Curriculum Vitae DR Dr Arto Yuwono Soeroto Sp

Curriculum Vitae DR. Dr. Arto Yuwono Soeroto, Sp. PD-KP, FCCP, FINASIM E-mail: aysoeroto@yahoo. co. id Pendidikan: S 1 Sp 1 Konsultan Pulmonologi S 3 FK Universitas Padjadjaran KIPD FK Universitas Padjadjaran Pekerjaan: Kepala Divisi Respirologi & Penyakit Kritis IPD FKUP/RS Hasan Sadikin Ketua Tim TB RSUP Dr. Hasan Sadikin Kepala IRJ RSUP Dr Hasan Sadikin Organisasi: PB Perhimpunan Dokter Spesialis Penyakit Dalam (PAPDI) PB Perhimpunan Respirologi Indonesia (PERPARI) Fellow American College of Chest Physcian (ACCP) Member American Thoracic Society (ATS) Member European Respiratory Society (ERS)

Timing in Giving Anti Candida in Non Neutropenic Patients Arto Yuwono Soeroto

Introduction Fungal infections have become increasingly more frequent Immunocompromised patients AIDS organ transplantation Increased use of invasive instruments urinary catheters

Incidence of candidaemia (episodes/10, 000 patient-days/year) Increases in the prevalence of invasive Candida infections 3. 5 3. 0 2. 5 2. 0 1. 5 1. 0 0. 5 0 1999 2000 2001 Year Bassetti M, et al. BMC Infect Dis 2006; 6: 21 2002 2003

Why the issues are so important Co. NS : Coagulase Negative Staphylococcus Wisplinghoff H et al. Clin infect Dis. 2004 ; 39 : 309 -317

Mortality rates according to disease and patient characteristics Parameter Aetiological agent C. albicans C. glabrata C. parapsilosis C. tropicalis Underlying condition Surgery Intensive care Solid tumour Haematological malignancy HIV infection Premature birth Age group < 1 year 1– 19 years 20– 69 years ≥ 70 years Total population No. of episodes Mortality (%) p value 1, 090 269 263 140 38. 5 45. 0 25. 9 41. 4 0. 65 0. 02 < 0. 001 0. 42 892 791 442 35. 3 42. 4 49. 2 0. 26 0. 02 < 0. 001 247 44. 9 0. 03 61 123 23. 4 26. 8 0. 03 0. 02 148 1, 096 556 1, 942 26. 0 22. 3 36. 6 47. 7 37. 9 0. 006 < 0. 001 0. 46 < 0. 001 Tortorano AM, et al. Eur J Clin Microbiol Infect Dis 2004; 23: 317– 22

Relationship between hospital mortality and the timing of antifungal treatment Hospital mortality (%) 35 30 25 20 15 10 5 0 < 12 12– 24 24– 48 > 48 Delay in start of antifungal treatment (hours) Morrell M, et al. Antimicrob Agents Chemother 2005; 49: 3640– 5 9

The need for new, more effective treatments for invasive Candida infections • Recent medical advances have greatly improved the clinical outcome of major surgery, organ transplants and cancer 1 – This has been accompanied by an increased prevalence and risk of invasive fungal infections due to the immunosuppressive nature of treatments • Older treatments for fungal infections are limited by toxicity (amphotericin B formulations)2 and resistance (fluconazole)3 1. Richardson MD. J Antimicrob Chemother 2005; 56: i 5–i 11; 2. Dupont B. J Antimicrob Chemother 2002; 49 (Suppl. 1): 31– 6; 3. Messer SA, et al. J Clin Microbiol 2006; 44: 1782– 7

Different step of treatment strategies of IFI

Risk Factors for Invasive Candida • • Candida colonization Severity of illness Exposures to broadspectrum antibiotics Recent major surgery, particularly abdominal surgery Necrotizing pancreatitis Dialysis Parenteral nutrition Corticosteroids • The use of CVC IDSA GUIDELINE 2016

Early Diagnostic Test • Antigen and antibody detection Mannan and anti mannan • Beta-D-Glucan detection • Polymerase Chain Reaction IDSA Guideline 2016

Identified High Risk of Candida Critically Ill patients Colonization Index -n○ sites (+)/n○ screened 2 x weekly > 0. 5 or 0. 4 corrected Candida score • surgery on ICU admission • total parenteran nutrition • multifocal colonisation • severe sepsis - Cut off value 2. 5 Prediction rule 1 1 1 2 • > 4 th days of ICU stay Sepsis + CVC + Mech Vent + one of the following - TPN -mayor surgery - dialysis -pancreatitis - immunosuppresive agent or steroid Start empirical antifungal treatment Patients treated : 10 -15% Candidiasis captured : 85 -90% Patients treated : 15 -20% Candidiasis captured : 75 -85% Patients treated : 10 -15% Candidiasis captured : 60 -75% Eggimann Ann Intensive Care 2011

Selection of Appropriate Antifungal Agents • The appropriate antifungal injection must have the following factors, such as: – Good tolerability – Reliable efficacy – Limited drug interaction – Simple drug administration – Cost effectiveness 19

Therapeutic Options Polyenes Azoles Ampho B Deoxycholate Liposomal Ampho B (Ambisome) Ampho B Colloidal Dispersion (ABCD) Ampho B Lipid Complex (ABLC) Itraconazole, Fluconazole, Voriconazole Posaconazole, Ravuconazole Echinocandins Caspofungin, Caspofungin Micafungin, Anidulafungin Antimetabolite Flucytosine 20

Fungal Cell Wall Targets Fungal cell Cell membrane and cell wall Mannoproteins b-(1, 6)-glucan b-(1, 3)-glucan Chitin Phospholipid bilayer ECHINOCANDINS of cell membrane Ergosterol AZOLES Ergosterol Synthesis Pathway b-(1, 3)-glucan synthase POLYENES DNA/RNA Synthesis FLUCYTOSINE Squalene 21

In vitro sensitivity of Candida species Species Fluconazole Itraconazole Posaconazole Voriconazole Ampho B Echinocandins S S S S S (to I? ) S to S-DD S S S-DD to R S to I S C. krusei R S-DD to R S to I S C. lusitaniae S S S to R S C. albicans C. tropicalis C. parapsilosis C. dubliniensis C. glabrata S = sensitive I = intermediate R = resistant S-DD = sensitive dose-dependent

MIC 90 (µg/ml) Organism Number of isolates Micafungin Caspofungin Anidulafungin 2, 869 0. 03 0. 06 C. parapsilosis 759 2 1 2 C. glabrata 747 0. 015 0. 06 0. 12 C. tropicalis 625 0. 06 C. krusei 136 0. 12 0. 25 0. 06 C. guilliermondii 61 1 1 2 C. lusitaniae 58 0. 25 0. 5 C. kefyr 37 0. 06 0. 015 0. 12 C. famata 24 1 1 2 Candida spp. 30 0. 5 0. 25 1 5, 346 1 0. 25 2 C. albicans Total Pfaller MA, et al. J Clin Microbiol 2008; 46: 150– 6 (CLSI method – M 27 -A 2)

Activities against Biofilm Kaneko Y et al, Antimicrob Agents Chemother. 2013 Mar 4. [Epub ahead of print]

Guidelines Worldwide

1. Guidelines Worldwide 1) IDSA 2016 2) ESCMID 2012

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* *European Society of Clinical Microbiology and Infectious Diseases 33

Recommendations on initial targeted treatment of candidaemia and invasive candidiasis in adult patients

ESCMID 2012. Recommendations on Targeted Treatment of Candidemia and Invasive Candidiasis - Reasons for [So. R=A, Qo. E=I ] with Micafungin: Broader spectrum Resistance rare Biofilm activity Fungicidal Safety profile Less drug-drug interactions Superior to fluconazole in one RCT Consider local epidemiology Cornely OA , Bassetti M, Calandra T et al. Clin Microb Infect 2012; DOI: 10. 1111/1469 -0691. 12039

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Microbiology data of Micafungin to Candida & A. fumigatus Diagnostic Microbiology and Infectious Disease 69(2011) 45 -50 (Amp. B/Posaconazole are omitted due to space reason. Refer to the original for detail)