Objectives

Antibiotic essentials
Which one? Rationale?
Duration of treatment
Practical applications
Supportive Care
Neonatal septic shock
Adjunctive therapies
Follow up care

PARENTERAL ANTIBIOTICS
All about antibiotics - Basics
CASE SCENARIOs
CASE 1: B/o S
38 wk/ 2.8 Kg/ AFD/ Mch
Day 8 of life
Born in PGI via NVD
Discharged on D 2
Brought with 2d history of
Episodes of vomiting
Lethargy
Abnormal movements
Sepsis screen POSITIVE
CSF s/o meningitis
Which antibiotic will you start?
CASE 2: B/o M
34 wk/ 1.2 Kg/ SFD/ Fch
Day 1 of life
Born via NVD at home
Brought with
Poor feeding
Lethargy
Tachypnea
Examination shows sclerema
Which antibiotic will you start?
Empirical Antibiotic therapy
Choice of antibiotics

Based on the organisms responsible for the
infection in that region (local data)

Based on the sensitivity patterns of the
organisms in that region (local data)
REVIEW DATA 6 MONTHLY
EONS Vs. LONS
EONS /LONS in the developed world
Rationale for the concept
Indian data on EONS and LONS NNPD
2002-03 Different findings
EONS / LONS division ARTIFICAL
No difference between EONS and LONS in our settings
Organisms causing EOS/LOS
Author / year Isolates Outcome Comments
1. Zaidi et al
PIDJ 2009

Developing
countries 63
studies
(1980 2007)
3209 isolates
1st week of life



Klebsiella 25%
E.Coli 15%
S. aureus 18%
GBS 7%

WHO (Young
Infant study)
included


835 isolates
7 to 28 days

S.Aureus 14%
GBS 12%
Pneumococci- 12%
Klebsiella 4%

Home deliveries
77% Gram -ve
organisms

2. NNPD 2002-
03
Indian data
18 Tertiary
care neonatal
units
K.pneumonia-32.5%
S.aureus 13.6%
Intramural births
K.Pneumonia 27%
S.Aureus 15%
Extramural births
46
Original Article
Blood Culture Confirmed Bacterial Sepsis in Neonates in a North Indian
Tertiary Care Center: Changes over the Last Decade
Venkataseshan Sundaram, Praveen Kumar*, Sourabh Dutta, Kanya Mukhopadhyay,
Pallab Ray
1
, Vikas Gautam
1
, and Anil Narang
Department of Pediatrics and
1
Department of Microbiology, Postgraduate Institute of
Medical Education and Research, Chandigarh, India
(Received March 21, 2008. Accepted December 3, 2008)
SUMMARY: The spectrum of organisms causing sepsis is different in developing countries. Data on the recent
trends of organisms causing sepsis are limited. This study was conducted in a tertiary care neonatal unit in
Northern India. All inborn babies with blood-culture-positive sepsis from 1995 to 2006 were divided into two
epochs, viz. 1995 to 1998 (epoch I) and 2001 to 2006 (epoch II). Organisms were grouped into early (<72 h) and
late onset (72 h) sepsis groups. The overall incidence of sepsis, the incidence of sepsis stratified by weight
groups, the organism profile on different days of life, sepsis-related mortality and pathogen-specific case fatal-
ity rate were calculated and compared between the two epochs. Out of 34,362 live births during the study period,
organisms were isolated in 1,491 neonates. Out of these, 89% had bacterial sepsis. The incidence of neonatal
bacterial sepsis increased from epoch I to epoch II (35.8/1,000 versus 40.1/1,000 live births, P < 0.05). The
incidence of early onset sepsis (EOS) did not change between the epochs, but the incidence of late onset sepsis
(LOS) increased from 12 to 16.5 per 1,000 live births (P < 0.001). The incidence of bacterial sepsis decreased
significantly in the 1,000- to 1,999-g birth weight groups. Klebsiella pneumoniae and Enterobacter aerogenes
decreased, whereas Staphylococcus aureus increased in incidence during epoch II. Non-fermenting Gram-negative
bacilli emerged as a newly identified pathogen during epoch II. Sepsis-associated mortality decreased from 42 to
20%. The incidence of bacterial sepsis has decreased significantly in 1,000- to 1,999-g infants, with a significant
reduction in sepsis-related mortality. New organisms have emerged in recent years. The organism profile in
recent years has changed, with a significant overlap of organisms causing EOS and LOS.
Jpn. J. Infect. Dis., 62, 46-50, 2009
*Corresponding author: Mailing address: Neonatal Unit, Depart-
ment of Pediatrics, Postgraduate Institute of Medical Education
and Research, Chandigarh-160012, India. Tel: +91-172-2755308,
Fax: +91-172-2744401, E-mail: drpkumarpgi@gmail.com
INTRODUCTION
Neonatal infections are estimated to cause 1.6 million
deaths every year globally, and 40% of all neonatal deaths
occur in developing countries (1,2). The spectrum of organ-
isms causing neonatal sepsis is quite different in developed
countries in comparison with developing countries like India
(3,4). Within developing countries, regional variation exists
in the spectrum of organisms causing sepsis (5,6).
Significant changes have occurred in the care of the sick
and of immature newborns over the last decade. The use of
antenatal steroids has become more prevalent, and surfactant
is used in almost all preterm babies with respiratory distress.
These have increased the survival of such babies, but may
also have influenced the incidence and the profile of organ-
isms causing sepsis. However, data on the recent trends of
organisms causing sepsis in developing countries are limited
(7). Hence, we conducted this study to analyze the changes
in the incidence of bacterial sepsis and its causative organ-
isms over the last decade.
MATERIALS AND METHODS
This retrospective study was conducted in a tertiary care
neonatal unit in Northern India. All babies born in the hospital
from 1995 to 2006 formed the baseline population. Because
of major changes in neonatal care, the study period was
divided into two epochs, viz. 1995 to 1998 (epoch I) and 2001
to 2006 (epoch II). Since the changes in peri/neonatal care
were gradual, the intervening period of 1999- 2000 was
excluded to avoid a transition period, so that the two epochs
were distinctly separated in time. During the study period,
all neonates in whom sepsis was suspected were investigated
for evidence of infection; this investigation included a blood
culture. Sepsis was suspected if the mother showed evidence
of chorioamnionitis, prolonged rupture of membranes (>24
h), diarrhea, urinary tract infection or fever, and the neonate
manifested systemic signs like chest retractions, grunting,
abdominal distension, increased pre-feed aspirates, tachycar-
dia, hypothermia, lethargy, apnea, etc., within the first 72 h
of life. Even in the absence of maternal risk factors or after
72 h of life, sepsis was suspected if the baby manifested any
of the systemic signs listed above if they could not be
explained by other illnesses. The definition of clinical sepsis
and the clinical approach to suspected sepsis remained the
same in the two epochs. The data on neonates with proven
sepsis were extracted from the prospectively collected com-
puterized database of the unit into a structured proforma
template.
Blood for bacterial culture was collected aseptically and 2
ml of blood was added to each of two bottles containing 20
ml of Tryptone Soy broth and Bile broth (Hi-Media Labs,
Mumbai, India). Both the bottles were incubated aerobically
at 37C for 7 days and subcultured on sheep blood agar and
MacConkey agar overnight, for 48 h or for 7 days or for an
in-between period when visible turbidity appeared. In posi-
tive cases, Gram-positive isolates were identified at the
Empirical Antibiotics - PGI
Based on PGIMER NICU data
Ciprofloxacin / Amikacin : 75% isolates
Vancomycin/Pip-tazo: 90% isolates
Vancomycin/Meropenem: 95-100%

AVOID Cefotaxime as empirical
first line antibiotic


Production of ESBLs
Fungal colonization
Back to the case scenarios
CASE 1 B/o S
Cefotaxime 200 mg/kg/d
IV in 3 divided doses
slow push
Amikacin 15 mg/kg/day
IV Q 24hourly infuse over
1 hour
CASE 2 B/o M
Ciprofloxacin 10
mg/kg/dose Q12 hourly
IV infusion over 30-60
min
Amikacin 7.5 mg/kg/day
IV Q 24 hourly infuse
over
1 hour
Timeliness of initiation
First dose Important prognostic
factor
Delay in antibiotics worsening
outcomes
Route of administration
Only Intravenous
No role for any other route
Oral therapy not recommended


Antibiotics
Dose of Antibiotics
Always check before every dose- everyday- everytime
Dependent on postnatal age / weight / gestational age
Standard source of information
The Blue Book PGI NICU Handbook of Protocols 4
th

Edition 2010
NEOFAX & LEXI COMP Pediatric & Neonatal drug
dosage handbook

Newer drug dose info sources
EPOCRATES Free android & I pad app
Other applications/ software
Web MD
Drug Handbook

CSF penetration of commonly
used antibiotics
ANTIBIOTIC CSF penetration
Ciprofloxacin Good
Cefotaxime Very good
Amikacin Good* (inflamed meninges)
Gentamicin Good* (inflamed meninges)
Vancomycin Good* (inflamed meninges /
continuous infusion of 60 mg/kg/day)
Pip Tazobactam Poor (Poor penetration into CSF)
Imipenem Good (Propensity for seizures)
Meropenem Good* (higher doses/ infusion)
Amphotericin B Poor (both conventional & Liposomal)
Fluconazole Good
Practical points
ANTIBIOTIC Dose Shelf life
Vial size
Cost
per
day
Mode of
admin
Side effects
Cefotaxime <7d: 100-150 mg/kg/day
>7d: 150-200 mg/kg/day

Q8 hourly
24 hrs
125/250/
500 mg
vials
Rs.3
0
IV slow
push
Blunts AG
peak level

Na content
Amikacin <1.5 Kg <D7: 7.5 mg/kg
Others: 15 mg/kg/day

Q24 hourly
Stat

100mg/2
ml vial
Rs.7 IV
infusion
1 hour
Ototoxic
Nephrotoxic
Renal dose
modification
Ciprofloxacin 10 mg/kg/dose

Q12 hourly
200mg/1
00 ml
bottle
Rs.3 IV
infusion
30-60 min
Safe in
neonates
Aminophylline
toxicity
Vancomycin Both dose and interval
depend on weight and
postnatal age
14 days*
500 mg
vial
Rs.
175
IV
infusion
1 hour
Redman syn.
Oto/Nephro
Precipitates
with --------
Practical points
ANTIBIOTIC Dose Shelf life
Vial size
Cost
per day
Mode of
admin
Side effects
Piperacillin-
Tazobactam
Both dose and
interval depend
on weight and
postnatal age
2.25 gm /
4.5 gm
Rs. 300 IV infuse
30 min
Separate AG
Hypokalemia
Diarrhea/ skin rash
False +ve DCT
LFT/RFT changes
Meropenem 20-40
mg/kg/dose Q 8
hourly
Meningitis - 40
500mg/
1gm vial
Rs. 600 IV infuse
4 hours
Modify in
renal/hepatic failure
Ampho B 0.5-1 mg/kg/dse

5-7mg/kg/dose
50 mg
vial
Rs.300

Rs.2000
IV infuse
4 hours
NS incompatible
RFT/ K/ Mg/ CBC
LFT/ Anemia/
Tpenia/ chills/ fever
Fluconazole 6 mg/kg/dose 200
mg/100
ml
Rs. 50 IV slow
bolus
Vomiting/ Rashes
Not with Cisapride
Empirical modification of
empirical antibiotic therapy
Empirical upgradation of
antibiotics if no clinical
improvement within 48-72
hours
Extremely sick neonate
Even earlier after discussing
with consultant/ seniors
After POSITIVE blood c/s
report
S Narrower spectrum ABx / lower cost
DOWNGRADE even if neonate was improving
Use a single sensitive antibiotic
(Exception: Pseudomonas, S.aureus, E. fecalis, Acinetobacter spp.)
S Empirical antibiotics but clinical worsening
Possibility of in vitro resistance
Change antibiotics
R Empirical antibiotics but clinical improvement
Do not change antibiotics (exceptions*)
Possibility of in vivo sensitivity
Duration of antibiotic therapy
Meningitis (c/s proven) : 21 days
Urinary tract infections : 7-14 days
Proven bone/joint infections : 6 weeks
After NEGATIVE blood c/s
Asymptomatic neonate: Stop ABx
Suspected EOS/LOS, neonate improves
but not fully asymptomatic:
Repeat CRP assay & re-evaluate clinical data
CRP > 10 antibiotics for 7 days
CRP: negative & clinical data negative
Stop
Suspected EOS/LOS, neonate has
worsened clinically:
Evaluate for causes other than sepsis
Empirically upgrade antibiotics if sepsis suspected



Case 3 B/o K
34 wk/ 1.7 kg/ AFD/ F ch
Seen by you at a primary health centre at
least 300 km away from a tertiary hospital
Brought with rapid breathing/ poor feeding
You are unable to establish IV access
What will you do?
Stabilize ABC and Temperature
Administer first dose of IM Amikacin
Transport with appropriate support
Which other antibiotic can be given IM safely in neonates?
Now, tell me this
Highly protein bound
Displaces bilirubin
Risk of Kernicterus
Ref: Pediatrics 2012; 129: 1006
SUPPORTIVE CARE
Management of Organ dysfunction
Supportive Care
Equally important component
of care
Early recognition of organ
dysfunction
Development of MODS
significant rise in mortality
Watch for SEPTIC SHOCK in
particular
What all should you monitor?
CLINICAL
Temperature MOST IMPORTANT
Nurse in thermo-neutral environment
Avoid hypo as well as hyperthermia
Aggressive nutritional support
Early enteral feeding
Rigorous monitoring especially hemodynamic parameters
Closely watch core-periphery temperature difference
Capillary refill time/ urine output & others
Non-invasive BP monitoring

What all should you monitor?
LABORATORY
Monitor pH/ BE/ lactate (ABG/VBG)
ECG/ CXR/ Echo (if necessary)
Sugar / Na/ K/ other metabolic parameters
Conjugated jaundice (sepsis induced)
Hemoglobin/ platelets / counts
Coagulation profile / liver function tests



Supportive Care
Mechanical ventilation
Exogenous surfactant therapy
Timely volume & vasopressor support
Anti- convulsants for seizures
Echocardiography for PDA
Ultrasonography Head *
Early recognition determines survival
Distributive + Cardiogenic
Volume support: 10 20 ml/kg NS over 20 min
Correct negative ionotropic factors: Ca/ pH/ Sugar
Dopamine 5 20 mics/kg/min
Dobutamine 5 15 mics/kg/min
Adrenaline 0.05 0.3 mics/kg/min (inotrope)
0.3 1 mics/kg/min (vasopressor)
HYDROCORT 1-3 mg/kg Q 8 hourly
(poor response to dopamine)



CLUES to EARLY recognition of shock
Tachycardia / bradycardia in preterms
Cool/ pale skin/ mottling
Delayed capillary refill / cold peripheries
Weak peripheral pulses
Narrow pulse pressure (Raised DBP)
Oliguria / Ileus (s/o splanchnic vasoconstriction)
Wide pulse pressure
Lethargy / decreased urine output
Metabolic acidosis
Neonatal Septic Shock
Case 3: B/o M
38 wk/ 3.1 Kg/ AFD/ Mch D 17 of life
Brought to PGI Emg. in a state of shock
History of poor feeding/ lethargy along with
episodes of hypothermia over last 4 days
You start the baby on Cefotaxime &
Amikacin as per our protocol
What else would you like to do?
Answer
Would you not like to do a lumbar
puncture?
YES
But, if the baby is on multiple ionotropes?
YES ? NO ?
In an unstable neonate, the LP can be
deferred until stabilization

Cellular & Biochemical abnormalities persist for 72 hours
Gram positive bacteria clearance occurs in 36 hours
Gram negative bacteria clear in 120 hours
ADJUNCTIVE THERAPIES
Upcoming modalities
Level of Evidence No. of Infants Outcomes and Conclusions
Systematic review of therapeutic
RCTs in clinically suspected
infection: all infants

(Cochrane Database of Systematic
Reviews 2010)
10 RCTs and quasi
RCTs

Clinically suspected
infection n=378

Subsequently proven
infection n=262
In clinically suspected infection
group: Mortality reduced
typical RR 0.58 (95% CI; 0.38,
0.89); NNT 10 (95% CI; 6, 33); I
2
=
0%
In proven infection group
typical RR 0.55 (95% CI; 0.31,
0.98); I
2
= 0%
Systematic review of therapeutic
RCTs for sepsis and septic shock:
all infants
(Cochrane Database Syst Rev.
2010)
338 Subgroup analysis of polyclonal
IVIG in neonates showed no
significant reduction in mortality for
standard (n = 174) and IgM-
enriched polyclonal IVIG (n=164)
Systematic review of prophylactic
RCTs in preterm infants
(Cochrane Database of Systematic
Reviews 2010)
4986 Meta-analysis shows 3% reduction
in sepsis but no effect on mortality
No further similar RCTs needed
Intravenous Immunoglobulin
Intravenous Immunoglobulin
Level of
Evidence
No. of Infants Outcomes and
Conclusions
IVIG (monoclonal)

(The Cochrane
Library 2009)
Systematic review
of prophylactic
RCTs of
antistaphylococcal
IgG in
VLBW infants
2701
(two studies of
INH A -21 and one
study of
Altastaph)
No difference
shown in
mortality, sepsis,
or other
adverse outcomes
Use is not
recommended
International Neonatal Immunotherapy Study
NEJM 2011;365:120111

Multicentric randomized clinical trial
3493 neonates
Two doses at 500 mg/ kg or matching
placebo 48 hours apart
No difference in sepsis /mortality
No difference in long term (2yr) outcome
Granulocyte transfusion
Use justified by reduced number and
abnormal function
Produced by leukopheresis
Level of Evidence No. of
Infants
Outcomes and Conclusions
Systematic review of three
therapeutic RCTs
44
No difference shown in mortality or sepsis: more
RCTs needed
One trial (IVIG Vs. GT) 35
Reduction in all cause mortality of borderline
statistical signicance (RR 0.06, 95% CI 0.00 to 1.04;
RD-0.34, 95% CI -0.60 to 0.09; NNT 2.7)
The Cochrane Library 2011, Issue 10

GCSF & GM-CSF
Glycoprotein
Deficient in premies; Resistance also described
Dose 5-10mcg/kg/day for 3 days
Level of Evidence No. of Infants Outcomes and Conclusions
Systematic review of seven
therapeutic RCTs
257 No difference shown in mortality or sepsis:
more RCTs needed
Subgroup analysis of three
therapeutic RCTs
97 ?GM-CSF improves survival in sepsis with
neutropenia: more RCTs needed
Systematic reviews of three
prophylactic RCTs
359 No difference shown in mortality or sepsis:
more RCTs needed
Cochrane Database of Systematic Reviews 2009, Issue 3

Exchange transfusion
Removal of bacteria, endotoxins &
inflammatory mediators
Improved opsonic & granulocyte activity
Improved O2 carrying capacity
Level of Evidence No. of Infants Outcomes and Conclusions
Two therapeutic RCTs 70 Exchange transfusion improves
survival in gram-negative sepsis??
more RCTs needed
Clinics in perinatology,2010


Pentoxifylline
PD inhibitor and reduces TNF
Improves endothelial function and avoids excessive
coagulation
Level of Evidence No. of
Infants
Outcomes and Conclusions
Four therapeutic
RCTs
227 Signicant reduction in all cause mortality

Significant reduction in duration of hospital
stay, mortality in preterm/confirmed
sepsis/gram negative sepsis
The Cochrane Library 2011, Issue 10

Selenium & Melatonin
Free radical scavengers
Level of Evidence No. of
Infants
Outcomes and Conclusions
Selenium
Systematic review of three
prophylactic RCTs
583 ? Selenium reduces sepsis: more
RCTs needed
Melatonin
No RCTs in newborns
One non randomized trial

10 All babies had lower serum levels
of free radicals and all survived
Clinics in perinatology 2010

Glutamine
Anabolic for dividing immune and gut cells
Level of Evidence No. of
Infants
Outcomes and Conclusions
Systematic review of
seven prophylactic
RCTs
2365

No difference shown in mortality or
sepsis or disability free survival:
More RCTs

Clin Perinatol 37 (2010) 481499

FOLLOW-UP CARE
Growth monitoring
Hearing screen who received Aminoglycosides
Monitoring organ dysfunction
Meningitis babies on OPD F/U:
Weekly OFC
Neurological examination
Hearing screen (discharge + 3 months)
USG Head (1
st
week/ End of Rx/ Follow-up)
Anti-epileptics (stop before discharge/ 3 months)
If proven UTI, start AMOXICILLIN 10 mg/kg OD oral
prophylaxis & plan USG KUB, MCU & DMSA


TAKE HOME MESSAGE
Empirical antibiotics Start early, choice, in correct
dose, correct mode of administration, check CSF
penetration & side effects
Collect blood c/s, correlate with clinical picture & modify
therapy as early as possible
Supportive care & monitoring (clinical & lab) keeps the
baby alive & buys time for antibiotics to act
No proven role for any adjunctive therapies at present
Follow-up care with focus specific monitoring also
determines long term outcome
Hope we can save
neonates before they reach
this state of NO RETURN