Editorial
Multi-azole Resistance in Aspergillus – Only a Northern European Problem? David W Denning
Professor of Medicine and Medical Mycology, The National Aspergillosis Centre, School of Translational Medicine, The University of Manchester
Abstract
Azole resistance in Aspergillus has emerged since 2007, especially in northern Europe. Patients with untreatable infection are becoming more frequent. The link between azole fungicides in agriculture is compelling, but not proven. Environmental isolates which are resistant tend to have one marker mutation, whereas isolates arising during therapy have many mechanisms described. Susceptibility testing should be routine for clinical isolates of Aspergillus if treatment is given. Molecular detection of resistance mutations is now possible from polymerase chain reaction (PCR)-positive, culture-negative specimens.
Keywords Itraconazole, voriconazole, posaconazole, invasive aspergillosis, aspergilloma
Disclosure: David W Denning holds founder shares in F2G Ltd, a University of Manchester spin-out company and has received grant support from F2G as well as the Fungal Research Trust, the Wellcome Trust, the Moulton Trust, The Medical Research Council, The Chronic Granulomatous Disease Research Trust, the National Institute of Allergy and Infectious Diseases, the National Institute of Health Research, the European Union and AstraZeneca. He acts as an advisor/consultant to F2G and Myconostica (now part of Lab21 group) as well as other companies over the last five years, including Pfizer, Schering Plough (now Merck), Nektar, Astellas and Gilead. He has been paid for talks on behalf of Merck, Astellas, Novartis, Merck, Dainippon and Pfizer. Received: 8 August 2011 Accepted: 15 July 2011 Citation: European Infectious Disease, 2011;5(2):71 Correspondence: David W Denning, The National Aspergillosis Centre, School of Translational Medicine, The University of Manchester, The Mycology Reference Centre, Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester, Southmoor Road, Manchester, M23 9LT, UK. E:
david.denning@
manchester.ac.uk
In April 2011, the European Centre for Disease Prevention and Control (CDC) convened a meeting to discuss the increasing problem of azole resistance in Aspergillus fumigatus. Public health experts, clinicians, agrochemical researchers and mycology reference laboratories were represented. Striking and concerning observations included: mortality of patients with multi-azole resistance aspergillosis was 88 %; resistance to itraconazole and voriconazole has been found in A. fumigatus in most northern European countries including the Netherlands, the UK, Denmark, Sweden, Norway, Belgium, France and Spain, as well as in the US, China and Canada; long-term azole therapy for invasive, allergic and chronic pulmonary aspergillosis is the norm and is increasingly used; a dominant target mutation (tandem repeat[TR]/L98H in 14 alpha demethylase, the enzyme target of the azoles) appears to be present in the environment, in contrast to the emergence of resistance during therapy in which several other mechanisms appear to be responsible; of the ~30 agricultural azole fungicides, a minority (n=7) appear to show cross-resistance with medical azoles in A. fumigatus.1
Emergence of resistance in
environmental isolates in the Netherlands in 2007 followed the introduction of these azoles; and no other class of antifungal is orally active against Aspergillus, leaving some patients with no treatment option. The newly introduced azole fungicides have an important place in farming of certain crops, because of pre-existing resistance
1. Snelders E, Camps SM, Karawajczyk A, et al., Azole-resistance in Aspergillus fumigatus: collateral damage of fungicide use? Abstract O481, Presented at: the 21st European Congress of Clinical Microbiology and Infectious Diseases 27th International Congress of Chemotherapy, Milan, 7–10 May 2011.
2. Denning DW, Park S, Lass-Florl C, et al., High frequency
to older non-azole fungicides. Simply withdrawing these fungicides may leave some farmers with poor yields and diminish the food supply, pushing up prices. Continuing their use may lead to increased resistance rates in Aspergillus, with significant medical consequences. It may be that the rate of azole resistance attributable to the TR/L98H mutation is much higher than is revealed by cultures alone. We found this mutation in >55 % of 32 UK patients’ sputum using sophisticated nested polymerase chain reaction (PCR) on culture negative samples, most receiving azoles for chronic or allergic aspergillosis.2
Also of concern is whether current treatment recommendations for aspergillosis should change. Perhaps itraconazole is most likely to give rise to resistance on therapy and should be replaced with the more active azoles voriconazole and posaconazole. In life-threatening situations, at what frequency of resistance should an alternative therapy be used in place of voriconazole, even though voriconazole responses are 15–20 % superior to all other options currently?3–5
In the Netherlands, with a 7 % rate of multi-azole resistance, consideration is being given to combination therapy for this reason, as is common for bacterial infections. What is clear is that isolates of A. fumigatus from northern Europe should be susceptibility tested if antifungal treatment is to be given – a practice that is not currently routine. n
triazole resistance found in non-culturable Aspergillus fumigatus from lungs of patients with chronic fungal disease, Clin Infect Dis, 2011;52:1123–9.
3. Nivoix Y, Velten M, Letscher-Bru V, et al., Factors associated with overall and attributable mortality in invasive aspergillosis, Clin Infect Dis, 2008;47(9):1176–84.
4. Ramos ER, Jiang Y, Hachem R, et al., Outcome analysis of
invasive aspergillosis in hematologic malignancy and hematopoietic stem cell transplant patients: the role of novel antimold azoles, Oncologist, 2011;16(7):1049–60.
5. Lortholary O, Gangneux JP, Sitbon K, et al., for the French Mycosis Study Group, Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005–2007), Clin Microbiol Infect, 2011;[Epub ahead of print].
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