1. Curriculum Vitae DR. Dr. Arto Yuwono Soeroto, SpPD-KP, FCCP, FINASIM
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.
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2. Timing in Giving Anti Candida in Non Neutropenic Patients
Arto Yuwono Soeroto

3. 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

5. 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

6. 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 ; 39 : 6

7. 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

9. 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

10. 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

13. Different step of treatment strategies of IFI13

15. 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

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

18. 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
severe sepsis
- 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

19. 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

20. 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

21. 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

22. 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

23. 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)

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

25. Guidelines
Worldwide

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

33. *
*European Society of Clinical Microbiology and Infectious Diseases

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

38. Reasons for [SoR=A, QoE=I ] with Micafungin:
ESCMID 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: /

39. THANK YOU

40. 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)