1. NEONATAL SEPSIS AND
PREVENTION OF HEALTHCARE
ASSOCIATED INFECTIONS
Hesham Tawakol, MD, FAAP
Consultant Neonatologist
Al Corniche Hospital

2. Objectives

Neonatal sepsis

Drug Resistance

Prevention of Healthcare Associated Infections

3. Case



A preterm 28 weeks infant with history of RDS on nasal
cannula 2 lpm 30% O2 has only PIV
(DOL 20) Apnea – Bradycardia. Sepsis work up done.
Vancomycin and amikacin. On CPAP
(DOL 24) K. Pneumonia sensitive to meropenem,
ciprofloxacin, amikacin and resistant to cefotaxime and
ceftazidime. meropenem was initiated. Blood culture
repeated, Baby on CMV 40% O2

4. Case


(DOL 26) blood culture +, baby deteriorating, Amikacin
changed to ciprofloxacin. Blood culture repeated. , ECHO,
head and abdominal US done with no focus
(DOL 27) blood culture + Baby further deteriorates. On
HFOV. Baby died secondary to DIC.

5. Do you think we have a
problem?

6. Neonatal Sepsis

Bacterial

Viral
Fungal


7. Definition


In older medical literature, 1 week of age was considered
the limit between EOS and LOS.
More recently, EOS infection is any infection that manifest
in the first 72 hours, LOS manifest after 72 hours of birth

8. Source of Infection


EOS is usually due to vertical transmission by ascending
contaminated amniotic fluid or during vaginal delivery from
bacteria colonizing or infecting the mother's lower genital
tract
LOS can be vertical from the mother or horizontal
transmission from direct contact with care providers or
environmental sources

9. Early Onset Sepsis in Full Term in
USA
4
20
4
46
26
Soll PJ et al, Pediatr Infect Dis J. 2005;24(7):635–63
GBS
Other Strept
E coli
Enterococcus
S.Aureus

10. Early Onset Sepsis in VLBW in
USA
9
11
49
14
17
E coli
CONS
GBS
Other strept
Other Gram pos
Soll PJ et al, Pediatr Infect Dis J. 2005;24(7):635–63

11. Early Onset Sepsis in Developing
Countries
9
10
35
21
25
Klebseilla
S.Aureus
E coli
Pseudomonas
GBS
Ziadi et al, Pediatr Infect Dis J. 2009;28(suppl 1):S10–S18

12. Epidemiology



The overall incidence of neonatal sepsis ranges from 1 to 5
cases per 1000 live births.
The estimated incidence is lower in term infants, with a
reported rate of 1 to 2 cases per 1000 live births
The incidence of early-onset sepsis has decreased
primarily as a reduction of GBS infections due to the use of
intrapartum antibiotic prophylaxis

13. Epidemiology
CDC, GBS Prophylaxis guidelines 2010

15. Epidemiology
CDC, GBS Prophylaxis guidelines 2010

16. Intrapartum Antibiotics Prophylaxis
(IAP)





Penicillin or ampicillin
Cefazolin
Clindamycin
Erythromycin
Vancomycin

17. Epidemiology of LOS in Saudi
Arabia
CONS
Staph aureus
Enterococcus
GBS
E Coli
Klebsiella
Pseuomonas
Enterobacter
Serratia
Candida
Others
K. Alfaleh Sultan Qaboos Univ Med J. 2010 August

18. Neonatal Sepsis in the Arab
World

Twelve studies from eight Arabic countries including 2308
newborn with proven sepsis

Early onset sepsis ranged from 24 to 74%.

GBS in UAE 34 % early onset

Gram-negative organisms were the predominant
pathogens in Libya, Egypt, Jordan, and Iraq
Tosson et al, J Matern Fetal Neonatal Med. 2011

19. Risk Factors for LOS

20. Risk Factors for LOS
A recent study showed that empiric antibiotic
treatment resulted in a threefold increase in risk
of infection from resistant bacteria for every day
of ampicillin and gentamicin use and up to a 34fold increase with cephalosporin use in neonates
previously exposed to antibiotics.

Le Jet all, Pediatr Infect Dis J. 2008

21. Clinical Presentation
The primary clinical findings in a very low-birth weight infants




Apnea
(55%)
Feeding intolerance, abdominal distension
or guaiac-positive stools
(43%)
Increased respiratory support (29%)
lethargy and hypotonia
(23%)
Fanaroff et al, Pediatric Infect Dis J. Heart

22. Clinical Presentation


The most common clinical syndromes of early-onset
disease are sepsis and pneumonia; less frequently
meningitis. Late onset presents as sepsis and meningitis
The case-fatality ratio of early-onset disease has
declined from as high as 50% in the 1970 to 3-4 % in
Full term and 20% in preterm infant

23. Diagnosis – Blood Culture



Positive blood culture is considered the gold standard in
sepsis diagnosis.
Positive results from blood culture depend on the
technique used, microorganism density, previous
antibiotic treatment, and sample volume.
The automated method requires only 1.0 mL of blood
and with the radiometric technique is very sensitive, with
a high percentage of positive blood cultures, reaching
74% to 90.

24. Diagnosis – Blood Culture


Blood culture should be collected by peripheral
venipuncture before beginning antibiotic treatment, and if
positive, should be repeated during treatment to evaluate
treatment effect.
Patients who have central catheters can have blood
obtained by this route, but another sample should be
collected by peripheral access for better interpretation of
results

25. Diagnosis – Blood Culture


Positive blood culture confirms sepsis, and when the
blood culture is negative, the condition is considered as
clinical sepsis
An alarming fact in many neonatal intensive care units
(NICUs) is that for each confirmed case of
infection, between 11 and 23 uninfected newborns are
treated

26. Diagnosis - Urine culture


Urine culture obtained by catheter or bladder tap should be
included in the sepsis evaluation for infants >6 days of age.
A urine culture need not be routinely performed in the
evaluation of an infant ≤6 days of age because a positive
urine culture in this setting is a reflection of high-grade
bacteremia rather than an isolated urinary tract infection

27. Diagnosis – CSF Culture


The decision whether or when to perform a LP for CSF
analysis and culture remains controversial
As many as 25% of newborns who have sepsis have
meningitis, and 15% to 55% of patients who have
meningitis (positive CSF culture) have negative blood
cultures.

28. Diagnosis – CSF Culture

The approach outlined by the 2012 AAP clinical report
recommends that LP should be performed for an infant
with any of the following clinical conditions
 A positive
blood culture
 Clinical findings that are highly suggestive of sepsis
 Laboratory data strongly suggestive of sepsis
 Worsening clinical status while on antibiotic therapy

29. Diagnosis - CBC







CBC
6 to12 hours after delivery
Total white count
Absolute neutrophil count
Ratio of immature to total neutrophil counts (I/T ratio)
Both are more useful in identifying
Platelets count

30. Diagnosis – Cytokines, Acute phase
reactants and Surface Markers





IL 6 – IL 8 – IL 10
Tumor necrosis factor alpha
CD64
CRP
PCT

31. Diagnosis – CRP


C-reactive protein was the best single marker, with an
overall sensitivity and specificity of 84% and
96%, respectively.
At the beginning of sepsis, CRP concentrations are
increased 1 mg/dL) in only 16% of cases, After 24
hours, positivity increases to 92%

32. Diagnosis – CRP


Performing IL-6 and C-reactive protein on day
0, together with either TNF alpha on day 1 or C-reactive
protein on day 2, showed the best overall sensitivity
(98%) and specificity (91%) for the diagnosis of late
onset infection.
CRP levels can be considered as a criterion for the
discontinuation of antibiotic therapy to minimize antibiotic
exposure and shorten hospital stay.
Dia, HA et al,Pediatric Intern Child Health 2012

33. Diagnosis - Neutrophil CD64



Diagnostic Marker in Neonatal Sepsis.
Can be incorporated as a valuable marker for excluding
neonatal sepsis.
A cut-point value ,sensitivity, specificity and a negative
predictive values of 3.62, 75%, 77%,
Streimish et al,. Pediatr Infect Dis J. 2012 Apr 4

34. Accuracy of diagnostic tests in Late onset
Sepsis
Test
S%
SP%
Gram-specific PCR for Gram -ve
86
99
Gram-specific PCR for Gram +ve
74
98.5
Tumor necrosis factor -alpha
73-82
80-94
IL-6+CRP or PCT
100
96
IL-8+CRP
80
87
IL-8 urine
92
94
CD64+IL-6 or CRP
100
88

35. Diagnosis – Heart Rate
Characteristics

A new technology related to heart rate
characteristics (HRC) monitoring may be a
promising tool in the early diagnosis of LOS.

24 hours before clinical suggestions of
sepsis, neonates have reduced heart rate
variability and transient decelerations.

Although the mechanism by which sepsis leads to
these abnormalities is not known, it is speculated
that cytokines play a role.

37. Treatment


Choice of antibiotic therapy for suspected sepsis should be
tailored for the most likely organism with the highest
mortality risk with consideration to local resistance patterns
There is inadequate evidence from randomized trials in
favor of any particular antimicrobial regimen for the
empirical treatment especially for suspected LOS

38. Treatment


Optimal duration of empiric antimicrobial use decreases
the development of antimicrobial resistance, prevents
unwanted changes in flora found in the NICU, and
minimizes unnecessary expenses for infants who have
negative blood culture
Prolonged duration of initial empirical antibiotic therapy is
associated with adverse effects

39. Treatment


Vancomycin :CDC recommended against empirical
vancomycin therapy to prevent the emergence and spread
of vancomycin resistant strains and recommends its use in
areas where MRSA is prevalent.
An acceptable approach would be to start with cloxacillin
and gentamicin as initial antibiotics for LOS in a stable
neonate

40. Treatment

Third generation cephalosporin: provides less coverage for
the relevant disease causing organism and increase
resistance and risk for fungal infections. This rule does not
apply for meningitis
Muller-Pebody et al,Arch Dis Child Fetal Neonatal Ed
2011

41. 


10 days of therapy for culture-proven sepsis with minimal
or absent focal infection
Neonates with S. aureus infection may require 14 days of
antibiotic therapy
This applies to patients who are at least 32 weeks and
above and showed good initial response to antibiotics.

42. 


For neonates with late-onset meningitis, a regimen
containing an antistaphylococcal antibiotic, such plus
cefotaxime or ceftazidime with or without an
aminoglycoside is recommended
GBS meningitis is usually treated for 14 to 21 days
For meningitis caused by Gram-negative bacteria, a
minimum of 21 days is recommended

43. 
Avoid treating colonization and prophylactic
antibiotic use for invasive devices.

44. IVIG
The rationale for IVIg infusion is that it
could provide type-specific antibodies.
The main difficulties with IVIg therapy are
as follows:
 The effect has been transient
 Clinically available IVIg solutions do not
contain type-specific antibody
 The adverse effects associated with the
infusion of any blood product can occur


45. Complication

Meningitis: hearing and vision
impairment, convulsions, neurodevelop
mental impairment, behavioral
problems.
Polin R A et al,Semin Neonatal 2001

46. Complications

At school age, a majority of preterm
children with late-onset sepsis had motor
problems. And lower IQ was and memory
and attention were specifically impaired..

47. 
Healthcare associated infection

Multidrug resistant bacteria

48. Multidrug Resistant Bacteria

ESBL's history starts, as many histories do, with a
war: The war between us and the bacteria

Penicillin
Lactamase

Cephalosporins

Carbapenems
ESBL, NDM-1
Beta
ESBL
???
Pennington, Hugh (2010-08-11). "Can we stop the Indian superbug?

49. Selection Pressure
“Survival of the Fittest”

50. Bacterial DNA

51. Transfer of Bacterial Genetic
Material

52. Mechanisms of Antibiotics
Action
1
3
5
2
4

53. Mechanisms of Resistance
4
5
6
3
1
2

54. Definition

Nosocomial infection or Hospital acquired
infection

An infection occurring in a patient in a hospital
or other healthcare facility in whom the
infection was not present or incubating at the
time of admission.

This includes infections acquired in the
hospital but appearing after discharge
Benenson AS. Control of communicable diseases manual, 16th edition.
Washington, American Public Health Association, 1995

55. Prevention

56. Ignaz Semmelweis (1818-186

Hungarian obstetrician

Pioneer of antiseptic
procedures

Decreased incidence
puerperal fever and
maternal mortality by
90%

Hand hygiene
Hanninen, O infection Control 4 (5): 367–370

57. Chain of Infections

58. Prevention of HCAI
 Validated
and standardized prevention strategies
have been shown to reduce HCAI
 At
least 50% of HCAI could be prevented
 Most
solutions are simple and not resourcedemanding and can be implemented in
developed, as well as in transitional and
developing countries

59. Prevention of HCAI

Reducing person to person transmission

Controlling environmental risks for infection

Protecting patients with appropriate use of prophylactic
antimicrobials, nutrition, and vaccinations

Limiting the risk of endogenous infections by minimizing invasive
procedures , and promoting optimal antimicrobial use

Surveillance of infections, identifying and controlling outbreaks

Prevention of infection in staff members

Enhancing staff patient care practices, and continuing staff education.

60. Clean Hands..Save Lifes

61. WHO Hand Washing

62. The 5 Moments of Hand
Washing

63. Compliance with hand
hygiene

Compliance with hand hygiene differs across
facilities and countries, but is globally <40%1

Main reasons for non-compliance reported by
health-care workers2:
 Too
busy
 Skin irritation
 Glove use
 Don’t think about it
1Pittet
2Pittet
and Boyce. Lancet Infectious Diseases 2001;
D, et al. Ann Intern Med 1999

64. Time constraint = major
obstacle for hand hygiene

Adequate handwashing
with water and soap
requires
40–60 seconds

Average time usually
adopted by health-care
workers:
<10 seconds

Alcohol-based
handrubbing:
20–30 seconds