1. Neonatal Infections Dr. Mohamed Haseen Basha Assistant professor (Pediatrics) Faculty of Medicine Al Maarefa College of Science and Technology

2. Sepsis Neonatal sepsis is a clinical syndrome characterized by signs and symptoms of infection with or without accompanying bacteremia in the first month of life. It encompasses various systemic infections of the newborn such as septicemia, meningitis, pneumonia, arthritis, osteomyelitis, and urinary tract infections. Superficial infections like conjunctivitis and oral thrush are not usually included under neonatal sepsis.

3. Sepsis Sepsis in the newborn is defined when it meets the following criteria:(European Consensus statement 2010). 1)Any two clinical signs Temperature instability - Core temperature greater than 38.5°C or less than 36°C. Cardiovascular instability - Tachycardia (heart rate 180 beats/min) - Bradycardia (heart rate 100 beats/min) - Rhythm disturbances - Reduced blood pressure (systolic BP less than 65 mm Hg in first week and less than 75 mm Hg between 1 week and 1 month) - Mottled skin and impaired peripheral perfusion - Decreased urine output (less than 1 mL/kg/hour)

4. Respiratory instability - Apneic episodes - Respiratory rate greater than 2 SD (> 50 beats/ min in first week and 40 beats/min between 1 week and 1 month) - Increased oxygen need - Ventilation for acute process for causes other than neuromuscular or general anesthesia Gastrointestinal - Feed intolerance, abdominal distension, poor sucking Petechial rash or sclerema Nonspecific - lethargy irritability, hypotonia

5. 2) Any two laboratory signs Abnormal leukocyte count (> 20,000 × 109/L or less than 4000 × 109/L) Immature to total neutrophil (I/T) ratio (> 0.2) Platelet count less than 100,000 × 109/L C-reactive protein (CRP) greater than 15 mg/L Procalcitonin (PCT) greater than 2 ng/mL Metabolic acidosis; base excess (BE) greater than –10 Blood sugar greater than 180 mg/dL or less than 45 mg/dL confirmed at least two times on age appropriate infusions 3) in the presence of or as a result of suspect or proven infection Proven (positive culture or microscopy or polymerase chain reaction) Suspected (clinical syndrome like perforation of viscus, petechial or purpuric rash, chest X-ray consistent with pneumonia or white cells in normally sterile fluid).

6. Types of Sepsis  Early onset neonatal sepsis (EONS) - onset before 72 hours of life. Risk Factors for Early Onset Neonatal Sepsis Maternal fever (> 37.8°C) in the period from onset of labor to delivery Prolonged rupture of membranes (PROM) for more than 18 hours Spontaneous preterm (< 37 weeks) onset of labor (SPTOL) Preterm (< 37 weeks) premature rupture of membranes (pPROM) Maternal sepsis, urinary tract infection (UTI) or diarrhea within 7 days to the date of delivery Clinical chorioamnionitis in the mother.

7.  Late onset neonatal sepsis (EONS) - onset after 72 hours of life. Low birth weight Babies admitted to NICU and undergoing invasive procedures (ventilation, parenteral nutrition through central catheters, not feeding orally, admission to inadequately staffed units, poor compliance to unit policy on prevention of infections).

8. Etiological Agents Bacteria Common pathogens are Klebsiella, Staphylococcus, Escherichia coli and Pseudomonas. In the developed nations where Group B streptococci, coagulase negative staphylococci (CONS) and fungi dominate. Fungi Fungal infections are more common in babies weighing less than 1,500 g and are likely to be associated in babies with parenteral nutrition, central catheters, abdominal surgeries, broad-spectrum antibiotics or steroids. Both Candida albicans and non-albicans are isolated.

9. Viruses Herpes infection should be considered in a baby with sepsis like syndrome (presenting after 1 week of life) if markers of bacterial infection are negative. Other viral infections that neonates can be exposed to include chickenpox, vertically transmitted rubella and cytomegalovirus infections. Parasites Common parasitic infections that neonates can be exposed include toxoplasmosis, malaria and syphilis.

10. Clinical Features Systemic Infections Clinical features of systemic sepsis can be varied and nonspecific and have been described above under definition of sepsis. In neonates with systemic signs of sepsis, presence of convulsions, neck retraction or bulging fontanel must raise the possibility of meningitis. Neonates with septic arthritis or osteomyelitis may not have systemic symptoms and may present with painful limb movement and localized swelling with signs of inflammation. Localized Infections Infections of the eye (purulent discharge), Umbilicus (pus discharge and/or erythema of surrounding skin) Pustules

11. Initial Signs and Symptoms of Infection in Newborn Infants GENERAL Fever, temperature instability “Not doing well” Poor feeding Edema CARDIOVASCULAR SYSTEM Pallor; mottling; cold, clammy skin Tachycardia Hypotension Bradycardia GASTROINTESTINAL SYSTEM Abdominal distention Vomiting Diarrhea Hepatomegaly HEMATOLOGIC SYSTEM Jaundice Splenomegaly Pallor Petechiae, purpura Bleeding RESPIRATORY SYSTEM Apnea, dyspnea Tachypnea, retractions Flaring, grunting Cyanosis CENTRAL NERVOUS SYSTEM Irritability, lethargy Tremors, seizures Hyporeflexia, hypotonia Abnormal Moro reflex Irregular respirations Full fontanel High-pitched cry RENAL SYSTEM Oliguria

12. Diagnosis Hematological Indices Total leukocyte count (TLC) : has to be interpreted against age-specific normative data. The values as high as 24,000 and as low as 5,000 may be normal and do not suggest infection. Immature to total neutrophil (I/T) ratio (> 0.2) and absolute neutrophil counts have higher specificity, but are often normal early in the course of infection. Platelet count: A decreased platelet count is usually a late sign and is very nonspecific. ESR : may be elevated but usually not until well into the illness and therefore, is used rather infrequently in the initial workup.

13. sepsis screen ComponentsAbnormal value Total leukocyte count<5000/mm3 Absolute neutrophil countLow counts as per Manroe chart for term and Mouzinho’s chart for VLBW infants Immature/total neutrophil>0.2 Micro-ESR>15 mm in 1st hour C reactive protein (CRP)>1 mg/dl (ESR, erythrocyte sedimentation rate)

14. Blood Culture Is the gold standard. The value of cultures lies mostly in guiding antibiotic changes in treatment failures and planning antibiotic policy for empiric therapy in that population. Urine Culture It should be done in infants with failure to thrive, prolonged jaundice and fever since these could be features of UTI. In all infants with obstructive uropathy who are ill, urine cultures should be done.

15. Gram's stain of various fluids Gram-stained smears and cultures of amniotic fluid or of material obtained by gastric aspiration are often performed. C-Reactive Protein C-reactive protein has value in ruling out infection. Once started on antibiotics on clinical suspicion, two negative CRPs 24 hours apart after the baby is asymptomatic gives 99% confidence to stop antibiotics. in settings of EONS where antibiotics are started empirically, CRP at 48–72 hours helps in differentiating infected sick infants from those symptomatic due to noninfectious causes. A positive CRP is usually a value greater than 10 mg/L.

16. Cerebrospinal Fluid Examination Meningitis requires modifications in the choice of antibiotics, dose and duration, and hence cerebrospinal fluid examination must be performed in all symptomatic neonates or CRP/ blood culture positive neonates on antibiotics. Cerebrospinal fluid cytology of greater than 30 cells (more than 50% polymorphs), with raised protein (> 100 mg/dL) and/or sugar less than 30 mg/dL may suggest meningitis. Normal cerebrospinal fluid examination in neonates CSF ComponentsNormal range Cells/mm 3 8 (0-30 cells) PMN (%)60% CSF protein (mg/dL)90 (20-170) CSF glucose (mg/dL)52 (34-119) CSF/ blood glucose (%)51 (44-248) (PMN, polymorphonuclear cells; CSF, cerebrospinal fluid)

17. Management Supportive: Thermo-neutral environment taking care to avoid hypo/hyperthermia. Maintain Oxygen saturation. Mechanical ventilation if necessary. If hemodynamically unstable, intravenous fluids should be administered. Monitored for hypo/hyperglycemia. Volume expansion with crystalloids/colloids Inotropes are essential to maintain normal tissue perfusion and BP. Packed red cells and fresh frozen plasma might have to be used in the event of anemia or bleeding diathesis.

18. Antimicrobial therapy: The choice of antibiotics depends on the prevailing flora in the given unit and their antimicrobial sensitivity. Decision to start antibiotics is based upon clinical features and/ or a positive septic screen. However duration of antibiotic therapy is dependent upon the presence of a positive blood culture and meningitis

19. Indications for starting antibiotics: The indications for starting antibiotics in neonates at risk of EOS include: Presence of >3 risk factors for early onset sepsis Presence of foul smelling liquor Presence of 2 antenatal risk factor(s) and a positive septic screen and Strong clinical suspicion of sepsis. The indications for starting antibiotics in LOS include: Positive septic screen and/or Strong clinical suspicion of sepsis.

20. Choice of antibiotics: Empirical antibiotic therapy should be unit-specific and determined by the prevalent spectrum of etiological agents and their antibiotic sensitivity pattern. Antibiotics once started should be modified according to the sensitivity reports. Empirical choice of antibiotics for treatment of neonatal sepsis Clinical situationSepticemia & PneumoniaMeningitis FIRST LINE Community-acquired (Resistant strains unlikely) Penicillin or Ampicillin and Gentamicin Add Cefotaxime SECOND LINE Hospital-acquired and Some strains are likely to be resistant Ampicillin or Cloxacillin and Gentamicin or Amikacin Add Cefotaxime THIRD LINE Hospital-acquired sepsis (Most strains are Likely to be resistant) Cefotaxime or Piperacillin-Tazobactam or Ciprofloxacin And Amikacin; Same (Avoid Cipro) Consider Vancomycin if MRSA is suspected.

21. DiagnosisDuration Meningitis (with or without positive blood/CSF culture)21 days Blood culture positive but no meningitis14 days Culture negative, sepsis screen positive and clinical course consistent with sepsis 7-10 days Culture and sepsis screen negative, but clinical course compatible with sepsis 5-7 days

22. Reserve antibiotics: Newer antibiotics like aztreonam, meropenem and imipenem are also now available in the market. Aztreonam has excellent activity against gram-negative organisms while meropenem is effective against most bacterial pathogens except methicillin resistant staphylococcus aureus (MRSA) and enterococcus. Empirical use of these antibiotics should be avoided; they should be reserved for situations where sensitivity of the isolated organism warrants its use.

23. Adjunct Therapies in Treatment of Sepsis Intravenous Immunoglobulins Granulocyte Colony Stimulating Factors or Granulocyte Monocyte Colony Stimulating Factors When used in severely neutropenic neonates with proven sepsis, a survival benefit was demonstrated in some studies. Single-volume Exchange Transfusion A few studies have demonstrated good benefit in neonates with advanced sepsis—sclerema, persistent hypotension, coagulopathy and metabolic acidosis. Pentoxyphylline and recombinant human activated protein C

24. Complications Sepsis remains the leading cause of neonatal mortality world over. In the acute phase, hypoglycemia, coagulopathy, organ failures like pneumonia, pulmonary hypertension, shock due to myocardial dysfunction and capillary leaks, renal failure and cholestatic jaundice Meningitis can result in complications such as hydrocephalus and developmental delay.

25. Prevention Sepsis in the neonate can be prevented by Promoting exclusive breastfeeding Simple hand hygiene at the household level By preventing applications on the umbilical cord during the first few days of life. Hospital acquired infections can be minimized by Good hand hygiene Promoting provision of breast milk to sick LBW neonates Good adherence to asepsis protocols Strict antibiotic policy that limits its use when required.

26. Administration of penicillin or ampicillin 4 hr prior to parturition. Successfully reduces rates of EOS caused by GBS but No effect on LOS GBS. Fluconazole prophylaxis Administration of weight-based dosing to neonates weighing less than 1,500 g. Most beneficial in NICUs with high baseline rates of invasive candidiasis.