Azole resistance in Aspergillus: a growing public health menace

Abstract

Future MicrobiologyVol. 6, No. 11 EditorialFree AccessAzole resistance in Aspergillus: a growing public health menaceDavid W Denning & David S PerlinDavid W Denning† Author for correspondenceThe National Aspergillosis Centre, School of Translational Medicine, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK. The Mycology Reference Centre, Manchester; Manchester Academic Health Science Centre; University Hospital of South Manchester, Southmoor Road, Manchester, M23 9LT, UKSearch for more papers by this authorEmail the corresponding author at david.denning@manchester.ac.uk & David S PerlinPublic Health Research Institute, New Jersey Medical School-UMDNJ, Newark, NJ, USASearch for more papers by this authorPublished Online:14 Nov 2011https://doi.org/10.2217/fmb.11.118AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: antifungal resistanceAspergilluschronic pulmonary aspergillosisitraconazoletriazolesThe problem of antimicrobial dug resistance and the emergence of the so-called untreatable ‘superbugs’ is widely recognized for community- and hospital-associated bacterial diseases. Routes of transmission for such infections are usually well documented, although not always easy to overcome. Yet, the medical community has been slow to recognize the hidden dangers lurking in Aspergillus fumigatus, a saprophytic soil-borne organism that is transmitted globally through airborne conidia. In recent years, this organism has been rapidly acquiring resistance to triazole antifungal agents, the most effective group of drugs used to combat serious invasive mycoses, and the only orally active group. A ‘perfect storm’ combining extensive antifungal fungal exposure from the medical and agricultural communities, along with a highly efficient, evolutionarily perfected dispersal system, has led to our current situation. This growing menace threatens the health and well-being of tens of millions of individuals worldwide. Overcoming this growing threat requires a better understanding of the nature of the global problem, therapeutic strategies to mitigate resistance, new drugs with novel mechanisms of action, and a commitment to new molecular technology that can rapidly identify Aspergillus with a simultaneous evaluation of drug resistance.A growing mold problemInvasive, chronic and allergic mold infections caused by A. fumigatus are a major source of morbidity and mortality in both immunosuppressed and immunocompetent hosts. Treatment success requires potent therapy with triazole antifungal agents [1]. Positive identification of invasive mold infections is problematic, as cultures are commonly negative, molecular diagnosis is not widespread or fully clinically tuned, and biomarkers of disease are imperfect. Antifungal agents are often prescribed for prophylaxis, empiric or pre-emptive therapy for acute disease, and long-term maintenance therapy for chronic and allergic infection. Clearly, antifungal resistant strains threaten our ability to treat aspergillosis effectively.How big is the problem?The overall annual incidence for acute invasive aspergillosis among the immunosuppressed patient population varies from approximately 2 to 10% [2]. Globally, an estimated 300,000–500,000 patients are affected, and the number at risk is at least ten-times more [101]. Patients with multiazole resistant invasive aspergillosis have an 88% risk of mortality [3]. Chronic pulmonary aspergillosis (CPA) in mostly immunocompetent individuals is a major worldwide health problem, estimated to have a prevalence of 3 million, of which possibly one third follow pulmonary tuberculosis [4]. Allergic bronchopulmonary aspergillosis is estimated to affect approximately 4 million adults [5]. These last two are the principal patient groups impacted by therapeutic failures due to triazole resistance, as they require long-term therapy. No other class of antifungal is orally active against Aspergillus, leaving some patients with no treatment option.Chronic pulmonary aspergillosisChronic pulmonary aspergillosis is a complex and slowly progressive inflammatory disease caused by Aspergillus species. It includes simple aspergilloma, chronic cavitary pulmonary aspergillosis and chronic fibrosing pulmonary aspergillosis, both with or without an aspergilloma present. Unlike acute invasive pulmonary aspergillosis, CPA occurs in the immunocompetent host. Morbidity is considerable, including both systemic and respiratory symptoms and hemoptysis. Even when treated, CPA has a 20–33% short-term mortality and a 50% mortality over 5 years [4]. Numerous underlying pulmonary conditions are associated with CPA of which pulmonary tuberculosis is the most important [6]. Given the worldwide prevalence of individuals with a tuberculosis case history, the importance of CPA is significant.Allergic aspergillosisFungal-associated asthma is another very large patient group worldwide. The latest worldwide epidemiology projects that 3–15 million adults have severe asthma with fungal sensitization and 4 million adults with asthma have allergic bronchopulmonary aspergillosis (ABPA) worldwide [5]. ABPA and severe asthma with fungal sensitization patients partially benefit from first-line azole therapy involving oral itraconazole, with 60% having good or dramatic responses. Yet, 40% of patients with ABPA and severe asthma with fungal sensitization fail to respond to oral itraconazole therapy.Emerging drug resistanceIn 1997, we reported itraconazole resistance in two clinical isolates of A. fumigatus from patients in California treated with itraconazole in Phase II clinical trials [7]. A few sporadic resistant isolates appeared in Sweden, Spain, France and the UK over the next 10 years. Efforts to determine the resistance mechanisms and improve and standardize azole antifungal susceptibility testing proceeded, notably in Madrid, Nijmegen and Manchester. Suddenly in 2007, many more resistant isolates appeared in Nijmegen and Manchester and then later in Denmark, Norway, Belgium, the USA, China and Canada. Last year, two US laboratories reported itraconazole resistance rates of 50% in A. fumigatus[8,9], astonishingly high rates, exceeding the 15–20% rate in Manchester [10,11] and 7% rate in The Netherlands [12]. In a recent study involving respiratory colonization of 133 cystic fibrosis patients with Aspergillus, 4.5% of isolates harbored azole resistance [13]. A worldwide surveillance program (Artemis), noted a 5.8% resistance rate in 2008–2009, in 62 medical centers, with most resistant isolates coming from Hangzhou in China [14]. So azole resistance in A. fumigatus is widespread, but of highly variable frequency.Unfortunately, these rates may represent the tip of the global Aspergillus drug resistance iceberg, since they represent resistance in cultured isolates. The true frequency of triazole resistance is unknown because A. fumigatus is cultured from less than 30% of patients. We recently reported that PCR amplification of Aspergillus DNA allowed detection in 78.9% patients with ABPA and in 71.4% of those with CPA, compared with 0 and 16.7% by culture, respectively [15]. Importantly, we detected triazole resistance mutations within Cyp51A at an alarming 60.7% [14]. These findings have major implications for clinical practice and may help explain the modest overall response (∼50%) of patients to azole antifungal therapy. A better understanding of resistance mechanisms is needed to identify resistant strains at an earlier stage and to assess more effective intervention strategies.Classic target-site mechanism accounts for resistanceTarget-site modification is the principal mechanism underlying resistance in A. fumigatus. The target lanosterol 14α-demethylase catalyzes a central step in the biosynthetic pathway of the critical membrane sterol ergosterol. Mutations in cyp51A result in structural alterations to the enzyme, which appear to block binding of drugs. Mutational hotspots confirmed to cause resistance have been characterized at amino acid positions Gly54, Met220, Leu98, Gly138 and Gly448; and other mutations in Cyp51A have been reported [10,16]. In The Netherlands, most resistance is due to tandem mutations in Leu98 and the promoter region of Cyp51A. These resistant isolates appear to arise as a consequence of azole use in the agricultural world, and are selected out as primary resistance [17]. This specific resistance mechanism has not been observed in patients that evolve resistance during therapy. Overexpression of ABC and major facilitator superfamily drug transporters have also been described, as they confer resistance to itraconazole, voriconazole and posaconazole [18]. Finally, in a small percentage of isolates, the mechanism of triazole resistance is unclear and may be novel.There are circumstantial links between azole fungicide usage and resistance emergence [19]. Of approximately 30 agricultural frequently used azole fungicides, seven show cross-resistance with medical azoles in A. fumigatus, and the emergence of resistance in environmental isolates in The Netherlands in 2007 followed the introduction of these azoles [20]. By contrast, resistance was not found when specifically sought in Switzerland [20]. This geographical variability could reflect different crops. The newly introduced azole fungicides have an important place in farming of certain crops including grapes and strawberries, because of excellent activity and pathogen resistance to other fungicides [21].Addressing the problemSimply withdrawing these fungicides may leave some farmers with poor yields and diminish the food supply, pushing up prices. Proving the link beyond reasonable doubt may be difficult. The European Centre for Disease Prevention and Control is taking the issue seriously, engaging with the medical community, the agrochemical industry and politicians. It is recommended that isolates of A. fumigatus from northern Europe and the USA should be susceptibility tested, if antifungal treatment is prescribed. This is not currently routinely performed, as for cultured bacteria. Only when a large number of isolates are routinely susceptibility tested will the full extent of the problem be uncovered and patients treated optimally.Another key concern is whether current treatment recommendations for aspergillosis are still viable. In invasive aspergillosis, consideration is being given to combination therapy as is common for bacterial and some viral infections. Should itraconazole be replaced by the more active azoles voriconazole and posaconazole? Data and consensus are required to navigate the future in this area.Conclusion: what needs to be done now?We need a better understanding of the global reach of the triazole resistance problem in Aspergillus and a baseline for the true frequency of resistance. We need therapeutic strategies to overcome existing resistance, either by novel dosing mechanisms or by the introduction of new drugs with novel mechanisms of action. Finally, we need to implement molecular diagnostics that are capable of sensitive detection of Aspergillus with (probably) simultaneous identification of drug resistance markers.Financial & competing interests disclosureDW 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, National Institute of Health Research and the European Union, AstraZeneca, and Basilea. He is an advisor/consultant to F2G and Lab21, as well as other companies including Basilea, Pfizer, Schering Plough, Nektar, Daiichi, Astellas, Gilead and York Pharma. He has been paid for talks on behalf of Schering, Astellas, Merck, Dainippon and Pfizer. DS Perlin receives support from the US National Institute of Allergy and Infectious Diseases, Pfizer, Merck and Astellas, and he participates in expert panels for these companies. He has been paid for talks on behalf of Astellas, Merck, Pfizer, Novartis, Daiwoong and Astra-Zeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Walsh TJ, Anaissie EJ, Denning DW et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin. Infect. Dis.46,327–360 (2008).Crossref, Medline, CAS, Google Scholar2 Denning DW, Verweij PE. The challenge of invasive aspergillosis: increasing numbers in diverse patient groups. Int. J. Infect. 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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, National Institute of Health Research and the European Union, AstraZeneca, and Basilea. He is an advisor/consultant to F2G and Lab21, as well as other companies including Basilea, Pfizer, Schering Plough, Nektar, Daiichi, Astellas, Gilead and York Pharma. He has been paid for talks on behalf of Schering, Astellas, Merck, Dainippon and Pfizer. DS Perlin receives support from the US National Institute of Allergy and Infectious Diseases, Pfizer, Merck and Astellas, and he participates in expert panels for these companies. He has been paid for talks on behalf of Astellas, Merck, Pfizer, Novartis, Daiwoong and Astra-Zeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download