Recent Advances inNeonatal Septicemia Dr. Hemraj Soni MBBS, DCH, DNB(Paediatrics) Consultant Pediatrician & Neonatologist, Imperial Hospital and Research Centre Jaipur
Definition Neonatal septicemia is a clinical syndrome of systemic illness accompanied by bacteremia occurring in the first month of life.
Includes -meningitis, pneumonia, arthritis, osteomyelitis, andurinary tract infections.Superficial infections like conjunctivitis and oralthrush are not included under neonatal sepsis.
Epidemiology About 1.6 million deaths every year worldwide. Responsible for about 30-50% of the total neonatal deaths in developing countries Up to 20% of neonates develop sepsis and approximately 1% die of sepsis related causes.
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
Types of NNS 1. 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
2. Late onset sepsis (LOS) can present as either insidious or acute onset, focal infection or meningitis. from 3 to 90 days of life due to bacteria acquired after delivery (nosocomial or community sources)
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 commensal organisms such as coagulase-negative staphylococci (CONS). (Fanaroff and martins text book)
LATE ONSET (≥7 DAYS TO 3 EARLY ONSET (<7 DAYS) VERY LATE ONSET (>3 MONTHS) MONTHS)Intrapartum complications Often present Usually absent Varies Vertical; organism often acquired from Vertical or through postnatalTransmission Usually postnatal environment mother’s genital tract environment Fulminant course, multisystem Insidious or acute, focal infection,Clinical manifestations Insidious involvement, pneumonia common meningitis commonCase-fatality rate 5%–20% 5% Low
Risc Factors-Early onset sepsis 1. Low birth weight (<2500 grams) or prematurity 2. Febrile illness in the mother with evidence of bacterial infection within 2 weeks prior to delivery. 3. Foul smelling and/or meconium stained liquor. 4. Rupture of membranes > 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 <4 at 1 minute)
Late onset sepsisNosocomial (hospital-acquired) -> - 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.
Micro-organisms in EOS GBS – leading cause of EOS in term infants. gram negative enteric bacilli --the leading cause of EOS in preterm infants E. Coli, Klebsiella, Pseudomonas, Enterobacter. Less common- Listeria, Citrobacter, Staphylococcus, Enterococcus
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)
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
Specific features related to various systemsCNS : 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).
Hepatic: Hepatomegaly, direct hyperbilirubinaemia (especially with UTI)Renal: Acute renal failureHaematological: Bleeding, petechiae, purpuraSkin changes: Multiple pustules, abscess, sclerema, mottling, umbilical redness and discharge
Blood culture Gold standard Sould be performed in all cases of suspected sepsis prior to starting antibiotics A positive blood culture with sensitivity of the isolated organism is the best guide to antimicrobial therapy cultures should be collected only from a fresh veni- puncture site.
Blood culture contd. The volume of blood - 0.5 ml venous blood in a pediatric blood culture bottle or 1 ml in an adult blood culture bottle If catheter-associated sepsis is suspected, a culture should be obtained through the catheter as well as through a peripheral vein
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 (μ-ESR).
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
Serial CRP at 12-hour intervals -- sensitivity of CRP in detecting sepsis Quantitative CRP assayed by nephelometry is superior to CRP by ELISA and semi-quantitative CRP by a latex agglutination kit. Cut-off value for quantitative assay is 1 mg/dl.
Limitations- Infants with onset of infection in the first 12 hours of life and with GBS infection may not have an elevated CRP Noninfectious processes, including meconium aspiration pneumonitis, asphyxia can have an elevated CRP up to 10 times the normal concentration. CRP has a low positive predictive value and should not be used alone to diagnose sepsis.
IT Ratio= Immature neutrophils (band forms, metamyelocytes, myelocytes) Mature + immature neutrophils early predictor of sepsis. N value = 0.16 in first 24 hours, decreasing to 0.12 by 60 hours. Upper limit > 0.2. Limitation- many noninfectious processes, including prolonged induction with oxytocin, stressful labor, and even prolonged crying, are associated with increased I:T ratios.
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.
Presence of two abnormal parameters in a screen is associated with a sensitivity of 93-100%, specificity of 83%, positive and negative predictive values of 27% and 100% 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
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
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.)
Lumber Puncture Indication : In EOS - a positive blood culture or clinical picture consistent with septicemia. In late onset sepsis, LP should be done in all infants prior to starting antibiotics
Interpretation of CSF findings CSF - - > 32 WBC/mm3 > 60% PMN glucose < 50% - 75% of serum protein > 150 mg/dl organisms on gram stain
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
Role of Procalcitonin ProCT becomes detectable within 2 to 4 hours after a triggering event and peaks by 12 to 24 hours. ProCT secretion parallels -closely the severity of the inflammatory insult, with higher levels associated with more severe disease and declining levels with resolution of illness. In the absence of an ongoing stimulus, ProCT is eliminated with a half-life of 24 to 35 hours, making it suitable for serial monitoring.
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 levels should fall with a half-life of 24 to 35 hours.
Identification of secondary septic events – elevated noninfectious ProCT level, ProCT levels should fall at a predictable pace in the absence of secondary infection. Limitation - ProCT levels that are elevated in noninfectious conditions like after cesearean section, resuscitation at birth, perinatal steroid exposure BUT should start falling within 48 hours . Persistent high levels or secondary peaks suggest secondary infection.
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
Polymerase Chain Reaction(PCR) Under investigation for bacterial and fungal infection amplification of 16S rRNA, a gene universally present in bacteria but absent in humans Results in 9 h of sample acquisition
PCR Sensitivity 96% Specificity 99.4% positive predictive value 88.9% negative predictive value 99.8%
Bio-markers Cytokines IL-1ß, IL-6, IL-8, and TNF major mediators of the systemic response to infection Studies have shown that combined use of IL-8 and CRP as part of the workup for bacterial infection reduces unnecessary antibiotic treatment Surface neutrophil CD11 has been shown to be an excellent marker of early infection that correlates well with CRP but peaks earlier.
Management – Supportive Specific Antibiotics Exchange transfusion Intravenous immunoglobulins (IVIG) Myeloid colony stimulating factor (GM-CSF & G-CSF) Probiotics Lactoferrin Glutamine Recombinant human protein C
Indications for starting antibioticsIndications in neonates at risk of EOS include any one 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 septic screen and strong clinical suspicion of sepsis.
Indications for starting antibiotics in LOS include: positive septic screen and/or strong clinical suspicion of sepsis.
Starting empirical antibioticsPolicy for community acquired sepsis Ampicillin + Gentamicin/Amikacin (empirical) Staphylococcus : Cloxacillin + Gentamycin/Amikacin Meningitis: Add Cefotaxime
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 β-lactamases (ESBL), cephalosporinases and fungal colonization.
Upgradation of empirical antibiotics No Expected clinical improvement with ongoing line of antibiotics. At least 48-72 hours period of observation should be allowed before declaring Failure. Current evidence does not support the use of serial quantitative CRP as a guide for deciding whether or not antibiotics should be upgraded empirically
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 a history of prior exposure of antibiotics in the previous 72 hours .
Rationale use of antibiotics: If the organism is sensitive to an antibiotic with a narrower spectrum or lower cost, therapy must be changed to such an antibiotic. If possible, a single sensitive antibiotic must be used, the exception being Pseudomonas for which two sensitive antibiotics must be used.
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
Duration of antibiotics Culture positive sepsis: 10-14 days.
Culture negative sepsis:If the blood culture is reported sterile at 48 hours, the following guidelines must be adhered to: Asymptomatic neonate at risk of EOS: stop antibiotics Suspected EOS or LOS and the neonate becomes completely asymptomatic over time: stop antibiotics Suspected EOS or LOS and the neonate have not improved or have worsened: upgrade antibiotics as per the empiric antibiotic policy. Simultaneously, alternative explanations for the clinical signs must be actively sought for.
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.
Exchange transfusion Sadana et al. have evaluated the role of double volume exchange transfusion in septic neonates with sclerema and demonstrated a 50% reduction in sepsis related mortality in the treated group.
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 of intravenous immunoglobulins (IVIG) to prevent and treat neonatal sepsis in this population.
Meta-analyses of trials of intravenous immune globulin for suspected or proven neonatal sepsis suggest a reduced rate of death from any cause, but the trials have been small and have varied in quality. The INIS(International Neonatal Immunotherapy Study)Collaborative Group*(N Engl J Med 2011;365:1201-11) At 113 hospitals in nine countries, enrolled 3493 infants( from 2001 to 2007) receiving antibiotics for suspected or proven serious infection and randomly assigned them to receive two infusions of either polyvalent IgG immune globulin or matching placebo 48 hours apart. There was no significant between-group difference in the rates of the primary outcome in the rates of secondary outcomes, including the incidence of subsequent sepsis episodes. In follow-up of 2-year-old infants, there were no significant differences in the rates of major or nonmajor disability or of adverse events.
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)
Myeloid colony stimulating factor (GM-CSF & G-CSF): These are cytokines that stimulate the production of bone marrow neutrophils. As premature infants -- limited number and function of neutrophils investigators have evaluated the use of these factors in the prevention and adjuvant treatment of neonatal sepsis. A systematic review(Combination of five studies ) examined the effect of adjuvant G-CSF or GM-CSF on 14 and 28-day overall mortality in neonates with suspected or documented sepsis. Analysis showed a reduction in all-cause mortality in treated infants .
Colony stimulating factors are a safe treatment modality in older patients; however, the current evidence suggests a multi-center randomized clinical trial demonstrating clinical efficacy of CSF is needed prior to universal recommendation of this therapy in the nursery.
Probiotics Lactobacillus and Bi dobacterium sp., the most frequently used probiotic supplements, live microbial species that under physiologic conditions colonize the gastrointestinal tract of healthy individuals. Investigators have hypothesized that probiotic supplements may protect high-risk infants in the nursery from developing necrotizing enterocolitis (NEC) and sepsis.
A randomized controlled trial in VLBW infants of a mixed probiotic supplement(Lactobacillus acidophilus and Bifidobacterium infantis) to prevent NEC and mortality was conducted. The probiotic preparation was given twice daily to breast-fed infants until NICU discharge. Although the study was not powered to detect differences in sepsis rates, culture-proven systemic infection was lower among infants in the study group than controls
Honeycutt et al. - They evaluated the use of one capsule of Lactobacillus rhamnosus strain GG (10 ×109 cells/capsule) administered daily for the duration of hospitalization in the reduction of the incidence of nosocomial infections; -the product did not reduce the incidence of nosocomial infections Lactobacillus GG sepsis has been documented in the immunocompromised host
Therefore until larger randomized controlled-trials areconducted, the routine use of probiotics to preventinvasive bacterial and fungal infections in neonates isnot recommended.
Lactoferrin Lactoferrin is an iron-binding glycoprotein. It has broad-spectrum antimicrobial activity. A multicenter, randomized, placebo controlled trial involving VLBW infants who received daily orally administered 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 30– 45 days show that the incidence of culture-proven sepsis was lower in the groups that received lactoferrin. Final and complete results from this study are pending.
Glutamine Glutamine -- most abundant amino acid in plasma and human milk. Studies in immunocompromised adults have suggested that intravenous parenteral nutrition supplemented with glutamine decreases the risk of sepsis and mortality. A recently published Cochrane systematic review examined the effect of enteral or parenteral glutamine supplementation on the incidence of culture-proven invasive infection from 5 clinical trials (n= 2,240). The meta-analysis did not reveal a statistically significant difference between the glutamine supplemented and control groups (RR 1.01; 95% CI 0.91, 1.13).
Recombinant human protein C Activated protein C is an endogenous compound that promotes anticoagulation and modulates the inflammatory response. During severe systemic infections, the levels and degree of protein C activation are decreased; In one study, decreased activity of activated protein C was associated with increase mortality among neonates with sepsis. The largest randomized controlled-trial of recombinant activated protein C in children (n=477);approximately 6% young infants) failed to show an improvement in the clinical score used at the primary outcome and in the 28- day mortality when the drug was compared to placebo
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.