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correspondence
n engl j med 356;14 www.nejm.org april 5, 2007
1481
Raoult D. Afebrile blood culture-negative endocarditis. Ann
Intern Med 1999;131:144-6.
Boulos A, Rolain JM, Mallet MN, Raoult D. Molecular evalu-
1.
2.
ation of antibiotic susceptibility of Tropheryma whipplei in axenic
medium. J Antimicrob Chemother 2005;55:178-81.
Retraction: Hussain HM, Hotopf M, Oyebode F.
Atypical Antipsychotic Drugs and Alzheimer’s Disease.
N Engl J Med 2007;356:416.
To the Editor: A letter that I submitted to the
Journal was published in the January 25 issue.
1
Be-
cause there has been concern about the prove-
nance and authorship of that letter, I request that
it be retracted.
Hadi Meeran Hussain, M.B., B.S.
Military Hospital
Rawalpindi 46000, Pakistan
Hussain HM, Hotopf M, Oyebode F. Atypical antipsychotic
drugs and Alzheimer’s disease. N Engl J Med 2007;356:416.
1.
Multiple-Triazole–Resistant Aspergillosis
To the Editor: The use of voriconazole has be-
come common for the management of invasive as-
pergillosis. However, therapy with voriconazole
still sometimes fails, more often because of un-
responsive underlying disease than because of re-
sistance of the fungus. Since the first description
of itraconazole resistance in Aspergillus fumigatus,
1
three amino acid substitutions in the 14α-sterol
demethylase cyp51A gene, which is the target site
for azole drugs, have been described.
2
Our laboratory receives fungal isolates for iden-
tification and susceptibility testing from through-
out the Netherlands. Since 2002, using Clinical
and Laboratory Standards Institute methodol-
ogy, we have observed an increase in the number
of A. fumigatus isolates with elevated minimum
inhibitory concentrations of voriconazole (2 to
>16 mg per liter), itraconazole (>16 mg per liter),
the investigational azole ravuconazole (4 to >16 mg
per liter), and posaconazole (0.5 to 1.0 mg per
liter). Thirteen isolates were cultured from nine
patients from six hospitals in the Netherlands
(Table 1). Primary aspergillosis was diagnosed
in four patients, and five patients presented with
breakthrough invasive aspergillosis.
A new mechanism of resistance, consisting of
a Cyp51A amino acid substitution at codon 98
(L98H) together with a tandem repeat in the gene
promoter, was found to be responsible for the
azole-resistant phenotype. This resistance mech-
anism was present in 12 of the 13 isolates. Ge-
notyping of the isolates showed no evidence for
clonal spread of a single A. fumigatus genotype.
The prevalence of multiple-triazole resistance
was compared with a previously conducted nation-
wide survey of 170 A. fumigatus isolates collected
from 114 patients from 21 Dutch hospitals be-
tween 1945 and 1998.
4
In this period, no patients
with multiple-triazole–resistant isolates were found
as compared with 10 of 81 patients in the period
since 2002 (P<0.001).
Although the emergence of this new resistance
mechanism coincides with the approval of vori-
conazole, the factors that may explain this phe-
nomenon remain unclear. Four patients became
infected with a multiple-triazole–resistant strain
during long-term prophylaxis with itraconazole,
a drug that has been widely available for clinical
use since 1991. The recovery of multiple-triazole–
resistant strains in patients who had not been
previously treated with azoles suggests that alter-
native sources of azoles, such as the use of azole
compounds in agricultural environments, might
play a role.
5
Our observation underscores the need to make
an etiologic diagnosis of invasive mold infection
The New England Journal of Medicine
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T h e
n e w e n g l a n d j o u r n a l
o f
m e di c i n e
n engl j med 356;14 www.nejm.org april 5, 2007
1482
Table 1. Characteristics of Nine Patients from Whom A. fumigatus Resistant to Multiple Triazoles Was Cultured.
Sex
Yr of
Age
Underlying
Disease Date of Isolation Site of Isolation Disease Classification*
Previous Azole
Exposure Treatment Outcome
Male† 15 X-linked chronic granuloma-
tous disease
April 4, 2002 Sputum Breakthrough invasive pulmo-
nary aspergillosis, proven
Prophylaxis with itra-
conazole (for 6 yr)
Voriconazole (high-dose) Survived
Male 73 None Dec. 3, 2003 Ear swab Invasive aspergillosis of mas-
toid cavity, proven
None Surgery and topical
therapy
Survived
Male 16 Hyper-IgE syndrome Nov. 19, 2004 Bronchoalveolar-
lavage fluid
Breakthrough invasive pulmo-
nary aspergillosis, proven
Treatment with vori-
conazole (for 2 yr)
Surgery and posacon-
azole
Survived
Female 76 Pulmonary fibrosis June 26, 2005 Sputum Invasive pulmonary aspergil-
losis, possible
None Voriconazole Survived
Male 31 Chronic granulomatous
disease
Nov. 1, 2005 Lung aspirate Breakthrough invasive pulmo-
nary aspergillosis,
probable
Prophylaxis with itra-
conazole (for >10 yr)
Caspofungin and
posaconazole
Survived
Female 68 Acute myeloid leukemia Feb. 14, 2006 Bronchoalveolar-
lavage fluid
Disseminated invasive asper-
gillosis, probable
None Voriconazole Died
Female 62 Chronic obstructive pulmo-
nary disease
April 5, 2006 Bronchoalveolar-
lavage fluid
Invasive pulmonary aspergil-
losis, possible
None Voriconazole, amphoteri-
cin B, and posacon-
azole
Survived
Male 19 Chronic granulomatous
disease
April 15, 2006 Bone Breakthrough aspergillus
osteomyelitis, proven
Prophylaxis with itra-
conazole (for >2 yr)
Voriconazole, caspofun-
gin, and posacon-
azole
Survived
Male 45 Acute myeloid leukemia and
allogeneic hematopoietic
stem-cell transplantation
May 11, 2006 Nose swab Breakthrough aspergillus
sinusitis, proven
Prophylaxis with itra-
conazole (for 4 wk)
Posaconazole Died
* Diseases were classified according to consensus criteria defined by the European Organisation for Research and Treatment of Cancer and the National Institute of Allergy and
Infectious Diseases Mycoses Study Group.
† Information about this patient is from Warris et al.
3
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n engl j med 356;14 www.nejm.org april 5, 2007
1483
instructions
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any other form or medium.
and to determine antifungal drug activity in clini-
cally relevant A. fumigatus isolates. Furthermore,
international surveillance programs are warrant-
ed to investigate the spread of resistance in A. fu-
migatus.
Paul E. Verweij, M.D.
Radboud University Nijmegen Medical Center
6500 HB Nijmegen, the Netherlands
p.verweij@mmb.umcn.nl
Emilia Mellado, Ph.D.
Instituto de Salud Carlos III
28220 Madrid, Spain
Willem J.G. Melchers, Ph.D.
Radboud University Nijmegen Medical Center
6500 HB Nijmegen, the Netherlands
Denning DW, Venkateswarlu K, Oakley KL, et al. Itracona-
zole resistance in Aspergillus fumigatus. Antimicrob Agents Che-
mother 1997;41:1364-8.
Chamilos G, Kontoyiannis DP. Update on antifungal drug
resistance mechanisms of Aspergillus fumigatus. Drug Resist Up-
dat 2005;8:344-58.
Warris A, Weemaes CM, Verweij PE. Multidrug resistance in
Aspergillus fumigatus. N Engl J Med 2002;347:2173-4.
Verweij PE, Te Dorsthorst DTA, Rijs AJMM, De Vries-Hospers
HG, Meis JFGM. Nationwide survey of in vitro activities of itra-
conazole and voriconazole against clinical Aspergillus fumigatus
isolates cultured between 1945 and 1998. J Clin Microbiol 2002;
40:2648-50.
Meneau I, Sanglard D. Azole and fungicide resistance in
clinical and environmental Aspergillus fumigatus isolates. Med My-
col 2005;43:Suppl 1:S307-S311.
Correspondence Copyright © 2007 Massachusetts Medical Society.
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The New England Journal of Medicine
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