Problems in Treatment Arising from the Fungus • Treatment of Ifis Due to Mucorales

Problems in treatment arising from the fungus • Treatment of IFIs due to Mucorales

George Petrikkos, MD, Professor of Internal Medicine and Infectious© by Diseasesauthor National and Kapodistrian University of Athens Greece

[email protected] ESCMID Online Lecture Library

Zygomycetes

Mucorales Entomophthorales

Mucoraceae Cunninghamellaceae Ancylistaceae • Absidia • Cunninghamella • Conidiobolus • Apophysomces Saksenaceae Basidiobolaceae • Mucor • Saksenaea • Basidiobolus • Rhizomucor Syncephalastraceae • Rhizopus • Syncephalastrum© by author Thamnidaceae • Cokeromyces ESCMID Online Lecture Library Ribes et al. CMR 2000 INTRODUCTION

Zygomycosis has emerged as an increasingly important infection with a high mortality. It is the third Invasive Mycosis in order of importance after Candidiasis and Aspergillosis© by author

ESCMID Online Lecture Library INTRODUCTION (CONT/D)

Most of zygomycotic infections especially those caused by the order of Mucorales occur in patients with underlying diseases. However, species of the order of Endomopthorales are responsible for the chronic subcutaneous© by immunocompetentauthor patients in tropical and subtropical regions ESCMID Online Lecture Library • The genera in the Order Mucorales cause most human infection. • These organisms are ubiquitous in nature, and can be found on decaying vegetation and in the soil. • These fungi grow rapidly and release large numbers of ©spores by author that can become airborne. ESCMID Online Lecture Library Solid organ Burn AIDS 3% transplantation 1% Cancer 5% 5% Surgery 6%

Other 6%

Trauma © by author 10% Hematological Malignancy Diabetes 54% 10% ESCMID Online Lecture Library The mucorales most commonly found in human infections are : • Rhizopus, • Mucor, and Rhizomucor; • Cunninghamella, • Absidia, • Saksenaea, • and Apophysomyces© by author are genera that are less commonly implicated in infection . ESCMID Online Lecture Library Acrophialophora sp. 0% Rhizomucor 12% Absidia sp. 19% Cunninghamella sp Mucor sp 5% 30% © by Rhizopusauthor sp 33%

Apophysomyces ESCMIDsp Online Lecture Library 1% Mortality Due to Mold Infections

100%

80% 64,0%

60% 52,0% 42,0% 40% % of patientsof %

20% © by author 0% Aspergillus spp Zygomycetes Fusarium spp

11,802 patients (18 centers) ESCMID OnlinePagano Lecture L et al. Haematologica Library 2006;91:1068- 1075. Kaplan-Meier curve showing probability of survival for 53 transplant recipients with various types of mold infections (Pp.153, by the Mantel-Cox test).

ESCMID Online Lecture Library Mycelial Fungi and Transplantation • CID 2003:37 (15 July) • 227 High index of suspicion in patients with: • Diabetes • Hematological malignancies • Transplantation • Neutropenia • Therapy with corticosteroids or other immunosuppressive© by drugs author • Burns • TraumaESCMID Online Lecture Library DIAGNOSIS OF MUCORMYCOSIS Diagnostic tools include: Clinical signs

imaging endoscopy biopsies cultures © by author molecular techniques

ESCMID Online Lecture Library DIAGNOSIS OF MUCORMYCOSIS Clinical signs Early signs such as:

Persisting fever after broad spectrum antibiotics in a high-risk patient Sinusitis Pulmonary infiltration New skin lesion © by author should alert for prompt action implementing a diagnosticESCMID work Online up and initiateLecture therapy. Library Mucormycosis

The most frequenly observed clinical manifestations  Rhinocerebral

 pulmonary zygomycosis  cutaneous

While cases have been described  gastrointestinal © by author  CNS  disseminated and others…ESCMID Online Lecture Library DIAGNOSIS OF MUCORMYCOSIS

Clinical signs, imaging and endoscopy only SUGGEST the diagnosis of mucormycosis. Tissue testing is necessary for confirming the diagnosis

 Direct examination  Culture © by author  Histopathology  MolecularESCMID Onlinemethods Lecture Library

DIAGNOSIS OF MUCORMYCOSIS Imaging

non-specific Important for evaluating extent of disease

ESCMID Online Lecture Library Collection of specimen and specimen sampling Absence of non invasive test+++

Tissue biopsies or specimen obtained aseptically from sterile site should be preferred for histopathology and culture

Mucormycosis Specimen Location Cutaneous Skin biopsy Rhinocerebral Sinus aspirate, tissue biopsy Pulmonary Bronchoalveolar lavage Biopsy of pulmonary lesions (transbronchial or percutaneous© CT- by guided) author

Digestive Per surgical or per endoscopic tissue biopsy ESCMID Online Lecture Library Direct examination and histopathology • Direct examination: • Specific morphological characteristics: Hyaline hyphae, non septate, ribbon-like with a large and irregular diameter (5 to 25µm), with wide branching angles • Histopathology: © by author Necrosis, angioinvasion, infarction, neutrophilic reaction Hyphae ESCMID Online Lecture Library Culture

• Often negative • Slice biopsies, no grinding • Rapid growth [24h at 25- 37°C] • Genus and species identification

ESCMID Online Lecture Library Histopathology . The tissue reaction is usually slight.

. Acute suppurative inflammation predominates with focal areas of granulomatous inflammation.

. Hyphae usually vary from 6-50 um in diameter, are sparsely septate, and irregularly branched. © by author . The organism characteristically invades the walls of adjacent blood vessels, producing thrombosis and infarction, but rarely disseminatesESCMID through Online the Lecture vessels. Library

Why the lack of progress?

 Clinical manifestations are non-specific

 Conventional diagnostic tests insensitive, positive late in infection

 Inability to perform invasive diagnostic procedures© by author

ESCMID Online Lecture Library Why do we need new diagnostic methods?

Early initiation of therapy critical

Rx within 96h - 3 complete resolution - 3 partial response Rx delayed >2w - 11/11 died © by author - 7 diagnosed at PM

ESCMID OnlineAisner et Lecture al Ann Intern LibraryMed 1977; 86: 539-43 Molecular identification from tissue samples • No standardization • Fresh or frozen samples: • Molecular identification of zygomycetes: – Confirm diagnosis – Identify the fungus to the genus and species level • Different techniques: – DNA probes targeting 18S subunit – ITS1 sequencing after PCR with pan-fungal primers – 18S-targetted semi-nested PCR – Real-time PCR targeting© by cytochrome author b gene • Formalin-fixed paraffin-embedded tissues: lack of sensitivity ESCMID Online Lecture Library

TREATMENT OF MUCORMYCOSIS Successful therapy for zygomycosis involves a combined approach. It is based on early diagnosis, which leads to both prompt institution of medical therapy and extensive surgical debridement of all devitalized tissue. The overall survival rate in zygomycosis has© bybeen author about 50% and in the last 10 years about 80%.

ESCMID OnlineClin.Infect. Lecture Dis. 1999;28:160-1 Library Combined approach in the treatment of mucormycosis

High level of suspicion Early Diagnosis

Combined Approach Medical Therapy Surgical Debridement © by author

Improved Outcome ESCMID Online Lecture Library Treatment

• Liposomal amphotericin B • Posaconazole

• Surgical debridement • Hyperbaric oxygen in some cases

ESCMID Online Lecture Library Amphotericin B - Activity in vitro *

AMB PCZ ITC % ≤1ug/mL % ≤0.5µg/mL % ≤0.5µg/mL Rhizopus sp (101) 100 80 62 Rhizopus arrhizus (20) 100 64 50 Rhizopus microsporus (12) 100 78 60 Mucor sp. (41) 94 70 57 Mucor circinelloides (6) 100 0 0 Rhizomucor sp.(5) 100 67 67 Absidia corymbifera (9) © by100 author100 100 Cunninghamella sp. (13) 63 75 29 Apophysomyces elegans (6) 100 83 80 ESCMID Online Lecture Library * M38-A Almyroudis et al., AAC 07 Newer antifungals

• Among newer azoles Posaconazole is more active and promising

• Echinocandins have poor activity

• Voriconazole has been associated with breakthrough zygomycosis in high risk patients © by author

• Combination therapy of liposomal ampB+CaspofuginESCMID Online may Lecture be an Libraryapproach Other antifungal agents beside amphotericin B and posaconazole • Flucytosine, fluconazole, voriconazole and terbinafine have no meaningful activity • Itraconazole – Some variable in vitro and experimental activity, best activity being reported against Absidia spp. (Dannaoui et al, 2002) – Rare case reports (Eisen et al, 2004; Liao et al., 1995; Parthiban et al., 1998; Zhao et al., 2009), insufficient to support its use in zygomycosis • Isavuconazole – Broad spectrum triazole including Mucorales with MIC50 values of 1 to 4 mg/mL and MIC90 values of 4 to 16 mg/mL (Verweij et al., 2009) – So far no clinical data • Caspofungin, anidulafungin and micafungin – No efficacy in vitro against Zygomycetes (Almyroudis et al., 2007; Espinel- Ingroff et al., 1998; Isham et al., ©2006) by author – Caspofungin has shown efficacy in an animal model but with an inverse-dose response relationship: low dose more effective high dose (Ibrahim et al., 2005) No– No recommendation clinical data are available for the use with of echinocandin any of these in agents monotherapy as monotherapy ESCMID Online Lecture Library Combination therapy: clinical data

• Retrospective study in rhino-orbito-cerebral zygomycosis (Reed et al., 2008) –Monotherapy with AmB formulation (31 patients) or a combination of caspofungin and ABLC or L-AmB (6 patients) –Patients receiving a combination had a higher response rate and survival –Limitations: rhinocerebral only, most pts had diabetes and all had surgery

• Combination of deferasirox and L-AmB (Spellberg et al., 2009) –8 patients received deferasirox in addition to their antifungal therapy –Only events attributable to deferasirox were skin rashes in 2 patients. –7 of the 8 patients responded to therapy. –Limitations: low number of pts,© byvarious author combinations used in this study

ESCMID Online Lecture Library Guidelines for treatment of zygomycosis by ECIL 3 A. Skiada, A. Groll, R. Herbrecht, F. Lanternier, O. Lortholary, L. Pagano,© S.by Zimmerli, author G. Petrikkos.

ESCMID Online Lecture Library Guidelines for treatment of zygomycosis by ECIL 3 A. Skiada, A. Groll, R. Herbrecht, F. Lanternier, O. Lortholary, L. Pagano, S. Zimmerli, G. Petrikkos.

ESCMID Online Lecture Library Guidelines for treatment of zygomycosis by ECIL 3 Recommendation for first line (part 1) Management includes antifungal therapy, control of underlying conditions and surgery. A II Antifungal therapy AmB deoxycholate C II Liposomal AmB B II 1 ABLC B II 1 ABCD C II Posaconazole © by CIIIauthor2 Combination therapy CIII

1 Liposomal amphotericin B should be preferred in CNS infection and/or renal failure. ESCMID Online Lecture Library 2 No data to support its use as first line treatment. May be used as an alternative when amphotericin B is absolutely contraindicated. Recommendation for first line (part 2) Management includes antifungal therapy, control of underlying conditions and surgery. A II Control of underlying condition A II 3 Surgery - rhino-orbito-cerebral A II - soft tissue A II - localized pulmonary lesion B III - disseminated CIII4 Hyperbaric oxygen CIII

© by author 3 Control of underlying condition includes control of diabetes, hematopoietic growth factor if neutropenia, discontinuation/tapering of steroids, reduction of immunosuppressive therapy. 4 Surgery ESCMIDshould be considered Online on Lecture a case by Librarycase basis, using a multi-disciplinary approach. Recommendation for second line and maintenance therapy Second line Management includes antifungal therapy, control of underlying disease and surgery. A II

Posaconazole BII Combination lipid AmB and caspofungin BII Combination lipid AmB and posaconazole CIII Combination with deferasirox CIII

Maintenance therapy © by author Posaconazole B III 5 5 Overlap of a few days (at least 5) with first line therapy to obtain appropriate serum levels. Monitoring of serum levels might be indicated ESCMID Online Lecture Library Recommendation for second line and maintenance therapy Second line Management includes antifungal therapy, control of underlying disease and surgery. A II

Posaconazole BII Combination lipid AmB and caspofungin BII Combination lipid AmB and posaconazole CIII Combination with deferasirox CIII

Extensive surgical debridement of necrotic tissue is essential component in the treatment of zygomycosis.

ESCMID Online Lecture Library Role of surgery

• Pagano et al. BMJ 2009 ESCMID Online Lecture Library Rhinocerebral zygomycosis Surgical intervention

ESCMID Online Lecture Library 3-D CT after operation

ESCMID Online Lecture Library Patient after reconstruction

ESCMID Online Lecture Library Services implicated in the management of mucormycosis

ESCMID Online Lecture Library Conclusion

It is important to remember fungi as causes of necrotising soft-tissue infection because rapid diagnosis, surgery, and prompt treatment with antifungals can do much to reduce the high mortality of these infections. © by author

ESCMID Online Lecture Library Summary

• PROGRESS IN DIAGNOSIS

– Molecular methods are used more often – Better communication between various centers aid the diagnosis

• PROBLEMS IN DIAGNOSIS © by author – Not always possible to obtain tissue – Not all laboratories have trained personnel – SomeESCMID methods Online are not Lecture standardized. Library Summary

• PROGRESS IN TREATMENT

– Lipid formulations of amphotericin B – Newer drugs, such as posaconazole offer new options for salvage treatment. – New modalities, such as deferasirox and immunomodulating agents?.

• PROBLEMS IN TREATMENT – No ideal drug exists© by author – The treatment is multimodal and , if the underlying diseases cannot be controlled, it is often very difficult to control the fungal infection. ESCMID Online Lecture Library What do we need for effecting management of Mucormycosis?

• More rabid and accurate diagnosis • Prospective comparative clinical trials • Newer antifungals • Guidelines • Join power of ©scientists by author

ESCMID Online Lecture Library Zygomyco.net: an ECMM/ISHAM registry

ESCMID Online Lecture Library