FIRST LINE EMPIRICAL

ANTIBIOTIC FOR
NEONATAL SEPSIS: RSCM
EXPERIENCE
Rinawati Rohsiswatmo
Albert
Neonatology Division - Child Health Department
Faculty of Medicine University of Indonesia
Cipto Mangunkusumo Hospital
Neonatal sepsis

‘a systemic infection occurring in

infants at ≤28 days of life and is
an important cause of morbidity
and mortality of newborns’
simonsen, 2014
DIFFICULTY IN ESTABLISHING NEONATAL
SEPSIS
 Mimic the other diseases
 The smaller the babies, the more difficult the diagnosis
 No specific LAB reference
 Three Causes of Neonatal
Mortality
(in developing countries)
 Asphyxia / Respiratory Distress (23%)
 Prematurity (28%)
 Sepsis / Infection (36%, including pneumonia, tetanus and diarrhea)

http://www.who.int/pmnch/media/press_materials/fs/fs_newborndealth_illness/en/
 CMH neonatal unit (Dec 2017-Feb 2018)
Patients (357)

Inborn (303) Outborn (54)

Discharged (143) Treated in other dept(s) (9)

Hospitalized in neonatal unit (160) Hospitalized in neonatal unit (45)

Medical problem (154) Surgical (6) Medical problem (38) Surgical (7)

LOS (20) EOS (46) LOS (2) EOS (4) LOS (3) EOS (4) LOS (5) EOS (3)

proven 1 († 1) proven (0) proven (0) proven 1 († 0)

Proven 9 († 2) Proven 1 († 1) Proven 1 (†1) proven 5 († 1)
Isolate 12 Isolate 6
TOTAL DEATH (EXCEPT PROVEN SEPSIS = 31 (inborn) + 10 (outborn) = 41
 NEONATAL SEPSIS … WHO (2016) ~European
EMAMedical
(2010)
Agency~
‘presence of at least two clinical symptoms and at least two laboratory signs in the presence
of or as a result of suspected or proven infection
(positive culture, microscopy or polymerase chain reaction)’
Clinical signs
1. Modified body temperature: 5. Cardiovascular instability:
core temperature > 38,5 °/ < 36 °C AND/OR bradycardia (mean HR < 10th percentile for age in the absence of
temperature instability external vagal stimulus, beta- blockers or congenital heart
disease OR otherwise unexplained persistent depression over a
2. Respiratory instability: 0.5 h time period) OR tachycardia (mean HR greater than 2 SD
apnoea episodes OR tachypnea episodes (mean above normal for age in the absence of external stimulus, chronic
respiratory rate (RR) over 2 SD above normal for drugs and painful stimuli OR otherwise unexplained persistent
age) OR increased oxygen requirements OR elevation over a 0,5 h to 4 h time period) AND/OR rhythm
requirement for ventilation support instability reduced urinary output (less than 1 mL/kg/h),
hypotension (mean arterial pressure less than the 5th percentile
3. Gastrointestinal: for age), mottled skin, impaired peripheral perfusion
feeding intolerance, poor sucking, abdominal Skin and subcutaneous lesions: petechial rash, sclerema
distention

4. Non-specific:
irritability, lethargy and hypotonia
Fuchs, 2016
 NEONATAL SEPSIS … WHO (2016) EMA (2010)
Laboratory signs
• WBC:
<4,000 x109 cells/L OR
>20,000 x109 cells/L

• (I/T) ratio >0.2

• Platelet <100,000 x109 cells/L

• CRP > 15 mg/L OR

procalcitonin ≥ 2 ng/ml (cut-off not clearly defined)

• Glucose intolerance
confirmed at least 2 times: hyperglycaemia (blood glucose >180 mg/dL or 10
mMol/L) OR hypoglycaemia (glycaemia < 45 mg/dL or 2.5 mMol/L) when
receiving age specific normal range glucose amounts

• Metabolic acidosis:
Base excess (BE) <-10 mEq/L OR
Serum lactate > 2 mMol/L
Fuchs, 2016
 RISK FACTORS EOS NICE clinical guideline (2012), NHS (2016)
Invasive group B streptococcal infection in Intrapartum fever higher than 380C, or suspected or
a previous baby confirmed chorioamnionitis

Parenteral antibiotic treatment given to the mother

for confirmed or suspected invasive bacterial
Maternal group B streptococcal
infection (such as septicaemia)
colonization, bacteriuria or infection in the
at any time during labour, or
current pregnancy
in the 24 hour periods before and after the birth
(not referring to intrapartum antibiotic prophylaxis)

Suspected or confirmed infection in another baby

Prelabour rupture of membranes
in the case of a multiple pregnancy

Preterm birth following spontaneous Suspected or confirmed rupture of membranes

labour (before 37 weeks’ gestation) (> 18 hours) in a preterm birth
 CLINICAL INDICATORS EOS
Altered behaviour or responsiveness
Altered muscle tone (for example floppiness)
Feeding difficulties (for example feed refusal)
Feed intolerance, vomiting, excessive gastric
aspirates and abdominal distension
Signs of respiratory distress
Respiratory distress starting more than 4 hours
after birth
Hypoxia (for example central cyanosis or reduced
oxygen saturation level)
Jaundice within 24 hours of birth
Apnoea
Signs of neonatal encephalopathy
Seizures
NICE clinical guideline (2012), NHS (2016)
Need for cardio-pulmonary resuscitation
Need for mechanical ventilation in a pre-term baby
Need for mechanical ventilation in a term baby
Persistent foetal circulation
(persistent pulmonary hypertension)
Temperature abnormality (lower than 360C and higher
than 380C) unexplained by environmental factors
Signs of shock
Unexplained excessive bleeding, thrombocytopenia, or
abnormal coagulation (INR greater than 2.0)
Oliguria (persistent beyond 24 hours after birth)
Altered glucose homeostasis (hypoglycaemia or
hyperglycaemia)
Metabolic acidosis (base deficit of 10 mmol/litre or
greater
Local signs of infection (eye, skin, umbilicus)
 EOS
If a baby has no red flags and 1 risk factor/1 clinical
indicator use clinical judgement and consider:
 Safety of withholding antibiotics.
Necessity of monitoring by baby’s vital signs and
clinical condition
 If clinical concern increases, consider necessary
investigations and starting antibiotic treatment
 If no further concerns arise during the period of
observation, reassure the family

http://www.northdevonhealth.nhs.uk/wp-content/uploads/2016/09/Neonatal-Sepsis-Guidelines-V1.2-Sept-16.pdf
 EOS
If a baby has any red flags / 2 or more ‘non-red’ risk factors or
clinical indicators :
 Perform investigations prior to commencing antibiotics
 Blood tests
(Blood culture, Full blood count, CRP, BGA, Blood sugar),
 Lumbar puncture (consider),
 Chest X-Ray,
 Urine culture (not routine),
 Eye swabs for suspected infection,
 Umbilical swabs for suspected infection
Start antibiotics within one hour of decision to treat (do not wait
for test results)
[do not routinely give antibiotic treatment to babies without risk
factors or clinical indicators for infection or laboratory evidence
of possible infection]
http://www.northdevonhealth.nhs.uk/wp-content/uploads/2016/09/Neonatal-Sepsis-Guidelines-V1.2-Sept-16.pdf
 Risk Factors LOS Clinical Indicators LOS

Non-specific features
 Low birth weight
 Hypothermia or fever (former is more
 Prematurity
common in preterm low birth weight
patent ductus arteriosus,
infants)
bronchopulmonary dysplasia (BPD),
 Lethargy, poor cry, refusal to suck
necrotising enterocolitis (NEC)
 Poor perfusion, prolonged capillary
 Admission in intensive care unit
refill time
 Mechanical ventilation
 Hypotonia, absent neonatal reflexes
 Ιnvasive procedures
 Brady/tachycardia
 Invasive neonatal therapy
 Respiratory distress, apnea and
(especially indwelling intravenous
gasping respiration
catheters)
 Hypo/hyperglycemia
 Administration of parenteral fluids, and
 Metabolic acidosis.
use of stock solutions
 Generally looking unwell
WHO, 2014
 Clinical Indicators LOS (2)
specific features
Central nervous Bulging anterior fontanelle, vacant stare, high-pitched cry, excess
system (CNS) irritability, stupor/coma, seizures, neck retraction. Presence of
these features should raise a clinical suspicion of meningitis
Cardiac Hypotension, poor perfusion, shock
Gastrointestinal Feed intolerance, vomiting, diarrhea, abdominal distension,
paralytic ileus, necrotizing enterocolitis (NEC)

Hepatic Hepatomegaly, direct hyperbilirubinemia (especially with urinary

tract infections)

Renal Acute renal failure

Hematological Bleeding, petechiae, purpura
Skin changes Multiple pustules, abscess, sclerema, mottling, umbilical redness
and discharge. WHO, 2014
 Early-onset neonatal sepsis (EOS)
‘bacteremia/bacterial meningitis occurring at
≤72 hours in infants hospitalized in the NICU/
<7 days in term infants’

The predominant pathogens from the maternal

genital tract and are:
Group B Streptococcus (GBS)
E coli, other Streptococci,
Haemophilus influenzae,
Listeria monocytogenes.
http://www.northdevonhealth.nhs.uk/wp-content/uploads/2016/09/Neonatal-Sepsis-Guidelines-V1.2-Sept-16.pdf
 Late Onset Sepsis [LOS]
‘an infection occurring after the first 72
hours or 3 -7 days of life’
either nosocomial (hospital-acquired) or community-acquired
Gram-positive organisms Gram-negative
 Coagulase-negative organisms
staphylococci  E coli
 Staphylococcus aureus  Klebsiella species
 Enterococci  Pseudomonas spp
 Streptococcus spp

http://www.northdevonhealth.nhs.uk/wp-content/uploads/2016/09/Neonatal-Sepsis-Guidelines-V1.2-Sept-16.pdf
 CMH EOS AND LOS MICROBES (DEC 17- FEB 18)
Inborn (303) Outborn (54)

Medical problem (154) Surgical (6) Medical problem (38) Surgical (7)

LOS (20) EOS (46) LOS (2) EOS (4) LOS (3) EOS (4) LOS (5) EOS (3)

proven 1 († 1) proven (0) proven (0) proven 1 († 0)

Proven 9 († 2) Proven 1 († 1) Proven 1 (†1) proven 5 († 1)
Isolate 12 Isolate 6
LOS Microbes: TOTAL DEATH (EXCEPT PROVEN SEPSIS = 31 (inborn) + 10 (outborn) = 41
Kleb Pneumoni 5
Acine. Baumanii 2 EOS Microbes:
Bacillus sp 1 LOS Microbes: LOS Microbes:
Acine. Baumanii 1
Stap. Epiderminis 2
Ent. Cloaca 1 MRSE 1 MRSE 1
LOS Microbes:
MRSE 1
Kleb Pneumoni 3
Stap. Epiderminis 1
EOS Microbes:
Pseud. Aeruginosa 1
Stap. Epiderminis 1
MRSE 1
Of greater concern is the strikingly high preponderance of gram-negative enteric
organisms in early onset neonatal sepsis in our environment. The increasing prevalence
of these organisms in early onset neonatal sepsis is further supported by other workers
from India and Pakistan (14, 16, 17). The high incidence of operative and
instrumental deliveries in these patients indicates that prolonged
and complicated deliveries are a major risk factor. Most of the
neonates developing early sepsis many as early as 12-24 hours
after birth, were born in hospital and it is possible that poor
aseptic techniques, frequent examinations and instrumentation
led to colonisation of the maternal genital tract with gram-
negative bacteria and subsequent vertical transmission to the
newborn. The relatively high proportion of instrumental delivery (42%) and birth
asphyxia (58 Yo) in the early-onset infection group also tends to support this. The
spectrum of organisms causing late onset infections also consists mostly of gram-negative
organisms, reflecting the microbial environment that many of these neonates were
exposed to. Consonant with the findings of Lehtonen et al. (1 8), two of the three
neonates presenting with group A Streptococcal septicemia/had concomitant omphalitis.
 ANTIBIOTICS’ SENSITIVITY FOR EOS
CMH’S NEONATAL UNIT
(DEC 17- FEB 18)
ND RD
1ST LINE 2 LINE 3 LINE

piperacil-tazobac
chloramphenicol
cotrimoxazole

erythromycin

ciprofloxacin

amoxici-clav

lincomycin
levofloxacin
tetracycline

meropenem
ampi-sulbac

cephalothin

vancomycin
Cefo-sulbac
gentamycin

ceftriaxone

tigecycline
doripenem
aztreonam
kanamycin

ceftazidim
pennicillin

tecoplanin

cefpirome
cefotaxim
ampicillin

linezolid
amikacyn

cefepime
cefoxitin
oxacillin

colistin
ORGANISMS

acinetobacter
baumanii S S S S I S S
stap. Epidermidis S S S S S S SRR
S: sensitive
1stLine antibiotic resistancy for EOS (Ampi-Genta) I: intermediate
R: resistant
RSUP Sanglah Denpasar 2011 (ampi 63%, genta 60%)
RSUP H Adam Malik Medan 2012 (ampi 72%, genta 53%)
RSCM 2008 (ampi 80%, genta 33%)
 CMH’s NEONATAL BLOOD STREAM MICROORGANISM PATTERN (EOS AND LOS)
(JULI 2009 - OCT 2017)
300
700 678 636

278 275
250
231

200

150 142

100
84

50

0
Staphylococcus Acinetobacter Enterobacter Klebsiela Acinetobacter Pseudomonas Serratia
Epidermidis Baumanii Cloacae Pneumoni sp Aeruginosa marcessens
tot 2017 2016 2015 2014 2013 2012 2011 2010 2009
 Mean percentage

100

0
10
20
30
40
50
60
70
80
90
tecoplanin
vancomycin
colistin
imipenem
levofloxacin
meropenem
amikacyn
oxacillin
cefoxitin
tigecycline
cefpirome
ciprofloxacin
cefepime
piperacil-tazobac
chloramphenicol
ceftazidim
cotrimoxazole
(JULI 2009 - JULI 2017)

cefoperazone
gentamycin
aztreonam
tetracycline
ceftriaxone
kanamycin
ampi-sulbac
amoxici-clav
cephalothin
cefotaxim
erythromycin
CMH’s NEONATAL RESISTANCE AND SENSITIVITY TO ANTIBIOTICS (EOS AND LOS)

ampicillin
pennicillin
 1st LINE ANTIBIOTICS’ SENSITIVITY EOS AND LOS (7 MICROBES)
CMH’S NEONATAL UNIT
(JULI 2009-JUNI 2017)

Chart Title
40
35 chloramphenicol
30 cotrimoxazole
25 gentamycin
20 tetracycline
15 kanamycin
10 erythromycin
5 ampicillin
0 pennicillin
antibiotic
Microbes: Staphylococcus Epidermidis, Acinetobacter Baumanii, Enterobacter Cloacae, Klebsiela Pneumoni,
Acinetobacter sp, Pseudomonas Aeruginosa, Serratia marcessens
 2ND LINE ANTIBIOTICS’ SENSITIVITY EOS AND LOS (7 MICROBES)
CMH’S NEONATAL UNIT
(JULI 2009-JUNI 2017)

60 amikacyn
oxacillin
50 ciprofloxacin
piperacil-tazobac
40
ceftazidim
30 cefoperazone
aztreonam
20 ceftriaxone
10 ampi-sulbac
amoxici-clav
0 cephalothin
ANTIBIOTIC cefotaxim
Microbes: Staphylococcus Epidermidis, Acinetobacter Baumanii, Enterobacter Cloacae, Klebsiela Pneumoni,
Acinetobacter sp, Pseudomonas Aeruginosa, Serratia marcessens
 3RD LINE ANTIBIOTICS’ SENSITIVITY EOS AND LOS (7 MICROBES)
CMH’S NEONATAL UNIT
(JULI 2009-JUNI 2017)

100 tecoplanin
90 vancomycin
80 colistin
70
imipenem
60
levofloxacin
50
40 meropenem
30 cefoxitin
20 tigecycline
10 cefpirome
0 cefepime
ANTIBIOTIC
Microbes: Staphylococcus Epidermidis, Acinetobacter Baumanii, Enterobacter Cloacae, Klebsiela Pneumoni,
Acinetobacter sp, Pseudomonas Aeruginosa, Serratia marcessens
Blood culture in the NICU of S.P. Medical
College, Bikaner, Rajasthan, INDIA (January -
October 2014)
Singapore General Hospital NICU database (May 2005 to May 2007)
 Neonates’ blood cultures in 3 Hospital in Malaysia
(Hospital Raja Permaisuri Bainun Ipoh, Hospital Pulau Pinang and Hospital Sultanah Aminah Johor Bahru)
(2009 – 2012)
RIGHT ANTIBIOTIC
EMPIRIC THERAPY

• should be unit-specific and determined by the prevalent

spectrum of etiological agent and their antibiotic sensitivity
patern

DEFINITIVE THERAPY

• Observe blood culture result and change

empirical antibiotics based on sensitivity result
CMH NEONATAL’S ANTIBIOTIC PROTOCOL FOR NEONATAL SEPSIS (2017)
EON
Antibiotic duration:
1st Line
Gram + 7-10 days
Mild: Ampicillin
Gentamycin
Gram - 7-14 days
Severe : Ampicillin Sulbactam Meningitis 21 days
Gentamycin Abscess 4-6 weeks
LOS
Community septic screening:
Community (w/o meningitis) : Ampicillin Sulbactam
check blood smear
Gentamycin
Community (w/ meningitis) : Ampicillin Sulbactam
Gentamycin
All Susp. LOS:
Cefotaxime Check urinalysis + urine culture
Hospital LP/head USG (if indicated)
VAP, HAP, UTI* : Ceftazidime
SSI , BSI* : Cefosulbactam + Amikasin Every birth w/ risk factor:
CLABSI* : Meropenem
Check umbilical cord BGA + lactate
MDR* : Carbapenem
VAP (ventilator acquired pneumonia), HAP (ventilator acquired pneumonia), UTI (urinary tract infection), SSI(surgical site infection),
.
BSI (blood stream infection), CLABSI (central line associated blood stream infection), MDR (multi drug resistance)
ANY
QUESTION ??