Neonatal sepsis

1

• Neonatal sepsis
• early vs. late
• maternal vs. nosocomial vs. community acquired
• modes of vertical trasmission
• Overview of neonatal immune system
• Manifestations of neonatal sepsis
• Differential diagnosis
• Maternal screening for STD
• Diagnostic work up for neonatal sepsis
• Treatment duration
• Antibiotics (dose interval)

2

• Modes of transmission
• 1- transplacental
• 2- transvaginal
• 3- ascending
• 4- breast milk
• Chronology
• Early onset lt7days?(sepsis- pneumonia)
• Late onsetgt7days?(meningitis- local infections )
• Late late onsetgt1month
• Source
• Maternal (vertical)
• Hospital (nosocomial)
• Community
• 
  

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• Early onset sepsis Presents during the first
  week, usually during the first 72h of life . The
  clinical presentation is respiratory distress and
  pneumonia. Three common pathogens are GBS E
  coli Listeria monocytogen. UTI is not common.
• Late onset sepsis Presentation is after the first
  week. Pathogens are the same as early onset
  sepsis. Presentation with meningitis is more
  common than early onset sepsis.
• Nosocomial infection The CDC-NNIS system defines
  a nosocomial infection as a localized or systemic
  condition (1) that results from an adverse
  reaction to the presence of an infectious agent
  or its toxin and (2) that was not present or
  incubating at the time of admission to the
  hospital. (a)
• Pathogens are different from early and late onset
  sepsis and include klebsiella pseudomona
  enterobacter CONS staphylococcus aureus
  stenotrophomonas acintobacter candida
  enterococcus

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Characteristics of Neonatal Sepsis Characteristics of Neonatal Sepsis Characteristics of Neonatal Sepsis Characteristics of Neonatal Sepsis
Early Onset (lt7 Days) Late Onset 7 Days to 3Months Late, Late Onset (gt3 Months)
Intrapartum complications Often present Usually absent Varies
Transmission Vertical organism often acquired from mothers genital tract Vertical or through Postnatal environment Usually postnatal environment
Clinical manifestations Fulminant course multisystem involvement pneumonia common Insidious or acute, focal infection, meningitis common insidious
Case fatality rate 5-20 5 low
5

• Overview of neonatal immune system
• Immunoglobulin
• In premature infants, cord IgG levels are
  directly proportional to gestational age. Studies
  of type-specific IgG antibodies to GBS have shown
  that the ratio of cord to maternal serum
  concentrations is 1.0, 0.5, and 0.3 at term, 32
  wk, and 28 wk of gestation, respectively.
• Complement
• Full-term newborn infants have slightly
  diminished classical pathway complement activity
  and moderately diminished alternative pathway
  activity. Premature
• infants have lower levels of complement
  components and less complement activity than
  full-term newborns do.
• Monocyte macrophage system
• The number of circulating monocytes in neonatal
  blood is normal, but the mass or function of
  macrophages in the reticuloendothelial system is
  diminished, particularly in preterm infants. In
  both term and preterm infants, chemotaxis of
  monocytes is impaired.
• Natural killer cells
• neonatal NK cells have decreased cytotoxic
  activity and ADCC in comparison to adult cells.
  The diminished cytotoxicity against herpes
  simplex virus (HSV)-infected cells may predispose
  to disseminated HSV infection in newborn.

6

• Neutrophils
• Quantitative and qualitative deficiencies of the
  phagocyte system contribute to the newborns'
  susceptibility to infection. Neutrophil migration
  (chemotaxis) is abnormal at birth in both term
  and preterm infants. Neonatal neutrophils have
  decreased adhesion, aggregation, and
  deformability, all of which may delay the
  response to infection.
• The number of circulating neutrophils is elevated
  after birth in both term and preterm infants,
  with a peak at 12 hr that returns to normal by 22
  hr.
• Band neutrophils constitute less than 15 in
  normal newborns and may increase in newborns with
  infection and other stress responses such as
  asphyxia.
• Neutropenia is frequently observed in preterm
  infants and those with intrauterine growth
  restriction it increases the risk for sepsis.
• The neutrophil storage pool in newborn infants
  is 20-30 of that in adults and is more likely to
  be depleted in the face of infection. Mortality
  is increased when sepsis is associated with
  severe sepsis-induced neutropenia and bone marrow
  depletion.
• Granulocyte colony-stimulating factor (G-CSF)
  and granulocyte macrophage colony-stimulating
  factor (GM-CSF) are cytokines that play important
  roles in the proliferation, differentiation,
  functional activation, and survival of
  phagocytes.

7

• Placental transport of antibodies
• The transport of IgG is an active placental
  process, and the neonates serum IgG concentration
  at birth is 5 to 10 higher than that of the
  mother.
• Elevated levels of IgM or IgA in cord blood
  usually indicate that the infant has been exposed
  to antigen in utero and has synthesized antibody
  itself.
• The concentration of IgG falls postnatally
  (because of the catabolism of maternal IgG) and
  reaches a nadir (physiologic hypogammaglobulinemia
  ) at approximately 3 to 4 months of age.

8

• BACTERIAL SEPSIS
• Neonates with bacterial sepsis may have either
  nonspecific signs and symptoms or focal signs of
  infection , including
• temperature instability, hypotension,
• poor perfusion with pallor and mottled skin,
• metabolic acidosis, tachycardia or bradycardia,
  apnea, respiratory distress, grunting, cyanosis,
  irritability, lethargy, seizures, feeding
  intolerance, abdominal distention, jaundice,
  petechiae, purpura, and bleeding.

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• BACTERIAL SEPSIS
• The initial manifestation may involve only
  limited symptomatology and only 1 system, such as
  apnea alone or tachypnea with retractions or
  tachycardia, or it may be an acute catastrophic
  manifestation with multiorgan dysfunction.
• Infants should be reevaluated over time to
  determine whether the symptoms have progressed
  from mild to severe.
• Later complications of sepsis include
• respiratory failure, pulmonary hypertension,
  cardiac failure, shock, renal failure, liver
  dysfunction, cerebral edema or thrombosis,
  adrenal hemorrhage and/or insufficiency, bone
  marrow dysfunction (neutropenia, thrombocytopenia
  ,anemia), and disseminated intravascular
  coagulopathy (DIC).

12

• BACTERIAL SEPSIS
• A variety of noninfectious conditions can occur
  together with neonatal infection or can make the
  diagnosis of infection more difficult.
• Respiratory distress syndrome (RDS) secondary to
  surfactant deficiency can coexist with bacterial
  pneumonia.
• Because bacterial sepsis can be rapidly
  progressive, the physician must be alert to the
  signs and symptoms of possible infection and
  initiate diagnostic evaluation and empirical
  therapy in a timely manner. The differential
  diagnosis of many of the signs and symptoms that
  suggest infection is extensive these
  noninfectious disorders must also be considered.

13

• SIRS
• The clinical manifestations of infection depend
  on the virulence of the infecting organism and
  the body's inflammatory response.
• The term systemic inflammatory response syndrome
  (SIRS) is most frequently used to describe this
  unique process of infection and the subsequent
  systemic response.
• In addition to infection, SIRS may result from
  trauma, hemorrhagic shock, other causes of
  ischemia, and pancreatitis.
• Patients with SIRS have a spectrum of clinical
  symptoms that represent progressive stages of
  the pathologic process. In adults, SIRS is
  defined by the presence of 2 or more of the
  following
• (1) fever or hypothermia, (2) tachycardia, (3)
  tachypnea, and (4) abnormal WBC count or an
  increase in immature forms.

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• TNF? increased vascular permeability
• TNF IL1? fever vasodilation
• Arachidonic acid metabolites ?fever, tachypnea,
  V/Q abnormalities, lactic acidosis
• Nitric oxide ?hypotention
• Myocardial depressant factors? myocardial
  depression

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• SIRS
• In neonates and pediatric patients, SIRS is
  manifested as
• temperature instability,
• respiratory dysfunction (altered gas exchange,
  hypoxemia, acute respiratory distress syndrome
  ARDS,
• cardiac dysfunction (tachycardia, delayed
  capillary refill, hypotension), and
• perfusion abnormalities (oliguria, metabolic
  acidosis).
• Increased vascular permeability results in
  capillary leak into peripheral tissues and the
  lungs, with resultant pulmonary and peripheral
  edema. DIC results in the more severely affected
  cases. The cascade of escalating tissue injury
  may lead to multisystem organ failure and death.

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Sepsis signs in body systems
17

• Oliguria
• Irregular respiration
• High pitch cry
• Full fontanel

• Jaundice
  
• Splenomegaly
• Pallor
• Petechia
• Purpura
• Bleeding
  

18

• FEVER
• Only about 50 of infected newborn infants have a
  temperature higher than 37.8 (axillary).
• Fever in newborn infants does not always signify
  infection it may be caused by increased ambient
  temperature, isolette or radiant warmer
  malfunction, dehydration, central nervous system
  (CNS) disorders, hyperthyroidism, familial
  dysautonomia, or ectodermal dysplasia.

19

• RASH
• Cutaneous manifestations of infection include
  impetigo,
• cellulitis, mastitis, omphalitis, and
  subcutaneous abscesses.
• Ecthyma gangrenosum is indicative of infection
  with
• Pseudomonas species.
• The presence of small salmon-pink papules
• suggests L. monocytogenes infection.
• A vesicular rash
• is consistent with herpesvirus infection.

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• Ecthyma gangrenosum

21
OMPHALITIS

• Omphalitis is a neonatal infection resulting from
• inadequate care of the umbilical cord, which
  continues to be a
• problem, particularly in developing countries.
  The umbilical
• stump is colonized by bacteria from the maternal
  genital tract
• and the environment. The necrotic tissue of the
• umbilical cord is an excellent medium for
  bacterial growth.
• Omphalitis may remain a localized infection or
  may spread to
• the abdominal wall, the peritoneum, the umbilical
  or portal
• vessels, or the liver.
• Abdominal wall cellulitis or necrotizing
  fasciitis
• with associated sepsis and a high mortality rate
  may develop in infants with omphalitis.
• Prompt diagnosis and treatment is necessary to
  avoid serious complications.

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• TETANUS
• Neonatal tetanus is a serious neonatal
• infection in developing countries. It results
  from unclean delivery and unhygienic management
  of the umbilical cord in an infant born to a
  mother who has not been immunized against
  tetanus.
• The surveillance case definition of neonatal
  tetanus requires the
• ability of a newborn to suck at birth and for the
  1st few days of
• life, followed by an inability to suck starting
  between 3 and 10
• days of age, difficulty swallowing, spasms,
  stiffness, seizures, and
• death.
• Bronchopneumonia, presumably resulting from
  aspiration,
• is a common complication and cause of death.
  Neonatal tetanus
• is a preventable disease. It can be prevented by
  immunizing
• mothers before or during pregnancy and by
  ensuring a clean
• delivery, sterile cutting of the umbilical cord,
  and proper cord
• care after birth.

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Pneumonia

• Pneumonia
• Signs of pneumonia on physical examination, such
  as dullness to percussion, change in breath
  sounds, and the presence of rales or rhonchi, are
  very difficult to appreciate in a neonate.
• X-rays of the chest may reveal new infiltrates or
  an effusion, but if the neonate has underlying
  RDS or BPD, it is very difficult to determine
  whether the radiographic changes represent a new
  process or worsening of the underlying disease.

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• Afebrile pneumonia syndrome

• Bacterial pneumonia

• The progression of neonatal pneumonia can be
  variable. Fulminant infection is most commonly
  associated with pyogenic organisms such as GBS.
  Onset may be during the 1st hours or days of
  life, with the infant often manifesting rapidly
  progressive circulatory collapse and respiratory
  failure. With early-onset pneumonia, the clinical
  course and radiographs of the chest may be
  indistinguishable from severe RDS.

• In contrast to the rapid progression of pneumonia
  when caused by pyogenic organisms, older infants
  with community-acquired infection often have an
  indolent course. The onset is usually preceded by
  upper respiratory tract symptoms or
  conjunctivitis. A nonproductive cough ensues, and
  the degree of respiratory compromise is variable.
  Fever is usually absent, and radiographic
  examination of the chest shows focal or diffuse
  interstitial pneumonitis. This infection has been
  called the "afebrile pneumonia syndrome" and is
  generally caused by C. trachomatis, CMV,
  Ureaplasma urealyticum, or one of the respiratory
  viruses. Although Pneumocystis carinii was
  implicated in the original description of this
  syndrome, its etiologic role is now in doubt,
  except in newborns infected with HIV.

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• SCREENING
• Sexually transmitted infections (STls)
• that infect a pregnant woman are of particular
  concern to the fetus and newborn because of the
  possibility for intrauterine or perinatal
  transmission.
• All pregnant women and their partners should be
  queried about a history of STls. Women should
  also be counseled about the need for timely
  diagnosis and therapy for infections during
  pregnancy.

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• SCREENING
• The CDC recommends the following screening tests
  and appropriate treatment of infected mothers
  (1) All pregnant women should be offered
  voluntary and confidential HIV testing at the 1st
  prenatal visit. For women at high risk of
  infection during pregnancy (multiple sexual
  partners or STls during pregnancy, intravenous
  drug use), repeat testing in the 3rd trimester is
  recommended. (2) A serologic test for syphilis
  should be performed on all pregnant women at the
  1st prenatal visit. Repeat screening early in the
  3rd trimester and again at delivery is
  recommended for women who had positive serology
  in the 1st trimester and for those at high risk
  for infection during pregnancy. (3) A serologic
  test for hepatitis B surface antigen (HBsAg)
  should be performed at the 1st prenatal visit and
  repeated late in pregnancy in those who are
  initially negative but at high risk for
  infection. (4) A maternal genital culture for C.
  trachomatis should be performed at the 1st
  prenatal visit. Young women (under 25 yr) and
  those at increased risk for infection (new or
  multiple partners during pregnancy) should be
  retested during the 3rd trimester. (5) A maternal
  genital culture for Neisseria gonorrhoeae should
  be performed at the 1st prenatal visit for women
  at risk and for those who live in areas with a
  high prevalence of gonorrhea. Repeat testing in
  the 3rd trimester is recommended for those at
  continued risk. (6) Evaluation for bacterial
  vaginosis should be considered at the 1st
  prenatal visit for asymptomatic women at high
  risk for preterm labor. (7) The CDC has
  recommended universal screening for rectovaginal
  GBS colonization of all pregnant women at 35-37
  wk gestation and a screening-based approach to
  selective intrapartum antibiotic prophylaxis
  against GBS.

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• SCREENING
• 1-HIV
• 2- Syphilis
• 3- hepatitis B
• 4- C. trachomatis
• 5- Neisseria gonorrhoea
• 6- Bacterial vaginosis
• 7- GBS

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• Diagnostic workup
• Bacterial infection is diagnosed by isolating the
  etiologic agent from a normally sterile body site
  (blood, CSF, urine, joint fluid).
• Obtaining 2 blood culture specimens by
  venipuncture from different sites avoids
  confusion caused by skin contamination and
  increases the likelihood of bacterial detection.
  (size of sample0.5-1cc)
• Samples should be obtained from an umbilical
  catheter only at the time of initial insertion.

29

• Although the total WBC count and differential and
  the ratio of immature to total neutrophils have
  limitations in sensitivity and specificity,
• an immature-to-total neutrophil ratio of gt0.2
  suggests
• bacterial infection.
• Neutropenia is more common than neutrophilia
• in severe neonatal sepsis, but neutropenia also
  occurs
• in association with maternal hypertension,
  preeclampsia, and intrauterine growth
  restriction.

30

• Thrombocytopenia is a nonspecific indicator of
  infection.
• Tests to demonstrate an inflammatory
• response include
• C-reactive protein, procalcitonin, haptoglobin,
• GCSF - fibrinogen,
• inflammatory cytokines (including IL-6,
  IL-8,IL10 and TNF-a),
• and cell surface markers like CD64.

31

• When the clinical findings suggest an acute
  infection and the site of infection is unclear,
  additional studies should be performed, including
  blood cultures, lumbar puncture, urine
  examination, and a chest x-ray.
• (Urine should be collected by catheterization or
  suprapubic aspiration)
• urine culture for bacteria can be omitted in
  suspected early-onset infections because
  hematogenous spread to the urinary tract is rare
  at this point.

32

• When the clinical findings suggest an acute
  infection, the
• examination of the buffy coat with Gram or
  methylene blue stain may demonstrate
  intracellular pathogens.
• Demonstration of bacteria and inflammatory cells
  in Gram-stained gastric aspirates on the 1st day
  of life may reflect maternal amnionitis, which is
  a risk factor for early-onset infection.
• Stains of endotracheal secretions in infants with
  early-onset pneumonia may demonstrate
  intracellular bacteria, and cultures may reveal
  either pathogens or upper respiratory tract
  flora.
• Careful examination of the placenta
• can be helpful in the diagnosis of both chronic
  and acute intrauterine Infections.

33

• Diagnostic evaluation is indicated for
  asymptomatic infants born to mothers with
  chorioamnionitis.
• The probability of neonatal infection correlates
  with the degree of prematurity and bacterial
  contamination of the amniotic fluid.
• In an asymptomatic term infant whose mother has
  chorioamnionitis, 2 blood cultures should be
  performed and presumptive treatment initiated.
• Maternal chorioamnionitis
• Fever leukocytosis uterine tenderness foul
  smelling amniotic fluid

34

• There is controversy over
• whether
• a lumbar puncture is necessary for all term
  infants with suspected
• early-onset sepsis.

35

• LP indications
• 1- positive blood culture
• 2- seizure
• 3- drowsiness/unconsciousness
• 4- pneumonia
• 5- apnea

36

• CSF normal values
• Normal, un infected infants from 0-4 wk of age
  may have
• elevated CSF protein levels of 85 45 mg/ dL,
• glucose of 45 10 mg/ dL,
• and
• elevated CSF leukocyte counts of 11 10 with the
  90th percentile being 22.
• During the neonatal period presence of RBC in CSF
  (up to 800 in first day and 50 in the end of
  neonatal period ) can be considered a normal
  finding.

37

• Gram stain of CSF yields a positive result in
  most patients with
• bacterial meningitis. The leukocyte count is
  usually elevated, with a predominance of
  neutrophils (gt70-90) the number is often gt1,000
  but may be lt100 in infants with neutropenia or
  early in the disease. Microorganisms are
  recovered from most patients who have not been
  pretreated with antibiotics. Bacteria have also
  been isolated from CSF that did not have an
  abnormal number of cells (lt25) or an abnormal
  protein level (lt200 mg/dL), thus underscoring the
  importance of performing a culture and Gram stain
  on all CSF specimens. Contamination of CSF by
  bacteremia after traumatic lumbar puncture may
  occur rarely.
• Culture negative meningitis
• may be seen with antibiotic pretreatment, brain
  abscess, or infection with Mycobacterium hominis,
  U. urealyticum, Bactericides fragilis,
  enterovirus, or HSV. Head ultrasonography or,
  more often, CT with contrast enhancementmay be
  helpful in diagnosing ventriculitis and brain
  abscess.

38

• Head circumference chart is mandatory in neonatal
  meningitis.
• All the neonates should be reexamined for CSF
  (analysis and culture) 3-4 days after starting
  the treatment, to find out whether the antibiotic
  treatment has been effective or not in
  eradication of infection. The antibiotic regimen
  may be changed accordingly if necessary.
• A final examination on CSF should be done as well
  near the end of therapy, before discontinuation
  of antibiotics.
• Therapy for meningitis is continued for a minimum
  of 2 weeks after sterilization of CSF cultures.
  This equates to 14 days of therapy for meningitis
  caused by gram positive organisms and a minimum
  of 21 days of therapy for meningitis caused by
  gram negative pathogens. (a)
• Treatment for candida meningitis is with
  amphotericin B and flucytosine for a period of 3
  to 6 weeks. (a)
• Dexamethasone is not used in neonatal meningitis.
• Complications of neonatal meningitis the acute
  complications include communicating and
  noncommunicating hydrocephalus, subdural
  effusion, ventriculitis, and blindness. (a)

39

• Immature/total
• The IT ratio has been investigated as an early
  predictor of sepsis. The maximal IT ratio in
  uninfected neonates is 0.16 in the first 24hrs,
  decreasing to 0.12 by 60 hrs. the upper limit of
  normal for neonates of 32 weeks gestation or less
  is slightly higher, at 0.2.
• Prolonged induction with oxytocin
• Stressful labor
• Prolonged crying

40

• IVIG
• Meta-analysis of studies of IVIG for the
  treatment of neonates with sepsis has shown a
  significant decrease in the mortality rate
  compared with standard therapies.
• Dose 200mg/kg/dose over 2hr
• GCSF
• 10 mcg/kg sc 1-3doses

41

• 1- CBC diff ESR CRP BC PT ABG UA
  UC SC
• CSF analysis culture ETT culture clot for
  electrolytes
• 2- CXR
• 3- antibiotics
• 4- IVIG if indicated
• 5- G- CSF if indicated
• 6- exchange transfusion if indicated
• 7- acyclovir if indicated
• 8- amphotericin B if indicated
• 9- hyperglycemia management
• 10- duration of antibiotic 10days if started for
  a positive BC or 7days after improvement if AB
  is started based on clinical indication.
• 11- chart head circumference in meningitis to
  detect hydrocephalus.
• 12- repeat LP after 3-4 days of AB treatment to
  decide whether the current antibiotics are
  appropriate or should be changed.
• 13- always make sure of normal CSF profile before
  discontinuing the AB therapy ( repeat LP near the
  end of treatment period).

42

• ESR
• First 2 weeks of life
• 3 age in days
• Beyond 2 weeks of life
• the maximum rate varies between 10 and 20 mm per
  hour.

43

• CRP
• Normal concentrations in neonates are 1mg/dl or
  lower.
• An increasing CRP value is usually detectable
  within 6 18 hours,
• and the peak CRP is seen at 8 60 hours after
  onset of the inflammatory process.

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• RSV Immunoglobulin
• RSV IVIG
• Palivizumab (IM)
• Indications
• Candidates for immunoprophylaxis include children
  with lung
• disease or who were born very prematurely.
  Children lt2 yr of age
• with chronic lung disease requiring supplemental
  oxygen or other
• medical therapy currently or within the 6 mo
  before the RSV
• season should receive prophylaxis for the 1st 2
  RSV seasons if
• they have severe lung disease, and only for the
  1st RSV season
• with less severe lung disease.
• Children lt2 yr of age with hemodynamically
• significant congenital heart disease (heart
  failure,
• cyanosis, pulmonary hypertension) are also
  candidates for this
• therapy. Infants born at lt28 wk of gestation
  should receive seasonal
• RSV prophylaxis up to 12 mo of age, and up to 6
  mo of
• age if they were born at 29-32 wk of gestation.
  Infants born
• between 32 and 35 wk of gestation should only
  receive prophylaxis

45

• Is antibiotic therapy mandatory for all neonates
  who receive intravenous fluid?

46

Wgt2000 gt7days Wgt2000 0-7days W1200-2000 gt7days W1200-2000 0-7days Wlt1200 0-4w route AB
50q6h 25q6h 50q8h 25q8h 50q8h 25q8h 50q12h 25q12h 50 q12h 25q12h IM IV Ampicillin
10q8h 10q12h 7.5q8h 7.5q12h 7.5q12h IM IV Amikacin
50q8h 50q12h 50q8h 50q12h 50q12h IM IV Cefotaxime
50q8h 50q8h 50q8h 50q12h 50q12h IM IV Ceftazidime
10q8h 10q8h 10q12h 10q12h 15q24h IV Vancomycin
15q12h 7.5q12h 7.5q12h 7.5q24h 7.5q48h IV PO metronidazole
20q8h 20q12h 20q12h 20q12h - IM IV Imipenem
20-30q12h - 10-20q24h - - IV Ciprofloxacin
20q6h 20q8h 20q8h 20q12h 20q12h IV Cephalothin
75q24h 50q24h 50q24h 50q24h 50q24h IM IV Ceftriaxone
47

• poor prognostic factors in GBS meningitis (f)
• 1- comatose or semicomatose state
• 2- poor perfusion
• 3- total peripheral leukocyte count lt5000
• 4- ANClt1000
• 5- CSF proteingt300mg/dl
• Seizure at presentation, the burden of bacteria
  observed on gram stain, and the severity of
  hypoglycorrhachia on the initial CSF sample were
  not predictive of outcome.

48

• Poor outcome in gram negative meningitis
• 1- CSF protein gt500mg/dl
• 2- CSF leukocyte countgt10,000
• 3- persistence of positive CSF cultures
• 4- presence and persistence of ?IL-1a and TNF
• poor outcome in E-coli meningitis
• The presence and persistence of K1 capsular
  polysaccharide Ag and the concentration of
  endotoxin in the CSF