Comparison of the Efficacy and Safety of Oral Fluconazole and Topical Clotrimazole in Patients with Candida Balanitis

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98 Genitourin Med 1996;72:98-102 Comparison of the efficacy and safety of oral fluconazole and topical clotrimazole in patients with candida balanitis

A Stary, J Soeltz-Szoets, C Ziegler, G R Kinghorn, R B Roy

One hundred fifty seven men with candidal balanitis were entered in a randomised, open-label parallel-group multicentre study comparing efficacy and safety of a single oral 150-mg fluconazole-dose with clotrimazole applied topically twice daily for 7 days. Of 64 fluconazole and 68 clotrimazole treated patients who were evaluable at short term follow up, 92% and 91 % respectively were clinically cured or improved. Candida albicans was eradicated in 78% and 83% of patients respectively. Median time to relief of erythema was 6 days for fluconazole and 7 days for clotrimazole. Twelve of 15 patients who had received previous topical therapy for balanitis said they preferred oral therapy. At the one month follow up visit, 24/36 and 29/33 patients in the two groups were clinically cured or improved. Nine in the fluconazole group experienced a relapse; 6 of these 9 patients reported previous episodes of this infection during the past year. Two patients in the clotrimazole group had a relapse; neither had a history of previous episodes. Mycological eradication was noted in 26/36 and 25/33 patients in the two groups. Both treatment regimens were well tolerated. Thus a single 150 mg dose of fluconazole was comparable in efficacy and safety to clotrimazole cream applied topically for 7 days when administered to patients with balanitis. (Genitourin Med 1996;72:98-102) Keywords: Fluconazole; clotrimazole; candida; candidiasis; balanitis

Introduction ing single-dose fluconazole in patients with Balanitis is an acute or chronic inflammation balanitis is a pilot open-label noncomparative of the glans penis. The typical case is mild study.'4 The purpose of the present study was with erythema and symptoms of pain and to compare the efficacy and safety of a single burning.' 2 However, patients with balanitis oral 150-mg dose of fluconazole with that of can also present with profuse subpreputial multiple-dose topical clotrimazole 1% cream discharge, oedema, and various degrees of in patients with candida balanitis. phimosis. The microorganism most often cul- tured in symptomatic patients is Candida albicans.3-7 There are several factors that Methods predispose patients to the development of bal- Study Design anitis including intercourse with an infected This was a randomised, open-label, parallel- Outpatients' Center partner, recent antibiotic therapy, and poorly group multicentre study. Male outpatients, 18 for Diagnosis of diabetes mellitus.3 4 89 Additionally, years of age or older, with a clinical and Infectious controlled Venerodermatological balanitis commonly occurs in uncircumcised microbiological diagnosis of balanitis were eli- Disease, Vienna, men.5 9 10 gible to enroll in the study. Signs and symp- Austria Conventional treatment of candida balanitis toms (mild, moderate, severe) of balanitis A Stary consists of topical application of an antifungal recorded included: white plaques, erythema, Ludwig-Baltzmann As Institute for Research cream for a period of 1 to 2 weeks.458 Topical soreness, phimosis and fungal cultures. of Infectious agents are messy and tend to rub off on cloth- culture results often require several days, there Venerodermatological ing, which can lead to noncompliance. An were some patients entered who clinically Diseases, Vienna, cultures were Austria alternative to topical therapy is short-course appeared to have balanitis, but J Soeltz-Szoets systemic therapy with an oral antifungal drug. negative (for unknown reasons). Those C Ziegler Oral treatment tends to result in better patient patients were thus not considered fully evalu- Royal Hallamshire compliance than topical creams. Better able because a fungal pathogen was not iso- Hospital, Sheffield, patient compliance to therapeutic regimens lated at baseline visit; however, clinical UK G R Kinghorn usually results in a better overall response to response (signs and symptoms) were recorded Royal Bournemouth therapy. This is especially important in gen- and thus reported. Excluded were patients Hospital, eral practice where compliance tends to be with urogenital infection other than balanitis, Bournemouth, UK less than in formal clinical studies. In this a history of allergy to azole antifungals, R B Roy regard, fluconazole has been considered impaired renal or hepatic function, and a his- Correspondence to: Dr Angelika Stary, because of its favourable absorption profile, tory of alcoholism, drug abuse or psychologi- Outpatients' Center for extensive distribution into tissues, and its lack cal problems. Other reasons for exclusion Diagnosis of Infectious 12 Venerodermatological of serious adverse effects." Single-dose from the study were participation in other Diseases, Franz-Jonas-Platz treatment with oral fluconazole is becoming investigational drug studies within the previ- 8/213, A-1210 Vienna, Austria. well-accepted as a safe and effective alterna- ous month, donation of blood or receipt of a Accepted for publication tive to topical treatment of candida vaginitis."3 blood transfusion within the previous 2 weeks, 15 January 1996 To date, the only published study evaluat- and treatment with any antifungal drug within Comparison ofthe efficacy and safety oforalfluconazole and topical clotrimazole in patients with candida balanitis 99

the previous 2 weeks, which was assumed to were also evaluated for the occurrence of be an adequate time period to eliminate the adverse events. During the short-term follow- presence of any residual previous topical or up visit, diary cards were collected and oral antifungal therapy. Concomitant treat- patients were queried as to their abstinence ment with nonstudy antifungal drugs was pro- from sexual intercourse since the baseline hibited during the trial period. A total of four visit. Patients in the fluconazole group who investigational centres located in the United had received previous topical antifungal ther- Kingdom (two) and in Austria (two) partici- apy were asked to rate their preference for pated in the study. Study participants gave either oral or topical treatment. informed consent in accordance with the Declaration of Helsinki, and local ethical Microbiological technique committee approval was obtained. Two dry cotton wool swabs were used to Eligible patients were randomly assigned to obtain samples for mycological analysis from receive treatment with either a single oral 150 different sites on the prepuce. The swab was mg dose of fluconazole or clotrimazole 1% plated onto Sabouraud's medium or Rice agar cream applied twice daily (morning and and incubated at 37°C. Candida albicans was evening) for 7 days. At the baseline visit, identified using a germ tube test. Other can- before initiation of study drug therapy, all dida species were identified using the API patients underwent a physical examination 20C system (Analatab Products Inc, and a medical history was obtained. Previous Plainview, NY). episodes of balanitis, recent antifungal drug therapy, and whether or not the patient was Efficacy evaluation circumcised were recorded. Pertinent infor- Clinical efficacy was categorised as cure (dis- mation about the signs, symptoms, and treat- appearance of all baseline signs and symptoms ment of any vaginal condition of the patient's of infection), improvement (partial disappear- partner was also recorded. Patients were evalu- ance of baseline signs and symptoms), or fail- ated for the clinical signs and symptoms of ure (no change or worsening). Improvement balanitis, including soreness, erythema, phi- or cure followed by reappearance or worsen- mosis and white plaques. Each sign and symp- ing of clinical symptoms at the long-term tom was graded as absent, mild, moderate, or follow-up was categorised as a relapse. severe. Other signs and symptoms not Mycological efficacy was categorised as eradi- included in this list could also be recorded and cation (negative post-treatment culture result graded. A preputial swab was obtained for for candida) or persistence (a positive post- microscopy and culture. Patients received a treatment candida culture). Eradication with diary card on which to record the presence or reinfection was defined as eradication of can- absence of signs/symptoms for the first 7 days dida at the short-term follow-up visit followed of the study. In addition, clotrimazole patients by reappearance of candida at the long-term recorded the date and time of application of follow-up visit. clotrimazole cream. The single dose of fluconazole was administered to fluconazole Statistical analysis patients in the clinic. Patients were instructed Demographic characteristics and duration of as to proper hygiene and also to refrain from infection were compared using the t test. The sexual intercourse until after the first follow- distributions of clinical and mycologic up visit. response rates at short-term and long-term Clinical and mycological evaluations were follow-up were compared between treatment repeated at follow-up visits scheduled 8 to 11 groups using a chi-square test with continuity days (short-term follow-up) and 28 to 32 days correction. They were also compared using as a (long-term follow-up) after the baseline visit. baseline factor whether or not the patients had The latter was selected as a practical time after suffered a previous episode of balanitis using this relatively minor infection that was thought the Mantel-Haenszel test. to rely on patients to return. Beyond one month, it was thought that many more patients in this population would be lost to Results follow up. At each follow-up visit patients A total of 157 patients were enrolled in the study and randomly assigned to one of the two treatment groups. Eighty one patients received Table 1 Demographic and infection characteristics of 157 patients with balanitis fluconazole and 76 received clotrimazole. The Fluconazole Clotrimazole two treatment groups were similar in terms of (n = 81) (n = 76) demographic characteristics (table 1), except Age (years) that a significantly (p < 0 05) higher percent- Mean (range) 331 (19-78) 34-5 (18-72) age of patients in the fluconazole group (47%) Patients with previous balanitis 38 (47%)* 21 (28%) Duration of current episode (days) had experienced a previous episode ofbalanitis Median (range) 8 (1-140) 7 (1-210) as compared with those in the clotrimazole Signs/symptoms Erythema 72 (89%) 72 (95%) group (28%). This difference was taken into Soreness 53 (65%) 51 (67%) consideration when response rates were com- White plaques 45 (56%) 45 (59%) Phinosis 14 (17%) 17 (22%) pared between treatments; however, the num- Mean severity scoret 3-9 4-1 bers were too small to establish a significant Patients with partners with vaginitis 35 (43%) 33 (43%) relationship with outcome. In the fluconazole *P < 0.05 group one patient was HIV positive, one had tBased on the sum of the scores of each sign and symptom of infection. type II diabetes mellitus, and one had viral 100 Stary, Soeltz-Szoets, Ziegler, Kinghorn, Roy

Table 2 Patient status at short-term and long-term evaluations and reasons for exclusion from efficacy analysis M Cure and improvement Number ofpatients 1 Failure Fluconazole (n = 81) Clottimazole (n = 76) 100 e- Q1 Short-term clinical evaluation (8-11 days) Lost to follow-up 12 4 Withdrawn from study 1 1 No data at this visit 1 1 No baseline signs/symptoms of infection 3 2 a)cc Total evaluable 64 68 C. Short-term mycological evaluation Co (8-1 1 days) 0cc 50K Lost to follow-up 12 4 01) Withdrawn from study 1 1 Co) No data at this visit 1 2 Negative baseline mycology* 4 5 (L) Total evaluable 63 64 a) Total evaluable at long-term evaluation (28-32 days) Clinical 36 33 _8 9 Mycological 36 33 *In addition, seven fluconazole patients and two clotrimazole patients who had no follow-upz data uconazole Clotrimazole also had negative baseline mycology results; these patients are not counted again in this category. (n = 64) (n = 68) Figure 2 Mycologic response to antifungal therapy with either single-dose 150 mg or topical warts. Two patients in the clotrimazole gr-oupP clotrimazole twiceoralfluconazoledailyfor 7 days at short-term follow-up had type II diabetes mellitus. None of the (8 to 11 days after baseline). (p = not significant). patients were circumcised before study eritry; one patient underwent circumcision du ring the study period. Forty three per cent of the for further medical assessment were likely to patients in both treatment groups reported be satisfied with their therapeutic outcome. If a having a partner with vaginitis. patient was dissatisfied with response to ther- The most common sign or symptom apy, he would be more likely to seek addi- reported at baseline was erythema, reported tional therapy. Of the two patients who were by 72 patients in each treatment group (table withdrawn from the study, one had a bacterial 1). Others included, in descending order of infection (fluconazole group) and one under- frequency, soreness, white plaques, and phi- went a pancreatectomy (clotrimazole group). mosis. There was no difference between the Fifty nine of the 64 (92%) fluconazole-treated groups in terms of the severity of clinical signs patients and 62 of the 68 (91%) clotrimazole- and symptoms at baseline. Most vvere treated patients were clinically cured or reported as mild or moderate. improved at short-term follow-up (fig 1). This At the short-term follow-up visit, 64 flu- difference was not statistically significant. conazole-treated patients and 68 clotrimaztole- Of the 157 patients enrolled in the study, treated patients had evaluable efficacy dlata. 139 (70 fluconazole; 69 clotrimazole) had a Reasons for exclusion from the efficacy analysis positive culture result for C albicans. In addi- were as follows: (1) patient lost to follov v-up tion, two patients also had other organisms after the baseline visit; (2) patient withdlrew present at baseline: Torulopsis glabrata (one from study; and (3) no baseline signs or symp- fluconazole patient) and Torulopsis sp (one toms were recorded. These are summarised in clotrimazole patient). For analysis of the table 2 along with the numbers of patiients short-term mycological data, four patients in excluded in each treatment group. Regar(ding the fluconazole group and five in the clotrima- the higher rate of loss to follow-up in the flu- zole were excluded because of a negative base- conazole group (12 patients) than in the line culture result for C albicans (table 2). clotrimazole group (4 patients) it can onl:y be Thus 63 fluconazole patients and 64 clotrima- hypothesised that patients who did not reiturn zole patients had evaluable mycology data at short-term follow-up. In 49 (78%) patients treated with fluconazole and 53 (83%) treated Figure 1 Clinical M Eradicati response to antifungal 100 e- M Persister nce with clotrimazole, the C albicans was eradi- therapy with either single- cated (fig 2). This difference was not statisti- dose oralfluconazole 150 The fluconazole-treated mg or topical clotrimazole cally significant. twice dailyfor 7 days at 78 patient with T glabrata showed clinical short-term follow-up (8 to '. improvement but due to persistence of this 1 1 days after baseline). (p organism was subsequently treated with clotri- = not significant). mazole/hydrocortisone. The Torulopsis sp was 0)Co 50K eradicated. C)cc Based on the patient's self assessment, the 0) C.) median time to relief of erythema for the 126 a) patients (59 fluconazole; 67 clotrimazole) who 17 reported it and returned for follow-up was 6 days in the fluconazole group and 7 days in the clotrimazole group. This difference was Fluconazole Clotrimazole not statistically significant. Of the 15 flucona- (n = 63) (n = 64) zole-treated patients who had previously Comparison ofthe efficacy and safety oforalfluconazole and topical clotrimazole in patients with candida balanitis 101

received topical therapy for balanitis, 12 compliance with follow-up visit schedules (80%) said they preferred the oral therapy. decreases. Therefore, a therapy that provides At the long-term follow-up visit, several high cure rates with minimal adverse effects patients did not return for evaluation, some after a single dose is ideal for these patients. did not return as scheduled, and others A number of topical and systemic antifun- received nonstudy antifungal therapy after the gal drugs are available for the treatment of short-term visit even though they were clini- candida balanitis. Topical application with cally cured or improved at this visit. Thus, 36 the polyene antifungals, nystatin'6 and nata- fluconazole-treated patients and 33 clotrima- mycin, '7 and the imidazole and triazole zole-treated patients were evaluable for effi- antifungals, bifonazole,'8 19 butaconazole,'0 cacy (table 2). Twenty four (67%) patients clotrimazole,'5 18 and miconazole,'6 have pro- treated with fluconazole and 29 (88%) treated duced excellent results with short-term myco- with clotrimazole were clinically cured or logic response rates in the range of 77% to improved. There were nine relapses and three 100%. All of the topical therapies, however, failures in the fluconazole group; two relapses require 1 to 2 weeks of application for effec- and two failures occurred in the clotrimazole tive cures, and patient compliance is ham- group. Seven of the nine patients in the flu- pered by the necessary prolonged course of conazole group who reported clinical relapse therapy. had mycologic confirmation of infection; two The newer azole antifungal agents have patients had a negative mycologic culture been developed to provide less frequent appli- result. Both patients in the clotrimazole group cation and shorter courses of treatment while who reported clinical relapse had mycologic maintaining the efficacy rates observed with confirmation of infection. Of the 36 evaluable the older drugs. This goal has been achieved fluconazole patients and 33 evaluable clo- with the use of single-dose oral fluconazole in trimazole patients, 26 (72%) and 25 (76%) the treatment of vulvovaginal candidiasis."3 patients, respectively, had a mycologic Fluconazole has several characteristics that are response of eradication. Reinfections in six appealing in the treatment of genital candidia- patients and persistence in four patients were sis. It is well-absorbed following oral adminis- reported in the fluconazole group. A total of tration, it has a long elimination half-life, and eight clotrimazole-treated patients had rein- it is primarily excreted unchanged in the fection or persistence (three and five patients, urine."12 21 Because of its low lipophilicity and respectively). Six (four fluconazole; two clotri- low degree of protein binding, fluconazole mazole) of the nine patients with reinfection penetrates body tissues and fluid rapidly and admitted to having sexual intercourse between efficiently. For example, high concentrations visits. of fluconazole are achieved in vaginal tissue." Both treatment regimens were well toler- In addition, fluconazole is well tolerated, with a ated. Only one patient in the fluconazole good safety profile.2' group reported mild diarrhoea 2 days after In their preliminary investigation of 14 men ingesting the single dose. The diarrhoea who presented with candida balanitis, resolved spontaneously. Kinghorn and Woolley"4 reported a 100% mycologic cure rate in 11 men who returned for follow-up evaluation after a single 150 mg Discussion dose of fluconazole. All 11 patients experi- Vulvovaginal candidiasis is a common infec- enced symptomatic improvement without tion in women; more recently, the importance adverse effects. In our randomised multicentre of genital candidiasis in men has become rec- controlled study, we found no significant dif- ognized.8915 Over the 10 year period from ference in cure rates between topical clotrima- 1976 to 1986, the number of men with genital zole 1% cream applied twice daily for 7 days candidiasis presenting to a genitourinary clinic and a single 150 mg dose of fluconazole. Of in the United Kingdom increased by 75%.14 the 15 patients who had previously received This infection is frequently associated with a topical antifungal treatment, 12 said they pre- concurrent vaginal candidiasis infection in a ferred oral fluconazole. sexual partner. The moist epithelium below Although the clinical response rate at long- the prepuce provides ideal growing conditions term follow-up was higher for clotrimazole for microorganisms, especially in uncircum- than for fluconazole, there was little difference cised men. Bacteria and yeast, especially can- between treatment groups in the mycologic dida, are abundant in the preputial sac. eradication rate. It is unclear why more clini- Although candida is usually saprophytic, this cal relapses occurred 4 weeks after therapy in organism may become pathogenic under con- patients treated with fluconazole, a systemi- ditions of lowered local or general resistance.' 8 cally active agent, as compared with those Although candidal balanitis is not a serious treated with topical clotrimazole. Several fac- infection, the distressing symptoms and asso- tors, however, should be considered when ciated discomfort necessitate rapid and effec- evaluating the difference in outcomes between tive treatment. As is evident from our study, the two treatment groups. Our first considera- as well as previously published balanitis treat- tion was that the number of patients with pre- ment studies,'51-8 the patient's motivation for vious episodes of candida balanitis was follow-up evaluation and treatment disappears significantly higher in the fluconazole group. rapidly. Once the patient realises he has a rela- Six of the nine (67%) patients who experi- tively benign condition and the anxiety of hav- enced clinical relapse in the fluconazole group ing an abnormal genital condition resolves, had previous episodes of balanitis. All of these 102 Stary, Soeltz-Szoets, Ziegler, Kinghorn, Roy

patients had at least two episodes during the ment of sexual partners with candidal balanitis previous 12 months. None of the clotrimazole and vaginitis, and in the prevention of so- patients in whom clinical relapse occurred called "ping-pong" infections. the previ- reported episodes ofbalanitis during The study was funded by a grant from the participating institu- ous 12 months. Secondly, of the 10 patients tions from Pfizer, the manufacturer of fluconazole. Data analy- with relapse/reinfection at long-term follow- sis was performed by the Pfizer clinical research unit. up, four fluconazole-treated but only two clotrimazole-treated patients reported having 1 Vohra S, Badlani G. Balanitis and balanoposthitis. Urol had sexual intercourse during the time Clin North Am 1992;19:143-7. between the last two visits. The importance of 2 Pariser DM. Cutaneous candidiasis. A practical guide for primary care physicians. Postgrad Med 1990;87:101-8. treating both partners simultaneously is gener- 3 Abdullah AN, Drake SM, Wade AAH, Walzman M. ally recognised.' Thirdly, it is possible that Balanitis (balanoposthitis) in patients attending a depart- ment of genitourinary medicine. Int J STD AIDS 1992; patients in the clotrimazole group practiced 3:128-9. better hygiene because they were applying 4 Csonka GW. Balanitis. Clin Med 1974;81: 15-9. 5 McCrossin ID. Genital skin disease: a guide to manage- topical medication twice a day. Perhaps future ment in general practice. Mod Med Aust 1993;36: investigations should place greater emphasis 51-62. 6 Lefevre J-C, Lepargneur J-P, Bauriaud R, Bertrand M-A, on good hygiene, particularly for the benefit of Blanc C. Clinical and microbiologic features of urethritis those receiving oral therapy. Another consid- in men in Toulouse, France. Sex Transm Dis 1991;18: 76-9. eration was that perhaps mycologic respon- 7 Forster GE, Harris JRW. 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