (LR) of specific signs and symptoms in the diagnosis of these infections, focusing on the physical examination findings,

pH, the wet mount, and the whiff test8. They concluded that symptoms alone do not allow clinicians to distinguish confidently between the different causes of vaginitis, and that microscopy was the only definitive diagnostic tool. However, they were able to make some generalisations based on their findings: a patient’s lack of itching makes candidiasis less likely (range of LRs, 0.18 [95% confidence interval [CI], 0.05-0.70] to 0.79 [95% CI, 0.72-0.87]); lack of perceived odor makes bacterial vaginosis unlikely (LR, 0.07 [95% CI, 0.01-0.51]); the presence of inflammatory signs is associated with candidiasis (range of LRs, 2.1 [95% CI, 1.5-2.8] to 8.4 [95% CI, 2.3-31]); the presence of a “high cheese” odor (whiff test) on examination is predictive of bacterial vaginosis (LR, 3.2 [95% CI, 2.1-4.7]) while a lack of odor is associated with candidiasis (LR, 2.9 [95% CI, 2.4-5.0]). A summary of the key information that you wish to gain from the history and examination can be found in figure 2a.

Diagnosis Asymptomatic women do not require testing for BV or candida. Microscopy of a swab taken from the vaginal wall is the only means of providing a definitive diagnosis, and this can be done either in the clinic or by sending to a laboratory. Ideally all women presenting with

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SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

It is generally acceptable

Figure 2b: Diagnostic criteria for bacterial vaginosis (BV), vulvovaginal candidosis (VVC) & Trichomoniasis vaginalis (TV)

to diagnose and manage

Criteria for diagnosis of BV

VVC or BV on the basis of the history alone, especially in a woman at low risk of an STI, and who has a clear history of discharge, itching

A.

Clinical diagnosis (Amsel): (the presence of three of the 4 criteria is required)

1. Homogeneous gray-white discharge

2. Vaginal fluid pH > 4.5;

3. Fishy odour (if not recognizable, use few drops of 10% KOH)

4. Clue cells present on wet mount microscopy

B. Nugent score – estimates the relative proportions of bacterial morphotypes on a Gram stained vaginal smear to give a score between 0 and 10. A score of <4 is normal, 4-6 is intermediate and >6 is BV. C. Hay Ison criteria – based on findings on a Gram stained smear and reflects the flora better than Nugent score.

Grade 0: Not related to BV, epithelial cells only, no lactobacilli; indicates recent antibiotics

Grade 1: (Normal): Lactobacillus morphotypes predominate

Grade 2: (Intermediate): Mixed flora with some Lactobacilli present, but Gardnerella or Mobiluncus morphotypes also present Grade 3 (BV): Predominantly Gardnerella and/or Mobiluncus morphotypes, clue cells. Few or absent Lactobacilli.

Grade 4: Not related to BV, Gram +ve cocci only, no lactobacilli (Aerobic vaginitis flora)

Criteria for diagnosis of VVC

or a fishy smell

- Absence of smell (in “whiff test” on speculum and in amine odour test on slide) are supportive, since candidiasis and BV/TV do not usually co-exist. Not diagnostic.

-

Yeasts or pseudohyphae on wet preparation (40 - 60% sensitivity) of vaginal discharge.

-

Yeasts or pseudohyphae on Gram stain (up to 65% sensitivity) of vaginal discharge

- Vaginal culture positive for a Candida species. If clarify as albicans or non-albicans.

Results sometimes reported as light, medium or heavy growth.

Criteria for diagnosis of TV A. Direct observation of the organism by a wet smear (normal saline) or acridine orange stained slide from the posterior vaginal fornix (sensitivity 40-70% cases). Microscopy for TV should be performed as soon as possible after the sample is taken as motility diminishes with time.

B.

Culture media are available and will diagnose up to 95% of cases.

C. Nucleic acid amplification tests (NAATs) have been developed with sensitivities and specificities that approach 100%.

abnormal vulval or vaginal symptoms should be tested, but this is especially the case when: TV is present on cervical cytology; a sexual partner has been diagnosed with TV; the vaginal discharge does not respond to empirical treatment; or there are severe and/or recurrent symptoms5,6,7,8. See figure 2b for the diagnostic criteria. Overall, when a combination of symptoms, physical examination, pH of vaginal fluid, microscopy, and the whiff test are used, the sensitivity and specificity has been found to be: 81 and 70 percent, respectively,

12 | www.primarycarereports.co.uk

for bacterial vaginosis; 84 and 85 percent for vulvovaginal candidiasis; and 85 and 100 percent for trichomoniasis when compared with the DNA probe standard9. Therefore, it is generally acceptable to diagnose and manage VVC or BV on the basis of the history alone, especially in a woman at low risk of an STI, and who has a clear history of discharge, itching or a fishy smell. Where TV is suspected, and subsequently diagnosed, a full sexually transmitted infection screen is necessary, as well as partner notification and treatment.

SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

References: 1

H elen Mitchell. Vaginal discharge—causes, diagnosis, and treatment. ABC of sexually transmitted infections. BMJ. 2004 May 29; 328(7451): 1306–1308.

2

Neil Lazaro. Sexually Transmitted Infections in Primary Care. RCGP (Royal College of General Practitioners) Sex, Drugs and HIV Task Group.

British Association for Sexual Health and HIV. 1st Edition March 2006. Available at www.rcgp.org.uk and the BAASH website.

3

Mylonas I, Bergauer F. Diagnosis of vaginal discharge by wet mount microscopy: a simple and underrated method. Obstet Gynecol Surv. 2011 Jun;66(6):359-68.

4

Sherrard J, et al. 2011 European (IUSTI/WHO) Guideline on the Management of Vaginal Discharge.

5

White, D. Robertson, C. Guideline on the Management of Vulvovaginal Candidiasis (2007). Clinical Effectiveness Group.

British Association of Sexual Health and HIV.

6

Phillip et al. UK National Guideline for the management of Bacterial Vaginosis 2012. Clinical Effectiveness Group.

British Association for Sexual Health and HIV

7

Sherrard, J. United Kingdom National Guideline on the Management of Trichomonas vaginalis (2007). Clinical Effectiveness Group, British Association of Sexual Health and HIV.

8

Anderson MR, Klink K, Cohrssen A. Evaluation of vaginal complaints. JAMA. 2004 Mar 17;291(11):1368-79.

9

Lowe NK, Neal JL, Ryan-Wenger NA. Accuracy of the clinical diagnosis of vaginitis compared with a DNA probe laboratory standard.

Obstet Gynecol. 2009;113(1):89–95.

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SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

A Guide to the Management of Vaginal Discharge In most cases, syndromic management is appropriate – where clinicians follow clinical symptoms and signs to prescribe appropriate therapy while waiting for definitive diagnosis through microscopy

14 | www.primarycarereports.co.uk

A

lthough vaginitis was once thought to be of only minimal concern, there is increasing evidence that this is not necessarily the case. Infection with either bacterial vaginosis (BV) or trichomoniasis (TV) can, for example, increase the risk of acquiring STI’s such as genital herpes and HIV1,2, which aside from having their own unique challenges, can lead to PID and even infertility3,4. There is also an association between BV and spontaneous miscarriage5,6, preterm labor7,8, post abortion endometritis 9, and post hysterectomy cuff infection10,11. Added to this, the significant discomfort that can be caused by vulvovaginal candidiasis (VVC) infections, it is apparent that there is a need to manage these conditions definitively.

In most cases, syndromic management is appropriate – where clinicians follow clinical symptoms and signs to prescribe appropriate therapy while waiting for definitive diagnosis through microscopy12.

This article will outline this syndromic management, falling short of the management options available in recurrent or hard to treat infections, as well as those in special circumstance such as pregnancy. These additional areas will be discussed in the final article in this report. Figure one, on pages 13 and 14 of the report by the royal

college of general practitioners (RCGP) on sexually transmitted infections (STIs) 2006, provides an excellent diagrammatic overview of the syndromic management of vaginal discharge, and I strongly recommend that you refer to this when unclear13. Most of the guidance in this article is based on the 2011 European guidelines on the management of vaginal discharge14, with input from the 2006 RCGP13 and CDC15 guidelines where appropriate.

Management Pointers The proper management of a patient with vaginal discharge involves an empathic approach, that provides clear information and explanations, and that offers disease-specific advice12,14,15. It is important with TV for example, to counsel that this is a sexually transmitted infection (STI) and as such, screening for coexisting infection and partner notification need to take place. Also, that a positive test for TV requires treatment of both the woman and her partners, regardless of symptoms. In BV, positive testing in pregnant women (particularly when there has been prematurity or second trimester loss in the past), and in those undergoing specific gynaecological surgical procedures, raises important management concerns. In both VVC and BV, neither asymptomatic women nor their partners, require treatment.

SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

Figure 3a: Management of BV General advice • Patients should be advised to avoid vaginal douching, use of shower gel, and use of antiseptic agents or shampoo in the bath (grade of recommendation C).

Treatment •

Treatment is indicated for:

o Symptomatic women

o Women undergoing some surgical procedures

o Women who do not volunteer symptoms may elect to take treatment if offered. They may report a beneficial change in their discharge following treatment.

•

Recommended regimens

o Metronidazole 400mg twice daily for 5-7 days

o Metronidazole 2 g single dose

o Intravaginal metronidazole gel (0.75%) once daily for 5 days

o Intravaginal clindamycin cream (2%) once daily for 7 days.

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Figure 3b: Management of TV General advice • Sexual partner(s) should be treated simultaneously.

• Patients should be advised to avoid sexual intercourse (including oral sex) until they and their partner(s) have completed treatment and follow-up.

• Patients should be given a detailed explanation of their condition with particular emphasis on the longterm implications for the health of themselves and their partner(s). This should be reinforced by giving them clear and accurate written information.

Further Investigations • Screening for coexistent sexually transmitted infections should be undertaken in both men and women.

Treatment • Recommended regimes • Metronidazole 2g orally in a single dose or • Metronidazole 400 – 500mg twice daily for 5 - 7 days

Recommended Regimes for BV and TV The nitroimidazoles are the only drug class that are consistently effective against most strains of TV, and BV pathogens16,17. Systemic therapy is preferred in TV due to the fact that the protozoon often infects the urethra and paraurethral glands, making topical treatment often ineffective18. Metronidazole 400 - 500 mg given orally, twice daily for five to seven days is suitable for either TV or BV18,19, although a single oral dose of metronidazole 2g (or Tinidazole 2g) has been reported to have cost and compliance advantages20. Unfortunately, single dose treatments often have higher failure rates, especially if partners are not treated concurrently. Finally, metronidazole is associated with a metallic taste in the mouth, gastrointestinal disturbance, and a disulfiram reaction

with alcohol. Patients should be advised to avoid alcohol during and for up to 48 hours after treatment.

For BV, topical treatment is an additional option for monotherapy, and clindamycin has equal efficacy to metronidazole19. Therefore, in addition to the above options, intra-vaginal preparations are available (metronidazole gel (0.75%) once daily for five days; clindamycin cream (2%) once daily for seven days), as is oral clindamycin (300 mg orally twice daily for seven days). Figures 3a and 3b summarise the management of TV and BV according to UK guidance19,21.

Recommended Regimens for VVC Much of the rational for treating VVC have been covered elsewhere in this report. However, it

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SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

Women with vulvitis caused by VVC may

Figure 3c: Management of VVC General advice • Routinely recommend the use of vulval moisturisers as a soap substitute (not internal).

• Avoid tight fitting synthetic clothing

respond best to

• Avoid local irritants e.g. perfumed products, Treatment

intravaginal and topical vulval therapy. In cases of BV and TV, a course

• All topical and oral azole therapies give high rates of clinical and mycological cure in uncomplicated acute vulvovaginal candidiasis, • ,Choice is a matter of personal preference, availability and affordability.

• There is no evidence to support the treatment of asymptomatic male sexual partners in either episodic or recurrent vulvovaginal candidiasis.

o Topical Therapies

• Clotrimazole Pessary 500mg stat • Clotrimazole Pessary 200mg x 3 nights

of oral metronidazole is usually sufficient to

• Clotrimazole Pessary 100mg x 6 nights • Clotrimazole Vaginal cream (10%) 5g stat

o Oral Therapies (Avoid in pregnancy/risk of pregnancy and breastfeeding)

• Fluconazole (oral capsule) 150mg stat • Itraconazole (oral capsule) 200mg bd x 1 day

effect cure is important to recap that intravaginal and oral therapy with azoles provide equally effective treatment21. Treatment with azoles relives not only the symptoms but also results in negative cultures in approximately 90% of patients, and a single treatment course can be effective for up to six months after the initial treatment is completed, whether administered orally or topically22,23. Additionally, single dose treatments are as effective as longer courses. Clotrimazole offers a well-established therapeutic option.

However, some creams and suppositories can be oil-based and might weaken latex condoms and diaphragms. Figure 3c summarises the treatment options available for uncomplicated VVC.

Self-Treatment Over-the-counter (OTC) drugs are now available direct to the patient for the treatment of vulvovaginitis. Unfortunately, problems with self-diagnosis frequently result in incomplete or inadequate, at either the first or subsequent bouts of vulvovaginitis24. This can complicate the clinical picture. It is important to note that unnecessary or inappropriate use of OTC preparations is common, and can lead to

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a delay in the treatment of the true diagnosis, which can result in adverse clinical outcomes15.

However, empowering women to correctly identify and treat their symptoms with the proper medications will alleviate their discomfort and prevent both those outcomes, and unnecessary visits to the doctor25. This is particularly true of the treatment of VVC, which bears little risk of serious sequelae, or risk to partners (who themselves can self-treat).

Summary Women with vulvitis caused by VVC may respond best to intravaginal and topical vulval therapy. In cases of BV and TV, a course of oral metronidazole is usually sufficient to effect cure.

It is essential to bear in mind when managing women with vaginal discharge that many women self-diagnose and self-treat episodes of vaginal infection with over the counter treatments, and may subsequently present with a history of “recurrent thrush” having never had a formal diagnosis confirmed by microbiology. When unsure, the diagnosis should be confirmed by microbiology, and a full sexual health screen should be completed to exclude concurrent infection.

SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

References: 1

S chwebke JR. Abnormal vaginal flora as a biological risk factor for acquisition of HIV infection and sexually transmitted diseases.

J Infect Dis 2005; 192(8):1315-1317.

2

Atashili J, et al. Bacterial vaginosis and HIV acquisition: a metaanalysis of published studies. AIDS 2008; 22(12):1493-1501.

3

Sobel JD. Vaginitis. The New England Journal of Medicine. 1997;337(26):1896–1903.

Spence D. Candidiasis (vulvovaginal) Clinical Evidence. 2005;(14):2200–2215.

4

Oakeshott P, et al. Association between bacterial vaginosis or chlamydial infection and miscarriage before 16 weeks’ gestation:

5

prospective community based cohort study. BMJ 2002; 325(7376):1334.

Ralph SG, Rutherford AJ, Wilson JD. Influence of bacterial vaginosis on conception and miscarriage in the first trimester:

6

cohort study. BMJ 1999; 319(7204):220-223.

Donders G, et al. Predictive value for preterm birth of abnormal vaginal flora, bacterial vaginosis and aerobic vaginitis during the first trimester of

7

pregnancy. BJOG 2009.

8

Thorp JM, Jr.,et al. Alteration in vaginal microflora, douching prior to pregnancy, and preterm birth. Paediatr Perinat Epidemiol 2008; 22(6):530-537.

9

haronis G, Larsson PG. Use of pH/whiff test or QuickVue Advanced pH and Amines test for the diagnosis of bacterial vaginosis and prevention of postabortion pelvic inflammatory disease. Acta Obstet Gynecol Scand 2006; 85(7):837-843.

10

Persson E, Bergstrom M, Larsson PG, Moberg P, Platz-Christensen JJ, Schedvins K et al. Infections after hysterectomy. A prospective nation-wide Swedish study. The Study Group on Infectious Diseases in Obstetrics and Gynecology within the Swedish Society of Obstetrics and Gynecology.

Acta Obstet Gynecol Scand 1996; 75(8):757-761.

11

Liang BA. Diagnosis and treatment of infectious vaginitis. Hospital Physician. 1999;35(10):46–58.

12

Helen Mitchell. ABC of sexually transmitted infections. Vaginal discharge – causes, diagnosis, and treatment.

BMJ. 2004 May 29; 328(7451): 1306–1308.

13

Neil Lazaro. Sexually Transmitted Infections in Primary Care. RCGP (Royal College of General Practitioners) Sex, Drugs and HIV Task Group.

British Association for Sexual Health and HIV. 1st Edition March 2006. Available at www.rcgp.org.uk and the BAASH website.

14

Sherrard, J. Donders, G. et al. 2011 European (IUSTI/WHO) Guideline on the Management of Vaginal Discharge. The international uniona against sexually transmitted infection & the world health organization.

15

Centers for Disease Control and Prevention (CDC). 2006 Sexually Transmitted Diseases Guidelines: Diseases Characterized by Vaginal Discharge.

2006. Accessed online: http://www.cdc.gov/std/treatment/2006/vaginal-discharge.htm

16

Hanson JM, et al. Metronidazole for bacterial vaginosis. A comparison of vaginal gel vs. oral therapy. J Reprod Med 2000; 45(11):889-896.

17

Oduyebo OO, Anorlu RI, Ogunsola FT. The effects of antimicrobial therapy on bacterial vaginosis in nonpregnant women. Cochrane Database Syst Rev 2009;(3):CD006055.

18

Sherrard, J. United Kingdom National Guideline on the Management of Trichomonas vaginalis (2007). Clinical Effectiveness Group, British Association of Sexual Health and HIV. Available at http://www.bashh.org/guidelines

19

Phillip et al. UK National Guideline for the management of Bacterial Vaginosis 2012. Clinical Effectiveness Group. British Association for Sexual Health and HIV. Available at http://www.bashh.org/guidelines

20

Forna F, Gulmezoglu AM. Interventions for treating trichomoniasis in women. Cochrane Database Syst Rev 2003;2:CD000218.

21

Watson MC, et al. Oral versus intra-vaginal imidazole and triazole anti-fungal agents for the treatment of uncomplicated vulvovaginal candidiasis (thrush): a systematic review. BJOG: an International Journal of Obstetrics & Gynaecology 2002; 109(1):85-95.

22

White, D. Robertson, C. Guideline on the Management of Vulvovaginal Candidiasis (2007). Clinical Effectiveness Group. British Association of Sexual Health and HIV. Available at http://www.bashh.org/guidelines

23

Sobel J, et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. The New England journal of medicine 2004; 351(9):876-883.

24

Ferris DG, Nyirjesy P, Sobel JD, Soper DE, Pavletic A, Litaker MS. Over-the-counter antifungal drug misuse associated with patient-diagnosed vulvovaginal candidiasis. Obstetrics and Gynecology. 2002;99(3):419–425.

25

Lauren B. Angotti, Lara C. Lambert, and David E. Soper. Vaginitis: Making Sense of Over-the-Counter Treatment Options. Infect Dis Obstet Gynecol.

2007; 2007: 97424.

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SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

Managing Recurrent Infection, Hard to Treat Infection, and Infection in Special Circumstances

Recurrent BV is common, and the diagnosis should be confirmed, predisposing factors excluded, and empirical treatment commenced

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W

e have looked at the diagnosis and management of Trichomonas (TV), bacterial vaginosis (BV) and vuvlovaginal candidiasis (VVC) in routine cases thus far in this report. However, there are circumstances in which the routine rules do not apply, or in which alternative treatment regimens need to be considered. These include cases of recurrent or hard to treat infection, as well as infection in special circumstances. All UK and international guidelines provide recommendations for the management of TV, BV and VVC in these situations, and this article summarises some of the key aspects of those guidelines. However, consideration of specific cases of immunocompromised hosts, or the management of allergy and intolerance is considered beyond the scope of this report. In the majority of these cases, extending antimicrobial therapy over 7-14 days usually suffices for the management of immunocompromised hosts, and suspected allergy or sensitivity to the prescribed therapy would necessitate an alternative approach1,2,3.

2. Probiotic therapy applied daily on alternate weeks (i.e. seven days on, seven days off)6.

3. Antibiotics and probiotic therapy: clindamycin cream plus human lactobacilli has been shown to increase response rates by up to one-third7.

Recurrent and Hard to Treat Infections

Trichomonas Vaginalis Recurrent, if not all, cases of TV should be referred to a genitourinary medicine (GUM) clinic4. However, the primary care physician should at least have a basic awareness of the management options. Treatment failure is anecdotally due to: compliance or tolerance issues with metronidazole; reinfection from a partner; or, reinfection from another source3. In the vast majority of cases, a patient who has failed to respond to standard treatment will respond to a repeat of that course8, and in very rare cases only, higher doses of metronidazole will be necessary8. It has been reported3 that commensal organisms in the vagina prevent the full efficacy of metronidazole.

Therefore, broad spectrum antibiotics may have a role, as may clotrimazole which has Trichomonas and gram positive activity9,10. Finally, high doses of oral tinidazole (e.g., 2g twice daily for 2 weeks), with or without intravaginal tinidazole, has good cure rates11.

Bacterial Vaginosis Recurrent BV is common, and the diagnosis should be confirmed, predisposing factors excluded, and empirical treatment commenced4.

Several options remain available for women with recurrent BV: 1. Suppressive 0.75% metronidazole vaginal gel twice weekly. A placebo controlled trial using this regime for sixteen weeks has been demonstrated to be superior to placebo, with almost double the rate of resolution during therapy5. However, this improvement did not continue after stopping therapy, and the regime appeared to promote candidal infection5.

Candidiasis Recurrent VVC is defined as four or more episodes of symptomatic VVC in one year, and affects only a small percentage of women (<5%)4,12. Therefore, if symptoms persist, alternative diagnoses and predisposing factors should be considered. For example, recurrent vulval irritation that is often attributed to candida, is frequently due to a mild sub-clinical dermatitis that sometimes develops after candidal infection.

In addition, changes in the vulvovaginal flora may lead to mixed infections with aerobic bacteria.

Vulval dermatitis usually responds to a combined anti-fungal and mild steroid cream13.

SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

Primary Care Reports

Severe vulvovaginitis with extensive vulvar erythema, oedema, and excoriation, is associated with lower clinical response rates with standard therapy. First line therapy would be to repeat the dose of fluconazole 150mg after three days, which is proven to improve symptomatic response14. The same applies to the use of topical therapy, such as intravaginal clotrimazole pessaries (i.e. 500mg, repeated after one week) 9.

Typical regimes for recurrent VVC include2: 1. O ral Fluconazole: Induction with three doses of 150mg every 72 hours, followed by 150mg maintenance fluconazole once a week for 6 months. (Avoid in pregnancy/ risk of pregnancy and breastfeeding). Approximately 90% of women will remain disease-free at 6 months and 40% at 1 year.

2. T opical clotrimazole: For maintenance, a 500-mg dose vaginal suppository used once weekly, (or other topical treatments). These are also safe in pregnancy. In severe infections, the duration of topical therapy with standard topical creams can be increased to 10-14 days.

C. glabrata and other non-albicans Candida species are observed in 10%–20% of patients with recurrent VVC, and are typically hard to treat. Here, conventional antimycotics are less effective and options include longer duration of therapy (7–14 days) and/or a nonfluconazole azole drug (either oral or topical) and/or 600 mg of vaginally administered boric acid once daily for 2 weeks15. The latter regime has eradication rates of approximately 70%.

Amphotericin B vaginal suppositories 50mg once a day for 14 days has a 70% success rate too16.

Special Circumstances BV & TV: BV has been associated with adverse pregnancy outcomes including infection (chorioamnionitis

postpartum endometritis, and post-cesarean wound infection) and preterm labor17,18. Screening and treatment with oral therapy may therefore be appropriate in BV, especially in cases of asymptomatic pregnant women that are at an increased risk due to previous premature births or miscarriage12,19. Additionally, TV has been associated with adverse pregnancy outcomes, including prematurity, and low birth weight, and treatment may be necessary12.

Treatment of both BV and TV is typically with Metronidazole, which is a pregnancy category B drug with no recognised or proven mutagenic effects. Metronidazole can be used cautiously in all stages of pregnancy and breast-feeding, although most guidance recommend that high dose regimens are best avoided as the risk at these levels is unknown1,3,17,18. Standard oral dosing regimens can be used for both TV and BV1,3. However, none of the regimens have been proven to be effective in reducing preterm birth in any group of women12. In lactating women who are administered metronidazole, withholding breastfeeding during treatment, and for 12–24 hours after the last dose, will reduce the exposure of metronidazole to the infant. Choosing to treat pregnant women for TV and BV infection remains controversial and they are best managed by the obstetric team.

VVC: In pregnancy, asymptomatic colonization with Candida species is more common (30-40%)20 as is symptomatic candidiasis. Crucially, it is not associated with low birth weight or premature delivery.21 Topical imidazoles can be used safely since oral therapy is contraindicated , and there is no evidence to suggest that asymptomatic women need to be treated23. When treated, it is best to prescribe a slightly longer course of around four days23. Amphotericin and Nystatin pessaries can be considered but limited availability often prohibit their use16.

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SPECIAL REPORT: TREATING CANDIDAL VAGINITIS AND MIXED VAGINAL INFECTIONS IN PRIMARY CARE

References: 1

P hillip et al. UK National Guideline for the management of Bacterial Vaginosis 2012. Clinical Effectiveness Group.

British Association for Sexual Health and HIV. Available at http://www.bashh.org/guidelines White, D. Robertson, C. Guideline on the Management of Vulvovaginal Candidiasis (2007). Clinical Effectiveness Group.

2

British Association of Sexual Health and HIV. Available at http://www.bashh.org/guidelines 3

Sherrard, J. United Kingdom National Guideline on the Management of Trichomonas vaginalis (2007). Clinical Effectiveness Group, British Association of Sexual Health and HIV. Available at http://www.bashh.org/guidelines Helen Mitchell. ABC of sexually transmitted infections. Vaginal discharge—causes, diagnosis, and treatment. BMJ. 2004 May 29; 328(7451):

4

1306–1308.

Sobel JD, et al. Suppressive antibacterial therapy with 0.75% metronidazole vaginal gel to prevent recurrent bacterial vaginosis.

5

Am J Obstet Gynecol 2006 May;194(5):1283-9.

Ya W, Reifer C, Miller LE. Efficacy of vaginal probiotic capsules for recurrent bacterial vaginosis: a double-blind, randomized, placebo controlled

6

study. Am J Obstet Gynecol 2010 August;203(2):120-6.

Eriksson K, et al A double-blind treatment study of bacterial vaginosis with normal vaginal lactobacilli after an open treatment with vaginal

7

clindamycin ovules. Acta Derm Venereol 2005;85:42-6.

Das S, Huegnsberg M, Shahmanesh M. Treatment failure of vaginal trichomoniasis in clinical practice. Intl J STD & AIDS 2005;16:284-286

8

9

Medicines and Healthcare products Regulatory Agency (MHRA).

Accessed at: http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con134819.pdf

10

Stover KR, et al. What would we do without metronidazole? Am J Med Sci. 2012 Apr;343(4):316-9.

11

Mannen-Tobin A, Wilson JD. Management of metronidazole-resistant Trichomonas vaginalis – a new approach. Intl J STD & AIDS 2005;16:488490

12

Centers for Disease Control and Prevention (CDC). 2006 Sexually Transmitted Diseases Guidelines: Diseases Characterized by Vaginal Discharge.

2006. Accessed online: http://www.cdc.gov/std/treatment/2006/vaginal-discharge.htm

13

Sobel JD, et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. American Journal of Obstetrics & Gynecology 1998; 178(2):203-211.

14

Sobel JD, et al. Treatment of complicated Candida vaginitis: comparison of single and sequential doses of fluconazole. American Journal of Obstetrics & Gynecology 2001; 185(2):363-369.

15

Sobel JD, et al. Treatment of vaginitis caused by Candida glabrata: use of topical boric acid and flucytosine. Am J Obstet Gynecol 2003;

189:1297–300.

16

Phillips A. Treatment of non-albicans Candida vaginitis with amphotericin B vaginal suppositories. American journal of obstetrics and gynecology 2005; 192(6):2009-2012.

17

Sherrard J, et al. 2011 European (IUSTI/WHO) Guideline on the Management of Vaginal Discharge.2011

18

Neil Lazaro. Sexually Transmitted Infections in Primary Care. RCGP (Royal College of General Practitioners) Sex, Drugs and HIV Task Group.

British Association for Sexual Health and HIV. 1st Edition March 2006. Available at www.rcgp.org.uk and the BAASH website.

19

20

Carey JC, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis.

N Engl J Med 2000;342:534–40.

Bauters T, et al. Prevalence of vulvovaginal candidiasis and susceptibility to fluconazole in women. American journal of obstetrics and gynecology 2002; 187(3):569-574.

21

Cotch MF, et al. Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. Vaginal Infections and Prematurity Study Group. American Journal of Obstetrics & Gynecology 1998; 178(2):374-380.

22

The British National Formulary 2013. BNF March 2013 > 5 Infections > 5.2 Antifungal drugs > 5.2.1 Triazole antifungals > Additional information > Pregnancy. Accessed online via http://www.bnf.org Search result: http://www.medicinescomplete.com/mc/bnf/current/PHP3699-fluconazole.htm?q=pregnancy%20fluconazole&t=search&ss=text&p=3#_hit

23

Young GL, Jewell D. Topical treatment for vaginal candidiasis (thrush) in pregnancy. Cochrane Database of Systematic Reviews 2001;(4):CD000225.

20 | www.primarycarereports.co.uk

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