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UDC 618.16-002: 616.594.171.2
ACUTE VULVOVAGINAL CANDIDIASIS: NEW TREATMENT OPTIONS
Irkutsk State Medical University, Irkutsk I.O. Malova, I.G. Afanasyeva
There was studied the effectiveness of the azole medication of fenticonazole in terms of local therapy for acute vulvovaginal candidiasis in 111 patients of reproductive age. At the first stage of the study, 54 patients received 600 mgfenticonazole in a vaginal capsule once. 47 (100%) patients with acute uncomplicated candidiasis ascertained clinical and etiologic recovery on the 4th day. 7 patients with acute complicated VVC who had inflammatory symptoms on the control of cure and microscopic elements of yeast-like fungi were detected, were given a second capsule of fenticonazole on the fourth day, and on the 10th day clinical and etiological recovery was noted. At the second stage of the study 57 patients with acute complicated VVC received 2 capsules of fenticonazole intravaginally: on the first and fourth days of treatment. Clinical and etiological efficacy in acute complicated process was 96.9%. 106 patients had no side effects during the treatment, only 5 (4.5%) had slight itching and burning, regressed independently for 1.5-3 hours and did not require withdrawal of the drug. A conclusion is made about the high efficiency and good tolerability of fenticonazole in the form of vaginal capsules of 600 mg with acute VVC.
Key words: yeast-like fungi of the genus Candida, acute vulvovaginal candidiasis, local azoles, fenticonazole.
Vulvovaginal candidiasis (VVC) continues to be one of the most serious problems of recent decades. In spite of modern fundamental scientific researches and new trends in etiology and patho-genesis of the disease, the approaches to diagnosis and treatment of VVC remain traditional.
VVC still ranks first in the structure of inflammatory diseases of female genital organs, for example, 30-45% of all infectious vaginal diseases [1]. Regardless of the termination of its official registration since 1999, the data on the increase of frequency of occurrence and the growth of its rate in the overall structure of gynecological pathology are actively discussed and do not encourage optimism [2].
At the present time, there are known quite many various factors predisposing to the development of the given disease, both endo- and exogenous: metabolic disorders, primarily carbohydrate and lipid; concomitant endocrine pathology; chronic inflammatory diseases of female genital sphere; hematological diseases; HIV infection; long-term uncontrolled intake of antibiotic, cytostatic, glu-cocorticosteroid drugs, hormonal contraceptives, chemical and radiation therapy; wearing of tight synthetic under-clothes; use of daily pantyshields, various vaginal syringes, deodorants; smoking, alcohol and drug abuse, etc. [3].
The development of acute VVC is always accompanied by expressed subjective symptomrn (painful itching, frequently - intense burning, painful urination, painful sexual transactions) which, apparently, decreases the quality of life of a woman and her working ability. An important clinical feature of the disease is a more repeated in recent times combination of candidiasis of lower female genitals with urethritis, urethrocystitis, pelvic organ diseases and pyelonephritis [4,5].
It is known, that the VVC structure gradually begins to be prevailed by chronic forms of the disease, while the role of Candida non-albicans in its development is growing [6]. In the literature there is discussed the probability of haematogenous dissemination of fungi Candida by their deep penetration into the sub mucous membrane and vessels [7]. Due to the presence of common antigens with kidneys, skin, vaginal and gastro-intestinal mucous membrane in Candida albicans a particular category of patients are exposed to the development of an autoimmune process [8].
At the present time, there arises another important problem connected with the reduction of sensitivity of Candida fungi to antimycotic agents, particularly, to azole antifungal agents which are most widely prescribed medications by VVC and hold first positions in all recommendations for VVC treatment [2, 9, 10]. Nevertheless, at this time, the sensitivity of Candida fungi to azole drugs grows [11]. Thus, the search of new drugs with more improved mechanism of action is quite topical, as it allows to broaden the range of therapeutic means in a complicated situation of antimycotic activity reduction.
A respectively new medication for Russia is fen-ticonazole - an imidazole derivative acting against Candida fungi and dermathophytes [12, 13]. Fenticonazole has been authorized for use by BBC treatment since 1986. In Europe it has been clinically used by VVC for 30 years. In Russia the drug is registered in the form of 2% cream and vaginal capsules containing 600 and 1000 mg of the drug. Several randomized studies conducted in Europe show the advantages and higher therapeutic effectiveness of fenticonazole in relation to clotrimazole in patients with VVC [14, 15].
The studies conducted with 72 women with VVC demonstrated high (92%) therapeutic and microbiological effectiveness of one vaginal capsule of fenticonazole 600 mg in 1 week after the intake, and also revealed high tolerability of the drug: no systemic and local side effects were observed [16].
In recent times, the given medication has been actively studied also in Russia. According to P.R. Abakarova et al., the therapeutic effectiveness of fenticonazole by acute VVC taken in the dose of 600 mg intravaginally two times with the interval of 3 days constituted 96,7% [17]. The results of the study of effectiveness of fenticonazole in the form of 2% vaginal cream by acute VVC in 30 women of reproductive age conducted by L.S. Lo-gutova et al. also demonstrated clinical and etiological recovery in 96,7% [18].
The scientific research of fenticonazole mechanism of activity earlier performed in Europe showed that the drug inhibits synthesis of ergos-terol increasing the permeability of fungal cell walls, destroying lysosomes and releasing lyso-somal enzymes which leads to the self-destruction of the fungal cell. This is the activity of all imi-dasoles. However, in the fenticonazole mechanism of activity there was revealed another pathogeni-cally important moment: the inhibiting of acid pro-teinase aspartate synthesis playing the basic role in the adhesion of fungi to the vaginal epithelium, their penetration into epithelial cells and further invasion. This fenticonazole mechanism of activity is unique and not typical for any of imidazole drugs [19]. The optimal environment for the adequate an-timycotic activity of fenticonazole is acid, which corresponds to the condition of genuine VVC development. Moreover, fenticonazole is characterized by long-term inhibiting activity (during 48-72 h after application) and low level of systemic absorption, and also high tolerability and safety [14, 15, 20].
Research objective: to determine the effectiveness of fenticonazole by the treatment of patients with acute vulvovaginal candidiasis.
Materials and methods
The study of fenticonazole (Lomexin, Recor-daty) effectiveness by the treatment of patients with acute vulvovaginal candidiasis was carried on the clinical base of the Department of derma-tovenerology of the Advanced Training Faculty and teaching stuff of FSBEI HE Irkutsk State Medical University of the Ministry of Health of the Russian Federation.
There were observed 111 female patients with acute VVC. Their clinical examination included: complaints for the moment of first examination; anamnesis of the disease and life, previous diseases, concomitant pathology. In every patient there were analyzed factors predisposing to VVC development. The objective study of patients included
the examination of external genital organs, observation of uterine cervix and vagina in the mirrors, palpation of genital organs, pH determination, aminotest and also clinical material sampling for laboratory testing.
The stage of laboratory examination included microscopy of native, methylene-blue and Gram-stained preparations from vaginal, ure-thral and cervical secretions. The STD causative agents (T.vaginalis, N.gonorrhoeae, C.trachomatis, M. genitalium, Herpes Simplex Virus, Human Papilloma Virus) were revealed by means of PCR-based diagnostics. The examination for syphilis was conducted by means of micro precipitation test. 14 patients with symptoms of cervicitis accompanied by low fluor zervikalis were exposed to the cultural study of cervical secretions aimed at the microbiocenosis study.
The main criteria of inclusion of patients into the study group was the proven diagnosis of acute vulvovaginal candidiasis, lack of chronic VVC, decompensated diabetes mellitus, oncological and hematological diseases and also other severe concomitant pathology requiring continuous intake of antibiotic, immunosuppressive, chemical or radiation therapy, lack of pregnancy, lack of pathogenic and other opportunistic pathogens.
The female patients were divided into two groups. At the first stage of study 54 patients with acute VVC (group 1) received 600 mg of fenti-conazole in the form of vaginal capsule once before bed. After the analysis of treatment results, and, particularly, its failures, there was performed the second stage during which 57 patients with acute complicated VVC (group 2) received 600 mg of fenticonazole intravaginally twice: on the 1st and 4th day (before bed).
The control of recovery was performed in the 1st group of patients on the 4th and 10th day after the end of treatment, in patients of the 2nd group - in 10 days after the end of treatment by means of clinical examination and microscopy of urogenital secretions. By the preservation of clinical symptoms of inflammation in the urogenital tract by the control of recovery there were prescribed systemic an-timycotic agents.
Results and discussion
111 women with acute VVC (from 15 to 51 years) had the following age groups: under 20 - 14 patients, from 21 to 30 - 49 patients, from 31 to 40 - 34 patients, from 41 - 14 patients. The majority were 83 women at the age from 21 to 40 (74,8%).
Among the factors predisposing to the development of VVC prevailed: in the first group - use of daily pantyshields - in 33 (61,1%) women, wearing of tight synthetic under-clothes - in 21 (38,8%), recent administration of antibiotics against concomitant diseases - in 15 (27,7%), long-term administration of oral contraceptives - 12 (22,2%), smok-
ing - in 15 (27,8%) women; in the second group
- use of daily pantyshields and wearing of tight synthetic under-clothes - in 44 (77,2%), smoking -in 27 (47,4%), long-term administration of oral contraceptives - in 12 (21,1%), recent administration of antibiotics against concomitant diseases - in 3 (5,3%), alcohol abuse - in 1 (1,8%).
From the concomitant pathology in 7 patients of the first group there were revealed chronic inflammatory diseases, in the majority of them -in various combinations: urinary diseases - in 3 (5,6%), gastro-intestinal diseases - in 3 (5,6%), respiratory diseases - in 2 (3,7%). In 3 women there was revealed cystic ovary, in 2 - endocrine pathology.
In 18 (31,6%) patients of the second group there were revealed chronic gynecological diseases: en-dometriosis - in 14,1%, cervicitis - in 8,8%, cervical erosion - in 3,5%, polycystosis, cystic ovary and uterine myoma - in 1,8%. Menstrual disorders were observed in 13 women (22,8%). Various endocrine disorders were registered in 4 (7,0%) patients, gastro-intestinal diseases - in 4 (7,0%), HIV infection - in 3 (5,3%).
The age of the inflammatory process in the area of external genital organs ranged from 2 to 7 days. Subjective symptoms were traditional for acute VVC and were characterized by intensive itching -in 84 (75,7%), burning - in 69 (62,2%), dyspareunia
- in 56 (50,5%), excessive secretions from genital tracts - in 54 (48,6%) patients, expressed painful-ness by urination - in 16 (14,4%), dull lower abdominal pain - in 6 (5,4%).
The objective examination of all 111 patients revealed symptoms of vulvitis apparently being secondary in nature: edema, hyperemia of labia minora, rarer - of labia majora, of vaginal orifice, clitoris, epithalamic commissure, and also layering of secretions of caseous type. The vaginal examination revealed: intense hyperemia - in 101 (91,0%) patients and expressed edema of vaginal walls -in 96 (86,5%), more often - intensive (in 57 - 51,4%) or moderate (in 54 - 48,6%) secretions from vagina; the secretions were primarily caseous - in 61 (55,0%) patients. Objective symptoms of urethritis in more than the half of patients were characterized by hyperemia (in 66 - 59,5%), accompanied by edema (in 54 - 48,6%) of urethral sponges. 31 (27,9%) had stated symptoms of cervicitis with hyperemia and slight edema of the vaginal part of uterine cervix with caseous "fur". 14 patients had slight secretions from the cervical channel, the external os of the channel was hyperemic and edemic.
The microscopy of vaginal secretion in all patients revealed the elements of yeast-like fungi -blastospores and pseudomycelium accompanied by leukocytosis of 25-50 neutrophils per field of vision and exceeded number of epithelial cells. In 24 patients out of 66 patients with symptoms of ure-thritis there was revealed an exceeded number
of leucocytes - more than 10 cells - per field of vision. The PCR-test did not reveal any STD causative agents. The cultural examination of cervical secretion revealed in 14 patients with symptoms of cervicitis E. faecalis, E.coli, St. aureus, St. epider-midis in concentration over 104 cfu/ml.
The control of recovery showed clinical and eti-ological recovery on the 4th day after fenticonazole administration in 47 (87,0%) patients of the first group.
7 women of the first group retained inflammatory symptoms in the vaginal area on the 4th day after the start of treatment (slight hyperemia without edema, slight secretions from the posterolateral vaginal fornix of mainly creamy type, in 3 patients - recurrent moderate itching). The microscopy of vaginal secretions in all 7 patients revealed blas-tospores, in 3 - excessive leucocytes (up to 30 cells per field of vision). The microscopy of urethral secretion corresponded to the norm.
The analysis of anamnestic data in 7 patients showed that all patients had chronic inflammatory diseases of urogenital tract, respiratory system and gastro-intestinal tract, 6 of them had concomitant nonspecific (aerobic) cervicitis. 5 patients constantly used daily pantyshields and tight synthetic under-clothes. 4 women marked long-term administration of antibacterial medications 2-3 weeks before VVC development, in 3 patients there were revealed occupational hazards: occupation of nurse in the treatment room (in 2) and pastrycook (in 1). In all 7 women these factors were stated in various combinations, thus, every patient was characterized by complicated acute VVC. Due to the preservation of inflammatory symptoms in vagina blastospores by microscopy (on the 4th day after the first fenticonazole administration) these patients were exposed to the repeated introduction of the vaginal capsule. Six patients with revealed aerobic cervicitis together with fenticonazole received co-amoxiclav for 5 days. On the 10th day after the end of treatment the clinical laboratory control showed regression of Candida vaginitis in all patients with the absence of elements of yeast-like fungi and excessive leucocytes in vagina. 6 patients receiving co-amoxiclav showed regression of cervi-citis symptoms.
According to the analysis of treatment results in patients of the first group, all 47 (100%) patients with acute uncomplicated VVC showed clinical and microbiological recovery after the intake of one capsule of fenticonazole. Seven patients with diagnosed complicated acute VVC receiving 2 capsules of fenticonazole per the course of treatment also showed clinical and microbiological recovery.
The data obtained during the first stage of study allowed to assume that it is reasonable to prescribe 2 capsules of fenticonazole per the course of treatment with 3-day break to the patients with complicated acute VVC, which was proved during
the second stage of study: clinical and etiological effectiveness of the stated course of treatment constituted 95,5% (55 patients) on the 10th day after the end of therapy.
In 2 women of the second group there remained itching and vaginal inflammatory symptoms: moderate hyperemia, secretions of creamy type. The microscopy showed blastospores and mycelium fibers.
The analysis of anamnestic data of these patients showed that constantly used tight synthetic under-clothes and one woman used daily pantyshields. Moreover, both patients had chronic inflammatory diseases of the urinary tract (cervi-citis, cervical erosion), menstrual disorders, endocrine pathologies (thyroid gland nodule), long-term administration of contraceptives, violation of intimate hygiene rules. Due to the preservation of inflammatory symptoms in vagina blasto-spores by microscopy these patients were exposed to the systemic therapy with fluconazole.
The analysis of fenticonazole safety in 106 patients did not reveal any side effect - neither local, nor systemic. Only 5 (4,5%) patients complained for slight burning and itching by the drug administration which disappeared in 1,5-3 hours.
Consequently, two stages of our study showed that therapeutic activity of one vaginal capsule of fenticonazole 600 mg by acute uncomplicated VVC constituted 100% (71 out of 47 patients), of two capsules by complicated VVC - 96,9% (62 out pf 64 patients).
Conclusions
1. Fenticonazole in the form of vaginal capsule in the dose of 600 mg is a highly effective and safe medicine by the treatment of acute VVC possessing high compliance and allowing to reach clinical and etiological recovery in the majority of patients.
2. The indication to one-time administration of vaginal capsule of fenticonazole 600 mg is acute uncomplicated VVC, to two-time administration of fenticonazole 600 mg with 3-day break - complicated acute VVC.
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Contacts:
Corresponding author - Malova Irina Olegov-na, Doctore of Medical Sciences, Professor, Head of the Department of dermatovenerology of the Advanced Training Faculty and teaching stuff of Irkutsk State Medical Universit, Irkutsk. 664025, Irkutsk, Rossiyskaya Ulitsa, 16. Tel.: (3952) 242313. Email: marinakartina@mail.ru
