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Treatment of Mucormycosis

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Treatment of Mucormycosis Anna Skiada, MD National and Kapodistrian University of Athens Greece ESCMID Online Lecture Library @ by author Financial disclosures • None pertaining to this presentation ESCMID Online Lecture Library @ by author Mucormycosis • Emerging fungal infection with high morbidity and mortality • Third cause of invasive fungal infections after Candida and Aspergillus • Second most common opportunistic mold infection (after aspergillosis) among patients with hematologic malignancies ESCMID Online Lecture Library @ by author Mucormycosis • Infection due to fungi of the class Zygomycetes, order Mucorales • Most common geni • Rhizopus • Mucor • Rhizomucor • Lichtheimia • Apophysomyces ESCMID• Cunninghamella Online Lecture Library @ by author Case Report • A 32-y.o. female patient was admitted to the hospital because of severe thrombocytopenia • Initial diagnosis: Idiopathic thrombocytopenic purpura • Methylprednisolone, 16mg tid • Danazol • One month later: Diagnosis of myelodysplastic syndrome ESCMID• Chemotherapy Online Lecture Library @ by author Case report (cont’ d) • A week later: The patient returns to the hospital with swelling over the left maxilla and intense pain • Examination of the oral cavity: normal • X-ray of sinuses: Sinusitis on the left side. ESCMID Online Lecture Library @ by author How should we manage the patient? 1. Start broad-spectrum antibiotics 2. Start an antifungal with activity against Mucorales 3. Arrange for a CT-scan of sinuses 4. Obtain an urgent ENT evaluation 5. Taper the dose of corticosteroids 6. 2, 3, 4 and 5 ESCMID Online Lecture Library @ by author How should we manage the patient? 1. Start broad-spectrum antibiotics 2. Start an antifungal with activity against Mucorales 3. Arrange for a CT-scan of sinuses 4. Obtain an urgent ENT evaluation 5. Taper the dose of corticosteroids 6. 2, 3, 4 and 5 ESCMID Online Lecture Library @ by author Problems in the diagnosis of mucormycosis The clinical signs and symptoms are non-specific Imaging signs are non-specific Various non-invasive tests (PCR, antigens etc) are not yet standardized Biopsy cannot always be performed due to severe thrombocytopenia in many cases Definite diagnosis is usually made in an advanced stage of the diseaseESCMID Online Lecture Library @ by author Early Initiation of Treatment Makes a Difference • 70 consecutive hematological patients • Start of treatment ≥6 days after diagnosis resulted in increased mortality at week 12 ESCMID Online Lecture Library @ by authorClin Infect Dis. 2008; 47: 503-509 Benefits of early diagnosis of Mucormycosis • Prevention of angioinvasion and dissemination of infection • Reduced need for extensive surgical resection • Reduced need for disfiguring surgery • Reduced suffering (invasion of sensory nerve fibers) • ImprovedESCMID outcome Online Lecture Library @ byAdapted author from Walsh TJ et al. CID suppl 2011 Underlying diseases- Risk factors • Diabetes mellitus • Hematologic malignancies (neutropenia) • Transplantation • Corticosteroids • AIDS • Hemochromatosis ESCMID Online Lecture Library • Occasionally, immunocompetent. @ by author Case report (cont’ d) • The symptoms were attributed to dental infection and amoxicillin was started. • Panoramic x-ray of teeth: No evidence of dental infection. • Metronidazole added to treatment. ESCMID Online Lecture Library @ by author Case report (cont’ d) • Three days later: Patient complains of diplopia, in addition to previous symptoms • Physical examination: black eschar on left side of hard palate, peripheral left facial nerve palsy and left abducens nerve palsy • Platelets: 28.000, neutrophils 5.000 ESCMID Online Lecture Library @ by author How should we proceed? 1. Obtain tissue from the eschar for direct microscopy, culture and histology 2. Start an anti-fungal active against Mucorales 3. Taper the corticosteroids 4. All of the above ESCMID Online Lecture Library @ by author How should we proceed? 1. Obtain tissue from the eschar for direct microscopy, culture and histology 2. Start an anti-fungal active against Mucorales 3. Taper the corticosteroids 4. All of the above ESCMID Online Lecture Library @ by author Imaging CT-scan: Opacity of left ethmoid and nasal cavity. No evidence of erosion. ESCMID Online Lecture Library @ by author Material taken from necrotic eschar, at the bedside, for culture and biopsy Direct microscopy of tissue: hyphae, non-septate, branching at right angles ESCMID Online Lecture Library @ by author Culture: Rhizopus sp. ESCMID Online Lecture Library @ by author Material taken from necrotic eschar, at the bedside, for histological examination ESCMID Online Lecture Library @ by author Case report (cont’d) • Liposomal amphotericin B, 5 mg/kg daily • Surgical debridement of hard palate ESCMID Online Lecture Library @ by author Antifungal drugs • Mucormycosis is resistant to most antifungal agents • Often encountered as a breakthrough infection in patients who are receiving antifungal agents against Aspergillus species (voriconazole) ESCMID Online Lecture Library @ by author Mucorales are Resistant to Most Antifungal Agents in vitro Inherently resistant to 5-flucytosine, ketoconazole, fluconazole, voriconazole Resistant to echinocandins? Limited in vitro activity of itraconazole and isavuconazole Amphotericin B is the most active agent Posaconazole has in vitro activity Cunninghamella are the most resistant spp Sun Q, Fothergill AW, McCarthy D et al. Antimicrob Agents Chemother. 2002; 46: 1581-1582 ESCMIDDannaoui E, Afeltra J,Online Meis J et al. Antimicrob Lecture Agents Chemother. 2002; Library 46: 2708-2711 Almyroudis N, Sutton DA, Fothergill A et al. Antimicrob Agents Chemother. 2007; 51: 2587-2590 @ byPerkhofer author S et al., Antimicrob Agents Chemother. 2009; 53:1645-47 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) 100 100 100 Cunninghamella sp. (13) 63 75 29 ApophysomycesESCMID elegans Online(6) 100 Lecture83 Library80 * M38-A @ by author Almyroudis et al., AAC 07 Eight days later: MRI: Lesion extends in epidural space, forming an epidural abscess ESCMID Online Lecture Library @ by author What is the most important next step? 1. Perform radical surgery 2. Change liposomal ampho B to ABLC 3. Increase the dose of liposomal amphotericin B to 10 mg/kg 4. Add an echinocandin to ampho-B 5. All of the above ESCMID Online Lecture Library @ by author What is the most important next step? 1. Perform radical surgery 2. Change liposomal ampho B to ABLC 3. Increase the dose of liposomal amphotericin B to 10 mg/kg 4. Add an echinocandin to ampho-B 5. All of the above ESCMID Online Lecture Library @ by author Surgical treatment The patient underwent surgical debridement, which included: • enucleation of the left eye • resection of the left paranasal sinuses and • partial resection of ESCMIDthe left maxilla. Online Lecture Library @ by author Case report (cont’d) • One month later and while the patient was still receiving liposomal amphotericin B, a new necrotic eschar was noted. Tissue taken for biopsy: Hyphae still present. ESCMID Online Lecture Library @ by author How should we proceed? 1. Increase dose of liposomal amphotericin B to 10 mg/kg/d 2. Add an echinocandin to ampho-B 3. Start posaconazole 200mg qid 4. Start treatment with hyperbaric oxygen ESCMID5. Start treatment Online with deferasiroxLecture Library @ by author Echinocandins • Traditionally: no in vitro activity as single agents against agents of mucormycosis • However: Rhizopus oryzae expresses the gene encoding for the proteins of 1,3- β-D-glucan synthase complex • When combined with AmB lipid complex (ABLC), caspofungin was more active than ABLC alone or caspofungin alone, for the treatment of experimental, disseminated mucormycosis in ESCMIDdiabetic mice. Online Lecture Library @ by author Isavuconazole is under investigation in phase 3 studies on the safety and efficacy in treatment of fungal infections caused by Candida spp., Aspergillus spp., other filamentous fungi, rare molds, yeasts, and dimorphic fungi ESCMID Online Lecture Library @ by author Case report (cont’d) • New surgical debridement was performed • The dose of Ambisome was increased to 7mg/kg • Hyperbaric oxygen treatment was also started. • Cure after 4.5 months treatment with liposomal amphotericin B • Patient underwent reconstructive surgery. ESCMID Online Lecture Library @ by author Patient after reconstruction ESCMID Online Lecture Library @ by author ECIL-5 (2013) ECIL-5 (2013) Recommendation for first line (part 1) Management includes antifungal therapy, control of underlying conditions and surgery A II Antifungal therapy - AmB deoxycholate C II 1 - Liposomal AmB B II 1 - ABLC B II - ABCD C II 2 - Posaconazole CIII - Combination therapy CIII 1 Liposomal amphotericin B should be preferred in CNS infection and/or renal failure. 2 No data to support its use as first line treatment. May be used as an alternative when amphotericinESCMID B is absolutely Online contraindicated. Lecture Library @ by author ECIL-5 (2013) ECIL-5 (2013) 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
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