23rd ECCMID, Apr Berlin

Transcription

1 23rd ECCMID, Apr Berlin Prof. Sevtap Arikan-Akdagli, MD Hacettepe University Medical School Department of Medical Microbiology Ankara Turkey

2 Background information & moulds as causative agents of infections Diversity of epidemiology per the risk factor HSCT & hematological malignancies Organ tx ICU Mould infections : (Changing?) epidemiology, reported outbreaks, and in vitro susceptibility Aspergillosis Mucormycosis Fusariosis Conclusions Scedosporiosis Agenda Other emerging mould infections in high risk patients

3 Dermatophytes & dermatophytosis

4 Epidemiology of dermatophytosis Among the most frequent human infections Affects > 20-25% of world s population Increase in incidence Geographical variations- Homogeneous distribution vs. geographical restriction for some species Changes in epidemiology overtime (migrations, life style, socioeconomics, comorbidities) Havlickova et al. Mycoses 2008; 51(Suppl. 4): 2; Ameen et al. Clin Dermatol 2010; 28: 197

5 Italy Gradual decrease in frequency: Tinea cruris Tinea corporis Tinea capitis Progressive increase in frequency: Tinea pedis Tinea unguium Progressive decrease in isolation : T. violaceum M. canis E. floccosum Increase in isolation: T. rubrum

6 Epidemiology of IFIs: General Perspective Geographical and temporal variability Local epidemiological trends Changes in incidence and the infecting species in the last two decades Changes in antifungal susceptibility profiles Poor outcome Montagna et al. Infection 2013; March 6 Epub

7 Median excess cost of US $, Prolonged length of stay of 13 days, All-cause inpatient mortality 38x higher for the scedosporiosis cases as compared to control patients with comparable underlying hematologic disorders

8 Opportunistic IFIs: THE HOST and the associated risk factors Immunosupressed Debilitated, postoperative ICU Cancer Transplantation Severely-ill Bille et al. Curr Opin Infect Dis 2005; 18: 314

9 Major changes in IFIs in the last decades - More mucosal and invasive fungal infections - Infections due to more resistant species and strains - Infections due to uncommon genera and species - More antifungal drugs in clinical practice Groll et al. J Infect 1996;33:23 Marr et al. Clin Infect Dis 2002;34:909 Fridkin and Jarvis. Clin Microbiol Rev 1996;9:499 Montagna et al. Infection 2013; March 6 Epub

10 More isolates belonging to "uncommon" genera & species Emerged and/or Newly recognized Altered hosts Fungi Selective antifungal pressure Changes in environmental conditions Emerging fungal infection Walsh TJ, Groll AH. Transpl Infect Dis 1999;1:247

11 Opportunistic IFI: Causative agents CANDIDA Mucormycetes C. neoformans Fusarium Scedosporium Dematiaceous moulds... ASPERGILLUS OTHERS

12 Emerging fungal pathogens in immunocompromised patients 1985 Trichosporon Scopulariopsis 1990 Fusarium Mucormycetes B. capitatus P. marneffei Acremonium Paecilomyces C. immitis Trichoderma Azole-R C. albicans Malassezia s Non-albicans Candida Hansenula Emergence and awareness of resistant Aspergillus Walsh & Groll. Transpl Infect Dis 1999;1:247; Walsh et al. Clin Microbiol Infect 2004;10:48; Alastruey-Izquierdo et al. ICAAC 2012; abst. No. M-321

13 Search of: Worldwide Database for nosocomial outbreaks & PubMed- Medline OUTBREAK: >2 more nosocomial unusual fungal inf.s diagnosed in a short period Common genera (Candida, Aspergillus) excluded Reports: 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis Acremonium Fusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis)

14 Vehreschild et al. ICAAC 2012, abst. no. M-338 Chair: O.A. Cornely Coordination: M.J.G.T. Vehreschild, K. Wahlers Clinicalsurveys.net: J.J. Vehreschild Documentation: S. Proske GOALS: Collect epidemiological & clinical data Develop an evidence-based approach for diagnosis and treatment of IFIs due to emerging fungi ISHAM and ECMM Working Group Culture Banking: G. Fischer, A. Hamprecht Molecular Biology: S. De Hoog Pharmacokinetics: C. Mueller, F. Farowski Supported by unrestricted grants from Astellas Pharma, Merck/MSD, Gilead Sciences, Pfizer Courtesy of Prof. Oliver Cornely

15 Web-based electronic case form for registry Collection of clinical data & infecting strains Courtesy of Prof. Oliver Cornely

16 March 2013: 328 valid cases Courtesy of Prof. Oliver Cornely

17 LIFE- Leading International Fungal Education) LIFE is a growing organisation. Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy). The overall goal is to greatly improve fungal infection outcomes in patients through awareness, improved diagnosis and access to appropriate antifungal therapies, worldwide. Leaded by: Prof. David Denning 23rd ECCMID 2013-Berlin 27 April :30-16:30 - -POSTER SESSION Globe trotting: The burden of serious fungal infections P1034 P1045 (in association with the LIFE program) PUBLICATION ONLY Fungal Infections R2855, R2873 (in association with the LIFE program)

18 Background information & moulds as causative agents of infections Diversity of epidemiology per the risk factor HSCT & hematological malignancies Organ tx ICU Mould infections : (Changing?) epidemiology, reported outbreaks, and in vitro susceptibility Aspergillosis Mucormycosis Fusariosis Conclusions Scedosporiosis Agenda Other emerging mould infections in high risk patients

19 HSCT Allogeneic HSCT - - Timing of IFI with respect to the infecting mould Fig. 2. Timing of invasive fungal infections in allogeneic stem-cell transplant recipients. Reprinted with permission (Warnock David, 2003, personalcommunication). Maschmeyer G. Int J Antimicrob Agents 27S (2006): S3

20 HSCT Timing of IFI for non-aspergillus moulds Marr et al. CID 2002; 34: 909

21 Incidence of IA SEIFEM-2004 Study HSCT Cohort-retrospective study Years: cases of HSCT (1249 allo, 1979 oto) General IFI incidence: 3.7% Italy 11 Transplantation Units 7.8% of the episodes in cases of allo HSCT 1.2% o f the episodes in cases of auto HSCT Infecting fungi: Aspergillus (86 episodes) Candida (30 episodes) Pagano et al. CID 2007: 45: 1161

22 HSCT 983 IFIs among 875 HSCT recipients IA: 43 % IC: 28% Mucormycosis: 8% One-year cumulative incidences based on the first IFI: 7.7 cases / 100 tx (matched unrelated allogeneic) 8.1 cases / 100 tx (mismatched-related allogeneic) 5.8 cases / 100 tx (matched-related allogeneic) 1.2 cases / 100 tx (autologous HSCT)

23 TRANSNET: HSCT Cumulative incidence for each IFI Highest for aspergillosis Followed by candidiasis Non-Asp Non-Muc

24 Which fungus for which SOT? SOT Neofytos et al. Transplant Infect Dis 2010

25 SOT March 2001-March IFIs among 1063 organ tx recipients IC: 53 % IA: 19% Cryptococcosis: 8% Non-Asp moulds: 8% Endemic fungi: 5% Mucormycosis: 2% One-year cumulative incidences per each tx type and based on the first IFI: 11.6% (Small bowel tx) 8.6% (Lung tx) 4.7% (Liver tx) 4% (Heart tx) 3.4% (Pancreas tx) 1.3% (Kidney tx)

26 TRANSNET: Cumulative incidence for each IFI SOT 6 and 12 months after tx. Non-ASP

27 TRANSNET SOT Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged

28 Risk factors and infecting fungi ICU Shoham et al. J Intensive Care Med Dec 1, 2009

29 Incidence of IA in ICU ICU 17-26% in lung tx recipients IA (Leuven,Belgium-Univ. Hosp.) 5.8% in Medical ICU (COPD, liver failure) 5-24% in acute leukemia patients 5-15 % in allogenic bone marrow tx patients 2-13 % in heart tx recipients 1-3 % in lymphoma patients Patterson et al. Transpl Infect Dis 2000; 2: 22; Kontoyiannis & Bodey. Eur J Clin Microbiol Infect Dis 2002; 21: 161; Meersseman et al. CID 2007; 45: 205

30 Montagna et al. Infection 2013; March 6 Epub 2.3 cases / 1000 admissions Mortality: 61.5% AURORA Project Southern Italy 18 ICUs ICU (observational study) Febr 2007-Aug % 12 Asp 1 Scedo

31 Background information & moulds as causative agents of infections Diversity of epidemiology per the risk factor HSCT & hematological malignancies Organ tx ICU Mould infections : (Changing?) epidemiology, reported outbreaks, and in vitro susceptibility Aspergillosis Mucormycosis Fusariosis Conclusions Scedosporiosis Agenda Other emerging mould infections in high risk patients

32 EUCAST method and brkpt.s ICAAC 2012, San Francisco Abst. no. M-321 Population-Based Program of Aspergillus spp. Antifungal Resistance in Spain (FILPOP STUDY) Seven Spanish Hospitals Freq. of antifungal resistance in two different periods: Oct 2010 May 2011 Aspergillus strains isolated from resp. samples, paranasal sinus aspirates, blood cultures, and biopsies 277 strains isolated: % Species Alastruey-Izquierdo et al. 56% A. fumigatus sensu stricto 9% A. flavus 9% A. terreus 8% A. tubingensis 7.5% A. niger 3% A. nidulans 7.5% Other species

33 Incidence of aspergillosis in Europe Lass-Flörl et al. Mycoses 2009; 52: 197

34 Incidence of IA SEIFEMB-2004 Study HSCT 3228 cases of HSCT (1249 allo, 1979 oto) Italy 11 Transplantation Units General IFI incidence: 3.7% 7.8% of the episodes in cases of allo HSCT 1.2% o f the episodes in cases of auto HSCT Infecting fungi: Aspergillus (86 episodes) Candida (30 episodes) Pagano et al. CID 2007: 45: 1161

35 Sri Lanka July 2005 Five previously healthy women Asp meningitis following anesthesia for C/S.. Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster

36 USA Outbreak of fungal infection due to contaminated methylprednisolone injection Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy United States, 2012 Weekly CDC October 19, 2012 / 61(41); Four categories of cases following injection: 1. Fungal meningitis 2. Basilar stroke 3. Spinal osteomyelitis or epidural abscess at the site of injection 4. Septic arthritis or osteomyelitis following injection of that joint 14,000 persons potentially exposed to medications from at least one of the contaminated lots Evidence of a fungal inf. in 26 (37%) cases (Culture, histopath. or PCR) Aspergillus Exserohilum Fungal spp. identification n=13 in 14 cases: fumigatus n=1

37 Spain Seven patients Nonimmunocompromised postoperative patients High A. fumigatus airborne conidia levels

38 Antifungal Susceptibility Geo mean MIC (μg/ml) (MEC for Caspo) CLSI, 24 h 3 2,5 2 1,5 fumigatus flavus nidulans terreus ustus niger 1 0,5 0 AMB Itra Vori Caspo Arikan et al. Antimicrob Agents Chemother 2001, 45: 327; Arikan et al. Antimicrob Agents Chemother 2002, 46: 3084; Arikan et al. J Clin Microbiol 1999, 37: 3946; Meletiadis et al. J Clin Microbiol 2002, 40: 2876; Kanj et al. Medicine 1996, 75: 142; Iwen et al. J Clin Microbiol 1998, 36: 3713; Denning et al. Antimicrob Agents Chemother 1997, 41: 1364; Cuenca-Estrella et al. ICAAC 2012 San Francisco; M-321

39

40 EUCAST method and brkpt.s ICAAC 2012, San Francisco Abst. no. M-321 Population-Based Program of Aspergillus spp. Antifungal Resistance in Spain (FILPOP STUDY) Seven Spanish Hospitals Freq. of antifungal resistance in two different periods: Oct 2010 May 2011 Resistance reported for: Alastruey-Izquierdo et al. Average prevalence of R: < 8% Resistance rate in cryptic/sibling species: >50% AMB resistance: A. alliaceus A. fumigatiaffinis A. insuetus A. westerdijikiae A. lentulus (66%) A. flavus (22%) A. terreus (27%) Azole resistance: Section Usti (all azoles) A. lentulus (Itra, all isolates) A. fumigatiaffinis (Itra, all isolates) A. tubingensis (Itra, one isolate) A. fumigatus (Posa, one isolate)

41 Background information & moulds as causative agents of infections Diversity of epidemiology per the risk factor HSCT & hematological malignancies Organ tx ICU Mould infections : (Changing?) epidemiology, reported outbreaks, and in vitro susceptibility Aspergillosis Mucormycosis Fusariosis Conclusions Scedosporiosis Agenda Other emerging mould infections in high risk patients

42 Routes of entry Order Mucorales Soil, decaying vegetation, manure, foodstuff.. INHALATION of the aerosolized spores Entry of spores through the disrupted SKIN following trauma/burn INGESTION of contaminated foodstuff Renovation

43 Any increase in non-aspergillus moulds? Fusarium Zygomycetes Scedosporium Figure 2. Frequency of non-aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle). The number of patients who developed proven or probable infection with Fusarium species ( ), Zygomycetes ( ), and Scedosporium species ( ) from 1985 through 1999 are shown. Marr et al. CID 2002; 34: 909

44 Any increase in incidence of mucormycosis? M.D. Anderson Cancer Center, Houston, TX Underlying reason? cases/ admissions Kontoyiannis et al. Clin Infect Dis 2000; 30:851

45 Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole Vori for IA Cunninghamella spp. Acute GVHD Vori for IA Rhizopus arrhizus Vori for inv fusariosis Histopathologic evidence Chronic GVHD Prophylactic vori Histopathologic evidence Vori for IA Histopathologic evidence Chronic GVHD Prophylactic vori Rhizopus microsporus Siwek GT et al. Clin Infect Dis 2004;39:584 Four cases of invasive mucormycosis (HSCT recipients) Receiving immunosuppressive therapy for presumed GVHD Receiving voriconazole prophylaxis Marty FM et al. New Engl J Med 2004;350:950 Four cases of invasive mucormycosis (HSCT recipients) Receiving immunosuppressive therapy for presumed GVHD Three receiving voriconazole prophylaxis One receiving empirical voriconazole therapy Imhof et al. Clin Infect Dis 2004,39:743

46 13 European countries

47

48 Nosocomial mucormycosis o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical Gastric mucormycosis Primary cutaneous mucormycosis Necrotizing fasciitis Maravi-Poma et al. Intensive Care Med. 2004;30:724; Linder et al. Am J Perinatol 1998;15:35; Mathews et al. J Med Vet Mycol. 1997;35:61; Mitchell et al. Lancet. 1996; 17:348:441; Patterson et al. Yale J Biol Med 1986; 59:453; Boyce et al. South Med J 1981;74:1132; Mead et al. JAMA; 1979; 20: 242:272

49 12-bed ICU Gastric mucormycosis-an outbreak of 5 patients (4 pneumonia, 1 polytrauma) CONCLUSIONS: Wooden tongue depressors contaminated by R. microsporus var. rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40%.

50 Christiaens et al. J Hosp Infect 2005; 61: 88 May-September 2004 Burns Unit Admission: 27 patients Burn wounds: Infected with Absidia: 5 Colonized with Absidia: 2 (attack rate: 25.9/100) Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients.

51 Cutaneous zygomycosis following attempted radial artery cannulation Kapadia & Polenakovik. Skinmed 2004; 3: 336 A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of the left arm. The patient had multiple medical problems, including advanced liver disease due to alcohol, diabetes mellitus, congestive heart failure, atrial fibrillation, chronic renal in sufficiency, and hypopituitarism requiring steroid replacement. Most recently, he was admitted to the intensive care unit, where he required intubation and mechanical ventilation support following respiratory failure secondary to pneumonia. At that time, an attempt was also made to place an arterial line in the left radial artery. A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement. Subsequently, the lesion drained serosanguineous fluid, and, during the next 2 days, it ulcerated with necrosis extending around the wrist and to the elbow...small tissue clippings were taken from the edge of the lesion and placed on culture plates. By the next morning, the patient's tissue culture grew a mold, later identified as Rhizopus.

52 Antifungal susceptibility CLSI 24 h, Geo mean MIC Itra Posa Vori Terbi AMB 0 Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces Dannaoui et al. J Antimicrob Chemother 2003, 51: 45; Sun et al. Antimicrob Agents Chemother 2002, 46: 1581; Tawara et al. Antimicrob Agents Chemother 2000, 44: 57; Sun et al. Antimicrob Agents Chemother 2002, 46: 2310, Sancak et al. 3rd National Congress of Fungal Diseases and Clinical Mycology, S-13, 378

53 Mucorales AFST Routine testing Not indicated Clinical relevance unknown In vitro-in vivo correlation? MIC R. oryzae & R. microsporus Posaconazole more effective in inf.s due to strains with MICs of 0.25 µg/ml as compared to those with MICs of 2 µg/ml MFC High posaconazole MFC Clinical failure (R. oryzae, single strain) CLSI M38-A2, EUCAST Def. Doc. E.Def 9.1, Rodriguez et al. AAC 2009; 53: 5022; Rodriguez et al. AAC 2010; 54: 1665, Spreghini et al. JAC 2010; 65: 2158

54 Mucorales AFST Epidemiologic knowledge: Genus-, species-, & strain-based variations Cunninghamella Relatively high posaconazole MICs (spec. for C. echinulata) C. bertholletiae Posaconazole MICs lower than AMB MICs Mucor Relatively high posaconazole MICs Rhizopus & Mucor Species-based differences in azole susceptibility Rhizopus oryzae Strain-based variations in posaconazole susceptibility Sun et al. AAC 2002; 46: 1581; Dannaoui et al. JAC 2003; 51: 45; Almyroudis et al. AAC 2007; 51: 2587; Arikan et al. Med Mycol 2008; 46: 567; Rodriguez et al. AAC 2009; 53: 5022; Alastruey-Izuierdo et al. AAC 2009; 53: 1686; Pastor et al. AAC 2010; 54: 4550; Rodriguez et al. AAC 2010; 54: 1665; Vitale et al. JCM 2012; 50: 66; Drogari-Apiranthitou et al. JAC 2012; 67: 1937

55 Background information & moulds as causative agents of infections Diversity of epidemiology per the risk factor HSCT & hematological malignancies Organ tx ICU Mould infections : (Changing?) epidemiology, reported outbreaks, and in vitro susceptibility Aspergillosis Mucormycosis Fusariosis Conclusions Scedosporiosis Agenda Other emerging mould infections in high risk patients

56 Fusarium infections - Incidence Italy Multicenter SEIFEM-2004 project 234 HSCT rec.s 250 IFIs Hematological malignancy Pagano et al. Hematologica 2006; 91: 1068

57 Fusarium infections - Incidence North America Multicenter PATH Project HSCT Neofytos et al. CID 2009; 48 (1 Febr): 265

58 Trends in epidemiology of fusariosis Girmenia et al.

59 Risk factors for fusariosis Courtesy of Prof. Oliver Cornely

60 Fusarium is isolated during monitorization of airborne fungi in ICUs (Portugal) Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumaná, state of Sucre, Venezuela [Article in Spanish] Centeno S, Machado S. Invest Clin Jun;45(2): Surveillance of nosocomial fungal infections in a burn care unit. Infection May-Jun;20(3): India. Chakrabarti A, Nayak N, Kumar PS, Talwar P, Chari PS, Panigrahi D.

61 Hospital water system as the reservoir for Fusarium 283 hospital water system samples 43% (water tanks, water, showers, sinks, and swabs from sink, shower heads, and wall) 57% Molecular match of strains of 8 fusariosis patients (F. solani) with an environmental or another patient s isolate Fusarium spp. (+) Fusarium spp. (-) Anaissie et al. CID 2001, 33: 1871; Anaissie et al. Blood 2003, 101: 2542

62 Nosocomial fusariosis Possible routes of acquisition Inhalation of spores: primarily from air secondarily by aerosolization from water

63 GM MIC (range) (µg/ml) In vitro susceptibility CLSI M38 microdilutio n24h F. solani F. oxysporum MIC range (µg/ml) AMB (1>16) (2->16) Itra >16 (>16) 0.11 ( ) Vori (0.25-8) (0.25-2) Posa 19.3 (1->16) 1 (1) Ravu 27.4 (4->16) 5.6 (4-8) Caspo (16->16) (16->16) Macro/microdil. adapted from CLSI method F. proliferatum F. verticilloides AMB Vori Ravu 0.5 >16 Arikan et al. J Clin Microbiol 1999, 37: 3946; Arikan et al. Antimicrob Agents Chemother 2002, 46: 245; Paphitou et al. Antimicrob Agents Chemother 2002, 46: 3298; Pfaller et al. Antimicrob Agents Chemother 2002, 46: 1032; Clancy et al. EJ Clin Microbiol ID 1998, 17: 573 Clancy CJ, Nguyen MH. Eur J Clin Microbiol Infect Dis 1998;17:573 5; Minassian B et al. Clin Microbiol Infect 2003;9:1250 2; Lionakis MS et al. Antimicrob Agents Chemother 2003,47:3252 9

64 F.solani: high azole MICs F. verticillioides: low posa MICs

65 Ireland J Hosp Infec 2008; 1 BAL from 4 ICU patients grew F. solani. The bronchoscope was in use only in ICU. Fusarium was isolated from the water supply of the endoscopy department. However, water entering the endoscope washer-disinfector is passed through a 0.2 µm filter and rinse water cultures from the washer-disinfector were negative. The origin of the contamination of the bronchoscope could not be established.

66 Khor et al. Asia North America France Switzerland Chang et al. Donnio et al. Am J Ophthalmol; 2007: 143: 356 Gorscak et al. Cornea 2007; 26: 1187 Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al. Klin Monbl Augenheilkd. 2008;225:418 Gaujoux et al.

67 Background information & moulds as causative agents of infections Diversity of epidemiology per the risk factor HSCT & hematological malignancies Organ tx ICU Mould infections : (Changing?) epidemiology, reported outbreaks, and in vitro susceptibility Aspergillosis Mucormycosis Fusariosis Conclusions Scedosporiosis Agenda Other emerging mould infections in high risk patients

68 Scedosporium: Routes of Entry Airborne outbreaks Inhalation Air-borne outbreak of nosocomial S. prolificans infection has been reported. (leukemic patients in the same ward, in rooms without HEPA filters/laminar airflows) Guerrero et al. Lancet 2001; 357: 1267 Trauma

69 Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans) Wise et al. Pathology 1993; 25: 187 Two fatal infections caused by Scedosporium inflatum in immunocompromised patients are described. One patient developed peritonitis with this fungus 3 mths post renal transplantation. After a stormy course in the intensive care unit he eventually died. The other patient was suffering from non- Hodgkin's lymphoma and showed persistent neutropenia. Progressive deterioration occurred, and disseminated fungal infection was found at post mortem. Both isolates were resistant to all commonly available antifungal agents.

70 Caira et al. Still very rare...

71 Cooley et al. 2007; 13: 1170 renovation renovation No significant change in the incidence of S. apiospermum infections in time

72 Grenouillet et al. But, increased incidence in some centers

73 Scedosporium: In vitro antifungal susceptibility MIC 90 (µg/ml) apiospermum prolificans miconazole voriconazole albaconazole nystatin Meletiadis et al. Antimicrob Agents Chemother 2002; 46: 62; Meletiadis et al Antimicrob Agents Chemother 2003; 47: 106

74 AAC 2012; 56: 2635 N=332 CLSI M38-A2 AMB, Itra, Vori, Posa, Isavu, Caspo, Mica, Anidula Lowest MICs (MIC 90 < 2 µg/ml) of voriconazole as compared to to other drugs against P. apiosperma and P. boydii Voriconazole being the only drug with meaningful activity against S. aurantiacum (MIC 90 = 1 µg/ml) Bimodal distribution of MICs in general (except for voriconazole), rendering speciesbased susceptibility predictions difficult Moderate activity of posaconazole and micafungin against a number of Scedosporium strains

75 Background information & moulds as causative agents of infections Diversity of epidemiology per the risk factor HSCT & hematological malignancies Organ tx ICU Mould infections : (Changing?) epidemiology, reported outbreaks, and in vitro susceptibility Aspergillosis Mucormycosis Fusariosis Conclusions Scedosporiosis Agenda Other emerging mould infections in high risk patients

76 Acremonium Resistance noted for AMB (some cases) Azoles (Fluconazole) Flucytosine Strabelli et al. Rev Soc Bras Med Trop 1990, 23: 233; Fung-Tomc et al. Antimicrob Agents Chemother 1998; 42: 313; Ioakimidou et al. DMID 2013; 75: 313;

77 An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al. DMID 2013; 75: 313 Greece Acremonium skin and soft tissue infection in a kidney transplant recipient Israel et al. Transplantation 2013; 95: e20 USA Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al. Int J Pediatr Otorhinolaryngol 2012 ;76:1387 Acremonium kiliense: reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al. JCM 2011; 49: 2342 USA Kuwait Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Díaz-Couselo & Zylberman Case Rep Infect Dis 2011;2011: Argentina

78 Paecilomyces Resistance noted for AMB (P. lilanicus) Fluconazole, itraconazole, flucytosine (P. lilanicus) Aguilar et al. Antimicrob Agents Chemother 1998, 42: 1601; Fung-Tonc et al. Antimicrob Agents Chemother 1998; 42: 313

79 Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections: Case Presentation and Review of Published Literature Rimawi et al. Mycopathologia 2013; 175: 3459 (-Imm.compromised host) USA Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al. Transpl Infect Dis 2012;14:E156 Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al. Perit Dial Int 2012;32:364 France A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host, Presenting as a Subcutaneous Swelling Permi et al. J Lab Physicians 2011;3:46 India Paecilomyces lilacinus in transplant patients: an emerging infection Rosmaninho et al. Eur J Dermatol 2010; 20: 643 Portugal

80 Trichoderma Resistance noted for Fluconazole Flucytosine Itraconazole MIC (μg/ml) AMB 1-2 Itra 16 Vori 2 Cases of invasive infections; hematologic malignancy / organ transplant rec. Munoz et al. J Clin Microbiol 1997, 35: 499; Richter et al. J Clin Microbiol 1999, 37: 1154; Chouaki et al. Clin Infect Dis 2002, 35: 1360

81 Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al. J Med Microbiol (Pt 12):1869 USA First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al. Tunis Med 2010 ;88: 52 Tunisia Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al. Med Mycol 2009; 47: 207 Turkey Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al. CMI 2008; 14: 1190 France Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al. CID 2008; 46:e116 France

82 Dematiaceous moulds other than S. prolificans Resistance noted for Fluconazole Flucytosine Alternaria Bipolaris Cladosporium Husain et al. Clin Infect Dis 2003, 37: 221; Mc Ginnis et al. J Clin Microbiol 1998, 36: 2353; Sharkey et al. J Am Acad Dermatol 1990; 23: 577; Mc Ginnis et al. Med Mycol 1998, 36: 243

83 .. Though they are uncommon causes of disease, melanized fungi have been increasingly recognized as important pathogens, with most reports occurring in the past 20 years. The spectrum of diseases with which they are associated has also broadened and includes allergic disease, superficial and deep local infections, pneumonia, brain abscess, and disseminated infection. For some infections in immunocompetent individuals, such as allergic fungal sinusitis and brain abscess, they are among the most common etiologic fungi. Melanin is a likely virulence factor for these fungi...triazoles such as voriconazole, posaconazole, and itraconazole have the most consistent in vitro activity.

84 Risk factors for infections due to dematiaceous fungi Courtesy of Prof. Oliver Cornely

85 Background information & moulds as causative agents of infections Diversity of epidemiology per the risk factor HSCT & hematological malignancies Organ tx ICU Mould infections : (Changing?) epidemiology, reported outbreaks, and in vitro susceptibility Aspergillosis Mucormycosis Fusariosis Conclusions Scedosporiosis Agenda Other emerging mould infections in high risk patients

86 Conclusions Epidemiology of mould infections displays a variable trend. Increase in incidence of some of these infections is reported in some centers. Among these, genera that are less-susceptible or resistant to antifungal drugs do exist. Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal therapy.

87 Thank you...