Local Treatment of Vulvovaginal Candidosis

Drugs 2008; 68 (13): 1787-1802THERAPY IN PRACTICE 0012-6667/08/0013-1787/$53.45/0

© 2008 Adis Data Information BV. All rights reserved.

Local Treatment ofVulvovaginal CandidosisGeneral and Practical Considerations

Jose das Neves,1,2,3 Eugenia Pinto,1 Branca Teixeira,3 Gustavo Dias,3 Patrocinia Rocha,3Teresa Cunha,3 Barbara Santos,3 Maria H. Amaral2 and Maria F. Bahia2

1 Department of Microbiology, CEQUIMED, Faculty of Pharmacy, University of Porto,Porto, Portugal

2 Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto,Porto, Portugal

3 Department of Pharmacy, Hospital Geral de Santo Antonio, Porto, Portugal

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17871. Basic Concepts on Vulvovaginal Candidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1788

1.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17881.2 Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17891.3 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17891.4 Clinical Findings and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17901.5 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1791

2. Treatment of Vulvovaginal Candidosis: General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17922.1 Local versus Oral Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1792

3. Local Treatment of Vulvovaginal Candidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17933.1 General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17933.2 Antifungal Drugs for Local Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17953.3 Other Potential Local Therapeutic Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1795

4. Selection of Topical Antifungal Drug Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17964.1 General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17964.2 Conventional and Novel Antifungal Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17974.3 Potential and Investigational Antifungal Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17984.4 Safety Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1798

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1799

Vulvovaginal candidosis is a common worldwide female medical problem,Abstractoccurring mostly in women of childbearing age. Currently available options forthe treatment of this condition include local and oral (systemic) therapy. Bothalternatives have been considered equally effective in the treatment of uncompli-cated vulvovaginal candidosis, although oral regimens are often preferred byphysicians and women. However, local treatment presents several advantageousand unique features that may favour this therapeutic approach. The availability ofnumerous antifungal drugs and products for topical administration makes theselection quite challenging as this task is mostly based on personal experience or

1788 das Neves et al.

anecdotal data. Also, recent advances have been made in topical antifungalformulations and there is an increasing availability of over-the-counter products.Therefore, a review of both general and practical considerations related to thelocal treatment of vulvovaginal candidosis is timely.

In summary, azoles and short-term regimens are usually recommended for thelocal treatment of vulvovaginal candidosis, with nystatin and boric acid consid-ered as second-line alternatives. Unconventional approaches may also be regardedas suitable in patients refractory to usual treatments. In addition to the susceptibil-ity of implicated Candida spp. to the antifungal agents, this choice should takeinto consideration other important issues such as particular situations (e.g. preg-nancy, menopause, drug hypersensitivity), women’s preferences, and the availa-bility, particularities and cost of antifungal formulations.

Vulvovaginal candidosis is a mucocutaneous in- several over-the-counter (OTC) vaginal productsfection by yeasts of the genus Candida involving the and their wide use increases the responsibility ofvulva and vagina. It is a common worldwide prob- non-physician healthcare providers to adequatelylem, particularly in women of reproductive age.[1] respond to this situation. Therefore, it is important toVulvovaginal candidosis is also frequently referred review several general and practical considerationsto as vulvovaginal candidiasis, thrush and, rarely, related to the local treatment of vulvovaginal candi-moniliasis. However, recent standardization trends dosis in order to optimize its use in clinical practice.suggest that the nomenclature of fungal diseases

1. Basic Concepts oncaused by specific pathogens should include theVulvovaginal Candidosisgenus name followed by the suffix -osis. Although

not considered a severely debilitating condition, itsThe objective of this article is not to thoroughlyhigh prevalence and interference with daily activi-

review the subject of vulvovaginal candidosis be-ties and the well-being of women makes this diseasecause this has been recently addressed elsewhere byan important medical condition. Various highly ef-Sobel.[1] However, it is important to highlight sever-fective oral or local treatment regimens includingal important aspects related to the epidemiology,different drugs (mostly azole antifungals), regimens,classification, pathogenesis, clinical manifestations,durations of treatment and pharmaceutical dosagediagnosis and risk factors implicated in this infec-forms have been proposed and routinely used intion before discussing its local treatment. A briefclinical practice. Recent reports on the comparativeoverview is provided in the following sections.efficacy of local versus oral treatment of uncompli-

cated vulvovaginal candidosis found no significant1.1 Epidemiology

differences, or at least no conclusive differences,between either treatment modalities.[2,3] In addition, Vulvovaginal candidosis is one of the three mosttreatment guidelines issued worldwide do not favour common vaginal infections among women in theireither local or oral therapy. fertile years and accounts for 20–30% of all cases.[5]

Even if only equally effective as oral therapy, Epidemiological studies indicate that approximatelylocal treatment of vulvovaginal candidosis may pre- 75% of all women will have at least one episode ofsent several advantages when compared with oral vulvovaginal candidosis throughout their lifetime,therapy. However, physicians are not always aware while 40–50% will experience one or more subse-of the benefits and limitations of both treatment quent episodes. It is also noteworthy that the simplemodalities as they frequently prefer oral regimens presence of Candida spp. in the vulvovaginal areawhen prescribing.[4] Moreover, the availability of does not necessarily mean infection. Approximately

© 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (13)

Local Treatment of Vulvovaginal Candidosis 1789

10–20% of healthy women have vulvovaginal colo- and duration of symptoms (acute or chronic).[8] Un-nization by these yeasts without showing typical complicated vulvovaginal candidosis is character-symptoms of vulvovaginal candidosis; in some ized by sporadic episodes with light to mild symp-women (e.g. HIV-positive or pregnant women), this toms that are usually caused by C. albicans. Thisrate may be higher.[6,7] Vulvovaginal candidosis is situation corresponds to the majority of all vulvo-rarely associated with trichomoniasis or bacterial vaginal candidosis cases as they are sensitive tovaginosis, although mixed infections are possible.[8] almost all therapeutic regimens, including short-

course regimens. In contrast, complicated vulvo-The frequency with which several Candida spp.vaginal candidosis commonly refers to recurrent orare involved in vulvovaginal candidosis is relativelysevere cases that are usually caused by non-albicanswell known. C. albicans is the main species respon-Candida spp. Although recurrent vulvovaginalsible and accounts for 80–90% of all infections,candidosis corresponds to approximately 6–8% offollowed by C. glabrata, C. tropicalis and C. kruseiall cases in otherwise healthy women, this form ofwith 5–10%, 5% and 1%, respectively.[9-11] Uncom-the disease presents as more preoccupant and ismonly, other non-albicans Candida spp. may alsocharacterized by four or more confirmed episodesbe responsible. However, non-albicans Candidaper year.[8] Recurrence seems to be related to thespp. are more resistant to conventional antifungalincomplete eradication of Candida spp. after symp-therapies, making them important organisms in thetomatic relief because of either yeast virulence orprevalence of vulvovaginal candidosis. In fact,host factors (exacerbated immune response mayvulvovaginal candidosis caused by non-albicansplay an important role).[15,16] Nonetheless, other fac-Candida spp. has been increasing in recent years, ators may be implicated, namely the possibility offact that may be related to the widespread and inade-reinoculation from a persistent intestinal source.quate use of antifungal drugs, namely those avail-Vulvovaginal candidosis can also be classified asable as OTC products.[12,13] It is thought that inade-chronic when symptoms last for ≥6 months and isquate use of these drugs contributed to the elimina-usually associated with azole-resistant non-albicanstion of azole-sensitive C. albicans, allowing theCandida spp.[17] Lastly, this vaginal infection is notdevelopment of azole-resistant non-albicans Candi-considered a sexually transmitted disease (STD).da spp. However, a contradictory study thatHowever, vulvovaginal candidosis is usually con-analysed the prevalence of non-albicans Candidasidered in this group of infectious diseases, as it isstrains among women before and after the introduc-often diagnosed in women being evaluated for ation of OTC products seem to refute this claim.[14] ItSTD.has been estimated that only approximately 50% of

all cases of vulvovaginal candidosis caused by non-albicans Candida spp. respond to conventional oral 1.3 Pathogenesisor local therapy with azoles.

Although not entirely understood, vaginalimmune and non-immune defences in healthy1.2 Classificationwomen are important in the pathophysiology ofvulvovaginal candidosis. As stated in section 1.2,Although not a potentially fatal pathology,vulvovaginal colonization by Candida spp. does notvulvovaginal candidosis is a common problem andnecessarily mean symptomatic infection.includes all women with positive cultures for Candi-

da spp., symptomatic or not.[1] Hence, this broad Indeed, several species are part of the normaldefinition means that vulvovaginal candidosis can vaginal flora but may become pathogens when thebe classified according to various criteria, namely vaginal environment undergoes change, such as inepisode frequency (sporadic or recurrent), severity the levels of lactobacilli (e.g. as a result of antibac-(complicated or uncomplicated), symptoms (asymp- terial therapy). These bacteria are capable of inhib-tomatic, mild to moderate, or severely symptomatic) iting the growth of a wide range of pathogens. In the



Mucus layer

Stratified squamousepithelium

Basement membrane

Lamina propria

Blastospores Hyphae

a b c

Fig. 1. Schematic drawing of the pathogenic mechanism of vaginal infection by Candida albicans. (a) Blastospores (budding yeast) are thedissemination and transmission form of C. albicans, and are associated with asymptomatic colonization of the vagina; (b) dimorphictransition to the filamentous form (hyphae) can be stimulated by various environmental conditions, resulting in increased adhesiveproperties to epithelial cells and production of lytic enzymes (mainly proteinases); (c) these enzymes facilitate epithelial invasion, resulting invaginal wall damage and inflammation, responsible for symptom occurrence.

case of vulvovaginal candidosis, lactobacilli may ure 1). This morphological conversion is dependenton multiple factors, namely vaginal pH, and humor-prevent the adhesion and/or germination of Candidaal and cellular immune status.[20] Factors that en-spp., thus providing a natural mechanism of defencehance or facilitate germination (e.g. estrogen ther-against symptomatic infection.[18] However, aapy, pregnancy) tend to precipitate symptomaticstraightforward relationship between colonizationvulvovaginal candidosis, whereas others that inhibitwith lactobacilli and the onset of vulvovaginalthis dimorphic change (e.g. bacterial flora) maycandidosis is unclear, as this pathology is also fre-prevent acute symptoms in women who are asymp-quently observed in women with normal levels oftomatic carriers. In addition, virulence of Candidalactobacilli.[19]

spp. is related to their capacity for adhesion toReproductive hormones (estrogens and proges-epithelial cells, which is a complex process that istogens) also play an important role in local immuni-not yet fully understood, and their increased proteo-ty as they are responsible for increased susceptibilitylytic activity.[21,22]

to infection with Candida spp. when their levels areelevated. These hormones decrease both humoral

1.4 Clinical Findings and Diagnosisand cellular immune response (and possibly chemo-taxis) while augmenting glycogen deposition in epi- Clinical manifestations of vulvovaginal candido-thelial cells. Taken together, these changes may sis are often inconclusive and unspecific for thisinduce growth, adhesion to the vaginal epithelium condition, making its recognition intricate and notand germination of Candida spp.[15] A major indica- always readily available (figure 2).[1,23-25] The abilitytor of the importance of these hormones on the of women to recognize this condition is frequentlypathogenesis of vulvovaginal candidosis is the low unreliable, and it is estimated that only about one-incidence of this condition in prepubertal and post- third of self-diagnosed cases are indeed confirmedmenopausal women as both ages are characterized by clinical examination and laboratory testing.[13]

by low levels of sexual hormones. This fact is particularly worrying if we consider theThe budding form of C. albicans is associated increasing number of women who use OTC anti-

with asymptomatic colonization and the need to fungal products (up to nine of ten) without consult-convert to their filamentous form (germination) to ing a physician or other licensed healthcare pro-become pathogenic and invade the epithelium (fig- vider.[26,27] Although important, diagnosis should



not be based solely on a patient’s clinical history, toms frequently emerge 1 week before menses anddisappear with the onset of menstruation. Vaginalpelvic examination and symptomatic assessment, asdischarge may be present or not, with variableonly microscopic observation (10% potassium hy-amounts and physicochemical properties (usuallydroxide) or mycological culture can accurately diag-without pronounced odour). Possible vulval symp-nose vulvovaginal candidosis.[28] The Whiff test andtoms also include erythema, oedema and swelling,pH determination are also useful tools, particularlyparticularly near the introitus.[1,8] The cervix is usu-in office-based practice.[29] Vaginal pH associatedally unaffected, while the vaginal mucosa presentswith vulvovaginal candidosis is similar to that ob-erythema and white plaques, this last feature beingserved in otherwise healthy women during theirtypical in women with vulvovaginal candidosisfertile years (approximately 3.5–4.5), which con-during pregnancy.[28]

trasts with increased values associated with bacterialvaginosis, trichomoniasis or mixed infections.[5] The

1.5 Risk Factorsmain symptom of vulvovaginal candidosis is pruri-tus, which can be accompanied by burning sensa- Several risk factors have been described fortion, pain, dysuria and dyspareunia. These symp- vulvovaginal candidosis,[30-41] even if most affected

Woman presenting vaginal symptoms

Pharmacist or other licensed healthcare providerPhysician1

Symptomassessmentand pelvic

examinationsuggest VVC?

Consider otherconditions

Wet mount microscopyreveals the presence

of yeast?

pH >5, excess WBC,trichomonads or

clue cells?

pH <5 and noexcess of WBC?

Initiate VVCtreatment

Considermixed

infectiontreatment

Considerother

conditions

Request laboratoryculture and consider

VVC treatment4

Proceed according tolaboratory information

Any of the following applies: Never diagnosed for VVC OR <16 or >60 years of age OR symptoms

suggesting other conditions OR pregnancy/breast feedingOR two or more VVC episodes in the last 6 mo OR

other predisposing condititions (e.g. diabetes mellitus)

Typical symptomsof VVC?

Symptomssuggesting

other condition?

Counseling

Refer to

Symptoms onset suggestsother than an acute episode?

Previous OTC treatment?

RecommendOTC treatment

Failure ofprevious OTC

treatment?

Recommend sameOTC treatment

Patientfeedback3Patient

feedback2

No

No

No

Yes

Yes

Yes NoYesNo

No

No

No

No

No

Yes

Yes

Yes

Yes

Individualsituationsmay justify

Yes

Yes

Fig. 2. Combined algorithm for office-based and over-the-counter (OTC) management of women presenting vaginal symptoms allegedlydue to vulvovaginal candidosis (VVC).[1,23-25] 1 Complicated cases may require reference to an experienced gynaecologist and/or infectiousdisease specialist. 2 In cases of treatment failure or short-term relapse consider possible drug-resistant or recurrent VVC, respectively. 3 Incases of treatment failure or relapse refer to physician. 4 Laboratory culture may also be required in other cases (e.g. chronic, recurrent orpresumably azole-resistant cases). WBC = white blood cells.



women may not present any of these. Table I pre- eral Candida spp. to antifungal drugs is document-sents a synopsis of the most important predisposing ed,[43] but individual isolates may not always fit thisfactors to vulvovaginal infection by Candida spp. pattern. Thus, laboratory susceptibility tests should

be performed whenever empirical therapy does not2. Treatment of Vulvovaginal produce a response.Candidosis: General Considerations

2.1 Local versus Oral TherapyGeneral guidelines for the management ofvulvovaginal candidosis have been issued by several

As mentioned in the introduction, efficacy ofgroups and organizations worldwide.[42-46] The

both oral and local therapy has been shown to bemain goal of vulvovaginal candidosis treatment

equivalent.[2,3] However, there are several other is-is to achieve rapid and complete relief of signs and

sues that may favour one therapeutic approach oversymptoms of vulvovaginal inflammation after

the other.48–72 hours, and mycological cure following

Local treatment presents several advantages.4–7 days.[43] Prevention of recurrence is also sought.Antifungal products administered in the vagina areMain therapeutic regimens include azoles (imidaz-usually designed to avoid extensive drug absorption,oles or triazoles), although others can be used. Thewith blood concentrations frequently being negligi-selection of individual drugs for vulvovaginalble. The incidence of adverse effects, particularlycandidosis therapy (oral or local) should be baseddue to prolonged systemic exposure to antifungals,upon their pharmacology and implicated Candidamay therefore be decreased with local therapy.[47,48]

spp. susceptibility. In general, the sensitivity of sev-Drug interactions frequently observed during oraladministration are uncommon when using topicalantifungals, with this fact being an important advan-tage over oral regimens. Nonetheless, their occur-rence should not be ignored since some reportsindicate that these interactions might also be observ-ed during local treatment, e.g. between topicalazoles and oral anticoagulants.[49,50] Oral azoles arecontraindicated or, at least, should be avoidedduring pregnancy and breast feeding because ofsafety issues to the fetus or baby, with local therapyusually being recommended.[51,52] For the same rea-sons, it is also prudent to choose local therapy whentreating women who are not using reliable birthcontrol methods or who are planning to becomepregnant.

Vaginal administration of antifungals also pre-sents some disadvantages. Women’s preferences donot favour local therapy. A review study in the early1990s found that approximately 50% of womenfavoured oral antifungal therapy, while only 5%preferred local therapy; the remaining women show-ed no preferences.[53] A study published in 2001corroborated these results; among 1348 women,58% preferred oral treatment, while 36% and 8%favoured vaginal suppositories and vaginal tablets,

Table I. Risk factors contributing for vulvovaginal candidosis occur-rence[30-41]

Hormonal Increased levels of endogenous estrogens (mainlyfactors during pregnancy)

Use of exogenous estrogens (oral contraceptives orhormonal replacement therapy)Increased levels of progesterone (?)

Immune Decreased cellular immunityfactors Immunosuppressed patients

High predisposition for atopia, allergic andhypersensitivity reactionsHIV infection (?)

Antibacterial Broad-spectrum antibacterials (systemic or local;use mostly during prolonged treatments)

Diabetes Particularly in patients with type 1 diabetes or inmellitus whom diabetes is not well controlled

Others ObesityDietary (?)Debilitating conditionsHeat, moisture and occlusive underwearIntrauterine contraceptive deviceContraceptive sponges or irritating vaginal products[e.g. containing nonoxynol-9] (?)Corticosteroids (?)Nappy or diaper dermatitis or sexual abuse inchildrenSexual activity [namely orogenital or high frequencyintercourse] (?)Stress factors

(?) = role in the occurrence of vulvovaginal candidosis remainscontroversial.



respectively.[54] However, these results may be ment), with symptomatic and mycological cure be-changing towards local therapy as a result of the ing achieved in approximately 80–90% of patientsadvances in the formulation of vaginal products and who have completed the treatment. Prolonged ther-decrease of genitalia related taboos.[55] Antifungals apy (>7 days) is necessary for complicated or non-used for local treatment may cause local reactions, albicans Candida infections; after a symptomaticnamely burning or irritation. Although mild and cure, a maintenance regimen may be initiatedsomewhat occasional, these symptoms may cause and prolonged for 6 months (oral regimens) or inter-women to discontinue treatment or may even be mittently (local therapy).[42,43] Some experts recom-misinterpreted by healthcare providers as being mend clotrimazole 200 mg twice weekly, clo-caused by fungal persistence and lead to inadequate trimazole 500 mg once weekly, nystatincontinuation of local therapy. 100 000 units every other day or boric acid 600 mg

Another relevant aspect when comparing both every other day (then twice weekly) as examples oftreatment modalities is their cost. Affordability is, in local intermittent therapy.[59] Even if considered ef-fact, a critical issue related to treatment compliance fective, maintenance therapy does not guarantee aand should not be disregarded by clinicians. A rapid cure, with 30–50% or 50–70% of women experienc-analysis of US and UK markets reveals a wide range ing relapses in the following month or followingof prices among oral and local treatment options; 2 months after treatment cessation, respectively.[48]

this variability is observed between different drugs, This can be explained by the fungistatic action of thedosage regimens or even formulations (see table II drugs that are used and immunopathogenesis of thefor prices of local therapy regimens). A typical disease. In these patients with relapsing infections,example of an oral regimen is that of fluconazole subsequent maintenance therapy regimens may be(150 mg, single dose), which costs approximately considered. It is also important to further consider$US26 or £12.50 (2008 costings). Also, patients’ relevant factors related to the patient (e.g. identifica-healthcare plan financing and worldwide price vari- tion and control of risk factors, tolerability to theability may substantially influence treatment af- antifungal regimen), disease-causing Candida spp.fordability. Hence, general comparison between oral (particularly antifungal drug resistance), drug andand local regimen costs and specific recommenda- drug formulation (e.g. safety profile).tions on the subject are hard to perform. The golden

Special populations may have specific require-rule should always be ‘the best treatment at the bestments. In pregnant women, it is advisable to dupli-price’.cate the treatment period. In this particular group,miconazole, clotrimazole, butoconazole and ter-3. Local Treatment ofconazole are generally considered the most effectiveVulvovaginal Candidosisdrugs.[46] Alongside oral antifungals, several otherdrugs have been considered unsafe during preg-

3.1 General Considerationsnancy (either locally or systemically), namely flu-cytosine and potassium iodide.[60] Boric acid useSeveral local drug regimens have been recom-also seems contraindicated in pregnant women.[61]mended and used in clinical practice (table II).[42-46]

HIV-positive women are usually treated forAzoles are recommended as first-line treatment un-vulvovaginal candidosis in the same way as HIV-less a confirmed or suspected azole-resistant Candi-negative women, although their vaginal coloniza-da strain is involved. Other situations may alsotion rates with Candida spp. are usually higher.[42]contraindicate azole therapy (e.g. hypersensitivity toPostmenopausal women should also be treated asthese agents) in which nystatin or boric acid shouldyounger fertile women, although several age-relatedbe used. Uncomplicated vulvovaginal candidosisaspects should be taken into consideration (e.g.usually responds quite rapidly to any empiricalhigher incidence of type 2 diabetes mellitus, highershort-course local regimen (up to 3 days of treat-




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9.60

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$US

19.2

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sup

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£3.6

310

0 m

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tab

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drug usage and vaginal dryness).[62] The treatment ofmale sexual partners is usually not considered, ex-cept in women with recurrent vulvovaginalcandidosis or when partners present with genitalsymptoms.[42] In this situation, topical application ofnystatin or clotrimazole, lotion or cream, twice dailyfor 7 days may be useful.[46]

Alongside antifungal therapy, several other localtherapeutic approaches may be helpful, namely inthe relief of vulval dermatitis or intense pruritus.These measures may include the utilization of corti-costeroids (e.g. 1% hydrocortisone ointment) andapplying cold compresses on the affected areas.[63]

Corticosteroids should only be considered in severecases and used with caution as rebound effects maybe observed. Use of non-irritating moisturizers, im-plementation of adequate hygiene practices andavoidance of soap-containing cleansers are equallyimportant in the prevention and exacerbation ofthese symptoms.

3.2 Antifungal Drugs for Local Treatment

A considerable number of antifungal agents forthe local treatment of vulvovaginal candidosis arecurrently available. However, a thorough discussionof in-depth pharmacological, chemical or pharma-ceutical aspects for each drug is beyond the scope ofthis review. Interested readers are referred to moreextensive and specialized review literature;[64] a gen-eral overview of antifungal drugs used in the localtreatment of vulvovaginal candidosis is presented intable III.[65-79]

3.3 Other Potential LocalTherapeutic Options

Although current vulvovaginal candidosis drugtherapy provides high efficacy and safety, the recentemergence of complicated infections and drug resis-tance has led to the development and research ofnew oral and local therapeutic options. Alongsideexisting antifungal agents, innovative and improveddrugs are reaching the market such as second-gener-ation azoles (e.g. voriconazole, posaconazole) andechinocandins (e.g. caspofungin, micafungin). Al-though their use is still reserved for severe systemic


Tab

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reat

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tage

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tions

Com

men

ts

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les

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e br

oad

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erse

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tly im

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sef

fect

s m

ay o

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Pre

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ntia

l dru

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or t

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t of

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conditions, these drugs may find in the future a place tree oil)[88] demonstrated high antifungal activity invitro against Candida spp. commonly involved inin the therapy of complicated vulvovaginal candido-vulvovaginal candidosis. An interesting feature ofsis. The use of drugs with different mechanisms ofthese natural products is their similar activity againstaction may also be an interesting strategy. In vitroboth azole-sensitive and -resistant Candida spp.and animal data show synergistic effects between

commonly used azoles and other substances show-ing antifungal activity.[80] In addition, limited clin- 4. Selection of Topical Antifungalical case reports using flucytosine and amphotericin Drug FormulationsB seem to point in this direction.[75] However, fur-ther studies are required to test the possibility ofsynergistic drug use. 4.1 General Considerations

Probiotic local therapy with products containinglactobacilli has been proposed as an alternative op- As well as choosing an effective drug, an ade-tion for the prevention of vulvovaginal candidosis, quate antifungal product must be selected or evenparticularly for recurrent cases. A relatively com- sometimes compounded in order to fulfil a treatmentmon practice recommended by some gynaecologists regimen. This task should not be neglected as inade-

quate vaginal drug delivery systems may lead tohas been the administration of yogurt containingpoor clinical outcomes. Features related to the anat-lactobacilli into the vagina. Nevertheless, availableomy, histology and physiology of the vulva andclinical data fail to clearly demonstrate the benefi-vagina (figure 3) should be taken into account whencial outcome of this strategy.[81,82] Immunotherapy ischoosing a topical antifungal formulation for localalso being investigated, particularly in the field oftreatment of vulvovaginal candidosis.[89,90] Also, it isvaccine, antibody and cytokine development.[83,84]

occasionally necessary to compound antifungal for-The purpose of this strategy is to induce or regulatemulations in pharmacies when products are notthe local immune response against infection by Can-commercially available (e.g. boric acid capsules,dida spp., either by passive or active immunization.amphotericin B vaginal suppositories). WheneverFindings from a recent review of preclinical datapossible, these compounded formulations should beseems to support that the vaginal administration offully characterized and optimized for their biophar-diverse immunomodulatory compounds (e.g. anti-maceutical and pharmacotechnological features, as

bodies) can kill Candida spp. or inhibit its germina-vehicles are recognized to dramatically influence

tion and epithelial adhesion, thus reducing sympto-the release, in loco residence, and rate and extent of

matic infection; reduction of inflammatory humoral drug penetration into the mucosa. This last feature isand cellular response associated with vulvovaginal particularly important, as inadequate mucosal pene-candidosis also seems to be possible.[85] Although tration of antifungal drugs may lead to toxicity (withimmunotherapy is considered very promising, sev- excessive penetration) or poor cure rates (with pooreral important issues related to the correlation be- penetration). Although antifungal products are ad-tween disease, success and protection of this thera- ministered topically, their action is not merely on thepeutic approach still have to be resolved before mucosal surface or vaginal lumen; these agents needtranslation to clinical practice is possible. Natural to penetrate deep into the epithelium to reach inva-products have also shown antifungal activity in vitro sive Candida hyphae (figure 1) and exert a localagainst Candida spp., with their use being a poten- antifungal action there. Moreover, other importanttial option for the treatment of vulvovaginal candi- issues should not be disregarded such as women’sdosis in the future.[86] For example, Thymus spp. preferences, their ability to fully comply with theessential oil (thyme oil),[87] a commonly used food treatment (e.g. correct use of vaginal applicators)spice, and Melaleuca alternifolia essential oil (tea and treatment affordability.



Colon

VulvaIncludes all the genital structures surrounding the

vaginal entrance. Composed of keratinized stratifiedsquamous epithelium (similar to the skin)

VaginaS-shaped, tubular, fibromuscular

organ (≈9−12 cm length) descendingfrom the cervix to the introitus

Vaginal mucosaNon-keratinized stratified squamousepithelium (thickness dependent on

sexual hormones); deprived ofsecreting glands; able to absorb

drugs into the systemic circulation(richly supplied by blood vessels).

Significant thinning of the epitheliumduring menopause, childhood

and pregnancy

Ovary CervixPresence of cervical mucus

(pH ≈7.0 but variableduring menstrual cycle)

Uterus

Bladder

Vaginal milieuPresence of variable quantities of an acidic fluid (pH 3.5−4.5)

during fertile years due to acid-producing lactobacillicolonization. Increased pH during menopause (5.5−6.8 orhigher) and sparse amount of fluid. Low enzymatic activity

Fig. 3. Some of the most important features of the anatomy, histology and physiology of the vulva and vagina related to the administration ofantifungal drugs.

4.2 Conventional and Novel vagina and allow prolonged action of active drugs.Antifungal Formulations The main strategies used to achieve these goals

include mucoadhesive and controlled-release for-Current antifungal products are mostly formulat- mulations. Some products have already reached the

ed as ointments, creams or vaginal suppositories, market and offer new and valuable options for short-capsules and tablets. However, these products do not

er and highly acceptable therapeutic regimens. Anreliably control the release of active drugs, with the

example is the Site Release® 1 (SR) vaginal deliveryrelease and presence in the vagina of the drug fre-system, which is based on a water-in-oil creamquently depending on the properties of the drug.comprising a highly concentrated, drug-loadedThis results in longer treatment regimens and expo-internal phase.[91] This technology is characterizedsure to higher amounts of the active drug, which canby high mucoadhesiveness (improves product resi-lead to increased toxicity. Another negative aspectdence in the vagina by adhering to the mucosa for upof these traditional formulations is associated withto 6 days) and the possibility of prolonged release ofthe leakage and messiness of products; in order toactive drugs (reduces the number of administrationsalleviate these problems, women are usually recom-and total amount of drug exposure). Prolonged re-mended to administer antifungal products at bed-lease is achieved by controlling drug diffusiontime. Taken together, most available products canthrough the outer hydrophobic phase.[92] A productlead to poor compliance and, ultimately, poor clin-based on SR technology, Gynazole-1® (2% buto-ical outcomes.[91]

conazole) is available in the US as a single-doseEfforts have been made in the past few years tooptimize the retention of antifungal products in the treatment for vulvovaginal candidosis. Results from

1 The use of trade names is for product identification only and does not imply any kind of endorsement.



clinical trials demonstrated that treatment with SR prolonged drug release is valuable (e.g. maintenancecream is as safe and effective as 7-day treatment therapy for recurrent vulvovaginal candidosis). Oth-with conventional 2% miconazole cream or oral er interesting drug delivery approaches have alsofluconazole, with the advantage of allowing faster been proposed. Chang et al.[99] and Bilensoy etrelief of symptoms.[93,94] Clinical data also suggest al.[100] designed thermosensitive formulations thatthat SR technology may be used for the vaginal are able to release clotrimazole in a controlled fash-administration of other antifungal agents (e.g. flu- ion. Besides allowing longer administration inter-trimazole).[95] Another currently commercially vals than conventional products, the fact that theseavailable prolonged-release product in the US is formulations are liquids at room temperature andMonistat-1® (1.2 g miconazole); in the UK it is mucoadhesive semisolid gels at body temperaturecommercialized as Gyno-Daktarin® 1200 mg vagi- facilitates their administration while guaranteeingnal capsule. This ovule-shaped insert is comprised good retention in the vagina.of miconazole suspended in an ointment base (min- Nanocarriers, such as liposomes,[101] prolipo-eral oil, white petrolatum and lecithin), which is somes[102] or niosomes,[103] may also play a futurecovered by a soft gelatin hydrogel layer that controls role in the treatment of vulvovaginal candidosis.drug release. Single-dose Monistat-1® was shown to These spherical vesicles have been shown to effec-be as effective as 7-day treatment with conventional tively deliver antifungals (e.g. clotrimazole) deeply2% miconazole cream and achieved symptom relief into the vaginal epithelium and provide prolongedfaster.[96] Moreover, it demonstrated the convenient drug release without being submitted to the naturalfeature of equal efficacy either with daytime or vaginal cleansing mechanism responsible for leak-bedtime use.[97] The same product is available in age of conventional products.combination with a 2% miconazole cream to beapplied in the vulva for symptomatic relief (Monis-

4.4 Safety Issuestat-1® Combination Pack). Similar single-dose, pro-longed-release vaginal products are also availableworldwide that contain econazole 150 mg (Ecosta- Safety concerns with antifungal products are nottin-1® E.R. and Gyno-Pevaryl® LP) or sertacon- exclusively related to the toxic effects of activeazole 300 mg (Monazol®), and have been shown to drugs. Excipients commonly present in antifungalbe effective and well tolerated in vulvovaginal products administered in the vulvovaginal area maycandidosis.[98] be responsible for adverse effects, particularly local

ones. For example, local irritation or allergic reac-tion has been attributed to propylene glycol,[104]4.3 Potential and Investigational Antifungalpolysorbates[105] and benzyl alcohol.[106] Thus, it isDelivery Systemsimportant to assess the patient’s hypersensitivity

Recent investigations in drug delivery have history to the ingredients of antifungal formulations.opened the way for some new and interesting ap- Conversely, some excipients (acidic polymers orproaches for the vaginal administration of antifun- moisturizers) may contribute to the re-establishmentgals. Key objectives remain the same: to improve in of a healthy vaginal milieu.[107,108] Women shouldloco residence and achieve prolonged drug release. also be informed that the use of vaginal antifungalThe development of user-acceptable products is also products may damage condoms or other vaginaldesirable. For example, drugs for Candida infec- contraceptive devices (e.g. diaphragms); when ap-tions may benefit from innovative drug dose forms, plicable, a 3-day break is usually recommendedsuch as mucoadhesive gels, foams or vaginal before using condoms or contraceptive devices. Inrings.[89] These dosage forms, which are already all cases, information about individual productscommercially available for the management of other should be checked before prescribing and/or dis-conditions, may be particularly advantageous when pensing.



4. McCaig LF, McNeill MM. Trends in prescribing for5. Conclusionsvulvovaginal candidiasis in the United States. Pharmacoepi-demiol Drug Saf 2005 Feb; 14 (2): 113-20

In addition to equivalent efficacy, local treatment 5. Sobel JD. Vaginitis. N Engl J Med 1997 Dec 25; 337 (26): 1896-903of vulvovaginal candidosis presents several advan-

6. Ferrer J. Vaginal candidosis: epidemiological and etiologicaltageous features when compared with oral therapy.factors. Int J Gynaecol Obstet 2000 Dec; 71 Suppl. 1: 21-7

These include a low rate of adverse events (partic- 7. Mitchell H. Vaginal discharge: causes, diagnosis, and treatment.BMJ 2004 May 29; 328 (7451): 1306-8ularly systemic ones), safe utilization during preg-

8. Sobel JD, Faro S, Force RW, et al. Vulvovaginal candidiasis:nancy and breast feeding, and the availability ofepidemiologic, diagnostic, and therapeutic considerations. Am

several efficacious agents against azole-resistant J Obstet Gynecol 1998 Feb; 178 (2): 203-119. Richardson MD, Warnock DW. Fungal infection: diagnosis andCandida spp. However, the wide variety of anti-

management. 3rd ed. Malden (MA): Blackwell Publishing,fungal drugs, regimens and products that is currently 2003available for the local treatment of vulvovaginal 10. Singh S, Sobel JD, Bhargava P, et al. Vaginitis due to Candida

krusei: epidemiology, clinical aspects, and therapy. Clin Infectcandidosis requires an adequate choice of therapeu-Dis 2002 Nov 1; 35 (9): 1066-70

tic approach that is based on a systematic assess- 11. Spinillo A, Capuzzo E, Egbe TO, et al. Torulopsis glabratavaginitis. Obstet Gynecol 1995 Jun; 85 (6): 993-8ment of diverse aspects related to the women, and

12. Martens MG, Hoffman P, El-Zaatari M. Fungal species changesCandida spp. responsible for episode. Azoles andin the female genital tract. J Low Genit Tract Dis 2004 Jan; 8

short-course regimens are used as first-line treat- (1): 21-413. Ferris DG, Nyirjesy P, Sobel JD, et al. Over-the-counter anti-ment, with nystatin and boric acid usually consid-

fungal drug misuse associated with patient-diagnosed vulvo-ered as alternative agents. However, particular situa-vaginal candidiasis. Obstet Gynecol 2002 Mar; 99 (3): 419-25

tions may benefit from other drugs and regimens 14. Walker PP, Reynolds MT, Ashbee HR, et al. Vaginal yeasts inthe era of “over the counter” antifungals. Sex Transm Infectwhen previous therapy has failed. Choosing a con-2000 Dec; 76 (6): 437-8venient antifungal drug formulation should not be 15. Fidel Jr PL, Sobel JD. Immunopathogenesis of recurrent

neglected as they can facilitate or complicate the vulvovaginal candidiasis. Clin Microbiol Rev 1996 Jul; 9 (3):335-48clinical outcome; recent advances in vaginal drug

16. Giraldo P, Neuer A, Korneeva IL, et al. Vaginal heat shockdelivery have brought interesting and convenient protein expression in symptom-free women with a history of

recurrent vulvovaginitis. Am J Obstet Gynecol 1999 Mar; 180options for the local treatment of vulvovaginal(3 Pt 1): 524-9candidosis. Additionally, non-physician healthcare

17. Nyirjesy P. Chronic vulvovaginal candidiasis. Am Fam Physi-providers must be made aware of the main features cian 2001 Feb 15; 63 (4): 697-702

18. Strus M, Kucharska A, Kukla G, et al. The in vitro activity ofof vulvovaginal candidosis in order to correctlyvaginal Lactobacillus with probiotic properties against Candi-counsel women about OTC antifungal products, or da. Infect Dis Obstet Gynecol 2005 Jun; 13 (2): 69-75

effectively identify those patients who require a 19. Sobel JD, Chaim W. Vaginal microbiology of women withacute recurrent vulvovaginal candidiasis. J Clin Microbiolphysician’s attention.1996 Oct; 34 (10): 2497-9

20. Fidel Jr PL. Immunity in vaginal candidiasis. Curr Opin InfectAcknowledgements Dis 2005 Apr; 18 (2): 107-11

21. Sundstrom P. Adhesion in Candida spp. Cell Microbiol 2002No sources of funding were used to assist in the prepara- Aug; 4 (8): 461-9

tion of this review. The authors have no conflicts of interest 22. Schaller M, Bein M, Korting HC, et al. The secreted aspartylproteinases Sap1 and Sap2 cause tissue damage in an in vitrothat are directly relevant to the content of this review.model of vaginal candidiasis based on reconstituted humanvaginal epithelium. Infect Immun 2003 Jun; 71 (6): 3227-34

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Local Treatment of Vulvovaginal Candidosis

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