Volume 23Number 3, Part 2September 1990

itraconazole therapy, receIVIng intermittent an-tiluekemia therapy, he remained without evidentpulmonary disease.

Side effects, in contrast to previously availabletherapy, were again found to be rare.

This experience suggests itraconazole may be animportant advance in the treatment of aspergillosis.

REFERENCES

1. Hay RJ, Dupont B, Graybill JR, eds. First InternationalSymposium on Itraconazole. Rev Infect Dis 1987;9(suppl1):S1-152.

2. Ganer A, Arathoon EG, Stevens DA. Initial experience intherapy of progressive mycoses with itraconazole, the first

Itraconazole in cryptococcosis and aspergillosis

triazole in clinical studies. Rev Infect Dis 1987;9{supp!1):877-86.

3. Tucker RM, Arathoon EG, Williams PL, et aI. Therapy ofmycoses with itraconazole. Ann NYAcad Sci 1988;544:451-70.

4. Hoeprich PD, Finn PD. Obfuscation of the activity of anti-fungal antibiotics by culture media. J Infect Dis 1972;126:353-61.

5. MacKerrow 8D, N erry IN, Hoeprich PD. Effect ofbulferson testing of Candida species susceptibility to flucytosine. JClin MicrobioI1987;25:885-8.

6. Denning DW, Tucker RM, Hanson LH, et al. Itraconazoletherapy ofcryptococcal meningitis and cryptococcosis. ArchIntern Moo. 1989;149:2301-8.

7. Denning DW, Tucker RM, Hanson LH, et al. Treatment ofinvasive aspergillosis with itraconazole. Am J Med 1989;86:791-800.

Itraconazole therapy in aspergillosis: Study in 49patientsBertrand Dupont, MD Paris, France

Itraconaz01e, 200 to 400 mg once daily, was administered to 49 patients with different typesof aspergillosis: pulmonary aspergilloma (14 patients), chronic necrotizing pulmonaryaspergillosis (14), and invasive aspergillosis (21). Itraconazole was prescribed alone or incombination or after treatment with amphotericin Band flucytosine. Of 14 aspergilloma pa-tients, 2were cured and 8 had symptomatic improvement. In chronic necrotizing pulmonaryaspergillosis, 7 of 14 patients were cured and 6 improved significantly. In invasive aspergillo-sis treatment failed in 6 patients and 15 were cured. Itraconazole can be an alternative toamphotericin Bin the treatment of invasive aspergillosis and chronic necrotizing pulmonaryaspergillosis. In aspergilloma itraconazole may be useful in inoperable cases. (J AM ACADDERMATOL 1990;23:607-14.)

The clinical signs of aspergillosis display a widediversity and depend on the host's immunity and thelocal anatomic bronchopulmonary conditions. Theyinclude colonization (aspergilloma), invasion (inva-sive pulmonary aspergillosis), and allergy (allergicbronchopulmonary aspergillosis). In addition, thereare intermediary clinical conditions. Certain as-pergillomas become invasive, invasive pneumonop-athies may develop into a residual aspergilloma, andpneumonopathies may have a chronic local evolu-

From Unite de Mycologie, H6pital de l'Institut Pasteur.

Reprint requests: Bertrand Dupont, MD, Professor of InfectiousDiseases, Unite de Mycologic, H6pital de l'lnslitut Pasteur, 211 ruede Vaugirard, F 75724 Paris Cedex 15, France.

16/0/21851

tion without any extrathoracic diffusion in patientscharacterized by little or no immunosuppression(chronic necrotizing pneumonopathies). In addition,allergic types (such as certain allergic bronchopul-monary aspergillosis, particularly in patients withcystic fibrosis), which do not or only marginally re-act to corticosteroids, appear to respond favorably toantimycotic therapy.

This highly heterogeneous clinical group and theirdiagnostic difficulties illustrate the problem of es-tablishing efficacy criteria for an antifungal agent.Moreover, healing criteria are often difficult to de-termine except after a long follow-up. Finally, thenumber of patients in the same center for each clin-ical form tends to be limited.

The currently available therapeutic options are

607

608 Dupont

Table I. Aspergillomas: Characteristics ofpatients and dosage of itraconazole

Journal of theAmerican Academy of

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Table II. Patients and predisposing factors inchronic necrotizing pulmonary aspergillosis

113

1468

60 (range 33-88)

pergillosis was diagnosed by the criteria of Gefter et al.7:radiologic pneumonopathy (14/14), signs and symptoms(fever, chest pain, weight loss, increased sedimentationrate; 14/14), and presence of at least four serumanti-Aspergillus precipitin bands on electrosyneresis (11/14). A. fumigatus was isolated in 11 patients from anendobronchial swab (6 patients), pulmonary biopsy (4) orpurulent emesis (1). No patient showed evidence ofextrathoracic dissemination of the infection, and the pre-disposing factors (Table II) did not include severe immu-nosuppression such as chronic agranuloc:ytosis. One pa-tient with familial septic granulomatosis was included(Table III).

In 21 patients invasive aspergillosis was diagnosed(Table IV). All had severe immunosuppression thatresulted from chemotherapy for a malignant blood dis-ease, a graft, or an organ transplant (Table V). Sixpatients had less than 1000 polynuclear neutrophils percubic millimeter. The diagnosis was confirmed by biopsyof endobronchial sampling (protected distal bronchialswab, bronchoalveolar lavage, transtracheal puncture)with a positive direct examination for the presence of fil-aments, and a positive culture (Table V). The isolatedAspergillus species wereA.fumigatus (17 patients), A.fumigatus plus Aspergillus nidulans (1 case), Aspergil-lusflavus (2), and histologic findings only (1). The infec-tion sites were lungs (14 patients), bronchi (2), sinusmaxillaris (3, of whom 2 had cerebral extension), verte-brae (1), and liver, spleen, kidneys (1) (Table IV).

TreatmentItraconazole, 200 or 400 mg, was orally administered

once daily at mealtime for 2 to 13 months (average 7

No. of patientsM .F

Mean age (yr)Patients with underlying condition

Previous tuberculosis (cavity) 10Ankylosing spondylitis (cavity) 2Previous bacterial abscess (cavity) 2

Patients receiving dosage ofitraconazole

2oomg/day4OOmg/day

restricted to amphotericin B intravenously, possiblyin combination with flucytosine. Their toxicity andlimited efficacy necessitate the 'urgent investigationof new agents.

Among the antimycotic drugs with possible ac-tivity against aspergillosis, itraconazole appearspromising.1 Its high efficacy in vitro,2 comparable tothat of amphotericin B,3 and especially in vivo invarious experimental animal models,2 includingendocarditis,4 warrants clinical investigation.5,6 Theaim of this study is to assess itraconazole's clinicalantimycotic efficacy against aspergilloma, chronicnecrotizing pulmonary aspergillosis, and invasiveaspergillosis.

PATIENTS AND METHODS

This open, multicenter French study focuses on the ef-ficacy and tolerance of itraconazole in aspergillosis. Allpatients a~eed to follow treatment, and 49 patients withpulmonary aspergilloma (14 cases), chronic necrotizingpulmonary aspergillosis (14), or invasive aspergillosis(21) could be analyzed.

PatientsIn 14 patients aspergilloma was diagnosed on the basis

ofa previously existing pulmonary cavity, a radiogram ofa bell-shaped fungus ball ina cavity, and a positive searchfor precipitating antibodies in electrosyneresis againstmetabolic or somatic Aspergillus fumigatus antigenswith at leastfour precipitinarches. No patient was treatedfor leukemia or cancer, and in certain patients pulmonarybiopsy or the examination ofa lobe excision corroboratedthe diagnosis. The detailed patient data are shown in Ta-ble I.

In 14 other patients chronic necrotizing pulmonary as-

No. of patientsMF

Mean age (yr)Patients with predisposing factors*

CorticosteroidsChronic granulomatous disease,

bronchiectasis, sarcoidosis,allergic bronchopulmonaryaspergillosis

Lung cancerRadiotherapyChemotherapyAspergillomaPrevious tuberculosisBacterial pneumonia

*More than one factor per patient.

14104

45 (range 22-58)

56

553221

Volume 23Number 3, Part 2September 1990 Itraconazole therapy in aspergillosis 609

Table III. Survey of patients with semi-invasive aspergillosis treated with itraconazole

Mycologic/ Itraconazole Follow-up' afterPatient Sex/Age (yr)! Underlying serologic dosage (mg/day)/ discontinuation

No. Body wt (kg) condition lincIing.

610 Dupont

Table IV. Survey of patients with invasive aspergillosis treated with itraconazole

Journal of theAmerican Academy of

Dermatology

IC dosage Other antifungalPatient SexlAge (yr) Underlying PMN Myologic (mg/day)/ Tx (before/in

No. Body wt(kg) condition withIC Site type Duration (mo) combination)

F/54/66 Promyelocyte AL >1000 Lungs (bone?) Bronchoaspira- 200/6 AB and FC (2.5tion, transpari- rna); stopped 15etal sputum days before ITZdrainage, +; A.fumigatus

2 M/49/72 Diabetes AML 1000 Lungs BAL, +; A.fu- 40010.5 AB (7 days) be-migatlls fore ITZ

4 M/62/40 Thrombocytope- >1000 Lungs Pulmonary biopsy 400/0.6 Nonenia, pulmonary culture, +; NDfibrosis

5 M/61 /55 AML >1000 Lungs BAL, +; A.fu- 200/2.5 Nonemigatlls

6 F/57/58 AML >1000 Lungs Distal branch. 20013 Nonebrush, +; A.fumigatus

7 M/36j80 AL 1000 Lungs BAL +;A.fu- 600-400/6 AB 1.5 mo beforemigatus ITZ, then AB

and ITZ (2mol, then ITZ

9 Fj48j56 AL >1000 Lungs BAL, sputum +; 200/1 AB 1 mo beforeA. fumigatus ITZ

10 M/50/67 Testis cancer, >1000 Lungs BAL, sputum +; 400-200/8 AB (6 days), thenbone marrow A·fumigatus ITZtransplant

11 Mj45/82 Kidney transplant >1000 Lungs BAL, tra nstra- 400/2 Nonecheal puncture,+; A.fumiga-tus

12 M/47/60 Kidney transplant >1000 Bronchi BAL, +; A.fu- 40012 Nonemigatus

13 M/51/62 Kidney transplant >1000 Lungs BAL, +; A. fu- 400/1 Nonemigatus

14 M/42/52 Kidney transplant >1000 Lungs, bronchi Bronchial aspira- 400/4 Nonetion, +; A.fu-migatus

15 F/24/40 Heart/lung trans- >1000 Bronchi Bronchial aspira- 200/3 AB (8 days) be-plant tion, +; A.fu- fore ITZ, then

migatus ITZ and ABaerosol

16 M/34/63 AML >1000 Lungs Bal, +; a. fumiga- 200/6 AB (20 days) be-tus fore ITZ

17 M/IO/30 ALL Spleen, kidneys, Spleen biopsy; +; 150-200/4.5 AB and FC (6liver A. fumigatus days) before

and 6 days to-gether \\lith ITZ

18 M/6J25 AL

Volume 23Number 3, Part 2September 1990 Itraconazole therapy in aspergillosis 611

Follow-upImmunosuppressive Oinical Radiologic Mycologic afterITZ

Tx efficacy efficacy efficacy discontinuation Result Comments

Chemotherapy Improved Improved Negative >3 yr Cure Surgicalexcision of as-pergilloma 9mo after end ofTx

Chemotherapy Improved, then Improved, then Negative Death Failedrelapsed pulmonary and

cerebral relapse

Chemotherapy Stable Stable Failure Death Failed

Chemotherapy Improved Improved ND Death Not assessable(failed); septicshock

Chemotherapy Cured Cured Negative Zmo Cured Excavated opacity

Chemotherapy Cured Cured Negative 4mo Cured Bell-shapedmasses

Chemotherapy Cured Cured ND 16 mo Cured Bell-shapedmasses, contin-ues with 200mg/day

Chemotherapy Cured Cured ND lOrna Cured Bell shapedmasses, failureAB,marrowtransplant dur-inglTZ

Chemotherapy Cured Cured ND 9mo Cured

Chemotherapy Cured Cured Negative 7ma Cured

Corticosteroids, Cured Cured ND 6mo Curedazathioprine

Corticosteroids, Cured Normal before ITZ Negative Curedazathioprine

Corticosteroids, Cured Cured Negative 6mo Curedazathioprine

Corticosteroids, Cured Cured Negative 3mo Cured Excavated pneu-cyclosporine mon0hi.thy,

bronc ial gran-ulation

Corticosteroids, Cured Normal before ITZ Negative Zmo Cured Purulent bronchi-cyclosporine tis

Chemotherapy Cured Cured ND 6mo Cured Excavated pneu-monopathy

Chemotherapy Cured Normal before ITZ ND 8 mo Cured Ravish histology

Chemotherapy Failure Failure Failure Death Failure

Chemotherapy Failure Failure Failure Death Failure

Chemotherapy Cured Unchanged ND Relapse at end Failureof ITZ Tx,death

Chemotherapy Cured Cured Negative (biopsy) 4mo Cured Bell-shaped mass

612 Dupont

Journal of theAmerican Academy of

Dermatology

*All intensively immunosuppressed by chemotherapy (polymorphonu·clear neutrophils

Volume 23Number 3, Part 2September 1990

these patients included six with pneumonopathyafter itraconazole monotherapy (three kidneytransplant and three acute leukemia patients), andnine patients after combination therapy (itracona-zole preceded by amphotericin Band flucytosine[n = 5] or itraconazole associated with amphoteri-cin Band fiucytosine for a period of days orweeks [n =4]). The average follow-up period af-ter treatment was 9.5 months (range 2 to 48months).

Tolerance was excellent. Treatment did not haveto be modified or discontinued because of toxicity.Two patients reported gastrointestinal complaints,hypokalemia was observed in four patients, andhyperka1cemia was seen in one patient. In four pa-tients an elevated liver transaminase level developedand two had an increased alkaline phosphataselevel.

DISCUSSION

Pulmonary asiwrgilloma. Itraconazolehas a mod-est and partial effect on pulmonary aspergilloma.Two patients appeared to have been cured, butspontaneous cure cannot be excluded. Itraconazolehad a marked effect on the symptoms in eightpatients (57%), but the mechanism of action has notyet been clarified. A partial effect on the fungus ballwith a reduced production of toxic or irritating sub-stances by Aspergillus offers one possible explana-tion. The disappearance of A. !urnigatus from thesputum of five patients and the marked (>- 50%) re-duction of the antiaspergillosis precipitin concentra-tions in six patients point to a direct antimycotic ef-fect. Because of itraconazole's gradual start ofaction, treatment should be continued for severalmonths. Itraconazole's penetration of the fungusball is still unknown. Most improved patients hadrelapse in the weeks or months after the discontin-uation of itraconazole.

Chronic necrotizing pulmonary aspergillosis. Theinfrequent disorder chronic necrotizing pulmonaryaspergillosis appears to be one of the best indicationsfor itraconazole. The drug is particularly effectiveagainst fever and chest pain. All patients but one re-sponded to itraconazole treatment. The underlyingdisorder, especially bronchopulmonary carcinoma,may continue to develop, sometimes complicatingthe long-term efficacy evaluation. In certain patientsthe pneumonopathy developed into an aspergilloma.

Itraconazole therapy in aspergillosis 613

These localized types of aspergillosis tend to have afairly favorable prognosis because the general im-munodefense system and phagocytosis are not af-fected. Other antimycotics, including amphotericinBand fiucytosine, may be effective.?,8 However,itraconazole has the advantage of easy adminis-tration and low toxicity, even with long-term treat-ment.

Invasive aspergillosis. Invasive aspergillosis is dif-ficult to treat, particularly in the presence ofchronicagranulocytosis; the mortality rate is high.8 In thisstudy its unfavorable prognosis was confirmed inpatients with cerebral extension and invasive sinusi-tis. Osseous and pulmonary involvement were curedin 15 patients with itraconazole alone (six patients),or itraconazole in combination with (at least ini-tially) amphotericin Band flucytosine (nine pa-tients). Itraconazole therapy may be indicated afterdiscontinuation of amphotericin B or during theaplastic periods in cured patients who ultimatelyhave to undergo chemotherapy or a bone marrowtransplant again. I, 6, 9

Itraconazole's excellent tolerance, even with long-term treatment, facilitates treatment in patients inwhom amphotericin B-induced renal toxicity repre-sents a major disadvantage in kidney and hearttransplant recipients.

Itraconazole's efficacy appears to be due to its lowminimum inhibitory concentration for most As-pergillus strains and high tissue concentration, es-pecially in the lungs, with concentrations rangingfrom 0.9 to 2.4 times the serum levels. 10

In summary, itraconazole, 200 or 400 mg/day,can be a good alternative to amphotericin B in thetreatment of invasive osseous and pulmonary as-pergillosis and chronic necrotizing pulmonary as-pergillosis. Randomized comparative trials, al-though difficult, are recommended.

The efficacy demonstrated in this study warrantsfurther investigation of the use of itraconazole afteramphotericin B or during aplastic periods in chemo-therapy patients with a history ofinvasive aspergillo-sis for whom antimycotic treatment is recom-mended.9

REFERENCES

1. Grant SM, Clissold SP. Itraconazole: a review of its phar-macodynamic and pharmacokinetic properties, and thera-peutic use in superficial and systemic mycoses. Drugs1989;18:310-44.

614 Dupont

2. Van Cutsem J, Janssen PAl. In vitro and in vivo models tostudy the activity of antifungals against Aspergillus. In:Van den Bossche H, Mackenzie DWR, Cauwenbergh G,eds. Aspergillus and aspergillosis. New York: PlenumPress, 1988:215-27.

3. Dupont B, Drouhet E. Early experience with itraconazolein vitro and in patients: pharmacokinetic studies and clin-ical results. Rev Infect Dis 1987;9:71-6.

4. Longman LP, Martin MV. A comparison of the efficacy ofitraconazole, amphotericin Band 5-fluorocytosine in thetreatment of Aspergillus fumigatus endocarditis in therabbit. J Antimicrob Chemother 1987;20:719-24.

5. Denning DW, Tucker RM, Hansen LH, et al. Treatmentof invasive aspergillosis with itraconazole. Am J Med1989;86:791-800.

6. Viviani MA, Tortorano AM, Langer M, et al. Experience

Journal of theAmerican Academy of

Dermatology

with itraconazole in cryptococcosis and aspergillosis. J In-fect 1989;18:151-65.

7. Gefter WB, Weingrad TR, Epstein DM, et al. "Semi-inva-sive" pulmonary aspergillosis. Radiology 1981 ;140:313-21.

8. Rinaldi MG. Invasive aspergillosis. Rev Infect Dis 1983;5:1061-77.

9. Karp JE, Burch PA, Merz WG. An approach to intensiveantileukemia therapy in patients with previous invasive as-pergillosis. Am J Med 1988;85:203-6.

10. Heykants J, Michiels M, Meuldermans W, et al. Thepharmacokinetics of itraconazole in animals and man: anoverview. In: Fromtling RA, ed. Recent trends in the dis-covery, development and evaluation of antifungal agents.Barcelona, Spain: JR Prous Science Publishers, 1987:57-83.