Pharmacology and therapeutios

Treatment of chromoblastomycosis with itraconazole,cryosurgery, and a combination of both

Alexandro Bonifaz, MB, Esperanza Martinez-Soto, MD,Eugenio Carrasco-Gerard, MD, MSc, and Jorge Peniche, MD

From the Dermatology Service andttie Mycology Department, GeneralHospital ot Mexico, Mexico

CorrespondenceA. Bonifaz, MBZempoala 60-101NarvarteMexico D.F.CP. 03020Mexico

Drug namesamptiotericin B: Fungizoneergo calciferol: Detalin, Drisdoldicioxaciiiin: Dynapen; Pathocilfluorocytosine: Ancobonitraconazole: Sporanoxketoconazole: Nizoralthiabendendazole: Mintezol

A b s t r a c t ^ - - ' • " > '•'- - :-'-^'^-;-^•••- " - ' - - v : ; : - " r ' : - a w . " : - # ; : , > f - ; y " - : ' ' - - - ' ' ^

Background Chromoblastomycosis is a subcutaneous mycosis, seen frequently in

tropical areas, and caused by dematiaceous fungi. It produces nodulo-verrucous lesions

in the arms and legs. There is no treatment of choice for this disease and sometimes a

combination of chemotherapy and physical therapy is necessary.

Methods The study included 12 patients diagnosed with chromoblastomycosis by means

of fungal and histopathologic tests. The patients were assigned to three treatment groups:

patients with small lesions, not greater than 15 cm^ in area, were assigned to Group 1, in

which the treatment consisted of itraconazole 300 mg/day, or to Group 2, in which the

treatment consisted of one or more sessions of open-spray cryosurgery. Patients with

large lesions were assigned to Group 3 and started treatment with itraconazole 300 mg/day,

until a maximal reduction of lesions occurred, and then underwent one or several

cryosurgery sessions. Clinical, fungal, and laboratory tests were performed in each group

before, during, and at the completion of treatment.

Results Positive cultures of Fonsecaea pedrosoi were obtained in 11 out of 12 patients.

Two out of four patients in Groups 1 and 3 had a clinical and fungal cure and the

remaining patients experienced significant improvement. All four patients included in

Group 2 achieved a cure. No important side-effects were seen among the patients

included in any of the two itraconazole groups, and only two out of eight patients reported

gastric discomfort. The cryosurgery group reported only normal complications of the

process, such as edema and pain; two out of eight patients had a superimposed infection.

Conclusions The results of itraconazole and cryosurgery were good in cases with small

lesions; antifungal therapy being more appropriate for flexion areas. The combination of

itraconazole, to reduce the size of the lesions, with subsequent treatment of the remaining

lesions with cryosurgery, represents a new alternative in the treatment of patients with

large lesions. Both types of therapy are considered safe, with few side-effects.

542

Chromoblastomycosis is a subcutaneous mycosis seen fre-quently in tropical countries such as Mexico. It is causedby a variety of black or dematiaceous fungi. Most casesare caused by Fonsecaea pedrosoi (95%), and in a smallernumber of patients by Pbialophora verrucosa, F. compacta,Cladosporium carrioni, and Rhinocladiella aquaspersa. Itis a benign and chronic disease affecting mainly peasantsin tropical regions; it primarily involves the arms and legsin the form of vegetating, nodulo-verrucous plaques, thatgrow slowly. "'* \ ;.

Chromoblastotnycosis may be considered as "the mostsuperficial of subcutaneous mycoses," but, in spite of this.

the chances of it being treated successfully are minimal. Awide variety of therapies have been used throughout theyears with varying results, but, so far, a treatment of choicehas not yet been found. Modes of therapy may be dividedinto simple or combined drug regimens, that include sys-temic or intralesional amphotericin B, the most widelyused drug, and potassium iodide, calciferol, thiabendazoie,ketoconazole, and 5-fluorocytosine (5-FC). The best resultshave been obtained with the latter, although it is not readilyavailable in Mexico and high doses are required.^"'^ Othertherapies include physical methods such as conventionalsurgery, laser surgery, thermotherapy, and cryotherapy. 3-i<i

International Journal of Dermatology 1997, 36, 542-547 © 1997 Blackwell Science Ltd

Bonifaz el al. Chromoblastomycosis Pharmacology and therapeutics 543

Figure 1 Itraconazole treatment, patient 3: (a) beforetreatment; (b) after 8 months

Two treatments have been used recently for chromo-blastomycosis. One of them is itraconazole, which hasproven to be active with few side-effects, particularly in highdoses;^''''^ the other is cryosurgery, which has developed anincreasingly appropriate technology and has been usedwith good results to treat this type of condition.'3 iau;,:^}

Based on these considerations, we undertook an cjpen-label, comparative study treating the small number of casesof chromoblastomycosis with itraconazole or cryosurgeryand using both methods to treat extensive lesions; itracona-zole was administered initially until maximal reduction oflesions was achieved, cryosurgery was then applied toeliminate any residual or active lesions.

IMaterials and methods . i

Twelve patients with chromoblastomycosis, diagnosed using

fungal tests (direct examination and cultures) and optional

histopathologic tests, were included in the study. Ali patients

were seen at the Dermatology Service, General i-iospitai of

Mexico, Ministry of Health, . j^ i j -x.^i ,^.: d vun ?;'••:«,. i-':

A compiete epidemiologic record of each patient was

prepared. The diagnosis of chromoblastomycosis was proven

Figure 2 Cryosurgery treatment, patient 5: (a) beforetreatment; (b) 5 days after cryotherapy; (c) after 8 months

by means of direct examination with potassium hydroxide

(KOH) to show the presence of sclerotic bodies or ceils, or

Sabouraud dextrose agar and mycosei agar (Sabouraud +

antibiotics). Each strain was identified based on its microscopic

characteristics. A punch biopsy was taken only in cases with a

negative or doubtful KOH result.

Once the diagnosis of chromobiastomycosis was confirmed,

the patients were assigned to the following groups: Group 1,

cases with smali iesions, i.e. no greater than 15 cm^ in area,

treatment with itraconazoie 300 mg/day; Group 2, cases with

© 1997 Blackwell Science Ltd International Journal of Dermatology 1997. 36, 542-547

544 Pharmacology and therapeutics Chromoblastomycosis Bonifaz et al.

Figure 3 Itraconazole and cryosurgery treatment, patient i i :(a) before treatment; (b) after 7 months treatment with •-"<"'itraconazole; (c) 6 months after cryotberapy

small lesions, treatment with one or more sessions of

cryosurgery; Group 3, cases with extensive lesions, treatment

with itraconazole and one or more sessions of cryosurgery.

For Group 3, itraconazole at a dose of 300 mg/day was

given initially to achieve the maximum reduction of the

verrucous plaques, the patients then underwent several

sessions of cryosurgery. When the residual lesion had become

very small and limited, one solid freezing cycle was applied;

the more extensive lesions were divided into zones for

cryosurgery.

Itraconazole was administered in 100 mg capsules after

meals. The patients received treatment as outpatients and

underwent periodic clinical and fungal examinations. Complete

blood counts and hepatic function tests were performed in

patients treated with itraconazole before, during, and after

treatment.

The open-spray cryosurgery technique was used, 1-2 cm

away from the lesions, at an angle of approximately 90°, during

variable time periods until an adequate freezing front with a

5 mm margin was obtained.

The evaluation of the therapeutic regimes was based on the

following classification: (i) clinical and fungal cure; (ii) clinical

improvement, without fungal cure; and (iii) little or no clinical

improvement and no fungal cure.

Results

The main characteristics of the cases studied are shown inTable i. A clear predominance of men is seen (10/12),accounting for 83.3% of the patients. The mean age was46.4 years, with the youngest patient being 15 and theoldest being 75. The average duration of the disease was7.2 years. The disease involved basically the legs (9/12),mainly the feet. In only two cases were the main lesionsobserved on the hand, and in one on the arm. The mostcommon clinical variety was the nodulo-verrucous type,and all the isolated species (ii/iz) were identified asF. pedrosoi.

The results for each treatment group are shown in Tables2-4. The treatment duration and side-effects are indicatedfor the groups treated with itraconazole; in the cryosurgerygroups, the number of sessions and likely complications areshown. The patients who complained of gastric discomfortresulting from itraconazole did not need to discontinue thetreatment; they were told to take the medication with milk.Blood counts and hepatic function tests of the patientstreated with itraconazole remained within the normal rangeduring and after treatment.

Common analgesics were used in patients who had painafter cryosurgery. The two patients who had a pyogenicinfection were given 500 mg of dicloxacilin every 8 h for7 days and topical fusidic acid; the complication resolvedwithin this period. ,, ,T:-,;

Discussion

In cases of chromoblastomycosis, the therapeutic successis determined by several factors, including the causal agent,because it may be susceptible to drugs. Unfortunately,F. pedrosoi, which is the most commonly isolated organism,is the least susceptible to the fungal agents used, and

International Journal of Dermatology 1997, 36, 542-547 © 1997 Blackwell Science Ltd

Bonifaz et al. Chromoblastomycosis Pharmacology and therapeutics 545

Table 1 Data for all patients with chromoblastomycosis

Patient Age/sexno.

Duration ofdisease (years)

Site of iesion Ciinicai appearance KOH Culture Biopsy

1234 ,

567- • "

89 ' ;••

10 ;

n12

39/f\/l54/M37/F58/M43/M23/M48/M25/M52/M48/M75/F55/M

364

257

351

1225

20

LegFoot, leg

. , Foot, ankleFoot, leg, ttiighLeg

ArmLeg

- ---:.•• H a n d

Foot, legLegHandFoot, leg

Verrucous plaque +Nodular-verrucous +Verrucous plaque +

Nodular-verrucous, tumor +Verrucous plaque +Verrucous plaque +Nodular verrucous +Verrucous plaque +

Nodular-verrucous +Verrucous +Verrucous plaque +Nodular-verrucous +

F. pedrosoiF. pedrosoiF. pedrosoi

F. pedrosoiF. pedrosoiF. pedrosoiF. pedrosoi

Not identifiedF. pedrosoiF. pedrosoi

F. pedrosoiF. pedrosoi

ND

ND G-ND

NDSCN D ' '•''

N D '"-•'•

SC "SCND >-se ;?!«>&

N D . , ;':•-•••'•

ND ..

SC, sclerotic cells; ND, not done.

Table 2 Chromoblastomycosis Group i, results withitraconazole 300 mg/day

Patientno.

1

234

Length oftherapy(months)

11

89

14

Side-effects

GastricdiscomfortNoneNoneNone

Posttreatmentfollow-up(months)

20

121824

Results

Improvement (ii)

Cured (i)Cured (i)Improvement (ii)

becomes resistant quite easily.' 4.7 j ^ g g\2e of the lesionsis also relevant, hecause small lesions resolve easily withphysical means such as conventional surgery, laser, or localheat.'t' "'"^^ Nevertheless, chemotherapy is mandatory inextensive cases. In our experience,5 5-FC has good clinicaland fungal effects, although many authors '"*- '? use com-bination therapy. One of the combined therapies that hasgiven good results consists of amphotericin B plus 5-FC,although there are inconvenient side-effects of amphotericinB and the strains, particularly F. pedrosoi, readily becomeresistant to 5-FC.'' It is important to emphasize that, when5-FC is used initially (either alone or in combination), arapid reduction of lesions occurs, although sometimes notall lesions are completely cleared, despite a dose increase,and relapses may occur frequently.

Itraconazole has proven activity against fungi causingchromoblastomycosis. As with other drugs, C. carrioni ismore susceptible than F. pedrosoi. Borelli'^ studied twoseries of patients with these causal organisms and obtainedcure in almost all cases due to C. carrioni, even at dosesof 100-200 mg, whereas cases due to F. pedrosoi onlyimproved. Ever since the first studies of itraconazole in

chromoblastomycosis were carried out, there has been atendency to use high doses. Now most authors''''^"'^recommend optimal doses ranging from 200 to 400 mg/day,for variable periods of time, depending upon the extent ofthe lesions. Nevertheless, there are cases that respondedwell, such as those reported by Smith et al.^° using a dailydose of 100 mg, but given for 18 months. Recently,Queiroz-Tellez et al.^^ reported a series of 19 cases causedby F. pedrosoi, treated with itraconazole200-400 mg/day. They classified the patients according tothe severity of the infection; on clinical and fungal evalu-ation, a cure was achieved in 42% and an importantimprovement was seen in the remaining cases. The durationof treatment was quite variable, but it was without signific-ant side-effects, despite the fact that some patients weretreated for more than 2 years.

We used itraconazole as a single drug for small lesionswith variable results. Clitiical and fungal cure was achievedin two patients and the improvement persisted. The use ofitraconazole for small lesions is aimed at cases in whichthe disease involves flexion areas such as the wrists, knees,ankles, etc. (Case 3), because cryosurgery is contraindicatedin these cases due to the fibrosis it might cause.

Medina-Ramirez^^ was the first to treat chromoblasto-mycosis with liquid nitrogen and achieved good resultsusing cotton swabs in several sessions. Nevertheless, oneof us (Peniche) used this same technique and obtainedvarious degrees of improvement but without clinical cure,probably because the use of liquid nitrogen with swabsdoes not provide enough freezing depth to eradicate thelesions. With the recent developments in cryosurgery, betterresults have been obtained in the treatment of variousconditions, mainly because better freezing depths have beenachieved. In a recent review chromoblastomycosis wasconsidered as one of the 56 benign conditions for which

I 1997 Blackwell Science Ltd international Journal of Dermatology 1997, 36, 542-547

546 Pharmacology and therapeutics Chromoblastomycosis Bonitaz et al.

Table 3 Ghromoblastomycosis Group z,results with cryosurgery Patient

no.Sessions ofcryosurgery

Compiications Length of therapy(months)

Posttreatmentfollow-up (months)

Results

56

78

16

31

Edema, painPyogenicinfection

Edema, painEdema, pain

318

41

1210

205

Cured (i)Cured (i)

Cured (i)Cured (i)

Table 4 Ghromoblastomycosis Group 3, results with itraconazole and cryosurgery

Patient no.

9101112

Length of therapywith itraconazole(months)

89

125

Side-effects

NoneNoneGastric discomfortNone

Sessions ofcryosurgery

688

12

Compiications

Edema, painEdema, painEdema, painPyogenic infection

Posttreatmentfoiiow-up(months)

81210 .20

Results

improvement (ii)Cured (i)Cured (i)improvement (ii)

crydsurgery is recommended.^' Most of the cases treatedwith cryosurgery used liquid nitrogen with the open-spraymethod, but the results are variable and depend on theinvolved area.^3'^4-i7

Cryosurgery may be used to treat chromoblastomycosis,but is only suitable for the small, residual lesions that arenot located in areas of flexion; total or section-freezingmay be used. This therapy has a series of advantages overothers: it has a low cost, it does not require generalanesthesia, it is a simple procedure that can be carried outin the doctor's office, its cosmetic results are usually good,it is independent of the causal agent, etc. In general, it hasfew contraindications, such as, for instance, patients withcold urticaria, cryoglobulinemia, or cryofibrinogenemia,and it should not be applied in flexion areas or overimportant nerves. 3.2-8-3°

A clinical and fungal cure was obtained in all casestreated with cryosurgery included in our study. The analysisby groups shows that cryosurgery achieved the best results;however, we do not consider it to be the treatment ofchoice for all cases of chromoblastomycosis, since we onlyused it in certain patients, i.e. those with .small lesions,and in defined areas. The side-effects reported in twocryosurgery groups were minimal. Most patients had edemaand pain after the procedure; two additional patients hadsuperimposed infections that were treated with systemicand topical antibiotics. An infection is relatively common,since our patients are farmers who go home after theprocedure and live under poor hygienic conditions. There-fore, in our setting, we suggest the use of prophylacticantibiotics after cryosurgery.

In the third group, which included the cases with large

lesions, two of the patients achieved a cure and theremaining patients improved. These patients are usuallydifficult to treat with other therapies, and we thus consid-ered that 300 mg/day of itraconazole could be used toachieve the maximum reduction of the lesions, leaving onlylimited areas where cryosurgery could be used. We believethat the combination of both therapies significantlyimproves the therapeutic results. _-. _

Conclusions " : ?

The treatment of choice for small lesions of chromoblasto-mycosis should be cryosurgery with liquid nitrogen usedin an open-spray fashion. In patients with lesions inthe flexures or in whom cryotherapy is contraindicated,itraconazole is indicated at a dose of 300-400 mg/day. Inpatients with large lesions, chemotherapy should be usedto reduce the size of the lesions. The drugs suggested are5-FG or itraconazole until a maximal reduction is achievedand then cryosurgery may be used.

References -iifWHi*- mi t,!\ H-if

.II Vollum DI. Ghromomycosis: a review. Br J Dermatol

1977; 96: 454-458. ... ._ _z McGinnis MR, Hill G. Ghromohlastomycosis and

phaeohyphomycosis: new concepts, diagnosis, andmycology. / Am Acad Dermatol 1983; 8; 1-16.

3 Bonifaz A. Gromomicosis. In: Bonifaz A, ed. MicologtaMedica Bdsica, ist edn. Mexico DF: Mendez-Gervantes,1990: 187.

4 Restrepo A. Treatment of topical mycoses. / Am Acad JDermatol 1994; 31: S91-102. ,-j,

Internafional Journal of Dermafoiogy 1997, 36, 542-547 I 1997 Blackweii Science Ltd

Bonlfaz et al.

5 Peniche J, Lavalle P. El tratamiento de la cromomicosiscon 5-fluorocitosina. Memorias del VII Congreso

• Mexicano de Dermatologia, Morelia Mich, 1973;604-609.

6 Lopes CF, Alvarenga RJ, Cispalpino EO, et al. Six yearsexperience in treatment of chromomycosis with5-fluorocytosine. Int J Dermatol 1978; 17: 414-418. 5

7 Oliviera LG, Resende MA, Cisalpino EO, et al. In vitrosensitivity to 5-fluorocytosine of strains isolated from

J patients under treatment chromomycosis. Int ] Dermatol

••• 1975; 14: 141-143-8 Bopp C. Cura da cromoblastomicose por novo metodo

de tratamiento. Med Cut ILA 1976; 4: Z85-292.9 Astorga B, Bonilla E, Martinez C, Mora W. Tratamiento

de la cromomicosis con anfotericina B y 5-fluorocitosina.Med Cut ILA 1981; 9: 125-128.

10 Solano AE. Tratamiento de la cromomicosis conthiabendazole. Med Cut ILA 1966; 3: Z77-2.86.

11 Bayles MA. Chromomycosis: treatment withthiabendazole. Arch Dermatol 1971; 104: 476-485.

iz Silher JG, Gombert ME, Green KM, Shalita AR.Treatment of chromomycosis with ketoconazole and5-fluorocytosine. / Am Acad Dermatol 1983; 8:Z36-Z38.

13 Pimentel ER, Castro LG, Cuce LC, et al. Treatment ofchromomycosis by cryosurgery with liquid nitrogen: a

' report of eleven cases. / Dermatol Surg Oncol 1989; 15:7Z-79.

14 Tagami H, Ginoza M, Imaizumi S, et al. Successfultreatment of chromoblastomycosis with topical heattherapy. / Am Acad Dermatol 1984; 10: 615-619.

15 Yanase K, Yamada M. "Pocket-warmer" therapy ofchromomycosis. Arch Dermatol 1978; 114: 1095.

16 Kuttner BJ, Siegle BJ. Treatment of chromomycosis withCOj laser. / Dermatol Surg Oncol 1986; iz: 965-968.

17 Borelli D. A clinical trial of itraconazole in the treatment

Chromoblastomycosis Pharmacology and therapeutics 547

of deep mycoses and leishmaniasis. Rev Infect Dis 1987;9: 57-63-

18 Lavalle P, Suchil P, De Ovando F, et al. Itraconazole for •deep mycoses; preliminary experience in Mexico. RevInfect Dis 1987; 9: 64-70. |

19 Restrepo A, Gonzalez A, Gomez I, et al. Treatment ofchromoblastomycosis with itraconazole. Ann NY Acad iSci 1988; 544: 504-516.

zo Smith CH, Barker JN, Hay RJ. A case ofchromoblastomycosis responding to treatment withitraconazole. Br J Dermatol 19931, 128: 436-439.

z i Queiroz-Tellez F, Purim K, Fillus JN, et al. Itraconazolein the treatment of chromoblastomycosis due toFonsecaea pedrosoi. Int J Dermatol 1992; 31: 805-812.

22 Medina-Ramirez M. Treatment of chromomycosis withliquid nitrogen. Int ] Dermatol 1973; 12: 250-254.

23 Kuflik EG. Cryosurgery updated. / Am Acad Dermatol1994; 31: 92.5-944-

24 Lubritz RR, Spence JE. Chromoblastomycosis: cure by ', •cryosurgery. hit ] Dermatol 1978; 17: 830-832.

Z5 Nobre G, Oliviera AS, Verde F. Chromomycosis: report .of a case and management by cryosurgery, topicalchemotherapy and conventional surgery. / DermatolSurg Oncol 1980; 6: 576-578.

z6 Sittart JAS, Valente NY. Fragments da cromomicose pelonitrogenio liquido. Med Cut ILA 1986; 14: Z27-232. '

27 Souza AS, Sakai YV. Tratamiento da cromomicose pelo 'nitrogenio liquido. Med Cut ILA 1986; 14: 227-232.

z8 Dachow-Siwiec E. Treatment by cryosurgery in the -premalignant and benign lesions of the skin. In: • - •Breitbart EW, Dachow-Siwiec E, eds. Clinics in -iv>; •Dermatology: Advances in Cryosurgery. New York: • .Elsevier, 1990: 69-79.

29 Graham GF. Advances in cryosurgery during the pastdecade. Cutis 1993; 52: 365-372.

30 Graham GF. Cryosurgery. Clin Plast Surg 1993; zo:

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