ARTICLE
Auteur(s) : Izumi
Kikuchi1, Kensuke Morimoto1, Seiji
Kawana1, Hiroyuki Tanuma2
1Department of Dermatology, Nippon Medical School,
1-1-5 Sendagi Bunkyo-ku Tokyo 113-8603, Japan
2Tanuma Dermatology Clinic
accepté le 24 Août 2005
Sporotrichosis is a refractory granulomatous disease which develops
on the face or upper extremities due to sporothrix schenckii, which
exists in soil and trees, invading through a small trauma on the
skin [1].In Japan, about 3,500 cases of cutaneous sporotrichosis
have been reported [2, 3]. According to the classification by
Sampio and Lacaz, cutaneous sporotrichosis is divided into the
following three types: 1) the fixed cutaneous type, which occurs at
the site of a small trauma and expands only around the primary
lesion, 2) the lymphatic vessel type, in which subcutaneous nodules
occur along the lymphatic vessels within several months after onset
of the primary lesion, and 3) the disseminated type, in which the
lesion is diffused via blood flow and extends bilaterally or
remotely.The ratio of the fixed subcutaneous type to the
lymphangial type of sporotrichosis in Japan is nearly 1:1 [2] and
the frequency of the fixed subcutaneous type is slightly higher [4,
5], while in Europe the frequency of the lymphangial type has been
reported to be higher [6-9]. One possible reason for this
difference is the higher protease activity of the strain of
sporothrix schenckii in Europe [10].The first choice for the
pharmacological treatment of sporotrichosis is ITCZ in Europe [11,
12], as compared to potassium iodide (KI) in Japan [13]. However,
KI is not formally covered for this purpose by health insurance.
Thus, oral antifungals such as ITCZ have been increasingly
used.Itraconazole (ITCZ) is a triazole antifungal released on the
market in 1993.This report presents three cases of sporotrichosis
treated with ITCZ and reviews the efficacy of this drug.
Subjects
- • Case 1: 52 year-old male living in Yoshikawa City,
Saitama Prefecture; occupation, farmer.Past History (PA):
Hyperlipidemia, borderline diabetes.Family history (FH): None in
particular.History of Present Illness (HPI): the patient developed
a nodule on his left cheek a year ago. Because the nodule gradually
increased in size, he visited a nearby doctor and was referred to
our hospital.Current Medical Condition: In the first examination,
we found a slightly flat protruding nodule measuring 1 cm in
diameter with scales and crust on the surface of the left cheek at
the nose wing (( figure
1 )). Suspecting sporotrichosis, we performed a
biopsy.Laboratory findings: Sporotrochin reaction, 12 × 9 mm
(the antigen was manufactured by Department of Dermatology,
Kanazawa Medical University).
- • Histopathological findings: A granulomatous
inflammation with many neutrophils and lymphocytes observed was
found mainly around the upper to middle layer of the dermis ((
figure 2 )).
Giant cells were seen but not asteroid bodies (( figure 3 )). PAS staining
indicated positive free spores (( figure 4 )), as did
Methenamine silver – nitrate stain (Gomori) – Grocott’s
variation.Microbiological findings: Results of a one-week Sabouraud
Glucose Agar culture showed characteristic gray to black moist
colonies. Slide culture also indicated fine hyphae and oval to
round conidiophores.
- • Case 2: 56 year-old female living in Chichibu-gun,
Saitama Prefecture; occupation, farmer.PH: None in particular.FH:
None in particular.HPI: She developed a nodule measuring 2 mm
in diameter at the outer lower side of the left eye six months ago.
As it started to grow in size when left untreated, she visited a
nearby doctor, who referred her to our hospital.
- • Current Medical Condition: In the first examination,
we found several inverted nodules at the outer lower area of her
left eye, accompanied by infiltrating erythema in the surrounding
area (( figure 5
)).Laboratory findings: Sporotrichin reaction, 10 ×
8 mm.Culture findings: Colonies similar to Case 1 were
observed with Sabouraud glucose agar.
- • Case 3: 64 year-old female living in Noda City, Chiba
Prefecture; occupation, farmer.PH: None in particular.FH: None in
particular.HPI: Following a slow-to-heal erythrogenic swelling that
developed after a self-inflicted scratch on her left top eyelid,
she developed five nodules on her left cheek (( figure 6 )).Laboratory
findings: Sporotrichin reaction: 14 × 14 mm.Culture findings:
Colonies similar to Cases 1 and 2 were observed.
Diagnosis and treatment
All three cases were diagnosed with sporotrichosis caused by
sporothrix schenckii. They were placed on oral medication of 100 mg
of ITCZ per day. Symptoms improved in six weeks, and all were
healed in 10 to 12 weeks (table 1( Table
1 )).
Table 1 Profiles of 3 cases of sporotrichosis
|
Case
|
Age/sex
|
Associated bacteria
|
Type
|
Affected area
|
Period affected (month)
|
Sporotrichin reaction (mm)
|
Dose (mg/day)
|
Admin. period (week)
|
Improvement in symptom
|
|
1
|
52/M
|
S.schenckii
|
Fixed
|
Face
|
12
|
12 × 9
|
100
|
12
|
Completely cured
|
|
2
|
56/F
|
S.schenckii
|
Fixed
|
Face
|
6
|
10 × 8
|
100
|
12
|
Completely cured
|
|
3
|
64/F
|
S.schenckii
|
Inter-mediate
|
Face
|
4
|
14 × 14
|
100
|
12
|
Completely cured
|
Discussion
Sporotrichosis with small nodules can be treated by thermotherapy,
surgical resection, which is also performed for biopsy, and oral
drugs such ITCZ [2]. The first choice for sporotrichosis, however,
is potassium iodide [14] in Japan (table 2( Table 2 )).
In this study, we compared the therapeutic effects of ITCZ
against sporotrichosis before and after it was released on the
market.
The subjects consisted of 34 pre-release cases [1, 15-24] and 50
post-release cases [25-39]. The illness of many of the pre-release
subjects was fixed type. The mean age of the subjects ranged from
56 to 57 years, and no gender difference was found between the two
groups (table 3( Table 3 )).
Of the subjects using ITCZ for the treatment of sporotrichosis,
those who showed remarkable improvement accounted for 90.9% before
release, and the rate decreased to 74.4% after release (table 4(
Table 4 )).
By type of illness, there was no difference in the remarkable
improvement percentage before and after release for fixed-type
sporotrichosis. There were only a few subjects with lymphatic
vessel type, and statistically significant differences could not be
ascertained. However, the percentage decreased after release (table
5( Table 5 )).
Subjects placed on combination therapy who showed remarkable
improvement were treated by variant medication such as fluconazole
[40], thermotherapy [40-43], or topical terbinafine [44, 45]. One
patient given concomitant potassium iodide [46] also improved
significantly (table 6( Table 6 )).
On the other hand, there were five cases that showed resistance
or no response [47]. They did not improve or had recurrences after
four to twenty-four weeks of oral ITCZ. Of these, three cases
[48-50] had been treated by potassium iodide. One case was cured by
thermotherapy [51] (table 7( Table 7
)).
Furthermore, there were three cases which showed no response to
other treatments but marked improvement with ITCZ (including two
cases [52, 53] whose symptoms did not alleviate with potassium
iodide) [54] (table 8( Table 8 )).
Based on these results, ITCZ is expected to provide essentially
the same therapeutic effects as potassium iodide against
sporotrichosis. Since its release on the market, however, cases
resistant to ITCZ treatment are occasionally reported, more often
in patients with lymphatic vessel-type sporotrichosis. This
indicates the need to give careful consideration to the method of
administration, including compliance of the patients
themselves.
Potassium iodide, used conventionally for treating
sporotrichosis, is difficult to tolerate due to its taste. In
addition, mycotic diseases including sporotrichosis are not
indications of the drug [55]. Antifungal agents such as ITCZ have
such indications and are considered useful as they are easy to take
and produce sufficient therapeutic effects. Nevertheless, because
potassium iodide is highly effective for the treatment of
sporotrichosis and is inexpensive, the indications of the agent
should include sporotrichosis in the future.
Table 2 Effectiveness of itraconazole against
sporotrichosis
|
No. of cases
|
Markedly effective cured
|
Effective
|
Slightly effective
|
Ineffective resistant
|
Unknown cancelled
|
|
Pre-marketing
|
34
|
Fixed
|
19
|
17
|
2
|
0
|
0
|
0
|
|
Lymphatic
|
9
|
9
|
0
|
0
|
0
|
0
|
|
Intermediate
|
0
|
0
|
0
|
0
|
0
|
0
|
|
Disseminated
|
1
|
1
|
0
|
0
|
0
|
0
|
|
Unknown
|
5
|
3
|
0
|
1
|
0
|
1
|
|
Subtotal
|
34
|
30
|
2
|
1
|
0
|
1
|
|
Post-marketing
|
50
|
Fixed
|
23
|
18
|
1
|
0
|
3
|
1
|
|
Lymphatic
|
19
|
10
|
5
|
0
|
2
|
2
|
|
Intermediate
|
2
|
2
|
0
|
0
|
0
|
0
|
|
Disseminated
|
0
|
0
|
0
|
0
|
0
|
0
|
|
Unknown
|
6
|
5
|
0
|
0
|
1
|
0
|
|
Subtotal
|
50
|
35
|
6
|
0
|
6
|
3
|
Table 3 Comparison of cases on itraconazole before and
after marketing
|
Pre-marketing
|
Post-marketing
|
|
No. of cases on itraconazole (ITCZ)
|
34
|
50
|
|
Type
|
17 fixed; 9 lymphatic
|
23 fixed; 19 lymphatic
|
|
Mean age and sex
|
No inter-group difference in age (56-57 years old) and sex
|
|
Period affected
|
Mostly unknown; specifics irretrievable
|
|
Affected area
|
Most found in the arms, followed by the face: no inter-group
difference
|
|
Administration method of ITCZ
|
- Adults: 100 mg for 2-3 months
- Children: 50 mg for 2-3 months
|
- Adults: 100-200 mg for 2-3 months
- Children: 25-50 mg for 2-3 months
- Incl. Pulse therapy (200 mg/1 week)
- Incl. Concurrent therapies with thermotherapy, FLCZ, and
potassium iodide
|
Table 4 Effectiveness of itraconazole against
sporotrichosis
|
Pre-marketing
|
Post-marketing
|
|
Markedly effective/Cured
|
90.9% (30/33)
|
74.4% (35/47)
|
|
Effective
|
6.0% (2/33)
|
12.8% (6/47)
|
|
Slightly effective
|
3.0% (1/33)
|
0% (0/47)
|
|
Ineffective
|
0% (0/33)
|
12.8% (6/47)
|
Table 5 Comparison in effectiveness rates by type of
sporotrichosis. Excluding cases on concurrent therapies and those
of unknown type
|
Pre-marketing
|
Post-marketing
|
|
Fixed
|
89.5% (18/19)
|
94.7% (18/19)
|
|
Lymphatic
|
100% (9/9)
|
66.7% (8/12)
|
Table 6 8 Cases on ITCZ in concurrent with other
therapies
|
Case (age/sex)
|
Reason for concurrent therapy
|
Method of concurrent therapy
|
Final outcome
|
|
72/F
|
Nausea caused by potassium iodide
|
Concurrent use of ITCZ, FLCZ and thermotherapy
|
Cured
|
|
75/F
|
Scars cured with a 2-week oral application of 100-150 mg of ITCZ
along with thermotherapy; recurred after the patient stopped
visiting
|
ITCZ and thermotherapy
|
Rash disappeared
|
|
|
Use of 50 mg of ITCZ oraly and terbinafine externally (2 cases)
|
Completely cured (2 cases)
|
|
68/F
|
Improved at 10 week with100mg of ITCZ and thermotherapy
|
Concurrent use of 1 g of potassium iodide for 8 weeks
|
Completely cured
|
|
|
Concurrent use of thermotherapy only (including1 case whose
affected region has been removed)
|
Cured (3 cases)
|
Table 7 5 Cases where ITCZ was ineffective or
resisted
|
Case (age/sex)
|
Type of sporotrichosis
|
ITCZ
|
Switch to another treatment method
|
|
61/M
|
Lymphatic
|
8 weeks of oral application
|
Switched to potassium iodide
|
|
69/M
|
Unknown
|
Symptoms exacerbated after 4 weeks of internal application at a
dose of 100 mg
|
Recovered with internal use of potassium iodide and
thermotherapy
|
|
73/M
|
Fixed
|
Symptoms improved after 10 weeks of 100-mg oral application;
patient suspended the medication on his own; ulcers redeveloped;
re-administration of 100 mg of ITCZ for 8 weeks, resulted in
exacerbation of the symptoms
|
Scars cured after an 8-week internal application of potassium
iodide
|
|
65/M
|
Fixed
|
Lesion spread after 6 weeks of oral application at a dose of 100
mg
|
Cured after 2 weeks of thermotherapy
|
|
2/F
|
Fixed
|
Lesion grew after 8 weeks of 50-mg oral application; dose increased
to100 mg; scars cured after 16 weeks of internal application;
symptoms reoccurred
|
Cured after 21 weeks of oral application of 0.3 mg potassium
iodide
|
Table 8 3 Cases where switch to ITCZ was made due to
ineffectiveness of other treatments
|
Case (age/sex)
|
Previous treatment
|
ITCZ internal use
|
Results
|
|
59/F
|
No improvement with oral application of potassium iodide
|
8 weeks oral application
|
Scars flattened; subsequently wholly removed
|
|
58/F
|
No improvement with thermotherapy and oral use of potassium
iodide
|
3 months oral application
|
Scars disappeared
|
|
3 months/M
|
Scars spread after 14 weeks of thermotherapy
|
Switched to ITCZ oral application
|
Under observation
|
References
1 Noguchi H, Hiruma M, Kawada A. Case report.
Sporotrichosis successfully treated with itraconazole in Japan.
Mycoses 1999; 42: 571-6.
2 Tanuma H, Asai T, Abe M, et al. Case
report. Lymphatic vessel-type sporotrichosis: immunohistochemical
evaluation and cytokine expression pattern. Mycoses 2001; 41:
316-20.
3 Tanuma H, Wakita K, Tone T. A case of lymphatic
sporotrichosis successfully treated with itraconazole. Jap J
Clinical Dermatol 2001; 55: 92-3; (S).
4 Kusuhara M, Hachisuka H, Sasai Y. Statistical
survey of 150 cases with sporotrichosis. Mycopthologia 1988; 102:
129-33.
5 Kondo C, Kaji H. Statistical survey on 100 cases of
sporotrichosis. The Nishinihon J Dermatol 1982; 44: 983-7.
6 da Rosa ACM, Scroferneker ML, Vettorato R,
et al. Epidemiology of sporotrichosis: A study of 304 cases in
Brazil. J Am Acad Dermatol 2005; 52: 451-9.
7 Barie F, Mastrolonardo M, Loconsole F,
Rantuccio F. Cutaneous sporotrichosis in the period 1978-1992
in the province of Bari, Apula, Southern Italy. Mycoses 1993; 36:
181-5.
8 Morris-Jones R. Sporotrichosis. Clin Exp Dermatol 2002;
27: 427-31.
9 Tsubboi R, Sanada T, Ogawa H, et al.
Isolation and Properties of Extracellular Proteinases from
Sporothrix schenckii. J Bacteriol 1987; 44: 4104-9.
10 Kauffman CA. Sporotrichosis. Clin Infect Dis 1999; 29:
231-7.
11 Kauffman CA. Rana Hajjeh, Stanley W Chapman for the
Mycoses Study Group. Practice guidelines for the management of
patients with sporotrichosis. Clin Infect Dis 2000; 30: 684-7.
12 Lortholary O, et al. Endemic mycosis: A treatment
update. J Antimicrob Chemother 1999; 43: 321-31.
13 Fukushiro R. Fungal infections: Sporotrichosis. In:
Dermatology MOOK. Tokyo: Kanehara and Co., Ltd, 1988: 208-18.
14 Fukushiro R. In: Watanabe S, ed. Dermatology Mook.
No. 11. Tokyo: Kanehara and co., LTD, 1989: 208.
15 Iiyoshi E, Iemoto I, Takahashi Y. Two cases of
successful treatment of sporotrichosis with itraconazole. Clin
Dermmatol 1989; 31: 1347-50.
16 Takase T, Matsushima Y, Baba T, et al.
Sporotrichosis: married couple cases. Clin Dermmatol 1990; 32:
1715-20.
17 Suzuki H, Aihara M, Serikawa K, et al.
Case of sporotrichosis with unique clinical symptoms and statistic
data collected in St. Marianna University School of Medicine for 13
years. The Nishinihon J Dermatol 1990; 52: 36-41.
18 Ebihara T, Sugiura M, Matsuda M, et al.
Successful treatment of sporotrichosis with itraconazole. J
Dermatol Treat 1991; 2: 31-3.
19 Itraconazole Research Group Dermatological Field. Clinical
studies on a novel oral antifungal agent itraconazole against
chronic cutaneous candidiasis and mycosis profunda. Clin Rep 1991;
25: 449-62.
20 Kato T, Sano T, Nishioka K, et al.
Treatment with a novel oral antifungal itraconazole. Clin Rep 1991;
25: 131-7.
21 Takase T, Ueno K. Clinical effects of itraconazole
in the treatment of our 12 cases of sporotrichosis. Clin Rep 1991;
25: 563-70.
22 Hiruma S, Kawada A, Ohata H, et al.
Clinical results of oral itraconazole against cutaneous mycosis.
Clin Rep 1991; 25: 571-7.
23 Nishimoto K. Clinical effects of itraconazole against
mycosis profunda. Clin Rep 1991; 25: 203-6.
24 Kasai T, Okochi R. Sporotrichosis. Pract Dermatol
1994; 14: 337-40.
25 Akamatsu M, Kawakubo H, Ishii Y, et al. A
case of sporotrichosis successfully treated with itraconazol. 36th
Kanagawa Mycosis Workshop. 1994.
26 Yoshimi K, Ekikawa J, Nishimoto K, et al.
Statistical observations of 118 cases of sporotrichosis in Nagasaki
area. The Nishinihon J Dermatol 1994; 56: 518-24.
27 Otani M, Aoyama Y, Yamada T, et al. A
case of sporotrichosis multiplex on the right bucca. Jpn J Dermatol
1994; 104: 1190.
28 Suzuki Y, Yokote R, Wakita H, et al. Six
cases of sporotrichosis. Jpn J Dermatol 1995; 105: 484.
29 Oshitani Y, Iketani T, Matsui S. A case of
sporotrichosis successfully treated with oral itraconazole. Jpn J
Dermatol 1995; 105: 761.
30 Watanabe K, Maruyama T, Nishioka K,
et al. A case of sporotrichosis responding to itraconazole
therapy. Jpn J Dermatol 1995; 105: 867-8.
31 Kudo K, Matsuuchi R, Aoyama H, et al.
Three cases of sporotrichosis: Treatments by our department and
affiliated hospitals. Jpn J Dermatol 1995; 105: 1363.
32 Suzuki T, Sai Y. Sporotrichosis with atypical
clinical findings. Pract Dermatol 1995; 17: 673-6.
33 Iizumi Y, Kitamura K. Treatment of sporotrichosis
with Itrizole. Pract Dermatol 1995; 17: 865.
34 Ujihara M, Hamanaka S. A case of cutaneous
lymphatic vessel-type sporotrichosis successfully treated with oral
itraconazole. Rinsho derma 1995; 37: 686-7.
35 Matsuura K, Matsushima Y, Tanaka K. Two cases
of lymphatic vessel-type sporotrichosis successfully treated with
oral itraconazole. The Nishinihon J Dermatol 1995; 57: 379-81.
36 Akimoto S, Ishikawa O, Miyachi Y. Three cases
of sporotrichosis treated with itraconazole. Acta dermatologica
1995; 90: 505-7.
37 Takahashi K, Takahashi I, Nakajima H,
et al. A case of sporotrichosis. Jpn J Dermatol 1996; 106:
353.
38 Oba M, Sakurai M, Matsumoto K, et al.
Effect of H2 blockers on itraconazole therapy for sporotrichosis: A
case report. Clin Dermmatol 1999; 53: 985-7.
39 Kinoshita J, Morimoto K, Kawana S, et al.
A case of middle-type sporotrichosis faciale. Intermediate type
sporotrichosis on the face. Rinsho derma 2002; 44: 1117-9.
40 Matsuura H, Makino E, Awata J, et al.
Sporotrichosis with plenty of fungus element observed in tissue.
Jpn J Dermatol 1995; 105: 749.
41 Isobe T, Yamashiro M, Koga M, et al. A
case of sporotrichosis. Jpn J Dermatol 1995; 105: 1025.
42 Misaki H, Tani M, Imaizumi K, et al. A
case of sporotrichosis. Hifu 1994; 36: 588.
43 Nitta Y, Matsuura M. Treatment-resistant,
relapsing, lymphatic vessel-type sporotrichosis. Pract Dermatol
1995; 17: 865-8.
44 Saito K, Hotei Y, Kihana I, et al. A case
of cutaneous fixed-type sporotrichosis. Clin Dermmatol 1998; 52:
57-9.
45 Ogiwara Y, Ogiwara S, Oyama T, et al. Two
cases of sporotrichosis. Rinsho derma 1999; 41: 2077-80.
46 Okinaka R, Banno S, Nitta Y. A case of
lymphatic vessel-type sporotrichosis in the bilateral upper
extrimities. Clin Dermmatol 2000; 54: 1094-6.
47 Lee S, Ota K, Matsuda T, et al. In:
Treatment of sporotrichosis with oral azoles. 9th Korea-Japan Joint
Meeting of Dermatology. Korea: Pusan, 1995: 108.
48 Teramoto T, Teramoto M, Matsuda K, et al.
A case of sporotrichosis against which itraconazole therapy was
ineffective. Jpn J Med Mycol 2000; 41: 96.
49 Shimizu T, Muto M, Asagami C, et al. A
case of sporotrichosis resistant to oral itraconazole. The
Nishinihon J Dermatol 1997; 59: 720-2.
50 Matsumoto H, Sugiura T, Hata Y, et al. A
case of infant sporotrichosis relapsing after almost healing with
oral itraconazole. Jpn J Med Mycol 2000; 41: 83-7.
51 Kusunoki T, Kusunoki M, Iizumi Y. A case of
sporotrichosis resistant to oral itraconazole. Jpn J Dermatol 1998;
108: 1087.
52 Nakayama K, Yanagikawa S, Hata Y, et al.
A case of sporotrichosis treated as black fungal infections in the
first examination. Jpn J Dermatol 1995; 106: 155.
53 Miyazaki T, Utsui K. A case of sporotrichosis
against which oral itraconazole was markedly effective. Jpn J
Dermatol 1996; 105: 344.
54 Sakashita S, Takino C, Ootaki M, et al. A
case of infant sporotrichosis. Clin Dermmatol 1999; 51: 714-6.
55 Japan Pharmaceutical Information Center. In: Drugs in Japan.
Ethical drugs. Tokyo: Jiho. Inc, 2001: 2064-5.
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