Curriculum Vitae

Nama : Dr. Ronald Irwanto Natadidjaja, SpPD – KPTI, FINASIM

Pendidikan :
SMP - SMA : Kolese KANISIUS, 1994
Dokter Umum : FK TRISAKTI, 2002
Spesialis Penyakit Dalam (Internist) : FKUI, 2009
Konsultan Penyakit Tropik & Infeksi : FKUI / PAPDI, 2013

Pekerjaan :
Bendahara Pengurus Besar Perhimpunan Konsultan Penyakit Tropik dan
Infeksi Indonesia (PB PETRI)

SekJen PP. Perhimpunan Pengendalian Infeksi Indonesia (PP. PERDALIN)

Tim Panel Ahli PNPK Sepsis, Kemenkes RI

Staf Pengajar Bagian Ilmu Penyakit Dalam, FK TRISAKTI

Ketua PPRA, RS PONDOK INDAH – PURI INDAH

Wakil Ketua Komite Medik, RS PONDOK INDAH – PURI INDAH

Internist - Konsultan, RS PONDOK INDAH – PURI INDAH dan RS PONDOK

INDAH – BINTARO JAYA
RONALD IRWANTO

PP. PERDALIN
 INTERNIST - INFECTIOUS DISEASE (ID) CONSULTANT

Tropical Disease Infectious Disease

 Bacterial Acute Diarrhea  Surgical Prophylaxis
 Typhoid Fever  Pneumonia
 Leptospirosis  cIAI
 Urinary Tract Infection
 Amebiasis
 SSTIs
 Primary BSIs
NON ANTIBIOTIC USAGE  Sepsis
Dengue
 Febrile Neutropenia
Chikungunya
Measles  HIV + Opportunistic Infection
Pox  MDR/XDR/PDR Issue
EMERGING INFECTIOUS DISEASE
AVIAN INFLUENZA
SWINE FLU
SARS / MERS CO-V
EBOLA
ACTUAL ISSUES in Antibiotics for
Tropical Disease

 Amebiasis
 cIAI, Acute Diarrhea : E.coli & ESBL
 MDR Salmonella typhi (MDR-ST)
 Drug Resistant Microorganism
AMEBIASIS
Amebiasis is a disease caused
by the parasite Entamoeba
histolytica

Several protozoan species in the

genus Entamoeba colonize humans,
but not all of them are associated
with disease. Entamoeba histolytica
is well recognized as a pathogenic
ameba, associated with intestinal
and extraintestinal infections.

CDC,2010
LIFE CYCLE

CDC,2010
Pathogenesis of Amebiasis

Lysis of the colonic

mucosa in intestinal
amebiasis has been
related to a variety
of molecules produced
By E. histolytica :

Adhesins
Amebapores
Proteases

Cantellano ME, Palomo AM, Clin Microbiol Rev : 2000 ; 13(2) : 218-321
Amebiasis Clinical Presentation
 Amebic colitis
 Fever (10-30%)
 Weight loss (40%)
 Diffuse abdominal tenderness (12-85%)
 Heme-positive stools (70-100%)
 Abdominal pain, distension, and rebound tenderness likely in
fulminant colitis

 Amebic liver abscess

 Fever (85-90%)
 Right upper quadrant abdominal tenderness (84-90%)
 Weight loss (33-50%)
 Hepatomegaly (30-50%)
 Jaundice (6-10%)

Lacasse A, Cunha BA, 2012

Amebiasis Clinical Presentation
 Pleuropulmonary amebiasis
Cough, pleuritic chest pain, and respiratory distress may be
clues to rupture through the diaphragm, a rare but serious
complication of amebic liver abscess.

 Cerebral amebiasis
Occurring in 0.6% of amebic liver abscess cases, abrupt
onset of nausea, vomiting, headache, and mental status
change should prompt rapid investigation for CNS
involvement.
Progression can be very rapid.

Lacasse A, Cunha BA, 2012

E.coli Diarrhea Manifestation
 Top 5 Gram-negative bacteria associated with IAIs, SMART study
2009, Asia Pacific (n= 1239)
< 48 hours after hospitalization

E.coli 55%
K. pneumoniae 20%
E.coli and K.pnemoniae P. aeruginosa 5%
are common in most E. cloacae 5%
community acquired Intra
A.baumanii 2%
Abdominal infections
0% 20% 40% 60%

*Adapted from Study for Monitoring

Antimicrobial Resistance Trends (SMART):
2009
Prevalance of ESBL E.coli in IAI by region
SMART 2002-2011
% ESBL

In Indonesia ESBL resistance is 25%-50%

(ANSORP* Study 2011)
Adapted from Study for Monitoring Antimicrobial Resistance Trends (SMART): 2011
*ANSORP – Asian Network for Surveillance of Resistant Pathogens
Typhoid Fever
 Typhoid fever is an acute systemic infection
caused by Salmonella enterica serotype typhi or
paratyphi which is also known as Salmonella
typhi
 Risk factors for Typhoid & Paratyphoid Fever
in Jakarta

 Among 1019 subjects with fever, Salmonella typhi was

identified in 88 (9%) and Salmonella paratyphi A in 26 (3%)
patients
 Paratyphoid fever was independently associated with:
 consumption of food from street vendors
 and and flooding.
 Typhoid fever using the community control group were mostly
related to the household, ie, to recent typhoid fever in the
household:
 no use of soap for handwashing;
 sharing food from the same plate,
 and no toilet in the household.
 also, typhoid fever was associated with young age in years.

Vollaard, AM., JAMA. 2004;291(21):2607-2615

Factors that Influence Infectivity
 Ingestion of
 105 organism cause clinical disease in 25%
 107 organisms caused disease in 50%
 109 organisms caused disease in 95%

 Strains that do not have ‘Vi antigen’ are less

infective and less virulent
What is MDR-ST?
 MDR-ST is Salmonella typhi which has a mutagen
(Gyr-A or TEM-1) that can resistant to fluorquinolens
or partially to beta-lactam (not all)
 MDR Salmonella Typhi(MDR-ST)
Case Possibility
The possibility of MDR-ST showed by
clinical impression in which there’s no good
response after empirical adequate therapy
By :
- Penicillin : Amoxycillin,
Ampicillin
- Fluorquinolones : Ciprofloxacin
Levofloxacin
- Cephalosporines : Ceftriaxone
Yoon HJ, Cho SH, Kim SH, A case of MDR Salmonella enterica serovar typhi treated with a bench to bedside
Approach, Yonsei J Med, 2009 : 50(1) : 147-51
  A Multi-Drug Resistant Salmonella typhi
 (MDRST) was appeared by the present of
 gyrA and TEM-1 gene.

GENERAL MECHANISM of RESISTANCE

Gyr A Fluorquinolone
Gene Resistance

MDR-ST

Betalactamase
TEM-1 Type A
Gene ESBL

Yoon HJ, Cho SH, Kim SH, A case of MDR Salmonella enterica serovar typhi treated with a bench to bedside
Approach, Yonsei J Med, 2009 : 50(1) : 147-51
 Native
Organisms

Perl TM. Gram Negative Bacterial Resistance in Healthcare: The Brave New World Healthcare
Resistance in Gram-negatives
 MDR (multidrug-resistant)
 Resistance to 3 classes of antimicrobial agents
 CR( carbapenems resistant)
 Resistant to imipenem or meropenem

 XDR (extensively drug-resistant)

 Resistance to all but 1 or 2 (colistin or tigecycline)

 PDR (pandrug-resistant)
 Resistance to all*

*Antimicrobial agents that are available at the time of use of the

definition and in most parts of the world and that are regarded
as potentially effective against the respective pathogens
Falagas ME et al. Clin Infect Dis 2008;41:848-54.
Mechanism of
Antimicrobial Resistant

Tenover FC, Mechanism of Antimicrobial resistance in Bacteria,

American Journal of Medicine,2006
Mechanism of Antimicrobial Resistance:
“Selective Pressure” for Antimicrobial-Resistant Strains

Resistant Strains
Rare
Antimicrobial
Exposure

Resistant Strains
Dominant

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings, CDC 2002

 Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Emergence of Antimicrobial Resistance

Susceptible Bacteria

Resistant Bacteria

Resistance Gene Transfer

New Resistant Bacteria
THANK YOU
RONALD IRWANTO

PP. PERDALIN
Adequate antimicrobial treatment in critically ill
patients

Changes to
Empiric Treatment
Pathogen (de-escalation) Timely
Coverage Initiation
(appropriate) (early)

Optimal
Correct
Therapy Correct
Dose Route
(adequate) (adequate)

Increased Survival

Rello J. Eur Respir Rev. 2007;16:33-39.

Optimizing the Antimicrobial Usage
 De-escalation strategy
 Optimizing the PKPD of antimicrobial
 Combination therapy
 Short course antimicrobial treatment
 Using biomarkers to guide antimicrobial usage
PKPD relationship
 Consideration When Using
an Antibacterial Agent
Outcome
Microbiology
 Clinical efficacy
 Mechanism of action
Concentration  Bacterial eradication
 Antibacterial spectrum
at infection site  Compliance with
Drug dosing regimen
 Tolerability
Pathogen MIC
PK  Rate of resolution
 Prevention of resistance
 Absorption PD
 Distribution
 Metabolism
 Time vs. concentration
 Excretion dependent killing
 Optimal dosing  Bactericidal vs. bacteriostatic
regimen activity
 Tissue penetration
(Scaglione, 2002)  Persistence of antibacterial effect
Parameters of Antimicrobial Activity
• Potency : MIC
MBC
• Time Course of Activity

Persistent effects
Post Antibiotic Effect (PAE)
MIC
 Minimum inhibitory concentration
 in mg/L or ug/mL
 Is the lowest concentration in a series
of twofold concentrations that will
inhibit the growth of a microorganism,
as measured by the naked eye.
 PK/PD parameters affecting antibiotic efficacy in
vivo
Concentration Cmax:MIC
Time dependent
AUC:MIC T>MIC (CEF)
Concentration dependent
Cmax>MIC (AM)
AUC/MIC (FQ)
T>MIC

MIC

PAE
0
Time (hours)
MIC = minimum inhibitory concentration; AUC = area under the curve; T = time;
PAE = post antibiotic effect
Antibiotic Characteristic base on PKPD
Cmax = Peak Concentration Dependent
Cmax / MIC AUC / MIC
Aminoglycosides1,2 Aminoglycosides2
Fluoroquinolones1,2 Fluoroquinolones1,2
Oxazolidanones1,2
Glycopeptides2
Concentration

Lincosamides2
Lipopeptides1,2
Tetracyclines2
Macrolides2
MIC
Penicillins1
Cephalosporins1 T > MIC
Carbapenems1 Cmin = Trough
Macrolides1,2
Glycopeptides2
Lincosamides2
Time (hours)

1. Nicolau DP. J Infect Chemother. 2003;9:292-296.

2. Ambrose PG, et al. Clin Infect Dis. 2007;44:79-86.
Cmax:MIC (aminoglycosides)
Concentration
Target value: Cmax:>8–10 MIC
Cmax:MIC

MIC

0
Time (hours)
Cmax = maximum plasma concentration
T>MIC (β-lactams)
Concentration

MIC
T>MIC
0
Time (hours)
Turnridge. Clin Infect Dis 1998;27:1022; Manduru, et al. Antimicrob Agents Chemother 1997;41:2053–2056;
Tam, et al. J Antimicrob Chemother 2002;50:425–428; Tam, et al. Antimicrob Agents Chemother 2005;49:4920
24 hour Area Under Curve
24 H AUC : cummulative dosage in 24 H
Related to efficacy and drug toxicity
Concentration Target Attaintment : 24 H AUC/MIC : 125
if MIC = 2 24 H AUC : 250
average concentration 250/24 : 10 ug/mL

MIC

0 Time
Time (hours)
Ambrose, et al. Antimicrob Agents Chemother 2001;45:2793–2797;
Forrest, et al. Antimicrob Agents Chemother 1993;37:1073–1081
Cunha,2010
 In VITRO
MIC90
CLSI
EUCAST

ANTIBIOTICS EFFECT MICROBIOLOGIST

TO MICROORGANISM

CLINICIAN
Blood Lining Level

In VIVO PK Cmax > MIC

T>MIC PD
Cmax > MIC
T>MIC 24AUC>MIC
PK
24AUC>MIC
Tissue Level
 Antimicrobial Treatment based on
Microbiological Culture Results
Microbiological culture results

Colonization Pathogen

No treat Sensitive Resistant

Treat with Antibiotics Optimized

Recommended Combination PKPD
Antibiotics
Conclusion
 Antibiotic PK/PD should be known by every clinician
 Antibiotic PK/PD will influence the rational antibiotic
usage
 PK is dosed that related to in vivo concentration
 PD is in vivo concentration related to effect to
microorganism
 PK/PD will determine the potency of antibiotic
 Based on the antibiotic potency there are three types
of antibiotic : dose / concentration dependent, time
dependent type II and time dependent type III
THANK YOU