The document discusses the importance of rational antibiotic use in newborns, highlighting the consequences of incorrect use, including antimicrobial resistance and adverse drug reactions. It emphasizes that appropriate medicine use requires correct dosage and duration while addressing factors that contribute to misuse, such as lack of knowledge and unethical pharmaceutical promotion. The text also outlines strategies to improve antibiotic stewardship and summarizes data on bacterial resistance patterns and antibiotic susceptibility in neonatal care settings.

1. Rational antibiotic use in
newborn
Nischal Maskey
Department of Child Health
Mahrajgunj Medical Campus, IOM

2. Contents
• Introduction to rational use of medicine
• Effect of antibiotics on neonates
• Clinical data
• Overview on antibiotics
• NICE guidelines on sepsis
• Choice and duration of antibiotics
• Prophylactic antibiotic use

3. Definition
• Rational use of medicines refers to the
correct, proper and appropriate use of
medicines. Rational use requires that patients
receive the appropriate medicine, in the
proper dose, for an adequate period of
time, and at the lowest cost to them and their
community. (WHO)

4. What are the consequences of
incorrect use of medicines?
• Antimicrobial resistance.
• Adverse drug reactions and medication errors
• Lost resources
• Eroded patient confidence

5. What factors contribute to incorrect
use of medicines?
• Lack of skills and knowledge
• Inappropriate unethical promotion of medicines
by pharmaceutical companies
• Profits from selling medicines
• Unrestricted availability of medicines
• Overworked health personnel
• Unaffordable medicines
• Lack of coordinated national pharmaceutical
policy

6. What can be done to improve rational
use of medicines?
• A national body to coordinate policies on medicine use
and monitor their impact
• Evidence-based clinical guidelines for
training, supervision and supporting decision-making
about medicines
• Drug (medicines) and therapeutics committees in
districts and hospitals to monitor and implement
interventions to improve the use of medicines
• Problem-based training in pharmacotherapy and
prescribing in undergraduate curricula
• Continuing medical education as a requirement of
licensure

7. • Publicly available independent and unbiased
information about medicines for health
personnel and consumers
• Public education about medicines
• Elimination of financial incentives that lead to
improper prescribing, such as prescribers selling
medicines for profit to supplement their income
• Regulations to ensure that promotional activities
meet ethical criteria
• Adequate funding to ensure availability of
medicines and health personnel.

8. Introduction
• Antibiotics are the commonest drugs used in the
NICU.
• Virtually all extremely low birth weight infants
receive antibiotics and for all other birth weight
groups admitted to the NICU the vast majority
are treated with antibiotics
• Only a small number eventually have culture
proven infection. Clark et al : 98% of preterm
infants who received empiric antibiotics were
culture negative.

9. Effect of antibiotics on the neonate
• Newborn: sterile gut.
• Normal flora: early days of life.
• Antibiotics : delay in microflora colonisation
with most anaerobes, importantly
Bifidobacterium and Lactobacillus.
• At 30 days of life Bifidobacterium and
Lactobacillus sp: 1/15 breastfed preterm
infants who had received antibiotics.

10. • Antibiotics also limit the number of bacterial
species in the normal flora.
• As few as 3 species in their flora at Day 10 of life
• An inverse dose- response between the duration
of antibiotics and the number of species in the
flora at Day 30 of life.
• Bacterial overgrowth of other species
• A major role in restricting the diversity and the
volume of the normal flora thus reducing
protection from invading pathogens.

11. • Animal studies : normal gut development is dependent on a diverse and
high volume flora and the normal flora also plays a significant role in the
physiological and immunodevelopment of the gut .
• Normal flora create a physical defence, a role in immune responses.
• Polysaccharide produced by Bacteroides fragilis : the cellular and physical
maturation of the gut.
• Bifidobacterium : immunomodulation, balance proinflammatory and anti-
inflammatory cytokine production in the gut resulting in a net
antiinflammatory response .
• Low bacterial counts and lack of diversity of anaerobes caused by
antibiotic use : necrotising enterocolitis (NEC).

12. Resistance and antibiotics
• Antibiotics alter the gut flora: colonisation
with resistant organisms.
• Resistance is usually to multiple drugs with a
higher mortality .

13. • One NICU : an empiric antibiotic regime of
tobramycin and penicillin for EOS and
tobramycin and flucloxacillin for LOS and the
second unit : cefotaxime and ampicillin.
• After 6 months the regimes were reversed.
Respiratory and rectal cultures were taken
weekly.

14. • Cefotaxime and ampicillin regime: RR=18 for
colonisation with resistant strains and this reversed
when the regimes were reversed.
• Four LOS occurred, 3 in the cefotaxime and ampicillin
group and one in the other group .
• Beta-lactam antibiotics : colonisation with
multiresistant organisms and regimes that restrict
the use of beta-lactam antibiotics reduce resistance.

15. • Use of aminoglycosides : not associated with
significant emergence of resistant organisms.
• Cefotaxime: association with increased mortality.
• A retrospective study of over 100,000 infants
given either gentamicin or cefotaxime with
ampicillin empirically in the first 3 days of life.
• The relative risk of mortality was increase 1.5
times for infants receiving cefotaxime.
Cefotaxime use may increase the risk of fungal
infection.

16. NICU TUTH ( 2070 Baisakh to Bhadra)
Acinetobactor (12.5%)
Staph aureus (40%)
CONS (15%)
Klebsiella (10%)
E Coli (12.5%)
Enterobactor (2.5%)
237 admissions: 30 cases of microbial growth (28 in blood/ 2 in ET tube)

17. A
m
p
i
A
m
I
k
a
O
f
l
o
C
e
f
o
t
a
x
V
a
n
c
o
M
e
r
o
L
e
v
o
G
e
n
t
a
C
i
p
r
o
T
Z
P
C
l
o
r
a
m
C
l
O
x
C
l
i
n
d
T
i
g
e
C
o
l
i
s
t
i
n
R S S S
S S R R S
S S S
E Coli

18. A
m
p
i
A
m
I
k
a
O
f
l
o
C
e
f
o
t
a
x
V
a
n
c
o
M
e
r
o
L
e
v
o
G
e
n
t
a
C
i
p
r
o
T
Z
P
C
l
o
r
a
m
C
l
O
x
C
l
i
n
d
T
i
g
e
C
o
l
i
s
t
i
n
S S S S R
S S R R S
R S S S
E Coli

19. Staph aureus

20. A
m
p
i
A
m
I
k
a
O
f
l
o
C
e
f
o
t
a
x
V
a
n
c
o
M
e
r
o
L
e
v
o
G
e
n
t
a
C
i
p
r
o
T
Z
P
C
l
o
r
a
m
C
l
O
x
C
l
i
n
d
T
i
g
e
C
o
l
i
s
t
i
n
S S S S
R S S S R
R S S S R S
S S S S S
R S S S
S S S R

21. A
m
p
i
A
m
I
k
a
O
f
l
o
C
e
f
o
t
a
x
V
a
n
c
o
M
e
r
o
L
e
v
o
G
e
n
t
a
C
i
p
r
o
T
Z
P
C
l
o
r
a
m
C
l
O
x
C
l
i
n
d
T
i
g
e
C
o
l
i
s
t
i
n
S R S S S
S S S S S S
S S S S S S S
S S S S S
S S S S
R S R S R R
S S S S S S S

22. A
m
p
i
A
m
I
k
a
O
f
l
o
C
e
f
o
t
a
x
V
a
n
c
o
M
e
r
o
L
e
v
o
G
e
n
t
a
C
i
p
r
o
T
Z
P
C
l
o
r
a
m
C
l
O
x
C
l
i
n
d
T
i
g
e
C
o
l
i
s
t
i
n
R S S R R S S R S
R R S S R S S
R S S S
S S S S S R S
S R R R S R S
Acinetobactor

23. A
m
p
i
A
m
I
k
a
O
f
l
o
C
e
f
o
t
a
x
V
a
n
c
o
M
e
r
o
L
e
v
o
G
e
n
t
a
C
i
p
r
o
T
Z
P
C
l
o
r
a
m
C
l
O
x
C
l
i
n
d
T
i
g
e
C
o
l
i
s
t
i
n
S R S R S R
R S S S R
S S
Klebsiella

24. A
m
p
i
A
m
I
k
a
O
f
l
o
C
e
f
o
t
a
x
V
a
n
c
o
M
e
r
o
L
e
v
o
G
e
n
t
a
C
i
p
r
o
T
Z
P
C
l
o
r
a
m
C
l
O
x
C
l
i
n
d
T
i
g
e
C
o
l
i
s
t
i
n
R S S S S S
R S R S S
S S S
S S S S S
CONS

25. Floroquino
lones
Aminoglyco
sides
Meropenem Ampicillin Cefotaxim
EColi + +/- + +/- +/-
Staph + +/- + +/- +
Acinetobactor + +/- +/- +/- +/-
Klebsiella + + + +/- +
CONS + + + + +
Meropenem and fluoroquinolones: almost 100% coverage

26. Antimicrobial Stewardship
• Antimicrobial Stewardship is an activity that
promotes:
1. The appropriate selection of antimicrobials.
2. The appropriate dosing of antimicrobials.
3. The appropriate route and duration of
antimicrobial therapy.

27. • After confirming that the patient has a indication for
antimicrobial therapy, antimicrobial stewardship is the
8 R’s:
1. Right drug,
2. Right time
3. Right dose
4. Right route
5. Right resident
6. Right documentation
7. Right reason
8. Right response

28. • Core Members of the Antimicrobial Stewardship Team
• Infectious disease physician (Director or Co-director)
• Clinical pharmacist with infectious disease training (Co-
director or core member)
• Other members of the team
 Microbiologist
 Information system specialist
 Infection control professional
 Hospital epidemiologist

29. Antimicrobial Stewardship Program:
The Components
• Prospective audit with intervention and feedback
• Formulary restriction and preauthorization
• Education
• Guidelines and clinical pathways
• Antimicrobial order forms
• Dose optimization
• Parenteral to oral conversion

30. Amikacin Aminoglycoside antibiotic active against gram-negative bacilli,
especially Escherichia coli, Klebsiella, Proteus, Enterobacter,
Serratia, and Pseudomonas.
Ampicillin Penicillinase-susceptible β-lactam: gram-positive pathogens
except Staphylococcus; Salmonella, Shigella, Neisseria, E. coli, and
Proteus mirabilis
Aztreonam β-Lactam (monobactam) antibiotic with activity against gram-
negative aerobic bacteria, Enterobacteriaceae, and Pseudomonas
aeruginosa.
Carbenicillin Extended-spectrum penicillin (remains susceptible to penicillinase
destruction) active against Enterobacter, indole-positive Proteus,
and Pseudomonas.
Cefotaxime 3rd generation cephalosporin active against gram-positive and
gram-negative pathogens. No antipseudomonal activity.
Ceftazidime 3rd generation cephalosporin active against gram-positive and
gram-negative pathogens, including Pseudomonas aeruginosa.

31. Chloramphenicol Broad-spectrum protein synthesis inhibitor active against many
gram-positive and gram-negative bacteria, Salmonella,
vancomycin-resistant Enterococcus faecium, Bacteroides, other
anaerobes, Mycoplasma, Chlamydia, and Rickettsia; usually
inactive against Pseudomonas.
Ciprofloxacin Quinolone antibiotic active against P. aeruginosa, Serratia,
Enterobacter, Shigella, Salmonella, Campylobacter, N.
gonorrhoeae, H. influenzae, M. catarrhalis, some S. aureus, and
some Streptococcus.
Clindamycin Protein synthesis inhibitor active against most gram-positive
aerobic and anaerobic cocci except Enterococcus.
Cloxacillin Penicillinase-resistant penicillin active against S. aureus and
other gram-positive cocci except Enterococcus and coagulase-
negative staphylococci.

32. Gentamicin Aminoglycoside antibiotic active against gram-negative bacilli,
especially E. coli, Klebsiella, Proteus, Enterobacter, Serratia, and
Pseudomonas.
Imipenem-
cilastatin
Carbapenem antibiotic with broad-spectrum activity against gram-
positive cocci and gram-negative bacilli, including P. aeruginosa
and anaerobes.
Meropenem Carbapenem antibiotic with broad-spectrum activity against gram-
positive cocci and gram-negative bacilli, including P. aeruginosa
and anaerobes.
Metronidazole Highly effective in the treatment of infections due to anaerobes.

33. Ofloxacin Quinolone antibiotic for treatment of conjunctivitis or corneal
ulcers (ophthalmic solution) and otitis externa or chronic
suppurative otitis media (otic solution) caused by susceptible
gram-positive, gram-negative, anaerobic bacteria, or Chlamydia
trachomatis.
Penicillin G Penicillin active against most gram-positive cocci; S. pneumoniae
(resistance is increasing), group A streptococcus, and some gram-
negative bacteria (e.g., N. gonorrhoeae, N. meningitidis).
Piperacillin Extended-spectrum penicillin active against E. coli, Enterobacter,
Serratia, P. aeruginosa, and Bacteroides
Piperacillin-
tazobactam
Extended-spectrum penicillin (piperacillin) combined with a β-
lactamase inhibitor (tazobactam) active against S. aureus, H.
influenzae, E. coli, Enterobacter, Serratia, Acinetobacter, P.
aeruginosa, and Bacteroides.

34. Tigecycline Tetracycline-class antibiotic (glycylcycline) active against
Enterobacteriaceae, including ESBL producers; streptococci
(including VRE); staphylococci (including MRSA); and anaerobes.
Tobramycin Folic acid antagonist effective in the prophylaxis and treatment of
E. coli, Klebsiella, P. mirabilis, and Enterobacter urinary tract
infections; P. carinii pneumonia
Vancomycin Glycopeptide antibiotic active against most gram-positive
pathogens including Staphylococcus (including MRSA and
coagulase-negative staphylococci), S. pneumoniae including
penicillin-resistant strains, Enterococcus (resistance is increasing),
and C. difficile–associated colitis.

35. Gyawali N, Sanjana RK. Indian J Pediatr. 2013 May;80(5):371-4
Bacteriological profile and antibiogram of neonatal septicemia.
• 1,572 samples
• Blood culture was positive : 238 (15.13 %) samples.
• Gram positive and gram negative organisms were 44.1 % and
55.9 % respectively.
• Staphylococcus aureus : predominant isolate followed by Klebsiella
spp.
• Most of the gram positive isolates exhibited higher resistance to
penicillin and cephalosporin.
• Susceptibility : aminoglycosides and quinolones.
• More than two third isolates of gram negative Enterobacteriaceae
showed resistance to ampicillin.
• Third generation cephalosporin and aminoglycosides were found to
be more satisfactory among gram negative organisms as compared
to gram positive.

36. Shrestha S, Adhikari N, Rai BK, Shreepaili A. Antibiotic resistance pattern of bacterial
isolates in neonatal care unit. JNMA J Nepal Med Assoc. 2010 Oct-Dec;50(180):277-81.
• The positive yield of blood cultures was 19.56%.
• Most common: coagulase negative
Staphylococcus, Acinetobacter, Enterobacter and
non-haemolytic Streptococcus.
• A significant percent of the isolates were resistant
to the first line antibiotics.
• Gram negative: more than 30% are resistant to
cefotaxime and more than 50% are resistant to
gentamicin.

37. Shrestha S, Shrestha NC, Dongol Singh S, Shrestha RB, Kayestha S, Shrestha M, Thakur NK
Bacterial Isolates and its Antibiotic Susceptibility Pattern in NICU.
. Kathmandu Univ Med J (KUMJ). 2013 Jan-Mar;11(41):66-70.
• The blood culture yield : 44.13% with nosocomial sepsis - 10.79%.
• 84.08% early onset sepsis and 15.95% late onset sepsis.
• Klebsiella infection : commonest organism
• Gram positive organisms : 39.36% (Staphylococcus aureus then CONS)
• Gram negative organisms: 60.64% (Klebsiella followed by Pseudomonas)
• Klebsiella was 87.5% and 78.3% resistance to ampicillin and gentamycin
respectively.
• Gram negative isolates :87.5% and 77.2% were resistance to ampicillin and
gentamycin respectively.
• Among gram positive isolates 58.5% and 31.5% resistance to ampicillin
and gentamycin respectively.
• Resistance to cefotaxim to gram negative and gram positive isolates were
87.34% and 59.35% respectively.

38. Bhat Y R, Lewis LE, K E V.
.
Bacterial isolates of early-onset neonatal sepsis and their antibiotic susceptibility pattern between 1998 and
2004: an audit from a center in India. Ital J Pediatr. 2011 Jul 11;37:32. doi: 10.1186/1824-7288-37-32
• 2182 neonates screened, 389 (17.8%) positive blood cultures.
• Gram negative species 90.8% of culture isolates.
• Pseudomonas (33.2%) and Klebsiella (31.4%)
• Acinetobacter (14.4%), Staphylococcus aureus (9.2%), E.coli (4.4%),
Enterobacter (2.2%), Citrobacter (3.1%) and Enterococci (2.2%).
• In Gram negative group, best susceptibility was to Amikacin
(74.5%), followed by other aminoglycosides, ciprofloxacin and
cefotaxime. The susceptibility was remarkably low to ampicillin
(8.4%).
• Gram positive group: susceptibility of 42.9% to erythromycin, 47.6%
to ciprofloxacin and above 50% to aminoglycosides.
• Of all isolates, 83.8% were susceptible to either cefotaxime or
amikacin

39. NICE GUIDELINE ON EARLY
NEONATAL INFECTION
• Risk factors for infection
 Pre-labour rupture of membranes
 Preterm birth (<37 weeks), especially with pre-labour
rupture of membranes
 Confirmed or suspected chorioamnioitis it is (e.g.
intrapartum fever)
 Invasive GBS infection in a previous baby
 Antibiotic treatment given to mother for confirmed or
suspected invasive bacterial infection 24 hours before,
during, or 24 hours post labour

40. Clinical Indicators Suggestive of
Infection
• Altered behaviour or responsiveness
• Altered muscle tone
• Feeding difficulties (e.g. feed refusal)
• Feed intolerance (e.g. abdominal distension, vomiting)
• Altered heart rate
• Signs of respiratory distress
• Oxygen desaturation
• Apnoea
• Signs of perinatal asphyxia or hypoxic ischaemia
• Seizures
• Need for mechanical ventilation (especially term baby)

41. • PPHN
• Temperature abnormality not explained by
environment
• Signs of shock
• Unexplained bleeding disorder ( e.g.
thrombocytopenia, INR <2)
• Oliguria
• Hypo/hyperglycaemia
• Metabolic acidosis (BE -10 or greater)
• Local signs of infection e.g. skin, eyes
• Confirmed or suspected sepsis in a co-twin

42. Red Flag Signs Suggestive of Neonatal
Infection
• Systemic antibiotics given to mother for
suspected bacterial infection within 24 hours
of birth
• Seizures
• Signs of shock
• Need for mechanical ventilation in a term
baby
• Suspected or confirmed infection in a co-twin

43. Actions
• Any red flags or no red flags but 2 or more risk
factors or clinical indicators, perform
investigations including blood cultures and
start antibiotics

44. • No red flag or clinical indicators but one risk factor or
no red flags or risk factors but one clinical indicator
1. Use clinical judgement and consider withholding
antibiotics
2. Monitor baby for clinical indicators of possible
infection, including the vital signs
3. Monitor for at least 12 hours from birth (at 1 hors, 2
hours and then 2 hourly for 10 hours)
4. If further clinical concerns perform investigations
including blood cultures and start antibiotics

45. • If a decision is made to give antibiotics aim to
start within 30 minutes and always within 1
hour of the decision

46. Choice of Antibiotics
• Use benzyl penicillin and gentamicin as first choice for
empirical treatment of suspected infection
• Benzylpenicillin
 25mg/kg 12 hourly
 50mg/kg 12 hourly if baby appears very ill
• Gentamicin
 4.5 mg/kg
 If a second does is to be given (see below) give 36 hours
after the first dose
 The interval may be shorted based on clinical judgement
e.g. for gram –ve infection or if the baby appears very ill

47. Duration of antibiotic treatment
• Consider stopping after 36 hours
 If initial clinical suspicion of infection was not strong and
 CRP < 10mg/l on both tests and
 Blood culture is negative and
 The baby is well with no clinical indicators of possible
infection
• Treat for 5 days if
 Strong clinical suggestion of infection
 Continued clinical concerns about infection at 36 hours
 CRP > 10 mg/l on either measurement
 Positive blood culture

48. • Continue antibiotics beyond 5 days if
The baby did not fully recovered at 5 days or
This is advisable based on the blood culture
result and expert microbiological advice if
necessary

49. Meningitis
• If meningitis is suspected but gram stain is uninformative
use an antibiotic regimen based on local expert
microbiological advice
• Review treatment decisions taking into account subsequent
CSF results
• If CSF Gram stain suggest Group B Streptococcus give
benzyl penicillin 50mg/kg 12 hourly and gentamicin 4.5
mg/kg every 36 hours
• If culture confirms GBS continue benzylpenicillin for at least
14 days and gentamicin for 5 days
• If CSF Gram stain or culture suggests any organism other
than GBS. use an antibiotic regimen based on local expert
microbiological advice

50. • In a randomized study, Metsvaht et al.
• Ampicillin versus penicillin G both combined with gentamicin
in the empirical treatment of neonates ( = 2 8 3)
• The clinical failure rate was not different between the two
groups (14.1% versus 14.2%).

51. Choice and Duration of Antimicrobial Therapy for Neonatal Sepsis and Meningitis
International Journal of Pediatrics
Volume 2011 (2011)
• Based on current available evidence, the combination
of ampicillin and gentamicin is an appropriate choice
for empirical therapy of EOS in neonates, where GBS
and E. coli continue to be the predominant organisms.
• Expansion of antimicrobial spectrum and also offers
synergistic bacterial killing.
• Low cost and low rates of emergence of bacterial
resistance.
• In developing countries, empiric antibiotic therapy
should be based individualized for each hospital or
region.

52. Late onset sepsis
• CoNS : most common pathogen in LOS followed
by S. aureus, Enterococcus spp., and GBS; Gram-
negative organisms account for 18–20% of LOS.
• The empirical antimicrobial therapy : both Gram-
positive and Gram-negative organisms.
• In the developed countries, where CoNS is the
predominant nosocomial pathogen and where
resistance of these isolates to penicillin,
semisynthetic penicillin, and gentamicin are
common, experts recommend the use of
vancomycin as empirical therapy.

53. • Among 18 participating NICUs in Australasian study
group for neonatal infection, nine units used
vancomycin and an aminoglycoside as the first-line
empirical treatment for LOS
• Their mortality from CoNS sepsis was comparable to
ampicillin or flucloxacillin together with an
aminoglycoside.

54. • In developing nations, higher percentage of Gram-
negative bacteria and greater antimicrobial
resistance
• About 70% of these isolates may not be covered by
the empiric regimen of ampicillin and gentamicin.(
Zaidi et al)
• High proportion of methicillin-resistant S.
aureus (MRSA) strains in many areas, especially
south Asia (56%)

55. • The Cochrane review : study by Miall-Allen et al
• Timentin (ticarcillin and clavulanic acid)
monotherapy with a combination of flucloxacillin and
gentamicin in 28 neonates with suspected LOS
• No difference in outcome (mortality/treatment
failure) between the two groups.

56. • Inadequate evidence from randomized trials in favor
of any particular antimicrobial regimen for the
empirical treatment of suspected LOS.
• Vancomycin and third-generation cephalosporin
(e.g., cefotaxime) : cardiorespiratory instability and in
areas where MRSA is prevalent.
• Vancomycin as the initial therapy: emergence of
vancomycin-resistant enterococci and its overuse in
cases where CoNS isolates represent mere
contaminants.

57. Duration of antibiotic therapy
• The duration of antimicrobial therapy for
culture-proven sepsis depends on the initial
response to the appropriate antimicrobial
agent.
• Paucity of RCTs evaluating the rationale and
safety of the appropriate duration of therapy

58. • Engle et al. randomized cases of neonatal pneumonia
to either 4-day or 7-day course of antibiotics.
• Randomization was done on day 4 of antibiotic
therapy if the infants were completely asymptomatic
for at least 48 hours.
• The success of therapy was similar in both the groups

59. • Chowdhary et al. compared the effectiveness of 7-day
versus 14-day antibiotic therapy in 69 infants with
blood culture-proven bacterial sepsis.
• Randomization on day 7 of antibiotics if the infant had
clinical remission by day 5.
• More treatment failures in 7-day group
• Treatment failures occurred in subjects with S.
aureus infection receiving 7-day course

60. • Gathwala et al.
• 10-day versus 14-day course culture-proven neonatal
sepsis
• Sixty infants were included.
• Clinical remission with negative C-reactive protein
(CRP).
• Cefotaxime and amikacin
• 10-day antibiotic therapy is as effective as 14-day
therapy in blood-culture-proven neonatal sepsis, if the
infant has achieved clinical remission by day 7 of
therapy.

61. • There is limited evidence for infants with younger
gestational age (<32 weeks), who are at the highest risk
for sepsis.
• It is reasonable to treat for 10–14 days with
appropriate antimicrobial agents in infants with blood-
culture-proven sepsis.
• However, in selected situations (neonates ≥32 weeks
gestation and ≥1500 grams, who become
asymptomatic within 5 days of appropriate therapy),
consider stopping antibiotics at 7–10 days, provided
appropriate followup can be ensured.

62. Antimicrobial Choice and Duration of
Therapy for Neonatal Meningitis
• In 2004, Infectious Disease Society of America
1. EOS, ampicillin with either an aminoglycoside or
cefotaxime
2. Late-onset meningitis, a regimen containing an
antistaphylococcal antibiotic, such as nafcillin or
vancomycin, plus cefotaxime or ceftazidime with or
without an aminoglycoside is recommended

63. • The duration of antimicrobial therapy in the patient
with bacterial meningitis has often been based more
on tradition than on evidence-based data.
• GBS meningitis is usually treated for 14 to 21 days
• For uncomplicated neonatal meningitis caused by
Gram-negative bacteria, a minimum of 21 days is
recommended .
• However, these guidelines are not standardized and
the duration of therapy may need to be individualized
on the basis of the patient’s clinical response.

64. • Combination of ampicillin and cefotaxime or ampicillin
and aminoglycoside is appropriate for treatment of
suspected early-onset neonatal meningitis.
• For suspected late-onset meningitis, a combination of
vancomycin plus a third-generation cephalosporin is
recommended while awaiting CSF culture and
susceptibility results. The duration of antimicrobial
therapy for neonatal meningitis should be 14 to 21
days for GBS, ≥21 days for L.
monocytogenes meningitis, and minimum of 21 days
for Gram-negative meningitis.

65. Adverse Effects with Prolonged
Duration of Antibiotic Therapy
• A 19-center study of 5693 ELBW
• Infants with sterile cultures who began initial empirical
antibiotic treatment within the first 3 postnatal days
• Median duration of empirical antibiotic treatment was
5 days.
• Prolonged duration of antibiotic therapy defined as >5
days) was associated with NEC or death (OR 1.30) or
death alone (OR 1.46)
• Each additional day of antibiotic therapy was
associated with a 4% increase in the odds of NEC or
death, a 7% increase in the odds of NEC alone, and a
16% increase in the odds of death alone.

66. • A case-control study in single center.
• 124 NEC cases vrs 248 controls on the basis of
gestational age, birth weight, and year of admission.
• Each day of antibiotic exposure was associated with a
20% increase in the risk of NEC.

67. • Prolonged antibiotic therapy has also been
associated with LOS
• 5693 subjects, increased risk of the combined
outcome of LOS caused by organisms other
than coagulase-negative Staphylococcus or
death (4 days: OR: 1.32 ) (5 days: OR: 1.24)

68. Nosocomial sepsis
• Klebsiella spp. (39.6%), Pseudomonas aeruginosa
(11.3%) and Coagulase-negative staphylococci
(9.4%). Baş AY, Demirel N, Zenciroglu A, Göl N, Tanir G. Nosocomial blood stream infections in a neonatal intensive care unit in
Ankara, Turkey. Turk J Pediatr. 2010 Sep-Oct;52(5):464-70.
• Staphylococcus aureus (18.5%), Acinectobacter
baumannii (16.3%), Klebsiella pneumoniae (11.9%),
Escherichia coli (9.6%), and Pseudomonas aeruginosa
(8.1%). Tseng YC, Chiu YC, Wang JH, Lin HC, Lin HC, Su BH, Chiu HH. Nosocomial bloodstream infection in
a neonatal intensive care unit of a medical center: a three-year review. J Microbiol Immunol Infect. 2002
Sep;35(3):168-72.

69. • Acinetobacter spp. (47.9%), Pseudomonas spp,
(23.6%), Klebsiella/Enterobacter spp. (8.3%),
Coagulase-negative staphylococci (8.3%) and
Staphylococcus aureus (6.3%) Markovid-Denid L, Durisid J, Nikolid T, Ramadani R, Ilid
S, Stevanovid S. Causative agents of neonatal nosocomial infections and their resistance to antibioticsMed Pregl. 2006
Mar-Apr;59(3-4):155-9.

70. Ventillator associated pneumonia
• Pseudomonas aeruginosa, Klebsiella
pneumoniae and Acinetobacter spp
predominant. (Witaya Petdachai in 2004)

71. Catheter-related bloodstream
infection
• Gram-positive cocci, which are responsible for at
least two-thirds of infections
• De Brito et al : coagulase-
negative Staphylococci (CoNS) the most common
and S. aureus the second leading cause

72. Amino
glycosides
Ampicillin Meropenem Cefotaxim Ceftazidime
Pseudomonas + + +
Klebsiella + + + +
CONS
Staph +
E Coli + + + +
Acinetobactor +

73. Fluro
Quino
lones
Cloxa
cillin
Piperac
illin
tazobac
tam
Vancomycin Aztreo
nam
Linezolid
Pseudomo
nas
+ + +
Klebsiella + +
CONS + +
Staph + + + + +
E Coli + + +
Acinetoba
ctor
+

74. • Prophylactic antibiotics
• They are given to prevent infection.
• Not indicated in almost all situations in
neonatology.
• High level evidence: not useful for the prevention
of infection following umbilical vessel or central
venous catheterisation
• Antibiotics for all infants receiving mechanical
ventilation not supported by evidence from
randomised controlled trials.

75. • The only prophylactic use of antimicrobials: fungal
prophylaxis in preterm infants on broad spectrum
antibiotics or with central arterial or venous lines.
• A Cochrane systematic review: antifungals reduce the
incidence of systemic fungal infections.
• To date there is no evidence that use of oral
prophylactic antifungal agents has changed the
susceptibility of infecting organisms.

76. Prophylactic
antifungal agents
• The antifungal prophylaxis guideline (Royal Maternity
Hospital, Belfast)
• VLBW baby should be considered for antifungal
prophylaxis if :
• under treatment with a third generation cephalosporin
• under treatment for more than 10 consecutive days with
a systemic broad spectrum antibiotic
• fungal colonisation from surface sites and a central
venous catheter in situ.

77. Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth
weight infants. Austin N, McGuire W. Cochrane Database Syst Rev. 2013
• 11 eligible trials enrolling a total of 1136 infants
• Seven trials (involving 880 infants) compared
systemic antifungal prophylaxis versus placebo or no
drug
• Statistically significant reduction in the incidence of
invasive fungal infection in infants
• Meta-analysis did not find a statistically significant
difference in the risk of death prior to hospital
discharge
• Very limited data on long-term neurodevelopmental
outcomes were available.

78. Prophylactic oral antifungal agents to prevent systemic candida infection in preterm infants.
Austin N, McGuire W. Cochrane Database Syst Rev. 2004
• 3 eligible trials
• Nystatin with no treatment (67 infants)
• Miconazole with placebo (600 infants)
• Nystatin with fluconazole (21 infants).

79. • Nystatin versus no treatment, systemic fungal
infection was significantly reduced
• Miconazole with placebo: no significant effect
• Neither study found a significant effect on mortality,
• No significant difference in the mean number of days
infants received ventilation or stayed in the neonatal
intensive care unit.
• Oral fluconazole with nystatin, no significant
difference in systemic fungal infection or mortality
was reported.

80. Selective fluconazole prophylaxis in high‐risk babies to reduce invasive fungal
infection
Brian A McCrossan, Elaine McHenry, Fiona O'Neill, Grace Ong, and David G Sweet
Arch Dis Child Fetal Neonatal Ed
v.92(6); Nov 2007
• Fluconazole 6 mg/kg for 3 weeks. Dose interval
every 72 h during the first 2 weeks of life.
Thereafter, dose interval reduced to every 48 h until
3 weeks old when daily fluconazole is given.
• 6/33 babies eligible for prophylaxis developed
culture proven Candida sepsis before compared with
no (0/31) babies after the guideline was
implemented (p=0.03).
• Selective antifungal prophylaxis has reduced invasive
fungal sepsis

81. References
• Choice and Duration of Antimicrobial Therapy for Neonatal
Sepsis and Meningitis International Journal of Pediatrics
Volume 2011 (2011)
• Cochrane Database Syst Rev. 2013
• Prolonged Initial Empirical Antibiotic Treatment is
Associated with Adverse Outcomes in Premature Infants J
Pediatr. 2011 November ; 159(5): 720–725.
• Choosing the right empirical antibiotics for neonates Arch
Dis Child Fetal Neonatal Ed. 2011 January ; 96(1): F2–F3.
• Rationing antibiotic use in neonatal units Arch Dis Child
Fetal Neonatal Ed 2000;82:F1–F2
• Antibiotic Use and Misuse in the Neonatal Intensive Care
Unit Clin Perinatol. 2012 March ; 39(1): 61–68.