Genitourin Med 1996;72:98-102

Comparison of the efficacy and safety of oralfluconazole and topical clotrimazole in patientswith 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-labelparallel-group multicentre study comparing efficacy and safety of a single oral 150-mg flucona-zole-dose with clotrimazole applied topically twice daily for 7 days. Of 64 fluconazole and 68clotrimazole treated patients who were evaluable at short term follow up, 92% and 91% respec-tively were clinically cured or improved. Candida albicans was eradicated in 78% and 83% ofpatients respectively. Median time to relief of erythema was 6 days for fluconazole and 7 days forclotrimazole. Twelve of 15 patients who had received previous topical therapy for balanitis saidthey preferred oral therapy. At the one month follow up visit, 24/36 and 29/33 patients in the twogroups were clinically cured or improved. Nine in the fluconazole group experienced a relapse; 6of these 9 patients reported previous episodes of this infection during the past year. Twopatients 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 treat-ment 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 topatients with balanitis.(Genitourin Med 1996;72:98-102)

Keywords: Fluconazole; clotrimazole; candida; candidiasis; balanitis

Outpatients' Centerfor Diagnosis ofInfectiousVenerodermatologicalDisease, Vienna,AustriaA StaryLudwig-BaltzmannInstitute for Researchof InfectiousVenerodermatologicalDiseases, Vienna,AustriaJ Soeltz-SzoetsC ZieglerRoyal HallamshireHospital, Sheffield,UKG R KinghornRoyal BournemouthHospital,Bournemouth, UKR B RoyCorrespondence to:Dr Angelika Stary,Outpatients' Center forDiagnosis of InfectiousVenerodermatologicalDiseases, Franz-Jonas-Platz8/213, A-1210 Vienna,Austria.

Accepted for publication15 January 1996

IntroductionBalanitis is an acute or chronic inflammationof the glans penis. The typical case is mildwith erythema and symptoms of pain andburning.' 2 However, patients with balanitiscan also present with profuse subpreputialdischarge, oedema, and various degrees ofphimosis. The microorganism most often cul-tured in symptomatic patients is Candida albi-cans.3-7 There are several factors thatpredispose patients to the development of bal-anitis including intercourse with an infectedpartner, recent antibiotic therapy, and poorlycontrolled diabetes mellitus.3 4 89 Additionally,balanitis commonly occurs in uncircumcisedmen.5 9 10

Conventional treatment of candida balanitisconsists of topical application of an antifungalcream for a period of 1 to 2 weeks.458 Topicalagents are messy and tend to rub off on cloth-ing, which can lead to noncompliance. Analternative to topical therapy is short-coursesystemic therapy with an oral antifungal drug.Oral treatment tends to result in better patientcompliance than topical creams. Betterpatient compliance to therapeutic regimensusually results in a better overall response totherapy. This is especially important in gen-

eral practice where compliance tends to beless than in formal clinical studies. In thisregard, fluconazole has been consideredbecause of its favourable absorption profile,extensive distribution into tissues, and its lackof serious adverse effects." 12 Single-dosetreatment with oral fluconazole is becomingwell-accepted as a safe and effective alterna-tive to topical treatment of candida vaginitis."3To date, the only published study evaluat-

ing single-dose fluconazole in patients withbalanitis is a pilot open-label noncomparativestudy.'4 The purpose of the present study wasto compare the efficacy and safety of a singleoral 150-mg dose of fluconazole with that ofmultiple-dose topical clotrimazole 1% creamin patients with candida balanitis.

MethodsStudy DesignThis was a randomised, open-label, parallel-group multicentre study. Male outpatients, 18years of age or older, with a clinical andmicrobiological diagnosis of balanitis were eli-gible to enroll in the study. Signs and symp-toms (mild, moderate, severe) of balanitisrecorded included: white plaques, erythema,soreness, phimosis and fungal cultures. Asculture results often require several days, therewere some patients entered who clinicallyappeared to have balanitis, but cultures werenegative (for unknown reasons). Thosepatients were thus not considered fully evalu-able because a fungal pathogen was not iso-lated at baseline visit; however, clinicalresponse (signs and symptoms) were recordedand thus reported. Excluded were patientswith urogenital infection other than balanitis,a history of allergy to azole antifungals,impaired renal or hepatic function, and a his-tory of alcoholism, drug abuse or psychologi-cal problems. Other reasons for exclusionfrom the study were participation in otherinvestigational drug studies within the previ-ous month, donation of blood or receipt of ablood transfusion within the previous 2 weeks,and treatment with any antifungal drug within

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Comparison of the efficacy and safety oforalfluconazole and topical clotrimazole in patients with candida balanitis

the previous 2 weeks, which was assumed tobe an adequate time period to eliminate thepresence of any residual previous topical ororal antifungal therapy. Concomitant treat-ment with nonstudy antifungal drugs was pro-hibited during the trial period. A total of fourinvestigational centres located in the UnitedKingdom (two) and in Austria (two) partici-pated in the study. Study participants gaveinformed consent in accordance with theDeclaration of Helsinki, and local ethicalcommittee approval was obtained.

Eligible patients were randomly assigned toreceive treatment with either a single oral 150mg dose of fluconazole or clotrimazole 1%cream applied twice daily (morning andevening) for 7 days. At the baseline visit,before initiation of study drug therapy, allpatients underwent a physical examinationand a medical history was obtained. Previousepisodes of balanitis, recent antifungal drugtherapy, and whether or not the patient wascircumcised were recorded. Pertinent infor-mation about the signs, symptoms, and treat-ment of any vaginal condition of the patient'spartner was also recorded. Patients were evalu-ated for the clinical signs and symptoms ofbalanitis, including soreness, erythema, phi-mosis and white plaques. Each sign and symp-tom was graded as absent, mild, moderate, orsevere. Other signs and symptoms notincluded in this list could also be recorded andgraded. A preputial swab was obtained formicroscopy and culture. Patients received adiary card on which to record the presence orabsence of signs/symptoms for the first 7 daysof the study. In addition, clotrimazole patientsrecorded the date and time of application ofclotrimazole cream. The single dose of flu-conazole was administered to fluconazolepatients in the clinic. Patients were instructedas to proper hygiene and also to refrain fromsexual intercourse until after the first follow-up visit.

Clinical and mycological evaluations wererepeated at follow-up visits scheduled 8 to 11days (short-term follow-up) and 28 to 32 days(long-term follow-up) after the baseline visit.The latter was selected as a practical time afterthis relatively minor infection that was thoughtto rely on patients to return. Beyond onemonth, it was thought that many morepatients in this population would be lost tofollow up. At each follow-up visit patients

Table 1 Demographic and infection characteristics of 157 patients with balanitis

Fluconazole Clotrimazole(n = 81) (n = 76)

Age (years)Mean (range) 331 (19-78) 34-5 (18-72)

Patients with previous balanitis 38 (47%)* 21 (28%)Duration of current episode (days)Median (range) 8 (1-140) 7 (1-210)

Signs/symptomsErythema 72 (89%) 72 (95%)Soreness 53 (65%) 51 (67%)White plaques 45 (56%) 45 (59%)Phinosis 14 (17%) 17 (22%)

Mean severity scoret 3-9 4-1Patients with partners with vaginitis 35 (43%) 33 (43%)

*P < 0.05tBased on the sum of the scores of each sign and symptom of infection.

were also evaluated for the occurrence ofadverse events. During the short-term follow-up visit, diary cards were collected andpatients were queried as to their abstinencefrom sexual intercourse since the baselinevisit. Patients in the fluconazole group whohad received previous topical antifungal ther-apy were asked to rate their preference foreither oral or topical treatment.

Microbiological techniqueTwo dry cotton wool swabs were used toobtain samples for mycological analysis fromdifferent sites on the prepuce. The swab wasplated onto Sabouraud's medium or Rice agarand incubated at 37°C. Candida albicans wasidentified using a germ tube test. Other can-dida species were identified using the API20C system (Analatab Products Inc,Plainview, NY).

Efficacy evaluationClinical efficacy was categorised as cure (dis-appearance of all baseline signs and symptomsof infection), improvement (partial disappear-ance of baseline signs and symptoms), or fail-ure (no change or worsening). Improvementor cure followed by reappearance or worsen-ing of clinical symptoms at the long-termfollow-up was categorised as a relapse.Mycological efficacy was categorised as eradi-cation (negative post-treatment culture resultfor candida) or persistence (a positive post-treatment candida culture). Eradication withreinfection was defined as eradication of can-dida at the short-term follow-up visit followedby reappearance of candida at the long-termfollow-up visit.

Statistical analysisDemographic characteristics and duration ofinfection were compared using the t test. Thedistributions of clinical and mycologicresponse rates at short-term and long-termfollow-up were compared between treatmentgroups using a chi-square test with continuitycorrection. They were also compared using as abaseline factor whether or not the patients hadsuffered a previous episode of balanitis usingthe Mantel-Haenszel test.

ResultsA total of 157 patients were enrolled in thestudy and randomly assigned to one of the twotreatment groups. Eighty one patients receivedfluconazole and 76 received clotrimazole. Thetwo treatment groups were similar in terms ofdemographic characteristics (table 1), exceptthat a significantly (p < 0 05) higher percent-age of patients in the fluconazole group (47%)had experienced a previous episode of balanitisas compared with those in the clotrimazolegroup (28%). This difference was taken intoconsideration when response rates were com-pared between treatments; however, the num-bers were too small to establish a significantrelationship with outcome. In the fluconazolegroup one patient was HIV positive, one hadtype II diabetes mellitus, and one had viral

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Table 2 Patient status at short-term and long-term evaluations and reasons for exclusionfrom efficacy analysis

Number ofpatients

Fluconazole (n = 81) Clottimazole (n = 76)

Short-term clinical evaluation(8-11 days)Lost to follow-up 12 4Withdrawn from study 1 1No data at this visit 1 1No baseline signs/symptoms of infection 3 2Total evaluable 64 68Short-term mycological evaluation(8-1 1 days)Lost to follow-up 12 4Withdrawn from study 1 1No data at this visit 1 2Negative baseline mycology* 4 5Total evaluable 63 64

Total evaluable at long-term evaluation(28-32 days)Clinical 36 33Mycological 36 33

*In addition, seven fluconazole patients and two clotrimazole patients who had no follow-upalso had negative baseline mycology results; these patients are not counted again in this cate

warts. Two patients in the clotrimazole grhad type II diabetes mellitus. None ofpatients were circumcised before study erone patient underwent circumcision duthe study period. Forty three per cent ofpatients in both treatment groups repohaving a partner with vaginitis.The most common sign or symp

reported at baseline was erythema, repoby 72 patients in each treatment group (t1). Others included, in descending ordefrequency, soreness, white plaques, andmosis. There was no difference betweengroups in terms of the severity of clinical sand symptoms at baseline. Most v

reported as mild or moderate.At the short-term follow-up visit, 64

conazole-treated patients and 68 clotrimaztreated patients had evaluable efficacy dReasons for exclusion from the efficacy anawere as follows: (1) patient lost to follovafter the baseline visit; (2) patient withdfrom study; and (3) no baseline signs or sytoms were recorded. These are summarisetable 2 along with the numbers of patiiexcluded in each treatment group. Regar(the higher rate of loss to follow-up in theconazole group (12 patients) than inclotrimazole group (4 patients) it can onl:hypothesised that patients who did not rei

Figure 1 Clinicalresponse to antifungaltherapy with either single-dose oralfluconazole 150mg or topical clotrimazoletwice daily for 7 days atshort-term follow-up (8 to11 days after baseline). (p= not significant).

M EradicatiM Persister100 e-

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78

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Fluconazole Clotrimazole(n = 63) (n = 64)

100 e-

cca)

Cocc

C.001)Co)(L)

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M Cure andimprovement

1 Failure

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uconazole(n = 64)

9

Clotrimazole(n = 68)

Figure 2 Mycologic response to antifungal therapy with-oup either single-dose oralfluconazole 150 mg or topical

P clotrimazole twice daily for 7 days at short-term follow-upthe (8 to 11 days after baseline). (p = not significant).

itry;ringthe for further medical assessment were likely torted be satisfied with their therapeutic outcome. If a

patient was dissatisfied with response to ther-tom apy, he would be more likely to seek addi-rted tional therapy. Of the two patients who wereable withdrawn from the study, one had a bacterialr of infection (fluconazole group) and one under-phi- went a pancreatectomy (clotrimazole group).the Fifty nine of the 64 (92%) fluconazole-treatedigns patients and 62 of the 68 (91%) clotrimazole-vere treated patients were clinically cured or

improved at short-term follow-up (fig 1). Thisflu- difference was not statistically significant.tole- Of the 157 patients enrolled in the study,lata. 139 (70 fluconazole; 69 clotrimazole) had alysis positive culture result for C albicans. In addi-v-up tion, two patients also had other organismslrew present at baseline: Torulopsis glabrata (onemp- fluconazole patient) and Torulopsis sp (oned in clotrimazole patient). For analysis of theents short-term mycological data, four patients inding the fluconazole group and five in the clotrima-flu- zole were excluded because of a negative base-the line culture result for C albicans (table 2).

y be Thus 63 fluconazole patients and 64 clotrima-turn zole patients had evaluable mycology data at

short-term follow-up. In 49 (78%) patientstreated with fluconazole and 53 (83%) treated

nce with clotrimazole, the C albicans was eradi-cated (fig 2). This difference was not statisti-cally significant. The fluconazole-treatedpatient with T glabrata showed clinicalimprovement but due to persistence of thisorganism was subsequently treated with clotri-mazole/hydrocortisone. The Torulopsis sp waseradicated.

Based on the patient's self assessment, themedian time to relief of erythema for the 126patients (59 fluconazole; 67 clotrimazole) whoreported it and returned for follow-up was 6days in the fluconazole group and 7 days inthe clotrimazole group. This difference wasnot statistically significant. Of the 15 flucona-zole-treated patients who had previously

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received topical therapy for balanitis, 12(80%) said they preferred the oral therapy.At the long-term follow-up visit, several

patients did not return for evaluation, somedid not return as scheduled, and othersreceived nonstudy antifungal therapy after theshort-term visit even though they were clini-cally cured or improved at this visit. Thus, 36fluconazole-treated patients and 33 clotrima-zole-treated patients were evaluable for effi-cacy (table 2). Twenty four (67%) patientstreated with fluconazole and 29 (88%) treatedwith clotrimazole were clinically cured orimproved. There were nine relapses and threefailures in the fluconazole group; two relapsesand two failures occurred in the clotrimazolegroup. Seven of the nine patients in the flu-conazole group who reported clinical relapsehad mycologic confirmation of infection; twopatients had a negative mycologic cultureresult. Both patients in the clotrimazole groupwho reported clinical relapse had mycologicconfirmation of infection. Of the 36 evaluablefluconazole patients and 33 evaluable clo-trimazole patients, 26 (72%) and 25 (76%)patients, respectively, had a mycologicresponse of eradication. Reinfections in sixpatients and persistence in four patients werereported in the fluconazole group. A total ofeight clotrimazole-treated patients had rein-fection or persistence (three and five patients,respectively). Six (four fluconazole; two clotri-mazole) of the nine patients with reinfectionadmitted to having sexual intercourse betweenvisits.

Both treatment regimens were well toler-ated. Only one patient in the fluconazolegroup reported mild diarrhoea 2 days afteringesting the single dose. The diarrhoearesolved spontaneously.

DiscussionVulvovaginal candidiasis is a common infec-tion in women; more recently, the importanceof genital candidiasis in men has become rec-ognized.8915 Over the 10 year period from1976 to 1986, the number of men with genitalcandidiasis presenting to a genitourinary clinicin the United Kingdom increased by 75%.14This infection is frequently associated with aconcurrent vaginal candidiasis infection in asexual partner. The moist epithelium belowthe prepuce provides ideal growing conditionsfor microorganisms, especially in uncircum-cised men. Bacteria and yeast, especially can-dida, are abundant in the preputial sac.Although candida is usually saprophytic, thisorganism may become pathogenic under con-ditions of lowered local or general resistance.' 8

Although candidal balanitis is not a seriousinfection, the distressing symptoms and asso-ciated discomfort necessitate rapid and effec-tive treatment. As is evident from our study,as well as previously published balanitis treat-ment studies,'51-8 the patient's motivation forfollow-up evaluation and treatment disappearsrapidly. Once the patient realises he has a rela-tively benign condition and the anxiety of hav-ing an abnormal genital condition resolves,

compliance with follow-up visit schedulesdecreases. Therefore, a therapy that provideshigh cure rates with minimal adverse effectsafter a single dose is ideal for these patients.A number of topical and systemic antifun-

gal drugs are available for the treatment ofcandida balanitis. Topical application withthe polyene antifungals, nystatin'6 and nata-mycin, '7 and the imidazole and triazoleantifungals, bifonazole,'8 19 butaconazole,'0clotrimazole,'5 18 and miconazole,'6 have pro-duced excellent results with short-term myco-logic response rates in the range of 77% to100%. All of the topical therapies, however,require 1 to 2 weeks of application for effec-tive cures, and patient compliance is ham-pered by the necessary prolonged course oftherapy.The newer azole antifungal agents have

been developed to provide less frequent appli-cation and shorter courses of treatment whilemaintaining the efficacy rates observed withthe older drugs. This goal has been achievedwith the use of single-dose oral fluconazole inthe treatment of vulvovaginal candidiasis."3Fluconazole has several characteristics that areappealing in the treatment of genital candidia-sis. It is well-absorbed following oral adminis-tration, it has a long elimination half-life, andit is primarily excreted unchanged in theurine."12 21 Because of its low lipophilicity andlow degree of protein binding, fluconazolepenetrates body tissues and fluid rapidly andefficiently. For example, high concentrationsof fluconazole are achieved in vaginal tissue."In addition, fluconazole is well tolerated, with agood safety profile.2'

In their preliminary investigation of 14 menwho presented with candida balanitis,Kinghorn and Woolley"4 reported a 100%mycologic cure rate in 11 men who returnedfor follow-up evaluation after a single 150 mgdose of fluconazole. All 11 patients experi-enced symptomatic improvement withoutadverse effects. In our randomised multicentrecontrolled study, we found no significant dif-ference in cure rates between topical clotrima-zole 1% cream applied twice daily for 7 daysand a single 150 mg dose of fluconazole. Ofthe 15 patients who had previously receivedtopical antifungal treatment, 12 said they pre-ferred oral fluconazole.

Although the clinical response rate at long-term follow-up was higher for clotrimazolethan for fluconazole, there was little differencebetween treatment groups in the mycologiceradication rate. It is unclear why more clini-cal relapses occurred 4 weeks after therapy inpatients treated with fluconazole, a systemi-cally active agent, as compared with thosetreated with topical clotrimazole. Several fac-tors, however, should be considered whenevaluating the difference in outcomes betweenthe two treatment groups. Our first considera-tion was that the number of patients with pre-vious episodes of candida balanitis wassignificantly higher in the fluconazole group.Six of the nine (67%) patients who experi-enced clinical relapse in the fluconazole grouphad previous episodes of balanitis. All of these

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patients had at least two episodes during theprevious 12 months. None of the clotrimazolepatients in whom clinical relapse occurredreported episodes of balanitis during the previ-ous 12 months. Secondly, of the 10 patientswith relapse/reinfection at long-term follow-up, four fluconazole-treated but only twoclotrimazole-treated patients reported havinghad sexual intercourse during the timebetween the last two visits. The importance oftreating both partners simultaneously is gener-ally recognised.' Thirdly, it is possible thatpatients in the clotrimazole group practicedbetter hygiene because they were applyingtopical medication twice a day. Perhaps futureinvestigations should place greater emphasison good hygiene, particularly for the benefit ofthose receiving oral therapy. Another consid-eration was that perhaps mycologic respon-

ders and nonresponders should be comparedwith respect to fluconazole dose on the basisof mg-per-kg body weight or body mass.

Indeed, at the short-term visit heavier patientswere more likely to have a response of persis-tence than eradication. The mean weight offluconazole-treated patients in whom candidawas eradicated was 77.5 kg compared with83.8 kg for patients who had a response ofpersistence (p = 002). A final consideration isthat global ratings may be inappropriate fordetecting small differences in efficacy.

In summary, we found similar clinical andmycologic response rates to treatment witheither a single oral 150-mg dose of fluconazoleor topical clotrimazole 1% cream adminis-tered twice daily for 7 days to patients withcandida balanitis. Clinical cure or improve-ment occurred in over 90% of evaluablepatients treated with either fluconazole or

clotrimazole, and mycologic eradication rateswere comparably high. Both treatments were

well-tolerated. Fluconazole given as a singleoral dose is a more convenient therapy thanconventional multiple-dose topical regimens.These factors may contribute to improvedpatient acceptability and compliance. Futurestudies may further define the role of single-dose fluconazole in the simultaneous treat-

ment of sexual partners with candidal balanitisand vaginitis, and in the prevention of so-called "ping-pong" infections.

The study was funded by a grant from the participating institu-tions from Pfizer, the manufacturer of fluconazole. Data analy-sis was performed by the Pfizer clinical research unit.

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2 Pariser DM. Cutaneous candidiasis. A practical guide forprimary care physicians. Postgrad Med 1990;87:101-8.

3 Abdullah AN, Drake SM, Wade AAH, Walzman M.Balanitis (balanoposthitis) in patients attending a depart-ment of genitourinary medicine. Int J STD AIDS 1992;3:128-9.

4 Csonka GW. Balanitis. Clin Med 1974;81: 15-9.5 McCrossin ID. Genital skin disease: a guide to manage-

ment in general practice. Mod Med Aust 1993;36:51-62.

6 Lefevre J-C, Lepargneur J-P, Bauriaud R, Bertrand M-A,Blanc C. Clinical and microbiologic features of urethritisin men in Toulouse, France. Sex Transm Dis 1991;18:76-9.

7 Forster GE, Harris JRW. A clinical and microbiologicalstudy of balanitis. EurJSex Transm Dis 1985;3:31-4.

8 Wise GJ, Silver DA. Fungal infections of the genitourinarysystem. _J Urol 1993;149:1377-88.

9 Waugh MA. Clinical presentation of candidal balanitis-itsdifferential diagnosis and treatment. Chemotherapy 1982;28(suppl 1):56-60.

10 Fakjian N, Hunter S, Cole GW, Miller J. An argument forcircumcision. Prevention of balanitis in the adult. ArchDermatol 1990;126:1046-7.

11 Lazar JD, Hilligoss DM. The clinical pharmacology of flu-conazole. Semin Oncol 1990;17(suppl 6):14-8.

12 Brammer KW, Farrow PR, Faulkner JK. Pharmacokineticsand tissue penetration of fluconazole in humans. RevInfect Dis 1990;12(suppl3):S318-26.

13 Patel HS, Peters MD, Smith CL. Is there a role for flu-conazole in the treatment of vulvovaginal candidiasis?Ann Pharmacother 1992;26:350-3.

14 Kinghorn GR, Woolley PD. Single-dose fluconazole in thetreatment of Candida albicans balanoposthitis. Int J STDAIDS 1990;1:366-7.

15 Waugh MA, Evans EGV, Nayyar KC, Fong R.Clotrimazole (Canesten) in the treatment of candidalbalanitis in men. With incidental observations on diabeticcandidal balanoposthitis. Br J Venereal Dis 1978;54:184-6.

16 Forster GE, Harris JRW. Double blind therapeutic trial inbalanitis-miconazole and nystatin. Eur J Sex Trans Dis1986;3:81-3.

17 Masterton G, Sengupta SM, Schofield CBS. Natamycin ingenital candidosis in men. Br J Venereal Dis 1975;51:210-2.

18 Maw RD, Homer T, Evans J. A comparative trial of bifon-azole 1% cream and clotrimazole 1% cream in the treat-ment of candidal balanoposthitis. Mykosen 1987;30:229-32.

19 Tosi E, Bertani E, Pavone PS, Bianchi W, Viscovo R. 1%bifonazole cream in the treatment of candida balanitis: aclinical trial. Eur Rev Med Pharmacol Sci 1987;9:265-7.

20 Nolting S. An open study of butoconazole nitrate 2%cream in patients with candidal balanoposthitis or balani-tis. Curr Ther Res 1990;47:899-904.

21 Como JA, Dismukes WE. Oral azole drugs as systemic anti-fungal therapy. N Engl _'Med 1994;330:263-72.

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