oftioconazole Cream 1% versus

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1 The Journal ofinternational Medical Research 1987; IS: 2~3l Comparative and Non-comparative Studies ofthe Efficacy and Tolerance oftioconazole Cream 1% versus Another Imidazole and/or Placebo in Neonates and Infants with Candidal Diaper Rash and/or Impetigo D. L. Gibbs, P. Kashin and S. Jevons Medical Division, Pfizer International, 235 East 42nd Street, New York, NY10017, USA Eleven open multicentre studies were conducted to evaluate the efficacy of tioconazole cream 1% as a treatment for diaper rash with or without fungal (Candida) involvement, or impetigo in neonates and infants. In the dermal /diaper rash group, 320 patients had either tioconazole (n = 220), a comparative imidazole (n = 43), or vehicle cream (n = 57) applied to the affected area twice daily. Twenty-one impetigo patients had only tioconazole cream 1% applied three times daily to lesions. The overall cure rate (patients with both clinical and mycological cure) at the end of treatment for tioconazole treated patients was 78%, for the comparative imidazole group it was 76% and for vehicle cream it was At the long-term follow-up evaluation approximately 6 weeks after treatment for patients with diaper rash, the overall cure rate was about the same in both tioconazole- and comparative imidazole-treated patients (87% and 90%, respectively), and 14% in patients using vehicle cream. Sideeffects were coincident with disease symptoms and consisted primarily of erythema localized to the treatment area; they occurred in 5.4% (13/241) of the patients who received tioconazole and in 21% (9/43) of the patients who received comparative imidazole (econazole or miconazole). No side-effects were reported in this open study for the 57 patients who used vehicle cream. The results of these studies show that tioconazole cream 1% is safe and effective for the treatment of neonates and infants with dermal, diaper rash and impetigo. Received for publication 21 October 1986; accepted 30 October Address for correspondence: Dr. D. L. Gibbs, Medical Division, Pfizer International Inc., 235 East 42nd Street, New York, NY 10017, USA. ccopyright 1987 by Cambridge Medical Publications Ltd. 23

2 N.,.. 0 r Table 1 0 6' DistnDution ofpatients sr J" :-a No. ofpatients treated p Vehicle ~ Investigator Country Indication Tioconazole Imidazoles4' cream Total... (II Dr. J. C. Badoual and France Neonatal and infantile Prof. E. Drouhet Prof. R. Gilly France Neonatal and infantile Dr. D. Grigoriu Switzerland Neonatal and infantile Dr. D. Grigoriu Switzerland Neonatal and infantile Dr. E. Haneke West Germany Neonatal and infantile Prof. Z. Itani West Germany Neonatal and infantile Prof. R. M. MacKie Scotland Neonatal and infantile Dr. L. Stimmler UK Neonatal and infantile Dr. L. Stimmler UK Neonatal and infantile Prof. C. F. H. Vickers UK Neonates and infants with fungal infection Prof. J. Maleville France Impetigo ;;0::: I'> '" cr. < 0 ::3 '" Total Comparative imidazoles included miconazole and econazole.

3 Efficacy and tolerance of tioconazole cream rtzz: INTRODUCTION (Trosyd'"), an imidazole derivative, has proven to be a potent broad spectrum anti-fungal agent that also has in vitro activity against certain Gram-positive bacteria'r' both in laboratory evaluations and in the clinical treatment of dermal fungal infections! and vaginal.' The majority of patients treated so far have been adults, and this study was established to investigate the safety and efficacy of topically applied tioconazole dermal cream 1% in the treatment of very young patients. The clinical conditions treated were primarily dermal (predominantly diaper rash) and impetigo. Diaper rash is a clinical condition with various causative factors including overhydration, friction, detergents, disinfectants and faeces. Dermal is rarely found in infants with normal skin but is reported to occur in 40-75% of those with diaper rash. 5 6 Where intense erythema in groin folds and perianal skin is evident, the recovery rate of Candida albicans may be as high as 80%.7 ~ Registered Trade Mark of Pfizer InternationalInc. This report presents the findings of 11 European open multicentre clinical trials (five comparative and six noncomparative) on patients with diaper rash and/or culture-positive superficial Candida or Gram-positive bacterial infections. PATIENTS AND METHODS The 11 studies investigated a total of 341 patients with dermal or diaper rash and impetigo (21 patients in one study). The dermal /diaper rash studies were conducted by nine investigators in France, Switzerland, West Germany, Scotland and England. One investigator in France investigated impetigo (Table l). Of the 341 patients studied, 241 (71%) used tioconazole dermal cream 1%,43 patients (13%) used a comparative imidazole (37 used econazole and six used miconazole) and 57 patients (17%) used a vehicle cream (Table 2). Patients with mycologically proven candidal infections and/or diaper rash were included in the efficacy assessment. In the impetigo study, patients whose clinical diagnosis was confirmed microbiologically were included in the efficacy assessment. Informed consent Table 2 Summary ofpatients by infection category and treatment group No. of patients treated Type of infection Tioconazole Econazole Miconazole Vehicle cream Total Dermal /diaper rash Impetigo Total

4 D. L. Gibbs, P. Kashin, S.Jevons 26 from patients' parents or legal guardian was obtained. Patients requiring other anti-fungal or antibiotic therapy (systemic antibiotic therapy in the impetigo group) and patients receiving treatment with any other investigational drugs were excluded. All patients had their clinical histories taken and were given a physical examination. In the /diaper rash group, swabs or scrapings of the infected skin were taken prior to treatment. Part of the specimen was examined microscopically and part was cultured on Sabourad agar plates. In the impetigo group, specimens for Gram staining and culture were obtained from the lesions. Minimum inhibitory concentrations (MICs) of tioconazole were determined. Although review times varied, in most of the /diaper rash studies reviews were performed every 7 days during treatment and again at the end of treatment. In patients who were clinically cured, a follow-up review was conducted approximately 6 weeks after completion of treatment to determine whether or not relapse or re-infection had occurred. Impetigo patients were reviewed every 3-4 days after the start of treatment. For all patients, each review entailed clinical assessments of the signs and symptoms of infection, independent of mycological or bacteriological findings. Clinical response to treatment was graded as 'cured', 'improved' or 'treatment failure'. Mycological examinations by microscopy and culture were performed at all reviews in the majority of studies. Note was made of the time required to bring about symptom relief and to clear the lesions clinically. Criteriafor efficacy evaluation A clinical cure was achieved if there was complete resolution of the signs and symptoms of infection, and clearing of lesions from the affected area. Improvement required considerable resolution of the signs and symptoms, and treatment failure occurred if the condition remained unchanged or worsened. Mycological cures were based on microscopy showing the absence of yeast in skin scrapings from the affected area(s) and on culture results showing the absence of fungal growth in standard media. Drug administration Tioconazole dermal cream 1% and the comparative agents were supplied in identical 30 g tubes. All active agents were supplied as a 1% cream. In the /diaper rash group, the cream was applied to the affected area(s) thinly and evenly, and rubbed in gently twice daily in the majority of cases for up to 28 days. In the impetigo group, infected areas were bathed three times daily by swabbing with warm water for approximately 10 min. Debris was removed and the lesions dried prior to tioconazole application. Tioconazole was applied liberally to the lesions and rubbed in gently three times daily for up to 21 days. Treatment was stopped if the rash worsened or an increased irritation occurred. Safety At each review, a record was made of the nature, severity, time of onset, course, duration and any symptomatic treatment of observed side-effects. RESULTS A total of 341 in- and out-patients were included in the 11 studies: 241 were treated with tioconazole dermal cream 1%; 43 were randomized to a compara-

5 Efficacy and tolerance of tioconazole cream Table 3 Patient demographics: age distribution Group 1 Candidiasis/diaper rash Group 2t Impetigo Age ranges Comparative Vehicle (months) Tioconazole imidazole cream Tloconazole Patients (%) <I > Total Group 1 consisted of all patients treated for and/or diaper rash. t Group 2 consisted of all patients treated for impetigo. tive imidazole (econazole, 37 patients; miconazole, six patients); and 57 were assigned to the vehicle cream. Patients were pooled into two groups for purposes of analysis: group 1 included the /diaper rash patients (n = 320), and group 2 included the impetigo patients (n = 21). Patient ages in group 1 ranged from 3 days to 14 years; the majority were 1 year or less. In group 2 (impetigo patients), ages ranged from 21 months to 14 years; 12 patients were older than 3 years and the rest were between 1 and 3 years (fable 3). The majority of patients in both groups were between 3 and 12 months old. In group I (/diaper rash), Table 4 Mycological diagnoses of all /diaper rash patients (group I) No. of patients Comparative Vehicle Pathogen Tioconazole imidazole cream Total Patients (%) Candida spp C. albicans C. parapsilosis I C. tropicalis Unidentified microscopy Patients without fungal involvement No culture/microscopy 20 I 2 2~ 7.2 Total IOO.v 27

6 D. L. Gibbs, P. Kashin, S. Jevons Table S Bacteriological diagnoses ofall impetigo patients (group 2) Pathogen Staphylococcus aureus Streptococci S. aureus + Streptococci S. aureus + Gram-negative bacilli S. aureus + Streptococci + Enterobacter Acinetobacter Not identified Total No. of patients Patients (%) % (248/320) of patients had dermal with confirmed Candida as the infecting organism (Table 4). Of the remaining 72 patients in group I, 65% (47/72) did not have a candidal infection while 0.6% had unidentified microscopy. Histological data were missing for 32% of the patients. In one study, three patients were concomitantly infected with Staphylococcus, aureus. The diaper and adjacent areas were the primary sites of infection in the majority of candidal patients. 'Impetigo was diagnosed at 34 sites in the 21 patients in this group. Bacteriological diagnoses for these patients are shown in Table 5. Sites of infection involved the limbs, head and body. Staphylococcus aureus was identified as the sole organism in 38% of the infection sites and, together with other organisms, was found in 43% of the sites. Other infecting organisms included Gram-negative bacilli, Enterobacter and Acinetobacter In group 1 (/diaper rash), 93 patients were excluded from the efficacy analysis and four patients were excluded from group 2 (impetigo group). These patients were excluded due to default and/or lack of mycological or bacteriological data. Efficacy Table 6 summarizes the mean duration of therapy for all patients in each treatment group: 15 days for tioconazole, 19 days for comparative imidazoles and 12 days for the vehicle cream. For impetigo patients, the mean duration of tioconazole therapy was 8.5 days. Candidal diaper rash patients were clinically and mycologically assessed at the end of treatment and again at followup (approximately 6 weeks after treatment). Table 7 shows the clinical and mycological response rates, and the candidal patients who exhibited both clinical and mycological cures (overall cure) at the end of treatment and at the long-term follow-up. At the end of treatment, 78% of tioconazole-treated patients were cured overall compared with 76% of patients given comparative imidazoles and 26% of patients given vehicle cream. Of the patients seen at follow-up who were cured at the end of treatment, 86% of tioconazole-treated patients remained cured. In the study comparing tioconazole to vehicle cream in treating diaper rash patients with and without fungal involvement, clinical cure rates at the end of treatment in patients with fungal involvement were 78% for

7 Efficacy and tolerance of tioconazole cream Table 6 Mean duration oftherapy Treatment duration (days) Group 1 Candidiasis/diaper rash Group 2 Impetigo Tioconazole (n=220) Comparative imidazole (n=43) Vehicle cream (n=51) Tioconazole (n=21) Mean Range Patients with <1 day of treatment o Patients with I day of treatment or less are not included in the mean duration (includes one tioconazole-treated candida!patient who had no duration recorded). tioconazole-treated patients and 39% for vehicle cream-treated patients (P<O.Ol). In patients with no fungal involvement, tioconazole and vehicle cream were equally effective (tioconazole, 68%; vehicle cream, 71%). Seventeen impetigo patients were assessed clinically and bacteriologically at the end of treatment and follow-up (Table 8). At the end of treatment, a clinical cure was seen in 71% (12/17) of patients; 47% (8/17) of patients were bacteriologically cured. Of the patients seen at follow-up, all remained cured. Tolerance Side-effects were coincident with disease symptoms and occurred in 5% (13/241) of the tioconazole-treated patients who Table 7 Clinical and mycological response rates at the end of treatment and after 6 weeks' posttreatment follow-up for patients with candidal diaper rash" End oftreatment Follow-up Overall CUnically cure End oftreatment cured or Mycologically (clinical and Overall cures who remained Treatment Improved cured mycological) cure cured at fouow-up Tioconazole 142/ / /147 77/89 70/81 (90) (92) (78) (87) (86) Comparative 39/41 28/37 28/37 28/31 28/28 imidazole (95) (76) (76) (90) (100) Vehicle cream 11/28 9/23 6/23 1/7 1/1 (39) (39) (26) (14) (100) Valuesin parentheses are percentages. 29

8 D. L. Gibbs, P. Kashin, S. Jevons Table 8 Clinical and bacterial response rates at the end of treatment and follow-up for patients with impetigo End of treatment Overall cure Clinical Bacterial (clinical and Treatment cure cure bacterial) Tioconazole 12/17 8/17 8/17 (71) (47) (47) Overall cure 8/8 (100) Follow-up End of treatment cures who remained cured at fouow-up 6/6 (100) Values in parentheses are percentages. had 17 treatment-related side-effects. In the comparative imidazole treatment group, 21% (9/43) of the patients experienced 13 treatment-related sideeffects. The most frequently reported side-effect in all treatment groups was erythema, localized to the treatment area. Eight patients were withdrawn from the study because of drug-related side-effects, seven (3%) in the tioconazole group and one (2%) in the comparative imidazole group. No side-effects were experienced by any patients treated with the vehicle cream. DISCUSSION Diaper rash is a common condition with no well defined aetiology or treatment. Suggested management varies from palliative methods, such as exposure to air, to treatment with barrier creams and non-specific anti-microbial agents. The treatment of fungal skin and vaginal yeast infections with topically applied tioconazole is a widely accepted and successful form of therapy. The 11 studies reported here assessed the benefit of anti-fungal therapy by comparing the efficacy of tioconazole, the comparative imidazole creams econazole and miconazole, and vehicle cream in the treatment of diaper rash with and without fungal involvement. The incidence of fungal involvement in diaper rash was shown to be 56% in one study (Stimmler); Candida was the infecting organism in the majority of cases. In patients with proven fungal involvement, 78% were clinically cured with tioconazole, whereas vehicle cream resulted in clinical success in only 39% of patients. The difference in cure rates was significant (P< 0.01). In diaper rash patients without fungal involvement, both tioconazole and vehicle creams were effective with no difference between cure rates. It was concluded from this study (Stimmler) that. while treatment of diaper rash with tioconazole was beneficial with or without mycological confirmation of infection, vehicle cream was only effective in the group without evidence of candidal involvement. In the remainder of the studies, with the exception of one for impetigo, the majority of patients were treated with tioconazole or comparative imidazole creams for mycologically proven of the skin, predominantly diaper rash. The pooled results for all patients with mycologically proven infection again showed tioconazole to be highly effective in the treatment of this condition; 78% of patients were clinically and mycologically cured at the 30

9 Efficacy and tolerance of tioconazole cream end of treatment. This cure rate was similar to that seen with the comparative imidazoles (76%), econazole and miconazole, although the small number of patients treated with other imidazoles precludes any statistical comparison. The incidence of side-effects associated with tioconazole was markedly lower than comparative imidazoles and side-effects were all local. The incidence and nature of the sideeffects in this study were similar to those seen in much larger numbers of adult patients treated with tioconazole dermal cream. It is concluded that tioconazole cream 1% is a safe and effective treatment for infants and neonates with fungal infection of the skin. ACKNOWLEDGEMENT The assistance of Ms. Rosemarie T. Eccleston in the preparation of the manuscript is gratefully acknowledged. REFERENCES I. Jevons S, Gymer GE, Brammer KW, et al: Antifungal activity of tioconazole (UK-20, 349), a new imidazole derivative. Antimicrob Agents Chemother 1979; 15: Marriott MS, Baird JCR, Brammer KW, et al: Tioconazole, a new antifungal agent for the treatment of dermatomycoses. Dermatologica 1983; l66(suppll): East O'Neill M, Henderson JT, Jevons S: Tioconazole in the treatment of fungal infections of the skin. Dermatologica 1983; 166(suppll): Henderson JT, Neilson W, Wilson AB, et al: Tioconazole in the treatment of vaginal. Gynakof Rundsch 1983; 23(suppll): Dixon PN, Warin RP, English MP: Role of Candida albicans infections in napkin rashes. Br Med J 1969; 2: Montes LF, Pittillo RP, Hunt D, et al: Microbial flora of infants skin: comparison of types of micro-organisms between normal skin and diaper dermatitis. Arch Dermatol 1971; 103: Leyden JJ, Kligman AM: The role of microorganisms in diaper dermatitis. Arch Dermatol 1978; 114: