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Ahead of consensus: a paediatric
antifungal prophylaxis census
We commend the authors of the Australian and New
Zealand Antifungal Consensus Guideline.1To context-
ualise this guideline in children, we surveyed current
routine primary antifungal prophylaxis practice for
patients with haematological malignancies at the seven
Australian children’s hospitals with major haematology-
oncology services across six states.
Formal guidelines were used at three of seven centres.
Conditions considered high risk for invasive fungal infec-
tion (IFI) were consistent with the consensus guideline,
with every hospital including acute myeloid leukaemia
(AML), myelodysplastic syndrome, aplastic anaemia,
high-risk acute lymphoblastic leukaemia (ALL), relapsed
leukaemia and post-haemopoietic stem cell transplant
(HSCT) with neutropenia or stage II-IV graft-versus-host
disease. Some hospitals identified other factors including
high-dose corticosteroids, prolonged neutropenia, young
age and comorbidities.
Prophylaxis type differed between conditions and hos-
pitals (Table 1). No hospital routinely offered prophylaxis
for patients with standard-risk ALL. One hospital used
yeast prophylaxis (i.e. fluconazole) with higher-intensity
chemotherapy regimens and another noted sporadic use
for patients perceived to be at higher risk (e.g. in
nappies). Of six institutions undertaking allogeneic HSCT,
three used yeast and three mould prophylaxis, including
one routinely using intermittent liposomal amphotericin.
Despite moderate evidence for decreased IFI in adult
autologous HSCT, yeast prophylaxis was used in only
three of six centres.2
Regarding choice of mould prophylaxis, five hospitals
preferentially used posaconazole for older children,
extrapolating from its success in adolescents and adults
with AML,3despite a lack of strong paediatric comparative
data.4Four of these hospitals used voriconazole for
younger patients and one itraconazole. Itraconazole was
used first-line for all ages at one institution. At another,
posaconazole was only used for older children with AML,
perhaps reflecting pharmaceutical benefit scheme restric-
tions. Two hospitals advised a cut-off age for posaconazole
use of >8 years and two used >13 years, while noting some
use under these age cut-offs, reflecting the still-limited
paediatric pharmacokinetic data available.5–7 For high-risk
patients not tolerating oral intake, voriconazole, liposomal
amphotericin and caspofungin were used. For patients
receiving vinca alkaloids, most hospitals use intermittent
liposomal amphotericin despite lack of strong evidence for
this strategy.8–11
Therapeutic drug monitoring (TDM) was readily acces-
sible for azoles at all centres. Two hospitals used serum
galactomannan for screening (for some groups) and diag-
nosis, one hospital planned to do so and three other
hospitals only used galactomannan as a diagnostic test.
One hospital did not use it. TDM and galactomannan
turnaround times ranged from 24 h to 5 days and 48 h to
7 days, respectively, with wide variations even within
institutions, depending on onsite availability and labora-
tory schedules.
Prophylaxis can be an effective strategy for reduc-
ing the impact of IFI for vulnerable paediatric
haematology-oncology patients. Areas of uncertainty
include risk stratification, choice of mould prophylaxis,
practical application of TDM and biomarkers,
posaconazole pharmacokinetics, and use of non-azole
agents. The consensus guideline provides a uniform
approach based largely on expert opinion due to scarce
paediatric data. The need remains for prospective data
collection in children. Study of prevention and manage-
ment of infection should be integrated into compr-
ehensive paediatric haematology-oncology research
protocols.
Table 1 Spectrum of routine primary antifungal prophylaxis by condition and hospital
Hospitals
AB C D E F G
ALL – standard risk None None None/yeast† None None None None/yeast†
ALL – high risk Mould None None/yeast† Mould None/yeast/mould† Mould Yeast/mould†
AML Mould Mould None/mould† Mould Yeast Mould Mould
Relapsed leukaemia Mould Mould Mould Mould Mould Mould Mould
AA/MDS Mould Mould Yeast Mould Mould Mould Mould
Autologous HSCT‡ None N/a None None Yeast Yeast Yeast
Allogeneic HSCT‡ Yeast N/a Mould Yeast Yeast/mould† Mould Yeast
†Dependent on patient (e.g. Down syndrome, children in nappies), intensity of chemotherapy and protocol factors. ‡Neutropenic phase. AA, aplastic
anaemia; ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; HSCT,haemopoietic stem cell transplant ; MDS, myelodysplastic syndrome.
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Letters to the Editor
© 2015 Royal Australasian College of Physicians
364
Received 9 December 2014; accepted 21 December 2014.
doi:10.1111/imj.12690
J. Osowicki,1,2 C. C. Blyth,3,4,5,6 P. N. Britton,7,8 J. Clark,9
C. M. Cooper,10 G. M. Haeusler,11,12 B. McMullan13,14
and P. A. Bryant1,2,15
1Infectious Diseases Unit, The Royal Children’s Hospital
Melbourne, 2Murdoch Children’s Research Institute, 15Department
of Paediatrics, The University of Melbourne, 11Department of
Paediatric Infectious Diseases, Monash Children’s Hospital,
12Department of Infectious Diseases, Peter MacCallum Cancer
Centre, Melbourne, Victoria, 3Department of General Paediatrics,
Princess Margaret Hospital for Children, 5PathWest Laboratory
Medicine WA, Princess Margaret Hospital, Perth, 4School of
Paediatrics and Child Health, University of Western Australia,
6Telethon Kids Institute, University of Western Australia, , Perth,
Western Australia, 7Department of Infectious Diseases and
Microbiology, The Children’s Hospital at Sydney, Westmead,
8Discipline of Paediatrics and Child Health, Sydney Medical School,
University of Sydney, 14School of Women’s and Children’s Health,
University of New South Wales, 13Department of Immunology and
Infectious Diseases, Sydney Children’s Hospital, Sydney, New
South Wales, 9Infection Management and Prevention Service, Lady
Cilento Children’s Hospital, Brisbane, Queensland, and 10SA
Pathology, Women’s and Children’s Hospital, Adelaide, South
Australia, Australia
References
1 Slavin MA, Thursky KA, Worth LJ,
Chang CC, Morrissey CO, Blyth CC et al.
Revised Australian and New Zealand
antifungal consensus guideline 2014.
Intern Med J 2014; 44: 1267–397.
2 Goodman JL, Winston DJ, Greenfield
RA, Chandrasekar PH, Fox B, Kaizer H
et al. A controlled trial of fluconazole to
prevent fungal infections in patients
undergoing bone marrow
transplantation. N Engl J Med 1992; 326:
845–51.
3 Cornely OA, Maertens J, Winston DJ,
Perfect J, Ullmann AJ, Walsh TJ et al.
Posaconazole vs. fluconazole or
itraconazole prophylaxis in patients with
neutropenia. N Engl J Med 2007; 356:
348–59.
4 Doring M, Blume O, Haufe S, Hartmann
U, Kimmig A, Schwarze CP et al.
Comparison of itraconazole,
voriconazole, and posaconazole as oral
antifungal prophylaxis in pediatric
patients following allogeneic
hematopoietic stem cell transplantation.
Eur J Clin Microbiol Infect Dis 2014; 33:
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5 Doring M, Muller C, Johann PD,
Erbacher A, Kimmig A, Schwarze CP
et al. Analysis of posaconazole as oral
antifungal prophylaxis in pediatric
patients under 12 years of age following
allogeneic stem cell transplantation. BMC
Infect Dis 2012; 12: 263.
6 Krishna G, Sansone-Parsons A,
Martinho M, Kantesaria B, Pedicone L.
Posaconazole plasma concentrations in
juvenile patients with invasive fungal
infection. Antimicrob Agents Chemother
2007; 51: 812–18.
7 Bernardo VA, Cross SJ, Crews KR, Flynn
PM, Hoffman JM, Knapp KM et al.
Posaconazole therapeutic drug
monitoring in pediatric patients and
young adults with cancer. Ann
Pharmacother 2013; 47: 976–83.
8 Moriyama B, Henning SA, Leung J,
Falade-Nwulia O, Jarosinski P, Penzak
SR et al. Adverse interactions between
antifungal azoles and vincristine: review
and analysis of cases. Mycoses 2012; 55:
290–7.
9 Bochennek K, Tramsen L, Schedler N,
Becker M, Klingebiel T, Groll AH et al.
Liposomal amphotericin B twice weekly
as antifungal prophylaxis in paediatric
haematological malignancy patients.
Clini Microbiol Infect 2011; 17: 1868–74.
10 Roman E, Osunkwo I, Militano O,
Cooney E, van de Ven C, Cairo MS.
Liposomal amphotericin B prophylaxis
of invasive mold infections in children
post allogeneic stem cell trans-
plantation. Pediatr Blood Cancer 2008; 50:
325–30.
11 Uhlenbrock S, Zimmermann M, Fegeler
W, Jurgens H, Ritter J. Liposomal
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Mycoses 2001; 44: 455–63.
Regional differences in
ventilation-perfusion ratio may help
explain the differential diagnosis in
interstitial lung disease
Interstitial lung disease is a well-recognised respiratory
condition often seen in respiratory and general medicine
clinics. Not surprisingly, because their physical signs on
chest examination are relatively stable, and due to the fact
that their investigations offer a multitude of potential
questions relating to diagnosis and management, patients
with interstitial lung disease are often invited to partici-
pate in the Fellowship of the Royal Australasian College of
Physicians (clinical examination, part 1). Over the past 25
years, a whole generation of doctors, who grew up with
the highly regarded textbooks written by Nicholas Talley
and Simon O’Connor,1,2 have used the mnemonics
SCHART (for upper lobe predominant) and RASIO (for
lower lobe-predominant interstitial lung disease) to aid
prompt recitation of the differential diagnosis of interstitial
lung disease (Table 1). The utility of all mnemonics,
however, is affected by time, due to changes in disease
prevalence. Pneumoconioses, in particular, have become
much less common in the past decade,3especially with
improvements in mining technology and disease preven-
tion efforts. Epidemiology data relating to the prevalence
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Letters to the Editor
© 2015 Royal Australasian College of Physicians
365
