This document discusses the management of neonatal sepsis and identifies areas of potential malpractice. It presents two case studies of neonates with sepsis that were potentially mismanaged. The document then outlines key topics to be covered, including features of neonatal sepsis, the role of CRP and procalcitonin in diagnosis, treatment planning considerations, controversies around certain drug uses, the role of blood exchange transfusions, and potential adjuvant therapies. Overall, the document aims to improve management of neonatal sepsis by revising basic knowledge around appropriate diagnosis and treatment.

1. MALPRACTICE IN MANAGEMENT OF
NEONATL SEPSIS.
By:
Dr: Osama Abuelfoutoh Elfiky
Professor of pediatric and
neonatology
Benha Faculty OF medicine

2. CASE(1)
 A male full term neonate 3.5 kg 15 days old
 Vigorous; active; stable vital signs ;bottle fed on
demand
 His lab is completely normal except for elevated
CRP(96mglL).
 He is receving:vancomycin;meorenam;diflucan and
 Metronidazole.

3. CASE(2)
 A male neonate 7 days 34 weeks gestation
 History of premature rupture of membranes
 Clinically poor activity on mechanical ventilation;
abdominal distention feeding intolerance ;bloody
aspirate ;generalized edema and shocked
 elevated CRP; thrombocytopenic receiving at these 7
days all the available antimicrobial drugs and IVG.

4.  These two cases are examples of bad management.
 On what bases the first one is still receiving all these
drugs
 Why the second case is deteriorating in spite of the
use of about 20 antimicrobial agents and IVG in one
weak duration .
 What is going wrong and how to overcome like these
situations?


5.  Revision of our basic knowledge of
some aspects of neonatal sepsis is the
corner stone to improve the situation and
consequently outcome of neonatal sepsis

6. POINTS TO BE COVERED IN THIS TALK
 1-Some features of neonatal sepsis.
 2-Role of CRP in diagnosis and follow up
marker.
 3-Procalcitonin can it play a diagnostic and a
prognostic role in neonatal sepsis?
 4-How can we plan treatment of neonatal
sepsis?

7.  5-Contovesies about use of some drugs
 6-Role of double volume exchange transfusion
by fresh whole blood in treating severe
fulminant Cases of sepsis
7-Adjuvant therapeutic agents ,Do it have a
role?

8. 1-Some features of neonatal sepsis.

9. DEFINTION:
Neonatal sepsis is a term used to describe the
systemic response to infection in the
neonatal period.

12. Incidence:
It is reported to be 23-38 per 1000 live births
in Asia and Africa but in USA it is about 1.5-
3.5 per 1000 live birth.(Leal et al 2012)
Proven early-onset sepsis has mortality rates
as high as 30% in high-income countries and
up to 60% in low-income countries

13. In Egypt 45.9% in a study developed sepsis with a
mortality rate of 51% and 42.9% among proven
EOS and LOS cases respectively.(Eman et al
2015)

14. Neonatal mortality currently represents 40% of
all childhood mortality
Global, regional, and national levels of neonatal, infant, and under-5 mortality
during 1990-2013: a systematic analysis for the Global Burden of Disease Study
2013

15. Neonatal sepsis is the third leading cause of neonatal mortality, only
behind prematurity and intrapartum-related complications (or birth
asphyxia)
It is responsible for 13% of all neonatal mortality, and 42% of deaths
in the first week of life
4 million neonatal deaths: when? Where? Why?Lawn JE, Cousens S, Zupan J,
Lancet Neonatal Survival Steering Team.
Lancet. 2005 Mar 5-11; 365(9462):891-900.
[PubMed] [Ref list]
Neonatal mortality currently represents 40% of all
childhood mortality
Global, regional, and national levels of neonatal, infant, and under-5 mortality during
1990-2013: a systematic analysis for the Global Burden of Disease Study 2013

16.  Sepsis free NICU is a great dream
 In spite of the great advance in the recent
diagnostic and therapeutic modalities
neonatal sepsis is still a big challenge and
responsible for about 16% of deaths in
NICUS
 The situation is more complicated by
misdiagnosis and abuse of antimicrobial
drugs which results in resistant strains of
microorganisms

17. 2-ROLE OF CRP IN DIAGNOSES OF
NEONATAL SEPSIS

18. C-reactive protein (CRP)

19.  C RP is sensitized by the liver in response to inflammatory
cytokines and may increase more than 1000 fold during an
acute phase response (Imam et al., 2004)
 CRP is released 4 to 6 hours after the onset of stimulus then
diminishes over time as the inflammation resolves (Gerdes,
2004).

20. a number of perinatal conditions that may cause an
inflammatory response without having proven
infection such as:
Maternal fever
Prolonged PROM
Fetal distress
Stressful delivery
Perinatal asphyxia,
Intraventricular hemorrhage
Meconium aspiration syndrome (MAS)
cause elevated CRP level (Gerdes, 2004).

22.  So in NICU when the neonate is intubated ;has a CV
line exposed to many maneuvers as suction and
frequent sampling tissue damage will cause marked
CRP elevation
 It is concluded that diagnosis of sepsis is not an
elevated CRP and it must be correlated with the
clinical picture and hematological changes

23. If CRP is elevated but the patient is clinically well
and Hematological parameters are improving I think
that a negative blood culture will help us to judge
improvement.
Do not forget that persistently elevated CRP may
Be seen in septic arthritis and tissue necrosis
Caused by extravasated calcium
We recommend other markers as procalcitonin

24. 3-Procalcitonin, can it play diagnostic and
prognostic role in neonatal sepsis?

25. Procalcitonin is a propeptide of calcitonin produced
mainly by monocytes and hepatocytes that is
significantly elevated during infections in neonates,
children, and adults
Procalcitonin measurement at 24 hours of age may be helpful in the prompt diagnosis of early-
onset neonatal sepsis.Altunhan H, Annagür A, Örs R, Mehmetoğlu I
Int J Infect Dis. 2011 Dec; 15(12):e854-8.
[PubMed] [Ref list]

26. Procalcitonin-guided decision making for duration of
antibiotic therapy in neonates with suspected early-onset
sepsis (NeoPIns) published in THE LANCET VOLUME 390,
ISSUE 10097, P871-881, AUGUST 26, 2017
During this clinical trial, 18 hospitals in Europe and
North America investigated whether PCT-guided
decision making can safely shorten the duration of
antibiotic therapy in newborns with suspected early
onset sepsis.
The results demonstrate that PCT-guided decision
making leads to a significant reduction in duration of
empirical antibiotic therapy

27. 4.HOW CAN WE PLAN TREATMENT OF
NEONATAL SEPSIS?

28.  THE PLANE OF TREATMENT MUST ANSWER
THE FOLOWING :
 1-What is the possible pathogen.
 2-The empiric choice of antibiotics.
 3-when to decide failure of response.
 4-Choise according to results of culture.
 5-Duration of antibiotic therapy.
 6-When to stop treatment?

29. CAUSATIVE AGENTS OF
NEONATAL SEPSIS

30. Causative Pathogens Responsible for Sepsis
 Pathogens associated with neonatal sepsis vary in
different countries.
 Gram negative bacilli are the most common
pathogen in Egypt.

31. The most common causes of EOS are
GBS and enteric bacteria acquired
from the maternal genital tract
(Chiesa et al., 2004).

33. B) Causative organisms for LOS and
Nosocomial infection

35. FUNGAL INFECTON
 Risk factors:
 Serve Prematurity less than 1500 g ms
 Prematures requiring prolonged ventilation; cv line
and TPN specially intralipids
 Prolonged administration of broad spectrum
antibiotics; steroids and H2 blockers.

36. ANTHMICROBIAL THERAPY OF
NEONATAL SEPSIS
A)-Empiric therapy.
B)-According to results of culture.

37.  A)-EMPIRIC ANTIBIOTIC CHOICE:
 Cultures should be obtained first.
 Then empiric antibiotic therapy must be
initiated according the possible pathogen.

39. EMPERIC ANTIMICROBIAL CHOISE

40. Treatment
 In conclusion treatment will be as follow:
 Early Sepsis:
 Combination of Ampicillin and Aminoglycosides.
 Late Sepsis:
 Combination of Vancomycin or Cloxacillin with amino
glycosides

41. Treatment (cont.)
 Anaerobic Infection.
 Clindamycin.
 Fungal Infection.
 Amphotericin-B , Diflucan

42. UPGRADING OF ANTIBIOTICS
 At least 48-72 hours period of observation must be
allowed to declare failure of the chosen antibiotics

43.  B)-ACCORDING YO RESULT OF CULTURE :
 Once a pathogen is identified, antibiotic coverage
should be narrowed based on susceptibility testing
(Kaufman and Fairchild, 2004).

44. DURATION OF ANTIMICROBIAL THERAPY

45.  For bacteraemia, the duration of therapy is
usually 7-10 days
 or 7 days after the initial negative results are
obtained.
 For meningitis, the duration of therapy is 14 to
21 days.

46. For Candida sepsis unaccompanied by meningitis,
2-4 week or longer courses have been used.
In the presence of candidal meningitis addition of
5-flucytosine is recommended because of its
excellent penetration into CSF.
In the presence of endocarditis and osteomyelitis
or septic arthritis a longer courses of antibiotics are
needed 4-6 weeks. (Rodrigo, 2002).

47. NB : continue antimicrobial agents for 48-72
hours after negative culture is obtained
.

48. 5-Contovesies about use of some drugs

49. THIRD GENERATION CEPHALOSPORINES
AND AMINOGLYCOSIDES.

50.  It is a fact that raising the generation of
cephalosporines increases its efficacy against gram
negative bacteria.
 Many practioners use third generation
cephalosporines as anti gram negative drugs because
they are afraid of ototxicity and nephrotoxicity of
amino glycosides.
 We don’t support this concept as all protocols of
management of neonatal sepsis recommend the use of
amino glycosides


51. the recommended empirical treatment for neonatal sepsis
remains ampicillin and gentamicin.
Polin RA, Committee on Fetus and Newborn. 2012. Management of neonates
with suspected or proven early-onset bacterial sepsis. Pediatrics 129:1006–
1015. doi:10.1542/peds.2012-0541.
An alternative initial empirical treatment that has been proposed is
a combination of ampicillin and cefotaxime
However, there is evidence that in early neonatal sepsis, this
combination leads to more resistant Gram-negative organisms
being isolated in neonatal intensive care units (NICUs),
and there may be an increase in serious complications such as
necrotizing enterocolitis (NEC) and death
Moreover, some studies have noted an increase in the prevalence
of invasive candidiasis in NICUs

52.  However third-generation cephalosporin such as
cefotaxime are valuable additions for treating
documented neonatal sepsis and meningitis because
of its high penetration to the blood brain barrier.

53.  We do not agree with this concept because of:
1-Side effects of any drug does not prevent its use.
 2-Aminglycosides can be used even in patients with.
impaired renal functions .
 3- A ll guidelines of management of neonatal sepsis
 consider aminoglycosidesd a corner stone .

54. ANTI FUNGAL DRUGS

55.  There is a growing concept to add antifungal drugs to
other antimicrobial agents in sepsis case not
responding to treatment blindly without culture
results
 Risk factors:
 Serve Prematurity less than 1500 g ms
 Prematures requiring prolonged ventilation; cv line
and TPN specially intralipids
 Prolonged administration of broad spectrum
antibiotics; steroids and H2 blockers.
 We don’t support this concept because of:

56.  For Candida sepsis unaccompanied by meningitis, 2-4
week or longer courses have been used.
 In the presence of Candidal meningitis a longer
duration may be needed .
 These antifungal drugs have many toxic effects
especially when used for a long duration.
 So these drugs must be used if culture results yield a
fungal pathogens or there is a risk of fungal infection.

57. 6-Role of double volume exchange transfusion
of fresh whole blood in treating severe
fulminant Cases of sepsis

58. Indications
fulminant neonatal sepsis, with or without toxic shock
disseminated intravascular coagulation,

59.  RATIONALE :
 Provides WBCS; platelets and removes bacteria,
 Removal of endotoxins ;cytokines and molocules that
 Increase permiability of vascular endothelium.
 Provides complement;antibodies and coagulation
factors .
 Improve lung and tissue perfusion and oxygen delivery.
 (Stronati and Borghesi;2012)

60.  whole blood exchange transfusion do present
significant risk, including graft-versus-host disease;
blood group sensitization; and transmission of
infections such as CMV, HIV, and viral hepatitis
(Puopolo, 2)
 INDICATIONS:
 Neonates with severe sepsis ;septic shock ;DIC and
 Sclredema . (Stronati and Borghesi;2012)

61.  Lorenz pugni et al(2016):
 Exchange transfusion in the treatment of neonatal
septic shock A ten years experience(2005-2015)
neonatal intensive care unit university of Milan Italy .
 International journal of molecular sciences.

64. To conclude, DVET showed a trend towards reduction in
mortality of 21 % in comparison to ST in severely septic
neonates of >1000 g birth weight. A significant improvement
was observed in the cardiovascular and hematological organ
functions following DVET. DVET was associated with a
significant improvement in IgA, IgG, IgM, complement 3 and
metabolic acidosis in comparison to the standard therapy.

65. Conclusions
In conclusion, a significant reduction of mortality in
patients who underwent ET, together with the lack of
adverse effects observed, suggest that this procedure should
be considered for the treatment of neonates with septic
shock.

66. 7-Adjuvant therapeutic agents ,Do it have a
role?

67. INTRAVENOUS IMMUNOGLOBULINE.

68.  RATIONALE:
 Could produce type specific antibodies there by
improving opsonization and phagocytosis of bacteria
 And clinicaly complement activation and chemotaxis
of neonatal neotrophils.
 DIFFICULTIES:
 Transient effect
 Avilable IVG do not contain type specific antibodies.
 Adverse effect of transfusion of blood products.
 Expensive.

71. Adjuvant therapies like intravenous
immunoglobulins and granulocyte colony
stimulating factors have been ineffective in
improving the outcome .
Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or proven infection in
neonates. Cochrane Database Syst Rev. 2013;7: CD001239.
Carr R, Modi N, Doré C. G-CSF and GM-CSF for treating or preventing neonatal infections.
Cochrane Database Syst Rev. 2003;3:CD003066.

72. GRANULOCYTE TRANSFUSION

74. MYLOID COLONY STIMULATING FACTORS.

75. GM-CSF AND G-CSF
 These cytokines induce the production of neutrophils
by bone marrow .
 Since prematures have limited number and function
of neutrophils these factors may be used as adjunct
therapy in neonatal sepsis to increase the production
of neutrophils by bone marrow.

76. PROBIOTICS.

77.  Some investigators use daily dose of probiotics during
the period of stay in NICU to decrease the risk of
nosocomial infection.
 These trials showed no valuable results.
 Use of probiotics may be complicated by sepsis caused
by contamination with pathogenic strains.

78. RECCOMENDATIONS

79. Sepsis free NICU is a great dream all of us
must cooperate to make it a truth.
 Antimicrobial agents are the weapons
against microorganisms .Be wise and do not
exhaust your weapons.

80.  The ability of microorganisms to produce
resistance markedly exceeds the ability of
Pharmaceutical companies to develop new
antimicrobial agents so we may face fatal
epidemics caused by resistant microorganism
 Do not forget exchange transfusion in rapidly
Deteriorating neonates with severe fulminant
sepsis.

81.  Infection control policies must be revised
 and strict infection control policies must
 Be followed.
 We must cooperate to develop our Egyptian
guidelines for management of neonatal
sepsis.

88. The highly protein-bound agent ceftriaxone is not recommended for
neonates with concerns of meningitis due to the risk of acute
bilirubin encephalopathy from displacement of free bilirubin by the
drug
It has also been rarely associated with biliary pseudolithiasis,
nephrolithiasis, and pulmonary impairment due to precipitation with
calcium ions in neonates with both elevated and normal serum
calcium levels
Ceftriaxone effect on bilirubin-albumin binding.Fink S, Karp W, Robertson A
Pediatrics. 1987 Dec; 80(6):873-5.
[PubMed] [Ref list]
Schaad UB, Wedgwood-Krucko J, Tschaeppeler H. 1988. Reversible ceftriaxone-associated
biliary pseudolithiasis in children. Lancet ii:1411–1413 [PubMed]
Avci Z, Koktener A, Uras N, Catal F, Karadag A, Tekin O, Degirmencioglu H, Baskin E.
2004.Nephrolithiasis associated with ceftriaxone therapy: a prospective study in 51
children. Arch. Dis. Child.89:1069–1072. 10.1136/adc.2003.044156 [PMC free
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