Abstract Background <it>Fusarium </it>spp. is being isolated with increasing frequency as a pathogen in oncohematologic patients. Caspofungin and amphotericin B have been reported to have synergistic activity against <it>Fusarium </it>spp. Case presentation We herein report a case of disseminated fusariosis diagnosed by chest CT scan and positive blood cultures to <it>Fusarium </it>spp. Because the patient's clinical condition deteriorated, CRP levels increased, and blood cultures continued to yield <it>Fusarium </it>spp. despite liposomal amphotericin B monotherapy up to 5 mg/kg daily, treatment with caspofungin was added. Within 2 weeks of onset of combined antifungal therapy, the chest CT scan demonstrated a progressive resolution of the pulmonary lesions. Upon discontinuation of intravenous antifungals, the patient received suppressive therapy with oral voriconazole. Three months later, a chest CT scan showed no abnormalities. Twenty-five months after discontinuation of all antifungal therapy, the patient remains in complete remission of her neoplastic disease with no signs of clinical activity of the <it>Fusarium </it>infection. Conclusion This is the first description of successful treatment of disseminated fusariosis in a pediatric patient with acute lymphoblastic leukemia with caspofungin and amphotericin B followed by oral suppressive therapy with voriconazole.</p

A Fatoye

CA Rodriguez

Cesar Sanz-Rodriguez

EI Boutati

EJ Anaissie

Francisco Garcia de la Llana

II Raad

J Apostolidis

JA Guzman-Cottrill

José-Manuel Vagace

LR Baden

Luis Zarallo

M Cuenca-Estrella

M Ortoneda

Manuel Garcia-Dominguez

Maria-Soledad Casado

Miguel Fajardo

MJ Makowsky

Nieves Alonso

Roberto Bajo

S Arikan

The European Agency for the Evaluation of Medicinal Products

English

PubMed

Springer - Publisher Connector

BioMed CentralBMC Infectious Diseases
ssOpen AcceCase report
Resolution of disseminated fusariosis in a child with acute leukemia 
treated with combined antifungal therapy: a case report
José-Manuel Vagace*1, Cesar Sanz-Rodriguez2, Maria-Soledad Casado1, 
Nieves Alonso1, Manuel Garcia-Dominguez1, Francisco Garcia de la Llana3, 
Luis Zarallo4, Miguel Fajardo5 and Roberto Bajo1
Address: 1Department of Hematology, Complejo Hospitalario Infanta Cristina, Badajoz, Spain, 2Department of Clinical Research, Merck Sharp & 
Dohme of Spain, Madrid, Spain, 3Department of Internal Medicine, Complejo Hospitalario Infanta Cristina, Badajoz, Spain, 4Department of 
Pediatrics, Complejo Hospitalario Infanta Cristina, Badajoz, Spain and 5Department of Microbiology, Complejo Hospitalario Infanta Cristina, 
Badajoz, Spain
Email: José-Manuel Vagace* - jvagacev@aehh.org; Cesar Sanz-Rodriguez - cesar_sanzrodriguez@merck.com; Maria-
Soledad Casado - marisol.casado@ses.juntaex.es; Nieves Alonso - malonsoe@aehh.org; Manuel Garcia-Dominguez - garciadoz@yahoo.es; 
Francisco Garcia de la Llana - francisco.garcial@ses.juntaex.es; Luis Zarallo - luis.zarallo@ses.juntaex.es; 
Miguel Fajardo - miguel.fajardo@ses.juntaex.es; Roberto Bajo - roberto.bajo@ses.juntaex.es
* Corresponding author    
Abstract
Background: Fusarium spp. is being isolated with increasing frequency as a pathogen in
oncohematologic patients. Caspofungin and amphotericin B have been reported to have synergistic
activity against Fusarium spp.
Case presentation: We herein report a case of disseminated fusariosis diagnosed by chest CT
scan and positive blood cultures to Fusarium spp. Because the patient's clinical condition
deteriorated, CRP levels increased, and blood cultures continued to yield Fusarium spp. despite
liposomal amphotericin B monotherapy up to 5 mg/kg daily, treatment with caspofungin was added.
Within 2 weeks of onset of combined antifungal therapy, the chest CT scan demonstrated a
progressive resolution of the pulmonary lesions. Upon discontinuation of intravenous antifungals,
the patient received suppressive therapy with oral voriconazole. Three months later, a chest CT
scan showed no abnormalities. Twenty-five months after discontinuation of all antifungal therapy,
the patient remains in complete remission of her neoplastic disease with no signs of clinical activity
of the Fusarium infection.
Conclusion: This is the first description of successful treatment of disseminated fusariosis in a
pediatric patient with acute lymphoblastic leukemia with caspofungin and amphotericin B followed
by oral suppressive therapy with voriconazole.
Background
Fusarium spp. is a saprophytic mould that is ubiquitous in
the soil. Invasive fusariosis may follow the inhalation of
airborne conidia or the inoculation of conidia through a
skin breach associated with indwelling catheters, wounds,
burns, or onychomycosis. Deep-seated and disseminated
infections caused by Fusarium spp. are being diagnosed
with increasing frequency in patients with hematological
Published: 10 May 2007
BMC Infectious Diseases 2007, 7:40 doi:10.1186/1471-2334-7-40
Received: 19 August 2006
Accepted: 10 May 2007
This article is available from: http://www.biomedcentral.com/1471-2334/7/40
© 2007 Vagace et al; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 4
(page number not for citation purposes)
BMC Infectious Diseases 2007, 7:40 http://www.biomedcentral.com/1471-2334/7/40malignancies [1]. The Fusarium species most frequently
involved in human infections are Fusarium solani, F.
oxysporum, F. verticilloides, and F. moniliforme [1]. Of note,
Fusarium species are often confused with Aspergillus spp. as
both pathogens have similar histopathologic appearance
with septate, dichotomously branching hyphae. Yet, the
prognosis of invasive fusariosis is much poorer than for
invasive aspergillosis, with very low response rates and
most patients with disseminated Fusarium infection dying
[1]. We describe here the first case of a favorable response
of disseminated fusariosis to combination caspofungin
and liposomal amphotericin B followed by oral suppres-
sive therapy with voriconazole in a pediatric patient with
acute lymphoblastic leukaemia (ALL).
Case presentation
A 11-year-old, 50-kg female with a diagnosis of CD10+
ALL was admitted to the hospital with fever and intermit-
tent chest pain. The patient was in complete remission
(CR) following SHOP-99 chemotherapy. At the time of
hospital admission, she was receiving G-CSF for severe
granulocytopenia post-intensification with cytarabine,
and had also received broad-spectrum antibiotics and flu-
conazole prophylaxis during previous episodes of febrile
neutropenia.
The physical examination was normal and the patient's
general condition good. The blood examination showed
12,500 leukocytes/mm3 (82% neutrophils). An urine
examination, a chest X-ray, and an abdominal ultrasonog-
raphy did not reveal abnormal findings. Blood, urine, and
stool cultures were also negative. She was initially treated
with cefepime and teicoplanin. G-CSF was discontinued,
after which the neutrophil count stabilized at around
1,700/mm3. CRP increased steadily up to 5.6 mg/dL
despite broad-spectrum antibiotic therapy. One week
later, while continuously febrile, the patient experienced
worsening chest pain. A chest CT scan revealed several
nodules 1 cm or smaller in diameter at the apex of both
lungs (Figure 1). The Aspergillus galactomannan antigen
was negative. Cultures of separate blood samples
obtained percutaneously and from the central venous
catheter, yielded Fusarium spp. The species of the infecting
Fusarium could not be identified and in vitro susceptibility
could not be tested. Liposomal amphotericin B (3 mg/kg/
day) was then started. Although the dose of liposomal
amphotericin B was increased to 5 mg/kg daily and the
central venous catheter was removed (cultures of the cath-
eter tip were sterile), the patient remained febrile and
chest pain continued to worsen over the following 7 days.
Blood cultures remained positive for Fusarium spp. and
CRP levels increased up to 10.6 mg/dL (Figure 1). Caspo-
fungin was then initiated (70-mg load followed by 50 mg
daily). Fever disappeared within 48 hours of caspofungin
onset (Figure 1). Chest pain improved significantly, blood
cultures became negative, and CRP levels went down to
the 1–2 mg/dL range over the following days. The patient
presented two isolated fever spikes 8 and 12 days after the
onset of caspofungin, which corresponded to a phlebitis
episode and a limited reaction to L-asparaginase, respec-
tively. Two weeks later, a new chest CT scan demonstrated
progressive resolution of the lung nodules (Figure 1).
Intravenous antifungals were discontinued and chemo-
therapy and suppressive therapy with oral voriconazole
200 mg twice daily was started. Three months later, a chest
CT scan showed complete resolution of the pulmonary
lesions, while the patient was asymptomatic (Figure 1).
Thus, voriconazole was discontinued. Twenty-five
months after discontinuation of all antifungal therapy,
the patient remains healthy in the absence of any symp-
toms of fungal infection and in CR of her neoplastic dis-
ease.
Fusarium resistance to most antifungals and the severe
immunosuppression-notably long-lasting, severe neutro-
penia – in oncohematological patients make Fusarium
infections commonly fatal [1]. Despite its low activity
against Fusarium [2], amphotericin B remains the drug of
choice. Voriconazole is licensed for the treatment of fusa-
riosis based on in vitro data and a series of case reports
with a reported response rate of ~40% [3]. Posaconazole
also has potential for therapy of systemic fusariosis [4]. In
any case, responses obtained with monotherapies remain
too low and unsatisfactory.
We decided to treat our patient with amphotericin B and
caspofungin for two reasons: (i) In our view amphotericin
B remains the mainstay of therapy for fusariosis in pediat-
ric patients; experience with voriconazole in this patient
segment is limited [5-7]; (ii) Concurrent antifungal ther-
apy is now generally considered an alternative way of
improving outcome in difficult-to-treat invasive mycoses.
In a recent in vitro study amphotericin B and voriconazole
rendered mainly additive or subadditive interactions
against Fusarium spp. [8]. Yet, the concern remains that
combining amphotericin B and azoles may lead to antag-
onism. In addition to the azole inhibition of the synthesis
of amphotericin B's pharmacological target ergosterol,
amphotericin B-related damage to the fungal cell mem-
brane may interfere with the influx of azoles [9]. In vitro
caspofungin-inactive against Fusarium-showed synergistic
or synergistic-to-additive interactions with amphotericin
B for at least half of the Fusarium isolates [10]. By inhibit-
ing cell wall synthesis, caspofungin may presumably
enhance the penetration of amphotericin B [9].
We hypothesize that combination antifungal therapy
likely contributed to the sucessful treatment of our
patient's severe invasive fusariosis, since clinical improve-
ment only became evident after initiating caspofungin.Page 2 of 4
(page number not for citation purposes)
BMC Infectious Diseases 2007, 7:40 http://www.biomedcentral.com/1471-2334/7/40
Page 3 of 4
(page number not for citation purposes)
Clinical, bio logical, and radiographic evolution and drug therapyFigure 1
Clinical, bio logical, and radiographic evolution and drug therapy.
0
3
6
9
12
15
36
37
38
39
40
41
0
3000
6000
9000
12000
15000
0 5 10 15 20 25 30 35 40 45 50 55 60
C Reactive Protein
Temperature
Neutrophil Count
Day Post-Admission
[º
C
]
[m
g/
dL
]
[c
el
ls
/m
m
3 ]
Onset of
chest pain
Worsening
chest pain
Fusarium
isolated in 
blood culture
Negative blood
cultures
Phlebitis
Reaction to
L-asparaginase
Clinical
improvement
Cefepime
Teicoplanin
Liposomal Amphotericin B
Caspofungin
Voriconazole PO
//
12
BMC Infectious Diseases 2007, 7:40 http://www.biomedcentral.com/1471-2334/7/40Yet, the effect of caspofungin in the successful outcome of
our case is not completely clear. The clinical response
observed could also be the result of prolonged adminis-
tration of liposomal amphotericin B and the lack of severe
neutropenia. Finally, the administration of suppressive
voriconazole and the early re-initiation of chemotherapy
allowed by rapid infection control probably also contrib-
uted to the good long-term outcome. Of note, there have
been a few case reports of response to caspofungin in
combination with amphotericin B [11,12] and as mono-
therapy [13], although in some of these reports there was
a clear association of response to recovery from neutrope-
nia.
Conclusion
We herein report an episode of disseminated fusariosis in
a pediatric ALL patient treated successfully with caspofun-
gin and amphotericin B followed by suppressive therapy
with voriconazole. While our anecdotal observation is
encouraging, the use of combination antifungal therapy is
debatable and further in vivo studies are warranted to
establish its true role in deep-seated and disseminated
Fusarium infections.
Abbreviations
CD10+: Cluster differentiation 10-positive
CT: Computed tomography.
SHOP-99: The standard protocol of the Spanish Society of
Pediatric Hematology and Oncology for high risk acute
lymphoblastic leukemia, which includes induction (pred-
nisone, daunomycin, vincristine, cyclophosphamide,
metothrexate, L-asparaginase), consolidation (metothrex-
ate, cytarabine, mercaptopurine), and intensification
(adriamycin, vincristine, dexamethasone, cyclophospha-
mide, metothrexate, cytarabine, L-asparaginase) chemo-
therapy.
G-CSF: Granulocyte-colony stimulating factor.
CRP: C reactive protein.
Competing interests
C. Sanz-Rodriguez is an employee of Merck Sharp &
Dohme de España, S.A.. The remaining authors declare
that they have no competing interests.
Authors' contributions
J-M. Vagace, M-S. Casado, N. Alonso, M. Garcia-
Dominguez, F. Garcia de la Llana, L. Zarallo, M. Fajardo,
and R. Bajo participated actively in the diagnosis, care,
and follow-up of the patient.
J-M. Vagace obtained consent from the patient's parents
for this case report, reviewed the literature, provided clin-
ical details, and drafted the manuscript.
C. Sanz-Rodriguez reviewed the literature and gave help-
ful comments regarding the scientific content of the man-
uscript.
All authors read and approved the final manuscript.
Acknowledgements
Written consent was obtained from the patient's parents for publication of 
study. There was no financial support for the preparation of this manu-
script.
References
1. Boutati EI, Anaissie EJ: Fusarium, a significant emerging patho-
gen in patients with hematologic malignancy: ten years' expe-
rience at a cancer center and implications for management.
Blood 1997, 90:999-1008.
2. Anaissie EJ, Hachem R, Legrand C, Legenne P, Nelson P, Bodey GP:
Lack of activity of amphotericin B in systemic murine fusarial
infection.  J Infect Dis 1992, 165:1155-1157.
3. The European Agency for the Evaluation of Medicinal Products: Vfend
(voriconazole), Scientific Discussion, European Public Assessment Report. Lon-
don 2005 [http://www.emea.eu.int/humandocs/Humans/EPAR/vfend/
vfend.htm]. Accessed October 4, 2005
4. Raad II, Hachem RY, Herbrecht R, Graybill JR, Hare R, Corcoran R,
Kontoyiannis DP: Posaconazole as salvage treatment for inva-
sive fusariosis in patients with underlying hematologic malig-
nancy and other conditions.  Clin Infect Dis 2006, 42:1398-403.
5. Baden LR, Katz JT, Fishman JA, Koziol C, Del Vecchio A, Doran M,
Rubin RH: Salvage therapy with voriconazole for invasive fun-
gal infections in patients failing or intolerant to standard anti-
fungal therapy.  Transplantation 2003, 76:1632-1637.
6. Guzman-Cottrill JA, Zheng X, Chadwick EG: Fusarium solani endo-
carditis successfully treated with liposomal amphotericin B
and voriconazole.  Pediatr Infect Dis J 2004, 23:1059-1061.
7. Rodriguez CA, Lujan-Zilbermann J, Woodard P, Andreansky M, Adder-
son EE: Successful treatment of disseminated fusariosis.  Bone
Marrow Transplant 2003, 31:411-412.
8. Ortoneda M, Capilla J, Javier Pastor F, Pujol I, Guarro J: In vitro inter-
actions of licensed and novel antifungal drugs against Fusar-
ium spp.  Diagn Microbiol Infect Dis 2004, 48:69-71.
9. Cuenca-Estrella M: Combinations of antifungal agents in therapy
– what value are they?  J Antimicrob Chemother 2004, 54:854-869.
10. Arikan S, Lozano-Chiu M, Paetznick V, Rex JH: In vitro synergy of
caspofungin and amphotericin B against Aspergillus and
Fusarium spp.  Antimicrob Agents Chemother 2002, 46:245-247.
11. Makowsky MJ, Warkentin DI, Savoie ML: Caspofungin and ampho-
tericin B for disseminated Fusarium verticillioides in leuke-
mia.  Ann Pharmacother 2005, 39:1365-1366.
12. Fatoye A, Bow EJ, Loewen R: Amphotericin B lipid complex and
caspofungin as combination therapy for disseminated fusario-
sis in a patient with acute myeloid leukemia [abstract].  In Pro-
ceedings of the 13th Congress of the International Society for Human and
Animal Mycology: 25–29 May 2003; San Antonio, TX the International
Society for Human and Animal Mycology; 2003:392. 
13. Apostolidis J, Bouzani M, Platsouka E, Belasiotou H, Stamouli M, Harh-
alakis N, Boutati EI, Paniara O, Nikiforakis E: Resolution of fungemia
due to Fusarium species in a patient with acute leukemia
treated with caspofungin.  Clin Infect Dis 2003, 36:1349-1350.
Pre-publication history
The pre-publication history for this paper can be accessed
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Resolution of disseminated fusariosis in a child with acute leukemia treated with combined antifungal therapy: a case report

José-Manuel  Vagace

Crossref

BioMed CentralBMC Infectious DiseasesssOpen AcceCase reportResolution of disseminated fusariosis in a child with acute leukemia treated with combined antifungal therapy: a case reportJosé-Manuel Vagace*1, Cesar Sanz-Rodriguez2, Maria-Soledad Casado1, Nieves Alonso1, Manuel Garcia-Dominguez1, Francisco Garcia de la Llana3, Luis Zarallo4, Miguel Fajardo5 and Roberto Bajo1Address: 1Department of Hematology, Complejo Hospitalario Infanta Cristina, Badajoz, Spain, 2Department of Clinical Research, Merck Sharp & Dohme of Spain, Madrid, Spain, 3Department of Internal Medicine, Complejo Hospitalario Infanta Cristina, Badajoz, Spain, 4Department of Pediatrics, Complejo Hospitalario Infanta Cristina, Badajoz, Spain and 5Department of Microbiology, Complejo Hospitalario Infanta Cristina, Badajoz, SpainEmail: José-Manuel Vagace* - jvagacev@aehh.org; Cesar Sanz-Rodriguez - cesar_sanzrodriguez@merck.com; Maria-Soledad Casado - marisol.casado@ses.juntaex.es; Nieves Alonso - malonsoe@aehh.org; Manuel Garcia-Dominguez - garciadoz@yahoo.es; Francisco Garcia de la Llana - francisco.garcial@ses.juntaex.es; Luis Zarallo - luis.zarallo@ses.juntaex.es; Miguel Fajardo - miguel.fajardo@ses.juntaex.es; Roberto Bajo - roberto.bajo@ses.juntaex.es* Corresponding author    AbstractBackground: Fusarium spp. is being isolated with increasing frequency as a pathogen inoncohematologic patients. Caspofungin and amphotericin B have been reported to have synergisticactivity against Fusarium spp.Case presentation: We herein report a case of disseminated fusariosis diagnosed by chest CTscan and positive blood cultures to Fusarium spp. Because the patient's clinical conditiondeteriorated, CRP levels increased, and blood cultures continued to yield Fusarium spp. despiteliposomal amphotericin B monotherapy up to 5 mg/kg daily, treatment with caspofungin was added.Within 2 weeks of onset of combined antifungal therapy, the chest CT scan demonstrated aprogressive resolution of the pulmonary lesions. Upon discontinuation of intravenous antifungals,the patient received suppressive therapy with oral voriconazole. Three months later, a chest CTscan showed no abnormalities. Twenty-five months after discontinuation of all antifungal therapy,the patient remains in complete remission of her neoplastic disease with no signs of clinical activityof the Fusarium infection.Conclusion: This is the first description of successful treatment of disseminated fusariosis in apediatric patient with acute lymphoblastic leukemia with caspofungin and amphotericin B followedby oral suppressive therapy with voriconazole.BackgroundFusarium spp. is a saprophytic mould that is ubiquitous inthe soil. Invasive fusariosis may follow the inhalation ofairborne conidia or the inoculation of conidia through askin breach associated with indwelling catheters, wounds,burns, or onychomycosis. Deep-seated and disseminatedinfections caused by Fusarium spp. are being diagnosedwith increasing frequency in patients with hematologicalPublished: 10 May 2007BMC Infectious Diseases 2007, 7:40 doi:10.1186/1471-2334-7-40Received: 19 August 2006Accepted: 10 May 2007This article is available from: http://www.biomedcentral.com/1471-2334/7/40© 2007 Vagace et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 4(page number not for citation purposes)BMC Infectious Diseases 2007, 7:40 http://www.biomedcentral.com/1471-2334/7/40malignancies [1]. The Fusarium species most frequentlyinvolved in human infections are Fusarium solani, F.oxysporum, F. verticilloides, and F. moniliforme [1]. Of note,Fusarium species are often confused with Aspergillus spp. asboth pathogens have similar histopathologic appearancewith septate, dichotomously branching hyphae. Yet, theprognosis of invasive fusariosis is much poorer than forinvasive aspergillosis, with very low response rates andmost patients with disseminated Fusarium infection dying[1]. We describe here the first case of a favorable responseof disseminated fusariosis to combination caspofunginand liposomal amphotericin B followed by oral suppres-sive therapy with voriconazole in a pediatric patient withacute lymphoblastic leukaemia (ALL).Case presentationA 11-year-old, 50-kg female with a diagnosis of CD10+ALL was admitted to the hospital with fever and intermit-tent chest pain. The patient was in complete remission(CR) following SHOP-99 chemotherapy. At the time ofhospital admission, she was receiving G-CSF for severegranulocytopenia post-intensification with cytarabine,and had also received broad-spectrum antibiotics and flu-conazole prophylaxis during previous episodes of febrileneutropenia.The physical examination was normal and the patient'sgeneral condition good. The blood examination showed12,500 leukocytes/mm3 (82% neutrophils). An urineexamination, a chest X-ray, and an abdominal ultrasonog-raphy did not reveal abnormal findings. Blood, urine, andstool cultures were also negative. She was initially treatedwith cefepime and teicoplanin. G-CSF was discontinued,after which the neutrophil count stabilized at around1,700/mm3. CRP increased steadily up to 5.6 mg/dLdespite broad-spectrum antibiotic therapy. One weeklater, while continuously febrile, the patient experiencedworsening chest pain. A chest CT scan revealed severalnodules 1 cm or smaller in diameter at the apex of bothlungs (Figure 1). The Aspergillus galactomannan antigenwas negative. Cultures of separate blood samplesobtained percutaneously and from the central venouscatheter, yielded Fusarium spp. The species of the infectingFusarium could not be identified and in vitro susceptibilitycould not be tested. Liposomal amphotericin B (3 mg/kg/day) was then started. Although the dose of liposomalamphotericin B was increased to 5 mg/kg daily and thecentral venous catheter was removed (cultures of the cath-eter tip were sterile), the patient remained febrile andchest pain continued to worsen over the following 7 days.Blood cultures remained positive for Fusarium spp. andCRP levels increased up to 10.6 mg/dL (Figure 1). Caspo-fungin was then initiated (70-mg load followed by 50 mgdaily). Fever disappeared within 48 hours of caspofunginonset (Figure 1). Chest pain improved significantly, bloodcultures became negative, and CRP levels went down tothe 1–2 mg/dL range over the following days. The patientpresented two isolated fever spikes 8 and 12 days after theonset of caspofungin, which corresponded to a phlebitisepisode and a limited reaction to L-asparaginase, respec-tively. Two weeks later, a new chest CT scan demonstratedprogressive resolution of the lung nodules (Figure 1).Intravenous antifungals were discontinued and chemo-therapy and suppressive therapy with oral voriconazole200 mg twice daily was started. Three months later, a chestCT scan showed complete resolution of the pulmonarylesions, while the patient was asymptomatic (Figure 1).Thus, voriconazole was discontinued. Twenty-fivemonths after discontinuation of all antifungal therapy,the patient remains healthy in the absence of any symp-toms of fungal infection and in CR of her neoplastic dis-ease.Fusarium resistance to most antifungals and the severeimmunosuppression-notably long-lasting, severe neutro-penia – in oncohematological patients make Fusariuminfections commonly fatal [1]. Despite its low activityagainst Fusarium [2], amphotericin B remains the drug ofchoice. Voriconazole is licensed for the treatment of fusa-riosis based on in vitro data and a series of case reportswith a reported response rate of ~40% [3]. Posaconazolealso has potential for therapy of systemic fusariosis [4]. Inany case, responses obtained with monotherapies remaintoo low and unsatisfactory.We decided to treat our patient with amphotericin B andcaspofungin for two reasons: (i) In our view amphotericinB remains the mainstay of therapy for fusariosis in pediat-ric patients; experience with voriconazole in this patientsegment is limited [5-7]; (ii) Concurrent antifungal ther-apy is now generally considered an alternative way ofimproving outcome in difficult-to-treat invasive mycoses.In a recent in vitro study amphotericin B and voriconazolerendered mainly additive or subadditive interactionsagainst Fusarium spp. [8]. Yet, the concern remains thatcombining amphotericin B and azoles may lead to antag-onism. In addition to the azole inhibition of the synthesisof amphotericin B's pharmacological target ergosterol,amphotericin B-related damage to the fungal cell mem-brane may interfere with the influx of azoles [9]. In vitrocaspofungin-inactive against Fusarium-showed synergisticor synergistic-to-additive interactions with amphotericinB for at least half of the Fusarium isolates [10]. By inhibit-ing cell wall synthesis, caspofungin may presumablyenhance the penetration of amphotericin B [9].We hypothesize that combination antifungal therapylikely contributed to the sucessful treatment of ourpatient's severe invasive fusariosis, since clinical improve-ment only became evident after initiating caspofungin.Page 2 of 4(page number not for citation purposes)BMC Infectious Diseases 2007, 7:40 http://www.biomedcentral.com/1471-2334/7/40Page 3 of 4(page number not for citation purposes)Clinical, bio logical, and radiographic evolution and drug therapyFigure 1Clinical, bio logical, and radiographic evolution and drug therapy.03691215363738394041030006000900012000150000 5 10 15 20 25 30 35 40 45 50 55 60C Reactive ProteinTemperatureNeutrophil CountDay Post-Admission[ºC][mg/dL][cells/mm3 ]Onset ofchest painWorseningchest painFusariumisolated in blood cultureNegative bloodculturesPhlebitisReaction toL-asparaginaseClinicalimprovementCefepimeTeicoplaninLiposomal Amphotericin BCaspofunginVoriconazole PO//12BMC Infectious Diseases 2007, 7:40 http://www.biomedcentral.com/1471-2334/7/40Yet, the effect of caspofungin in the successful outcome ofour case is not completely clear. The clinical responseobserved could also be the result of prolonged adminis-tration of liposomal amphotericin B and the lack of severeneutropenia. Finally, the administration of suppressivevoriconazole and the early re-initiation of chemotherapyallowed by rapid infection control probably also contrib-uted to the good long-term outcome. Of note, there havebeen a few case reports of response to caspofungin incombination with amphotericin B [11,12] and as mono-therapy [13], although in some of these reports there wasa clear association of response to recovery from neutrope-nia.ConclusionWe herein report an episode of disseminated fusariosis ina pediatric ALL patient treated successfully with caspofun-gin and amphotericin B followed by suppressive therapywith voriconazole. While our anecdotal observation isencouraging, the use of combination antifungal therapy isdebatable and further in vivo studies are warranted toestablish its true role in deep-seated and disseminatedFusarium infections.AbbreviationsCD10+: Cluster differentiation 10-positiveCT: Computed tomography.SHOP-99: The standard protocol of the Spanish Society ofPediatric Hematology and Oncology for high risk acutelymphoblastic leukemia, which includes induction (pred-nisone, daunomycin, vincristine, cyclophosphamide,metothrexate, L-asparaginase), consolidation (metothrex-ate, cytarabine, mercaptopurine), and intensification(adriamycin, vincristine, dexamethasone, cyclophospha-mide, metothrexate, cytarabine, L-asparaginase) chemo-therapy.G-CSF: Granulocyte-colony stimulating factor.CRP: C reactive protein.Competing interestsC. Sanz-Rodriguez is an employee of Merck Sharp &Dohme de España, S.A.. The remaining authors declarethat they have no competing interests.Authors' contributionsJ-M. Vagace, M-S. Casado, N. Alonso, M. Garcia-Dominguez, F. Garcia de la Llana, L. Zarallo, M. Fajardo,and R. Bajo participated actively in the diagnosis, care,and follow-up of the patient.J-M. Vagace obtained consent from the patient's parentsfor this case report, reviewed the literature, provided clin-ical details, and drafted the manuscript.C. Sanz-Rodriguez reviewed the literature and gave help-ful comments regarding the scientific content of the man-uscript.All authors read and approved the final manuscript.AcknowledgementsWritten consent was obtained from the patient's parents for publication of study. There was no financial support for the preparation of this manu-script.References1. Boutati EI, Anaissie EJ: Fusarium, a significant emerging patho-gen in patients with hematologic malignancy: ten years' expe-rience at a cancer center and implications for management.Blood 1997, 90:999-1008.2. Anaissie EJ, Hachem R, Legrand C, Legenne P, Nelson P, Bodey GP:Lack of activity of amphotericin B in systemic murine fusarialinfection.  J Infect Dis 1992, 165:1155-1157.3. The European Agency for the Evaluation of Medicinal Products: Vfend(voriconazole), Scientific Discussion, European Public Assessment Report. Lon-don 2005 [http://www.emea.eu.int/humandocs/Humans/EPAR/vfend/vfend.htm]. Accessed October 4, 20054. Raad II, Hachem RY, Herbrecht R, Graybill JR, Hare R, Corcoran R,Kontoyiannis DP: Posaconazole as salvage treatment for inva-sive fusariosis in patients with underlying hematologic malig-nancy and other conditions.  Clin Infect Dis 2006, 42:1398-403.5. Baden LR, Katz JT, Fishman JA, Koziol C, Del Vecchio A, Doran M,Rubin RH: Salvage therapy with voriconazole for invasive fun-gal infections in patients failing or intolerant to standard anti-fungal therapy.  Transplantation 2003, 76:1632-1637.6. Guzman-Cottrill JA, Zheng X, Chadwick EG: Fusarium solani endo-carditis successfully treated with liposomal amphotericin Band voriconazole.  Pediatr Infect Dis J 2004, 23:1059-1061.7. Rodriguez CA, Lujan-Zilbermann J, Woodard P, Andreansky M, Adder-son EE: Successful treatment of disseminated fusariosis.  BoneMarrow Transplant 2003, 31:411-412.8. Ortoneda M, Capilla J, Javier Pastor F, Pujol I, Guarro J: In vitro inter-actions of licensed and novel antifungal drugs against Fusar-ium spp.  Diagn Microbiol Infect Dis 2004, 48:69-71.9. Cuenca-Estrella M: Combinations of antifungal agents in therapy– what value are they?  J Antimicrob Chemother 2004, 54:854-869.10. Arikan S, Lozano-Chiu M, Paetznick V, Rex JH: In vitro synergy ofcaspofungin and amphotericin B against Aspergillus andFusarium spp.  Antimicrob Agents Chemother 2002, 46:245-247.11. Makowsky MJ, Warkentin DI, Savoie ML: Caspofungin and ampho-tericin B for disseminated Fusarium verticillioides in leuke-mia.  Ann Pharmacother 2005, 39:1365-1366.12. Fatoye A, Bow EJ, Loewen R: Amphotericin B lipid complex andcaspofungin as combination therapy for disseminated fusario-sis in a patient with acute myeloid leukemia [abstract].  In Pro-ceedings of the 13th Congress of the International Society for Human andAnimal Mycology: 25–29 May 2003; San Antonio, TX the InternationalSociety for Human and Animal Mycology; 2003:392. 13. Apostolidis J, Bouzani M, Platsouka E, Belasiotou H, Stamouli M, Harh-alakis N, Boutati EI, Paniara O, Nikiforakis E: Resolution of fungemiadue to Fusarium species in a patient with acute leukemiatreated with caspofungin.  Clin Infect Dis 2003, 36:1349-1350.Pre-publication historyThe pre-publication history for this paper can be accessedhere:http://www.biomedcentral.com/1471-2334/7/40/prepubPage 4 of 4(page number not for citation purposes)

Abstract Background Fusarium spp. is being isolated with increasing frequency as a pathogen in oncohematologic patients. Caspofungin and amphotericin B have been reported to have synergistic activity against Fusarium spp. Case presentation We herein report a case of disseminated fusariosis diagnosed by chest CT scan and positive blood cultures to Fusarium spp. Because the patient's clinical condition deteriorated, CRP levels increased, and blood cultures continued to yield Fusarium spp. despite liposomal amphotericin B monotherapy up to 5 mg/kg daily, treatment with caspofungin was added. Within 2 weeks of onset of combined antifungal therapy, the chest CT scan demonstrated a progressive resolution of the pulmonary lesions. Upon discontinuation of intravenous antifungals, the patient received suppressive therapy with oral voriconazole. Three months later, a chest CT scan showed no abnormalities. Twenty-five months after discontinuation of all antifungal therapy, the patient remains in complete remission of her neoplastic disease with no signs of clinical activity of the Fusarium infection. Conclusion This is the first description of successful treatment of disseminated fusariosis in a pediatric patient with acute lymphoblastic leukemia with caspofungin and amphotericin B followed by oral suppressive therapy with voriconazole.</p

Zarallo Luis

de la Llana Francisco

Garcia-Dominguez Manuel

Alonso Nieves

Casado Maria-Soledad

Sanz-Rodriguez Cesar

Vagace José-Manuel

Fajardo Miguel

Bajo Roberto

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Adderson EE: Successful treatment of disseminated fusariosis. Bone Marrow Transplant

Amphotericin B lipid complex and caspofungin as combination therapy for disseminated fusariosis in a patient with acute myeloid leukemia [abstract].

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Resolution of disseminated fusariosis in a child with acute leukemia treated with combined antifungal therapy: a case report

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