Clinical and Experimental Dermatology 1992; 17: 402-406.
Once-weekly oral doses of fluconazole 150 mg in the treatment of tinea pedis R.DEL AGUILA, F.MONTERO GKI,* M.ROBLES,t A.PERERA-RAMIRE/4 AND O.MALE§ Dermatology Department, Instituto Angel Rojfo, Buenos /tires, Argentina, ^University of Costa Rica, San Jose, Costa Rica, ^Instituto Guatemalteco de Seguridad Social. Guatemala City, Guatemala, ]Universidad Nacional, Heredia, San Jose, Costa Rica and ^First Dermatological Clinic, University of Vienna, Vienna, Austria Accepted for publication \{i June 1992
Topically applied broad-spectrum imidazoles are the most widely used treatment for dermatophyte infections. Seventy adult out-patients with tinea pedis participated When used consistently and for the recommended in a muiticentre open non-comparative study of the safety treatment duration, these products are highly effective. and efficacy of once-weekly doses of oral fluconazole 150 Oral antifungais have traditionally had a secondary role, mg. A mean of 3 doses of fluconazole was administered; being prescribed in recurrent and/or resistant cases when patients infected with Candida required an average of 2 compliance with a topical product is poor and, in patients doses compared to 3-4 doses in patients infected with intolerant of topical products. Orally administered grisother organisms. Ciinicai cure was obtained in 45 of 61 eofulvin has been in use for many years but its efficacy (74%) evaiuable patients at the last post-treatment against chronic T. rubrum infections is often unsatisfacevaluation, with 15 patients being substantially improved tory.' Ketoconazole is one of the earliest developed and one patient failing clinicaiiy. At long-term follow-up, imidazole derivatives, but it has been associated with 28-30 days after the last dose was administered, 46 of 60 hepatotoxicity.- Itraconazole offers a valuable alternative, (77%) patients were clinicaiiy cured, 13 (11%) patients although its potentially erratic absorption makes comwere improved and one patient failed. Trichophyton pliance to the daily administration schedule vital.-' rubrum was isolated most frequently (47 of 60 mycoloPluconazoic is a bts-tv\a.m\G antifungal that is very well gically evaiuable patients). Mycological evidence of absorbed after oral administration (bioavailability infection was eradicated from 52 of 60 (87'Jo) patients exceeding 90*^/o) even in the presence of food, antacid, or post-treatment. At the long-term follow-up, infection Hi-receptor antagonist therapy."^ (.ompared with curwas eradicated from 46 of 59 (78%) patients, persisted in rently available oral antifungal agents, fluconazoie five (8%) patients and relapsed in eight (14%) patients, appears to have a different pharmacokinetic profile: six of whom were infected with T. rubrum and two of protein binding is minimal (approximately 11%), the whom were infected with both T. rubrum and Candida. drug is relatively stable to metabolic conversion, and The number of doses received did not correlate with either the mycological response or relapse rates at long- there is widespread distribution to body fluids. This term follow-up. The subgroup of 16 patients with results in high concentrations of unbound drug in plasma, infection of the sole of the foot, which is often considered urine, sputum, saliva and cerebrospinal fluid.^ Pharmato be more difficult to eradicate, responded similarly. cokinetic studies have also shown that fiuconazole 50 mg/ Only 5 of 70 (7*^/;,) fluconazole-treated patients reported day rapidly penetrates the skin, attaining concentrations adverse effects, which were mild to moderate in severity, that are up to 10-times higher than serum concentrations transient and did not result in discontinuation of therapy. after single or multiple administration.' Elimination from The high level of tolerance to fluconazole in comparison the skin appears to be slower than from the plasma to some other oral antifungals and the convenience of the suggesting that less frequent administration of fluconaonce-weekiy oral-administration schedule relative to zole may be pos.sible.'' Fluconazole is safe and effective in the treatment of existing topical and oral therapies, make once-weekly oral patients with dermatophyte infections in doses of 50 mg/ doses of fluconazole a valuable alternative for the treatday for 2-4 weeks for tinea corporis/cruris and for up to 6 ment of tinea pedis. weeks for tinea pedis.' '* Shorter courses of treatment or intermittent administration should, however, improve CLorrespondenee: Dr R. Del Aguila, Yerbal 27.^7, 2nd Fluor, Dept patient compliance and lower the cost of therapy. ]••, 1406 Huenos Aires, Argentina. Summary
402
ONCE-WEEKLY DOSES Ol' ORAL FLUCONAZOLK AND The purpose of the present muiticentre open noncomparative study was to investigate the safety and efficacy of oncc-weekh" doses of fluconazole 1-^0 mg for the treatment of out-patients with tinea pedis and to determine the shortest course of therapy if iiiore than 1 dose is required. Patients and methods Siudy design
TLNF.A P E D L S
403
post-treatment with evidence of infection at the longterm follow-up evaluation). Laboratorv examination included haematology (haemoglobin, haematocrit, RBC ar'd platelet counts, and total and differential WBC; counts)> biochemistry (AST, ALT, gamma glutamyl transpePtidase, creatine phosphoi^inase, hilirubin, alkaline phosphatase, lJUN and serum creatinine) and urinalysis. Results
Healthy adult male and non-pregnant/npn-Iactating Palienls female out-patients with a diagnosis of mild fo moderate tinea pedis of the toes, interdigital spaces anti dorsum of Seventy patients received 1 5 (n"^an 3) weekly doses of the foot (confirmed by microscopic examination of a iluconazolc 150 mg; nine patients were excluded from the specimen of infected skin after treatment with potassium clmicaVefficacy analysis (Table 1 )• One additionai patient hydroxide) were advised on the study details and gave was exciuded from the mycologicai-eflicacy anaiysis written or oral informed consent prior to ciirolment. A because of a contaminated cuiture. One patient was physical and laboratory examination was made, medical excluded only from the iong-terrn follow-up clinical- and history was recorded and signs and symptonis of tinea mycologiciil-eflicacy analyses because of treatment with pedis were evaluated. Patients whose culture results potassium permanganate following the last post-treatshowed I'richophyton^ Epidermophyton, or C^^dida spe- ment e\aluation. Two patients \*'ho received S doses of fluconazole did not return for a post-treatment visit after cies were included in the study. the fifth dose but did return for the long-term follow-up \ single oral capsule of fluconazole ir'O mg was evaluation. administered in the presence of the investitfator at the Sixteen of the 70 patients deviatt-'^l from the protocol by baseline visit. Patients returned 7 10 day-'^ later for the presence of tinea pedis on the soles of the feet (as well clinical, mycological and laboratory examination. If as on the toes and in the interdigital spaces), which is clinical and/or mycological cure or significat^t improveoften considered more severe and more difficult to treat. ment was not evident, a second treatm(;nt of oral 'I'hese patients were inciuded in the overall analysis of fluconazole 150 nig was administered. This pattern of efficacy and safetv but a separate analysis of clinical and assessment every 7 10 days with additional doses of mycological response was also conducted. fluconazole being administered in the event t'f treatment failure, was repeated for a total of 4 doses of fluconazole. Long-term follow-up ciinicai and mycologicat assessment Clinical response (and laboratory examination if indicated) wa^ performed 28-30 days after administration of the l^^t dose of The cumulative clinical results and the number of clinical fluconazole. Adverse effects were recorded at each visit. Assessmenls
Signs and symptoms of infection, including itching, rash, pain, redness, colour change, fissuring, scaling, maceration, cellulitis and the presence of vesicles, were graded on a four-point scale: O = ahsent; I =mild; 2=^nioderate; 3 —severe. (~hnical response was based on signs and symptoms and was defined as cure (complete eradication), improvement (partial relief or alleviatiofi) or fiiilure (no appreciable change). The cumulative clinical-rcsponsc rate foliowing 1-4 doses of fluconazole 1 50 mg was also calculated. iMycoIogical assessment was made of scrapings or other suitable samples. A portion was examined microscopically after treatment with potassium hydroxide and the remainder was cultured. Mycological response was defined as eradication, persistence or relapse (eradication
Table 1. Parient demographics and total weekly doses iifHucona/olc 15(1 mg Number of paticf'^ Toral (sex) /0(57male/i3 Mean age (nmge) ;i4(l8 65) years Moan height (range) 170 (145 -194) cm Mean weight (range) 70(50 125) kg Total 1 5 (7",,): I excluded from eilitacy analysis* 2 22 (,?1",,): 4excli-'ded from cHkac> analysis* 16 (2.^",,): 3 cxclUtlcd from efficacy analysis* "25 (3b",,)- 1 exdU'^leiJ from eflicacy analysis*
* Reasons for exclusion from the efticii'-^y analysis were: failure of investigator Ui follow the dosage regimcH («~5), use of eoncurrenr antifnngal therapy (« —.^) and assessnicnl oursidc the lime limit ("=!).
404
R.DEL AGUILA ei aL Table 2. Clinical ;md mycological responses Assessmenis Fosl-t reatment — Dose 1 Number evaluated 61 C^linically 60 Myeologically Cumulative clinical results 3/61 (5) CureC'o) 54/61 (89) Improvement ("o) 4/61 (7) Failure ("„) Cumulative mycological results 6/60(10) Eradication ("„) 54/60 (90) Persistence C',,) 0 Relapse ("„) Number of patients receivingonly specified dose 4 3/4(75) Cure rate/dose ("„)
Dose 2
Dose 3
Dose 4
I .ong-term follow-up
57 56
39 39
26 26
f)0 .S9
18/61(30) 43/61 (70) 0
33/61 (54) 28/61(46) 0
45/61 (74) 15/61(25) 1/61(2)
46/60 (77) 13/60(22) 1/60 (2)
26/60 (43) 34,60 (57) 0
37/60 (62) 21/60(35) 2/60 (3)
52/60 (87) 8/60(13) 0
46/59 (78) 5/59 (8) 8/59(14)
18 14/18(78)
13 12/13* (92)
24 16/241(67)
* One patient was cured after 2 doses. t Includes four paiients H ho were cured after 3 doses, twi> patients who received 5 doses but were cured after 4.
Table 3. Mycological response by pathogen at the posr-treatment visit
Pathogen
Doses Total patients mean±s.d. Eradication Persistence
6 Candida 2 Epidermophyton floccosum 'I'rtebophyton menla'.;riiphyles 5 41 Trtehopbyton rubrum .1 Trichophyton nihrum and Candida Trichophyton rut'rum and Epidermophyton Jioccosum 1
Total
cures at each dose level are listed in Table 2. Cumulative data show that, after 1-4 weekly doses of fluconazole 150 mg, 45 of 61 (74^,,) patients were clinically cured at the last post-treatment evaluation, 15 (25"o) patients were substantially improved and one patient failed. Among the 15 patients considered improved and relative to baseline, the mean number of signs and symptoms decreased from 5-5 to 1-5 and the mean severity grade decreased from 10 to L5. At long-term follow-up, 46 of 60 (77%) patients were assessed as clinically cured, 13 (22%) patients were improved and one {!%) patient failed. Mycological response F. rubrum was isolated from 41 of 60 (68%) mycologicalh evaiuable patients and Truhophyton mentagrophytes was
60
1'8 fO-8 ^•5 + 0-7 3-4 ± 0 - 9 3-3 + l'O
2-0 + 0-0 4'0±0 3-0 + 0-6
6 (UK)",,) 2(l(H)"o) 5(100%) 35 (85'4",,) 4(80-0'\,) 0 (0"«) 52(86-7%)
0 (l)"o) 0(0",.) 0 (0"o) 6(14-6".,) 1 (20-0",,) 1 (100"o) 8(13-3%)
isolated from five {%%) patients. Candida and E. jioccosum were the only organisms present in six (10"'o) and two (3%) patients, respectively, and were isolated in addition to T. rubrum in five iJ^'Q and one (2**o) patient respectively. The cumulative mycological results are listed in Table 2. Details of the pathogen eradication rates are provided in Table 3. After 1-4 weekly doses of fluconazole 150 mg, 52 of 60 (87*^o) patients had mycological eradication of the infecting organism. At the long-term follow-up, the originally infecting organism(s) remained eradicated from 46 of 59 (78*'/o) patients and persisted in only five (8'^^'o) patients (four of whom were clinically improved; Table 2). Eight (\A%) patients from whom the infecting organism was previously eradicated had a relapse of infection. There was no correlation between the number of doses received
ONC:E-\VEEKLY DOSES OF ORAL FLUCONAZOLE AND TINEA PEDIS and the mycological-response rate or relapse rate at longterm follow-up. Response by organism
At the post-treatment visits there were no major differences noted in the clinical- and mycological-response rates between various organisms, although the numbers in each group were too small for statistical analysis; patients infected with Candida required an average 2 doses of fluconazole, as compared to 3 4 doses in patients infected with other organisms. At long-term follow-up, six of 40 (15%) patients infected with T. rubrum and tw-o of five (40'',^) patients infected with '/'. rubrum plus Candida, had mycological relapse of their infection following initial eradication; no other patient relapsed mycologicaliy.
405
normal with continued therapy. The third patient had elevations of AST, ALT and GGT values at the second post-treatment visit; however, these tests were not repeated because the values were not considered by the investigator to he of clinical significance. Two patients had an increased eosinophil count which returned to normal during continued therapy with fluconazole. Discussion
The results of the present study indicate that orai tluconazole 150 mg administered once weekly for up to 4 weeks is well tolerated and highly effective for the treatment of tinea pedis. The once-weekly oral-administration schedule may have advantages over topical therapy in patient acceptabihty that are likely to result in improved compliance. Similarly, relative to the single or multiple dailv administration schedules of other oral Clinicaljtnycological response in patients wilh sole involve- therapies available for the treatment of dermatophytic infections, once-weekly administration of fluconazole 150 ment mg is more convenient and therefore would probably Fifteen of the 16 patients with tinea pedis involving the result in improved compliance. soles of the feet were evaluable for clinical and mycologiAnother recent study examining the impact of the cal efficacy. These patients received an average 3-7 doses shorter duration of drug therapy on cure rates in of fluconazole. Two patients received 5 doses of flucona- dermatophyte infections compared itraconazoie 100 mg zole and did not return for a post-treatment evaluation with griseofulvin 500 mg, both given daily for 15 days.'" after the fifth dose but were clinically cured with The authors concluded that itraconazole satisfied the mycological eradication at the long-term follow-up evalu- reported need for a shorter treatment regimen. The 15ation. Clinical cure and mycological eradication were day treatment regimen does, however, still constitute a demonstrated in 10 of 13 (77'\,) patients evaluated at the longer schedule than the single-dose regimen of fluconalast post-treatment visit. Chnical improvement with zole. mycological persistence was seen in two patients and In summary, while oral therapy of tinea pedis with clinical improvement with mycological eradication v\as gri.scofuhin or ketoconazole is typically reserved for seen in one patient. Only one patient from whom the infections unresponsive to topical therapy, the safety, lnfectmg organism was eradicated post-treatment had a efficac}' and convenience of once-weekly oral fluconazole relapse of infection at the long-term follow-up evaluation. suggest that it should he considered for more widespread use. Studies examining the use of the drug in treatments for periods greater than 4 weeks are underway. Safety Among the 70 patients who received at least 1 dose of fluconazole, five patients reported a total of seven adverse Conclusions effects, that were transient, mild to moderate in severity Once-weekly oral dose of fluconazole 150 mg are a highly and did not result in discontinuation of therapy. Two effective treatment for tinea pedis. The high level of patients reported both abdominal pain and dy.spepsia, tolerance to fluconazole compared to some other oral two patients reported acne and one patient reported antifimgahs and the convenience of the once-weekly oralheadache. administration schedule relative to existing topical and Transient laboratory abnormalities, which did not oral therapies, make once-weekiy oral fluconazole a result in discontinuation of therapy, were noted in five of vaiuable alternative to the treatment of this common the 49 paticnis who had laboratory tests performed at dermatoiogicai infection. baseline and at the post-treatment visits. Three patients had elevations of liver function tests. One of these References patients had an elevation in the gamma glutamyl tran.s1. I-egendre R, Steltz MA. Mulri-center, double-blind comparison peptidase (GGT) level at the long-term follow-up visit of kctocona/ole and griseofulvin in the treaiment of infections due only (31 days after the last dose of fluconazole). Another to dermatophytes. Reviews of Infectious Diseases 1980; 2: 586-591. patient had an elevated AST value that returned to 2. Lewis JH, Zimmerman HJ, Benson GD, Isbak KG. Hepatic
406
3. 4.
5. 6. 7.
R.DEL AGUILA et al. injury associated with ketoconazole therapy. Analysis of 33 cases. 8. Ha> RJ. Recent developments in the treatment of dcrniatophjte infections, abstract. First Internationat Confercnee on firug Castroenlerohgy 1984; «6: 503 513. Research in Immunologic and Infectious Disea.'^es. Antifungal drugs: Hardin TC, Gra\bil] JR, T'etehick R et al. Pbarmacokinetics of syntbesis, preclinica! and clinical evaluation. New V'ork 1987, 8itraconazole foHowing orai administration to normal volunteers. ]'{) Oct. Antimicrobial Agents and Chemotherapy 1988; 32: 1310 1313. 9, Naeyaert JM, De Bersaques J, de (Cuyper C;, Hindryckx P, \an Grant SM, Clissold SP. Fluconazole; a rc\icu of its pbarmacodyLanduyt 11, Fluconazole: a novel oral antifunga!, in the treatment namic and pharmacokinetic properties, and therapeutic potential of f~ungal skin infections. Ninth International (Congress uJ Infectious in superficial and systemic mycoses. Drugs 1990; 39: 877-916. Parasitic Diseases. Abstract 213, Munich 1986, 20-2f) July. 1 lay RJ- New oral treatment for dermatophytes, Annats of the New 10, Bourland A, Lachapelle JM, Aussems J et al. Double-blind York Academy of Sciences 1988; 544: 580, comparison of itracona/ole wirh griseofulvin in the treatment of Haneke F., Pharmacodynamic and pbarmacokinetic evaluation of tinea corporis and tinea cruris, Internatioual Journat of Dermatoflucona/ole in plasma, epidermis and blister fluid. Internalionul logy 1989; 28: 410-412, Journal of Dermatology 1990; 123: 273-274, (Coppini M. Esperienza clinica con fluconazolo nelle dermatomicosi. Congresso Nazionale Societa Italiana
Veneriotogia, Palermo 1989, 1-3 June.
di Dermatologia e
Once-weekly oral doses of fluconazole 150 mg in the treatment of tinea pedis R.DEL AGUILA, F.MONTERO GKI,* M.ROBLES,t A.PERERA-RAMIRE/4 AND O.MALE§ Dermatology Department, Instituto Angel Rojfo, Buenos /tires, Argentina, ^University of Costa Rica, San Jose, Costa Rica, ^Instituto Guatemalteco de Seguridad Social. Guatemala City, Guatemala, ]Universidad Nacional, Heredia, San Jose, Costa Rica and ^First Dermatological Clinic, University of Vienna, Vienna, Austria Accepted for publication \{i June 1992
Topically applied broad-spectrum imidazoles are the most widely used treatment for dermatophyte infections. Seventy adult out-patients with tinea pedis participated When used consistently and for the recommended in a muiticentre open non-comparative study of the safety treatment duration, these products are highly effective. and efficacy of once-weekly doses of oral fluconazole 150 Oral antifungais have traditionally had a secondary role, mg. A mean of 3 doses of fluconazole was administered; being prescribed in recurrent and/or resistant cases when patients infected with Candida required an average of 2 compliance with a topical product is poor and, in patients doses compared to 3-4 doses in patients infected with intolerant of topical products. Orally administered grisother organisms. Ciinicai cure was obtained in 45 of 61 eofulvin has been in use for many years but its efficacy (74%) evaiuable patients at the last post-treatment against chronic T. rubrum infections is often unsatisfacevaluation, with 15 patients being substantially improved tory.' Ketoconazole is one of the earliest developed and one patient failing clinicaiiy. At long-term follow-up, imidazole derivatives, but it has been associated with 28-30 days after the last dose was administered, 46 of 60 hepatotoxicity.- Itraconazole offers a valuable alternative, (77%) patients were clinicaiiy cured, 13 (11%) patients although its potentially erratic absorption makes comwere improved and one patient failed. Trichophyton pliance to the daily administration schedule vital.-' rubrum was isolated most frequently (47 of 60 mycoloPluconazoic is a bts-tv\a.m\G antifungal that is very well gically evaiuable patients). Mycological evidence of absorbed after oral administration (bioavailability infection was eradicated from 52 of 60 (87'Jo) patients exceeding 90*^/o) even in the presence of food, antacid, or post-treatment. At the long-term follow-up, infection Hi-receptor antagonist therapy."^ (.ompared with curwas eradicated from 46 of 59 (78%) patients, persisted in rently available oral antifungal agents, fluconazoie five (8%) patients and relapsed in eight (14%) patients, appears to have a different pharmacokinetic profile: six of whom were infected with T. rubrum and two of protein binding is minimal (approximately 11%), the whom were infected with both T. rubrum and Candida. drug is relatively stable to metabolic conversion, and The number of doses received did not correlate with either the mycological response or relapse rates at long- there is widespread distribution to body fluids. This term follow-up. The subgroup of 16 patients with results in high concentrations of unbound drug in plasma, infection of the sole of the foot, which is often considered urine, sputum, saliva and cerebrospinal fluid.^ Pharmato be more difficult to eradicate, responded similarly. cokinetic studies have also shown that fiuconazole 50 mg/ Only 5 of 70 (7*^/;,) fluconazole-treated patients reported day rapidly penetrates the skin, attaining concentrations adverse effects, which were mild to moderate in severity, that are up to 10-times higher than serum concentrations transient and did not result in discontinuation of therapy. after single or multiple administration.' Elimination from The high level of tolerance to fluconazole in comparison the skin appears to be slower than from the plasma to some other oral antifungals and the convenience of the suggesting that less frequent administration of fluconaonce-weekiy oral-administration schedule relative to zole may be pos.sible.'' Fluconazole is safe and effective in the treatment of existing topical and oral therapies, make once-weekly oral patients with dermatophyte infections in doses of 50 mg/ doses of fluconazole a valuable alternative for the treatday for 2-4 weeks for tinea corporis/cruris and for up to 6 ment of tinea pedis. weeks for tinea pedis.' '* Shorter courses of treatment or intermittent administration should, however, improve CLorrespondenee: Dr R. Del Aguila, Yerbal 27.^7, 2nd Fluor, Dept patient compliance and lower the cost of therapy. ]••, 1406 Huenos Aires, Argentina. Summary
402
ONCE-WEEKLY DOSES Ol' ORAL FLUCONAZOLK AND The purpose of the present muiticentre open noncomparative study was to investigate the safety and efficacy of oncc-weekh" doses of fluconazole 1-^0 mg for the treatment of out-patients with tinea pedis and to determine the shortest course of therapy if iiiore than 1 dose is required. Patients and methods Siudy design
TLNF.A P E D L S
403
post-treatment with evidence of infection at the longterm follow-up evaluation). Laboratorv examination included haematology (haemoglobin, haematocrit, RBC ar'd platelet counts, and total and differential WBC; counts)> biochemistry (AST, ALT, gamma glutamyl transpePtidase, creatine phosphoi^inase, hilirubin, alkaline phosphatase, lJUN and serum creatinine) and urinalysis. Results
Healthy adult male and non-pregnant/npn-Iactating Palienls female out-patients with a diagnosis of mild fo moderate tinea pedis of the toes, interdigital spaces anti dorsum of Seventy patients received 1 5 (n"^an 3) weekly doses of the foot (confirmed by microscopic examination of a iluconazolc 150 mg; nine patients were excluded from the specimen of infected skin after treatment with potassium clmicaVefficacy analysis (Table 1 )• One additionai patient hydroxide) were advised on the study details and gave was exciuded from the mycologicai-eflicacy anaiysis written or oral informed consent prior to ciirolment. A because of a contaminated cuiture. One patient was physical and laboratory examination was made, medical excluded only from the iong-terrn follow-up clinical- and history was recorded and signs and symptonis of tinea mycologiciil-eflicacy analyses because of treatment with pedis were evaluated. Patients whose culture results potassium permanganate following the last post-treatshowed I'richophyton^ Epidermophyton, or C^^dida spe- ment e\aluation. Two patients \*'ho received S doses of fluconazole did not return for a post-treatment visit after cies were included in the study. the fifth dose but did return for the long-term follow-up \ single oral capsule of fluconazole ir'O mg was evaluation. administered in the presence of the investitfator at the Sixteen of the 70 patients deviatt-'^l from the protocol by baseline visit. Patients returned 7 10 day-'^ later for the presence of tinea pedis on the soles of the feet (as well clinical, mycological and laboratory examination. If as on the toes and in the interdigital spaces), which is clinical and/or mycological cure or significat^t improveoften considered more severe and more difficult to treat. ment was not evident, a second treatm(;nt of oral 'I'hese patients were inciuded in the overall analysis of fluconazole 150 nig was administered. This pattern of efficacy and safetv but a separate analysis of clinical and assessment every 7 10 days with additional doses of mycological response was also conducted. fluconazole being administered in the event t'f treatment failure, was repeated for a total of 4 doses of fluconazole. Long-term follow-up ciinicai and mycologicat assessment Clinical response (and laboratory examination if indicated) wa^ performed 28-30 days after administration of the l^^t dose of The cumulative clinical results and the number of clinical fluconazole. Adverse effects were recorded at each visit. Assessmenls
Signs and symptoms of infection, including itching, rash, pain, redness, colour change, fissuring, scaling, maceration, cellulitis and the presence of vesicles, were graded on a four-point scale: O = ahsent; I =mild; 2=^nioderate; 3 —severe. (~hnical response was based on signs and symptoms and was defined as cure (complete eradication), improvement (partial relief or alleviatiofi) or fiiilure (no appreciable change). The cumulative clinical-rcsponsc rate foliowing 1-4 doses of fluconazole 1 50 mg was also calculated. iMycoIogical assessment was made of scrapings or other suitable samples. A portion was examined microscopically after treatment with potassium hydroxide and the remainder was cultured. Mycological response was defined as eradication, persistence or relapse (eradication
Table 1. Parient demographics and total weekly doses iifHucona/olc 15(1 mg Number of paticf'^ Toral (sex) /0(57male/i3 Mean age (nmge) ;i4(l8 65) years Moan height (range) 170 (145 -194) cm Mean weight (range) 70(50 125) kg Total 1 5 (7",,): I excluded from eilitacy analysis* 2 22 (,?1",,): 4excli-'ded from cHkac> analysis* 16 (2.^",,): 3 cxclUtlcd from efficacy analysis* "25 (3b",,)- 1 exdU'^leiJ from eflicacy analysis*
* Reasons for exclusion from the efticii'-^y analysis were: failure of investigator Ui follow the dosage regimcH («~5), use of eoncurrenr antifnngal therapy (« —.^) and assessnicnl oursidc the lime limit ("=!).
404
R.DEL AGUILA ei aL Table 2. Clinical ;md mycological responses Assessmenis Fosl-t reatment — Dose 1 Number evaluated 61 C^linically 60 Myeologically Cumulative clinical results 3/61 (5) CureC'o) 54/61 (89) Improvement ("o) 4/61 (7) Failure ("„) Cumulative mycological results 6/60(10) Eradication ("„) 54/60 (90) Persistence C',,) 0 Relapse ("„) Number of patients receivingonly specified dose 4 3/4(75) Cure rate/dose ("„)
Dose 2
Dose 3
Dose 4
I .ong-term follow-up
57 56
39 39
26 26
f)0 .S9
18/61(30) 43/61 (70) 0
33/61 (54) 28/61(46) 0
45/61 (74) 15/61(25) 1/61(2)
46/60 (77) 13/60(22) 1/60 (2)
26/60 (43) 34,60 (57) 0
37/60 (62) 21/60(35) 2/60 (3)
52/60 (87) 8/60(13) 0
46/59 (78) 5/59 (8) 8/59(14)
18 14/18(78)
13 12/13* (92)
24 16/241(67)
* One patient was cured after 2 doses. t Includes four paiients H ho were cured after 3 doses, twi> patients who received 5 doses but were cured after 4.
Table 3. Mycological response by pathogen at the posr-treatment visit
Pathogen
Doses Total patients mean±s.d. Eradication Persistence
6 Candida 2 Epidermophyton floccosum 'I'rtebophyton menla'.;riiphyles 5 41 Trtehopbyton rubrum .1 Trichophyton nihrum and Candida Trichophyton rut'rum and Epidermophyton Jioccosum 1
Total
cures at each dose level are listed in Table 2. Cumulative data show that, after 1-4 weekly doses of fluconazole 150 mg, 45 of 61 (74^,,) patients were clinically cured at the last post-treatment evaluation, 15 (25"o) patients were substantially improved and one patient failed. Among the 15 patients considered improved and relative to baseline, the mean number of signs and symptoms decreased from 5-5 to 1-5 and the mean severity grade decreased from 10 to L5. At long-term follow-up, 46 of 60 (77%) patients were assessed as clinically cured, 13 (22%) patients were improved and one {!%) patient failed. Mycological response F. rubrum was isolated from 41 of 60 (68%) mycologicalh evaiuable patients and Truhophyton mentagrophytes was
60
1'8 fO-8 ^•5 + 0-7 3-4 ± 0 - 9 3-3 + l'O
2-0 + 0-0 4'0±0 3-0 + 0-6
6 (UK)",,) 2(l(H)"o) 5(100%) 35 (85'4",,) 4(80-0'\,) 0 (0"«) 52(86-7%)
0 (l)"o) 0(0",.) 0 (0"o) 6(14-6".,) 1 (20-0",,) 1 (100"o) 8(13-3%)
isolated from five {%%) patients. Candida and E. jioccosum were the only organisms present in six (10"'o) and two (3%) patients, respectively, and were isolated in addition to T. rubrum in five iJ^'Q and one (2**o) patient respectively. The cumulative mycological results are listed in Table 2. Details of the pathogen eradication rates are provided in Table 3. After 1-4 weekly doses of fluconazole 150 mg, 52 of 60 (87*^o) patients had mycological eradication of the infecting organism. At the long-term follow-up, the originally infecting organism(s) remained eradicated from 46 of 59 (78*'/o) patients and persisted in only five (8'^^'o) patients (four of whom were clinically improved; Table 2). Eight (\A%) patients from whom the infecting organism was previously eradicated had a relapse of infection. There was no correlation between the number of doses received
ONC:E-\VEEKLY DOSES OF ORAL FLUCONAZOLE AND TINEA PEDIS and the mycological-response rate or relapse rate at longterm follow-up. Response by organism
At the post-treatment visits there were no major differences noted in the clinical- and mycological-response rates between various organisms, although the numbers in each group were too small for statistical analysis; patients infected with Candida required an average 2 doses of fluconazole, as compared to 3 4 doses in patients infected with other organisms. At long-term follow-up, six of 40 (15%) patients infected with T. rubrum and tw-o of five (40'',^) patients infected with '/'. rubrum plus Candida, had mycological relapse of their infection following initial eradication; no other patient relapsed mycologicaliy.
405
normal with continued therapy. The third patient had elevations of AST, ALT and GGT values at the second post-treatment visit; however, these tests were not repeated because the values were not considered by the investigator to he of clinical significance. Two patients had an increased eosinophil count which returned to normal during continued therapy with fluconazole. Discussion
The results of the present study indicate that orai tluconazole 150 mg administered once weekly for up to 4 weeks is well tolerated and highly effective for the treatment of tinea pedis. The once-weekly oral-administration schedule may have advantages over topical therapy in patient acceptabihty that are likely to result in improved compliance. Similarly, relative to the single or multiple dailv administration schedules of other oral Clinicaljtnycological response in patients wilh sole involve- therapies available for the treatment of dermatophytic infections, once-weekly administration of fluconazole 150 ment mg is more convenient and therefore would probably Fifteen of the 16 patients with tinea pedis involving the result in improved compliance. soles of the feet were evaluable for clinical and mycologiAnother recent study examining the impact of the cal efficacy. These patients received an average 3-7 doses shorter duration of drug therapy on cure rates in of fluconazole. Two patients received 5 doses of flucona- dermatophyte infections compared itraconazoie 100 mg zole and did not return for a post-treatment evaluation with griseofulvin 500 mg, both given daily for 15 days.'" after the fifth dose but were clinically cured with The authors concluded that itraconazole satisfied the mycological eradication at the long-term follow-up evalu- reported need for a shorter treatment regimen. The 15ation. Clinical cure and mycological eradication were day treatment regimen does, however, still constitute a demonstrated in 10 of 13 (77'\,) patients evaluated at the longer schedule than the single-dose regimen of fluconalast post-treatment visit. Chnical improvement with zole. mycological persistence was seen in two patients and In summary, while oral therapy of tinea pedis with clinical improvement with mycological eradication v\as gri.scofuhin or ketoconazole is typically reserved for seen in one patient. Only one patient from whom the infections unresponsive to topical therapy, the safety, lnfectmg organism was eradicated post-treatment had a efficac}' and convenience of once-weekly oral fluconazole relapse of infection at the long-term follow-up evaluation. suggest that it should he considered for more widespread use. Studies examining the use of the drug in treatments for periods greater than 4 weeks are underway. Safety Among the 70 patients who received at least 1 dose of fluconazole, five patients reported a total of seven adverse Conclusions effects, that were transient, mild to moderate in severity Once-weekly oral dose of fluconazole 150 mg are a highly and did not result in discontinuation of therapy. Two effective treatment for tinea pedis. The high level of patients reported both abdominal pain and dy.spepsia, tolerance to fluconazole compared to some other oral two patients reported acne and one patient reported antifimgahs and the convenience of the once-weekly oralheadache. administration schedule relative to existing topical and Transient laboratory abnormalities, which did not oral therapies, make once-weekiy oral fluconazole a result in discontinuation of therapy, were noted in five of vaiuable alternative to the treatment of this common the 49 paticnis who had laboratory tests performed at dermatoiogicai infection. baseline and at the post-treatment visits. Three patients had elevations of liver function tests. One of these References patients had an elevation in the gamma glutamyl tran.s1. I-egendre R, Steltz MA. Mulri-center, double-blind comparison peptidase (GGT) level at the long-term follow-up visit of kctocona/ole and griseofulvin in the treaiment of infections due only (31 days after the last dose of fluconazole). Another to dermatophytes. Reviews of Infectious Diseases 1980; 2: 586-591. patient had an elevated AST value that returned to 2. Lewis JH, Zimmerman HJ, Benson GD, Isbak KG. Hepatic
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3. 4.
5. 6. 7.
R.DEL AGUILA et al. injury associated with ketoconazole therapy. Analysis of 33 cases. 8. Ha> RJ. Recent developments in the treatment of dcrniatophjte infections, abstract. First Internationat Confercnee on firug Castroenlerohgy 1984; «6: 503 513. Research in Immunologic and Infectious Disea.'^es. Antifungal drugs: Hardin TC, Gra\bil] JR, T'etehick R et al. Pbarmacokinetics of syntbesis, preclinica! and clinical evaluation. New V'ork 1987, 8itraconazole foHowing orai administration to normal volunteers. ]'{) Oct. Antimicrobial Agents and Chemotherapy 1988; 32: 1310 1313. 9, Naeyaert JM, De Bersaques J, de (Cuyper C;, Hindryckx P, \an Grant SM, Clissold SP. Fluconazole; a rc\icu of its pbarmacodyLanduyt 11, Fluconazole: a novel oral antifunga!, in the treatment namic and pharmacokinetic properties, and therapeutic potential of f~ungal skin infections. Ninth International (Congress uJ Infectious in superficial and systemic mycoses. Drugs 1990; 39: 877-916. Parasitic Diseases. Abstract 213, Munich 1986, 20-2f) July. 1 lay RJ- New oral treatment for dermatophytes, Annats of the New 10, Bourland A, Lachapelle JM, Aussems J et al. Double-blind York Academy of Sciences 1988; 544: 580, comparison of itracona/ole wirh griseofulvin in the treatment of Haneke F., Pharmacodynamic and pbarmacokinetic evaluation of tinea corporis and tinea cruris, Internatioual Journat of Dermatoflucona/ole in plasma, epidermis and blister fluid. Internalionul logy 1989; 28: 410-412, Journal of Dermatology 1990; 123: 273-274, (Coppini M. Esperienza clinica con fluconazolo nelle dermatomicosi. Congresso Nazionale Societa Italiana
Veneriotogia, Palermo 1989, 1-3 June.
di Dermatologia e
