Terapia delle Micosi Invasive Trieste, PneumoTrieste 2017 Roberto Luzzati SC Malattie Infettive, Ospedale Maggiore Azienda Ospedale/Università ASUITS, Trieste

Emerg Infect Dis 2014

Emerg Infect Dis 2014

EJCMID 2017

Principali antifungini disponibili per uso clinico o in sviluppo Polieni Amfotericina B (AMB) desossicolato (D-AMB) AMB liposomiale (L-AMB) AMB complessi lipidici (ABLC) Azolici Fluconazolo Itraconazolo Voriconazolo Posaconazolo Flucitosina Echinocandine Caspofungin Anidulafungin Micafungin Novità approvate o in fase II/IIIa -Isavuconazolo (Basilea) -Posaconazolo e.v (MSD) -echinocandina long-acting (Cidara, US)

ANTIFUNGAL AGENTS Range of Activity for Selected Pathogens Moulds Yeasts AMB FCZ ITZ VCZ PCZ IVZ CF MF AF Candida albicans Candida tropicalis Candida parapsilosis Candida krusei Candida glabrata* Cryptococcus neoformans Aspergillus fumigatus Mucor spp Rhizopus spp Fusarium spp AmBisome® exhibits a broad range of activity against yeasts and moulds, and its activity is comparable to conventional amphotericin B1 Although not depicted in this slide, recent data have suggested that voriconazole has variable activity against Fusarium spp2   1. Adapted from JP Donnelly by Malcolm Richardson. Presented at: New Challenges and New Options in the Treatment of Invasive Fungal Infections in Stem Cell Transplant Patients, a Satellite Symposium at the 20th Annual Meeting of the EBMT; March 24, 2002; Montreux, Switzerland. 2. Vfend [package insert]. New York, NY, United States: Pfizer, Inc; 2002. * Strains with reduced susceptibility to azoles AMB, Amphotericin B Azole: FCZ, Fluconazole; ITZ, Itraconazole; VCZ, Voriconazole; PCZ, Posaconazole; IVZ, Isavuconazolo Echinocandin: CF, Caspofungin; MF, Micafungin; AF, Anidulafungin Adapted from JP Donnelly, by Malcolm Richardson.

Pathogenesis of Invasive Candidiasis. Figure 1 Pathogenesis of Invasive Candidiasis. Candida species that colonize the gut invade through translocation or through anastomotic leakage after laparotomy and cause either localized, deep-seated infection (e.g., peritonitis), or candidemia. In patients with indwelling intravascular catheters, candidemia that originates from the gut or the skin leads to colonization of the catheter and the formation of biofilm. Fungi are subsequently released from the biofilm, causing persistent candidemia. Once candidemia has developed, whether from a colonized intravascular catheter or by other means, the fungi may disseminate, leading to secondary, metastatic infections in the lung, liver, spleen, kidneys, bone, or eye. These deep-seated infections may remain localized or lead to secondary candidemia. During candidemia, the fungi in the bloodstream may enter the urine, leading to candiduria. Less frequently, deep-seated candidiasis may occur as a result of ascending pyelonephritis and may either remain localized or lead to secondary candidemia. Kullberg BJ, Arendrup MC. N Engl J Med 2015;373:1445-1456

S. aureus Pathogen Overall % - rank CLA-BSI % – rank CA-UTI VAP SSI Infect Control Hosp Epid, 2016 Pathogen Overall % - rank CLA-BSI % – rank CA-UTI VAP SSI TOTAL ISOLATES 408,151 96,532 153,805 8,805 149,009 CoNS 7.7 – 5 16,4 – 2 1.6 – 9 0.8 – 9 7.9 - 4 S. aureus 11.8 – 3 13.2 – 4 2.2 – 8 24.7 – 1 20.7 – 1 Enterocococ. spp 14.7 – 2 17.2 – 1 13.8 – 3 0.9 – 8 14.6 - 2 Candida spp 11.3 – 4 14.3 – 3 17.8 – 2 2.7 – 6 3.2 – 8 E. coli 15.4 – 1 5.4 – 6 23.9 – 1 5.4 – 5 13.7 - 3 P. aeruginosa 7.3 - 7 4.0 – 8 10.3 – 4 16.5 – 2 5.7 - 5 Klebsiella spp 7.7 – 6 8.4 – 5 10.1 – 5 10.2 – 3 4.7 – 6 Enterobacter spp 4.2 – 8 4.4 – 7 3.7 – 7 8.3 – 4 4.4 - 7 Proteus spp 2.8 – 9 4.0 - 6 1.4 – 7 2.8 – 9. CoNS, coagulase-negative stafilococci; CLABSI, central line associated bloodstream infection; CAUTI, catheter-associated urinary tract infection; VAP, ventilator associated pneumonia; SSI, surgical site inf.

EJIM 2017

EJIM 2017

2011-2013: 686 adult patients (52% males); mean age 70 + 15 yrs 21% 54% 25% Infection, 2016 2011-2013: 686 adult patients (52% males); mean age 70 + 15 yrs

variables OR (95%CI) P-value 30/266 (11.27) 83/333 (25) Table 4. Comparison of treatment and outcome according to ward admission variables Surgery/ICUs (319 pt) Medicine wards (367 pt) OR (95%CI) P-value Inadeguate antifungal therapy 30/266 (11.27) 83/333 (25) 2.61 (1.66-4.11) <0.001 No antifungal therapy 25/266 (9.3) 48/333 (14.4) 1.62 (0.97-2.71) 0.062 Adeguate therapy + CVC removal 147/212 (69.3) 97/208 (46) 0.39 (0.2 6-0.58) Surgery/ICUs, surgery and intensive care units; OR, odds ratio (misure quantitative OR per unit); CI, confidence interval; NA, not available Infection, 2016

Recommendations on Targeted Treatment of Candidemia and Invasive Candidiasis (ESCMID, 2012) Intervention SoR QoE Reference Comment Anidulafungin 200/100 mg A I Reboli NEJM 2007 Broad spectrum, resistance rare, fungicidal Consider local epidemiology (C. parapsilosis, C. krusei) Safety profile, less drug-drug interactions than caspofungin Caspofungin 70/50 mg Betts CID 2009 Mora-Duarte NEJM 2007 Pappas CID 2007 Consider local epidemiology (C. parapsilosis) Safety profile Micafungin 100 mg Kuse Lancet 2007 Pappas CID 2007 Less drug-drug interactions than caspofungin Consider EMA warning label

Interaction of Aspergillus with the host A unique microbial-host interaction Acute IA ABPA Allergic sinusitis Frequency of aspergillosis Frequency of aspergillosis CNPA Aspergilloma Immune dysfunction Immune hyperactivity . www.aspergillus.man.ac.uk www.aspergillus.man.ac.uk 17

Clin Infect Dis 2015

Clin Infect Dis 2015

Lancet 2016

Lancet 2016

Lancet 2016 Lancet 2016

Lancet 2016

Patients with Treatment-emergent Adverse Events (TEAEs) Isavuconazole N=257 % Voriconazole N=259 p-value Patients with any TEAE 96.1 98.5 NS Study drug-related TEAEs 42.4 59.8 <0.05 Serious TEAEs 52.1 57.5 Study drug-related serious TEAEs 10.9 11.2 TEAEs leading to study drug discontinuation 14.4 22.8 Study drug-related TEAEs leading to discontinuation 8.2 13.5 Death 31.5 33.6 Lancet 2016

CCPA CFPA CNPA Chronic cavitary pulmonary aspergillosis Chronic fibrosing pulmonary aspergillosis CNPA Chronic necrotizing pulmonary aspergillosis

63%

Effetti Avversi al Voriconazolo (28,5%) 2 casi di EPATITE 2 casi di REAZIONE PEMFIGOIDE 2 casi di ALLUCINAZIONI SOSPENSIONE del FARMACO a 3 e 4 mesi 1 caso lievi e transitorie 1 caso grave CHIRURGIA Continua terapia POSACONAZOLO Sospensione temporanea ripresa a diverso dosaggio 150 mg x3 volte al giorno Infection 2015

Clin Infect Dis 2016

Clin Infect Dis 2016

AAC 2016

Clin Infect Dis 2016