Georg Maschmeyer. Dept. of Hematology, Oncology & Palliative Care Klinikum Ernst von Bergmann Potsdam, Germany.

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1 Georg Maschmeyer Dept. of Hematology, Oncology & Palliative Care Klinikum Ernst von Bergmann Potsdam, Germany

2 519 A. fumigatus isolates: Itraconazole resistance 5%, significant increase since 2004 (p<0.001) 65% cross-resistant to voriconazole and 74% to posaconazole 13 of 14 evaluable patients had prior azole exposure; 8 infections failed therapy (progressed), and 5 failed to improve (remained stable) Molecular epidemiology shows that resistance evolved in infecting strains within the lung, rather than by superinfection with a resistant stain from the environment Howard SJ et al, Emerg Infect Dis 2009;15:

3 Azole Resistance in Clinical A.fumigatus Isolates (Manchester, ) Howard SJ et al, Emerg Infect Dis 2009;15:

4 Azole Resistance in Clinical A.fumigatus Isolates (Manchester, extended) Azole resistance is evolving and growing in frequency. Established and novel mechanisms may be responsible. Bueid A et al, J Antimicrob Chemother 2010; 65:2116 8

5 Multi-Azole-Resistant A. fumigatus 1,912 clinical A.fumigatus isolates collected from 1,219 patients Blue bars represent the number of patients with a positive A.fumigatus culture (left y-axis) and the red line represents the percentage of those patients with an ITZ+ isolate (right y-axis) Snelders E et al (Nijmegen), PLoS Med 2008;5:e219

6 Multi-Azole-Resistant A. fumigatus A substitution of leucine 98 for histidine in the cyp51a gene, together with two copies of a 34-base pair sequence in tandem in the Cyp51A gene promoter (TR/L98H), coding for the 14-alpha-demethylase, was found to be the dominant resistance mechanism Microsatellite analysis indicated that the ITZ-resistant isolates were genetically distinct but clustered Snelders E et al (Nijmegen), PLoS Med 2008;5:e219

7 Clinical Characteristics of 9 Patients with Invasive Aspergillosis and an Azole-Resistant A.fumigatus Isolate Snelders E et al (Nijmegen), PLoS Med 2008;5:e219

8 Clinical A.fumigatus Isolates Cultured from Dutch Hospitals and from Other Countries Snelders E et al (Nijmegen), PLoS Med 2008;5:e219

9 Multi-Azole Resistant A.fumigatus Isolates from China and other Countries 497 A.fumigatus isolates (ARTEMIS global surveillance study; ) 24 isolates with elevated triazole MIC values came from different centers in Hangzhou, China, 2 from Czech Republic, and 1 each from Portugal, Brazil, and the USA Lockhart SR et al (CDC; Iowa), Antimicrob Agents Chemother 2011;55:4465-8

10 Van der Linden JWM et al (Nijmegen NL), Clin Infect Dis 2009;48:1111 3

11 Three patients with CNS aspergillosis due to azoleresistant A.fumigatus (leucine substitution for histidine at codon 98 [L98H] and a 34 base pair tandem repeat in the Cyp51A gene promoter region) They were treated with combination therapy or with polyenes, but all patients died Van der Linden JWM et al (Nijmegen NL), Clin Infect Dis 2009; 48:1111 3

12 Source: Use of Azoles in Agriculture Environmental isolates of A.fumigatus with the TR/L98H mutation recovered in the Netherlands and Denmark from agricultural samples of soil Azoles are abundantly used in the environment and the presence of A.fumigatus resistant to medical triazoles is a major challenge because of the possibility of worldwide spread of resistant isolates. Snelders E et al (Nijmegen), PLoS Med 2008;5:e219 Mortensen KL et al (Copenhagen), Antimicrob Agents Chemother 2010;54: Verweij PE et al, Lancet Infect Dis 2009;9:789-95

13 Aspergillus resistance is only seen on the petri dish and not in the patient

14 Arguments Sound Familiar No resistance of gram-negative enterobacteria against fluoroquinolones now >20% of E.coli in the community are resistant No known mechanism of resistance to linezolid among staphylococci Only theoretical development of resistance to caspofungin in Candida spp. now breakthrough candidemias by C.parapsilosis and guilliermondii in patients under full-dose echinocandin treatment

15 Is Resistance Among Aspergillus spp. or Candida spp. Highly Unlikely? A.terreus and C.lusitaniae are already resistant to AmB

16 Is Resistance Among Aspergillus spp. Clinically Irrelevant? Papers by Verweij et al, Howard et al, and van der Linden et al have shown in-vitro resistance associated with clinical treatment failure Verweij PE et al, N Engl J Med 2007;356: Howard SJ et al, Emerg Infect Dis 2009;15: Van der Linden JWM et al, Clin Infect Dis 2009;48:1111 3

17 Is Azole Resistance Among Aspergillus spp. a Problem for Future Clinical Therapy? No (class of) new antifungal agents in the pipeline - maybe genomic targets?

18 A Philosophical View Moulds are very old organisms, highly conservated. They were here long before mankind, and they will still be here after the last human being has left this planet. They are here to digest what we leave behind, including ourselves. So, they will win the battle the only question is: sooner or later.

19 Sinking is only seen on water and not on the street