1.Recent Advances inNeonatal SepticemiaDr. Hemraj Soni MBBS, DCH, DNB(Paediatrics) Consultant Pediatrician & Neonatologist, Imperial Hospital and Research Centre Jaipur

2. DefinitionNeonatal septicemia is a clinical syndrome ofsystemic illness accompanied by bacteremiaoccurring in the first month of life. 3. Includes -meningitis, pneumonia, arthritis, osteomyelitis, andurinary tract infections.Superficial infections like conjunctivitis and oralthrush are not included under neonatal sepsis. 4. Epidemiology About 1.6 million deaths every year worldwide. Responsible for about 30-50% of the total neonatal deathsin developing countries Up to 20% of neonates develop sepsis andapproximately 1% die of sepsis related causes. 5. According to NNPD data (2002-03) , The commonestprimary cause of death was sepsis (37.6 %), followed byprematurity and related complications in 19.3 % andbirth asphyxia in 18.5 6. Types of NNS1. Early onset sepsis (EOS)often presents as a fulminant, multi-system illness within 72 hours of delivery (or in the first 7 days of life according to Fanaroff ) It is mainly due to bacteria acquired before and during delivery 7. 2. Late onset sepsis (LOS) can present as either insidious or acute onset, focalinfection or meningitis. from 3 to 90 days of life due to bacteria acquired after delivery (nosocomial orcommunity sources) 8. 3. Very-late-onset sepsis- after 3 months of life affects premature infants VLBW / ELBW in the NICU. Often caused by Candida species or by commensalorganisms such as coagulase-negative staphylococci(CONS). (Fanaroff and martins text book) 9. LATE ONSET (7 DAYS TO 3EARLY ONSET (3 MONTHS) MONTHS)Intrapartum complications Often presentUsually absent VariesVertical; organism often acquired from Vertical or through postnatalTransmissionUsually postnatal environmentmothers genital tract environmentFulminant course, multisystemInsidious or acute, focal infection,Clinical manifestations Insidiousinvolvement, pneumonia commonmeningitis commonCase-fatality rate5%20% 5% Low 10. Risc Factors-Early onset sepsis 1. Low birth weight ( 18 hours. 5. Single unclean or > 3 sterile vaginal examination(s) during labor 6. Prolonged labor (sum of 1st and 2nd stage of labor > 24 hrs) 7. Perinatal asphyxia (Apgar score - low birth weight, -prematurity, - admission in intensive care unit, - mechanical ventilation, - invasive procedures, - administration of parenteral fluids, - use of stock solutions.Community-acquired - poor hygiene, - poor cord care, -bottle-feeding, and prelacteal feeds. 12. Micro-organisms in EOS GBS leading cause of EOS in term infants. gram negative enteric bacilli --the leading cause of EOS inpreterm infantsE. Coli, Klebsiella, Pseudomonas, Enterobacter. Less common-Listeria, Citrobacter, Staphylococcus, Enterococcus 13. Micro-organisms in LOS CONS- most common NICHD, Pediatrics 2002; 110 -> - 50%- CONS -22% - other G+ organism (Staph aureus, Enterococcus, GBS) -18%- gram negative ( E.coli, klebsiella, pseudomonas )-12%- Fungal (Candida albicans , C. parapsilosis) 14. Presentation-Earliest signs: Often subtle and non-specific Hypothermia or fever (less common) Lethargy, poor cry, refusal to suck Poor perfusion, prolonged capillary refill time Hypotonia, absent neonatal reflexes Brady/tachycardia Respiratory distress, apnoea and gasping respiration Hypo/hyperglycaemia Metabolic acidosis 15. Specific features related to varioussystemsCNS : Bulging anterior fontanelle, vacant stare, high-pitched cry, excess irritability, stupor/coma, seizures, neckretraction.Cardiac: Hypotension, poor perfusion, shockGastrointestinal:Feed intolerance -vomiting, abdominal distension, paralytic ileus, necrotizingenterocolitis (NEC). 16. Hepatic: Hepatomegaly, direct hyperbilirubinaemia (especially with UTI)Renal: Acute renal failureHaematological: Bleeding, petechiae, purpuraSkin changes: Multiple pustules, abscess, sclerema, mottling, umbilical redness and discharge 17. Perinatal infection risk score. 18. Suggested Intervention 19. Diagnosis Modalities- Blood culture Gold Standard Sepsis screen Radiology Lumber Puncture Urine R/M, Culture RBS, Arterial blood gases, PT/ aPTT Advanced Diagnostic Methods 20. Advanced Diagnostic Methods CRP Procalcitonin Cytokine measurement IL-6, IL-8, IL-10, IL- 1b,G-CSF, TNF-, IgM Polymerase chain reaction (PCR) DNA microarray technology 21. Immunoassay Procalcitonin CD64 Mannose-binding lectin Amniotic fluid MR score ApoSAA Gene expression profiling 22. Blood culture Gold standard Sould be performed in all cases of suspected sepsis prior tostarting antibiotics A positive blood culture with sensitivity of the isolatedorganism is the best guide to antimicrobial therapy cultures should be collected only from a fresh veni-puncture site. 23. Blood culture contd. The volume of blood - 0.5 ml venous blood in a pediatric blood culture bottle or1 ml in an adult blood culture bottle If catheter-associated sepsis is suspected, a culture shouldbe obtained through the catheter as well as through aperipheral vein 24. Sepsis screenConsists of 5 items: 1. C-reactive protein (CRP), 2. Total leukocyte count 3. Absolute neutrophil count (ANC) 4. Immature to total neutrophil ratio(ITR) 5. Micro-erythrocyte sedimentation rate (-ESR). 25. CRP Non specific marker of inflammation and tissue necrosis Normal concentrations in neonates are 1 mg/dL or lower. Detectable increased CRP value-within 6 to 18 hours,Peak CRP -- 8 to 60 hours after onset Half-life is 5 to 7 hours. Decreases promptly in the presence of appropriate therapy 26. Serial CRP at 12-hour intervals -- sensitivity of CRP indetecting sepsis Quantitative CRP assayed by nephelometry is superior toCRP by ELISA and semi-quantitative CRP by a latexagglutination kit. Cut-off value for quantitative assay is 1 mg/dl. 27. Limitations- Infants with onset of infection in the first 12 hours oflife and with GBS infection may not have an elevatedCRP Noninfectious processes, including meconiumaspiration pneumonitis, asphyxia can have an elevatedCRP up to 10 times the normal concentration. CRP has a low positive predictive value and should notbe used alone to diagnose sepsis. 28. IT Ratio= Immature neutrophils (bandforms, metamyelocytes, myelocytes) Mature + immature neutrophils early predictor of sepsis. N value = 0.16 in first 24 hours, decreasing to 0.12 by 60hours. Upper limit > 0.2. Limitation- many noninfectious processes, includingprolonged induction with oxytocin, stressful labor, andeven prolonged crying, are associated with increased I:Tratios. 29. Micro-ESR : Positive Value (mm in first hour) > 3+ age in days (first week of life)> 10 thereafter Limitation- increased in noninfectious (anemia, hyperglobulinemia) -Values vary inversely with the hematocrit - superficial infections and -noninfectious processes, including asphyxia, aspiration pneumonia, and respiratory distress syndrome. 30. Presence of two abnormal parameters in a screen isassociated with a sensitivity of 93-100%, specificity of83%, positive and negative predictive values of 27% and100% respectively in detecting sepsis.Polinski C. The value of white blood cell count and differential in the prediction of neonatalsepsis. Neonatal Netw 1996;15:13-23Da Silva O, Ohlsson A, Kenyon C. Accuracy of leukocyte indices and C-reactive protein fordiagnosis of neonatal sepsis: a critical review. Pediatr Infect Dis J 1995;14:362-6 31. A practical sepsis screen 32. Reference ranges for total neutrophil values in very low birthweight neonatesfrom birth to 60 hours of life (A) and 61 hours to 28 days of life (B).(From Mouzinho A et al:Revised reference ranges for circulatingneutrophils in very-low-birth-weight neonates. Pediatrics 94:78, 199 33. The total neutrophil count reference range in the first 60 hours of life for a group of term neonates.Points represent single values; numbers represent the number of values at the same point;(From Manroe BL: The neonatal blood count in health and disease I: Reference values forneutrophilic cells. J Pediatr 95:91, 1979.) 34. Lumber Puncture Indication : In EOS - a positive blood culture or clinical pictureconsistent with septicemia. In late onset sepsis, LP should be done in all infants priorto starting antibiotics 35. Interpretation of CSF findings CSF - -> 32 WBC/mm3> 60% PMN glucose < 50% - 75% of serum protein > 150 mg/dlorganisms on gram stain 36. Radiology: Chest x-ray Abdominal x-ray Neurosonogram and computed tomography (CT scan) 37. Urine analysis Indication for urine analysis- Neonates with LOS-VLBW neonates- urinary tract anomalies- bladder catheterization- visibly turbid urine Supra pubic aspiration is the ideal method 38. Role of Procalcitonin ProCT becomes detectable within 2 to 4 hours after atriggering event and peaks by 12 to 24 hours. ProCT secretion parallels -closely the severity of theinflammatory insult, with higher levels associated withmore severe disease and declining levels with resolution ofillness. In the absence of an ongoing stimulus, ProCT is eliminatedwith a half-life of 24 to 35 hours, making it suitable forserial monitoring. 39. ProCT level of >2.0 ng/mL ---predicts sepsis and>10 ng/mL ---septic shock.>20 ng/mL --- guarded prognosis. higher the ProCT level -----worse the prognosis. When sepsis has been successfully treated, ProCT levelsshould fall with a half-life of 24 to 35 hours. 40. Identification of secondary septic events elevated noninfectious ProCT level, ProCT levels shouldfall at a predictable pace in the absence of secondaryinfection. Limitation - ProCT levels that are elevated innoninfectious conditions like after ceseareansection, resuscitation at birth, perinatal steroid exposureBUT should start falling within 48 hours . Persistent highlevels or secondary peaks suggest secondary infection. 41. The results show that the serum procalcitonin levelsseem to be significantly increased in proven sepsisand decrease dramatically in all types of sepsis afterappropriate treatment.Procalcitonin as a Marker of Neonatal SepsisIranian Journal of Pediatrics, Volume 19 (Number 2), June 2009, Pages:117122 42. Polymerase Chain Reaction(PCR) Under investigation for bacterial and fungalinfection amplification of 16S rRNA, a gene universally present in bacteria but absent in humans Results in 9 h of sample acquisition 43. PCR Sensitivity 96% Specificity 99.4% positive predictive value 88.9% negative predictive value 99.8% 44. Bio-markers Cytokines IL-1, IL-6, IL-8, and TNFmajor mediators of the systemic response to infection Studies have shown that combined use of IL-8 and CRPas part of the workup for bacterial infection reducesunnecessary antibiotic treatment Surface neutrophil CD11 has been shown to be an excellent marker of early infection that correlates well with CRP but peaks earlier. 45. Management Supportive Specific Antibiotics Exchange transfusion Intravenous immunoglobulins (IVIG) Myeloid colony stimulating factor (GM-CSF & G-CSF) Probiotics Lactoferrin Glutamine Recombinant human protein C 46. Indications for starting antibioticsIndications in neonates at risk of EOS include anyone of the following: presence of >3 risk factors for early onset sepsis presence of foul smelling liquor presence of 2 antenatal risk factor and a positive septicscreen and strong clinical suspicion of sepsis. 47. Indications for starting antibiotics in LOS include: positive septic screen and/or strong clinical suspicion of sepsis. 48. Starting empirical antibioticsPolicy for community acquired sepsis Ampicillin + Gentamicin/Amikacin (empirical) Staphylococcus : Cloxacillin + Gentamycin/Amikacin Meningitis: Add Cefotaxime 49. Policy for nosocomial sepsis It is not possible to suggest a single antibiotic policy for use in all newborn units. Every newborn unit must have its own antibiotic policy based on the local sensitivity patterns and the profile of pathogens. Preferably choose Penicillin + Aminoglycoside BE Aware--Cephalosporins rapidly induce the production of extended spectrum -lactamases (ESBL), cephalosporinases and fungal colonization. 50. Upgradation of empirical antibiotics No Expected clinical improvement with ongoing lineof antibiotics. At least 48-72 hours period of observation should beallowed before declaring Failure. Current evidence does not support the use of serialquantitative CRP as a guide for deciding whether ornot antibiotics should be upgraded empirically 51. Antibiotic therapy once culture report isavailable??whether the positive blood culture is a contaminant. --growth in only one bottle (if two had been sent), ------growth of non-pathogen organism-- onset of growth beyond 96 hours in the absence of ahistory of prior exposure of antibiotics in the previous72 hours . 52. Rationale use of antibiotics: If the organism is sensitive to an antibiotic with anarrower spectrum or lower cost, therapy must bechanged to such an antibiotic. If possible, a single sensitive antibiotic must beused, the exception being Pseudomonas for which twosensitive antibiotics must be used. 53. ORGANISM AND DRUGS GBS ampicillin or penicillin E .coli cefotaxime or ampicillin + gentamycin CONS Vancomycin Klebsiella - cefotaxime or meropenam +gentamycin Enterococcus ampicillin or vancomycin + gentamycin Listeria ampicillin + gentamycin Psudomonas ceftazidime or piperacillin-tazobactum+ gentamycin Staph. Aureas nafcillin MRSA - Vancomycin 54. Duration of antibiotics Culture positive sepsis: 10-14 days. 55. Culture negative sepsis:If the blood culture is reported sterile at 48 hours, thefollowing guidelines must be adhered to: Asymptomatic neonate at risk of EOS: stop antibiotics Suspected EOS or LOS and the neonate becomes completelyasymptomatic over time: stop antibiotics Suspected EOS or LOS and the neonate have not improvedor have worsened: upgrade antibiotics as per the empiricantibiotic policy. Simultaneously, alternative explanations for the clinicalsigns must be actively sought for. 56. Meningitis(Culture, Gm stain+, CSF) : 21-day course of parenteral antibiotics that cross uninflamed meninges. Anti-meningitic doses Only antibiotics with a proven in vitro sensitivity. 57. Quick review of Antibiotics-- 58. Exchange transfusion Sadana et al. have evaluated the role of double volumeexchange transfusion in septic neonates with sclerema anddemonstrated a 50% reduction in sepsis relatedmortality in the treated group. 59. Intravenous Immunoglobulin (IVIG): Endogenous immunoglobulin synthesis does not begin until 24 weeks of life: thus, young infants rely on in-utero maternally acquired immunoglobulins for protection against systemic infection. The placental transfer of these protective antibodies, however, does not occur until week 32 of gestation and post-natally IgG levels decrease due to reduced production in newborns Therefore, investigators have proposed the use ofintravenous immunoglobulins (IVIG) to prevent andtreat neonatal sepsis in this population. 60. Meta-analyses of trials of intravenous immune globulinfor suspected or proven neonatal sepsis suggest areduced rate of death from any cause, but the trials havebeen small and have varied in quality. The INIS(International Neonatal ImmunotherapyStudy)Collaborative Group*(N Engl J Med 2011;365:1201-11) At 113 hospitals in nine countries, enrolled 3493 infants( from2001 to 2007) receiving antibiotics for suspected or provenserious infection and randomly assigned them to receive twoinfusions of either polyvalent IgG immune globulin or matchingplacebo 48 hours apart. There was no significant between-group difference in the rates ofthe primary outcome in the rates of secondaryoutcomes, including the incidence of subsequent sepsisepisodes. In follow-up of 2-year-old infants, there were nosignificant differences in the rates of major or nonmajordisability or of adverse events. 61. Therapy with intravenous immune globulin had no effect on the outcomes of suspected or proven neonatal sepsis. The INIS(International Neonatal Immunotherapy Study)Collaborative Group*(N Engl J Med 2011;365:1201-11) 62. Myeloid colony stimulating factor (GM-CSF & G-CSF): These are cytokines that stimulate the production of bone marrowneutrophils. As premature infants -- limited number and function of neutrophils investigators have evaluated the use of these factors in the preventionand adjuvant treatment of neonatal sepsis. A systematic review(Combination of five studies ) examined the effectof adjuvant G-CSF or GM-CSF on 14 and 28-day overall mortality inneonates with suspected or documented sepsis. Analysis showed areduction in all-cause mortality in treated infants . 63. Colony stimulating factors are a safe treatmentmodality in older patients; however, the currentevidence suggests a multi-center randomizedclinical trial demonstrating clinical efficacy of CSF is needed prior to universal recommendation of this therapy in the nursery. 64. Probiotics Lactobacillus and Bi dobacterium sp., the mostfrequently used probiotic supplements, live microbial species that under physiologicconditions colonize the gastrointestinal tract ofhealthy individuals. Investigators have hypothesized that probioticsupplements may protect high-risk infants in thenursery from developing necrotizing enterocolitis(NEC) and sepsis. 65. A randomized controlled trial in VLBW infants of amixed probiotic supplement(Lactobacillus acidophilusand Bifidobacterium infantis) to prevent NEC andmortality was conducted. The probiotic preparationwas given twice daily to breast-fed infants until NICUdischarge. Although the study was not powered to detectdifferences in sepsis rates, culture-proven systemicinfection was lower among infants in the study groupthan controls 66. Honeycutt et al. - They evaluated the use of one capsule of Lactobacillusrhamnosus strain GG (10 109 cells/capsule)administered daily for the duration of hospitalizationin the reduction of the incidence of nosocomialinfections; -the product did not reduce the incidence ofnosocomial infections Lactobacillus GG sepsis has been documented in theimmunocompromised host 67. Therefore until larger randomized controlled-trials areconducted, the routine use of probiotics to preventinvasive bacterial and fungal infections in neonates isnot recommended. 68. Lactoferrin Lactoferrin is an iron-binding glycoprotein. It hasbroad-spectrum antimicrobial activity. A multicenter, randomized, placebo controlled trialinvolving VLBW infants who received daily orallyadministered Bovine lactoferrin alone (n=99, dose =100 mg/day), in combination with Lactobacillus GG(n=99, dose = 106 CFU/day), or placebo (n=104) for 3045 days show that the incidence of culture-provensepsis was lower in the groups that receivedlactoferrin. Final and complete results from this study arepending. 69. Glutamine Glutamine -- most abundant amino acid in plasma andhuman milk. Studies in immunocompromised adults have suggestedthat intravenous parenteral nutrition supplemented withglutamine decreases the risk of sepsis and mortality. A recently published Cochrane systematic review examinedthe effect of enteral or parenteral glutaminesupplementation on the incidence of culture-proveninvasive infection from 5 clinical trials (n= 2,240). Themeta-analysis did not reveal a statistically significantdifference between the glutamine supplemented andcontrol groups (RR 1.01; 95% CI 0.91, 1.13). 70. Recombinant human protein C Activated protein C is an endogenous compound thatpromotes anticoagulation and modulates theinflammatory response. During severe systemic infections, the levels and degree ofprotein C activation are decreased; In one study, decreased activity of activated protein C wasassociated with increase mortality among neonates withsepsis. The largest randomized controlled-trial of recombinantactivated protein C in children (n=477);approximately 6%young infants) failed to show an improvement in theclinical score used at the primary outcome and in the 28-day mortality when the drug was compared to placebo 71. Immunotherapy used as an adjuvant for the prevention and treatment of neonatal sepsis holds promise; however, for most of these therapies tested to date, clinical trials have failed to demonstrate a significant effect in neonatal outcomes. Some of these studies are limited by the study design, sample size, and outcome evaluation and therefore, trials specifically designed towards the neonatal population and appropriately powered to detect treatment differences are necessary prior to universal recommendation of these therapies in the nursery.