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Efficacy and tolerability of itraconazole in patients with fingernail onychomycosis: a 6-week pilot study
CURRENT THERAPEUTIC RESEARCH ® VOL. 56, NO. 10, OCTOBER 1995
EFFICACY AND TOLERABILITY OF ITRACONAZOLE IN PATIENTS WITH FINGERNAIL ONYCHOMYCOSIS: A 6-WEEK PILOT STUDY J E O N G - A E E KIM, 1 K Y U - J O O N G AHN, 2 JONG-MIN KIM, 8 AND JAI-IL Y O U N 1
1Department of Dermatology, College of Medicine, Seoul National University, 2Konkuk University, and 3Hallym University, Seoul, Korea
ABSTRACT
Twenty-one patients (6 men, 15 women) with fingernail onychomycosis participated in this open-label trial. They received 200-mg itraconazole once daily for 6 weeks and were followed up for 12 weeks after stopping treatment. All patients had fungal elements detected by using microscopic examination of potassium hydroxide (KOH) smear of their fingernail scrappings at the start of the trial. Cultures revealed that 7 patients were infected with Trichophllton rubrum; 6 with yeasts; and I with Fusarium species. At the end of treatment (week 6), 42.9% of patients were free of fungal colonization, as assessed by using KOH smear and fungus culture results. At the end of the follow-up period (week 18), 81.0% were clinically completely clear of lesion with a negative KOH smear and fungus culture, and an additional 9.5% were markedly improved, with a minimal residual lesion and a negative KOH smear and fungus culture. Three (14.3%) of 21 patients reported mild adverse events. The results of this trial confirm that a regimen of 200-rag itraconazole once daily for 6 weeks is effective and well tolerated in the treatment of patients with fingernail onychomycosis caused by either dermatophytes or yeasts. INTRODUCTION
Onychomycosis is one of the most frequent nail diseases and its incidence is estimated at about 2% to 13% in the general population. 1 Dermatophytes are the main causative agents of toenail infections,2 whereas in fingernail infections, yeasts are more common 3 or are isolated as f r e q u e n t l y as dermatophytes. 4 Among fingernail infections, Candida albicans is still the most frequently isolated organism, 2'3 but the pattern is shifting toward other Candida species, in particular, Candida parapsilosis. 3'4 Although fingernails tend to respond more quickly t h a n toenails to antifungal treatment, onychomycosis is notoriously difficult to treat. ProAddress correspondence to: Jeong-Aee Kim, MD, Department of Dermatology, College of Medicine, Seoul National University, 28 Yunkun-dong, Chongro-ku, Seoul 110-744, Korea. Receivedfor publication on July 10, 1995. Printed in the U.S.A. Reproduction in whole or part is not permitted. 1066
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J.A. KIM ET AL.
longed therapy is often required, and the overall response is poor. 1'2 Moreover, the drugs currently used for oral treatment (eg, griseofulvin and ketoconazole) have efficacy and safety limitations. 1'5 Itraconazole, a triazole derivative, has demonstrated a high activity in in vitro studies against dermatophytes, yeasts, and other pathogenic fungi. 6 Its broad-spectrum activity has been confirmed in various animal models, v It has been used successfully in the treatment of fingernail onychomycosis, but mostly as prolonged therapy, s Willemsen et al 9 measured posttreatment itraconazole levels in toenails and fingernails and studied the efficacy of a 3-month t r e a t m e n t with 200 mg once daily in the treatment of patients with onychomycosis. Their data indicated that therapeutic itraconazole concentrations were found in the nail plates of fingernails and toenails for up to 6 months after 3 months of treatment. This would suggest that a shorter course of therapy might be effective with daily doses of 200 mg. In fact, they reported that the cure rate with a 3-month regimen of 200 mg once daily could be compared favorably with those achieved with a 100 mg once daily schedule administered for longer periods (8 to 12 months). As fingernails grow more quickly than toenails, l° we thought that a shorter t r e a t m e n t c o u r s e - - f e w e r than 3 m o n t h s - - c o u l d be successful for fingernail onychomycosis. This pilot study was designed to evaluate the efficacy and tolerability of a 6-week t r e a t m e n t course with itraconazole* 200 mg daily for onychomycosis of the fingernails. Patients were followed up for 12 weeks after the termination of t r e a t m e n t to assess the healing process. PATIENTS AND METHODS
Twenty-one patients (6 men, 15 women; mean age, 46.2 -+ 13.7 years) with fingernail onychomycosis, diagnosed by the presence of fungal elements in a potassium hydroxide (KOH) smear, were included in this open-label study. The mean duration of infection was 2.8 -+ 3.2 years, and the mean number of infected nails was 2.3 +- 2.1. All patients provided verbal informed consent prior to the start of the study. None of the patients entered in the trial had been treated with itraconazole in the 3 months before the study, and none had received any other systemic or topical antimycotic within 1 month of the start of the study. All patients entering the trial were required to have normal results of a liver function test. Pregnant women were excluded, and women who entered the trial had to use adequate birth control methods. Patients suffering from serious concurrent disease or psoriasis were also excluded. * Trademark: Sporanox (Janssen Pharmaceutica Inc., Titusville,N e w Jersey).
1067
SHORT-TERM ITRACONAZOLEFOR FINGERNAIL ONYCHOMYCOSIS
Treatment consisted of two 100-mg capsules of itraconazole taken once a day for 6 weeks. Patients receiving drugs that reduced gastric secretion were instructed to delay the intake of those medications for 1 hour after having taken itraconazole. KOH smear microscopy and fungus cultures were carried out on potentially infected nails at the beginning of the trial (week 0), at the end of treatment (week 6), and at the end of the follow-up period (week 18). If a patient had several infected nails, we identified the most severely involved nail as a "target nail" before treatment for monitoring during the trial. Smears of fingernail scrappings were considered KOH positive when there were hyphae or pseudohyphae, or many spores identified in the sample. We used Sabouraud's dextrose agar as culture medium and identified the colonies by using gross and microscopic features. We performed sugar fermentation tests for identification of the yeasts. When yeasts or nondermatophytic molds were cultured, we repeated the KOH study and fungus culture, and considered the isolated fungus to be pathogenic only when the same fungus could be cultured purely and repeatedly. A visual estimate of the pathologically changed part of the nail plate as a percentage of the whole nail plate in a target nail was made at the start of the trial and at each subsequent clinic visit (3, 6, 12, and 18 weeks). Target nails were also photographed so that the visual estimate could be verified. At these visits, the nails were also scored for brittleness, onycholysis, subungual keratosis, perionyxis, and discoloration by using a fourpoint rating scale (0 = absent, 1 = traces, 2 = present, and 3 = pronounced). The sum of clinical scores of a target nail at a given time (week 0, 3, 6, 12, or 18) were calculated and the mean + SD of total clinical scores of the target nail was determined. Statistical analysis (Student's t test) was performed using mean scores. Overall evaluation was made at 6, 12, and 18 weeks, and patients were assigned to the following categories: cured (completely clear of lesion, with negative KOH smear and fungus culture); markedly improved (minimal residual lesion with negative KOH smear and fungus culture); moderately improved (small residual lesion with positive KOH smear and fungus culture); or unchanged (no clinical improvement of lesion). At the start of treatment (week 0) and at the end of treatment (week 6), blood samples were taken for complete blood count (white blood cell and red blood cell counts, hemoglobin, hematocrit, platelet count, and differential count) and liver function tests (cholesterol, total protein, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase [AST], and alanine aminotransferase [ALT]). Adverse reactions were recorded on case report form, which reported date of onset and termination of event, severity, frequency, causal relationship, action taken, and patient outcome.
1068
J.A. KIMET AL.
RESULTS
At the beginning of the study, all 21 patients had a KOH-positive smear and fungi were cultured from 14 patients (66.7%). Of the 14 fungal isolates, 7 were dermatophytes, 6 were yeasts, and 1 was a nondermatophyte mold (Table I). All dermatophyte infections were due to Trichophyton rubrum. Of the yeast infections, 3 cases were due to C albicans. Candida guilliermondii, C parapsilosis, and Fusarium species were pure cultured repeatedly in separate cases, and were considered to be pathogens in addition to T rubrum and C albicans. In another five cases, yeasts and/or mold were isolated but not pure cultured nor repeatedly isolated, so they were considered to be contaminants.
Efficacy The visually estimated percentage of involvement in the target nails was 74.8 - 23.6% at week 0, 52.2 ± 21.1% at week 3, 34.9 ± 22.6% at week 6, 16.0 ± 18.0% at week 12, and 6.8 ± 11.5% at week 18 (Figure 1). The mean total score of clinical signs of target nails was 9.2 ± 2.3 at week 0, 7.6 ± 2.5 at week 3, 5.4 ± 3.0 at week 6, 3.3 ± 3.1 at week 12, and 1.9 ± 2.4 at week 18 (Figure 2). Both results were statistically significant from week 3 onward (P < 0.05, Student's t test). At the end of t r e a t m e n t (week 6), 42.9% (9/21) of the patients were free
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Weeks Figure 1. Percentage of involvement in target nails of 21 patients with fingernail onychomycosis. Size of involved area was significantly decreased (P < 0.05) after 3 weeks of treatment with itraconazole 200 mg/d and continuously decreased during the follow-up period. Vertical bars indicate SD. 1069
SHORT-TERMITRACONAZOLEFOR FINGERNAILONYCHOMYCOSIS
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Weeks Figure 2. Mean ( - SD) total scores of clinical symptoms in target nails of 21 patients with fingernail onychomycosis. Total scores were significantly decreased (P < 0.05) after 3 weeks of t r e a t m e n t with itraconazole 200 mg/d and continuously decreased during the follow-up period. Score was based on a four-point r a t i n g scale: 0 = absent; 1 = traces; 2 = present; and 3 = pronounced.
of fungal colonization, as judged by KOH smear and fungus culture. At the end of follow-up (week 18), this percentage had increased to 90.5% (19/21). In terms of the overall clinical response, a total of 42.9% (9/21) of patients were markedly improved and 57.1% (12/21) moderately improved at the end of treatment (week 6). At week 18, 81.0% (17/21) of patients were cured, 9.5% (2/21) were markedly improved, and 9.5% (2/21) were moderately improved (Table II).
Tolerability Three (14.3%) of 21 patients reported mild adverse events (nausea, Table I. Classification of the identified organisms in cultures from patients with fingernail onychomycosis. Organism
No. of Patients
Dermatophytes Trichophyton rubrum Yeasts (pathogenic) Candida albicans Candida guilliermondii Candidaparapsilosis Molds (pathogenic) Fusarium sp Yeast and/or mold (saprophytic) No growth Total
7 3 2 1
1 5 2 21
1070
J.A.
KIM ET AL.
Table II. Overall efficacy of 6 weeks of itraconazole 200 mg/d in the treatment of 21 patients with fingernail onychomycosis. Values are numbers of patients (%).
Result*
End of Treatment (week 6)
1st Follow-Up (week 12)
Last Follow-Up (week 18)
Cured Markedly improved Moderately improved
0 (0.0) 9 (42.9%) 12 (57.1%)
6 (28.6%) 10 (47.6%) 5 (23.8%)
17 (81.0%) 2/9.5%) 2 (9.5%)
Unchanged
0 (0.0%)
0 (0.0%)
O (0.0%)
*Cured = complete clear of lesion and negative for fungal elements by KOH smear and fungus culture; markedly improved = minimal residual les~on with negative KOH smear and fungus culture; moderately improved = small residual lesion with positive KOH smear and fungus culture; unchanged = no clinical improvement of lesion.
indigestion, and dizziness), none of which was serious enough to discontinue treatment. The complete blood counts did not reveal any abnormalities. In one patient, liver function tests showed a slight increase in AST and ALT levels: 41 IU/L (normal range, 0 to 40 IU/L) and 62 IU/L (normal range, 0 to 40 IU/L), respectively, at week 6. This patient did not have a history of liver disease, nor use any drug other than itraconazole. Because she refused studies to determine the cause of the abnormal results of her liver function tests, we could not definitely link this to itraconazole administration. DISCUSSION AND CONCLUSION
The pharmacokinetics of itraconazole in the nail plate 9 and the rapid growth of fingernails l° suggest that a treatment regimen shorter than the 3 months used in previous fingernail onychomycosis trials 9 may be appropriate. The results obtained in this open-label trial, with a 6-week treatment course of 200 mg daily, support this hypothesis. A clinical response rate (cured and markedly improved) and negative KOH smear and fungus culture rate of 90.5% was obtained at the 12-week follow-up (week 18). This is comparable to the results achieved with a 3-month regimen. This study also illustrates the broad-spectrum antifungal activity of itraconazole. Itraconazole 200 mg/d for 6 weeks was efficacious in the treatment of fingernail onychomycosis caused by T rubrum (Figure 3); C albicans (Figure 4), or Fusarium species (Figure 5). In fingernail onychomycosis, dermatophytes still play an important role, but yeasts and nondermatophyte molds are becoming increasingly important. Thus broadspectrum antifungal activity should be considered essential in the face of this new array of nail pathogens. The data in this trial show that itraconazole 200 mg/d is well tolerated; the adverse events seen (nausea, indigestion, and dizziness) were 1071
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mild in intensity. Gastrointestinal upset and headaches are the most common adverse events as reported previously with itraconazole. 1'11 Whether a dose of itraconazole higher than 200 mg daily, for a shorter period than 6 weeks, would show comparable results to this study remains to be proved and merits further investigation. At the time this study was designed, the only possible comparator drugs were griseofulvin and ketoconazole. We did not think that these drugs would produce comparable results to itraconazole because of the short treatment period. A study comparing itraconazole with a currently available antifungal (allylamine) might be of interest.
Acknowledgment This study was supported in part by Janssen Korea Limited, Seoul, Korea. References:
1. Gupta AK, Sauder DN, Shear NH. Antifungal agents: An overview. Part II. J A m Acad Dermatol. 1994;30:911-933. 2. Haneke E. Fungal infections of the nail. Semin Dermatol. 1991;10:41-43. 3. Clayton YM. Clinical and mycological diagnostic aspects of onychomycosis and dermatomycoses. Clin Exp Dermatol. 1992;17(Suppl):S37-S40. 4. Midgley G, Moore MK, Cook JC, et al. Mycology of nail disorders. J A m Acad Dermatol. 1994;31(Suppl):S68- $74. 5. Pierard GE, Arrese-Estrada J, Pierard-Franchimont C. Treatment of onychomycosis: Traditional approaches. J A m Acad Dermatol. 1993;29(Suppl):S41-S45. 6. Van Cutsem J. The in-vitro antifungal spectrum of itraconazole. Mycoses. 1989; 32(Suppl):S7-S13. 7. Van Cutsem J, Van Gerven F, Janssen PAJ. Activity of orally, topically and parenterally administered itraconazole in the treatment of superficial and deep mycoses: Animal models. Rev I n f Dis. 1987;8(Suppl):S15-S32. 8. Piepponen T, Blomquist K, Brandt H, et al. Efficacy and safety of itraconazole in the long-term treatment of onychomycosis. J Antimicrob Chemother. 1992;29:195-205. 9. Willemsen M, De Concker P, Willems J, et al. Post-treatment itraconazole levels in the nail. J A m Acad Dermatol. 1992;26:731-735. 10. Zaias N. The Nail in Health and Disease. 2nd ed. Norwalk: Appleton & Lange; 1990:314. 11. De Beule K, Lubin G, Cauwenbergh G. Safety aspects of itraconazole in vaginal candidosis, dermatomycosis, and onychomycosis. A review. Curr Ther Res. 1991;49:814-822.
1075
EFFICACY AND TOLERABILITY OF ITRACONAZOLE IN PATIENTS WITH FINGERNAIL ONYCHOMYCOSIS: A 6-WEEK PILOT STUDY J E O N G - A E E KIM, 1 K Y U - J O O N G AHN, 2 JONG-MIN KIM, 8 AND JAI-IL Y O U N 1
1Department of Dermatology, College of Medicine, Seoul National University, 2Konkuk University, and 3Hallym University, Seoul, Korea
ABSTRACT
Twenty-one patients (6 men, 15 women) with fingernail onychomycosis participated in this open-label trial. They received 200-mg itraconazole once daily for 6 weeks and were followed up for 12 weeks after stopping treatment. All patients had fungal elements detected by using microscopic examination of potassium hydroxide (KOH) smear of their fingernail scrappings at the start of the trial. Cultures revealed that 7 patients were infected with Trichophllton rubrum; 6 with yeasts; and I with Fusarium species. At the end of treatment (week 6), 42.9% of patients were free of fungal colonization, as assessed by using KOH smear and fungus culture results. At the end of the follow-up period (week 18), 81.0% were clinically completely clear of lesion with a negative KOH smear and fungus culture, and an additional 9.5% were markedly improved, with a minimal residual lesion and a negative KOH smear and fungus culture. Three (14.3%) of 21 patients reported mild adverse events. The results of this trial confirm that a regimen of 200-rag itraconazole once daily for 6 weeks is effective and well tolerated in the treatment of patients with fingernail onychomycosis caused by either dermatophytes or yeasts. INTRODUCTION
Onychomycosis is one of the most frequent nail diseases and its incidence is estimated at about 2% to 13% in the general population. 1 Dermatophytes are the main causative agents of toenail infections,2 whereas in fingernail infections, yeasts are more common 3 or are isolated as f r e q u e n t l y as dermatophytes. 4 Among fingernail infections, Candida albicans is still the most frequently isolated organism, 2'3 but the pattern is shifting toward other Candida species, in particular, Candida parapsilosis. 3'4 Although fingernails tend to respond more quickly t h a n toenails to antifungal treatment, onychomycosis is notoriously difficult to treat. ProAddress correspondence to: Jeong-Aee Kim, MD, Department of Dermatology, College of Medicine, Seoul National University, 28 Yunkun-dong, Chongro-ku, Seoul 110-744, Korea. Receivedfor publication on July 10, 1995. Printed in the U.S.A. Reproduction in whole or part is not permitted. 1066
0011-393X/95/$3.50
J.A. KIM ET AL.
longed therapy is often required, and the overall response is poor. 1'2 Moreover, the drugs currently used for oral treatment (eg, griseofulvin and ketoconazole) have efficacy and safety limitations. 1'5 Itraconazole, a triazole derivative, has demonstrated a high activity in in vitro studies against dermatophytes, yeasts, and other pathogenic fungi. 6 Its broad-spectrum activity has been confirmed in various animal models, v It has been used successfully in the treatment of fingernail onychomycosis, but mostly as prolonged therapy, s Willemsen et al 9 measured posttreatment itraconazole levels in toenails and fingernails and studied the efficacy of a 3-month t r e a t m e n t with 200 mg once daily in the treatment of patients with onychomycosis. Their data indicated that therapeutic itraconazole concentrations were found in the nail plates of fingernails and toenails for up to 6 months after 3 months of treatment. This would suggest that a shorter course of therapy might be effective with daily doses of 200 mg. In fact, they reported that the cure rate with a 3-month regimen of 200 mg once daily could be compared favorably with those achieved with a 100 mg once daily schedule administered for longer periods (8 to 12 months). As fingernails grow more quickly than toenails, l° we thought that a shorter t r e a t m e n t c o u r s e - - f e w e r than 3 m o n t h s - - c o u l d be successful for fingernail onychomycosis. This pilot study was designed to evaluate the efficacy and tolerability of a 6-week t r e a t m e n t course with itraconazole* 200 mg daily for onychomycosis of the fingernails. Patients were followed up for 12 weeks after the termination of t r e a t m e n t to assess the healing process. PATIENTS AND METHODS
Twenty-one patients (6 men, 15 women; mean age, 46.2 -+ 13.7 years) with fingernail onychomycosis, diagnosed by the presence of fungal elements in a potassium hydroxide (KOH) smear, were included in this open-label study. The mean duration of infection was 2.8 -+ 3.2 years, and the mean number of infected nails was 2.3 +- 2.1. All patients provided verbal informed consent prior to the start of the study. None of the patients entered in the trial had been treated with itraconazole in the 3 months before the study, and none had received any other systemic or topical antimycotic within 1 month of the start of the study. All patients entering the trial were required to have normal results of a liver function test. Pregnant women were excluded, and women who entered the trial had to use adequate birth control methods. Patients suffering from serious concurrent disease or psoriasis were also excluded. * Trademark: Sporanox (Janssen Pharmaceutica Inc., Titusville,N e w Jersey).
1067
SHORT-TERM ITRACONAZOLEFOR FINGERNAIL ONYCHOMYCOSIS
Treatment consisted of two 100-mg capsules of itraconazole taken once a day for 6 weeks. Patients receiving drugs that reduced gastric secretion were instructed to delay the intake of those medications for 1 hour after having taken itraconazole. KOH smear microscopy and fungus cultures were carried out on potentially infected nails at the beginning of the trial (week 0), at the end of treatment (week 6), and at the end of the follow-up period (week 18). If a patient had several infected nails, we identified the most severely involved nail as a "target nail" before treatment for monitoring during the trial. Smears of fingernail scrappings were considered KOH positive when there were hyphae or pseudohyphae, or many spores identified in the sample. We used Sabouraud's dextrose agar as culture medium and identified the colonies by using gross and microscopic features. We performed sugar fermentation tests for identification of the yeasts. When yeasts or nondermatophytic molds were cultured, we repeated the KOH study and fungus culture, and considered the isolated fungus to be pathogenic only when the same fungus could be cultured purely and repeatedly. A visual estimate of the pathologically changed part of the nail plate as a percentage of the whole nail plate in a target nail was made at the start of the trial and at each subsequent clinic visit (3, 6, 12, and 18 weeks). Target nails were also photographed so that the visual estimate could be verified. At these visits, the nails were also scored for brittleness, onycholysis, subungual keratosis, perionyxis, and discoloration by using a fourpoint rating scale (0 = absent, 1 = traces, 2 = present, and 3 = pronounced). The sum of clinical scores of a target nail at a given time (week 0, 3, 6, 12, or 18) were calculated and the mean + SD of total clinical scores of the target nail was determined. Statistical analysis (Student's t test) was performed using mean scores. Overall evaluation was made at 6, 12, and 18 weeks, and patients were assigned to the following categories: cured (completely clear of lesion, with negative KOH smear and fungus culture); markedly improved (minimal residual lesion with negative KOH smear and fungus culture); moderately improved (small residual lesion with positive KOH smear and fungus culture); or unchanged (no clinical improvement of lesion). At the start of treatment (week 0) and at the end of treatment (week 6), blood samples were taken for complete blood count (white blood cell and red blood cell counts, hemoglobin, hematocrit, platelet count, and differential count) and liver function tests (cholesterol, total protein, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase [AST], and alanine aminotransferase [ALT]). Adverse reactions were recorded on case report form, which reported date of onset and termination of event, severity, frequency, causal relationship, action taken, and patient outcome.
1068
J.A. KIMET AL.
RESULTS
At the beginning of the study, all 21 patients had a KOH-positive smear and fungi were cultured from 14 patients (66.7%). Of the 14 fungal isolates, 7 were dermatophytes, 6 were yeasts, and 1 was a nondermatophyte mold (Table I). All dermatophyte infections were due to Trichophyton rubrum. Of the yeast infections, 3 cases were due to C albicans. Candida guilliermondii, C parapsilosis, and Fusarium species were pure cultured repeatedly in separate cases, and were considered to be pathogens in addition to T rubrum and C albicans. In another five cases, yeasts and/or mold were isolated but not pure cultured nor repeatedly isolated, so they were considered to be contaminants.
Efficacy The visually estimated percentage of involvement in the target nails was 74.8 - 23.6% at week 0, 52.2 ± 21.1% at week 3, 34.9 ± 22.6% at week 6, 16.0 ± 18.0% at week 12, and 6.8 ± 11.5% at week 18 (Figure 1). The mean total score of clinical signs of target nails was 9.2 ± 2.3 at week 0, 7.6 ± 2.5 at week 3, 5.4 ± 3.0 at week 6, 3.3 ± 3.1 at week 12, and 1.9 ± 2.4 at week 18 (Figure 2). Both results were statistically significant from week 3 onward (P < 0.05, Student's t test). At the end of t r e a t m e n t (week 6), 42.9% (9/21) of the patients were free
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Weeks Figure 1. Percentage of involvement in target nails of 21 patients with fingernail onychomycosis. Size of involved area was significantly decreased (P < 0.05) after 3 weeks of treatment with itraconazole 200 mg/d and continuously decreased during the follow-up period. Vertical bars indicate SD. 1069
SHORT-TERMITRACONAZOLEFOR FINGERNAILONYCHOMYCOSIS
12
10
8
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0 0
3
6
9
12
15
18
Weeks Figure 2. Mean ( - SD) total scores of clinical symptoms in target nails of 21 patients with fingernail onychomycosis. Total scores were significantly decreased (P < 0.05) after 3 weeks of t r e a t m e n t with itraconazole 200 mg/d and continuously decreased during the follow-up period. Score was based on a four-point r a t i n g scale: 0 = absent; 1 = traces; 2 = present; and 3 = pronounced.
of fungal colonization, as judged by KOH smear and fungus culture. At the end of follow-up (week 18), this percentage had increased to 90.5% (19/21). In terms of the overall clinical response, a total of 42.9% (9/21) of patients were markedly improved and 57.1% (12/21) moderately improved at the end of treatment (week 6). At week 18, 81.0% (17/21) of patients were cured, 9.5% (2/21) were markedly improved, and 9.5% (2/21) were moderately improved (Table II).
Tolerability Three (14.3%) of 21 patients reported mild adverse events (nausea, Table I. Classification of the identified organisms in cultures from patients with fingernail onychomycosis. Organism
No. of Patients
Dermatophytes Trichophyton rubrum Yeasts (pathogenic) Candida albicans Candida guilliermondii Candidaparapsilosis Molds (pathogenic) Fusarium sp Yeast and/or mold (saprophytic) No growth Total
7 3 2 1
1 5 2 21
1070
J.A.
KIM ET AL.
Table II. Overall efficacy of 6 weeks of itraconazole 200 mg/d in the treatment of 21 patients with fingernail onychomycosis. Values are numbers of patients (%).
Result*
End of Treatment (week 6)
1st Follow-Up (week 12)
Last Follow-Up (week 18)
Cured Markedly improved Moderately improved
0 (0.0) 9 (42.9%) 12 (57.1%)
6 (28.6%) 10 (47.6%) 5 (23.8%)
17 (81.0%) 2/9.5%) 2 (9.5%)
Unchanged
0 (0.0%)
0 (0.0%)
O (0.0%)
*Cured = complete clear of lesion and negative for fungal elements by KOH smear and fungus culture; markedly improved = minimal residual les~on with negative KOH smear and fungus culture; moderately improved = small residual lesion with positive KOH smear and fungus culture; unchanged = no clinical improvement of lesion.
indigestion, and dizziness), none of which was serious enough to discontinue treatment. The complete blood counts did not reveal any abnormalities. In one patient, liver function tests showed a slight increase in AST and ALT levels: 41 IU/L (normal range, 0 to 40 IU/L) and 62 IU/L (normal range, 0 to 40 IU/L), respectively, at week 6. This patient did not have a history of liver disease, nor use any drug other than itraconazole. Because she refused studies to determine the cause of the abnormal results of her liver function tests, we could not definitely link this to itraconazole administration. DISCUSSION AND CONCLUSION
The pharmacokinetics of itraconazole in the nail plate 9 and the rapid growth of fingernails l° suggest that a treatment regimen shorter than the 3 months used in previous fingernail onychomycosis trials 9 may be appropriate. The results obtained in this open-label trial, with a 6-week treatment course of 200 mg daily, support this hypothesis. A clinical response rate (cured and markedly improved) and negative KOH smear and fungus culture rate of 90.5% was obtained at the 12-week follow-up (week 18). This is comparable to the results achieved with a 3-month regimen. This study also illustrates the broad-spectrum antifungal activity of itraconazole. Itraconazole 200 mg/d for 6 weeks was efficacious in the treatment of fingernail onychomycosis caused by T rubrum (Figure 3); C albicans (Figure 4), or Fusarium species (Figure 5). In fingernail onychomycosis, dermatophytes still play an important role, but yeasts and nondermatophyte molds are becoming increasingly important. Thus broadspectrum antifungal activity should be considered essential in the face of this new array of nail pathogens. The data in this trial show that itraconazole 200 mg/d is well tolerated; the adverse events seen (nausea, indigestion, and dizziness) were 1071
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J.A. KIMET AL.
mild in intensity. Gastrointestinal upset and headaches are the most common adverse events as reported previously with itraconazole. 1'11 Whether a dose of itraconazole higher than 200 mg daily, for a shorter period than 6 weeks, would show comparable results to this study remains to be proved and merits further investigation. At the time this study was designed, the only possible comparator drugs were griseofulvin and ketoconazole. We did not think that these drugs would produce comparable results to itraconazole because of the short treatment period. A study comparing itraconazole with a currently available antifungal (allylamine) might be of interest.
Acknowledgment This study was supported in part by Janssen Korea Limited, Seoul, Korea. References:
1. Gupta AK, Sauder DN, Shear NH. Antifungal agents: An overview. Part II. J A m Acad Dermatol. 1994;30:911-933. 2. Haneke E. Fungal infections of the nail. Semin Dermatol. 1991;10:41-43. 3. Clayton YM. Clinical and mycological diagnostic aspects of onychomycosis and dermatomycoses. Clin Exp Dermatol. 1992;17(Suppl):S37-S40. 4. Midgley G, Moore MK, Cook JC, et al. Mycology of nail disorders. J A m Acad Dermatol. 1994;31(Suppl):S68- $74. 5. Pierard GE, Arrese-Estrada J, Pierard-Franchimont C. Treatment of onychomycosis: Traditional approaches. J A m Acad Dermatol. 1993;29(Suppl):S41-S45. 6. Van Cutsem J. The in-vitro antifungal spectrum of itraconazole. Mycoses. 1989; 32(Suppl):S7-S13. 7. Van Cutsem J, Van Gerven F, Janssen PAJ. Activity of orally, topically and parenterally administered itraconazole in the treatment of superficial and deep mycoses: Animal models. Rev I n f Dis. 1987;8(Suppl):S15-S32. 8. Piepponen T, Blomquist K, Brandt H, et al. Efficacy and safety of itraconazole in the long-term treatment of onychomycosis. J Antimicrob Chemother. 1992;29:195-205. 9. Willemsen M, De Concker P, Willems J, et al. Post-treatment itraconazole levels in the nail. J A m Acad Dermatol. 1992;26:731-735. 10. Zaias N. The Nail in Health and Disease. 2nd ed. Norwalk: Appleton & Lange; 1990:314. 11. De Beule K, Lubin G, Cauwenbergh G. Safety aspects of itraconazole in vaginal candidosis, dermatomycosis, and onychomycosis. A review. Curr Ther Res. 1991;49:814-822.
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