Mulya Rahma Karyanti, MD, MSc

Head Division of Infection and Tropical Pediatrics, head of ARCP,

Departemen of Pediatrics, Cipto Mangunkusumo hospital, Universitas Indonesia
• Education
• General Practitioner - Faculty of Medicine, University of Indonesia, 1994
• Pediatrician - Faculty of Medicine, University of Indonesia, 2004
• Training tropical Infectious disease on public health, WHO-SEARO, April 2009
• Master of Science in Clinical Epidemiology, Utrecht University 2009-2011
• Consultant Infection and Tropical Pediatrics, 2011
• Organization
• Treasurer of National Indonesia Pediatric Society, 2008-2010
• Member Asian Society of Pediatric Infectious Disease ( ASPID ), 2005 until now
• Working group of Infection and Tropical Pediatrics, Indonesia Pediatric Society, 2017-
2020
• Chair of Pediatric Pharmacy, Indonesia Pediatric Society 2015-2017 and 2017-2020
• Expert committee team of DHF, Malaria, Measles, Rubella elimination, diphtheria,
MOH RI
Antimicrobial Stewardship
in NICU
Mulya Rahma Karyanti, MD, M.Sc

Head of the Antimicrobial Resistance Control Program,

Division of Infection and Tropical Pediatric,
Department of Child Health, Cipto Mangunkusumo Hospital,
University of Indonesia, Jakarta
Outline
• Antimicrobial resistance increasing
• Antimicrobial stewardship (AMS) in NICU
• Implementation AMS in Cipto Mangunkusumo hospital
• Monitoring Success of AMS
Background
Antibiotics are one of the most commonly prescribed drugs in NICU

But, often used inappropriately

• Over-consumption of antibiotics can lead to multidrug resistence and

threatens the achievements of the modern medicine.
• Prolonged use of broad-spectrum antibiotics can increase the risk of
Candida colonization and invasive infection, necrotizing enterocolitis,
late onset neonatal sepsis, and also death
• Neonatal infections from multidrug-resistant strains associated with
increased mortality, excessive cost, prolonged hospitalization, and
therapeutic challages.
Antimicrobial Stewardship (AMS)
• AMS is recognized as a critical patient safety and quality imperative to
combat the emergence of antimicrobial resistance (AMR) and
preserve the activity of existing agents.

• All the coordinated interventions design to improve and measure he

appropriate use of antimicrobials by promoting the selection of the
optimal antimicrobial drug regimen, dose, duration of therapy, adn
route of administration

• Goals: optimal clinical outcome, minimize toxicity and other adverse

events, reduce the cost of health care, and limit the selection for
antimicrobial resistant strains
Current Pediatric Review. 2019;1
Principles of AMS
• When and whom antimicrobial treatment should be given (timely and
appropriate treatment)
• Which antimicrobial (suitability)
• How (dose, duration, route)
• Continous monitoring of antimicrobial use
• Use of resources, human resources, and education

Current Pediatric Review. 2019;1

AMS Implementation in NICU
• Diagnosis of Neonatal Septicaemia
• Choice of Empirical Antimicrobial Treatment
• Reassessment of the Initial Antimicrobial Treatment when Culture
Results are Available
• Dosage and Monitoring of Antimicrobial Levels
• Measurement of Antimicrobial Use and Continuous Assessment
• Development of AMS teams

Current Pediatric Review. 2019;1

Diagnosis of Neonatal Septicaemia
• Biomarkers: CRP, procalcitonin, Interleukins 6 and 8
• Obtain a suficient amount of blood from newborn for potential
pathogens grow: two blood cultures, at least 1 ml.
Infectious Diseases and Immunization 2019:31:127-132.

Infectious Diseases and Immunization 2019:31:127-132.

Choice of Empirical Antimicrobial Treatment
• The proposed empirical antimicrobial treatments are based on
distiction between early onset sepsis (EOS) and late onset sepsis (LOS)
• Common causes of EOS worldwide: beta hemolytic streptococci group
B and Enterobacteriaceae
• Common use regimens for EOS: combination ampicillin and
gentamicin
• Common use regimens for LOS: combination semisynthetic penicillin
and aminoglycoside
• Avoid cephalosporins! --> can increase risk of candidiasis. Only use if
there is a suspicion of meningitis

Infectious Diseases and Immunization 2019:31:127-132.

Reassessment of the Initial Antimicrobial Treatment

• When? -> when the culture results are available

• If the newborn remains in good condition and the pathogen seems
like not true infections (areas for sampling are not sterile) then
stopped the treatment imediately.
• If the culture results are out within 48 hours, immideate change the
treatment based on pathogen and its sensitivities

Infectious Diseases and Immunization 2019:31:127-132.

Dosage and Monitoring of Antimicrobial Levels
• Due to the particularities of of pharmacokinetics and toxicity of certain
antibiotics (such as gentamicin in neonates), including reduced renal
function and longer half-lives, it is necessary to administer higher doses at
longer intervals in preterm infants.

• Clinician should messure the postmenstrual and chronological age of the

infant before prescribing antibiotic

• Dosing schdules should be appropriate for gestational age, chronological

age, and current weight.

• Infants should be monitored for toxicity, particular if renal function is

changing, or if prolonged courses of therapy are administered.
Infectious Diseases and Immunization 2019:31:127-132.
Measurement of Antimicrobial Use and Continuous
Assessment
• Days of therapy (DOTs) is a commonly used metric in pediatrics and
reflects total days of antimicrobial therapy administrated, irrespective
of dosing by weight or renal function.
• DOT are often adjusted for 1000 patient-days of hospitalization

• The microbiology report with antibiotic susceptibility testing (AST) is

an invaluable tool to determine if antibiotics should be continued,
modified, or discontinued

Infectious Diseases and Immunization 2019:31:127-132.

Days of therapy (DOT)

Antimicrobial Stewardship in the NICU. Infect Dis Clin N Am. 2014

Antibiotics Prescribing Issues in NICU
• Diagnostic challenges
• Culture Negative Neonatal Sepsis
• Chorioamnionitis
• Duration and Type of Antimicrobial Treatment
• Dosage and Levels of Antimicrobials
• Perioperative Chemoprophylaxis
Diagnostic Challenges
• Neonatal sepsis can present with non-spesific symptoms and sign,
and also many overlap findings with noninfectious causes

• At present there is no combination of laboratory testing with

sufficient sensitivity to preclude infection.

• There is a very low threshold for clinician to obtain cultures and start
empiric therapy for clinical signs that could be consistent with sepsis.
Culture Negative Neonatal Sepsis
• Many preterm infants have clinical signs caused by their prematurity
but are indistinguishable from sepsis (such as respiratory distress and
hypotension). These infants may recieve prolonged antibiotic
despite sterile culture.

• Mother who receive intrapartum antibiotic prophylaxis (IAP). Some

clinician think that IAP can mask a true sepsis episode and make the
culture falsely negative. But actually these infants has lower risk of
sepsis because of maternal IAP
Chorioamnionitis
• Mother with chorioamnionitis is another clinical situation that leading to a
high volume of antibiotic use in infant

• If there are asymptomatic infants, follow-up for at laest 48 hours without

treatment is advised.

• For asymptomatic infants of mothers who have been diagnosed with

chorioamnionitis:
• Discontinuation of antimicrobials in infant that appear clinically well and have normal
laboratory investigations 48 hours after their onset
• If there is abnormal laboratory results, the possibility of antimicrobial treatment
should be considered for up to 72 hours
Duration and Type of Antimicrobial Treatment

• There is no consensus on the duration and type of antimicrobial that

should be administrated. As a result, there is a wide variation in
treatment of both neonatal septicaemias with negative cultures as
well as microbiologically confirmed septicaemia
Dosage and Levels of Antimicrobial
• Neonates have both reduced glomerular filtration and tubular
secretion compared with older children, and hepatic metabolic
activity may very extensively between preterm and term infants.
Perioperative Chemoprophylaxis
• There are guidelines recommending one antibiotic agent before
surgery. But the recommendations have not been extended to
neonates.
• Many infants continue to recieve prolonged perioperative prophylaxis
 Antibiotic susceptibility testing (AST)
1. Body site from positive culture isolated should be reviewed.
2. Susceptibility results provide opportunity to treat with a narrow
spectrum, less toxic, and more efficacious antibiotic.
3. Minimun inhibitory concentration (MIC) can guide treatment for
infections at sequestered sites (lung or central nervous system).
4. Date and time of the microbiology report, provide an opportunity
for timely discontinuation of therapy when infection is not
suspcted. Cultures with growth after 48 hours are more likely to be
contaminants or colonizing organisms.
Development of AMS Teams
• Neonatologist
• Infectious diseases specialists
• Microbiologists
• Pharmacists
• Infection control nurses
• Representatives of ICU

Semin Perinatol.2012;36(6): 431-436

Examples of AMS strategies

Semin Perinatol.2012;36(6): 431-436

1. Establish national infection control programs :
National programs to control antimicrobial
resistance (ARCP/PPRA) since 2005
2. Establish effective, hospital-based therapeutics
committees for monitoring antimicrobial usage
3. Develop and regularly update on guidelines for
antimicrobial usage, especially on treatment &
prophylaxis
4. Ensure access to microbiology labs

(National Programme)
1. ARCP recommendation on a nationwide conference in 2005 :
a strategy to Combat the Emergence and Spread of
Antimicrobial Resistant Bacteria in Indonesia  obliged
hospitals to implement prevention steps towards
antimicrobial resistance, e.g : reinforce handwashing in the
hospital setting
2. ARCP proposal to the Indonesian Ministry of Health :
Prevent the occurrence and distribution
antimicrobial resistance through rationale
antimicrobial usage and improved control on
infection management
 Indonesian Ministry of Health has

announced a policy (SK DIRJEN Bina

Pelayanan Medik DEPKES RI

no: HK.00.06.1.1.4168/ Date: 23rd

September 2005), assessing hospital’s

Release of “National
infrastructure to support antimicrobial
guidelines on antimicrobial
resistance, antibiotic usage resistance management
and infection control”, 2005
Decree of Director of CM Hosp:
7139/TU.K/34/VII/2009

deciding:

Formation of Antimicrobial Resistance Controlling Program

(ARCP)
 Antimicrobial Resistance Controlling Programe
Hospital policy of Antimicrobial Usage

Antimicrobial Resistance Controlling Programe

- Decreasing Antimicrobial Resistance

.
•
IDSA/SHEA. Guidelines for developing an instutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007; 44: 159–77.
 Dr. Cipto Mangunkusumo Hospital
• National General Hospital
• Teaching Hospital
• Class :A
• Owner : Ministry of Health – Indonesia
• Address : Jl. Diponegoro No. 71, Jakarta
• Number of bed : 1220
• Department/unit : 32
 Aims
• Decreasing total use of antibiotics (quantitative)
• Increasing appropriate use of antimicrobial
(qualitative)

IDSA/SHEA. Guidelines for developing an instutional program to

enhance antimicrobial stewardship.. Clin Infect Dis 2007; 44: 159–77.
 Collaborative of ARCP
Divison
Divison
Nosoco Clinical
mial Pharmaco
Infection logist
Division Committe Divison

ARCP

Divison Divison
Clinical
Microbio Pharmacist
logist

Divison Divison
 Collaborative working system of ARCP

Pharmacy and
Therapeutic Committe
Clinical
Microbiologist

Nosocomial Infection Surveillance data

ARCP
Committe REPORT
Hospital and Hospital Director
Department
Team

Clinicians from Clinical Pharmacist

Departments

Nurse staffs
 The Concept of
INFECTIOUS DISEASE INTEGRATED SERVICE TEAM

KLINISI PERAWAT/BIDAN

SKFT
TFT
DALINPPIRS
Komite

FARMASI MIKROBIOLOGI
Klinik Klinik

Tim Pelaksana PPRA - RSCM Jakarta

 Working Task of ARCP Team
• Deciding hospital regulation of antimicrobial resistance
controling
• Deciding policy of antimicrobial usage
• Develop program of antimicrobial resistance controlling
• Monitoring and evaluation of ARCP
• Organizing discussion forum in managing infectious
disease
(and antimicrobial usage auditing)
• Socialization and education of appropriate antimicrobial
usage for physician/users
• Develop clinical researches related to ARCP
 ANTIBIOTIK POLICY SYSTEM
IN CIPTO MANGUNKUSUMO HOSPITAL

Dept/UPT/Inst
Medical committee
Cq Panitia Farmasi
dan Terapi

ARCP Team
Draft
Dept/Inst/UPT

AB BOOK
GUIDANCE
ARCP Team DIRECTOR
Clinical Microbiology
 Department of Child Health
• Regular Bed 40
• (Infection ward 20, non-infection ward 20)
• Bed in Isolation Ward 4
(for immunocompromised patient)
• Bed in Pediatric Intensive Care Unit 20
• Bed in Neonatal Intensive Care Unit 65
Total 129
 Divisions in Department of Child Health
1. Infection and Tropical 8. Endocrinology
Pediatri 9. Kidney
2. Pulmonology 10.Clinical Allergy and
3. Gastroenterology Immunology
11.Cardiology
4. Neurology
12.Hematology and
5. Nutrition and metabolic Oncology
diseases 13.Pediatric radiology
6. Hepatology 14.Neonatal intensive care
7. PICU unit (NICU)
Kartu Pedoman
Antibiotik
Departemen
Ilmu Kesehatan
Anak
RSUPN Cipto
Mangunkusumo
Penilaian Antibiotik Secara Kualitatif
Perinatologi RSCM 2013
Klasifikasi Gyssen PRE PPRA

I (Penggunaan tepat) 34.6% 56.8%

IIA (tdk tepat dosis) 16.2% 0%
IIB (tdk tepat interval) 0% 1%
IIC (tdk tepat cara pemberian) 0% 0%
IIIA (terlalu lama) 9.6% 6.8 %
IIIB (terlalu singkat) 23.8% 17.3%
IVA (ada obat lain lebih efektif) 2% 1%
IVB (ada obat lain kurang toksik) 0% 0%
IVC (ada obat lain lebih murah) 0% 0%
IVD (ada obat lain lebih spesifik) 0% 0%
V (tidak ada indikasi) 44.6% 15.7%
VI (rekam medik tidak dapat 0% 0%
dievaluasi)
Penilaian Antibiotik Secara Kuantitatif (gram)
Perinatologi RSCM 2013
Pre Pra
Amoxicillin
1 Clavulanate 54.457 189.04
Piperacillin
2 Tazobactam 39.29 137.922
3Meropenem 32.995 98.162
4Cefotaxim 6.75 12.73
5Amikacin 5.854083 15.07343
6Gentamisin 6.896 5.870167
7Metronidazol 16.895 0.977
Sefoperazon
8 Sulbaktam 2.04 0.236
9Doripenem 0.0634 1.84
10Eritromisin 0.05 1.152
CMH’s Antibiotic guidelines for neonatal sepsis 2017
Diagnosis Antibiotics
Early onset. Sepsis (EOS)

Mild Ampicillin AND gentamycin

Therapy duration
Severe Ampicillin sulbactam AND gentamycin - Proven sepsis:
Late Onset Sepsis (LOS) 7-14 days
- Meningitis: 21
Community acquired days

without meningitis Ampicillin sulbactam AND gentamycin

with meningitis Ampicillin sulbactam AND gentamycin AND cefotaxime
Hospital acquired
VAP, HAP, UTI Ceftazidime
SSI, IAD Cefoperazon sulbactam AND amikacin
CLABSI Vancomycin and amikacin
CLINICAL ROUND (Every Friday: 9-10 am)
 ARCP workshop in
Cipto Mangunkusumo hospital

September 2013
 ARCP workshop in
Cipto Mangunkusumo hospital

September 2013
 Working Task of ARCP Dep of Pediatrics
• Develop Hospital Guidelines of antimicrobial usage
• Perform socialization and education programe
• Perform antimicrobial usage controlling programe in
Dept of Internal Medicine
• Implementing antimicrobial auditing
• Implementing antimicrobial surveillance
Developing Antimicrobial Usage Guidelines

• Based on microbial pattern

• Existing national/international guidelines
• Suggestion from the users, clinical microbiologist
• Drug availability and cost
• Practical guidelines and easy to perfom
Hospital Antimicrobial Guidelines Pattern

1. Diseases Classification or stratification

e.g Pneumonia : CAP and HAP
2. Treatment approach : empirical
definite treatment
 Antibiotic classification
First line
Aminoglikosida: gentamisin,
amikasin.
Penisilin: amoksisilin,
ampisilin+sulbaktam,
amoksisilin+klavulanat
Sefalosporin gen.I: sefradin,
sefaleksin, sefadroksil
Sefalosporin gen.II: sefotiam,
sefaklor
Sefalosporin gen.III:
sefotaksim.
Fenikol: kloramfenikol,
tiamfenikol
Asam fusidat
Linkosamid: linkomisin,
klindamisin
Makrolida: eritromisin,
spiramisin, roksitromisin,
klaritromisin, azitromisin
TMP-SMX
Imidazol: metronidazol
Fosfomisin oral
Second line
Sefalosporin gen.III oral:
sefiksim, sefditoren,
sefpodoksim, seftibuten,
sefprozil.
Sefalosporin gen III injeksi:
seftriakson, sefoperazon*
(hanya pada pasien dengan
gangguan ginjal berat).
Seftazidim (terutama pada
infeksi Pseudomonas
aeroginosa )
Sefoperazon-sulbaktam*
(hanya pada pasien dengan
gangguan ginjal berat)
Fosfomisin IV
Third line
Glikopeptida: vankomisin,
teikoplanin
Oksazolidinon: linezolid
Sefalosporin generasi IV:
Sefepim, sefpirom
Karbapenem: imipenem,
meropenem, ertapenem,
doripenem
Glisilsiklin: tigesiklin
Kombinasi penisilin +
penghambat betalaktamase:
piperasilin-tazobaktam
Polimiksin: kolistin
Monobaktam: aztreonam
Fluorokuinolon gen.I dan II:
asam pipemidat,
siprofloksasin
Fluorokuinolon gen III-IV:
levofloksasin, ofloksasin,
moksifloksasin, perfloksasin,
norfloksasin, gatifloksasin
1. Quantitative : reduction on antibiotic usage
in term of types and doses
2. Qualitative : improved antibiotic
management
3. Higher antibiotic susceptibility on hospitals
4. Better health care services in term of :
 Lower morbidity, mortality and nosocomial
infections
 Decrease LOS
 Cost effective
 Infection control and management through
multidisciplinary team
Monitoring Success of AMS
• AMS programs should develop metrics to measure successful
implementation and safety rather than focusing on cost saving.
• In pediatric population, days of therapy are the preferred metric to
quantify antibiotic use.
• Metrics for appropriate antibiotic use should be developed with key
stakeholders as prescriber acceptance.
• Focus group and understanding the work flow of the NICU can be
useful to develop metrics that are meaningful to the prescribers.
Thank you