Clotrimazole associated with high cure rates – evidence backed by 47 years of clinical use

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What causes vaginitis and what are the symptoms?

Symptoms of vaginitis include itching, burning, irritation, dyspareunia, vaginal odour, and abnormal vaginal discharge. Symptoms specific to VVC include a thick, white, adherent cottage cheese discharge, vulvar erythema and pruritis. Vaginal symptoms negatively impact patients in terms of discomfort and pain, days lost from school, work, sexual functioning, and self-image.2,3

VVC is caused by infection with the Candida species - most commonly C. albicans. However, it may also be triggered by other Candida species or yeasts, including C. glabrata. An estimated 75% of women will have at least one episode of VVC during their lifetime, and 40%–45% will experience two or more episodes.2

The risk factor of VVC are pregnancy, contraceptive and antibiotic use, diabetes, and behavioural factors. Contraceptives method that trigger Candida infection are intrauterine devices, diaphragms, and condoms, with or without spermicide.4,5

In pregnancy, a high level of reproductive hormones provides glycogen, an excellent carbon source, for Candida organisms. Studies show that the risk of Candida colonisation increases by about 30% during pregnancy, especially in the last trimester. This increases the risk of pregnancy-related complexities (eg preterm labour, premature rupture of membranes, congenital cutaneous candidosis.5,6

It should be noted that some women (4.44% to 35.06%)  might present with mixed vaginitis (MV), described as the ‘the simultaneous presence of at least two types of vaginitis, contributing to an abnormal vaginal milieu and leading to vaginal symptoms and signs’.7

Symptoms vary among patients with MV. Clinical characteristics include vulvar erythema, vulvar swelling, thinning of the vaginal mucosa, vaginal congestion, scattered bleeding points, yellow-coloured vaginal secretion, increased discharge, or pruritus.7

How is vaginitis diagnosed?

BV, VVC and TV are three distinct entities caused by different organisms, requiring different treatment approaches. Therefore, clinicians cannot rely on symptoms alone to distinguish between the different causes of vaginitis. Apart from a physical examination, an accurate diagnosis of the cause of vaginosis include microscopy, and culture methods.2,7

Culture for yeast is the reference standard for diagnosing VVC. Examination of a wet mount with a potassium hydroxide (KOH) preparation should be performed for all women with symptoms or signs of VVC, and women with positive results should be treated. Microscopy also may be limited by self-treatment before evaluation, making it more difficult for the healthcare provider to visualise yeast on microscopy.2

Culture- and polymerase chain reaction-based tests offer alternatives for negative wet mounts or complex cases. Importantly, failed medical therapy for clinically suspected yeast infections and recurrent yeast may be related to resistance associated with the Candida species.2

How is vulvovaginal candidiasis treated?

VVC is considered to be complicated in the following settings:3

  • Immune-compromised patients (HIV positive, diabetic, malignancy, immunosuppressive drugs)
  • Pregnant patients
  • Patients with frequent recurrences
  • Severe disease
  • Those who are infected with non-albicans Candida This classification is important as the treatment differs between the two groups.

In South Africa, systemic treatment with oral fluconazole 150mg as single dose is recommended. Recommended topical treatment include azole therapy for seven days. Immunocompromised patients should be treated with oral fluconazole 150mg daily or topical azole therapy for seven to 14 days.3

In patients with severe VVC, treatment with topical azole for seven to 14 days or oral fluconazole 150mg every 72 hours for two to three doses, depending on severity, is recommended. In patients presenting with non-albicans VVC, therapy depends on the species identified. Further laboratory testing is needed to identify the specific species.3

British guidelines list fluconazole 150mg single dose and clotrimazole 500mg cream or pessary as first-line treatment.8

The choices for intravaginal treatment are:8

  • Clotrimazole - 1% vaginal cream or pessaries at night for six nights
  • Clotrimazole - 2% cream at night for three nights
  • Clotrimazole - 10% cream for one night
  • Nystatin vaginal cream 100 000 units for 14 nights or twice a day for one week.

The latest (2021) recommendations from the American Centres for Disease Control and Prevention (CDC) include the use of clotrimazole 1% cream 5g intravaginally daily for seven to 14 days, or clotrimazole 2% cream 5g intravaginally daily for three days.9

Recurrent VVC

More than 5% of women with VVC experience recurrence, defined as at least four microbiologically proven infections per year. Recurrent infection can be treated with suppressive fluconazole with or without initial intravaginal clotrimazole or nystatin. According to the CDC, recurrent VVC caused by C. albicans respond well to short-duration oral or topical azole therapy.3,8,9

However, to maintain clinical and mycologic control, a longer duration of initial therapy (eg seven to 14 days of topical therapy or a 100mg, 150mg, or 200mg oral dose of fluconazole every third day for a total of three doses [days one, four, and 7]) is recommended to attempt remission, before initiating a maintenance antifungal regimen.9

Oral fluconazole (eg a 100mg, 150mg, or 200mg dose) weekly for six months is the indicated maintenance regimen. If this regimen is not feasible, topical treatments used intermittently can also be considered.9

Suppressive maintenance therapies are effective at controlling recurrent VVC but are rarely curative long-term because C. albicans azole resistance is becoming more common. Susceptibility tests, if available, should be obtained among symptomatic patients who remain culture positive despite maintenance therapy. These patients should be managed in consultation with a specialist.9

Efficacy of clotrimazole

Clotrimazole is an imidazole antimycotic agent that was discovered in the 1960s. Clotrimazole has broad antimicrobial activity against C. albicans and other fungal species.10

Clotrimazole was first registered in Germany more than 47 years ago (in 1973). The initial formulation for local treatment of  VCC was the vaginal tablet followed by internal vaginal cream, external cream, and soft ovule (soft capsule).10

Clotrimazole mono-preparations for the management of VCC are available over the counter in most countries and cover a dose range from 100mg to 500mg mg (solid systems).10

Comparable local clotrimazole exposure can be achieved by administration of semi-solid systems (eg creams containing clotrimazole 1%, 2% or 10%) to the vagina and vulva. While many preparations are available as generics.10

Clotrimazole has poor oral bioavailability. When administered intravaginally, about 3% of the dose is systemically available. The latter explains the favourable systemic tolerability of clotrimazole following vaginal application. Clotrimazole resistance in VVC is rare and susceptibility testing is usually not recommended.10

Mendling et al conducted a systematic review of the safety and efficacy of clotrimazole in various patient populations. A total of 27 articles were included that studied intravaginal clotrimazole in adolescents (usually ≥16 years) and adults with uncomplicated (acute) symptomatic VVC.10

Generally, single doses of clotrimazole 500mg vaginal tablet provided cure rates of 70%–95% at one or two weeks following treatment. In studies reporting longer-term cure rates (eg after about four weeks), cure rates ranged roughly between 60% and 90%.10

Once-daily doses of clotrimazole 200mg and 100mg vaginal tablets for three and six to seven days, respectively, provided similar results. The single use of clotrimazole 10% internal cream resulted in a one week cure rate of 85%-91%.10

Combined treatment of clotrimazole 500mg vaginal tablet and clotrimazole 1% external cream led to cure in 80%–95% of subjects within two weeks after treatment, whereas the combined application of clotrimazole 10% internal cream and 2% external cream yielded a 2-week cure rate of 74% in one study.10

In five trials, single-dose therapies with topical clotrimazole and oral fluconazole were compared. There, clotrimazole 500mg vaginal tablet provided cure rates of 75%–95% at one or two weeks after therapy compared to 76%–87% with oral fluconazole 150mg.10

When intravaginal clotrimazole formulations or treatments were compared versus each other, it turned out that a single dose of clotrimazole 500mg was as effective as multiple doses of lower dose strengths (eg 200mg for three days).

Similarly, the single use of clotrimazole 10% internal cream or clotrimazole 500mg ovule (soft capsule) yielded cure rates that were comparable to those following a single dose of clotrimazole 500mg vaginal tablet.10

During pregnancy, the therapy of symptomatic vaginal yeast infections should be intense but restricted to topical preparations. Oral antifungals should be avoided. Specifically, topical azoles can be used at all stages of pregnancy because there is no or only minimal systemic exposure following intravaginal administration.10

The American Food and Drug Administration assigned topical clotrimazole to pregnancy category B. The other topical imidazoles and triazoles have been assigned to category C. In fact, several clinical trials confirmed the safety of clotrimazole in pregnancy with no association observed between vaginal application of clotrimazole and congenital abnormalities. 10

In pregnant women with symptomatic VCC, clotrimazole 100mg (vaginal tablet), administered for about a week, provided high cure rates (78%–88% at one or two to four weeks after therapy).10

Similar results were observed following one week application of clotrimazole 1% internal cream. Intravaginal clotrimazole was significantly more effective than placebo treatment.10

In the same and other studies, the prophylactic use of clotrimazole during pregnancy significantly lowered the frequency of Candida presence on the neonatal skin. 10

Furthermore, cure rates were markedly higher with multiple-dose clotrimazole compared with nystatin, while there was no difference with terconazole. There was a trend towards reduced effectiveness of clotrimazole when taken as a single intravaginal 500mg dose. In all five studies, topical clotrimazole was well tolerated. 10

Four randomised controlled studies investigating intravaginal clotrimazole in non-pregnant women with recurrent symptomatic VVC. Clotrimazole induction treatment for one to two weeks (eg clotrimazole 100mg once daily) resulted in short-term cure rates of >80%.10

  1. Leclair C, Stenson A. Common Causes of Vaginitis. JAMA, 2022.
  2. Brown H and Drexler BA. Improving the Diagnosis of Vulvovaginitis: Perspectives to Align Practice, Guidelines, and Awareness. Population Health Management, 2020.
  3. Kingsburgh C, Strydom K-A. The aetiology, diagnosis, and management of the vaginal discharge syndrome. Ampath Chat, 2020.
  4. Arfiputri DS, Hidayati AN, Ervianti E, et al. Risk Factors Of Vulvovaginal Candidiasis In Dermato-Venereology Outpatients Clinic Of Soetomo General Hospital, Surabaya, Indonesia. Afr J Infect Dis, 2018
  5. Disha T, Haque F. Prevalence and Risk Factors of Vulvovaginal Candidosis during Pregnancy: A Review. Infect Dis Obstet Gynecol, 2022.
  6. Jeanmonod R, Jeanmonod D. Vaginal Candidiasis. [Updated 2022 Jul 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
  7. Qi W, Li H, Wang C, et al. Recent Advances in Presentation, Diagnosis and Treatment for Mixed Vaginitis. Front Cell Infect Microbiol, 2021
  8. Sheppard C. Treatment of vulvovaginitis. Australian Prescriber, 2020.
  9. Vulvovaginal Candidiasis (VVC). Vulvovaginal Candidiasis (VVC).,for%203%20weeks%20is%20indicated.
  10. Mendling W, El Shazly MA, Zhang L. Clotrimazole for Vulvovaginal Candidosis: More Than 45 Years of Clinical Experience. Pharmaceuticals, 2020.

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