Due to Microascaceae and Thermoascaceae Species

Invasive fungal infections due to Microascaceae and

Thermoascaceae species

Mihai Mareș Laboratory of Antimicrobial© by author Chemotherapy University “Ion Ionescu de la Brad” Iași - Romania ESCMID Online Lecture Library

New aspects:

Nosocomial Emerging pathogens © infectionsby author

Risk patients Bioﬁlms on ESCMID Online Lecture Library indwelling devices The main players

Invasive candidiasis© by authorInvasive aspergilosis • average incidence: 2.9 cases per 100.000 in • average incidence: 2.3 cases per general population; 466 cases per 100.000 100.000 in general population; in neonates • attributable mortality: global 58% , • attributable mortality:ESCMID 49% Online Lecture• allogeneic-bone Library marrow Gudlaugsson, CID 2003 transplantation 86.7% Lin CID 2001 Emerging fungal pathogens

Zygomycetes

Scedosporium Paecilomyces

ESCMID Online Lecture Library Chair: Prof. Oliver Cornely Chair: Prof. George Petrikkos Emerging fungal pathogens belonging to Microascaceae and Thermoascaceae

• Taxonomic overview

• Clinical ﬁndings

• Treatment options © by author

ESCMID Online Lecture Library Taxonomic overview

ESCMID Online Lecture Library Taxonomic overview Microascaceae

Meiosporic genera: • Microascus • Pseudallescheria • Petriella Mitosporic genera: • Scopulariopsis (asexual relatives of Microascus) • Scedosporium (asexual relatives of Pseudalescheria and Petriella) © by author

ESCMID Online Lecture Library Taxonomic overview

ESCMID Online Lecture Library Issakainen 2009 Taxonomic overview

New trends in Pseudalescheria taxonomy • The former single species – Pseudallescheria boydii has become P. boydii complex or P. boydii© sensuby author lato. • P. boydii complex comprise: P. angusta, P. boydii sensu stricto, P. desertorum, P. ellipsoidea, P. fusoidea, P. minutispora, ScedosporiumESCMID apiospermum Online, S. Lecture aurantiacum Library, and S. dehoogii. Zeng et al. 2007, Med Mycol. Gilgado et al. 2009, Med Mycol. Taxonomic overview

New trends in Pseudalescheria taxonomy © by author • P. boydii and S. apiospermum, traditionally considered as the teleomorph and anamorph of the same species, belong to two different species.ESCMID Online Lecture Library Gilgado et al. 2008, JCM Taxonomic overview

ESCMID Online Lecture Library Gilgado et al. 2009, Med Mycol. Taxonomic overview

• Scedosporium proliﬁcans is not related to P. boydii complex, but to Petriella genus. • This species is homogenous from genetic point of view and is encountered only in its asexual stage.

Issakainen et al. 1999, Mycol Res. Gilgado et al. 2008, JCM ESCMID Online Lecture Library Ecology

• Pseudallescheria and Scedosporium species prefer human impacted environments such as agricultural and garden soil, sewage, polluted ponds and sediments (outdoor pathogens) • Hydrocarbon-contaminated soil was reported as a source of these fungi • P. boydii was isolated from brackish and salty water, oceanic estuaria, marine soil • These species are more abundant in soils containing high levels of ammonium and humic compounds • The proportion of S. dehoogii increases with the degree of human impact, whereas S. apiospermum is more abundant in agricultural soils, parks and© playgrounds by author than in industrial area. • S. proliﬁcans can be a nosocomial pathogen in some hospitals (air-borne, catheter-related) ESCMID Online Lecture Library Taxonomic overview Thermoascaceae

Meiosporic genera: • Thermoascus

Mitosporic genera: • Paecilomyces (asexual relatives of Thermoascus)

ESCMID Online Lecture Library Taxonomic overview Thermoascaceae Most important species

• Thermoascus crustaceus (Paecilomyces crustaceus) • Thermoascus taitungiacus (Paecilomyces taitungiacus) • Paecilomyces variotii • Paecilomyces lilacinus • Paecilomyces marquandii • Paecilomyces viridis • Paecilomyces javanicus © by author

ESCMID Online Lecture Library Taxonomic overview Thermoascaceae

• Paecilomyces variotii and its thermophilic relatives belong to the order Eurotiales (Trichocomaceae) • Mesophilic species related to Paecilomyces farinosus are in the order Hypocreales© by author ( Clavicipitaceae and Hypocreaceae).

Luangsa et al. 2004, Mycologia ESCMID Online Lecture Library Ecology

• Saprobic species commonly isolated from soil and a wide range of substrata, such as plants, animals, food products, air and indoor environment, and also from insects. • Two sections: Section Paecilomyces containing mostly thermotolerant to thermophilic taxa and Section Isarioidea containing mostly mesophilic species isolated from insects. • Some species can also grow above the body temperature of higher animals hence are potential human pathogens. • Some iatrogenic infections© by author reported (an outbreak of 12 patients associated with the use of an contaminated antiseptic solution in an IC setting) ESCMID Online Lecture LibraryLuangsa et al. 2004, Nat. Sci. Orth et al. 1996, Ann Intern Med. Clinical ﬁndings The Microascaceae as human pathogens Pseudallescheria Eumycetoma • A cronic, granulomatous, subcutaneous infection which is most common in the hot, arid areas of the world, but occurring also in the temperate Europe and USA because of an important cold-resistance exhibited by P. boydii. • Characteristic symptoms include painless swelling of the limbs after a soil- contaminated splinter of wood penetrate in the foot or hand. • The lesions mainly remain local but may slowly spread to adjacent tissues, including bones © by author • From the lesions (sometimes striking and invalidating deformities) is excreted a pus containing visible granules which consist of densely packedESCMID cells of theOnline causative Lecture Library organism.

emedicine.medscape.com Clinical findings The Microascaceae as human pathogens Pseudallescheria Other superficial infections • Skin infections other than mycetoma – painless subcutaneous nodules with serous contents, ulcerating or granulomatous masses, tinea-like interdigital maceration, papulo-bullous lesions • Eye infections – keratitis or even endophtalmitis after an injury of the eye surface with an contaminated foreign body (immunocompetent patients) or secondary to life-threatening, generalized infections through disemination (immunosupressed patients) • Ear infections – relatively benign© by authorand remain localized (chronic otitis) • Paranasal sinusitis – fungal ball (a spherule consisting of densely packed hyphae) due to P. boydii; rarely, the infection may gradually extendESCMID to the adjacentOnline Lecture bones and Library to the brain. Guarro et al. 2006 Issakainen 2009 Clinical findings The Microascaceae as human pathogens Pseudallescheria Infections of the lower respiratory tract • P. boydii usually is found as a colonizer of the lower airways • Colonization may proceed to the formation of a fungus ball – a compact spherule of densely packed hyphae measuring up to several centimeters • When special conditions occur (cystic fibrosis, long-term corticosteroid therapy), the fungus may spread in the lungs, thus leading to pneumonia. • P. boydii pneumonia is associated with a variety of symptoms including impaired respiratory functions and hemoptysis (half of cases were fatal) • In immunosuppressed patients, Pseudallescheria may disseminate from lungs to other organs (especially central nervous system) producing a disseminated infection with a poor prognosis.

• For S. proliﬁcans too, lungs are the© main by portalauthor of entry. • In patients with hematological malignancy or receiving immunosuppressive therapy, the fungus rapidly spread from lungs to virtually any organ, resulting in a fatal, disseminated infection • Rarely, relative ESCMIDbenign cases withOnline cough Lecture and fever occurLibrary (transient colonization) Issakainen 2009 Clinical ﬁndings The Microascaceae as human pathogens Pseudallescheria

Infections of the central nervous system

• P. boydii has a marked predilection for the nervous system, even in basically healthy person while for S. proliﬁcans, the nervous system is merely an organ among the others which are affected during the typically generalized infections

• Neural pseudallescheriasis often© starts by authorfrom near- drowning incidences of otherwise healthy people; other risk factors include general immunosuppression and various trauma, including surgicalESCMID Online treatments Lecture ofLibrary Issakainen 2009 immunocompetent persons Gelabert-Gonzales 2010, Neurocirurgia Clinical ﬁndings The Microascaceae as human pathogens Pseudallescheria

Infections of the central nervous system • Single or multiple brain abscesses are the most common phenomena during such infections • The symptoms are variable and include headache, facial paresis, neck stiffness, altered mental status, seizures, and infarcts. CSF typically has a high© count by author of white blood cells • Poor prognosis – the mortality rate is very high (80-90%) ESCMID Online Lecture Library Issakainen 2009 Caggiano 2011, Mycopathol. Clinical ﬁndings The Microascaceae as human pathogens Pseudallescheria

Infections of the central nervous system

• In S. proliﬁcans infections, the involvement of the brain is just a part of the patient’s life-threatening situation. • Usually, the patient has a background of immunosuppression • Meningoencephalitis, mental symptoms, brain hemorrhages and infarctions may occur © by author • Important, the fungus can be isolated from the brain, among other organs which are simultaneously positive (disseminated infection)ESCMID Online Lecture Library

Issakainen 2009 Clinical ﬁndings The Microascaceae as human pathogens Pseudallescheria

Other deep or disseminated infections

• Arthritis and osteomyelitis – infections can be acquired by healthy person after different traumas; under immunosupression, the infection may take a fatal course. • Endocarditis - the heart is an uncommon bur regular site of P. boydii infections; all recorded cases were fatal and moistly diagnosed post-mortem. Several patients had received a heart valve prosthesis before the infection. • Other deep or disseminated© infections by author – the angiotropism of the fungus allows the invasion of nearly any part of the body, such as muscles, testicles, kidneys or thyroid (with multiple organs involved at theESCMID same time) Online Lecture Library

Issakainen 2009 Clinical ﬁndings The Microascaceae as human pathogens Microascus/Scopulariopsis

Lower virulence and more benign symptoms !!!

• Fungal sinusitis – in immunosupressed individuals • External otitis – benign in healthy individuals, but complicated with mastoiditis and fatal infection in an immunocompromised patient • Nail infections – Scopulariopsis brevicaulis is the most frequent involved fungus in onychomycoses (5-6% of all nail fungal infections); most strains are genuinely keratinolytic, not merely keratinophilic and can enzymatically© by author invade the nails. The keratinolytic activity of Scopulariopsis is slower than that of dermatophytes, but sufﬁcient to warrant its status of primary nail pathogen.ESCMID Online Lecture Library

Issakainen 2009 Clinical ﬁndings The Microascaceae as human pathogens Microascus/Scopulariopsis

Deep infections are rare !!!

• Immunosupression status – mandatory for infection • endocarditis – in prosthetic valve recipients • Lower respiratory tract infections – pneumonia in a drug abuser • Infections of the CNS – few cases of severe CNS infections in immunocompromised individuals (cerebral abscess) • Soft tissue infections© by and author peritonitis – b o t h i n immunocompetent and –supressed patients

de Hoog et al. 2000 Mareș et al. 2007 ESCMID Online Lecture Library Issakainen 2009 Clinical ﬁndings The Microascaceae as human pathogens Microascus/Scopulariopsis

• 38-year-old paent under connuous peritoneal dialysis for 20 months • Under corcotherapy • Colonizaon of the intraabdominal catheter and subsequently fungal peritonis • Microascus cirrosus has been idenﬁed • Catheter removal, corcotherapy cancelaon and surgical treatment © by author • Favorable evoluon

ESCMID Online Lecture Library

Mareș et al. 2007 Clinical ﬁndings The Thermoascaceae as human pathogens Thermoascus/Paecilomyces

• Superﬁcial infecons are common, especially aer minor skin injuries • Keras, endophtalmis • Only few cases of deep-seated infecons: fungemia, prosthec valve endocardis, lung infecons, sinusis, and peritonis • Pneumonia due to T. crustaceus in a renal transplant recipient under corcotherapy (Mareș M. – unpublished data) – seems to be the ﬁrst case reported (favorable response under caspofungin treatment) © by author

ESCMID Online Lecture Library de Hoog, 2000 Korzets 2001, JCM Treatment options

In vitro suscepbility Scedosporium apiospermum

69 strains from deep infecons

Anfungals AMB ITC VRC POS TBF ATF %R Range 1-32 0,5-16 0,12-16 0,25-16 8,0-32 AMB 85 ITZ 100 GEO Mean 4,7 3,7 0,9 1,3 17,1 VOR 25 POS 40 MIC50 4,0 8,0 1,0 © by author 1,0 8,0 TER 100 MIC90 16,0 16,0 8,0 8,0 32,0 ESCMID Online Lecture Library Cuenca-Estrella et al. 2006, AAC Treatment options

In vitro suscepbility Scedosporium proliﬁcans

66 strains from deep infecons

Anfungals AMB ITC VRC POS TBF

Range 2-32 8-16 8-16 8-16 8-32

GEO Mean 12,8 9,6 9,4 10,5 19,2

MIC90 32,0 16,0 16,0 16,0 32,0 ESCMID Online Lecture Library Cuenca-Estrella et al. 2006, AAC Treatment options In vitro suscepbility 32 strains of Scopulariopsis brevicaulis

© by author • Mul-resistant organism • Combinaon of terbinafine and azoles has been considered as promising ESCMID Online LectureCuenca-Estrella Library et al. 2003, AAC Steinbach et al. 2004 Treatment options In vitro suscepbility 25 strains of Scopulariopsis brevicaulis • In a study concerning the activities of 10 combinations of antifungal agents against 25 clinical isolates of Scopulariopsis brevicaulis, it has been shown that all tested drugs had very high MICs (more than 8 mg/L) • An in vitro synergy was demonstrated for few combinations: posaconazole-terbinafine (68% of strains), amphotericin B-caspofungin (60%), and © by author posaconazole-caspofungin (48%). • Despite these findings, Scopulariopsis brevicaulis disseminatedESCMID infections Online are Lecture very difficult Library to treat. Cuenca-Estrella et al. 2006, AAC Treatment options In vitro suscepbility 58 strains of Paecilomyces

• Amphotericin B, itraconazole, and echinocandins showed poor activity against Paecilomyces lilacinus, while the new triazoles were active against it. • Paecilomyces variotii exhibited a different susceptibility pattern, being susceptible to most antifungal agents excepting voriconazole and ravuconazole. © by author

ESCMID Online Lecture LibraryCastelli et al. 2008, AAC Treatment options

Recommendaons for IFI

• Without an aggressive treatment, the prognosis is poor • Treatment must be start earlier • Combination between antifungals and surgery has better

results • Immunotherapy (G-CSF) may be of interest • Very difﬁcult in immunocompromised patients and disseminated infections • The fatality rate is still very© by high author

ESCMID Online Lecture Library Treatment options

ESCMID Online Lecture Library