Successful Outcome of Disseminated Fusarium Infection with Skin Localization Treated with Voriconazole and Amphotericin B-Lipid Complex in a Patient with Acute Leukemia

Article (PDF Available)inJournal of Clinical Microbiology 41(10):4898-900 · November 2003with21 Reads
DOI: 10.1128/JCM.41.10.4898-4900.2003 · Source: PubMed
Abstract
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.

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JOURNAL OF CLINICAL MICROBIOLOGY, Oct. 2003, p. 4898–4900 Vol. 41, No. 10
0095-1137/03/$08.000 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
Isabelle Durand-Joly,
1,2
* Serge Alfandari,
3
Zinne´dine Benchikh,
1
Marion Rodrigue,
1
Ana Espinel-Ingroff,
4
Benoit Catteau,
5
Christophe Cordevant,
2
Daniel Camus,
1,2
Eduardo Dei-Cas,
1,2
Francis Bauters,
6
Laurence Delhaes,
1,2
and Ste´phane De Botton
6
Parasitologie-Mycologie, Faculte´deMe´decine,
1
Service de Dermatologie,
5
and Service des Maladies du Sang,
6
CHRU de Lille, and
EA-3609-IFR17, Institut Pasteur de Lille,
2
Lille, and Maladies Infectieuses, Tourcoing,
3
France, and Medical Mycology Research
Laboratory, Medical College of Virginia, Richmond, Virginia
4
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.
CASE REPORT
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
3
) with 90% blastic forms and 500
polymorphonuclear leukocytes (PMN)/mm
3
.
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 (500 PMN/mm
3
) 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
3
). On day 28, the patient
recovered from neutropenia (1,000 PMN/mm
3
) 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
months.
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
and ABLC.
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@
chru-lille.fr.
4898
a 2-to 3-day incubation at 37°C on 50% Sabourauds glucose
agar medium (supplemented with amikacin). Colonies with
white to purple aerial mycelium grew rapidly. Microscopy
showed short phialides bearing fusiform, septate (35) 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
disease.
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. Briey,
MICs for the isolate were obtained simultaneously by the NC-
CLS M38-A broth microdilution (12) and E-test methods by
following the specic 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
infection (13).
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
prole (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 identication 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 denite
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 identication of the Fusarium genus (11).
Amphotericin B MICs for the strain of F. oxysporum recov-
ered from our patient were 2 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 lamentous 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 efciently 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 signicant 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.
V
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 identication 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).
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4900 CASE REPORTS J. CLIN.MICROBIOL.
    • "infections and high mortality potential. Amphotericin B plus voriconazole has showed favorable results in vitro [14] and in immunocompromised patients [15,16]. Despite reported success with antifungal agents such as AMB and/or voriconazole, there is no established treatment recommendation due to limited case reports and the difficulty of MIC interpretation in the setting of no defined breakpoints. "
    [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND Fusarium spp. infections have become an emerging and lethal threat to the immunocompromised patient population, especially those with neutropenia. Recently there have been increased reports in solid organ transplant recipients. Presentation is commonly as soft tissue infections several months post-transplant. With high morbidity and mortality, efficacious antifungal therapy is essential. This remains challenging with limited data and no established clinical breakpoints defined. CASE REPORT We report on a modified multi-visceral transplant patient that developed a Fusarium infection only 7 weeks post-transplant in the native hard palate and esophagus, without any soft tissue lesions, which persisted despite aggressive combination treatment with amphotericin B lipid complex and voriconazole. CONCLUSIONS Fusarium spp. infection in solid organ transplant is a significant challenge without clear diagnostic clinical indicators of infection, or specific time of onset, in addition to possible emergence of a more aggressive drug-resistant strain.
    Full-text · Article · Sep 2015
    • "To our knowledge, this is the first case reported in the literature of ecthyma gangrenosumlike lesions with simultaneous Pseudomonas sepsis and disseminated fusariosis. In the management of fusariosis, conventional or liposomal Amp B may be used singly; successful results were achieved also by combining it with voriconazole or posaconazole [8,9,10]. In the present case, voriconazole was combined with caspofungin instead of liposomal Amp B and complete response to treatment was achieved, with total resolution of cranial and pulmonary lesions. "
    [Show abstract] [Hide abstract] ABSTRACT: Fusarium spp. is an opportunistic mold that causes disseminated infections in immunocompromised patients. It is important to make a definite diagnosis because of high mortality rates. We present the case of a 27-year-old pregnant woman diagnosed with acute myeloid leukemia with a prolonged febrile neutropenic period. She developed ecthyma gangrenosum-like lesions and simultaneously had Pseudomonas bacteremia and disseminated fusariosis. Histopathological and microbiological features of skin lesions had a critical role in differential diagnosis. Ecthyma gangrenosum-like lesions due to disseminated fusariosis might be easily misdiagnosed as lesions associated with Pseudomonas unless tissue cultures and histopathological examinations are performed. Conflict of interest:None declared.
    Full-text · Article · Sep 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Fungal infections caused by Fusarium in the immunocompromised host are highly resistant to all antifungal agents. Fusarium endocarditis is a rare and usually fatal disease. We report an immunocompromised child who survived Fusarium solani endocarditis despite the in vitro resistance of the organism to all available antifungal agents.
    Article · Dec 2004
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