Antifungal therapy: Polyenes Antifungal therapy: Polyenes, posaconazole, or prayers Michael Kleinberg, MD, PhD Associate Professor of Medicine Head Infectious Diseases Section Head, Infectious Diseases Section Marlene and Stewart Greenebaum Cancer Center University of Maryland B lti Baltimore, Maryland M l d
Conflict of Interest Statement • Lectures/Honoraria Lectures/Honoraria • None anymore • Consultant relationships Consultant relationships • none • Research • Pfizer • Equity holdings - none • Oth Other - none
Completing the Carbon Cycle: The reason God created moulds
Human Zygomycosis: Review of 929 infections in literature Review of 929 infections in literature Underlying Conditions Percent Diabetes 36 Malignancy 17 Bone marrow transplantation p 5 Solid organ transplantation 7 Fe chelation therapy 6 IV drug use 5 Roden MM et al., Clin Infect Dis (2005) 41: 634-653
Zygomycosis: Sites of Infection yg y Site of Infection % of 929 Mortality (%) Patients Patients Rhinocerebral 21 62 Sino-orbital Sino orbital 8 8 24 24 Sinusitis 8 16 Pulmonary Pulmonary 24 24 76 76 Cutaneous 19 31 Disseminated Disseminated 3 3 100 100 Gastrointestinal 7 85 Cerebral Cerebral 9 9 79 79 Roden MM et al., Clin Infect Dis (2005) 41: 634-653
Zygomycetes: Pooled Outcomes Outcomes • > 10 subjects/trial 10 bj t /t i l • Success = improved + survived FDA approved 100 Patients s 75 50 25 0 AmB A B ABLC ABLC ABCD ABCD L A L-AmB B P Posa 100 nse (%) 75 50 50 Respo 25 0 0 Herbrecht Eur J Clin Microbiol Infect Dis 2000;20:460-6; van Burik, Clin Infect Dis 2006;42:e61-5; Larkin, Infect Med 2003;17:113-120; Walsh Clin Infect Dis 1998;26:1383-1396;
Clinical Responses: ABLC and Posaconazole ABLC and Posaconazole 91 65 100 Deteriorated 75 Stable Percent 50 P Cured + Improved Cured + Improved 25 0 Posaconazole ABLC Patient Status Larkin JA, Montero JA Infect. Med . 2003 17: 113-120; van Burik JH et al., Clin Infect Dis 2006; 42: e61-65
Clinical Responses to ABLC At End of Therapy At End of Therapy 34 31 65 100 Deteriorated 75 Stable Percent 50 Cured + Improved Cured + Improved P 25 0 First-line Second-line Total Patient Status Larkin JA, Montero JA Infect. Med . 2003 17: 113-120.
Clinical Responses to ABLC: End of Therapy End of Therapy 80 Indeterminate 60 ts o. of patient D t Deteriorated i t d 40 Stable No Cured + Improved 20 0 Disseminated Liver Lungs Oropharynx Sinus Total Site of Infection Larkin JA, Montero JA Infect. Med . 2003 17: 113-120.
Zygomycosis: Treatment yg y • Lipid-formulated Ampho B Li id f l t d A h B – 5 – 7.5 mg/kg IV daily dosing – Consensus choice for 1 st Rx because only IV choice • Posaconazole • Posaconazole – 800 mg divided bid, tid, qid – Must be given with fatty food and intact Must be given with fatty food and intact gastric acid production to maximize bioavailability
Zygomycosis: Prayers Zygomycosis: Prayers Does any of this antifungal outcomes data mean anything? outcomes data mean anything?
Zygomycosis: Non - Rx Determinants of Outcomes • Early Rx with antifungals – Chamilos et al., CID 2008 48:503-9 • High pathogen burden/overwhelming infection infection • Patient risk factors • Patient risk factors – Immunity is everything (almost) • David Stevens tomorrow 8:35 AM David Stevens, tomorrow 8:35 AM
Zygomycosis: Risk and I Immunity: Case #1 it 38 yo female 3 rd induction chemotherapy for relapsed AML. • Complicated by fever, neutropenia Rx with Abx. • New L lung nodular infiltrates. Rx with empirical New L lung nodular infiltrates. Rx with empirical voriconazole for presumptive aspergillosis. • Eventual progression to total L lung consolidation p g g with CT evidence of necrosis coincident with bone marrow recovery.
Zygomycosis: Risk and Immunity: Case #1 (cont) I it 38 yo female 3 rd induction chemotherapy for relapsed AML. • Outpatient Rx with voriconazole. O t ti t R ith i l • Four months later, developed hemoptysis. L pneumonectomy by our gutsy chest surgeon pneumonectomy by our gutsy chest surgeon. • Pathology showed mould consistent with zygomycosis (cultures negative) zygomycosis (cultures negative). • Patient doing well one year later on posaconazole despite 4 th AML relapse. despite 4 AML relapse.
Zygomycosis: Risk and Immunity: Case #2 I it 17 yo male with new MDS with excess blasts and “worst combination of multiple poor prognosis tumor genetics ever seen”. Myeloablative chemo followed by MUD allo HSCTx. • Voriconazole prophylaxis by protocol. V i l h l i b t l • Complicated by severe skin and GI GVHD leading to prolonged hospital stay and intense leading to prolonged hospital stay and intense anti-GVHD immune suppression.
Zygomycosis: Risk and I Immunity: Case #2 (cont) it 17 yo male with new MDS with blasts and “worst combination of multiple poor prognosis tumor genetics ever seen” Myeloablative chemo genetics ever seen . Myeloablative chemo followed by MUD allo HSCTx. • Discharged home on immune suppression taper Discharged home on immune suppression taper. • Readmitted one month later in acute respiratory distress. Started immediately on lipid AmB. y p • Progressive dyspnea, transfer to MICU, died. • Autopsy showed widespread zygomycosis Autopsy showed widespread zygomycosis.
Zygomycosis and Treatment: Final Comments • Antifungals are probably important for Antifungals are probably important for treatment. – Paradoxically, more important but less effective in patients with irreversible immune deficits – Immune recovery or at least avoidance of – Immune recovery or, at least, avoidance of more immune suppression is an important Rx goal • Lipid AmB and posaconazole antifungals of choice – Success rates dependent on immune S t d d t i deficiency
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