Curriculum Vitae DR. Dr. Arto Yuwono Soeroto, SpPD-KP, FCCP, FINASIM E-mail: aysoeroto@yahoo.co.id Pendidikan: S1 FK Universitas Padjadjaran Sp1 FK Universitas Padjadjaran Konsultan Pulmonologi KIPD S3 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) Date of preparation Sept 2007. Prescribing Information can be found at the end of this presentation and is available on request. Symbicort® and Turbuhaler® are trademarks owned by the AstraZeneca Group.

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

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

Increases in the prevalence of invasive Candida infections 3.5 3.0 2.5 2.0 Incidence of candidaemia (episodes/10,000 patient-days/year) 1.5 This slide provides evidence that the rates of invasive Candida infections in Europe have increased dramatically since the mid-1990s.1 Bassetti M, et al. Epidemiological trends in nosocomial candidemia in intensive care. BMC Infect Dis 2006; 6:21. 1.0 0.5 1999 2000 2001 2002 2003 Year Bassetti M, et al. BMC Infect Dis 2006; 6:21

Why the issues are so important Kandidemia menduduki urutan ketiga, yakni lebih tinggi dari Pseudomonas dengan crude mortality mencapai hampir 50%, dan memang kalau dilihat dari penelitian yang ada angka kematian akibat 2 penyebab infeksi jamur ini, tampak bahwa CoNS : Coagulase Negative Staphylococcus CoNS : Coagulase Negative Staphylococcus Wisplinghoff H et al. Clin infect Dis. 2004 ; 39 : 309-317 6

Mortality rates according to disease and patient characteristics Parameter No. of episodes Mortality (%) p value Aetiological agent C. albicans 1,090 38.5 0.65 C. glabrata 269 45.0 0.02 C. parapsilosis 263 25.9 < 0.001 C. tropicalis 140 41.4 0.42 Underlying condition Surgery 892 35.3 0.26 Intensive care 791 42.4 Solid tumour 442 49.2 Haematological malignancy 247 44.9 0.03 HIV infection 61 23.4 Premature birth 123 26.8 Age group < 1 year 142 26.0 0.006 1–19 years 148 22.3 20–69 years 1,096 36.6 0.46 ≥ 70 years 556 47.7 Total population 1,942 37.9 Mortality due to Candida infections remains high, despite the availability of several effective antifungal agents. In Europe, the Tortorano epidemiological study has shown that the overall mortality in Candida bloodstream infections is almost 40%.1 Worldwide, estimates of the attributable mortality owing to Candida infections vary considerably, with reported rates as high as 71% in liver transplant patients.2 Mortality varies according to a number of factors: Age: higher mortality rates are seen with increasing age (although this may reflect the trend in the general population).1 Infecting Candida species: for example, C. glabrata is associated with a higher than average mortality rate (45.0%) (although this may be a result of the increased incidence of C. glabrata in the elderly age group), while C. parapsilosis appears to have a lower mortality rate (25.9%).1 Underlying condition: differences in mortality rates are observed according to patients’ underlying conditions, although these may be explained by differences in the relative severity of the underlying condition.1 Tortorano AM, et al. Epidemiology of candidaemia in Europe: results of 28-month European Confederation of Medical Mycology (ECMM) hospital-based surveillance study. Eur J Clin Microbiol Infect Dis 2004; 23:317–322. Falagas ME, et al. Attributable mortality of candidemia: a systematic review of matched cohort and case-control studies. Eur J Clin Microbiol Infect Dis 2006; 25:419–425. Tortorano AM, et al. Eur J Clin Microbiol Infect Dis 2004; 23:317–22

Delay in start of antifungal treatment (hours) Relationship between hospital mortality and the timing of antifungal treatment 35 30 25 20 Hospital mortality (%) 15 10 5 This study provides further evidence that delayed treatment results in increased mortality.1 Morrell M, et al. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005; 49:3640–3645. < 12 12–24 24–48 > 48 Delay in start of antifungal treatment (hours) Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–5

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 cancer1 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 Improved outcomes for major surgery, organ and haematopoietic stem cell transplants and cancer have resulted from recent advances in medical treatment.1 The immunosuppressive nature of these treatments has led to an increased prevalence and risk of invasive fungal infections. The increase in prevalence of invasive fungal infections has not been fully matched with improved treatment options for these infections. Antifungal treatments currently regarded as standard of care are limited by: toxicity, as with amphotericin B formulations2 the increasing development of resistance in certain fungal species following the increased use of these agents as prophylaxis, for example, fluconazole.3 Novel agents with improved efficacy and tolerability profiles are required. Richardson MD. Changing patterns and trends in systemic fungal infections. J Antimicrob Chemother 2005; 56:i5–i11. Dupont B. Overview of the lipid formulations of amphotericin B. J Antimicrob Chemother 2002; 49(Suppl. 1):31–36. Messer SA, et al. International surveillance of Candida spp. and Aspergillus spp.: report from the SENTRY Antimicrobial Surveillance Program (2003). J Clin Microbiol 2006; 44:1782–1787. 1. Richardson MD. J Antimicrob Chemother 2005; 56:i5–i11; 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 13

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 Candida score Prediction rule n○ sites (+)/n○ screened 2 x weekly > 0.5 or 0.4 corrected surgery on ICU admission 1 total parenteran nutrition 1 multifocal colonisation 1 severe sepsis 2 - Cut off value 2.5 > 4th 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 Echinocandins Antimetabolite Ampho B Deoxycholate Liposomal Ampho B (Ambisome) Ampho B Colloidal Dispersion (ABCD) Ampho B Lipid Complex (ABLC) Polyenes Itraconazole, Fluconazole, Voriconazole Posaconazole, Ravuconazole Azoles Before we move on to look how at how antifungal agents work, these are the major therapeutic groups that we use. Echinocandins Caspofungin, Micafungin, Anidulafungin Antimetabolite Flucytosine 20

Fungal Cell Wall Targets Cell membrane and cell wall Mannoproteins b-(1,6)-glucan b-(1,3)-glucan Chitin Phospholipid bilayer of cell membrane ECHINOCANDINS b-(1,3)-glucan synthase In summary then we have 4 main ways of attacking the fungal/mold cell and increasingly the literature is exploring options for combined antifungal therapy, which would seem logical. One point on that is that there has been a concern that azole use would diminish the effectiveness of the polyenes by removing the substrate for their action. This does not appear to happen in clinical practice...is there another polyene target? Ergosterol POLYENES Ergosterol Synthesis Pathway AZOLES DNA/RNA Synthesis FLUCYTOSINE Squalene 21

In vitro sensitivity of Candida species Fluconazole Itraconazole Posaconazole Voriconazole Ampho B Echinocandins C. albicans S C. tropicalis C. parapsilosis S (to I?) C. dubliniensis S to S-DD C. glabrata S-DD to R S to I C. krusei R C. lusitaniae S to R This issue of in vitro sensitivity is brought out in a little more detail here. You can see that the potential for issues with C. glabrata and C. krusei is a class effect for the azoles and underlines the importance of local knowledge of organism sensitivity. Testing for fungal sensitivity will become even more important as new agents come on board. Candida resistance to echinocandins is not yet a major problem. S = sensitive I = intermediate R = resistant S-DD = sensitive dose-dependent 22 22

Organism MIC90 (µg/ml) Number of isolates Micafungin Caspofungin Anidulafungin 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 Total 5,346 Micafungin is more potent in vitro than both caspofungin and anidulafungin against C. glabrata and remained active against a strain of C. glabrata that was non-susceptible to both anidulafungin and caspofungin.1 Micafungin has also been shown to be active against isolates with acquired or inherent resistance to polyenes and azoles.1 Pfaller MA, et al. In vitro susceptibility of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J Clin Microbiol 2008; 46:150–156. Pfaller MA, et al. J Clin Microbiol 2008; 46:150–6 (CLSI method – M27-A2)

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

* *European Society of Clinical Microbiology and Infectious Diseases

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

Reasons for [SoR=A, QoE=I ] with Micafungin: ESCMID 2012. Recommendations on Targeted Treatment of Candidemia and Invasive Candidiasis Reasons for [SoR=A, QoE=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 (AmpB/Posaconazole are omitted due to space reason. Refer to the original for detail)