Robert Sinto

Birth place, date : Jakarta, 21 Juni

E-mail : rsinto@yahoo.com
Formal education
2008 : Medical Doctor, Universitas Indonesia, Jakarta
2014 : Internal Medicine Specialist, Universitas Indonesia, Jakarta
2018 : Tropical and Infectious Diseases Consultant, Universitas Indonesia, Jakarta

Informal education
2014 : Sepsis, France
2015 : Clinical training on Transplant-Oncology-Immunocompromised Host Infectious
Diseases, Singapore General Hospital, Singapore
2016 : Transplant Infectious Diseases Course, The Transplant Society, HongKong
2017 : Antimicrobial Stewardship Training Course, Singapore
2018 : Sepsis, Bangkok
2019 : Medical Mycology Training Network, Asia Fungal Work Group, Malaysia

Workplace & Position

2016-now : Department of Internal Medicine, FM Universitas Indonesia-RS Cipto Mangunkusumo
(Medical & academic staff, member of antimicrobial stewardship committee)
2015-now : Indonesian College of Internal Medicine (Officer)
2014-now : The Indonesian Society of Tropical Medicine and Infectious Diseases (Officer)
Prudent Anti-Candida Use in Sepsis

Robert Sinto
Division of Tropical and Infectious Diseases
Department of Internal Medicine
FM Universitas Indonesia - Cipto Mangunkusumo National Hospital
2019
Outline
 Sepsis Candida: magnitude of problem
 Empiric-”preemptive” approach in sepsis
Candida:
 Non-neutropenia
 Neutropenia

 Definitive approach in sepsis Candida

 Worldwide Epidemiology of Sepsis Candida

 USA, 2004:
◦ 8–10 % etiology of BSI.
◦ Fourth most common BSI pathogen.
 France, 2005-2006:
◦ 2–3 % etiology of BSI.
◦ Sixth–tenth most frequent pathogen.
 Europe, 2009:
◦ Candida was isolated in 17 % of infected culture-
positive patients.

Wisplinghoff H, et al. Clin Infect Dis. 2004;39:309-317.

Sinto, R. 2017 Leroy O, et al. Crit Care Med. 2009;37:1612-1618.
Vincent JL, et al. JAMA. 2009;302:2323–9.
 Invasive Candidiasis in Sepsis:
RSCM data 2012-2014

Sinto, R. 2017
Kalista KF, dkk. Jurnal Ilmu Penyakit Dalam Indonesia. 2017;4:56-61.
 Overall mortality in
invasive Candida infections
100%
90% 85.9%
80%
70% 64.0%
60% 53.4%
50% 42.6%
40% 35.2% 37.9%

30%
20%
10%
0%
EPIC II PATH ECMM SCOPE SCOPE RSCM
(non-ICU) (ICU)
Vincent JL, et al. JAMA. 2009;302:2323–9.
Pfaller MA, et al. PLoS One. 2014; 9(7): e101510.
Klingspor R, et al. Clin Microbiol Infect. 2015;21:e1-87.
Sinto, R. 2017
Pfaller MA, et al. Diagn Microbiol Infect Dis. 1998;30:121-9.
Kalista KF, dkk. Jurnal Ilmu Penyakit Dalam Indonesia. 2017;4:56-61.
 Worldwide Incidence of Candida spp.
ARTEMIS project (134,715 isolates, 127 medical centres,
39 countries, 1991-2006)

Pfaller MA, et al. Clin Microbiol Rev. 2007;20:133–6.

Sinto, R. 2017 Tortorano M, et al. Eur J Clin Micr Infect Dis. 2004; 23:317–22.
Colombo L, et al. Eur J Clin Microbiol Infect Dis. 2003;22:470–4.
 Invasive Candidiasis in Sepsis:
RSCM data 2012-2014

4, 5%
2, 3%
8, 10%

27, 35% C. albicans

C. tropicalis
11, 14% C. parapsilosis
Candida sp
C. glabrata
26, 33% C. krusei

Sinto, R. 2017
Kalista KF, dkk. Jurnal Ilmu Penyakit Dalam Indonesia. 2017;4:56-61.
Candida species Comorbidities and Risk Factors
Candida tropicalis Neutropenia and bone marrow transplantation

Candida krusei 1. Fluconazole use

2. Neutropenia and bone marrow transplantation
Candida glabrata 1. Fluconazole use
2. Surgery
3. Vascular catheters
4. Cancer
5. Older age
6. Diabetes Mellitus
Candida parapsilosis 1. Parenteral nutrition and hyperalimentation
2. Vascular catheters
3. Being neonate
Candida lusitaniae and Previous polyene use
Candida guilliermondii
Candida rugosa Burns

Sinto, R. 2017 Bassetti M, et al. Crit Care. 2010;14:244.

 Candida Spp.
In-vitro Sensitivity
Species Fluconazole Itraconazole Voriconazole Ampho B Echinocandins

C. albicans S S S S S
C. tropicalis S S S S S

C. parapsilosis S S S S S (to I?)

C. dubliniensis S to S-DD S S S S

C. glabrata S-DD to R S-DD to R S to I S to I S

C. krusei R S-DD to R S to I S to I S
C. lusitaniae S S S S to R S
S = sensitive I = Intermediate R = Resistant S-DD = Sensitive Dose-dependent

Sinto, R. 2017 Bassetti M, et al. Crit Care. 2010;14:244.

 Mortality per Candida spp.
60%
52.9%
50%
41.1%
40% 38.1%
35.6%

30%
23.7%
20%

10%

0%
C. Krusei C. albicans C. glabrata C. tropicalis C. parapsilosis

Sinto, R. 2017 Horn DL, et al. Clin Infect Dis 2009,48:1695-703.

 Timeline of IFI Treatment Options

Sinto, R. 2017
 Various definition of “Pre-emptive”…

Sinto, R. 2019

Intensive Care Med (2019) 45:789–805.

Outline
 Sepsis Candida: magnitude of problem
 Empiric-”preemptive” approach in
sepsis Candida:
 Non-neutropenia
 Neutropenia

 Definitive approach in sepsis Candida

 Why do we need empiric-
”preemptive” approach?
 Blood cultures lack sensitivity (<50%).
 Positive cultures are usually late.
 Invasive tissue sampling is often problematic.
◦ Deep seated infection
◦ Invasive procedures may be contraindicated
 “Rare” occurance of typical outlook of skin and mucosal
manifestations of systemic fungal infections.
 Radiological signs appear often late in the course of
infection.

Sinto, R. 2017
 Delaying the empiric treatment of Candida bloodstream
infection until positive blood culture results are obtained: a
potential risk factor for hospital mortality

Sinto, R. 2017
Morrell M, et al. Antimicrob Agents Chemother 2005;49:3640–5.
 Patients at Risk for Invasive Candidiasis

Colonization Index Candida Score Predictive Rule

N◦ sites +/N◦ site screened • Surgery on ICU admission (1) ≥ 4th day of ICU stay:
2X weekly • TPN (1) Sepsis+CVC+MV+1 of:
> 0.5 or ≥ 0.4 corrected • Severe sepsis (2) 1. TPN (day 1-3)
• Multifocal Candida colonization 2. HD (day 1-3)
- Oropharynx/ trachea (1) 3. Major surgery (within 7 days)
- Gatsric fluid >2.5 points 4. Pancreatitis (within 7 days)
- Perineal/ stool 5. Immunosuppression or steroids
(within 7 days)
- Urine
- Surgical wound/ drain
- Catheter insertion site

Start Empirical Antifungal Therapy

Patients treated: 10-15% Patients treated: 15-20% Patients treated: 10-15%

Candidiasis captured: 85-90% Candidiasis captured: 75-85% Candidiasis captured: 60-75%

Pittet D, et al. Ann Surg. 1994.;220:751-8.

Sinto, R. 2017 Leon C, et al. Crit Care Med. 2006;34:730-7.
Ostrosky-Zeichner L, et al. Eur J Clin Michrobiol Infect Dis 2007, 26:271-6.
 Performances of 1,3-b-D-glucan assay (BG), Candida score
(CS), and colonization index for detection of
invasive candidiasis in 95 patients

Sinto, R. 2017 Posteraro, et al. Crit Care. 2011;15:R249.

Sinto, R. 2019
JAMA. doi:10.1001/jama.2016.14655
Sinto, R. 2019 JAMA. doi:10.1001/jama.2016.14655
Sinto, R. 2019

JAMA. doi:10.1001/jama.2016.14655
Sinto, R. 2019 Intensive Care Med (2019) 45:789–805.
Sinto, R. 2019

Intensive Care Med (2019) 45:789–805.

Empiric management
of invasive candidiasis
in non-neutropenic pt

. 2009

Sinto, R. 2017
Appropriate Culture(s)
SSC 2016: Guideline recommendations

 Appropriate routine microbiologic cultures

(including blood) be obtained before starting
antimicrobial therapy if doing so results in no
substantial delay (45 minutes) in the start of
antimicrobials.
 At least 2 sets of blood cultures:
◦ at least 1 drawn percutaneously
◦ and 1 drawn through each vascular access device,
unless the device was recently (<48 hrs) inserted

Sinto, R. 2017
Crit Care Med 2017
  N=647 non-neutropenic adult critically ill pts
 Arms:
◦ SAT DE group: switched from initial SAT to
fluconazole or to SAT stop within five days
◦ SAT non-continuation group
 SAT DE not found to be associated with
increased day-28 mortality and associated with
decreased SAT consumption.
Sinto, R. 2017
Bailly et al. Intensive Care Medicine Experimental 2015, 3(Suppl 1):A5.
 Duration of Empirical Treatment
 If clinically improved, recommended
duration of empiric therapy is 2 weeks,
 Stop empiric therapy at 4-5 days if:
◦ No clinical response
◦ No subsequent evidence of invasive
candidiasis
◦ Negative non-culture-based diagnostic assay
with a high negative predictive value.

Pappas PG, et al. CID. 2016;62:e23.

Sinto, R. 2017
Outline
 Sepsis Candida: magnitude of problem
 Empiric-”preemptive” approach in
sepsis Candida:
 Non-neutropenia
 Neutropenia

 Definitive approach in sepsis Candida

Sinto, R. 2019
CID. 2011:52;e56-93.
Sinto, R. 2019
CID. 2011:52;e56-93.
 Pre-emptive Approach in Neutropenic Sepsis
 Witheld in a high risk neutropenic patients who
remain febrile after 4–7 days of broad-spectrum
antibiotics but
◦ Clinically stable
◦ No clinical, chest, sinus CT signs of fungal infection
◦ Negative serologic assay
◦ No recovery of fungi (such as Candida or Aspergillus
species) from any body site may have antifungal agents
 Antifungal therapy should be instituted if any of
the indicators of possible invasive fungal
infection are identified.
Sinto, R. 2019
CID. 2011:52;e56-93.
Outline
 Sepsis Candida: magnitude of problem
 Empiric-”preemptive” approach in
sepsis Candida:
 Non-neutropenia
 Neutropenia

 Definitive approach in sepsis Candida

 Which Candida specimens constitute a
“proven” infection?
Analysis and specimen
Microscopic Histopathologic, cytopathologic, or
analysis: sterile direct microscopic examination of a
material specimen obtained by needle aspiration
or biopsy from a normally sterile site
(other than mucous membranes)
Culture: Recovery of a yeast by culture of a
Sterile material sample obtained by a sterile procedure
& blood (including a freshly placed [<24 h ago]
drain) from a normally sterile site
showing a clinical or radiological
abnormality consistent with an
infectious disease process
Sinto, R. 2017 Pauw BD, et al. CID. 2008; 46:1813–21.
 Common Pitfalls
 Growth of Candida from
respiratory secretions usually
indicates colonization and
RARELY requires treatment with
antifungal therapy.

Sinto, R. 2017 Pappas PG, et al. CID. 2016;62:e23.

Sinto, R. 2019
Sinto, R. 2019
Intensive Care Med (2019) 45:789–805.
 Common Pitfalls
 Growth of Candida from
respiratory secretions usually
indicates colonization and
RARELY requires treatment with
antifungal therapy.

 Treatment with antifungal agents

in asymptomatic candiduria
is NOT recommended unless the
patient belongs to a group at high
risk for dissemination.
Sinto, R. 2017 Pappas PG, et al. CID. 2016;62:e23.
Sinto, R. 2019
 Antifungal of Choices

Sinto, R. 2017
 Antifungal of Choices

+ Source Control

Sinto, R. 2017
 Duration of Definitive Treatment
 Follow-up blood cultures to establish the time
point at which candidemia has been cleared
 Recommended duration of therapy:
◦ Candidemia without obvious metastatic
complications: 2 weeks after documented clearance
of Candida species from the bloodstream and
resolution of symptoms attributable to candidemia
◦ Candidemia with obvious metastatic complications:
depends on organ involved; step down to fluconazole
after clinically stable.

Sinto, R. 2017 Pappas PG, et al. CID. 2016;62:e23.

Echinocandins: Indications and Dosing
Caspofungina Micafunginb Anidulafunginc

Treatment of candidemia and the 70 mg load; 50 mg 100 mg QD 200 mg load; 100 mg

following Candida infections: QD QD
intra-abdominal abscesses,
peritonitis
Empirical therapy for presumed 70 mg load; 50 mg 100 mgQD 200 mg load; 100 mg
fungal infections in febrile QD QD
neutropenic patients

Treatment of invasive aspergillosis 70 mg load; 50 mg 100-150 mg/day IV

in patients who are refractory to QD
or intolerant of other therapies (ie,
amphotericin B, lipid formulations Not studied as initial
of amphotericin B, and/or therapy for invasive
itraconazole) aspergillosis
Prophylaxis of Candida infections 70 mg load; 50 mg 50 mg QD
in HSCT patients QD
aDosage adjustment to 35 mg QD after 70-mg loading dose recommended for moderate hepatic
insufficiency; not licensed for use in severe hepatic insufficiency
bLicensed for use in neonatal; not licensed for use in severe hepatic insufficiency
cLicensed for use in severe hepatic insufficiency
Conclusion
• Early treatment is a goal, thus proper empirical
or pre-emptive approach should always be
considered.
• Wise interpretation of diagnostic test result to
guide definitive treatment is warranted.
• Consideration of host, fungal species,
pharmacological profile of antifungal are
needed in deciding antifungal of choice.

Sinto, R. 2019