Intermittent itraconazole in onychomycosis C/inical study INTERMITTENT ITRACONAZOLE IN THE TREATMENT OF DISTOLATERAL ONYCHOMYCOSIS OUR EXPERIENCE I. Prelog and M. Dolenc-Voljč ABSTRACT Background. ltraconazole is a broad-spectrum triazole with known efficacy in pulse therapy for various dermatomycoses. Objectives. To perform an analysis of the efficacy of pulse therapy with itraconazole in treating distolateral toenail and fingernail onychomycosis and to evaluate the safety of intermittent treatment with itraconazole. Patients and methods. The study was completed by 17 patients. Treatment consisted of two pulses of itraconazole, 200 mg twice daily, for seven consecutive days each month for fingernail onychomycosis and of three pulses for toenail onychomycosis. Clinical evaluation was made before treatment, at each month during treatment period and at week 24, 36 and 48 post-treatment. Mycological examinations were performed at the beginning and the end of therapy as well as at each post-treatment visit. Results. Progressive improvement of ali clinical signs of onychomycosis was noted at each point of patient evaluations. Mycological cure results were statistically significant comparing pre-treatment status with the final visit at week 48. In two patients with toenail onychomycosis on the last visit relapse was considered. Conclusions. Very satisfactory clinical and mycological responses were observed in our patients. Itraconazole therapy was also associated with good tolerability and patient compliance. KEY WORDS onychomycosis, itraconazole, pulse therapy INTRODUCTION In the past, onychomycosis has been regarded more as a cosmetic problem and often remained untreated. This was mainly because treatment with traditional antifungal agents required long treatment with disappointing success rates. Relapses were freq- uent especially in toenail infections which are generally more recalcitrant to treatment than fingernail onycho- acta dermatovenerologica A .P.A. Vol 7, 98, No 3-4 mycosis. Besides, systemic therapy for onychomycosis represented a high risk of troublesome systemic side effects, which might become significant with prolonged drug use (1 ,2). In recent years, the introduction of new oral antifungal agents in the treatment of onychomycosis, especially itraconazole and terbinafine, resulted in improved cure rates with shorter treatment duration, lesser risk of side effects and lower relapse rates 153 Intennittent itraconazole in onychomycosis (2,3,4). Both itraconazole and terbinafine have been faund to be effective and safe in the therapy of onychomycoses. Pulse therapy with itraconazole was developed with the aim of maintaining efficacy, reducing costs, improving patient's compliance and maximizing tolerability during treatment of onychomycosis. Both continuous and pulse treatment regimens were faund effective, safe and well tolerated (5,6). The tata! amount of drug administered in the pulse treatment regimen is three times Iower than with continuous therapy. Following pulse therapy with itraconazole, the drug has been detected in the distal ends of nail plate in therapeutic concentrations. After the last pulse, the drug remains in the nail plate far severa! months (5,7). PATIENTS AND METHODS Seventeen patients, males and females, with distolateral subungual onychomycosis, were evaluated in a prospective, open and non-comparative study. In 15 patients onychomycosis was present on toenails and in 2 patients on fingernails. Patients were studied at the Clinical Center, Department of Dermatology in Ljubljana and at the Dermatology Department of Maribor Teaching Hospital. Inclusion criteria were: patients' age between 18 and 70 years of age, written or verbal infarmed consent, distolateral subungual onychomycosis, confir- med by direct mycological examination and with positive culture of a dermatophyte, yeast or mould , no previous antifungal therapy (systemic more than 3 months and topical more than two weeks befare the study). Exclusion criteria were: severe onychomycosis with more than 75% of nail surface affected, pregnancy or lactation, any severe underlying disease, psoriasis, diabetes, clinical evidence of peripheral vascular disease, disease or treatment inducing immuno- suppression, history of hepatopathy, concomitant use of drugs with potential interaction with itraconazole ( astemizole, terfenadine, digoxin, oral anticoagulants, phenitoin, cyclosporine, etc.). The therapeutic scheme used was 200 mg itraco- nazole twice daily ( 400 mg per day), far the first week of each month, fallowed by 3 weeks without therapy. Three monthly cycles were given far toenail onychomycosis and 2 monthly cycles far fingernail onychomycosis. Post-treatment fallow-up was 10 months far toenail onychomycosis and 8 months far fingernail onychomycosis. The study ended 48 weeks after the start of the therapy. Evaluation criteria Monthly clinical evaluations were perfarmed during treatment (eve1y faurth week) and at week 12, 24 and 36 far fingernail onychomycosis and additionally at week 48 far toenail onychomycosis. After completion of therapy patients with fingernail onychomycosis were fallowed far 8 months and patients with toenail onychomycosis far 10 months. The length of the unaffected part of the target nails was registered before the start of the treatment and at each subsequent clinical examination. Measurement was Iongitudinally made from the proximal ungueal edge up to the beginning of the involvement. Clinical response was defined as cured (more than 90% of clear nail), markedly improved (more than 50% clinical improvement) , moderately improved (less than 50% clinical improvement), unchanged and deteriorated. Besides, at each clinical assessment signs of onycholysis, hyperkeratosis and paronychia were also evaluated and defined as severe, moderate, mild or absent. Direct mycological examination and culture in Sabouraud's dextrose agar were performed at baseline, Table l. Clinical and mycological efficacy in onychomycosis after three months of pulse therapy with itraconazole. clinical efficacy (%) cured 5.9 35.3 64.7 73.3 marked improvement 35.3 52.9 35.3 26.4 moderate improvement 58.8 11.8 unchanged deterioration mycological cure* 35.3 88.2 82.4 80.0 *negative microscopy and cu/ture 154 acta dennatovenerologica A.P.A. Vol 7, 98, No 3-4 Intennittent itraconazole in onychomycosis 2,0 ,------------;:::=====::::;- ., --onycholysis Š 1,5 %--==:::::=~------7 _.. hyperkeratosis CII z;, 1,0 _._paronychia ·.:: CI) ~ 0,5 +----------==-------=- ;::------j en 0,0 t ====:=i!i====~~;;;;~~~;;;;;;:::::j w eek O week 12 week 24 week 36 week 48 Time Figure l. Regression of clinical signs of onychomycosis, onycholysis, hyperkeratosis and paronychia, during the study. at the end of the pulse therapy treatment and at each patient's visit during post-treatment follow-up. Laboratory tests including complete hemogram, transaminases, alkaline phosphatase, direct, indirect and total billirubin, urea, creatinine and total chole- sterol were performed at the screening visit . Ali adverse events were recorded at each visit during therapy and the follow-up period. Overall tolerability of the medication was rated by patients 1 or 2 months after completion of therapy for fingernail and toenail onychomycosis. RESULTS Of eighteen patients included at the start of the investigation, seventeen completed all the stages of the protocol, seven males, and ten females . Their ages varied from 31 to 69 years (median age 51 years). Duration of onychomycosis ranged from 0,7 to 18 years (mean duration 3.7 years). In two patients onychomycosis was located on fingernails and in 15 patients on toenails. One patient was dropped because he was !ost to follow-up. Dermatophytes were the most prevalent fungus isolated (altogether in 83% of patients), Trichophyton rubrum in 53%, Trichophyton mentagrophytes in 40% and Trichophyton venucosum in one patient. Derma- tophytes were isolated from toenails only. In one patient with toenail onychomycosis Scopulariopsis week O week 12 week 24 week 36 YJeek 48 -4•t-----1• -4•t-------------•~fore treatment phase follow-up phase Figure 2. Clinical and mycological cure rates in onycho- mycosis during and after itraconazole pulse therapy. acta de,matovenerologica A.P.A. Vol 7, 98, No 3-4 brevicaulis was the isolated pathogen. In the two patients with fingernail onychomycosis Candida species were isolated (12% ). Clinical response At week 12 marked improvement was present in 41.2% of the patients and in 5.9% clinical cure was established. At the last follow-up visit clinical response was recorded in all patients, 73% of them were considered cured and in 27% marked improvement had been achieved (Table 1). Median length of unaffected nail parts was increased at every subsequent examination, from 8 mm at baseline visit to 14 mm at the end of the study. This increase was statistically significant (p :S: 0.001). In all patients significant improvement of all three clinical signs, onycholysis, hyperkeratosis and paronychia were recorded, both during the treatment and post- treatment period. Severity of onycholysis decreased from 1.5 severity score at the first visit to 0.2 at the fina! evaluation. Severity of hyperkeratosis has also been decreased during ali stages of evaluations, from 1.3 to 0.1 of severity score. Severity of paronychia decreased at every subsequent examination as well (Figure 1). Mycological response At the end of the study 15 out of 17 cultures (88.2%) were negative. In two patients with toenail onychomycosis negative cultures had already been achieved during post-treatment period, but became positive again, in one at week 36 and in another at week 48. Trichophyton rubrum developed in both of them. In two patients with fingernail onychomycosis complete clinical and mycological cure was already achieved at week 24. Overall efficacy with clinical and mycological cure in patients with fingernail and toenail onychomycosis is presented in figure 2. Patient tolerance During the treatment period possibly drug related adverse events occurred in three patients (17% ). Two patients reported headache and one patient nausea and diarrhea. These patients experienced the adverse events during the week of drug administration. None of these events were serious and it was not necessary to suspend treatment. Laboratory · data were within normal range in ali patients at the beginning of the study. During therapy, the patients 155 Intennittent itraconazole in onychomycosis showed no evidence of laboratory data deterioration and it was not necessary to repeat them. DISCUSSION The number of patients in our study was rather small, with only two patients presenting onychomycosis due to Candida spec. on fingernails. Trichophyton rubrum was the most frequent fungus isolated on toenails, fallowed by Trichophyton mentagrophytes, as observed in other countries (5,8). Our results agreed with most of the data faund in the literature and confirm that itraconazole is a highly effective drug in the treatment of distolateral toenail onychomycosis, caused by dermatophytes as well as in fingernail onychomycosis due to yeasts. Two pulses were efficient far fingernail onycho- mycosis and three pulses far distolateral toenail onychomycosis. In none of our patients severe toenail onychomycosis with nail matrix involvement was present. For more extensive nail involvement addi- tional itraconazole pulses would be necessary (9). After drug discontinuation, an improvement of ali clinical signs was observed: the length of unaffected nail parts, onycholysis, hyperkeratosis and paronychia. At the fina! evaluation, 8 months after completion of therapy far fingernail and 10 months far toenail onychomycosis, clinical cure rates were 100% and 73%, respectively. Follow-up lasted severa! months in our patients allowing detection of possible relapses or reinfections. The data on relapses in toenail onychomycosis are rather contradictory in the literature. In our study in two patients with toenail onychomycosis (13.3 %) Trichophyton rubrum was cultured once again at the fina! visit. This was considered a relapse because in both cases complete clinical cure had not been achieved. CONCLUSION Pulse therapy with itraconazole was faund safe and well tolerated in our patients. Adverse events occurred in 17% of them (headache, nausea, and diarrhea) but only during the drug ingestion period and did not require drug suspension. Intermittent therapy was also faund convenient and was associated with good patient compliance. REFERENCES l. Pierard GE, Arrese-Estrada J, Pierard-Franchimont C. Treatment of onychomycosis: Traditional approaches. J Am Acad Dennatol 1993; 29: S41-S45. 2. Roseeuw D, De Doncker P. New approaches to the treatment of onychomycosis. J Am Acad Dennatol 1993; 29: S45-S50. 3. Hay RJ. Risk/benefit ratio of modem antifungal therapy: Focus on hepatic reactions. J Am Acad Dennatol 1993:29:S50-S54. 4. Denning DW et al. Fungal nail disease: a guide to good practice (report of a Working Group of the British Society for Medica! Mycology). BMJ 1995; 311: 1277-81. 5. De Doncker P et al. Antifungal Pulse Iherapy for Onychomycosis. A Phannacokinetic and Phannacodynamic Investigation of Monthly Cycles of 1-Week Pulse Iherapy Wzth Itraconazole. Arch Dennatol 1996; 132: 34-41. 6. Havu V et al. A double blind randomized study comparing itraconazole pulse therapy with continuous dosing for the treatment of toenail onychomycosis. B J Dennatol 1997; 136: 230-4. 7. Willemsen M, De Doncker P, Willems J et al. Post- treatment itraconazole levels in the nail. J Am Acad Dennatol 1992; 26(5): 731-5. 8. Heikkila H, Stubb S. Ihe prevalence of onychomycosis in Finland. Br J Dennatol 1995; 133: 699-703. 9. Ramos-e-Silva M et al. Efficacy and safety of itraconazole pulse therapy: Brazilian multicentric study on toenail onychomycosis caused by dennatophytes. J Eur Acad Dennatol 1998; 11: 117-21. AUTHORS' ADDRESSES Ida Prelog, MD, dermatologist, Head Department of Dermatology, Teaching Hospital Maribor, 2000 Maribor, Slovenia Mateja Dolenc-Voljč, MD, dermatologist, Department of Dermatology, University Medica! Center, 1525 Ljubljana, Slovenia 156 acta de,matovenerologica A.P.A. Vol 7, 98, No 3-4