INFEZIONI FUNGINE IN MEDICINA INTERNA Prof. Ercole Concia

Sepsi micotiche aumentate del 207% dal 1979 al 2001 NEJM 2003;348:1546-54

Candide isolate da emocolture e CVC: distribuzione per aree di degenza (2010-2011) I C U Med interna Udine 23 ottobre 2012

VERONA G. Lo Cascio 9

Quale realtà? Isolati da BSI 6% 4,4% 5% 5.3% Yeasts Anaerobes 2011 2012 2013 2014 AOUI - Azienda Ospedaliera Universitaria Integrata Verona 10

Incidenza Candidiasi AOUI VR 2008-2014 AOUI VR - Azienda Ospedaliera Universitaria Integrata Verona

2 8 14.2 48.5 21.3

Distribuzione delle diverse specie di Candida negli anni 30% CKR – C. krusei CTR – C. tropicalis CGL – C. glabrata CPA - C. parapsilosis CAL – C. albicans

Candida distribution in hospital Bassetti M et al. PLoS ONE ; 6(9): e24198

Candidaemia cases in hospital 955 candidaemia episodes (2008–2010) Bassetti M, et al. J Clin Microbiol 2013;51;:4167-72

145 episodi di candidemia nosocomiale in 140 pazienti 52% di sesso maschile età mediana 81 anni (range interquartile 70-86 anni)

CANDIDEMIE NEL TRIVENETO

R. Luzzati 2015

M. Merelli UD

Mortalità cruda a 30 giorni:36,3 %

CVC in situ al momento della candidemia: 81 CVC in situ al momento della candidemia: 81.2% RIMOZIONE CVC dopo la diagnosi: 74.6% Rimozione tardiva: 26.2% CANDIDEMIA PERSISTENTE: 29.6% (mediana 9 giorni) Fattore protettivo: impostazione terapia idonea (OR 0.6; 95% CI 0.16-0.83; p=0.02) MORTALITA’ CRUDA A 30 GIORNI: 36.5% VERONA 2004

Management terapeutico 44.8%

CID 2004;39: 309-17

MORTALITA “PER” LA CANDIDA O “CON” LA CANDIDA ?

Relationship Between Hospital Mortality and the Timing of Antifungal Treatment 35 30 25 20 Hospital mortality (%) 15 10 5 < 12 12–24 24–48 > 48 Delay in start of antifungal treatment (hours) Morrell M, et al. Antimicrob Agents Chemother 2005;49:3640–5

Bassetti CMI 2013

precoce

CASPOFUNGINA TERAPIA PRECOCE O TARDIVA HSU JAC 2010

Ruping MJ et al. Drugs 2008:18(14):1941-62 5 10 Ruping MJ et al. Drugs 2008:18(14):1941-62

EMOCOLTURE Numero raccomandato: 3 set Quantità: 60 ml x adulti, distribuire 10 ml in 3 bottiglie per aerobi e 10 ml in 3 bottiglie per anaerobi Timing: prelevare le tre emocolture una dopo l’altra nell’arco di 30 minuti da tre siti diversi SENSIBILITA’: da 50 a 75 %

The median Candida concentration within a first positive blood culture is 1 CFU/mL 26% - 65% of positive blood cultures have <1 CFU/mL.

Empiric Therapy: When is it Indicated? Population Intention Intervention SoR QoE Reference At risk + persistent FUO Reduce overall mortality Antifungal treatment (unspecified) C III Garey CID 2004 Morrell AAC 2005 Parkins JAC 2007 Kumar Chest 2009 Adult ICU patients with fever despite broad-spectrum antibiotics, APACHE II >16 Resolution of fever Fluconazole 400mg/d D I Schuster Ann Int Med 2008 Definitions: Empiric = persistent FUO / Fever driven approach Pre-emptive = treatment based on a validated marker / Diagnosis driven approach

What are the best tests for diagnosing candidaemia? Specimen Test Considerations Remarks/Recommendations Serum Mannan and Anti-Mannan Other antibodies (such as Serion ELISA classic) ß-D-Glucan Septifast In house PCR Combined detection Limited data for candidemia Not specific for Candida No third party validation data available RECOMMENDED Serial determinations may be necessary. High NPV No recommendation RECOMMENDED (for Fungitell) No recommendation for other tests. Serial determinations are recommended (twice a week). High NPV. Not validated in children ß-D-Glucan not advised in children

Beta D Glucan 3 different tests (2 Japan, 1 USA) Variable quality of data: retrospective vs. prospective; heterogenous Different cut offs used “pangungal” – except cryptococcus and mucorales Sensitivity 45-70%; specificity and NPV high High false-positives: up to 30% in ICU- bacteraemia, antibiotics, pre-/analytical contaminations Influence of ongoing antifungal prophylaxis/therapy not known Costs, complex analytical procedures: automated assay in the pipeline

Performance of (1-3) – β – D - Glucan No studies (patients) Sensitivity % (95% Cl) Specificity Karageorgopoulos, CID 2011 Proven & probable IFI 16(2979) 77% (67-84) 85% (80-90) Onishi, JCM 2012 A, IC, PJP IA, IC 31 PJP 12 80% (77-82) 96% (92-98) 82 % (81-83) 84% (83-86) Lu, Intern Med 2011 15 76% (67-83) 0.85 (73-92) Karageorgopoulos, CMI 2012 14 (2800) 95& (91-97) 86% (92-90) Lamoth, CID 2012 For 2 consecutive tests 6 (1771) 50% (64-65) 99% (97-99.5)

False positive BG results Haemodialysis using cellulose membranes Albumin Intravenous immune globulin Use of cellulose depht filters for intavenous administration Gauze packing of serosal surfaces (abdominal surgery) Intravenous amoxicillin-clavulanic acid (AZITROMICIN and PENTAMIDINE inhibit the BG assay)

Markers of sepsis and organ dysfunction at time of blood culture Bacterial sepsis Candida sepsis P value n CRP 190 [115-316] 94 [66-129] 0.002 PCT 12.9 [2.6-81.2] 0.71 [0.5-1.1] 0.001 SOFA 8 [7-13] 5[3-8] 0.010 WBC 14.3 [10.6-16.4] 11.6 [8.4-15.7] 0.336 T (°C) 38.0 [37.0-38.4] 37.8 [37.0-38.3] 0.493 PROCALCITONINA Journal of Infection 2010; 60:425-430

Dou Y – H et al Diagn Micr Inf Dis 2013

Risk predictive models for INVASIVE CANDIDIASIS in critically ill patients Colonization index Candida score Ostrosky, 2009 Nº sites/Nº sites screened 2 x weekly >0.5 or ≥ 0.4 corrected Surgery on ICU admission TPN Severe sepsis Candida colonization > 3 points 4th day of I ICU stay Major (two): Sepsis + CVC + MV + one of TPN (day 1-3) Dialysis (day 1-3) Major surgery (within 7 days) Pancreatitis (within 7 days) Immusup/steroids (within 7 days) Shorr, 2009 Dupont, 2003 Michalopoulos, 2003 Age > 65 y Tº < 36.7º Severe mental status Cachexia Previous hospit. 30 days Healthcare facility MV Female gender Upper GI origin peritonitis Cardiovasc. failure BAS 48 h before onset of peritonitis MV > 10 days Nosocomial bacterial infection Cardiop. bypass time > 120 m. Diabetes mellitus Lam SW. CCM 2009 - Playford GE. ICM 2009 - Eggimann P. COCC 2010 - Kratzer C. Mycoses 2011 45

Candidemia in non-neutropenic: ESCMID vs IDSA Fluconazole CI AI Voriconazole BI AI ( alternative agent) Lip-AMB B-D I-II AI ( alternative agents) D-AMB DI Echinocandins AI (for moderately severe to severe illness and for patients with recent azole exposure) Empiric treatment (as for candidemia) CIII BIII

IDSA additional recommendations Prefer echinocandin for severe illness Prefer echinocandin in patients with recent azole exposure Remove i.v. catheters, if possible Treat for 14 days after first negative BC and resoluition of signs and symptoms Perform ophthalmological examination in all cases

MAT October 2014   DOT MS% ±% IE ANTIFUNGINI IV MED INT 53.293 100,0 8,0 100 ECHINOCANDINE 25.300 47,5 18,9 110 CANCIDAS 16.292 30,6 11,0 103 ECALTA 6.967 13,1 31,1 121 MYCAMINE 2.041 3,8 59,9 148 AMPHOTERICIN B 2.698 5,1 -36,6 59 AMBISOME 1.791 3,4 -22,0 72 ABELCET 300 0,6 24,8 116 FUNGIZONE 606 1,1 -64,6 33 AZOLI 24.573 46,1 5,4 98 VFEND 7.216 13,5 3,1 95 FLUCONAZOLO 16.569 6,5 99 SPORANOX 789 1,5 96 ALTRO 722 1,4 48,6 137

MAT October 2014   DOT MS% ±% IE ANTIFUNGINI IV ICU 104.663 100,0 4,6 100 ECHINOCANDINE 67.453 64,4 14,5 109 CANCIDAS 38.347 36,6 12,4 108 ECALTA 20.990 20,1 9,7 105 MYCAMINE 8.116 7,8 42,8 137 AMPHOTERICIN B 10.053 9,6 -4,4 91 AMBISOME 8.266 7,9 8,3 104 ABELCET 1.398 1,3 -40,1 57 FUNGIZONE 389 0,4 -29,9 67 AZOLI 26.691 25,5 -11,8 84 VFEND 9.594 9,2 -21,8 75 FLUCONAZOLO 16.534 15,8 -3,8 92 SPORANOX 563 0,5 -30,9 66 ALTRO 466 25,3 120

D.P. Andes – CID 2012

Percentuali di resistenza riscontrate in infezioni fungine invasive (302 Candide) in ICU AM Tortorano 2012 ANIDULA CASPO MICA FLUCON POSACON VORICON C. albicans 5,3 3,6 C. parapsilosis 25,8 5,2 C. glabrata 9,7 19,3 C. tropicalis 22,2 14,8 18,5 C. kruzei 100 16,7

A.M. Tortorano et al Infection 2013 464 candide isolate in 34 centri:tutti gli isolati erano sensibili all’amfotericina B (MIC < 1 mg /L) A.M. Tortorano et al Infection 2013

Targeted Treatment of Candidaemia: Duration & Diagnostics Population Intention Intervention SoR QoE Reference No organ involvement Avoid organ involvement Treat for 14 days after the end of candidaemia B II Oude-Lashof CID 2011 Take 1 blood culture per day until negative III No reference found Detect organ involvement Transoesophageal echocardiography IIa Fernández-Cruz ICAAC 2010 Fundoscopy Rodriguez Med 2003 Brooks Arch Int Med 1989 Parke Ophthalmol 1982 If CVC, PICC, or intravascular devices, search for thrombus Any To simplify treatment Step down to flucona-zole after 10 days of IV, if Species is susceptible Patient tolerates PO Patient is stable Reboli NEJM 2007 Mora-Duarte NEJM 2002 Pappas CID 2007 CVC, Central venous catheter; PICC, Peripherally inserted central catheter.

FLUOCONAZOLO……………………………………………. FLUCONAZOLO…48/72………........ECHINOCANDINA ECHINOCANDINA………………………………………….. ECHINOCANDINA……4/5 gg……....FLUCONAZOLO ECHINOCANDINA……10 gg…………FLUCONAZOLO

Perlin TIMM 2015

Attività in vitro delle echinocandine nei confronti di Candida spp. Organismo MIC90 (µg/ml) Numero di isolati Micafungina Caspofungina Anidulafungina C. albicans 2.869 0.03 0.06 C. parapsilosis 759 2 1 C. glabrata 747 0.015 0.12 C. tropicalis 625 C. krusei 136 0.25 C. guilliermondii 61 C. lusitaniae 58 0.5 C. kefyr 37 C. famata 24 Candida spp. 30 Pfaller MA, et al. J Clin Microbiol 2008; 46:150–6

Drug Typical adult dosing Oral bioavail-ability Cmax (µg/mL) AUC (mgxh/L) Protein (%) CSF (%) Vitreus (%) Urine (%) Metabo-lism Elimina-tion T½ (h) PK:PD (total drug unless indicated) ANI 200 mg x 1 loading dose then 100 mg/d <5 6-7 99 84.0 <2 None Feces 26 Cmax:MIC>10 or serum (unbound) AUC:MIC >20 CAS 70 mg loading dose, then 50 mg/d 8-10 119 97.0 Hepatic Urine 30 MICA 100 – 150 mg/d; 50 mg/d (prophylaxis) 10-16 158 99.0 <1 15 Comparative Pharmacokinetic and Pharmacodynamic Properties of Systemic Antifungal Agents

Epatotossicità VS AUC : Riassunto delle caratteristiche del prodotto 1. CANCIDAS Riassunto delle Caratteristiche del Prodotto EU. 12/2008. 2. ECALTA Riassunto delle Caratteristiche del Prodotto EU 9/2007. CASPOFUNGIN 1 ANIDULAFUNGIN 2

Tolerability and hepatotoxicity of antifungals in the treatment of IFI of febrile neutropenia Percentage of patients with elevation of liver enzymes requiring treatment discontinuation 0.4% 1.5% 0.7% NA 0.8% 0.2% 2.7% Azoles Echinocandins Secondary outcome result. Percentage of patients with elevation of liver enzymes requiring treatment discontinuation Systematic review and meta-analysis (primary population, head-to-head studies) N= 8745 IFI: Invasive Fungal Diseases; NA: Not available Wang JL et al. Antimicrob Agents Chemother. 2010;54:2409-19

Indicazioni terapeutiche delle echinocandine Micafungina Caspofungina Anidulafungina Candidosi invasiva SI pazienti neutropenici pazienti pediatrici ≥ 12 MESI NO Profilassi in pazienti HSCT Adulti Pazienti pediatrici Neonati Candidosi esofagea Aspergillosi invasiva Salvataggio Terapia empirica neutropenia febbrile Costo 10 gg 70 Kg 3650 4119 3060

Antifungal lock therapy C.J. Walraven AAC 2013 Amfotericina desossicolato (0,33mg/ml) Amfotericina liposomiale (2,67 mg/ml) Caspofungina (3,33 mg/ml) Etanolo

Variazione posologica Studi clinici limitati Caspofungina Micafungina Anidulafungina Indicazioni terapeutiche Ampie Limitate Indicazioni pediatriche SI NO Variazioni in insuff. epatica Variazione posologica ? No Interazioni +/- Effetti collaterali + Limiti Warning EMEA Studi clinici limitati Costo +++ ++

D. Cattaneo

D. Cattaneo

D. Cattaneo

Antifungal resistance in Candida A.M. Tortorano 2015 ACCP Antifungal resistance in Candida 22.4% in C.parapsilosis biased by outbreak isolates Confirmed by mutations in fsk1 gene Candidemia 2009 (464 isolates)* Candidemia in ICU (302 isolates)** Echinocandins <2% (2 C.glabrata, 1 C. krusei isolates) 0% Fluconazole 24.9% (C.krusei + mainly C.glabrata and C.tropicalis isolates) 12.6% (C.krusei + mainly C.parapsilosis, C.tropicalis and C. glabrata isolates) AmphotericinB * Infection 2014 ** JMM 2012

Antifungal resistance in Candida: our experience Candidemia 2009 (464 isolates)* Candidemia in ICU 2006-08 (302 isolates)** Candidemia in Lombardia 2014-15 (229 isolates)*** Echino-candins <2% 0% Fluco-nazole 24.9% 12.6% 6.5% Ampho-tericinB * Infection 2014 ** JMM 2012 *** CAND-LO A.M. TORTORANO 2015 ACCP