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Candida Glabrata and Boric Acid

Candida Glabrata and Boric Acid

Vulvovaginal & Boric Treatments Author: Rebecca O’Grady BPharm, GradCertPharmPrac, MPS

AFTER COMPLETING THIS Vulvovaginal candida (VVC) infections are common in women, with ACTIVITY, PHARMACISTS the most common responsible. This article SHOULD BE ABLE TO: discusses treatment approaches to vaginal thrush, with special 1. List the different emphasis on treatment of the most common atypical candida species that commonly isolated in VVC, Candida glabrata. cause vulvovaginal patients with Candida glabrata Introduction the most common atypical 2. List the treatment options Vulvovaginal candida (VVC) species.3 There are a variety of for vulvovaginal candidiasis infections are a common health medical conditions, 3. Describe methods used problem for women, which cause and lifestyle factors which have in the preparation of significant morbidity, with over been shown to increase the risk compounded boric acid 75% of women affected at least 1,2 of developing a VVC .8,16 treatments once throughout their lifetime. Approximately 40-50% of women These include:8,16 will experience a second VVC • Diabetes 6 • Immunosuppressant The 2016 Standards addressed infection. These infections can medications by this activity include: 1.4, 1.5, affect both the physical and 2 • Pregnancy 2.1, 2.2, 2.3, 3.1, 3.3, 3.4. emotional health of women. In Western countries studies • Broad spectrum use have shown that candida and • Skin conditions including bacteria are the most common vulval psoriasis causes of vaginal infections.5,6 • Tight synthetic clothing First published in the Australian Candida are a family of Journal of Pharmacy online which inhabit the human VVC infections are most version. 1st February 2019. gastrointestinal and genital tract.7 commonly diagnosed through Reproduced and distributed VVC infections occur when there symptoms however a swab by the Medisca Group of is an overgrowth of candida should be taken to determine the companies with the permission within the vulvovaginal area.3 species of candida.3 Symptoms of of the publisher. Candida albicans is the most VVC infections include:8 common species responsible for VVC infections.1,2,3 However, Common symptoms atypical candida species are • Itch (the most common) isolated in approximately 5% of • Discharge that is often thick, white, and odourless (similar Complicated infections classified if complication is suspected. to cottage cheese), however as those which are infected Women with recurrent thrush can be watery or smooth. with other Candida species, must be referred to a doctor. The amount of discharge present with severe symptoms, This is of particular importance is variable and may be recurrent episodes (≥ 4 per 12 as C. glabrata seems to develop negligible. months), and in patients with co- resistance to many classes, Less common symptoms conditions including pregnancy, including the azole antifungals, • Soreness uncontrolled diabetes, and although the mechanism of why • Swelling and redness immunosuppression.8 resistance develops is not well • Burning understood22. This means that • Vulvar dysuria Misdiagnosis is a common treatment with over the counter • Dyspareunia (painful sexual occurrence when patients present (OTC) antifungals is unlikely to intercourse) with vaginal symptoms.8 As per treat a VVC infection caused by C. the Therapeutic Guidelines, a glabrata, and patients presenting VVC infections are classified as swab should be taken before with recurrent infections could uncomplicated or complicated.8 starting any treatment, to isolate potentially have an infection Uncomplicated infections and determine the Candida caused by C. glabrata which they are more than likely due to species responsible for the are ineffectively treating with OTC C. albicans, they present VVC infection, and confirm antifungals. sporadically with infrequent the diagnosis.3 Pharmacists episodes (≤3 per 12 months), with should encourage patients Treatments are available over mild-to moderate symptoms.8 to consult with their doctor the counter (OTC) as Pharmacist

Diagram 1. Treatment approach for vaginal thrush: A summary8 ©Pharmaceutical Society of Australia. Reproduced with permission 2018 Only (Schedule 3) medications.1 treatment for vaginal thrush.8 This treatment options as outlined in Scheduling these medications flow chart also outlines when the the Therapeutic Guidelines and as OTC, allows ease of access patient should be referred to their the APF 24. to treatment by patients and GP for diagnosis and treatment increases autonomy for self- (Diagram 1.).8 The efficacy of the commercially diagnosis. However, there available treatment options for is the risk of misdiagnosis Due to this ease of access to the treatment of C. albicans with consequential incorrect treatment, exact infection is supported by considerable treatment choice.1 Studies have rate numbers are difficult to evidence. In contrast, there shown that isolation swabs taken determine, as there is a lack of is a lack of studies available after a patient has used antifungal recording and reporting of the comparing the different treatment commonly report false condition.1,3 treatment options, and treatment negatives whilst the patient is still duration for treating vulvovaginal presenting with symptoms.3 Treatment options candida infections in general.3 There is a large variety of both The Australian Pharmaceutical topical and oral treatment If a patients sexual partner Formulary and Handbook (APF options available in Australia for is presenting with symptoms 24) lists a stepwise treatment the treatment of VVC infections.3, they need to be referred for approach for pharmacists to 8 confirmation of infection before follow when recommending Table 1 is a combination of the treatment is started.8 Candida

Table 1: Treatment options for Vaginal Thrush3,8

ACTIVE DOSAGE STRENGTH/ DURATION FREQUENCY ADVERSE PREGNANCY TREATMENT INGREDIENT FORM CONCENTRATION OF OF DOSE EFFECTS AND LINE TREATMENT BREASTFEEDING

Clotrimazole Vaginal 1% 6 nights One applicator full daily at bedtime Clotrimazole Vaginal cream 2% 3 nights One applicator full daily at bedtime

Clotrimazole Vaginal cream 10% 1 night One applicator full daily at Burning, Pregnancy bedtime stinging, Category A First line itching, Safe to use in treatment Clotrimazole Vaginal 100mg 6 nights One erythema breastfeeding suppository/ daily at pessary bedtime

Clotrimazole Vaginal 500mg 1 night One pessary suppository/ daily at pessary bedtime

Miconazole Vaginal cream 2% 7 nights One applicator full daily at bedtime

Nystatin Vaginal cream 100 000 units/5g 14 nights One applicator Well Pregnancy Second line full daily at tolerated Category A treatment. bedtime Safe to use in Less effective breastfeeding than the azoles Oral 150mg 1 day Single oral dose Nausea, Pregnancy Use if topical vomiting, category D therapy is not diarrhoea, Considered safe tolerated or headache, in breastfeeding woman prefers dizziness, oral treatment dyspepsia pathogenic species include bedtime for 7-14 days.3,4,6 The candidiasis caused by Candida C. albicans, C. dubliniensis, C. most common treatment plan glabrata and other non-albicans tropicalis, C. parapsilosis, C. being 600 mg once daily at species orthopsilosis, C. metapsilosis, bedtime for 14 days.3,4,6 Reported C. famata, C. lusitaniae, C. effectiveness of intravaginal boric Size #0 capsules have a volume guilliermondii, C. krusei, C. acid treatment for VVC infections of 0.68 mL and size #00 capsules glabrata, C. kefyr, C. norvegensis, varies between 70-98%.4,6,11,16 have a volume of 0.91 mL. C. inconspicua and C. lipolytica.18 Reported side effects include Pharmacists will need to carry out However only 5 of these species, erythema, burning sensation packing statistic calculations to C. albicans, C. glabrata, C. and watery discharge, however determine the most appropriate tropicalis, C. parapsilosis, and C. those reported are mild and size capsule for their preparation. krusei, are responsible for over infrequent. Intravaginal boric acid These calculations will need 90% of candida infections.18 is mostly well tolerated.4,6 There to be repeated each time a is a lack of safety data for the use new lot of boric acid is Candida glabrata of boric acid vaginal treatment sourced by the pharmacy. If after Candida glabrata, previously in pregnant women, therefore it determining these calculations, named Torulopsis glabrata, is an should be avoided where possible part of the capsule volume atypical form of candida causing in pregnancy.3 remains empty, an excipient filler VVC infections. When C. glabrata is required to bring the fill up to is isolated, intravaginal boric A number of studies have shown 100%. is an appropriate acid treatment is the effective effectiveness in the use of 600 filler to choose when preparing treatment of choice.3,4,6 Boric mg once daily at bedtime for vaginal capsule preparations.19 acid has bacteriostatic and 5 nights, whilst the woman is Capsules can be filled by hand or fungistatic properties, rather than menstruating, as a preventative by using a capsule filling machine. fungicidal properties, although measure for women with Clear capsule shells composed of the exact mechanism of action is recurrent infections.6,13,14 This either gelatin or cellulose should unknown.4,10 Vaginal acidification treatment is repeated every be chosen to compound the causing cell membrane month for 4-6 months.6,13,14 boric acid into. This is to avoid dysfunction is one theory the risk of staining of the skin proposed for the fungistatic Intravaginal boric acid treatment and clothing with the dye found properties.4,17 Boric acid is an can be compounded as either in coloured capsules. Patients inorganic acid with synonyms of a vaginal capsule or a vaginal should be counselled to wear a boracic acid and orthoboric acid.4 suppository, also known as a liner throughout treatment as Boric acid should not be orally pessary.3,4 Boric acid is listed as leakage of the preparation can ingested and there is the risk of a hazardous substance.12 When occur. potential toxicity if systemically preparing such medications, the The APF 24 allows a 6 month absorbed.9,10 pharmacist needs to ensure they expiry date to be placed upon are following correct handling powder filled capsules as long as There are currently no procedures of hazardous all components have 6 months commercial products available substances as listed in APF 24.8 or longer expiry remaining and on the market for intravaginal no component is hygroscopic boric acid treatment.15 When The following formulations can or light sensitive.8 However, presented with a prescription for be employed when compounding there is no guidance given to boric acid , a pharmacist either boric acid vaginal capsules determine the expiry date to trained in complex compounding or suppositories. be placed on capsules which may prepare this do contain hygroscopic or light extemporaneously.3 Boric Formulations sensitive components.8 Boric acid vaginal preparations are APF formula for boric acid acid is a hygroscopic active commonly prepared compounds vaginal capsule8 pharmaceutical ingredient (API).20 in Australian pharmacies. The Boric acid …………….. 600 mg Boric acid vaginal capsules need boric acid treatment protocol Method: Prepare capsules using to be stored below 25 degrees for C. glabrata is 600 mg – 1200 #0 or #00 gelatin capsules Celsius.8 mg intravaginally once daily at Use: Treatment of vaginal Formula for boric acid vaginal accurate method although can be assigned to the vaginal suppository11 very time consuming, suppositories, unless a stability Boric acid ………… 0.600 g 2. QS to volume method which studied formula with a longer Silica ………….. 0.025 g is not as accurate but also not expiry date is followed exactly.8 Fatty acid base …….. QS to volume as time consuming Suppositories need to be stored 3. Average displacement, between 2-8 degrees Celsius Boric acid vaginal suppositories normally 0.7, which is the unless otherwise specified by the are prepared by melting down the least accurate and also the formulation followed.8 fatty acid base. Pharmacists will least time consuming method. As with the boric acid vaginal need to undertake displacement capsules, patients should be factor calculations to determine To compound, the suppository counselled to wear a liner whilst the amount of fatty acid base base will be melted in a beaker using this treatment, as there that will be required to prepare at an appropriate temperature is the risk of leakage of the the suppositories. The boric acid for the base chosen. Once this preparation from the vagina. and silica gel are homogenously base has completely melted the A vaginal applicator should be mixed into the molten base. Silica boric acid and silica gel will be provided to the patient for ease gel acts as a suspending agent homogenously incorporated. of administration. for the boric acid powder to This preparation is to be poured achieve a homogenous blended into the suppository mold at Capsule or Suppository? mixture which is then poured congealing temperature. The The choice between the into suppository shells or molds. compounder needs to ensure use of a vaginal capsule or When choosing an appropriate they wait until this point to pour suppository is doctor and patient mold size to compound the preparation. If poured too preference. Vaginal capsules and suppositories pharmacists should early, despite the suspending suppositories both have their follow a number of rules. The agent (silica gel), there is the pros and cons. age of the patient needs to be risk that the API will sediment to considered with smaller mold the bottom of the mold and the Capsules have a smaller volume sizes, 1.3 mL and 1.7 mL, for suppository form incorrectly. The than the vaginal suppositories peadiatric patients. The API preparation is allowed to cool and there is the preference to should not compromise more and set before dispensing to the insert a smaller preparation. than approximately 30% of patient. However, vaginal capsules pose the suppository mold fill. To The suppositories will need to be a risk of being confused with determine this, the pharmacist left to cool at room temperature oral capsules and there is the will need to undertake a number before placing in the refrigerator. potential that the patient may of calculations. The of If the molds are placed straight swallow the capsule by mistake. the chosen suppository base into the refrigerator after pouring, Patients may be hesitant to use a will be used to undertake these there is the risk of shock cooling capsule vaginally due to patient calculations. The weight of and the suppository crumbling. expectations that a capsule can the base used to 100% fill the There are two different mold only be taken orally. As a part suppository mold will need to be types to choose from, disposable of the counselling process, the determined. This weight can then and reusable. With the disposable pharmacist must discuss the risk determine the percentage fill of molds, after the suppository has of accidental oral consumption the API. set, the compounder will need to and subsequent risk of toxicity/ Commonly used suppository sizes seal the mold and dispense to the poisoning.16 When dispensing include 2 mL and 2.4 mL. When patient. For the reusable molds, these preparations, pharmacists incorporating into a the compounder will need to should include the “Caution: Not suppository base a compounder demold the suppository and wrap to be taken” and “For Vaginal Use cannot assume a 1 to 1 in foil, which is a time consuming Only” labels. Vaginal capsules displacement of powder to base. process. Both mold choices are reliant on moisture in the There are three methods that can require that the patient be area to dissolve the capsule shell. be utilized:21 counselled to remove the foil or This poses issues if the patient 1. Conducting a double cast plastic shell before inserting. As experiences vaginal dryness. process. This is the most per APF 24, a 28 day expiry date Capsules will need to be stored in a cool dry place below 25 3. eTG complete [Internet]. Melbourne: 15. Search the TGA website [Internet]. degrees Celsius. Therapeutic Guidelines Limited; 2018 Jul. Therapeutic Goods Administration Accessed 2018 Oct 04 < https://tgldcdp- (TGA). 2018 [cited 25 October 2018]. tg-org-au.wwwproxy1.library.unsw.edu. Available from: https://tga-search. Boric acid vaginal suppositories au/viewTopic?topicfile=anogenital-skin- clients.funnelback.com/s/search.html?q take the compounder longer conditions&guidelineName=Dermatolog uery=boric+acid&collection=tga-artg to prepare than the vaginal y#toc_d1e247 >. 16. Vulvovaginal Candidiasis [Internet]. capsules, due to melting of 4. Prutting S, Cerveny J. Boric Acid Mshc.org.au. 2018 [cited 26 October the suppository base. As the Vaginal Suppositories: A Brief Review. 2018]. Available from: https://www. Infectious Diseases in Obstetrics and mshc.org.au/HealthProfessional/ fatty acid base is temperature Gynecology. 1998;6(4):191-194. MSHCTreatmentGuidelines/ sensitive, these preparations 5. Adolfsson A, Hagander A, VulvovaginalCandidiasis#.W9Jmr2gzbcs need to be stored in the Mahjoubipour F, Larsson P. How Vaginal 17. Shinohara Y, Tasker S. Successful Use refrigerator between 2-8 Infections Impact Women’s Everyday of Boric Acid to Control Azole-Refractory degrees Celsius in order to Life;—Women’s Lived Experiences Candida Vaginitis in a Woman With AIDS. of and Recurrent Journal of Acquired Immune Deficiency maintain their integrity. This is Vulvovaginal Candidiasis. Advances in Syndromes and Human Retrovirology. particularly pertinent during the Sexual Medicine. 2017;07(01):1-19. 1997;16(3):219-220. warmer months and warmer 6. Guaschino S, De Seta F, Sartore A, 18. Turner S, Butler G. The Candida parts of Australia. Patients can Ricci G, De Santo D, Piccoli M et al. Pathogenic Species Complex. Cold experience leakage of the fatty Efficacy of maintenance therapy with Spring Harbor Perspectives in Medicine. topical boric acid in comparison with 2014;4(9):a019778-a019778. acid suppository base. There is oral in the treatment of 19. Garg S, Tambwekar K, Vermani K, anecdotal evidence that women recurrent vulvovaginal candidiasis. Garg A, Kaul C, Zaneveld L. Compendium prefer to use the fatty acid based American Journal of Obstetrics and of Pharmaceutical Excipients for suppository preparation over the Gynecology. 2001;184(4):598-602. Vaginal Formulations. Pharmaceutical capsules, as they found them 7. Candida | DermNet New Zealand Technology . 2001;:14- [Internet]. Dermnetnz.org. 2018 [cited 24. easier to insert, soothing, and 16 October 2018]. Available from: 20. Fox S. Remington Education: moisturizing to the area. https://www.dermnetnz.org/topics/ Pharmaceutics. London: Pharmaceutical candida/ Press, UK distributor:Stationery Office; Conclusion 8. Sansom LN, ed. Australian 2014. pharmaceutical formulary and 21. The Science of Pharmaceutical Vaginal swabs, whilst might not handbook. 24th edition. Canberra: Compounding: Non-sterile Training. be considered practical, should Pharmaceutical Society of Australia, Sydney: Medisca Australia; 2018. be performed for all presenting 2018. cases of VVC infections in order 9. Moseman R. Chemical Disposition to isolate the causative species of in Animals and Humans. Environmental Health Perspectives. of candida. This will allow the 1994;102:113. most appropriate treatment for 10. De Seta F, Schmidt M, Vu B, Essmann the infection to be used as soon M, Larsen B. Antifungal mechanisms as possible. Pharmacists and supporting boric acid therapy of Candida physicians should be aware of vaginitis. Journal of Antimicrobial Chemotherapy. 2008;63(2):325-336. the treatment options available 11. Boric Acid 600-mg Vaginal to treat Candida infections, Suppository. International Journal including commercially available of Pharmaceutical Compounding. and compounded options. 2004;8(1):52. 12. [Internet]. Medisca.com.au. 2018 [cited 19 October 2018]. Available from: https://www.medisca.com.au/NDC_ References SPECS/MUS/0064/MSDS/0064.pdf 1. Pirotta M, Gunn J, Chondros P. “Not 13. Nyirjesy P, Seeney S, Terry Grody thrush again!” Women’s experience M, Jordan C, Buckley H. Chronic fungal of post-antibiotic vulvovaginitis. vaginitis: The value of cultures. American The Medical Journal of Australia. Journal of Obstetrics and Gynecology. 2003;179(1):43-46. 1995;173(3):820-823. 2. Pirotta M, Garland S. Genital Candida 14. Redondo-Lopez V, Lynch M, Species Detected in Samples from Schmitt C, Cook R, Sobel J. Torulopsis Women in Melbourne, Australia, before glabrata vaginitis: Clinical aspects and and after Treatment with . susceptibility to antifungal agents. Journal of Clinical Microbiology. International Journal of Gynecology & 2006;44(9):3213-3217. Obstetrics. 1991;35(3):286-286. CPD MULTIPLE CHOICE QUESTIONS

1. Which of the following is not a commercially available candida treatment?

A. Clotrimazole 2% vaginal cream B. Boric acid 600 mg vaginal suppository C. Clotrimazole 500 mg Vaginal suppository D. Fluconazole 150 mg oral capsule

2. Vulvovaginal candida infections are most commonly caused by which of the following candida species?

A. Candida tropicalis B. Candida glabrata C. Candida albicans D. Candida parapsilosis

3. Which of the following treatment regimens is most commonly used to treat Candida glabrata?

A. Intravaginal boric acid 600 mg once daily for 7 days B. Intravaginal boric acid 1200 mg once daily for 14 days C. Intravaginal boric acid 600 mg once nocte for 14 days D. Intravaginal boric acid 1200 mg twice daily for 7 days

4. The capsule shells used in the preparation of boric acid vaginal capsules should be:

A. Coloured gelatin capsules B. Clear gelatin capsules C. Clear vegetable capsules D. Coloured cellulose capsules

5. When compounding boric acid vaginal capsules, how often do packing statistics need to be repeated? A. Once only B. For every prescription C. Once a year D. With each new lot

6. Boric acid vaginal capsules can only be used to treat an existing infection. A. True B. False

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