Successful Outcome of Disseminated Fusarium Infection with Skin Localization Treated with Voriconazole and Amphotericin B-Lipid Complex in a Patient with Acute Leukemia
A disseminated Fusarium oxysporum infection with skin localization was diagnosed in a woman with a relapse of B-acute leukemia during induction chemotherapy. The infection was refractory to amphotericin B-lipid complex alone but responded successfully when voriconazole was added.
JOURNAL OF CLINICAL MICROBIOLOGY, Oct. 2003, p. 4898–4900 Vol. 41, No. 10
0095-1137/03/$08.00⫹0 DOI: 10.1128/JCM.41.10.4898–4900.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.
Successful Outcome of Disseminated Fusarium Infection with Skin
Localization Treated with Voriconazole and Amphotericin B-Lipid
Complex in a Patient with Acute Leukemia
* Serge Alfandari,
and Ste´phane De Botton
Service de Dermatologie,
and Service des Maladies du Sang,
CHRU de Lille, and
EA-3609-IFR17, Institut Pasteur de Lille,
Lille, and Maladies Infectieuses, Tourcoing,
France, and Medical Mycology Research
Laboratory, Medical College of Virginia, Richmond, Virginia
Received 17 March 2003/Returned for modiﬁcation 16 June 2003/Accepted 3 July 2003
A disseminated Fusarium oxysporum infection with skin localization was diagnosed in a woman with a relapse
of B-acute leukemia during induction chemotherapy. The infection was refractory to amphotericin B-lipid
complex alone but responded successfully when voriconazole was added.
A 32-year-old female with relapsing acute lymphoblastic leu-
kemia was hospitalized for induction chemotherapy on 14 June
2001. At the time of hospitalization, the patient did not show
clinical alteration. Blood examination showed hyperleukocyto-
sis (27,180 leukocytes/mm
) with 90% blastic forms and 500
polymorphonuclear leukocytes (PMN)/mm
She received broad-spectrum antibiotherapy (amino-penicil-
lin, amikacin, and ﬂuoroquinolone) and granulocyte-colony
stimulating factor (Neupogen 30; Roche). On July 1 (day 0),
she was aplastic. The patient left the hospital against medical
advice on day 3, but she returned on day 6 with fever and
neutropenia (ⱕ500 PMN/mm
) that lasted for 16 days. Clinical
and radiographic examination showed no abnormalities. How-
ever, as the patient presented again with fever, antibiotherapy
was changed empirically to a combination of piperacillin-ta-
zobactam (later changed to cefepime) and vancomycin and the
central venous catheter was removed and cultured. Both the
catheter and blood cultures remained negative. Four days after
the onset of fever (day 10), vesicular and necrotic lesions ap-
peared on both calves. The next day (day 11), the skin lesions
were extended to all the surfaces of the legs (Fig. 1). The
diagnosis of opportunistic mycosis was considered, and skin
biopsy and blood cultures were performed. Consistently, the
histopathological analysis of the skin biopsy showed fungal
hyphae deeply localized in the skin tissue. Amphotericin B-
lipid complex (ABLC) (5 mg/kg of body weight/day) was added
on day 12 and controlled until the patient was released on day
30. Biopsy and blood sample cultures yielded Fusarium oxy-
sporum, conﬁrming a systemic fungal infection with skin inva-
sion. Evidence of infection was not observed by either cere-
bral-, thoracic-, and abdominal-computed tomography or by
cardiac echography. Despite therapy, fever persisted and the
skin lesions extended to the whole body, conﬁrming the dis-
seminated character of the infection (Fig. 1). In this context,
voriconazole (VCZ; Pﬁzer, Inc., New York, N.Y.) (loading
dose, 6 mg/kg/day, followed by 4 mg/kg/day administered in-
travenously every 12 h) was added at day 18, 8 days after onset
of the rash. Further blood cultures were negative. After 9 days
of VCZ-ABLC treatment, the skin lesions improved remark-
ably and the fever disappeared, while the patient still had a
severe neutropenia (⬍100 PMN/mm
). On day 28, the patient
recovered from neutropenia (⬎1,000 PMN/mm
) and, 2 days
later, refused to remain hospitalized and was released with a
continued prescription of VCZ (400 mg per day taken orally).
Antibiotherapy and ABLC (cumulative dose, 3.6 g) were
stopped. Fusariosis did not relapse during a follow-up of nine
Fungi belonging to the genus Fusarium are ubiquitously
present in soil, air, and water and are parasites of numerous
plants. In humans, these microorganisms usually cause super-
ﬁcial or subcutaneous infections such as keratitis or onycho-
mycosis, but they may cause severe disseminated infections in
immunocompromised patients (1, 8, 13). Invasive or dissemi-
nated fusariosis is a rare but severe complication in hemato-
logical diseases (7, 9, 13, 14). To date, limited success with
diverse antifungal drugs has been obtained in patients with
persistent immune deﬁciency (13). In the present report, we
describe the case of a patient with leukemia who developed
disseminated fusariosis that was successfully treated with VCZ
Laboratory diagnosis of mycological infection. F. oxysporum
was recovered from 1 of 7 blood culture vials (Mycosis IC/F,
Bactec 9050 system; Becton Dickinson). The sole positive
blood culture was sampled on day 13. The time to detectable
growth was 2 days. F. oxysporum developed in subcultures from
both blood culture and skin biopsy (sampled on day 14) after
* Corresponding author. Mailing address: Parasitologie-Mycologie,
Faculte´deMe´decine et CHRU de Lille, 1 Place Verdun, 59045 Lille,
France. Phone: 33 3 20 44 55 77. Fax: 33 3 20 44 42 64. E-mail: i-joly@
a 2-to 3-day incubation at 37°C on 50% Sabouraud’s glucose
agar medium (supplemented with amikacin). Colonies with
white to purple aerial mycelium grew rapidly. Microscopy
showed short phialides bearing fusiform, septate (3–5) macro-
conidia and the presence of terminal or intercalary chlamydo-
spores. Rare one-celled microconidia on predominantly lateral
phialides were also observed. Cultures from peripheral sam-
ples (mouth, nose, and throat) and other clinical samples were
negative for bacteria, viruses, Fusarium, and other fungi. En-
zyme-linked immunosorbent assays for detecting either As-
pergillus galactomannan or Candida mannan (Platelia; Bio-
Rad, Paris, France) were also negative for several serum
samples. In our hospital, these tests are routinely used in this
kind of patient as part of a protocol to prevent systemic fungal
Antifungal susceptibility testing (for amphotericin B, itra-
conazole, and VCZ) of the Fusarium oxysporum strain was
performed both in France and in the United States. Brieﬂy,
MICs for the isolate were obtained simultaneously by the NC-
CLS M38-A broth microdilution (12) and E-test methods by
following the speciﬁc recommendations for each test.
Invasive or disseminated fungal infections are a frequent
complication in immunocompromised patients. The most com-
monly encountered genera are Candida and Aspergillus. How-
ever, other molds, like Fusarium spp., are emerging as serious
opportunistic pathogens. Fusarium infections are associated
with high mortality, ranging from 52 to 70% in patients with
blood disorders (3, 13) despite treatment with amphotericin B.
Patients in remission are generally observed to survive the
On the practical side, when fever in neutropenic patients
continues despite broad-spectrum antimicrobials, an antifun-
gal drug is usually added. The most commonly used drug is
amphotericin B, in either conventional or lipid-based formu-
lations. However, this compound has variable activity against
Fusarium spp. The response to amphotericin B treatment
seems to be closely related to neutrophil recovery (3, 11) or to
the concomitant administration of granulocyte colony-stimu-
lating factor (3, 7, 13).
VCZ is a new broad-spectrum triazole that has a good safety
proﬁle (5, 10). To our knowledge, only one case of fusariosis
treated with VCZ has been reported previously (16), in a
patient with invasive ocular infection who received the drug
intravenously and intracamerally. The outcome was favorable,
but the patient was not immunocompromised. In contrast, our
patient had persistent severe neutropenia for more than 44
days. Interestingly, even in this context, the addition of VCZ
ABLC therapy resulted in healing of the skin lesions within 3
weeks, marked clinical improvement, and negative blood cul-
tures. The present report underscores the importance of early
detection and identiﬁcation of the infecting organism in the
clinical specimen. Fusarial hyphae were detected during the
microscopical examination of the skin samples, but they can be
confused with Aspergillus hyphae. Therefore, even if hyphae
are detected microscopically in a clinical sample, a deﬁnite
laboratory diagnosis can be established only by culture. How-
ever, the presence of the diagnostic phialides and phialo-
conidia in the direct examination of blood cultures allowed a
presumptive identiﬁcation of the Fusarium genus (11).
Amphotericin B MICs for the strain of F. oxysporum recov-
ered from our patient were ⱕ2 g/ml by two methods (E-test
at 24 h and NCCLS broth microdilution). VCZ MICs for F.
oxysporum have ranged from 0.25 to 8 g of VCZ/ml (2, 6) with
the NCCLS 38-A method for ﬁlamentous fungi. In the present
report, our F. oxysporum isolate had different susceptibilities to
the two triazoles, while the VCZ MIC was 1 g/ml and the
itraconazole MIC was ⬎8 g/ml by both methods. Although in
vitro testing for susceptibility to azoles has not always corre-
lated with the in vivo response (4), the combination of VCZ
with ABLC resulted in a successful outcome in the present
case. Remarkably, no relapse of the fungal disease was ob-
served in this patient for the more-than-9-month follow-up,
even when she was submitted to new cytotoxic therapeutic
protocols. This result suggested that the Fusarium infection
was efﬁciently neutralized by the VCZ-ABLC combination.
In conclusion, although the risk for systemic fusariosis seems
lower than that for invasive aspergillosis, the frequency of the
former is highly signiﬁcant in patients suffering from hemato-
FIG. 1. Disseminated fusariosis infection. The patient presented multiple skin varicelliform lesions on the face (left) and on the leg (right). A
close-up view of a necrotic lesion (inset) shows more detail.
OL. 41, 2003 CASE REPORTS 4899
logical malignancies. In this context, fusariosis usually evolves
as a severe deep fungal disease, which is associated with a high
mortality rate. The description of the present case underlines
both the importance of early detection and identiﬁcation of the
infecting fungal agent and the potential role of VCZ in the
management of systemic fusariosis in the immunocompro-
mised host, as reported recently (15).
1. Anaissie, E., H. Kantarjian, P. Jones, B. Barlogie, M. Luna, G. Lopez-
Berestein, and G. P. Bodey. 1986. Fusarium. A newly recognized fungal
pathogen in immunosuppressed patients. Cancer 57:2141–2145.
2. Arikan, S., M. Lozano-Chiu, V. Paetznick, S. Nangia, and J. H. Rex. 1999.
Microdilution susceptibility testing of amphotericin B, itraconazole, and
voriconazole against clinical isolates of Aspergillus and Fusarium species.
J. Clin. Microbiol. 37:3946–39451.
3. Boutati, E. I., and E. J. Anaissie. 1997. Fusarium, a signiﬁcant emerging
pathogen in patients with hematologic malignancy: ten years’ experience at
a cancer center and implications for management. Blood 90:999–1008.
4. Dei-Cas, E., L. Dujardin, M. E. Ribeiro Pinto, F. Ajana, J. Fruit, D. Poulain,
D. Camus, and A. Vernes. 1991. Kinetic study of antifungal activity of am-
photericin B, 5-ﬂuorocytosine and ketoconazole against clinical yeast isolates
using liquid-phase turbidimetry. Mycoses 34:167–172.
5. Denning, D. W., P. Ribaud, N. Milpied, D. Caillot, R. Herbrecht, E. Thiel, A.
Haas, M. Ruhnke, and H. Lode. 2002. Efﬁcacy and safety of voriconazole in
the treatment of acute invasive aspergillosis. Clin. Infect. Dis. 34:563–571.
6. Espinel-Ingroff, A., K. Boyle, and D. J. Sheehan. 2001. In vitro antifungal
activities of voriconazole and reference agents as determined by NCCLS
methods: review of the literature. Mycopathologia 150:101–115.
7. Girmenia, C., A. P. Iori, F. Boecklin, A. Torosantucci, P. Chiani, P. De
Fabritiis, F. Taglietti, A. Cassone, and P. Martino. 1999. Fusarium infections
in patients with severe aplastic anemia: review and implications for manage-
ment. Haematologica 84:114–118.
8. Guarro, J., and J. Gene. 1995. Opportunistic fusarial infections in humans.
Eur. J. Clin. Microbiol. Infect. Dis. 14:741–754.
9. Hennequin, C., V. Lavarde, J. L. Poirot, M. Rabodonirina, A. Datry, S.
Aractingi, J. Dupouy-Camet, D. Caillot, F. Grange, L. Kures, O. Morin, B.
Lebeau, S. Bretagne, C. Guigen, D. Basset, and R. Grillot. 1997. Invasive
Fusarium infections: a retrospective survey of 31 cases. The French ‘Groupe
d’Etudes des Mycoses Opportunistes’ GEMO. J. Med. Vet. Mycol. 35:107–
10. Hoffman, H. L., and R. C. Rathbun. 2002. Review of the safety and efﬁcacy
of voriconazole. Expert Opin. Investig. Drugs 11:409–429.
11. Letscher-Bru, V., F. Campos, J. Waller, R. Randriamahazaka, E. Candolﬁ,
and R. Herbrecht. 2002. Successful outcome of treatment of a disseminated
infection due to Fusarium dimerum in a leukemia patient. J. Clin. Microbiol.
12. NCCLS. 2002. Reference method for broth dilution antifungal susceptibility
testing of ﬁlamentous fungi, vol. 22. Approved standard M-38A. NCCLS,
13. Okada, H., S. Hamatani, M. Kondo, T. Imai, S. Itoh, K. Isobe, and S. Onishi.
2000. Successful treatment of disseminated Fusarium infection in an infant
with leukemia. Int. J. Hematol. 72:494–498.
14. Pagano, L., C. Girmenia, L. Mele, P. Ricci, M. E. Tosti, A. Nosari, M. Buelli,
M. Picardi, B. Allione, L. Corvatta, D. D’Antonio, M. Montillo, L. Melillo, A.
Chierichini, A. Cenacchi, A. Tonso, L. Cudillo, A. Candoni, C. Savignano, A.
Bonini, P. Martino, and A. Del Favero. 2001. Infections caused by ﬁlamen-
tous fungi in patients with hematologic malignancies. A report of 391 cases
by GIMEMA Infection Program. Haematologica 86:862–870.
15. Perfect, J. R., K. A. Marr, T. J. Walsh, R. N. Greenberg, B. DuPont, J. de la
Torre-Cisneros, G. Just-Nubling, H. T. Schlamm, I. Lutsar, A. Espinel-
Ingroff, and E. Johnson. 2003. Voriconazole treatment for less-common,
emerging, or refractory fungal infections. Clin. Infect. Dis. 36:1122–1131.
16. Reis, A., R. Sundmacher, K. Tintelnot, H. Agostini, H. E. Jensen, and C.
Althaus. 2000. Successful treatment of ocular invasive mould infection (fusa-
riosis) with the new antifungal agent voriconazole. Br. J. Ophthalmol. 84:
4900 CASE REPORTS J. CLIN.MICROBIOL.