dr. Ronald Irwanto N., Sp.PD-KPTI, FINASIM

Spesialis Penyakit Dalam (Internist)

Konsultan Penyakit Tropik & Infeksi

Narasumber:

Internist – Infectious Disease (ID) Specialist

2016 - 2022

Internist – Infectious Disease (ID) Specialist

www.new.rasproindonesia.com

dr. Ronald Irwanto – Internist Consultant

IG: @rasproindonesia

Invasive Fungal Infections (IFIs) – Candida spp & Others :

The Role of Azole

Ronald Irwanto Natadidjaja

RASPRO Indonesia

Department of Internal Medicine - Trisakti University

Jakarta

www.new.rasproindonesia.com

IG @rasproindonesia

Issue : When to Start the Systemic Antifungal Treatment?

PATIENTS SAFETY

COST

​

​

​

​

​

Host Factor

​

​

Risk Factor

Considering

​

​

​

​

​

​

​

Definitive

Empiric

Pre-Emptive

(Prophylaxis?)

​

​

Approach

​

​

​

​

​

​

Amphoterisin

5FC

Azole

Echinocandin

​

Treatment

Option

Invasive Fungal Infections (IFIs)

​

​

​

​

​

​

​

Definitive

Empiric

Pre-Emptive

(Prophylaxis?)

​

​

Approach

+

+

+

+/-

+

DEFINITIVE

EMPIRIC

PRE-EMPTIVE

Host - Fungal Clearance

Lymphocytes (CD4+)

Cryptococcus spp

Histoplasma spp

​

Neutrophils

Candida spp

Aspergillus spp

Risk Factors

IFIs - Candida spp

Risk Factors

IFIs - Candida spp

Bassetti et al. Critical Care 2010

Sepsis

Long ICU stay

Using Total Parenteral Nutrition (TPN)

Candida sp multifocal colonization findings

Using deep vein catheters, including Central Venous Catheter (CVC)

Hemodialysis

History of long-term use of wide-spectrum antibiotics

History of abdominal surgery

Transplantation

Long ICU stay

Babies with low birth weight in ICU

References

Part of Guidelines

What Is the Treatment for Candidemia in Nonneutropenic Patients?

Recommendations

1. An echinocandin (caspofungin: loading dose 70 mg, then

50 mg daily; micafungin: 100 mg daily; anidulafungin: loading

dose 200 mg, then 100 mg daily) is recommended as initial

therapy (strong recommendation; high-quality evidence).

2. Fluconazole, intravenous or oral, 800-mg (12 mg/kg) loading

dose, then 400 mg (6 mg/kg) daily is an acceptable alternative

to an echinocandin as initial therapy in selected

patients, including those who are not critically ill and who

are considered unlikely to have a fluconazole-resistant Candida

species (strong recommendation; high-quality evidence).

3. Testing for azole susceptibility is recommended for all bloodstream

and other clinically relevant Candida isolates. Testing

for echinocandin susceptibility should be considered in patients

who have had prior treatment with an echinocandin

and among those who have infection with C. glabrata or

C. parapsilosis (strong recommendation; low-quality evidence).

4. Transition from an echinocandin to fluconazole (usually

within 5–7 days) is recommended for patients who are clinically

stable, have isolates that are susceptible to fluconazole

(eg, C. albicans), and have negative repeat blood cultures following

initiation of antifungal therapy (strong recommendation;

moderate-quality evidence).

5. For infection due to C. glabrata, transition to higher-dose

fluconazole 800 mg (12 mg/kg) daily or voriconazole 200–

300 (3–4 mg/kg) twice daily should only be considered

among patients with fluconazole-susceptible or voriconazole-

susceptible isolates (strong recommendation; low-quality

evidence).

6. Lipid formulation amphotericin B (AmB) (3–5 mg/kg daily)

is a reasonable alternative if there is intolerance, limited

availability, or resistance to other antifungal agents (strong

recommendation; high-quality evidence).

7. Transition from AmB to fluconazole is recommended after

5–7 days among patients who have isolates that are susceptible

to fluconazole, who are clinically stable, and in whom repeat cultures on antifungal therapy are negative (strong recommendation;

high-quality evidence).

Part of Guidelines

8. Among patients with suspected azole- and echinocandin resistant

Candida infections, lipid formulation AmB (3–5

mg/kg daily) is recommended (strong recommendation;

low-quality evidence).

9. Voriconazole 400 mg (6 mg/kg) twice daily for 2 doses, then

200 mg (3 mg/kg) twice daily is effective for candidemia, but

offers little advantage over fluconazole as initial therapy

(strong recommendation; moderate-quality evidence). Voriconazole

is recommended as step-down oral therapy for selected

cases of candidemia due to C. krusei (strong recommendation;

low-quality evidence).

10. All nonneutropenic patients with candidemia should have

a dilated ophthalmological examination, preferably performed

by an ophthalmologist, within the first week after

diagnosis (strong recommendation; low-quality evidence).

11. Follow-up blood cultures should be performed every day

or every other day to establish the time point at which

What Is the Treatment for Candidemia in Nonneutropenic Patients?

candidemia has been cleared (strong recommendation; lowquality

evidence).

12. Recommended duration of therapy for candidemia without

obvious metastatic complications is for 2 weeks after documented

clearance of Candida species from the bloodstream

and resolution of symptoms attributable to candidemia

(strong recommendation; moderate-quality evidence).

Part of Guidelines

What Is the Role of Empiric Treatment for Suspected Invasive

Candidiasis in Nonneutropenic Patients in the Intensive Care Unit?

Recommendations

​

28. Empiric antifungal therapy should be considered in critically

ill patients with risk factors for invasive candidiasis and no

other known cause of fever and should be based on clinical

assessment of risk factors, surrogate markers for invasive candidiasis,

and/or culture data from nonsterile sites (strong recommendation;

moderate-quality evidence). Empiric antifungal

therapy should be started as soon as possible in patients who

have the above risk factors and who have clinical signs of septic

shock (strong recommendation; moderate-quality evidence).

29. Preferred empiric therapy for suspected candidiasis in

nonneutropenic patients in the intensive care unit (ICU) is an echinocandin (caspofungin: loading dose of 70 mg, then

50 mg daily; micafungin: 100 mg daily; anidulafungin: loading

dose of 200 mg, then 100 mg daily) (strong recommendation;

moderate-quality evidence).

30. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400

mg (6 mg/kg) daily, is an acceptable alternative for patients

who have had no recent azole exposure and are not colonized

with azole-resistant Candida species (strong recommendation;

moderate-quality evidence).

31. Lipid formulation AmB, 3–5 mg/kg daily, is an alternative

if there is intolerance to other antifungal agents (strong recommendation;

low-quality evidence).

32. Recommended duration of empiric therapy for suspected

invasive candidiasis in those patients who improve is 2

weeks, the same as for treatment of documented candidemia

(weak recommendation; low-quality evidence).

33. For patients who have no clinical response to empiric antifungal

therapy at 4–5 days and who do not have subsequent

evidence of invasive candidiasis after the start of empiric

therapy or have a negative non-culture-based diagnostic

assay with a high negative predictive value, consideration

should be given to stopping antifungal therapy (strong recommendation;

low-quality evidence).

VI.

Infectious Diseases Society of America (IDSA) 2016 Clinical Practice Guideline for the Management of Candidiasis¹

• Strongly recommends an echinocandin (e.g. anidulafungin) with moderate quality evidence in treatment for candidemia in neutropenic patients

Sixth European Conference on Infections in Leukaemia (ECIL-6)²

• Strongly recommends an echinocandin (e.g. anidulafungin) as first line therapy of candidemia irrespective of the underlying predisposing factors

Global guideline recommendations of anidulafungin in neutropenic patients

References: 1. Pappas PG, et al. Clin Infect Dis. 2016;62(4):e1–e50. 2. Tissot F, et al. Haematologia. 2017;102(3):433–444.

Anidulafungin is the only echinocandin proven superior to fluconazole¹

Post-hoc analysis of patients with C albicans infection²

Anidulafungin versus

Fluconazole

Significantly fast clearance of positive blood cultures

(median 2 vs. 5 days, p <0.05)

Significantly fewer persistent infections

(2.7% vs. 13.1%, p <0.05)

Adapted from Reboli et al, 2011..

References: 1. Glockner A, et al. Mycoses. 2009;52(6):476–486. 2. Reboli AC, et al. BMC Infect Dis. 2011;11:261.

Part of Guidelines

INVASIVE SYNDROMES OF ASPERGILLUS

What Are the Recommended Treatment Regimens and Adjunctive Treatment Measures for the Various Clinical Presentation of Invasive Aspergillosis? How Should IPA (Invasive Pulmonary Aspergillosis) Be Treated?

Recommendations.

25. We recommend primary treatment with voriconazole (strong recommendation; high-quality evidence).

26. Early initiation of antifungal therapy in patients with strongly suspected IPA is warranted while a diagnostic evaluation is conducted (strong recommendation; high-quality evidence).

27. Alternative therapies include liposomal AmB (strong recommendation; moderate-quality evidence), isavuconazole (strong recommendation; moderate-quality evidence), or other lipid formulations of AmB (weak recommendation; low-quality evidence). 28. Combination antifungal therapy with voriconazole and an echinocandin may be considered in select patients with documented IPA (weak recommendation; moderate-quality evidence).

29. Primary therapy with an echinocandin is not recommended (strong recommendation; moderate-quality evidence). Echinocandins (micafungin or caspofungin) can be used in settings in which azole and polyene antifungals are contraindicated (weak recommendation; moderate-quality evidence).

30. We recommend that treatment of IPA be continued for a minimum of 6–12 weeks, largely dependent on the degree and duration of immunosuppression, site of disease, and evidence of disease improvement (strong recommendation; lowquality evidence).

31. For patients with successfully treated IPA who require subsequent immunosuppression, secondary prophylaxis should be initiated to prevent recurrence (strong recommendation; moderate-quality evidence).

Echinocandins are effective in salvage therapy (either alone or in combination) against IA, but we do not recommend their routine use as monotherapy for the primary treatment of IA (strong recommendation; moderatequality evidence).

Antifungal Agents with Activity against Aspergillus Species

Data extracted from: Patterson TF. Treatment of invasive aspergillosis: Polyenes, echinocandins, or azoles?. Medical Mycology. 2006 Sep 1;44(Supplement_1):S357-62.

Voriconazole

The first-line gold-standard treatment for IA ^1-5

IA, invasive aspergillosis.

IDSA: Infectious Diseases Society of America

ECIL: European Conference on Infections in Leukemia

​

​

References:

1. VFEND IV Summary of Product Characteristics, Jan 2017

2. VFEND tablet Summary of Product Characteristics, Jan 2017

3. Maschmeyer, G., et al. (2007). Invasive aspergillosis: epidemiology, diagnosis and management in immunocompromised patients. Drugs; 67(11), pp. 1567-1601.

4. Patterson, T.F., et al. (2016): Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis.;63(4):e1-e60.

5. Tissot F, et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2016 Dec 23. pii: haematol.2016.152900. doi: 10.3324/haematol.2016.152900.

6. Herbrecht, R., et al., (2002). Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med; 347(6), pp. 408-415.

Voriconazole is available in both IV and oral formulations and listed in e-catalog BPJS ^1,2

Approved indications

• Treatment of invasive aspergillosis.
• Treatment of candidemia in non-neutropenic patients
• Treatment of serious invasive Candida infections (including C. krusei)
• Treatment of esophageal candidiasis
• Treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in patients intolerant of, or refractory to, other therapy.

Part of Guidelines

Amphotericin B (AmB) deoxycholate (AmBd; 0.7–1.0 mg/kg per day intravenously [IV]) plus flucytosine (100 mg/ kg per day orally in 4 divided doses; IV formulations may be used in severe cases and in those without oral intake where the preparation is available) for at least 2 weeks,

followed by

fluconazole (400 mg [6 mg/kg] per day orally) for a minimum of 8 weeks (A-I). Lipid formulations of AmB (LFAmB), including liposomal AmB (3–4 mg/kg per day IV) and AmB lipid complex (ABLC; 5 mg/kg per day IV) for at least 2 weeks, could be substituted for AmBd among patients with or predisposed to renal dysfunction (B-II).

HIV-Infected Individuals

AmBd (0.7 mg/kg per day IV) plus fluconazole (800 mg per day orally) for 2 weeks, followed by fluconazole (800 mg per day orally) for a minimum of 8 weeks (B-I).

Fluconazole (800 mg per day orally; 1200 mg per day is favored) plus flucytosine (100 mg/kg per day orally) for 6 weeks (B-II).

Fluconazole (800–2000 mg per day orally) for 10–12 weeks; a dosage of 1200 mg per day is encouraged if fluconazole alone is used (B-II).

Itraconazole (200 mg twice per day orally) for 10–12 weeks (C-II), although use of this agent is discouraged.

Primary therapy: alternative regimens for induction and consolidation

Primary therapy: induction and consolidation

Part of Guidelines

The Infectious Diseases Society of America (IDSA) last updated clinical guidelines for the management of histoplasmosis in 2007, using literature from 1 January 1999 through 31 June 2006 [8]. Since the release of the guidelines, new treatment options have been developed. Posaconazole was approved by the United States (US) Food and Drug Administration shortly before the release of the 2007 guidelines and isavuconazole was approved in 2015. Both maintain in vitro activity against Histoplasma even in the setting of fluconazole resistance [9, 10], though there are limited clinical data to support their use in treating histoplasmosis [11–13]. Since the arrival of these new medications, there have been no changes to clinical practice recommendations [14], and very little new data have been published to guide therapy [15, 16]. Additionally, the population at risk to develop clinically significant histoplasmosis has increased substantially with millions of patients on an everexpanding variety of immunosuppressive medications and/or with immunosuppressive medical conditions [17–19].

Management of Acute Pulmonary and Progressive Disseminated Histoplasmosis

​

For a patient with mild-to-moderate acute pulmonary histoplasmosis, 75% (189/253) of respondents treat with itraconazole as is recommended in both the IDSA and the European Confederation of Medical Mycology guidelines [8, 14]. Six percent (16/253) chose treatment with another azole and 4% (9/ 253) chose amphotericin B. Forty-seven (19%) respondents recommended no treatment for the patient in this case. For a patient presenting with mild-to-moderate disseminated histoplasmosis in the outpatient setting, 75% (189/253) of respondents chose to treat with itraconazole in concordance with the guidelines. Fewer respondents recommended no treatment in this situation (14% [35/253]) and more recommended amphotericin B induction therapy (9% [22/253]). The remainder of respondents chose another azole.

Part of Guidelines

Preferences in Azole

Therapy Most respondents chose itraconazole as their azole of choice in each clinical scenario. Preferred formulations of itraconazole were evenly split between oral solution (46% [117/253]) and capsules (43% [110/253]). A minority of physicians (7% [18/ 253]) preferred the newest formulation, SUBA-itraconazole. There were 6 physicians (2%) who did not treat histoplasmosis with itraconazole.

Itraconazole was recommended for step-down therapy for severe disseminated histoplasmosis without central nervous system (CNS) involvement by 92% (232/253) of respondents. Where severe disseminated histoplasmosis was complicated by CNS involvement, a smaller majority (145/253 [57%]) recommended itraconazole. For CNS involvement, 19% (48/253) recommended voriconazole, 5% (12/253) posaconazole, 4% (9/253) isavuconazole, and 8% (20/253) fluconazole. Continued therapy with amphotericin B was recommended by 7% (17/253) of respondents.

1. Restrict or avoid antifungal prophylaxis
2. Differentiate infection from colonisation
3. Use non-culture-based diagnostics for early detection of IC
4. Limit the use of empirical therapy based on risk-factors
5. Promote early pre-emptive antifungal treatment based on risk factors and biomarkers
6. Get treatment right the first time with adequate drugs (echinocandins)
7. Have adequate source control within 48 hours (catheter removal, appropriate drainage, surgical control)
8. Use an adequate dose: low dose is associated with resistance
9. De-escalate whenever possible (if possible, within day 5)
10. Stop early useless therapy and check duration of therapy

Slide of Prof Basseti March 6^th, 2021

IC, invasive candidiasis.�Bassetti M et al. Intensive Care Med 2017: DOI: 10.1007/s00134-017-4922-x.

The 10 most remarkable rules for developing antifungal stewardship program in ICU

In Progress Publication

Cetakan I, 2023

Penyusun:

Prof. DR. Dr. Retno Wahyuningsih, MSi, Sp.Par.K, Subsp. Miko.(K)

Prof. DR. Dr. Tonny Loho, Sp.PK(K)

Prof. DR. Dr. Aryati, MS, Sp.PK(K)

Dr. Ronald Irwanto Natadidjaja, Sp.PD-KPTI, FINASIM

Dr. Meiliyana Wijaya, Sp.Par.K

DR. Dr. Robiatul Adawiyah, M.Biomed, Sp.Par.K, Subsp. Miko.(K)

Dr. Siti Pratiekauri, Sp.Par.K, Subsp. Miko.(K)

Dr. Aziza Ariyani, Sp.PK

Dr. Hadianti Adlani, Sp.PD-KPTI

Dr. Anti Dharmayanti, Sp.PK(K)

Dr. Hendarto Natadidjaja, MARS, Sp.PD, FINASIM

Editor:

Prof. DR. Dr. Retno Wahyuningsih, Sp.Par.K, Subsp. Miko.(K)

Dr. Ronald Irwanto Natadidjaja, Sp.PD-KPTI, FINASIM

DR. Dr. Robiatul Adawiyah, M.Biomed, Sp.Par.K, Subsp. Miko.(K)

Penerbit Universitas Trisakti

Universitas Trisakti, Kampus A, Gedung R

Jl. Kyai Tapa No. 1, Grogol, Jakarta Barat 11440

Anggota IKAPI, Jakarta

www.penerbitan.trisakti.ac.id

Hak cipta dilindungi oleh undang-undang

THANK YOU

www.new.rasproindonesia.com

​

IG: @rasproindonesia