Itraconazole for Vulvovaginal Candidiasis


A. K. Gupta MD, PhD, FRCPC1,2 and R. Bluhm BSc (Hons), BA, MA2,3

1Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook site) and the University of Toronto, Toronto, Canada.
2Mediprobe Laboratories Inc., Toronto, Ontario, Canada.
3University of Western Ontario, London, Ontario, Canada.

ABSTRACT

Vulvovaginal candidiasis is a common occurrence among women over 25 years of age. The likelihood of developing infection increases with pregnancy, the use of oral contraceptives or antibiotics, or immune disorders. However, in many cases, the etiology of the disorder is unknown. Sobel1 suggests that some cases of reinfection may actually be cases of relapse, due to either inadequate testing methods, which result in false-negative results after treatment, or to ineffective treatments. Misdiagnosis of the causative organism may also result in ineffective treatment. The most common causal Candida species is C. albicans. However, other, less easily eradicated species may also be involved.

Key Words:
itraconazole, vaginal candidiasis

Itraconazole (Sporanox®, Janssen Pharmaceuticals) is a triazole with fungistatic activity against Candida species, particularly C. albicans. Itraconazole reaches high concentrations in tissue due to a high affinity for proteins, particularly keratin.2 Active levels of the drug may persist in vaginal epithelium for four days after a one-day treatment.2 It has been suggested that a cause of relapse in women with vaginal candidiasis is the re-emergence of Candida organisms from deeper layers of vaginal tissue.3, 4 Oral therapy, unlike topical therapy, may be effective against these “hidden” organisms.

While the majority of cases of vulvovaginal candidiasis are caused by C. albicans, some infections are caused by other Candida species, including C. tropicalis and C. glabrata.5 An increasing number of infections appear to be caused by these other Candida species: 9.9% of cases in 1988 increased to 17.2% in 1995.6 Itraconazole may have a greater in vitro activity against non-albicans species than other azoles, like fluconazole.7 Therefore, itraconazole may be more effective against a broader range of causative organisms.

Clinical Trials

Itraconazole is effective and safe in the treatment of vulvovaginal candidiasis8-15 (see Table 1). Treatment regimens of itraconazole 200mg/day for 3 consecutive days8,9,11 or 200mg given twice in one day9,12,14 have resulted in a high mycological and clinical cure. Studies have also demonstrated mycological cure rates similar to standard treatments, like clotrimazole12,13 and fluconazole.14,15

Approximately 5% of women experience recurrent infection, which is defined as at least four episodes in one year, or three episodes known to be unrelated to the use of antibiotics.5 Itraconazole may be used prophylactically in order to reduce relapse rates16-18 (Table 2). Upon cessation of prophylactic treatment, recurrence rates tend to be high in women with a previous history of recurrent vulvovaginal candidiasis.

AuthorStudy DesignRegimen (n)Mycological CureComments (Clinical and Safety Evaluations)
Sanz Sanz, Hernanz9Randomized dose-finding
  • itraconazole 200mg itraconazole 200mg consecutive days consecutive days
  • consecutive days consecutive days (n=20) (Group B)
  • itraconazole 200mg itraconazole 200mg consecutive days (n=20) (Group C)
  • mycological cure + disappearance of clinical symptoms (complete cure) 1 week post-treatment: 85% Group A; 65% Group B; 85% Group C
  • mycological cure + disappearance of clinical symptoms (complete cure) 4 weeks post-treatment: 65% Group A; 65% Group B; 83% Group C
  • disappearance of clinical symptoms but positive mycological cultures (carrier)1 week post-treatment: 15% Group A; 20% Group B; 5% Group C
  • disappearance of clinical symptoms but positive mycological cultures (carrier) 4 weeks post-treatment: 5% Group A; 12% Group B; 0% Group C
  • 3 adverse events reported in Group C, including mild dyspepsia, burning sensation in stomach, stomach ache
Bloch, et al10Open, prospective, dose-finding
  • itraconazole 100mg twice/day for 1 day (n=30) (Group A)
  • itraconazole 100mg once/day for 2 days (n=32) (Group B)
  • mycological response 7 days post-treatment: 81% Group A; 83% Group B
  • mycological response 28 days post-treatment: 75% Group A; 63% Group B
  • no significant differences between groups with respect to clinical signs and symptoms
  • minimal, transient, non-severe side-effects including dizziness, abdominal cramps, nausea, diarrhea and muscle stiffness
Silva-Cruz, et al11Randomized, double-blind, placebo-controlled
  • itraconazole 200mg/day for 3 days (n=25)
  • placebo capsules for 3 days (n=25)
  • mycological cure 1 week post-treatment: % itraconazole; 52% placebo
  • significant difference between active and placebo groups in clinical signs (pruritus, vaginitis, and vulvitis)
  • one adverse event of epigastric pain reported in the placebo group
Tobin, et al12Multicentre, single-blind, randomized, parallel-group
  • itraconazole 200mg twice/day for one day (n=109)
  • clotrimazole 500mg vaginal tablet in a single dose (n=105)
  • mycological cure 1 week post-treatment: 74% itraconazole; 72% clotrimazole mycological cure 6 weeks post treatment: 51% itraconazole; 50% clotrimazole
  • mycological cure 6 weeks post treatment: 51% itraconazole; 50% clotrimazole
  • significantly, more patients preferred itraconazole treatment to previous treatments received
Stein, Mummaw13Randomized, controlled
  • itraconazole 200mg/day for 3 days
  • clotrimazolec 200mg/day for 3 days
  • placebo 2 capsules per day for 3 days
  • total n=95 with a randomization of 2:1:1
  • negative mycological cultures 1 week post-treatment: 73% itraconazole; 95% clotrimazole; 32% placebo
  • negative mycological cultures 4 weeks post-treatment: no statistical difference between itraconazole and clotrimazole
  • clinical success rate 1 week post-treatment: 96% itraconazole; 100% clotrimazole; 77% placebo
  • clinical failure rate 4 weeks post-treatment: 17% itraconazole; 30% clotrimazole (no significant difference [P>0.05; beta=0.81])
  • minor side-effects: 35% itraconazole; 4% clotrimazole; 41% placebo
  • side-effects with itraconazole included nausea and headache
Woolley, Higgins14Randomized, controlled
  • itraconazole 200mg twice/day for 1 day (n=75)
  • 500mg pessary of clotrimazole with a 1% clotrimazole cream (n=82)
  • fluconazole 150mg once/day for 1 day (n=72)
  • Candida-negative mycological response 7-10 days post-treatment: 96% itraconazole; 95% clotrimazole; 83% fluconazole
  • cured clinical response 7-10 days post-treatment: 80% itraconazole; 80% clotrimazole; 62% fluconazole
Mikamo, et al15Randomized, controlled
  • itraconazole 200mg daily for 3 days (n=50)
  • fluconazole single oral 150mg dose (n=50)
  • intravaginal clotrimazole 100mg daily for 6 days (n=50)
  • complete eradication of Candida species 5-15 days post-treatment: 80% itraconazole; 76% fluconazole; 72% clotrimazole
  • complete eradication of Candida species 30-60 days post-treatment: 74% itraconazole; 70% fluconazole; 60% clotrimazole
  • clinical effectiveness 5-15 days postet treatment: 92% itraconazole; 80% fluconazole; 72% clotrimazole
  • clinical effectiveness 30-60 days post-treatment: 88% itraconazole; 76% fluconazole; 58% clotrimazole

Table 1: Studies evaluating the efficacy of itraconazole in the treatment of vulvovaginal candidiasis.

AuthorStudy DesignRegimen (n)Mycological CureComments (Clinical Cure and Safety)
Creatas, et al16Open
  • maintenance phase lasting 6 consecutive menstrual cycles of 200mg itraconazole on the first day of menstruation (n=20)
  • mycological cure at maintenance phase 6: 20/20 patients (100%)
  • mycological cure 3 months post-treatment: 17/20 patients (85%)
  • clinical results were in total accordance with mycological results
  • complete cure (clinical and mycological cure) 3 months post-treatment: 85%
  • no adverse reactions were reported
  • compliance rate: 100%
Spinillo, et al17Randomized, controlled
  • itraconazole 200mg twice daily 12 hours apart on the 4th or 5th day of the menstrual cycle for 6 consecutive mos (n=55)
  • control, i.e., no treatment (n=53)
  • mycological recurrences were in accordance with symptomatic recurrences
  • clinical and mycological recurrence 6 months post-treatment: 36.4% itraconazole; 64.2% control
  • symptomatic recurrence during 6 months after cessation of prophylaxis: 38.9% itraconazole; 22.2% control
  • proportion of patients free of recurrence 1 year post-treatment: 38.9% itraconazole; 28.8% control
Guaschino, et al18Prospective, non-randomized
  • itraconazole 200mg once daily for 3 days followed by single dose of 200mg the first day of 5 subsequent menstrual cycles (n=11)
  • boric acid therapy 300mg daily in vaginal ovules of 14 days followed by 300mg daily for 5 days from the first day of 5 subsequent menstrual cycles (n=11)
  • positive mycological result at 6 month visit: 1/11 patients (9%) in each group
  • positive mycological result at 12 month visit (6 months post-treatment): 6/11 patients (54%) in each group
  • symptomatic infection at 6 month visit: 4/11 patients (36%) itraconazole; 3/11 patients (27%) boric acid
  • symptomatic infection at 12 month visit (6 months post-treatment): 6/11 patients (54%) in each group

Table 2: Studies evaluating the efficacy of itraconazole in the prophylactic treatment of vulvovaginal candidiasis.

Conclusion

Itraconazole appears to be an effective treatment for acute and chronic vulvovaginal candidiasis. Oral therapy tends to be shorter in duration than topical therapy. Moreover, patients often prefer oral treatment due to the shorter treatment period and to the ease of administration compared to topical treatments, resulting in increased patient compliance.3 As well, itraconazole used as a prophylactic treatment is a viable option in preventing future recurrence of infection.

Acknowledgement

We wish to thank J.E. Swan for her contribution to this manuscript.

References

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