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Objectives Antibiotic essentials
Which one? Rationale?
Duration of treatment
Practical applications
Supportive Care
Neonatal septic shock
Adjunctive therapies
Follow up care
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PARENTERAL ANTIBIOTICS
All about antibiotics - Basics
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CASE SCENARIOsCASE 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 screenPOSITIVE
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?
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Empirical Antibiotic therapy
Choice of antibiotics
Based on the organisms responsible for theinfection in that region (local data)
Based on the sensitivity patterns of theorganisms in that region (local data)
REVIEW DATA 6 MONTHLY
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EONS Vs. LONS
EONS /LONS in the developed worldRationale for the concept
Indian data on EONS and LONSNNPD
2002-03Different findings
EONS / LONS divisionARTIFICAL
No difference between EONS and LONS in our settings
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Organisms causing EOS/LOSAuthor / year Isolates Outcome Comments
1. Zaidi et al
PIDJ 2009
Developing
countries63studies
(19802007)
3209 isolates
1st week of life
Klebsiella25%
E.Coli15%
S. aureus18%
GBS7%
WHO (Young
Infant study)
included
835 isolates
7 to 28 days
S.Aureus14%
GBS12%
Pneumococci- 12%
Klebsiella4%
Home deliveries
77% Gram -ve
organisms
2. NNPD 2002-
03
Indian data
18 Tertiary
care neonatal
units
K.pneumonia-32.5%
S.aureus13.6%
Intramural births
K.Pneumonia27%
S.Aureus15%
Extramural births
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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 Ray1, Vikas Gautam1, and Anil Narang
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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
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Back to the case scenarios
CASE 1 B/o S Cefotaxime200 mg/kg/d
IV in 3 divided doses
slow push
Amikacin 15 mg/kg/dayIV Q 24hourly infuse over
1 hour
CASE 2 B/o M Ciprofloxacin10
mg/kg/dose Q12 hourly
IV infusion over 30-60
min
Amikacin7.5 mg/kg/day
IV Q 24 hourly infuse
over
1 hour
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Timeliness of initiation
First doseImportant prognostic
factor
Delay in antibioticsworsening
outcomes
Route of administration
Only Intravenous
No role for any other route
Oral therapynot recommended
Antibiotics
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Dose of Antibiotics Always check before every dose- everyday- everytime
Dependent on postnatal age / weight / gestational age
Standard source of information
The Blue BookPGI NICU Handbook of Protocols4th
Edition2010
NEOFAX & LEXI COMPPediatric & Neonatal drug
dosage handbook
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Newer drug dose info sourcesEPOCRATESFree android & I pad app
Other applications/ software
Web MD
Drug Handbook
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CSF penetration of commonly
used antibioticsANTIBIOTIC 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)
PipTazobactam Poor (Poor penetration into CSF)
Imipenem Good (Propensity for seizures)
Meropenem Good* (higher doses/ infusion)
Amphotericin B Poor (both conventional & Liposomal)
Fluconazole Good
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Practical points
ANTIBIOTIC Dose Shelf life
Vial size
Cost
perday
Mode of
admin
Side effects
Cefotaxime 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 contentAmikacin
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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 changesMeropenem 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 mgvial Rs.300
Rs.2000
IV infuse4 hours NS incompatibleRFT/ 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
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Empirical modification of
empirical antibiotic therapy
Empirical upgradation of
antibiotics if no clinical
improvement within 48-72
hours
Extremely sick neonate
Even earlierafter discussing
with consultant/ seniors
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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.)
SEmpirical antibiotics but clinical worsening
Possibility of in vitroresistance
Change antibiotics
REmpirical antibiotics but clinical improvement
Do not change antibiotics (exceptions*)
Possibility of in vivosensitivity
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Duration of antibiotic therapy
Meningitis (c/s proven) : 21 days
Urinary tract infections : 7-14 days
Proven bone/joint infections : 6 weeks
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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 > 10antibiotics 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
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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?
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Now, tell me this
Highly protein bound
Displaces bilirubin
Risk of Kernicterus
Ref: Pediatrics 2012; 129: 1006
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Management of Organ dysfunction
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Supportive Care
Equally important component
of careEarly recognition of organ
dysfunction
Development of MODS
significant rise in mortalityWatch for SEPTIC SHOCK in
particular
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What all should you monitor?
CLINICAL TemperatureMOST 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
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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
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Supportive Care
Mechanical ventilation Exogenous surfactant therapy
Timely volume & vasopressor support
Anti- convulsants for seizures
Echocardiography for PDA
Ultrasonography Head *
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Early recognitiondetermines survival
Distributive + Cardiogenic Volume support: 1020 ml/kg NS over 20 min
Correct negative ionotropic factors: Ca/ pH/ Sugar
Dopamine 520 mics/kg/min Dobutamine 515 mics/kg/min
Adrenaline 0.050.3 mics/kg/min (inotrope)
0.31 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
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Case 3: B/o M
38 wk/ 3.1 Kg/ AFD/ MchD 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?
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Answer
Would you not like to do a lumbarpuncture?
YES
But, if the baby is on multiple ionotropes? YES ? NO ?
In an unstable neonate, the LP can be
deferred until stabilizationCellular & Biochemical abnormalities persist for 72 hours
Gram positive bacteria clearance occurs in 36 hours
Gram negative bacteria clear in 120 hours
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Upcoming modalities
I I l b li
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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); I2=
0%
In proven infection group
typical RR 0.55 (95% CI; 0.31,
0.98); I2
= 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
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Intravenous Immunoglobulin
Level of
Evidence
No. of Infants Outcomes and
Conclusions
IVIG (monoclonal)
(The Cochrane
Library 2009)
Systematic review
of prophylactic
RCTs of
antistaphylococcalIgG in
VLBW infants
2701
(two studies of
INH A -21 and one
study ofAltastaph)
No difference
shown in
mortality, sepsis,
or otheradverse outcomes
Use is not
recommended
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International Neonatal Immunotherapy Study
NEJM 2011;365:120111
Multicentric randomized clinical trial
3493 neonates
Two doses at 500 mg/ kg or matchingplacebo 48 hours apart
No difference in sepsis /mortality
No difference in long term (2yr) outcome
G l t t f i
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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: moreRCTs needed
One trial (IVIG Vs. GT) 35 Reduction in all cause mortality of borderlinestatistical significance (RR0.06, 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
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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
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Exchange transfusion
Removal of bacteria, endotoxins &
inflammatory mediators
Improved opsonic & granulocyte activity
Improved O2carrying capacityLevel 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
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Pentoxifylline PD inhibitor and reduces TNF
Improves endothelial function and avoids excessivecoagulation
Level of Evidence No. of
Infants
Outcomes and Conclusions
Four therapeutic
RCTs
227 Significant 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
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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
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Glutamine
Anabolic for dividing immune and gut cells
Level of Evidence No. of
Infants
Outcomes and Conclusions
Systematic review of
seven prophylacticRCTs
2365 No difference shown in mortality or
sepsis or disability free survival:More RCTs
Clin Perinatol 37 (2010) 481499
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FOLLOW-UP CARE Growth monitoring
Hearing screenwho received Aminoglycosides Monitoring organ dysfunction
Meningitis babies on OPD F/U:
Weekly OFC
Neurological examination Hearing screen (discharge + 3 months)
USG Head (1stweek/ End of Rx/ Follow-up)
Anti-epileptics (stop before discharge/ 3 months)
If proven UTI, start AMOXICILLIN 10 mg/kg OD oralprophylaxis & plan USG KUB, MCU & DMSA
TAKE HOME MESSAGE
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TAKE HOME MESSAGE Empirical antibioticsStart 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 monitoringalso
determines long term outcome
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Hope we can save
neonates before they reach
this state of NO RETURN