Scedosporium Apiospermum© by Heterothallic Author Species (Gilgado Et Al 2009) Pseudallescheria Apiosperma Sp

Treatment of IFIs due to Scedosporium and Fusarium species Sambatakou Helen

ESCMID Online Lecture Library Non-Aspergillus Molds

• Similar clinical picture as seen in aspergillosis • May be indistinguisable from Aspergillus spp. in tissues • More frequent skin lesions • More frequent CNS involvement • Fungemia • Persistent fever in sever© byely author immunosuppressed patients receiving conventional antifungal therapy • Difficult-to-diagnose and -to-treat • HighESCMID mortality Online Lecture Library Mold Infections in HSCT Recipients

Aspergillus spp. N=327 (82%) 16 14 12 10 Fusarium (n=31) n 8 Mucorales (n=29) 6 Scedosporium (n=10) 4 2 © by author 0 1985-89 1990-94 1995-99

Time period

ESCMID Online LectureMarr K, et al. Clin InfectLibrary Dis 2002;34:909 Fusarium - a plant pathogen

ESCMID Online Lecture Library Ecological niche: what is known?

- anthropogenic influenced soils, human impacted environments - abundance correlates with temperature, ammonium concentration, pH-value [Kaltseis et al. 2009, Ulfig et al. 2004] -hydrocarbon contaminated soil [April et al. 1998, 2000] →alkanes as carbon© by source author -P. boydii growth was stimulated on Biodiesel-Agar [Ulfig et al. 2008] - BeneficialESCMID impact Online of Diesel, Lecture rapeseed Library oil on S. dehoogii [Kaltseis&Rainer 2010]

First report of P. boydii in CF patients

ESCMID Online Lecture Library Milestones for Scedosporium spp.

1911 Monosporium apiospermum (Pseudallescheria boydii) from mycetoma

1984: Infection in humans Near drowning syndrome Scedosporium inflatum (S.prolificans) in osteomyelitis neurotropism

2000: Clinical© significance by author of colonisation in CF S.prolificans separate species S apiospermum complex including S. aurantiacum, P. minutispora, and S. dehoogii. ESCMID Online Lecture Library • Taxonomy of many clinically important fungi rapidly changing due to advances in molecular analysis • P. boydii complex is a well described pathogen able to cause both asymptomatic colonisation and disseminated infection • Genetic distinction between P. boydii telomorph and its anamorph S. apiospermum , and description of new species S. auarantiacum and S. dehoogii © by author

ESCMID Online Lecture Library Taxonomic evolution

• The Pseudallescheria/Scedosporium complex consists of :

• Pseudallescheria boydii Proposed anamorph • Pseudallesc angusta Scedosporium boydii • Pseudallesc ellipsoidea • Pseudallesc fusoidea • Scedosporium apiospermum© by Heterothallic author species (Gilgado et al 2009) Pseudallescheria apiosperma sp. nov. Scedosporium aurantiacum Pseudallescheria minutispora new species ScedosporiumESCMID dehoogii Online Lecture Library Scedosporium aurantiacum

• Described by Gilgado et al. in 2005 –Clade I • Emergence of S. aurantiacum as causative agents of human mycoses has© bybeen author highlighted.

ESCMID Online (Heath Lecture 2009, Blyth Library 2009) Scedosporium species differences S. apiospermum/P. S. prolificans boydii complex Teleomorph Pseudallescheria none apiosperma Ecology Polluted water& soil Soil, potted plants ↑N and ↓pH Distribution World-wide temperate Spain, Australia, US: © by authorCalifornia, Southern Virulence + - +++ +++

Virulence Peptidases, proteases, Melanins factors ESCMIDsiderophores Online Lecturesiderophores Library Scedosporium: species differences

Clinical feature S. apiospermum/P. S. prolificans boydii Respiratory colonisation Cystic fibrosis, lung Less common as transplant, bronchiectasis coloniser airways

Pneumonia/brain Near drowning Neutropenia/GVH/SOT abscess/dissemination Rare cause CNS infection Soft tissue, bone, joint Immunosuppressed Trauma/surgery/burns infection especially post but otherwise corticosteroids/SOT© by author immunocompetent

Cortez et al, Clin Micro Reviews 2008;21:157. ESCMIDCooley etOnline al, Emerg Infect DisLecture 2007, 13:1170. Library Clinical relevance

• Mycetoma •Systemic infections: > mycoses in the CNS  immunocompromised patients have higher risk  immunocompetent patients (near-drowning event)  •Scedosporium aurantiacum (80 %) and S. dehoogii (70 %) are most virulent [Gilgado© by etauthor al. 2009]  •S. apiospermum (57 %) and P. boydii (33 %) are most common in clinical settings [Kaltseis et al. 2008, Gilgado et al. 2009] ESCMID Online Lecture Library

Scedosporium mycotic aneurysms (1990’s-2009)

Patient no. Comorbidity Pathogen Site Site infection aneurysm 1 Nr. drowning S.apiosperm Brain Int carotid 2 Renal Tx S.apiosperm BV Aorta 3 AML S. prolificans Brain, lung Basilar 4 Sinusitis S.apiosperm Sinus Basilar 5 Nr. drowning S.apiosperm Brain Post cerebral 6 HSCT S. prolificans Bone, sinus Hepatic 7 SI Tx S.prolificans© by author NA NA 8 Nr. drowning S.apiosperm Lung Int carotid 9 (Pt 1) Diabetes S.apiosperm Bone Superior cerebellar 10 (Pt 2)ESCMID Renal Tx OnlineS.apiosperm Lecture Skin, BV, Library Aorta bone Scedosporium mycotic aneurysms Patient no. Pathogen Therapy Outcome 1 S. apiospermum Surgery, AMB (IV, Death IT) 2 S. apiospermum Surgery, FLU, Mic Death 3 S. prolificans AMB, ITC Death 4 S. apiospermum Surgery, FLU, Mic Death 5 S. apiospermum Surgery Death 6 S. prolificans Surgery, CAS, Alive day 500 © byVOR, author terbinafine 7 S. prolificans ITC Death 8 S. apiospermum Surgery, FLU Death 9 (Pt 1) ESCMIDS. apiospermum Online Surgery,Lecture VOR LibraryDeath 10 (Pt 2) S. apiospermum Surgery, VOR Death Distal thoracic aorta with mural rupture scedosporiosis

ESCMID Online Lecture Library Scedosporium: species differences

Clinical S. S. prolificans feature apiospermum Positive blood 5% 30-40% cultures Multiple skin Rare Neutropenia/GVH/SOT lesions

Overall 10% 48% Mortality © by author

Husain et al, Clin Infect Dis 2005:40:89 Rodriguez-Tudela et al, Medical Mycology 2009: 47: 359-70. Cortez et al, Clin Micro Reviews 2008;21:157. Photos: Dr Chris Heath, ESCMID Online Lecture LibraryRoyal Perth Hospital Australian Scedosporium Study (AUSCEDO) Australia-wide population-based surveillance 2003-2005, 49 laboratories

• 180 cases: 118 (65.6%) colonization 62 (34.4%) infection. • 100 study isolates plus 40 additional isolates genotyped by ITS-RFLP analysis, ITS sequencing, and M13 PCR ﬁnger- printing. • A substantial numbers© of by S. aurantiacumauthor and its ability to cause a wide range of invasive infections. (Delhaes

2008, Cooley 2008, Heath 2009)

•Abundance of S. aurantiacum in the environment. (Harun, Med ESCMID OnlineMycol 2010)Lecture Library

S. aurantiacum vs. S. apiospermum (% isolations) Parameter S. aurantiacum S. apiospermum (n=29) (n=42) Solid tumour ca. 7 10 Lung Tx 7 10 Diabetes 17 14 Chr. lung disease 52 19 - CF 4 5 © by author - Other 48 14 Steroid receipt 24 31 InvasiveESCMID disease Online21 Lecture Library33 Scedosporium

S. aurantiacum S. prolificans

© by author S. aurantiacum:37% isolates previously identified as S. apiospermum in Australia Heath et al, Clin Microbiol Infect 2009:15:689-93. ESCMID Online Lecture Library Methods: culture Culture: SABD, Mycosel, SceSel+

Media Sensitivity

SABD 47%

Mycosel 50%* © by author SceSel+ 91%*

Blyth et al, 2010 ESCMID Online Lecture LibraryKaltseis et al, 2009 •Little to distinguish the organisms •Some S. aurantiacum demonstrated a yellow/gold colonial appearance after more than 7 days growth • Longer/ Obovoid conidia – subjective interpretation

ESCMID Online Lecture Library Outcome S. aurantiacum infection

• Lung , eye , sinus, ear, bone, skin, cardiac: (n=17)

• No deaths at 90 days • 14 received voriconazole (9 had surgery); 3 had surgery only • Benign outcome of note: virulence in © by author animal models of infection

Gilgado Med Mycol 2008; Harun Med Mycol 2010 ESCMID Online Lecture Library MIC90 of Scedosporium

AmB Itra Vori S. apiospermum (20) 16.0 0.5 0.125

S.prolificans (20) 16.0 8.0 4.0

Newer agents: Posa Albacon Caspo S. apiospermum (50+) 2.0 1.0 >16

David Ellis, Mycology Reference Laboratory, WCH, Adelaide Cortez et al, Clin Micro Reviews, 2008;21:157. ESCMIDMeletiadis Onlineet al, Antimicrob AgentsLecture Chemother 2002;46:62,Library Carilo et al Antimicrob Agents chemother 2001: 45:2151 Scedosporium: antifungal therapy • Synergy in vitro by checker board testing: – Australian S. prolificans (n=76): voriconazole/terbinafine 86%, itraconazole/terbinafine 58% – S. prolificans (n=12) ravuconazole/echinocandin 42% – S apiospermum (n=12) itraconazole/echinocandin 100% – Antagonism not seen; No animal models describing synergy • Treatment series voriconazole (n=107): 57% response • Case reports: voriconazole/terbinafine, voriconazole/caspofungin miltefosine plus voriconazole/terbinafine© by author

Cuenca-Estrella AAC 2008; Guarro JAC 2011; Troke AAC 2008; Kesson CID, 48: Steinbach , JCM 2003;Howden Eur J Clin Micro and Inf Dis 2003, Meletiades J, AAC2002, AAC 2003 ESCMID Online Lecture Library Scedosporium: adjunctive therapy

• Surgery: extensive debridement • Granulocytes: no survivors without recovery • Growth factors: G-CSF, GM-CSF, IFN-γ • S. prolificans (n=162): multivariate analysis risks for mortality – Reduced : surgery (p=0.006), recovery from aplasia (p=0.000) © by author – Higher : disseminated (p=0.002), CNS (p=0.008) infections

Rodriguez-TudelaESCMID et al, Medical Online Mycology Lecture 2009: 47: 359- Library70 Scedosporiasis – treatment recommendations

Sc.prolificans: primary: surgery+itraconazole (400mg/d po) alternative: vori+terbinafine © itra+terbinafine* by author  posaconazole successful in a case of brain abscess ( CID 2002;34:1648) *ScandESCMID J Infect Dis 2007;39:87Online Lecture Library Scedosporiasis – treatment recommendations

Sc.apiospermum: primary (Ps. boydii) voriconazole alternative surgery+itraconazole 200mg bid po © by author or posacona zole ESCMID Online Lecture 400mg bid Library

Fusarium spp immunocompetent hosts Peritonitis in association with peritoneal dialysis

Arthritis/osteomyelitis following trauma

Onychomycosis Keratitis consequence of corneal trauma © by author associated with contact lens wear

ESCMID Online Lecture LibraryHay & Baran AJAD 2011 Epidemic curve for the outbreak of Fusarium keratitis 2005-2006 outbreaks of associated with contact lens wear (Singapore). Fusarium keratitis associated with contact lens wear

Confirmed cases of Fusarium keratitis in the United States, June 2005-July 2006 Month of illness onset of confirmed cases of Fusarium keratitis reported to the Centers for Disease Control and Prevention. Khor, W. et al. JAMA 2006;295:2867-2873

Patients with fungal keratitis. Patient 1 has classic characteristics of fungal keratitis, which include stromal infiltrate with indistinct, feathery edges, and satellite lesions. © by author

Khor, W. et al.ESCMID JAMA Online LectureChang, D. C. et al. JAMA Library 2006;295:2867-2873 2006;296:953-963 Fusarium spp immunocompromised hosts

Portal of entry:

 sino-pulmonary  broken skin  pre-existing onychomycosis

Rapid dissemination of infection due to sustained release of conidia Metastatic skin lesions

Poor prognosis of Nucci & AnaissieESCMID CID 2002 Online Lecture disseminatedLibrary infection Fusarium: Paranasal Cellulitis and Sinusitis

Papular lesions Necrosis on hard palate

ESCMID OnlineNucci Lecture & Anaissie. Clin Infect Library Dis 2002; 35: 909 Fusarium infections: community acquired or hospital acquired?

Fusarium species present in outdoor air recovered from hospital water system (water, water storage tanks, shower and sink drains, shower heads, sink faucet aerators) present© inby hospital author air

ESCMID Online LectureAnaissie Library et al CID 2001 Fusarium species most frequent cause of invasive infection

60 Nucci & Anaissie CMR 2007 50 40

ESCMID Online Lecture Library High resistance of Fusarium strains to the available drugs F. solani shows the highest MICs no significant differences among the cryptic species Azor M et al AAC 2007

F. verticillioides ESCMID Online Lecture Library Amphotericin B - Fusarium

Efficacy rates 32% for amphotericin B 46% for amphotericin B lipid formulations

ESCMID Online Lecture Library

 47% success rate  Baseline neutropenia impacted success adversely  Success varied by underlying condition and infection site  Combination therapy (13 pts) was no better than treatment© with by voriconazole author alone

ESCMID Online Lecture Library Treatment of disseminated fusariosis

 Lack of data from clinical trials  Potential efficacy of posaconazole and of voriconazole recently shown by retrospective analyses

 Itra-, alba-, ravuconazole, limited efficacy  Isavuconazole: promising against some Fusarium sp  Combination therapy?  Complimentary therapy: surgical debridement Removal© by ofauthor CVC - G-CSF, GCSF, - granulocyte transfusions ESCMID Online Lecture Library - New therapies: MGCD290+Αzoles, E1210? E1210 Novel mechanism of action (inhibition of glycosylphosphatidylinositol biosynthesis)

 in vitro active against F. solani strains resistant to the azoles and echinocandins tested

 effective in treating disseminated fusariosis in a murine model: all mice treated with E1210 (20 mg/kg) survived compared to 20% survival of controls © by author

Hata K et al JCM 2011, 55: 4643- 51 Miyazaki M et al JCM 2011, 55: ESCMID Online Lecture Library4652-8 Fusariosis - treatment recommendations

• Primary ( esp. F. solani, F. verticillioides) -lipid-based AmphoB ( 5-10mg/kg/d ) -dAmphoB ( 1-1.5mg/kg/d ) • Alternative: -posaconazole -voriconazole © by author ( Fusarium Solani: R to azoles) • Surgical debridement for localized disease • RemovalESCMID of CVC Online Lecture Library

ESCMID Online Lecture Library AUSTRIA GERMANY PORTUGAL BELGIUM GREECE SERBIA CZECHOSLOVAKIA IRELAND SPAIN DENMARK ITALY SWEDEN

ESCMID Online Lecture Library

ESCMID Online Lecture Library Conclusions

• Fusarium and Scedosporium spp are important pathogens of immunocompromised and competent hosts • Disease manifestations dependent on species and host • Importance of local epidemiology • Taxonomy is still being elucidated • Need to correlate newly© by defined author species with risk groups, clinical outcomes and antifungal susceptibility

ESCMID Online Lecture Library

So called “rare Pathogens”

• however: • “the more you search, the more you find !” • clinical relevance often unknown • rare = hard to treat

ESCMID Online Lecture Library Diagnosis and management is a teamwork

ESCMID Online Lecture Library