S77
FUNGAL INFECTIONS IN NORMAL HOSTS
Therapy with Fluconazole for Tinea Corporis, Tinea Cruris, and Tinea Pedis F. Montero-Gei and A. Perera
From the School of Medical Sciences U.A.C.A. and San Juan de Dios Hospital, San Jose, Costa Rica
Fluconazole is a fluorine-substituted, bis-triazole agent that is water soluble, making it unique among currently available systemic azole antifungal agents. This distinction is reflected in its good oral absorption, high unbound plasma concentrations, and excellent total body distribution, including penetration into CSF, saliva, ocular fluids, skin, and nails [1]. In healthy volunteers, absorption of orally administered fluconazole is rapid; peak plasma concentrations are reached in —1-2 hours [2-3]. The bioavailability of fluconazole is —90% of an oral dose. There is no clinically significant effect on absorption when the drug is administered with food [3]. Its mechanism of action, like that of other azoles, involves interruption of the conversion of lanosterol to ergosterol via binding to fungal cytochrome P-450, which results in subsequent disruption of fungal membrane permeability [4]. Dermatophytosis is a clinical entity caused by members of the anamorphic fungal genera, Trichophyton, Microsporum, and Epidermophyton. In its restricted sense dermatophytosis is a colonization of the keratinized tissues including the nails, hair, and stratum corneum of the skin. The disease is a consequence of the host's reaction to the metabolic products of the fungus, rather than to the invasion of healthy tissue by the
Grant support: This work was supported in part by a grant from Pfizer International (New York). Reprints or correspondence: Dr. F. Montero-Gei, P.O. Box 2157-1000, San Jose, Costa Rica, Central America. Clinical Infectious Diseases 1992;14(Suppl 1):S77-81 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1403-0010802.00
organism [5]. Infections due to dermatophytes are pandemic, but the prevalence is higher in developing countries where socioeconomic factors play an important role in the transmission of superficial mycotic infections. The use of broadspectrum antibiotics, corticosteroids, and cytotoxic agents is associated with disseminated dermatophytosis, a condition in which granulomatous lesions that are similar histologically to Majocchi's granuloma extend to corporal areas [6]. Topical agents are commonly used to treat dermatophyte infections; however, these agents are occasionally associated with dermal sensitization and drug-induced eruptions. Treatment failure and relapses occur with use of the majority of the drugs that are presently available. Also, repeated applications of topical creams and ointments, especially to large areas of the skin, are not always acceptable and may lead to poor patient compliance. The need for better therapeutic agents is apparent, and oral therapy offers an effective, convenient alternative to topical agents. Recently, the new triazole antifungal agent, fluconazole, has been added to the armamentarium of drugs used to treat dermatophyte infections. In animal models, fluconazole was shown to be five-to-ten times more active than ketoconazole for treatment of shaved areas of the flank that were infected with a suspension of Trichophyton mentagrophytes or Trichophyton rubrum (in mice predisposed to infection because of topical triamcinolone use) and Microsporum canis (in guinea pigs) [7]. The efficacy of therapy with fluconazole (50 mg/d for 14-28 days) has been studied in patients with dermatophytosis; in cases of tinea pedis, the duration of therapy has been extended to 42 days. The clinical response rate (cure or improvement) was 100% at the end of treatment. At follow-
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on September 17, 2015
We treated 20 patients who had tinea corporis and/or tinea cruris and 20 patients who had tinea pedis with oral fluconazole. All patients were given a single 150-mg dose of fluconazole upon entry into the study; at that time, and at each follow-up visit, clinical signs and symptoms were evaluated and mycological and laboratory examinations were performed. If clinical and/or mycological cure or significant improvement in a patient's condition was not evident at the 7-day follow-up visit, a second dose of fluconazole (150 mg) was given. A maximum of four doses, one week apart, were given. A long-term evaluation of the efficacy of fluconazole in the treatment of these infections was performed 28-30 days after the last dose was administered to each patient. For the treatment of tinea corporis and/or tinea cruris, 70% of patients required two doses, 20% required three doses, and 10% required four doses. At the long-term follow-up visit the clinical and mycological response rates were determined to be 95% cure and 5% relapse. For the treatment of tinea pedis, 20% of the patients required two doses, 20% required three doses, and 60% required four doses. For these patients, the long-term clinical response rates were 70% cure and 30% improvement; mycological response rates were 75% eradication, 10% persistence of infection, and 15% relapse. This treatment was well tolerated; no adverse effects or clinically significant laboratory abnormalities were reported.
S78
Table 1. Demographic characteristics of patients with tinea corporis and/or tinea cruris.
Table 3. Frequency of diagnosis of tinea.
No. of patients (%)
Tinea corporis Tinea cruris Tinea corporis-cruris Tinea pedis
5 (25) 14 (70) 1 (5) 20 (100)
Diagnosis Male
Variable
19 (95%)
Female I (5%)
Total 20 (100%)
30 19-54
20 20-20
30 19-54
169 160-179
158 158-158
168 158-179
68 54-82.6
54 54-54
68 54-82.6
up 2-4 weeks after initiation of therapy, the clinical response rate was 90% [8]. Pharmacokinetic studies have demonstrated that fluconazole rapidly penetrates the skin, with concentrations up to 10 times those seen in the plasma [2]. Fluconazole also appears to be eliminated from the skin very slowly, a finding suggesting that a shorter course of treatment combined with less frequent administration may be an effective alternative to the regimen of 50 mg/d [9]. A regimen that consists of a once-weekly dose could have the advantage of better patient compliance and lower cost. Patients and Methods
This was an open, noncomparative study to assess the efficacy, safety, and tolerability of a single oral dose of fluconazole (150 mg) in the treatment of outpatients with mycologically proven tinea corporis, tinea cruris, or tinea pedis. For the patients with tinea pedis, the fungal infection was limited to the toes, interdigital spaces, and dorsum of the foot; it did not involve the sole or toenails. The diagnosis was confirmed on the basis of findings on microscopic examination of infected skin with 20% KOH and the isolation of the dermatophytes with use of Mycosel and Sabouraud dextrose agar (BBL, Baltimore). The identification of infecting fungi was
Table 2. Demographic characteristics of patients with tinea pedis. Variable No. of patients (%) Age (y) Mean Range Height (cm) Mean Range Weight (kg) Mean Range
Male 19 (95%)
Female 1 (5%)
made on the basis of the results of culture. A medical history was reported by each patient, and physical examinations and laboratory tests were performed. Any medications taken concomitantly on entry into the study or during the study were recorded. Each patient was informed of the details of the study and of potential adverse effects, and written or oral consent was obtained prior to enrollment in the study. On qualifying for entry into the study, the patients were given a single capsule that contained 150 mg of fluconazole in the presence of the investigator. The study drug was supplied by Pfizer International (New York). Seven to 10 days after administration of the drug, the patients returned for clinical, mycological, and laboratory evaluations. If clinical and/or mycological cure was not achieved or significant improvement—which in the judgment of the investigator would lead to probable cure—was lacking, a second 150-mg dose of fluconazole was administered. The patient returned 7-10 days later for follow-up examination, as previously described. If the second course of treatment failed, a third 150mg dose of fluconazole was administered, and the patient again returned for follow-up examination in 7-10 days. If the third course of treatment failed, the patient received a fourth and final dose of fluconazole and returned to the clinic in 7-10 days. Clinical and mycological evaluation of all patients' conditions was performed 28-30 days after the last dose of fluconazole was administered. The criterion for clinical cure was the disappearance of presenting signs and symptoms. Improvement was defined as partial relief from or alleviation of presenting signs and symptoms, and treatment failure was defined as no appreciable change in signs and symptoms. The criterion for mycological response was eradication of the fungus, as documented microscopically or in culture; the criterion for failure was the persistent presence of the pathogen in material from
Total 20 (100%)
28 18-46
21 21-21
27 18-46
171 164-183
158 158-158
171 158-183
68 57-95
50 50-50
67 50-95
Table 4. Pathogens associated with cases of tinea corporis and/or cruris. Diagnosis Tinea corporis Tinea cruris Tinea cruris Tinea corporis-cruris
Pathogens
No. of patients (%)
T. rubrum T. rubrum Epidermophytonfloccosum T. rubrum
5 (25) 7 (35) 7 (35) I (5)
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on September 17, 2015
No. of patients (%) Age (y) Mean Range Height (cm) Mean Range Weight (kg) Mean Range
CID 1992;14 (Suppl 1)
Montero-Gei and Perera
CID 1992;14 (Suppl I)
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Fluconazole Therapy for Tinea
Table 5. Pathogens associated with cases of tinea pedis. Pathogen associated with tinea pedis*
No. of patients (%)
17 (77) 3 (14) 1 (5) 1 (5)
T. rubrwn T. mentagrophytes Epidennophyton floccosum Candida albicans
* Two patients had tinea pedis due to two pathogens.
Figure 1. Clinical response to therapy with fluconazole (cumulative doses) in patients with tinea corporis and/or tinea cruris. All 20 patients received two doses; six received three doses and two received four doses.
Results and Discussion The demographic data for patients are listed in tables 1 and 2. The localization and etiology of infections are listed in tables 3, 4, and 5. All patients with tinea corporis or tinea cruris received two doses of fluconazole; six patients received three, and two patients received four doses. Treatment of tinea corporis or tinea cruris with fluconazole proved to be clinically effective; cure was noted for 75% of patients who received a second dose of the drug, 67% of patients who re-
ceived a third dose, and 100% of patients who received a fourth dose. Clinical cure was observed for 95% of patients at the long-term follow-up visit (table 6). The clinical response to cumulative doses is shown in figure 1. The cumulative clinical cure rate increased from 75% after two doses to 90% after three doses, and to 100% after four 150-mg doses of fluconazole. The mycological response pattern was similar to the clinical response pattern (table 6, figure 2). By the time of
Table 6. Clinical and mycological response to therapy with fluconazole in patients with tinea corporis and/or tinea cruris. Value at indicated time Variable Clinical No. of patients evaluated Response (%) Cure Improvement Failure Mycological No. of patients Response (%) Eradication Persistence Relapse
Long-term follow-up
Post—dose 1
Post—dose 2
20
20
6
2
20
25 75 0
75 25 0
67 33 0
100 0 0
95 0 5
20
20
6
2
20
10 90 0
80 20
100 0 0
100 0 0
95 0 5
0
Post—dose 3
Post—dose 4
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on September 17, 2015
the lesions during the entire study. At the long-term followup visit, the category of relapse was added, which was defined as negative results of microscopic examination and culture at the end-of-treatment visit, followed by reappearance of the organism in culture at baseline at the long-term follow-up visit. Information with regard to all adverse events, observed or volunteered, was recorded; data included the date of onset of the event, the duration and severity, and whether the event was considered to be drug-related. Urinalysis, hematologic tests, and tests of biochemistry were performed before treatment and at all follow-up visits. All female patients had a negative pregnancy test performed at pre-treatment.
Montero-Gei and Perera
S80
Figure 3. Clinical response to therapy with fluconazole (cumulative doses) in patients with tinea pedis. All 20 patients received two doses; 16 received three doses and 12 received four doses.
by the time of the long-term follow-up visit (table 7). Clinical response to cumulative doses is shown in figure 3. The cumulative clinical cure rate increased from 25% after the administration of two 150-mg doses of fluconazole to 50% after three doses and to 65% after four doses. Among the remaining patients, the conditions of 30% improved, and treatment failed in only one (5%) of 20 patients. This patient had experienced improvement after receiving the first three doses of fluconazole; however, this patient's signs and symptoms
the long-term follow-up visit the infecting fungus was eradicated in 95% of patients. Relapse was recorded for only one patient. All patients with tinea pedis received two doses of fluconazole, 16 patients received three doses, and 12 patients received four doses. Treatment with fluconazole resulted in clinical cure for 25% of patients who received a second dose, 31% of patients who received a third dose, 42% of patients who received a fourth dose, and 70% of patients
Table 7. Clinical and mycological response to therapy with fluconazole in patients with tinea pedis. Value at indicated time Variable Clinical No. of patients evaluated Response (%) Cure Improvement Failure Mycological No. of patients Response (%) Eradication Persistence Relapse
Post—dose 1
Post—dose 2
Post—dose 3
Post—dose 4
Long-term follow-up
20
20
16
12
20
0 95 5
25 75
31 69
0
0
42 50 8
70 30 0
20
20
16
12
20
0 100 0
40 60
50 38 13
75 25 0
75 10 15
0
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on September 17, 2015
Figure 2. Mycological response to therapy with fluconazole (cumulative doses) in patients with tinea corporis and/or cruris. All 20 patients received two doses; six received three doses and two received four doses.
CID 1992;14 (Suppl 1)
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Fluconazole Therapy for Tinea
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References
Figure 4. Mycological response to therapy with fluconazole (cu- mulative doses) in patients with tinea pedis. All 20 patients re- ceived two doses; 16 received three doses and 12 received four doses. score increased after the fourth dose was administered. The
culture remained negative for fungi and the patient was clinically cured by the time of the long-term follow-up visit. The mycological response pattern among patients after administration of each dose of fluconazole was similar to the clinical response pattern (table 7). The cumulative mycological eradication rate increased from 40% after two doses, to 60% after three doses, and to 85% after four doses of fluconazole (figure 4). For two patients the infecting organism was eradicated after they received two doses of fluconazole; however, their infections relapsed after they received the third dose, and the organism was detected at the follow-up visits. At the long-term follow-up visit, mycological relapse was noted for three (15%) of 20 patients. All patients whose infections had mycologically relapsed were considered to have experienced clinical improvement in their condition when the findings were compared with baseline findings; however, their signs and symptoms scores had increased
1.
Bennett J. Fluconazole: an overview. Langhorne, PA: ADIS Press International, 1990:39. 2. Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis 1990; 12(suppl ):S318-26. 3. Jevon S, Lees L, Tarbit M. Early clinical experience with UK-49,858 in human volunteers and patients [abstract no. S-64-3]. In: Program and abstracts of the 14th ICC, Kyoto, June 23-28, 1985. 4. Pasko MT, Piscitelli SC, Van Slooten AD. Fluconazole: a new triazole antifungal agent. DICP, 1990;24:860-7. 5. Rippon JW. Medical mycology: the pathogenic fungi and the pathogenic actinomycetes. 3rd ed. Philadelphia: WB Saunders, 1988:169. 6. Montero-Gei F. Presente y futuro de las micosis superficiales. Med Cut Suplemento 1987;15:9-12. 7. Troke FP. Efficacy of fluconazole in animal models of superficial and opportunistic systemic fungal infections. In: Fromtling RA, ed. Recent trends in the discovery, development and evaluation of antifungal agents. Barcelona: J. R. Prous Science Publishers, 1987:103-12. 8. Naeyaert MJ, de Bersaques J, de Cyper C, Hindryckx PH, Van Landuyt H, Gordts B. Fluconazole (UK-49,858), a novel oral antifungal in the treatment of fungal skin infections. Results of an open study in 43 patients. In: Fromtling RA, ed. Recent trends in the discovery, development and evaluation of antifungal agents. Barcelona: J. R. Prous Science Publishers, 1987:157-61. 9. Haneki E. Pharmacodynamic and pharmacokinetic evaluation of fluconazole in plasma, epidermis and blister fluid. Int J Dermatol 1990 (in press).
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on September 17, 2015
since the previous visit. Treatment was very well tolerated among the two groups of patients; no adverse effects or laboratory abnormalities related to fluconazole therapy were observed. The results of these small, non-comparative studies indicate that a single weekly dose of 150 mg of fluconazole is an effective and convenient form of treatment for mild-tomoderate tinea corporis, tinea cruris, and tinea pedis. These studies did not include patients with tinea pedis of the sole of the foot; therefore, it is not known whether this regimen will be effective in the treatment of this more resistant form of the disease. The good results achieved with an intermittent dosage schedule suggest that fluconazole may accumulate in the epidermis and have prolonged activity. Pharmacokinetic studies have shown that high levels of fluconazole are still detectable in the skin 10 days after therapy is discontinued [9]. These results are promising; however, large comparative studies with this novel regimen are needed.
FUNGAL INFECTIONS IN NORMAL HOSTS
Therapy with Fluconazole for Tinea Corporis, Tinea Cruris, and Tinea Pedis F. Montero-Gei and A. Perera
From the School of Medical Sciences U.A.C.A. and San Juan de Dios Hospital, San Jose, Costa Rica
Fluconazole is a fluorine-substituted, bis-triazole agent that is water soluble, making it unique among currently available systemic azole antifungal agents. This distinction is reflected in its good oral absorption, high unbound plasma concentrations, and excellent total body distribution, including penetration into CSF, saliva, ocular fluids, skin, and nails [1]. In healthy volunteers, absorption of orally administered fluconazole is rapid; peak plasma concentrations are reached in —1-2 hours [2-3]. The bioavailability of fluconazole is —90% of an oral dose. There is no clinically significant effect on absorption when the drug is administered with food [3]. Its mechanism of action, like that of other azoles, involves interruption of the conversion of lanosterol to ergosterol via binding to fungal cytochrome P-450, which results in subsequent disruption of fungal membrane permeability [4]. Dermatophytosis is a clinical entity caused by members of the anamorphic fungal genera, Trichophyton, Microsporum, and Epidermophyton. In its restricted sense dermatophytosis is a colonization of the keratinized tissues including the nails, hair, and stratum corneum of the skin. The disease is a consequence of the host's reaction to the metabolic products of the fungus, rather than to the invasion of healthy tissue by the
Grant support: This work was supported in part by a grant from Pfizer International (New York). Reprints or correspondence: Dr. F. Montero-Gei, P.O. Box 2157-1000, San Jose, Costa Rica, Central America. Clinical Infectious Diseases 1992;14(Suppl 1):S77-81 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1403-0010802.00
organism [5]. Infections due to dermatophytes are pandemic, but the prevalence is higher in developing countries where socioeconomic factors play an important role in the transmission of superficial mycotic infections. The use of broadspectrum antibiotics, corticosteroids, and cytotoxic agents is associated with disseminated dermatophytosis, a condition in which granulomatous lesions that are similar histologically to Majocchi's granuloma extend to corporal areas [6]. Topical agents are commonly used to treat dermatophyte infections; however, these agents are occasionally associated with dermal sensitization and drug-induced eruptions. Treatment failure and relapses occur with use of the majority of the drugs that are presently available. Also, repeated applications of topical creams and ointments, especially to large areas of the skin, are not always acceptable and may lead to poor patient compliance. The need for better therapeutic agents is apparent, and oral therapy offers an effective, convenient alternative to topical agents. Recently, the new triazole antifungal agent, fluconazole, has been added to the armamentarium of drugs used to treat dermatophyte infections. In animal models, fluconazole was shown to be five-to-ten times more active than ketoconazole for treatment of shaved areas of the flank that were infected with a suspension of Trichophyton mentagrophytes or Trichophyton rubrum (in mice predisposed to infection because of topical triamcinolone use) and Microsporum canis (in guinea pigs) [7]. The efficacy of therapy with fluconazole (50 mg/d for 14-28 days) has been studied in patients with dermatophytosis; in cases of tinea pedis, the duration of therapy has been extended to 42 days. The clinical response rate (cure or improvement) was 100% at the end of treatment. At follow-
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on September 17, 2015
We treated 20 patients who had tinea corporis and/or tinea cruris and 20 patients who had tinea pedis with oral fluconazole. All patients were given a single 150-mg dose of fluconazole upon entry into the study; at that time, and at each follow-up visit, clinical signs and symptoms were evaluated and mycological and laboratory examinations were performed. If clinical and/or mycological cure or significant improvement in a patient's condition was not evident at the 7-day follow-up visit, a second dose of fluconazole (150 mg) was given. A maximum of four doses, one week apart, were given. A long-term evaluation of the efficacy of fluconazole in the treatment of these infections was performed 28-30 days after the last dose was administered to each patient. For the treatment of tinea corporis and/or tinea cruris, 70% of patients required two doses, 20% required three doses, and 10% required four doses. At the long-term follow-up visit the clinical and mycological response rates were determined to be 95% cure and 5% relapse. For the treatment of tinea pedis, 20% of the patients required two doses, 20% required three doses, and 60% required four doses. For these patients, the long-term clinical response rates were 70% cure and 30% improvement; mycological response rates were 75% eradication, 10% persistence of infection, and 15% relapse. This treatment was well tolerated; no adverse effects or clinically significant laboratory abnormalities were reported.
S78
Table 1. Demographic characteristics of patients with tinea corporis and/or tinea cruris.
Table 3. Frequency of diagnosis of tinea.
No. of patients (%)
Tinea corporis Tinea cruris Tinea corporis-cruris Tinea pedis
5 (25) 14 (70) 1 (5) 20 (100)
Diagnosis Male
Variable
19 (95%)
Female I (5%)
Total 20 (100%)
30 19-54
20 20-20
30 19-54
169 160-179
158 158-158
168 158-179
68 54-82.6
54 54-54
68 54-82.6
up 2-4 weeks after initiation of therapy, the clinical response rate was 90% [8]. Pharmacokinetic studies have demonstrated that fluconazole rapidly penetrates the skin, with concentrations up to 10 times those seen in the plasma [2]. Fluconazole also appears to be eliminated from the skin very slowly, a finding suggesting that a shorter course of treatment combined with less frequent administration may be an effective alternative to the regimen of 50 mg/d [9]. A regimen that consists of a once-weekly dose could have the advantage of better patient compliance and lower cost. Patients and Methods
This was an open, noncomparative study to assess the efficacy, safety, and tolerability of a single oral dose of fluconazole (150 mg) in the treatment of outpatients with mycologically proven tinea corporis, tinea cruris, or tinea pedis. For the patients with tinea pedis, the fungal infection was limited to the toes, interdigital spaces, and dorsum of the foot; it did not involve the sole or toenails. The diagnosis was confirmed on the basis of findings on microscopic examination of infected skin with 20% KOH and the isolation of the dermatophytes with use of Mycosel and Sabouraud dextrose agar (BBL, Baltimore). The identification of infecting fungi was
Table 2. Demographic characteristics of patients with tinea pedis. Variable No. of patients (%) Age (y) Mean Range Height (cm) Mean Range Weight (kg) Mean Range
Male 19 (95%)
Female 1 (5%)
made on the basis of the results of culture. A medical history was reported by each patient, and physical examinations and laboratory tests were performed. Any medications taken concomitantly on entry into the study or during the study were recorded. Each patient was informed of the details of the study and of potential adverse effects, and written or oral consent was obtained prior to enrollment in the study. On qualifying for entry into the study, the patients were given a single capsule that contained 150 mg of fluconazole in the presence of the investigator. The study drug was supplied by Pfizer International (New York). Seven to 10 days after administration of the drug, the patients returned for clinical, mycological, and laboratory evaluations. If clinical and/or mycological cure was not achieved or significant improvement—which in the judgment of the investigator would lead to probable cure—was lacking, a second 150-mg dose of fluconazole was administered. The patient returned 7-10 days later for follow-up examination, as previously described. If the second course of treatment failed, a third 150mg dose of fluconazole was administered, and the patient again returned for follow-up examination in 7-10 days. If the third course of treatment failed, the patient received a fourth and final dose of fluconazole and returned to the clinic in 7-10 days. Clinical and mycological evaluation of all patients' conditions was performed 28-30 days after the last dose of fluconazole was administered. The criterion for clinical cure was the disappearance of presenting signs and symptoms. Improvement was defined as partial relief from or alleviation of presenting signs and symptoms, and treatment failure was defined as no appreciable change in signs and symptoms. The criterion for mycological response was eradication of the fungus, as documented microscopically or in culture; the criterion for failure was the persistent presence of the pathogen in material from
Total 20 (100%)
28 18-46
21 21-21
27 18-46
171 164-183
158 158-158
171 158-183
68 57-95
50 50-50
67 50-95
Table 4. Pathogens associated with cases of tinea corporis and/or cruris. Diagnosis Tinea corporis Tinea cruris Tinea cruris Tinea corporis-cruris
Pathogens
No. of patients (%)
T. rubrum T. rubrum Epidermophytonfloccosum T. rubrum
5 (25) 7 (35) 7 (35) I (5)
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on September 17, 2015
No. of patients (%) Age (y) Mean Range Height (cm) Mean Range Weight (kg) Mean Range
CID 1992;14 (Suppl 1)
Montero-Gei and Perera
CID 1992;14 (Suppl I)
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Fluconazole Therapy for Tinea
Table 5. Pathogens associated with cases of tinea pedis. Pathogen associated with tinea pedis*
No. of patients (%)
17 (77) 3 (14) 1 (5) 1 (5)
T. rubrwn T. mentagrophytes Epidennophyton floccosum Candida albicans
* Two patients had tinea pedis due to two pathogens.
Figure 1. Clinical response to therapy with fluconazole (cumulative doses) in patients with tinea corporis and/or tinea cruris. All 20 patients received two doses; six received three doses and two received four doses.
Results and Discussion The demographic data for patients are listed in tables 1 and 2. The localization and etiology of infections are listed in tables 3, 4, and 5. All patients with tinea corporis or tinea cruris received two doses of fluconazole; six patients received three, and two patients received four doses. Treatment of tinea corporis or tinea cruris with fluconazole proved to be clinically effective; cure was noted for 75% of patients who received a second dose of the drug, 67% of patients who re-
ceived a third dose, and 100% of patients who received a fourth dose. Clinical cure was observed for 95% of patients at the long-term follow-up visit (table 6). The clinical response to cumulative doses is shown in figure 1. The cumulative clinical cure rate increased from 75% after two doses to 90% after three doses, and to 100% after four 150-mg doses of fluconazole. The mycological response pattern was similar to the clinical response pattern (table 6, figure 2). By the time of
Table 6. Clinical and mycological response to therapy with fluconazole in patients with tinea corporis and/or tinea cruris. Value at indicated time Variable Clinical No. of patients evaluated Response (%) Cure Improvement Failure Mycological No. of patients Response (%) Eradication Persistence Relapse
Long-term follow-up
Post—dose 1
Post—dose 2
20
20
6
2
20
25 75 0
75 25 0
67 33 0
100 0 0
95 0 5
20
20
6
2
20
10 90 0
80 20
100 0 0
100 0 0
95 0 5
0
Post—dose 3
Post—dose 4
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on September 17, 2015
the lesions during the entire study. At the long-term followup visit, the category of relapse was added, which was defined as negative results of microscopic examination and culture at the end-of-treatment visit, followed by reappearance of the organism in culture at baseline at the long-term follow-up visit. Information with regard to all adverse events, observed or volunteered, was recorded; data included the date of onset of the event, the duration and severity, and whether the event was considered to be drug-related. Urinalysis, hematologic tests, and tests of biochemistry were performed before treatment and at all follow-up visits. All female patients had a negative pregnancy test performed at pre-treatment.
Montero-Gei and Perera
S80
Figure 3. Clinical response to therapy with fluconazole (cumulative doses) in patients with tinea pedis. All 20 patients received two doses; 16 received three doses and 12 received four doses.
by the time of the long-term follow-up visit (table 7). Clinical response to cumulative doses is shown in figure 3. The cumulative clinical cure rate increased from 25% after the administration of two 150-mg doses of fluconazole to 50% after three doses and to 65% after four doses. Among the remaining patients, the conditions of 30% improved, and treatment failed in only one (5%) of 20 patients. This patient had experienced improvement after receiving the first three doses of fluconazole; however, this patient's signs and symptoms
the long-term follow-up visit the infecting fungus was eradicated in 95% of patients. Relapse was recorded for only one patient. All patients with tinea pedis received two doses of fluconazole, 16 patients received three doses, and 12 patients received four doses. Treatment with fluconazole resulted in clinical cure for 25% of patients who received a second dose, 31% of patients who received a third dose, 42% of patients who received a fourth dose, and 70% of patients
Table 7. Clinical and mycological response to therapy with fluconazole in patients with tinea pedis. Value at indicated time Variable Clinical No. of patients evaluated Response (%) Cure Improvement Failure Mycological No. of patients Response (%) Eradication Persistence Relapse
Post—dose 1
Post—dose 2
Post—dose 3
Post—dose 4
Long-term follow-up
20
20
16
12
20
0 95 5
25 75
31 69
0
0
42 50 8
70 30 0
20
20
16
12
20
0 100 0
40 60
50 38 13
75 25 0
75 10 15
0
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on September 17, 2015
Figure 2. Mycological response to therapy with fluconazole (cumulative doses) in patients with tinea corporis and/or cruris. All 20 patients received two doses; six received three doses and two received four doses.
CID 1992;14 (Suppl 1)
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Fluconazole Therapy for Tinea
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References
Figure 4. Mycological response to therapy with fluconazole (cu- mulative doses) in patients with tinea pedis. All 20 patients re- ceived two doses; 16 received three doses and 12 received four doses. score increased after the fourth dose was administered. The
culture remained negative for fungi and the patient was clinically cured by the time of the long-term follow-up visit. The mycological response pattern among patients after administration of each dose of fluconazole was similar to the clinical response pattern (table 7). The cumulative mycological eradication rate increased from 40% after two doses, to 60% after three doses, and to 85% after four doses of fluconazole (figure 4). For two patients the infecting organism was eradicated after they received two doses of fluconazole; however, their infections relapsed after they received the third dose, and the organism was detected at the follow-up visits. At the long-term follow-up visit, mycological relapse was noted for three (15%) of 20 patients. All patients whose infections had mycologically relapsed were considered to have experienced clinical improvement in their condition when the findings were compared with baseline findings; however, their signs and symptoms scores had increased
1.
Bennett J. Fluconazole: an overview. Langhorne, PA: ADIS Press International, 1990:39. 2. Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis 1990; 12(suppl ):S318-26. 3. Jevon S, Lees L, Tarbit M. Early clinical experience with UK-49,858 in human volunteers and patients [abstract no. S-64-3]. In: Program and abstracts of the 14th ICC, Kyoto, June 23-28, 1985. 4. Pasko MT, Piscitelli SC, Van Slooten AD. Fluconazole: a new triazole antifungal agent. DICP, 1990;24:860-7. 5. Rippon JW. Medical mycology: the pathogenic fungi and the pathogenic actinomycetes. 3rd ed. Philadelphia: WB Saunders, 1988:169. 6. Montero-Gei F. Presente y futuro de las micosis superficiales. Med Cut Suplemento 1987;15:9-12. 7. Troke FP. Efficacy of fluconazole in animal models of superficial and opportunistic systemic fungal infections. In: Fromtling RA, ed. Recent trends in the discovery, development and evaluation of antifungal agents. Barcelona: J. R. Prous Science Publishers, 1987:103-12. 8. Naeyaert MJ, de Bersaques J, de Cyper C, Hindryckx PH, Van Landuyt H, Gordts B. Fluconazole (UK-49,858), a novel oral antifungal in the treatment of fungal skin infections. Results of an open study in 43 patients. In: Fromtling RA, ed. Recent trends in the discovery, development and evaluation of antifungal agents. Barcelona: J. R. Prous Science Publishers, 1987:157-61. 9. Haneki E. Pharmacodynamic and pharmacokinetic evaluation of fluconazole in plasma, epidermis and blister fluid. Int J Dermatol 1990 (in press).
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since the previous visit. Treatment was very well tolerated among the two groups of patients; no adverse effects or laboratory abnormalities related to fluconazole therapy were observed. The results of these small, non-comparative studies indicate that a single weekly dose of 150 mg of fluconazole is an effective and convenient form of treatment for mild-tomoderate tinea corporis, tinea cruris, and tinea pedis. These studies did not include patients with tinea pedis of the sole of the foot; therefore, it is not known whether this regimen will be effective in the treatment of this more resistant form of the disease. The good results achieved with an intermittent dosage schedule suggest that fluconazole may accumulate in the epidermis and have prolonged activity. Pharmacokinetic studies have shown that high levels of fluconazole are still detectable in the skin 10 days after therapy is discontinued [9]. These results are promising; however, large comparative studies with this novel regimen are needed.
