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 Second line Third line
Aminoglikosida: gentamisin, Sefalosporin gen.III oral: Glikopeptida: vankomisin,
amikasin. sefiksim, sefditoren, teikoplanin
Penisilin: amoksisilin, sefpodoksim, seftibuten, Oksazolidinon: linezolid
ampisilin+sulbaktam, sefprozil. Sefalosporin generasi IV:
amoksisilin+klavulanat Sefalosporin gen III injeksi: Sefepim, sefpirom
Sefalosporin gen.I: sefradin, seftriakson, sefoperazon* Karbapenem: imipenem,
sefaleksin, sefadroksil (hanya pada pasien dengan meropenem, ertapenem,
Sefalosporin gen.II: sefotiam, gangguan ginjal berat). doripenem
sefaklor Seftazidim (terutama pada Glisilsiklin: tigesiklin
Sefalosporin gen.III: infeksi Pseudomonas Kombinasi penisilin +
sefotaksim. aeroginosa ) penghambat betalaktamase:
Fenikol: kloramfenikol, Sefoperazon-sulbaktam* piperasilin-tazobaktam
tiamfenikol (hanya pada pasien dengan Polimiksin: kolistin
Asam fusidat gangguan ginjal berat) Monobaktam: aztreonam
Linkosamid: linkomisin, Fosfomisin IV Fluorokuinolon gen.I dan II:
klindamisin asam pipemidat,
Makrolida: eritromisin, siprofloksasin
spiramisin, roksitromisin, Fluorokuinolon gen III-IV:
klaritromisin, azitromisin levofloksasin, ofloksasin,
TMP-SMX moksifloksasin, perfloksasin,
Imidazol: metronidazol norfloksasin, gatifloksasin
Fosfomisin oral
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
