Laboratory and clinical assessment of ketoconazole in deep-seated mycoses

Laboratory and Clinical Assessment of Ketoconazole in Deep-Seated Mycoses

EDOUARD DROUHET, M.D. BERTRAND DUPONT, M.D., Paris, France

From the Pasteur Institute, Department of My-

cology,Paris, France. Requests for reprints should be addressed to Professeur Edouard Drouhet, Unit6 de Mycologic, lnstitut Pasteur, 28 rue de Docteur Roux, 75724 Paris, France.

30

January 24, 1983

Forty-eight cases of deep mycoses were studied and treated with ketoconazole, each with in vitro evaluation of the minimum inhibitory concentrations (MIC) of the causative fungi, in vivo pharmacokinetic, clinical, and mycologic evaluations, several months to two years after the treatment was stopped. Excellent results were obtalned in six cases of chronic mucocutaneous candidiasis, with restoration of immunologic disturbances; 23 cases of systemic candidiasis, including new aspects of heroin addicts with cutaneous, ocular, or osteoatlicular manifestations; eight cases of histoplasmosis, five due to Histoplasma capsulatum and three to Histoplasma duboisii, with cure in seven and remission in one; one case of African blastomycosis (Blastomyces dermatitidis); three cases of mycetoma, two due to Monosporium apiospermum, one due to a dematiacious fungus; three cases of entomophthoromycosis with cure; one case of fungal arthritis, due to new hyphomycete similar to M. apiospermum, pathogenic for laboratory animals; one case of Drechslera longirostrata causing vertebral arthritis, following a fungal endocarditis and cured by combination of ketoconazole with amphotericin B, each agent alone being ineffective; and other deep mycoses. There are numerous reports of the therapeutic activity of ketoconazole against various superficial and deep-seated mycoses, but there are only a few with concomitant studies of the sensitivity of the fungus and the absorption of the drug at the beginning and during treatment, with sufficient follow-up to determine final results. There are numerous reports on clinical, serologic, and mycologic response to treatment. Pharmacokinetic properties have been studied principally in healthy subjects, unrelated usually to the in vitro sensitivity of a fungus and to therapeutic activity. Contrary to Heel’s [l] statement that routine monitoring of serum concentrations would be of little value, we found variation in the absorption of ketoconazole, particularly in patients with deep mycoses. In consequence, an increase of dosage to 600 or 800 mg a day was necessary for favorable therapeutic effects, particularly when the fungus was less sensitive in vitro even when tested in a casitone complex medium, which gives lower MIC values than the synthetic YMA or Sabouraud’s media. Our data concern chronic mucocutaneous candidiasis or Candida albicans granuloma; a new systemic cutaneous, ocular, and osteoarticular C. albicans disease in heroin addicts; African and American forms of histoplasmosis; African blastomycosis due to B. dermatitidis; entomophthoromycoses; fungal mycetoma due to M. apiospermum; aspergillosis; dermatophytosis; osteoarticular localization of D. longirostrata; and arthritis due to an atypical strain of M.

The American Journal of Medicine

ASSESSMENT

apiospermum. Some of these cases were described two years ago at the First International Symposium on Ketoconazole at Medellin, Colombia, and subsequently published [2], but are now reported with further follow-up. MATERIAL AND METHODS In vitro studies were performed on synthetic YMA (Difco), Sabouraud’s glucose, and a casitone complex medium (Difco casitone, 9 g; yeast extract, 5 g; sodium citrate, 10 g; monobasic sodium phosphate, 1 g; aqueous dibasic sodium phosphate, 1 g; glucose, 10 g; agar, 20 g; and distilled water to 1,000 ml, at pH 6.6.). Serum concentrations were determined from blood samples taken before treatment and one, two, four, and six hours after the first ketoconazole tablet, and at the same time after the first dose on the second, fifth, and seven days. Levels were determined on casitone agar at pH 6.6 [2] with C. albicans strain 3153 A, in an assay that permitted detection of concentrations 0.0 19 pglml or greater. Sera were assayed 24 to 48 hours after collection. With the exception of children, in whom a daily dose of about 5 mglkg body weight was given, dose was usually two tablets (400 n-g/day), one each with the morning and evening TABLE I

OF KETOCONAZOLE

IN DEEP MYCOSES-DROUHET,

DUPONT

meals. When serum levels were less than 1 pg/ml, or when the therapeutic response was not rapidly favorable, the dose was raised to three or four tablets daily. Isolation of the fungi of the various mycoses was performed on Sabouraud’s medium. Fungal precipitating antibodies were detected by counterimmunoelectrophoresis with metabolic and somatic antigens prepared in the laboratory by previously described methods [3]. In studies of patients with chronic cutaneous candidiasis, T lymphocyte transformation in response to C. albicans, phytohemagglutinin, and concanavalin A, and specific inhibition of C. albicans lymphocyte proliferation by serum polysaccharide antigens were performed by previously described techniques [4]. Skin window tests, preparation of C. albicans antigens for delayed cutaneous hypersensitivity testing, and measurements of immunoglobulins G and E were also performed according to techniques previously described by our laboratory [ 2,3]. RESULTS In vitro sensitivity. The MIC obtained on the casitone complex agar medium were lower than those on synthetic YMA or on complex Sabouraud’s medium. Tables I and II show the results compared with those in the

In Vitro Activity of Ketoconarole Against Dermatophytes, Opportunistic Yeasts, Molds and Actlnomycetes

Fungi Dermatophytes Trichophyton violaceum Trichophyton violaceum Trichophyton schoenleinii Yeasts Candida albicans Candida albicans Candida albicans Candida albicans Candida tropicalis Candida pseudotropicalis Candida krusei Candida parapsilosis Torulopsis glabrata Trichosporon cutaneum Cryptococcus neoformans Cryptococcus neoformans Aspergillus fumigatus Aspergillus fumigatus Aspergillus fumigatus Aspergillus nidulans Aspergillus flavus Drechslera longirostrata Alternaria tenuis Alternaria tenuis Alternaria tenuis Actinomycetes Nocardia asteroides Nocardia brasiliensis Nocardia caviae

VariousReferences* No. of Strains Tested

Our Resultst MIC Wmf)

No. of Strains Tested*

4

1

1

472

0.0280

45 2 14 18 124 1 39

0.02-80 25-50 0.2-31 0.2-64 0.8-64 0.1 0.1-32

55

l-100

4

25 7 43 11 2 2 2 2 2 2 2 4 2 4 20

2

2

1 2

1 lo-32

4 1

MC

Wml) 0.78 6.25 0.78 0.01-0.09 0.18-0.78 1.56-6.25 12.5-50 0.04-50 0.04 1.56 0.18 0.36-0.78 0.36-0.78 0.04-0.09 0.18-0.78 0.12-0.36 3.12-6.25 12.5-25 3.12 0.5 0.78 0.36 0.78 6.25 12.5-25 6.25 3.12

Data from various references ouoted in Levine 161. t Casitone complex agar medium. t Strains from our patients. l

January 24, 1983

The American

Journal of Medicine

31

ASSESSMENT

OF KETOCONAZOLE

TABLE II

IN DEEP MYCOSES-DROUHET,

DUPONT

In Vitro Actlvity of Ketoconarole Against Dimorphic and Other Fungi

Fungi Agents of Deep Mycoses

Various References* No. 01 Strains Tested

Our Resultst MC

No. of Strains TesledS

(CcgW

MIC @g/ml)

Dimorphicfungi (systemic mycoses) Histoplasma Histoplasma Histoplasma Histoplasma Blastomyces

capsulatum capsulatum duboisii duboisii dermatitidis

Mycetoma and deep subcutaneousmycoses Petriellidiumboydii Monosporium apiospermum Hendersonula toruloidea Sporothrix schenckii Phycomycoses Conidiobolus Conidiobolus Conidiobolus Basidiobolus Basidiobolus

26

0.1-0.5

26

0.1-2

23

0.1-4

23

0.1-18

coronatus coronatus coronatus haptosporus haptosporus

(Y, M)

3 (Y, M 1 (Y, M 2 (Y, M 2 (Y, M 2 (M) 3 1 1 1

-

M) M) M) M)

0.78 1.56 0.18-0.78 1.56-3.12 0.18-0.78 0.36-0.78 3.12 0.36 6.25

1 1 1 3 3

1.56 (0.78)§ 12.5 (0.78) 25 (12.5) 0.18-0.36 6.25-12.5 (0.04-0.78)

5

0.04-0.36 1.56-6.25 100 12.5 (1.56)

Chromoblastomycoses Fonsecaea pedrosoi Fonsecaea pedrosoi

2 1 1

Exophiala jeanselmei Wangiella dermatitidis NOTE: Y = yeast phase; M = mycelial phase. Data from various references quoted in Levine [6]. 7 Casitone complex agar or liquid medium. t Strains from our patients. 5 Figure between parenthesis indicates 97 percent inhibition. l

literature. The only child with tinea capitis due to Trichophyton violaceum who was not cured after one month’s treatment had a strain sensitive to 6.25 pg/ml, whereas the other four children, cured after one month, had strains with MIC values of 0.78 pg/ml. Among the treated cases, we have not found strains of C. albicans with a MIC value higher than 1.56 pg/ml on casitone medium. Among other strains 12.8 percent had MIC values of 12.5 to 50, but on Eagle minimal essential medium with 5 percent carbon dioxide at 37OC germ tube inhibition was obtained with 0.04 pg/ml, a concentration theoretically achievable with treatment. Numerous strains of Aspergillus fumigatus had MIC values of 15 to 25 pg/ml, which explains partially the poor results obtained in patients with aspergilloma. Similar results were also obtained with some agents of chromoblastomycoses or pheohyphomycoses (Exophiala jeanselmei, Wangiella dermatitidis), which explains the difficulties in obtaining rapid and prolonged therapeutic effects and the necessity for increasing dosage. The agents of mycetoma and the phycomycases were sensitive to less than 1 pg/ml, with favorable results after prolonged therapy. The strain of Sporothrix schenckii was weakly sensitive (MIC of 6.25 pg/ml), which is consistent with the frequent relapses observed by us and others.

32

January 24,

1993

The American Journalof Medicine

Synergy. Synergy between ketoconazole and amphotericin B was observed with a D. longirostrata strain, causing a severe vertebral osteomyelitis following endocarditis. The MIC value of each separately tested antifungal agent on liquid casitone medium was 1, but there was complete inhibition with 0.12 amphotericin B and 0.25 pg/ml ketoconazole, thus explaining the excellent therapeutic effect when the two antifungal agents were used concomitantly. Synergy was also observed in an Aspergillus flavus strain responsible for septic arthritis of the knee: the MIC value for amphotericin B was 2.5 and for ketoconazole it was 0.5 pg/ml; combined total inhibition was obtained with 0.25 amphotericin B and 0.05 pg/ml ketoconazole, in keeping with the failure of single drug therapy and success in combined therapy. Serum and Biologic Fluid Levels. The serum levels obtained in 45 patients are shown in Table III. The highest recorded levels peaked at 7.1 and 10 pug/ml on the first and second day after a dosage of 400 mg a day, but the mean level was 1.72 and 1.86 pg/ml for the first day, higher for the next day at the same hours, without important changes subsequently, even when treatment was continued for several months. In the cases in which 1 pug/ml peak levels were not obtained or when the therapeutic effect was not seen (see Table Ill) dosages

ASSESSMENT

OF KETOCONAZOLE

IN DEEP MYCOSES-DROUHET,

DUPONT

were increased to 600 or 800 mg/day, and increased levels of ketoconazole were rapidly obtained; in some cases even 600 mg produced ketoconazole levels only 1 pg/ml. Ketoconazole diffused into articular fluid (0.20 to 0.30 mg/ml), urine (0.03 to 0.80 pg/ml at six hours and 0.03 to 0.30 pg/ml between six and 24 hours); aqueous and vitrous, pleural, peritoneal, and cerebrospinal fluid (0.04 pug/ml); and in bone, as revealed by a biopsy (2.5 pg/ml). Side effects. Only minor side effects were observed in about 15 percent of patients, even in the 45 treated for more than one month, the majority for two to three months and some even longer. Four patients showed a transitory increase of liver enzymes (SGOT, SGPT, alkaline phosphatase) of up to four times the normal values, but the treatment was continued, and enzyme levels returned to normal despite treatment. The case of arthritis caused by D. longirostrata was particularly impressive because of the increase of liver enzymes and of bilirubin levels when 600 mg of ketoconazole was given alone or with amphotericin B. When the therapeutic effect became evident, the enzyme level became normal. We believe that the transitory increase in these levels was due to the toxins liberated by the responsible fungi. Chronic Mucocutaneous Candidiasis. Of the six patients reported in this study (Table IV), four (Patients 1, 2, 3, 4) were described in 1980. The excellent response was maintained during the subsequent two years in Patients 2 and 3. Patient 1 had a minor relapse one year after treatment, with rapid response subsequently of a finger paronychia. Of the two new patients, one had a Buckley syndrome, cured in 45 days with 18 months of follow-up, and the other the most impressive that we have seen, had chronic mucocutaneous candidiasis. This patient was a 21 year old man, successfully treated 20 years before for chronic mucocutaneous candidiasis that had developed in the first months of life after antibacterial therapy. The disease relapsed three years after treatment, with widespread hyperkeratotic, granulomatous lesions of the scalp, face, and hands (Figures 1, 2, 3) and with chronic thrush. Ketoconazole cured the oral lesions in 10 days, the scalp lesions in three months, and the hand lesions in five months. Treatment was continued for a year. In immunologic studies circulating C. albicans antigen (mannan) was found in Patients 1 and 3 before, but not after, two months of treatment. Before treatment, T lymphocytes were not transformed by candidin, but were usually by the mitogens phytohemagglutinin and concanavalin A. After five months of treatment, T lymphocytes were transformed by candidin. In the candidin skin window test, before treatment, in these and the other three patients, an immediate intradermal reaction with an increase in eosinophils was observed;

January 24, 1983

The American Journal of Medicine

33

ASSESSMENT OF KETOCONAZOLE IN DEEP MYCOSES-DROUHET, DUPONT

Results of Treatment of Patients With Chronic Mucocutaneous Candidlasls

TABLE IV

A9s (yes@ Patient No. 1

Sex

34

Prior Trestmsst

17 M 68

Chronic thrush at age 8 months Chronic diarrhea Giuteai erythema Paronychia at-age 6 years Skin lesions of hands at age 11 years Allergic lesions of face

Transfer factor Ciotrimazoie

400 150

6 M 16

Thrush at 3 months of age Paronychia Hand and foot lesions Periorai lesions Digestive and pulmonary symptoms*

B-Fiuorocytosine plus econazoie (intolerance) Amphotericin B (total of 378 mg intravenously during a P-month period) improvement noted, but paronychia persisted.

100 210

9 F 20

Scalp granuioma. Face and ear lesions

200 120

27 F 45

Chronic thrush since 5 years of age Periorai, laryngeal, and allergic cutaneous lesions Bronchial and lower respiratory symptoms+

Amphotericin B orally for chronic thrush, disseminated granuiomatous lesions of the skin of head, hands, ears, and shoulders was successful, but relapse occurred 2 years later on scalp. 5-Fiuorocytosine Econazoie Miconazoie Amphotericin B (oral)

19 F 50

Chronic thrush and paronychia with nail involvement of hands, feet since 3 years. Buckley syndrome (IgE 2000 U, eosinophiiia. Staphyiococcal pyodermitis) Chronic thrush after birth. Widespread granuiomatous skin lesions of scalp, face, hands

21 M 50

l

Clinical Symptoms

Weight(kg)

Ketocssarsie Dosage(mg/ day) Duration (days)

400 four months

Amphotericin B intravenously at 1 year of age for chronic thrush scalp granuioma, hand lesions progressive, relapse in 3 years and permanent lesions thereafter

Diarrhea, coarse basilar raies, and cough. + Cough and coarse basilar raies. January 24, 1983

400 90

The American Journal of Medicine

400 one year

Rewits

Follow-UpYears

Lesions of mucous After 1 year membranes minor relapse clinically cured within of 1 fingernail 2 days. Skin lesions re-treated and clinically cured within cured 2 months. Lesions mycoiogicaiiy sterile within 10 days. Delayed cutaneous hypersensitivity to candidin acquired by third month. Lesions of skin and Cure 2 mucous membranes clinically cured within a week. Nails mycologically sterile within 2 months. Delayed cutaneous hypersensitivity to candidin acquired by seventh month. Scalp lesions clinically Cure cured within 2 months. 2 Lesions mycologically sterile within 10 days. Delayed cutaneous hypersensitivity to candidin acquired by third month. One year later negative deiayedtype hypersensitivity. improvement of clinical Cure l/4 symptoms within 3 days. Lesions clinically and mycologically cured within 10 days. Delayed cutaneous hypersensitivity to candidin acquired by third month. Remarkable cure of Cure 1112 thrush in few days, paronychia in 45 days.

Remarkable cure of thrush in 10 days. Granuiomatous lesions progressively cured in 3 months, 4 months for scalp and face and 6 months for hands. Circulating antigen disappeared.Transformation test of T lymphocytes became positive for candidin.

Cure 1

ASSESSMENT

OF KETOCONAZOLE

Figure 2. treatment. Figure 1. Patient 6 with chronic mucocutaneous candidiasis before (a, c) and after (b, d) ketoconazole treatment.

this reaction was lessened or was eliminated three months following ketoconazole treatment. In the skin window test, before treatment, Candida antigen stimulation was obtained for all the patients and was modified by ketoconazole. Precipitating antibodies (greater than five arcs by counterimmunoelectrophoresis) were still present one year after treatment was stopped, and we considered the possibility that C. albicans antigen was still present in tissues, in spite of the rapid disappearance of circulating antigen and the other immunologic tests being normal. Lingual Granuloma due to Candida albicans. In ad-

IN DEEP MYCOSES-DROUHET,

DUPONT

Patient 6 before (e) and after (f) ketoconazole

dition to the six patients with chronic mucocutaneous candidiasis, a 65 year old man with a lingual granuloma due to C. albicans, verified by microscopic examination of biopsy tissue, was treated with ketoconazole in a dosage of 400 mg a day for the first month and 600 mg a day thereafter. Previously, the patient had been treated unsuccessfully with amphotericin B, Sfluorocytosine, and econazole. The patient’s tongue, which had hypertrophied to the point of causing difficulty in speaking and eating, was improved after 45 days of treatment with ketoconazole. However, the patient died from an epithelioma 20 years after the granuloma began. Systemic, Cutaneous, Ocular, and Osteoartlcular Manifestation of Candlda albicans in Heroin Addicts. In the last two years, 34 cases of a distinctive syndrome

FlguIre 3. Patienf 6 before (g, i) and after h i) ketoconazole treatment. January 24, 1993

The American Journal of Medicine

35

ASSESSMENT

OF KETOCONAZOLE

IN DEEP MYCOSES-DROUHET,

of follicular and maculonodular candidiasis lesions of the beard, scalp, pubis, and, more rarely, other areas were observed in adolescent and young adult heroin addicts (Table V). In 21 patients there were ocular lesions (uveitis, hyalitis, and retinitis) and in seven there were osteoarticular lesions and septic inflammation of the intervertebral disks or of the knee; chondrocostal osteitis was observed concomitantly. The lesions were preceded by a fever. The hair was invaded by the hyphal form of C. albicans (Figures 4,5), although both yeast and hyphal forms were observed at the base of the follicle (Figures 6,7) and around the hair. Microscopic examination of potassium hydroxide or lactophenol preparation of the hair or a smear of the pus confirmed the diagnosis, and filaments were identified as C. albicans by culture. Several bands of precipitins were detectable progressively by immunoelectrodiffusion with C. albicans antigens. The fungal elements were observed also in the nodular lesions. Ketoconazole, in a dosage of 400 mg a day, cured the follicular lesions and the nodular lesions in several weeks, but the ocular and osteoarticular may require ketoconazole combined with 5fluorocytosine or amphotericin B (Tables V, VI). An alteration of the frequency of T and null lymphocytes in the peripheral blood of opiate addicts [5] may be the cause. In Table VI the principal clinical and biologic data on these patients are summarized. Of the seven patients listed in Table VI, five had bone biopsy or articular aspirate, which showed occasional yeast or hyphal forms on microscopic examination of tissue or stained smears, but abundant growth of C. albicans on culture. In the remaining two patients, Patient 1 had vertebral abscess revealed by scintigraphy; culture of C. albicans from disseminated follicular skin lesions, sputum, and mouth; and specific serum precipitins. In Patient 13 Candida albicans was not cultured from pus, but microscopic examination of synovial membrane tissue showed severe inflammation with abundant protein and numerous polymorphonuclear leukocytes. In all patients the erythrocyte sedimentation rate was at first elevated but became normal with treatment. Specific serum precipitin measurements showed four bands in two patients, three in two, and two in two; the remaining patient had no bands at onset of observation but one band at one week, and two at one month. With treatment, the number of bands decreased in all patients; radiologic examination revealed improvement in all. Reduction of pain was observed in all patients and disappearance of fever in Patients 9, 12, and 13 was the first sign of response. The 400 mg dose was raised to 600 or 800 when the serum level was less than 1 pg/ml or when the therapeutic effect was not sufficiently rapid (Patient 9). Five patients with osteoarticular disease were cured by ketoconazole alone, but in Patient 12 the therapeutic effect was slow, due to poor absorption, and

36

January 24, 1963

The American Journal of Medicine

DUPONT

amphotericin B was added to the therapeutic regimen, as it was in Patient 3 (Table VI). In Patient 11 the benefit seemed due to ketoconazole, since the disappearance of the abscess and recalcification of vertebra occurred when ketoconazole was increased to 600 mg and 5fluorocytosine was reduced to 3 g a day. The remainder were treated by ketoconazole alone. Of 22 patients treated, eight responded to ketoconazole, six responded to ketoconazole in combination with amphotericin B, two responded to amphotericin B after the failure of ketoconazole, two responded to ketoconazole in combination with !%fluorocytosine, and four responded to a combination of amphotericin B and 5-fluorocytosine after the failure of ketoconazole. Data are too incomplete to be extensively reported now, but we consider important the combination of 5fluorocytosine and ketoconazole and the substitution of ketoconazole for amphotericin B when amphotericin B causes toxicity or when the patient is discharged from the hospital. Septicemia. An excellent response was observed in a 24 year old woman with C. albicans septicemia following cesarean section. C. albicans had been cultured from several blood specimens, from urine, from disseminated pustular skin lesions, and from ovarian venous thrombi. Clinical improvement was evident in the first 10 days of treatment with ketoconazole at a dosage of 400 mg daily, although treatment was continued for an additional 35 days at a dosage of 600 mg daily. Cure was documented by disappearance of fever, inability to culture C. albicans from blood and urine specimens collected 10 days after onset of therapy, reduced to one band from four in serum precipitins, and decreased immunofluorescence titer to l/100 from 116400. Although she had sickle cell trait, neither the disease nor ketoconazole produced hemolysis. Aspergillosis. Eighteen patients were treated for aspergillosis. Of 11 patients with aspergillomas, with one or several pulmonary colonies, only two improved. The others failed to respond in spite of prolonged treatment with ketoconazole (400 mg a day) from two to seven months, with serum levels higher than 1 pg/ml. Im provement was defined as sterilization of the sputum, the disappearance of hemoptysis, and decrease of precipitin bands by immunoelectrophoresis. A patient with maxillary sinus aspergillosis failed to respond after three months of treatment, but a patient with otomycosis, due to A. flavus, responded well. Two patients with allergic bronchopulmonary aspergillosis with severe, persistent manifestation responded well, with one year post-treatment observation, but another patient and one with pleural aspergillosis failed to respond. In the last patient treatment with amphotericin B and 5-fluorocytosine also failed. In diffuse pulmonary aspergillosis in a 17 year old boy, there was a clinical, mycologic, and

ASSESSMENT

TABLE V

OF KETOCONAZOLE

IN DEEP MYCOSES-DROUHET,

DUPONT

New Aspects of Candidlasis of Heroin Addicts ClinicalManifestalions’t Sepikemic

Patients

Syndrome

34 cases

30

Cuianews 32 Pustulosis Folliculitis Nodules Alopecia

Ostesartlcular

Ocular 21

7

WcdogY C. albicans

1 spondylitis of disks D3-D9 1 spondylitis of disks D9-DlO 1 spondylitis, Ll-L2 1 spondylitls of disks L4-L5 + chondrocostal osteitis 1 sacroiliac arthritis 2 knee arthritis

Skin + eye Osteoarticular pus + immunology more than 2 to 3 bands of precipitins

Treatment consisted of ketoconazole orally, eight cases; ketoconazole after amphotericin B intravenously, six cases; ket oconazole replaced by amphoterin B intravenously, two cases; ketoconazole plus 5fluorocytosine. two cases; amphotericin B replaced by ketoconazole plus B-fluorocytosine, 4 cases; and none, 12 cases. + Cure occurred in patients with folliculitis in a few days; with nodules in one to two months; with uveitis in more than 2 months; with osteoarticular lesions in two to four months. l

Figures 4, 5, 6, f. (4) Systemic candidiasis in a heroin addict. Biopsy of scalp. Follicle with a hair invaded by filaments of C. albicans. PAS: magnification X 25. (5) Same biopsy magnification X 40. (6,7) Systemic candidiasis in a heroin addict with follicle with yeasts and filaments at the base, PAS, magnification X 25 and 50.

January 24, 1883

The American Journal of Medicine

37

Weight (kg)

20 M 80

22 F 44

24 M 53

34 M 60

22 F 49

7

8

9

10

11

Sex

Age (years)

Heroin addict for 1 year Foiiicuiitis, pustules of scalp and beard intensive lumbar pain, L-l, abscess (scintigraphy) Heroin addict for 5 years Scalp foiiicuiitis, pustules, alopecia. Spondyiitis of disks D-8, D-Q i- chondrocostai abscess (pus: C. aibicans)

0 0.8

0.09

1 20

2 8 2 x 200 3 x 200 150

Skin: Ca Pus: Ca Sputum: Ca Urine: Ca Precipitins: 3 bands

0.075 0.15

3 x 200 90

2 8

0

0 0.01 0.0

0

0.09 1.8

0.90 0.9

0.45 1.25

1.25

0.90 0.15 0.21

0.11 0.7

0.22

0.15 7

0.26 0.78

0.62

0.65 1.25 0.92

Resuits Follow-Up(years)

0.11

No remission after 1 month on ketoconazoie in combination with 5-fiuorocytosine; 8 g for 37 days and 3 g for 40 days. Skin cured in few days, fever in 12 days, pain in 3 to 5 months. Cure ili0

Radiologic examination revealed improvement after 1 month, cure after 3 months. Cure 1 0.62 Radiologic examination revealed improvement in 3 weeks, recaicification in 3 months. Cure 1 112 0.16 No improvement in 0.45 8 days. 2 weeks: positive culture. Sterilization, clinical cure after 3 months. Cure 2 0.038 Cure 0.36 1

0.075 4 1.8

(hours) 6 4

0.45 0.9

0.52 1.25

1.25

2.5 0.62 0.90

SerumLevels(pglmi) 1 2

Kefoconszoie

Skin: Ca Pharynx: Ca Expectoration: Ca Precipitins: 2 bands

2 x 200 7 4 x 200 75

1

2 x 200 90

Articuiar pus: Ca Precipitins: 4 bands

Heroin addict for 2 years Scalp nodules and foiiiculitis followed by alopecia Periphiebitis Spondyiitis of disks D-Q, D-10 Heroin addict for 7 years Fever 39.5% Thoracic foiiicuiitis (cicatrized) Sudden sacroiliac arthritis Articuiar pus: Ca Precipitins: 0 - 1 band

1 21 25

2 x 200 22 3 x 200 90

Bone biopsy: Ca Precipitins: 2 bands

Day’

Heroin addict for 2 years, sudden lumbar pain -I fever Spondyiitis of disks L-4, L-5 Scalp foiiicuiitis and multiple nodules

ClinicalC. albicans Compiicati0ns

Mycology(C. aibicans: Dosage(mg/day) Ca immunology) Duration (Ceusterimmunoeiscfropheresis) (gays)

Results of Treatment of Patients with C. albicans Systemic Osteoarticutar and Cutaneous Complications in Heroin Addicts

Patient No.

TABLE VI

ASSESSMENT

OF KETOCONAZOLE

IN DEEP MYCOSES-DROUHET,

DUPONT

serologic cure after seven months of ketoconazole therapy (400 mg a day), following 5fluorocytosine and econazole failure. Follow-up was one year. With the one exception (A. flavus), all patients were infected with A. fumigatus. Histoplasmosis. Eight patients were treated for histoplasmosis: five patients were infected with H. capsulatum and three with H. duboisii without any SpOnb ne0u.s resolution (Table VII). Seven patients were considered to be cured (four with H. capsulatum and three with H. duboisii), with a follow-up of one to three years. Patient 8, although improved, has been followed for only eight months. Oropharyngeal lesions cleared in eight to 15 days (Patients 1, 2, 5, 8), skin lesions in two patients cleared in 15 to 45 days. The only failure, Patient 5, improved, but fever reappeared after treatment, along with large round masses in both upper fields. The laryngeal ulceration did not recur, and H. capsulatum could not be cultured from sputum or bronchial aspiration. Despite good serum levels, ketoconazole was discontinued and amphotericin 6 begun. Shortly thereafter the patient became afebrile and returned to Africa, where he received further treatment without follow-up. Mean duration of treatment was 2.8 months, with vdriations from one (Patient 2) to five months (Patient 5). One patient discontinued ketoconazole after 30 days of treatment, but is considered cured. When fever persisted for longer than five days and peak serum levels were less than 1 pg/ml, we increased the dosage to 600 mg (Patients 3,4) or 800 mg a day (Patient 5). All patients were ambulatory, although Patients 4, 6, 7 began therapy while still hospitalized for surgery. Entomophthoromycoses. Three cases with entomophthoromycoses were successfully treated by ketoconazole (Table VIII). In the first patient, an African student from Yaounde (Cameroun) living in Paris for three months, a subcutaneous phycomycosis suddenly developed, and he was urgently operated on for a suspected sarcoma; he was admitted to Pasteur Institute Hospital nine months after operation with large subcutaneous, infiltrative lesions of the deltoid, scapular, and thoracic region due to Basidiobolus haptosporus (Figure 8). The response to ketoconazole was remarkable with improvement in a few days and cure in two months (Figures 9, 10). The second case, a rhinoentomophthoromycosis, due to Conidiobolus coronatus, observed in a patient from the Ivory Coast was successfully treated by Dr. J. Doucet and Dr. M. Therizol-Ferly of the Department Parasitology-Mycology, Universitary Hospital Center of Abidjan. The lionlike aspect of face (Figure 11) was also restored after four months of treatment, without relapse at six-months follow-up. The third case, a rhinoentomophthoromy-

January 24, 1983

The American Journal of Medicine

39

ASSESSMENT OF KETDCDNAZDLE IN DEEP MYCCSES-DffDUHET, DUPONT

TABLE VII

CkW No.

Resutts of Treatment of Patlents with H. capsulatum and H. dubolsli Hlstoplasmosls

Clhkal and Mycsbgtcal Data lhiratkrs sf A!Zs(Y.W Lx, Natlcnallty Dkesw Lkne Wsl9N (kg) Treatn& Laborat~ gdf@d ll&ctbm Reaultr (-1 50 M, French 58.5 lvoly coast or Colombia

58 M, French 78 Cameroun

45 M, French a5 French Guyana or Mexico 47 M, French 55 French Guyana

45 M, Senegalese 43

a

33 M, French 70 Benin (Dahomey)

7

40 M, Senegalese 63 Senegal

a

63 M. Creek 72 Zaire

4

ia

2.5

Mouth, skin: H. capsulatum smear + Culture + Histology + Skin test + Precipitins. 2 bands Nostril, epiglotis: l-f. capsulatum Culture + Histology + Skin test + Precipitins, 4bands Lungs: H. capsulatum Culture Skin test + Precipitins, 2 bands Lungs: H. capsulatum Culture + Histology + Skin test + Precipitins Larynx, liver, intestine, lungs: H. duboisii Culture + Histology + Skin test + Precipitins, 2 bands Lungs: H. duboisii Culture + Histology + Skin test + Precipitins Rib, subcutaneous abscess: H. duboisii Culture + Histology -ISkin test ++ Precipitins Tongue, upper lip: H. duboisii Culture + Skin test + Precipitins. 2 bands

Kdocceuole (Gz) Dustbrl

WV4

Peak 9eNln Level

Mtc’

w4

Wml)

RsnJks Folbwup

(Y?.W)

2 x 200 130

0.76 (0.04)

4.4. 3.8, 1.25

Cured 3

2 x 200 30

1.56 (0.09)

0.8, 1.8

CWd 2

2x200 3 x 200 2 x 200 + 200 135

0.55 2.5 5

Cured 2

Cured 2

2 x 200 135

0.78 (0.04)

1.8. 2.1, 4.2

2 x 200 3 x 200 x 200 + 2 x 200 142

0.78 (0.36)

0.03 0.3 1.7. 3.5

2 x 200 160

0.18

1.25, 1.25

2 x 200 x 200 + 200 2 x 200 96

1.56 (0.09)

0.84 3.5, 10

Cured 2 112

2 x 200 60

0.78

2

Cured 2

Larynx, Liver: Cured Lungs: Failure

ClNd 3

MlC @g/ml) of mycelttl gowth on casltone agar medium with yeast phase inoculum after five days at 30%. Number in parenthesis indicates partial inhibition. l

40

January 24,1983

The American Journalcf Medicine

ASSESSMENT

OF KETOCONAZOLE

IN DEEP MYCOSES-DROUHET,

DUPONT

Results of Treatment of Patients with Entomophthoromycoses

TABLE VIII

Ketoconszoie

-sex Patient

Weight Ika) 23 M 80

30 M 65

27 M 60

Resaits Clinical Data

Subcutaneous phycomycosis of deltoid, scapular, thoracic regions operated on for cancer. Relapse 9 months later. Rhinoentomophthoromycosis face, paranasai sinuses, subcutaneous edema, lioniike aspect. Rhinoentomophthoromycosis for 4 years; face, paranasai sinuses. Resistant to potassium iodide (2 g X 50 days); intravenous miconazoie (600 mg X 30 days).

Laboratory Rewtts

MC’ (w/ml)

Duration (Davs)

Basidioboius haptosporus Culture + Biopsy +

0.78

2 x 200 4 3 x 200 90

2 15 30

0.22

0.62 10

Conidioboius coronatus Culture + Biopsy-t

12.5 (0.78)

2 x 200 120

1 2 3 30 60

0 1.25

0 0.07 0.15 1.25

Conidioboius coronatus Culture + Biopsy +

1.56 (0.76)

First cure: 2 X 200 90 Second cure: 3 x 200 60 After surgery 3 x 200 10

13 1

0.15 0

Davr

0

Serum Levels &s/ml) (hours) 1 2 4 6 0.62 1.80 20

0.31 0

0.45 25

0.31 30

Fottsw-Up fvears) Remarkable improvement in 10 days, cured in 2 months Cure 1

0 0.15 0.30 1.80 2.5

0.62 0.62 1.25 2.8

0.90 Progressive 0.90 improvement 2.3 and cure. 3.6 Cure l/2

1.65 5.8

4 6

2.5 5.6

Clinical improvement in 12 days; progressive remission; relapse 1 week after treatment stopped (culture +); cure after new treatment (cutture -). Cure 112

inhibition was 100 or 97 percent. Partial inhibition is indicated by number in parentheses. 7 Day of treatment when ketoconazoie was measured after 200 mg, except Case 2 when two doses of 200 mg were given before assay. l

Figures 8, 9, 10. (8) Entomophthoromycosis due to Basidiobolus haptosporus (Patient 1) before treatment. The black line delimits the infiltrative zone. (9) Same patient as in Figure 8. Improvement after 10 days of treatment. (IO) Same patient after cure.

January 24, 1983

The American Journal of Mediclne

41

ASSESSMENT OF KETOCONAZOLE IN DEEP MYCOSES-DROUHET, DUPONT

Figures 72, 13, 14, 15. (1513) Entomophthoromycosis due to conidiobolus coronatus (Patient 2). ( 14,15) Patient 2. After ketoconazole treatment and plastic surgery. (Courtesy of Dr. J. Chauvin, Yaounde, Cameroun). 42

January 24, 1993

The American Journal of Medicine

ASSESSMENT

Resutts of Treatment

TABLE IX

of Patients With Mycetoma

OF KETDCONAZOLE

and Subcutaneous

Case No. 1

2

Laboratory Clfnkal Data

41 F 76

Calcaneum

osteitis

34 F 50

Subcutaneous foot mycetoma

RWUHS

Petriellidium boydii

MC WN

0.36

Petriellkfium boydii

0.78

3

59 M 74

Subcutaneous foot mycetoma

Hendersonula toruloidea

0.36

4

38 M 70

Chromoblastomycosis

Fonsecaea pedrosoi

0.36

5

55 M 87

DUPONT

Mycoses

Ketoconazole

Age (years) Sex Weight (kg)

IN DEEP MYCOSES-DROUHET,

Sporotrichosis

Sporothrix

schenckii

cosis due to C. coronatus was observed in Yaounde (Cameroun) by Dr. Chauvin of the Department of Otorhinolaryngology, Yaounde Hospital). This disease, which gives a monstrous (Figwas 12,13) aspect to the face and had been resistant to potassium iodide and miconazole, responded well to ketoconazole with progressive remission. After a first course (three months) of 400 mg daily, the dosage was increased after relapse to 600 mg a day. Cure was obtained and subsequent plastic surgery rendered a more human aspect to this patient, who previously had psychological disturbances (Figures 14, 15). Mycetoma and Subcutar~~ Mycoses. Three patients with fungal mycetoma were treated and followed-up for more than 16 months (TaMe IX). The first two patients were European with mycetomas due to M. apiospermum (anamorph of Petriellidiium boydii); the third was a patient from Martinique with a mycetoma, operated upon several times, due to a dematiacious fungus, similar to a Scytalidium, anamorph of Hendersonula toruloidea. The fourth patient became ill in France with chromoblastomycosis after trauma; he relapsed after two courses of ketoconazole, in spite of good serum levels and a highly sensitive strain of Fonsecaea pedrosoi, but he was not cured after combined therapy with ketoconazole and 5-fluorocytosine. The

6.25

Peak Serum Levels

(:;I Duatlon

MW

(days)

2 x 7 400 210 200 7 2 30 400 365 2 x 120

200

Results Follow-Up (years)

0.62 5

Cure 2 l/2

0.82 2.5 3.5-10

Markedly 2 l/2

0.31

Apparently Relapse 1 year

0.62 3.4-7.5 3.4

Cure. Relapse after 1 month. Cure. Relapse after l/4. Cure

+ 200

x 200

improved

+ 200 200

2 x 120 400 + 180 400 + + 5-FC 120 2 x 100 400 + 90 KI 2g 60

200 200 200 3g 200

0.8-0.9 10

200

cured. after

Relapse Cure. Relapse after l/6. Cure. Relapse after 1 month. Cure

patient with sporotrichosis relapsed twice and was finally cured with potassium iodide. Fungal Arthritis and Dsteitis. Three patients were successfully treated with ketoconazole. Patient 1 was a nine year old boy, weighing 20 kg, in whom septic arthritis developed (FIgure MA) a few days following a wound to his left knee. From synovial fluid and biopsy a fungus was cultured, which is similar to M. apiospermum, except that it had some morphologic differences in conidial attachment (Figure WB) and causes death from renal and cerebral involvement in either mice or rabbits a few days following intravenous inoculation of lo4 spores. Because there was progressive edema and pain, synovectomy was performed and a plaster of Paris cast was applied to immobilize the knee one month after injury. Two months after injury a second synovectomy was performed (Figure 16C), because he had continuing fever, weight loss, tachycardia, and progressive inflammatory bone changes were revealed radiologically (Figure MD). Microscopic examination of synovia showed acute inflammation without hyphal fragments and from the synovial fluid obtained at the second synovectomy three different specimens produced colonies of this fungus when cultured on Sabouraud’s agar medium. From June 7 to November 20, 1979, he received ketoconazole in daily

January 24,1993

The American

Journal

of Medicine

43

ASSESSMENT

OF KETOCONAZOLE

IN DEEP MYCOSES-DROUHET,

DUPONT

Figure 16.

Arthritis of the knee due to Monosporium apiospermum (Patient 7). (a) Filaments and conidia from growth at seven days on Sabouraud’s glucose agar. Lactophenol cotton blue; magnification; X 40. (b) Knee at synovectomy. Note inflammatory lesions. (c) Radiogram showing edema of soft tissues and radiolucencies of the tibia/ cortex.

dosage of 100 mg for seven days, then 200 mg a day. General and local findings improved progressively and the cast was removed two months after application. When examined three years after the injury, he was walking normally, in spite of a knee arthrodesis, and there was no sign of relapse. Patient 2 (observed with A. Chapman, D. Guilmet, J. F. Kovalchouk, J. Laudet, J. M. L. Ziza, Hospital Foch, Paris) was 20 years of age when she had surgical correction of a congenital ventricular septal defect and aortic insufficiency on October 16, 1979. In November fever developed and in December an aortic insufficiency murmur was heard. After transfer to the hospital, she was reoperated upon on January 21, 1980. At surgery there was an aortic valvular vegetation in which hyphal elements were seen microscopically and from which a fungus was isolated and identified as Drechslera longiiostrata (Figwe 17a). It was sensitive by disk to arnphotericin B and the imidazoles (ke&onaz ale, miconazole, and econazole) but resistant to 5fluorocytosine. On January 22, 1980, amphotericin B treatment was begun with maximal doses of 40 mg every other day. There was prompt disappearance of fever and improvement in cardiac function. About February 15

44

January 24, 1983

The American Journalof Medicine

lumbar pain and point tenderness at L-3 and L-4 developed. By the first part of March 1980, the number of precipitin arcs to a D. longirostrata antigen had increased from three to eight. Owing to the poor response, amphotericin B was discontinued and ketoconazole begun in initial dosage of 400 mg a day on March 7. By March 21 there were multiple radiolucenties at the adjoining surfaces of L-3 and L-4 with diminution of the intervertebral space (Figure 17b). Because peak serum levels were less than 1 pug/ml, ketoconazole dosage was increased on March 29 to 600 mg a day. By April 22 the inflammatory process had spread to L-2 (Figure 17~). The erythrocyte sedimentation rate had increased progressively (45 to 77 to 90 to 110 mm), the eosinophil count had mounted to 550/mm3, the SGOT to 190 IU and the alkaline phosphatase to three times normal. An initial trocar biopsy was followed by open surgical biopsy on May 14. A few colonies of D. longirostata but no bacteria were cultured. On May 9 amphotericin B therapy was combined, again, in maximal dosage of 40 mg every other day. In vitro synergy was subsequently demonstrated (Table X). Pain diminished and the erythrocyte sedimentation rate, alkaline phosphatase, and SGOT decreased progres-

ASSESSMENT

OF KETOCONAZOLE

IN DEEP MYCOSES-DROUHET,

DUPONT

Vertebral arthritis due to Drechslera longirostrata. (a) Macroconidia Figure 17. and elongated, multiseptate forms with as many as 15 segments and diameters as long as 150. (6) Radiotomogram of hkuch 21, 1980. Note the multiple radiolucencies at adjoining surfaces of L3-L4, and early lesions at L2-L3. (c) Repeat of same region April 27, 1980. Note progression of lesions and loss of intervertebral space and destruction of disc. (d) Radiogram of June 20, 1980. Note stabilization of lesions. (e) Radiogram of December 1980 with metallic prothesis in place.

TABL,E X

-

Combined Amphotericin B and Ketoconarole Inhibitory Effect on Spores of Drechslera longkostrata I Amphotericin B Wml) 5 2.5 1 0.5 0.25 0.12 0.06 0

+= : 100 NOTE:

percent Mycelial after tlhree and five days.

growth; f

0

0.025

0.05

0 0 0 f + + + +

0 0 0 f + + + +

0 0 0 f + + + +

= 25 percent

growth; lnoculum

Ketoconazole @g/ml) 0.10 0 0 0 f + + + +

0.25

0.5

0 0 0 0 0 0 + +

0 0 0 0 0 0 f f

= 2 X IO3 spores in 2 ml liquid casitone

January 24,1983

complex

1 0 0 0 0 0 0 0 0 medium

, culture

Tha Amarican Journal of Medklna

45

ASSESSMENT

OF KETOCONAZOLE

IN DEEP

MYCOSES-DROUHET,

sively. On radiogram of June 20, the stabilization of lesions is noted (Figure 17d). On July 2, it was possible to replace the body cast (applied March 29) by surgical arthrodesis of L-l to L-5 and fixation further by a metallic plate (Figure 178). The postoperative cast was bivalved in September and the patient began walking with assistance. Amphotericin B was stopped on October 7, and ketoconazole on November 19, 1980. On 1st examination, November 1981, the patient was asymptomatic and walking normally. Patient 3, a 41 year old European, had an osteitis of the patella of several months duration, due to a dematiacious fungus (histologic diagnosis). The cure was obtained after surgery and ketoconazole, 400 mg and then 600 mg a day for three months; follow-up is one year. Blastomycosis. The patient with African cutaneous blastomycosis observed in Rabat (Marocco), who was successfully treated by ketoconazole and described previously [2], has not had a relapse two years after treatment. COMMENTS Ketoconazole seems to be a powerful antifungal agent: all of our patients with chronic mucocutaneous candid&is, as well as with systemic cutaneous, ocular, and osteoarttcular localizations, systemic histoplasmosis, blastomycosis, mycetoma, such subcutaneous mycases as entomophthoromycosis, and fungal osteoarthritis, responded well to this new imidazole derivative without sustaining any adverse effects. This collaborates our previous report on superficial and deep mycases presented at the First International Symposium on Ketoconazole held in Medellin, Colombia, in 1979 ]61. The chronic mucocutaneous candidiasis, which we consider a model for systemic antifungal therapy, is proof of the value of this drug. The dramatic improvement and cure of patients with chronic granulomatous lesions of 22, 18, 10, five, and two years’ duration before receiving ketoconazole showed no relapse after two years. This is due to the complete elimination of C. albicans antigens, responsible for the immunologic cellular conditions. The five patients with chronic mucutaneous candidiasis reported by Graybill et al. [7] and the cases reported by Kirkpatrick et al. [8] confirm the efficacy and absence of adverse reactions, even with prolonged treatment is some patients. From these results, we believe that ketoconazole is able to destroy fungal cells, clear the lesions, and modify the immune reaction in patients with a basically normal immune system. However, we cannot determine whether ketoconazole acts on the immune system directly or on the fungal antigen, The suppression of the

46

January 24, lQ83

The American Journal of Medicine

DUPONT

fungus is probably the key to the cure of chronic mucocutaneous candidiasis. Only antifungal agents as effective as amphotericin B and ketoconazole can clear this severe disease. Ketoconazole has the advantage of lack of toxicity and the oral route of administration. In septicemic candidiasis and particularly in the new pathology of heroin addiction that we have observed in the last two years, ketoconazole seems to be a powerful agent. The deep osteoarticular localizations are well known for difficulty of cure, and of seven patients treated, five benefited by ketoconazole as the only therapy. In one patient amphotericin B was substituted due to the poor absorption of ketoconazole; for others the combination of amphotericin B or 5fluorocytosine was necessary. The response of entomophthoromycosis to ketoconazole is particularly interesting, for this is the first report in the literature of the successful treatment of this condition. Monitoring ketoconazole serum level seems to be very important for the control of treatment, in view of the necessity of increasing the dosage when the serum level does not reach 1 pg/ml cr when there is not a rapid therapeutic response to the classical dosage of 200 mg twice a day. A dosage of 200 mg three, four, or more times a day when necessary did not cause side effects. In ocular localizations of C. albicans it is difficult to make a definitive judgment: some traces of ketoconazole were found in vitrous and in the anterior chamber of the eye, and several patients seemed to respond. In any case, the substitution of amphotericin B during a short hospitalization for ketoconazole alone or combined with 5-fluorocytosine during a long ambulatory period seems to be favorable for some patients, but confirmatory data are necessary. Generally, our pharmacologic data agree with those of Brass et al. [9], although higher serum levels were not found by these authors. After 200 mg ketoconazole given orally our mean level two hours after administration is 1.86 pg/ml, whereas Brass et al. obtained a mean of 2.75 pg/ml; for both studies the serum level increases with dose: after 400 mg our peak mean is 7.65 pglml in seven cases, whereas Brass et al. obtained peak concentrations of 9 pg/ml, in three cases. These authors noted an interaction between ketoconazole and rifampin, which reduced the serum level of ketoconazole; in two patients we also observed this effect, suggesting that rifampin is capable of inducing more rapid metabolic clearance of ketoconazole. The studies with systemic candidiasis involve a relatively larger number of patients: they are still anecdotal and involve diseases whose course is less predictable than chronic mucocutaneous candidiasis. As suggested by Graybill and Drutz [lo], controlled trials are necessary, but because these mycoses may be life-threat-

ASSESSMENT

ening, the control has to be amphotericin placebo.

B rather a

The authors wish to thank Professor C. Lapresle, Director of Pasteur Institute Hospital, Paris, where several patients of this study were treated, to Dr. P. Ravisse (Pasteur Institute, Paris) for histologic studies, Professor G. Segretain and Dr. C. de Bievre, for mycologic assistance, Drs. A. Barois, A. Chapman, J. L. Chauvin, J.

OF KETOCONAZOLE

IN DEEP MYCOSES-DROUHET,

DUPONT

Doucet, F. Her&, L. Laudet, M. Therizol, J. M. L. Ziza, and other colleagues for medical assistance on clinical data of some patients. We thank L. Improvisi, 0. Ronin and A. Pietfroid for their excellent laboratory assistance and G. Monlleo and M. Cormier for secretarial assistance. We wish to acknowledge Professors J. P. Utz (Georgetown University Hospital, Washington) and J. R. Graybill (University of Texas, Health Science Center, San Antonio, Texas) for helpful assistance in the preparation of this manuscript.

REFERENCES 1.

Heel RC: Ketoconazole: pharmacological profile. In: Levine HR: Ketoconazole in the management of fungal disease. New York, Hong Kong: Adis Press International, 1982: 55. 2. Drouhet E, DuPontB: Chronic mucocutaneous candid&s and other superficial and systemic mycoses successfully treated with ketoconazole. Rev Infect Dis 1980; 2: 806619. 3. Drouhet E: Systemic candiiis and its immunology. fvlykosen 1978; Suppl 1: 175-191. 4. Fischer A, Ballet JJ, Griscelli C: Specific inhibition of in vitro Candida induced lymphocyte proliferation by polysaccharidic antigens present in the serum of patients with chronic mucocutaneous candidosis.J Clin Invest 1978; 62: 1005-1013. 5. McDonoughRJ, MaddenJJ, David AF, et al: Alteration of T and null lymphocyte frequencies in the peripheral blood of human opiate addicts: in vivo evidence for opiate receptor

6.

7.

8.

9.

10.

sites on T lymphocytes. J lmmunol 1980; 125: 25392543. Levine HB: Ketoconazole in the management of fungal disease. New York, Hong Kong: Adis Press International, 1982. Graybill JR, Hemdon JH, Kniter WT, Levine HB: Ketoconazole treatment of chronic mucocutaneous candidiasis. Arch Dermatol 1980; 116: 1137-1141. Kirkpatrick CH, Rich RR, Bennett JE: Chronic mucocutaneous candidiasis: model-building in cellular immunity: NIH conference. Ann Intern Med 1971; 74: 955-978. Brass C, Galgiani JN, Blaschke TF, Defelice R, O’Reilly RA, Stevens DA: Disposition of ketoconazole, an oral antifungal, in humans. Antimicrob Agents Chemother 1982; 21: 151-158. Graybill JR, Drutz DJ: Ketoconazole: a major innovation for treatment of fungal disease. Ann Intern Med 1980; 93: 921-923.

January 24, 1993 The American Journal of Medicine

47