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

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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). © by author 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 © by author 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 © by author 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 © by author 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
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