Neonatal Sepsis

Objectives Differentiate between the evaluation of a symptomatic newborn and the assessment of risk factors in an asymptomatic infant at risk for sepsis Review obstetric risk factors for neonatal sepsis in an asymptomatic newborn Review diagnostic tools for evaluation of sepsis in an asymptomatic newborn

Symptomatic infants Symptomatic infants require prompt diagnostic testing and institution of antibiotic therapy given the rapidity of deterioration and the high likelihood of successful treatment in infants with true bacteremia. The need for clinical judgment in this decision-making process precludes the use of an algorithm or protocol.

Symptoms of Neonatal Sepsis Respiratory distress/grunting Lethargy Irritability Hypothermia Hypoglycemia Hypotonia Acidosis Apnea Cyanotic spells Poor perfusion

Evaluation of the Symptomatic Infant CBC with manual differential-WBC corrected for NRBCs Blood culture A significant number of infants with meningitis will have a negative blood culture. A lumbar puncture may be considered if: the infant has specific symptoms of meningitis symptoms more suggestive of sepsis than MAS or RDS the blood culture is positive Urine culture is not indicated Tracheal aspirate/gastric cultures may be useful in the first 12 hours of life. A positive culture may be found in 44% of infants with clinical pneumonia and a negative blood culture.

Group B Streptococcus Gram positive, beta hemolytic bacteria Common colonizer of human gastrointestinal and genitourinary tracts Recognized as causing disease in humans in the 1930s Causes serious disease in young infants, pregnant women and older adults Emerged as most common cause of sepsis and meningitis in infants <3 months in the 1970s Group B Streptococcus Group B Streptococcus is a gram positive, beta hemolytic bacteria. It is a common colonizer of the human gastrointestinal and genitourinary tracts. It was first recognized as causing disease in humans in the 1930s. It can cause serious disease in young infants, pregnant women and older adults. It emerged as the most common cause of sepsis and meningitis in young infants in the 1970s

GBS Disease in Infants Before Prevention Efforts Early-onset: 0-6 days of life Late onset: 7-89 days of life GBS Disease In Infants Before Prevention Efforts This slide shows the distribution of infant GBS disease by age of onset. The data are taken from a study that was summarized in a review by Schuchat and published in Clin Micro Rev in 1998, Volume 11, pages 497-513. The data represent cases detected in the 1980s, before prevention efforts. Among infants under 90 days of age, the risk of GBS disease was not evenly distributed. The graph shows that 77.5% of GBS cases in infants were among those less than 1 week old. Cases occurring within the first week of life are called early-onset disease. Cases in infants 7-89 days of life are called late-onset. A Schuchat. Clin Micro Rev 1998;11:497-513.

Mother to Infant Transmission of GBS GBS colonized mother Non-colonized newborn 50% Colonized newborn Asymptomatic 98% Early-onset sepsis, pneumonia, meningitis 2% MATERNAL-TO-INFANT TRANSMISSION Most Group B Streptococcal Disease cases among newborns result from mother-to-infant transmission during labor and delivery. Many women are asymptomatically colonized by group B streptococcus in the genital and gastrointestinal tracts. Colonization is not altered by or dependent on pregnancy. About half the infants born to colonized mothers are themselves colonized on the skin and mucosal surfaces as a result of passage through the birth canal or as a result of GBS ascending into the amniotic fluid. The majority of colonized infants, 98%, are asymptomatic. About 2% will develop early-onset disease, presenting with sepsis, pneumonia or meningitis in the first few days of life.

Rate of Early- and Late-Onset GBS, 1990-2008 Early-onset GBS Late-onset GBS RATE OF EARLY- AND LATE-ONSET GBS DISEASE 1990-2008, U.S. This graph plots the incidence of early-and late-onset GBS disease in the ABCs areas from 1989 to 2008. The yellow line represents late-onset disease in this graph. Even with the implementation of guidelines recommending GBS prophylaxis, late-onset GBS disease rates have remained stable since 1990 at approximately 0.3 cases per 1,000 live births. The white line represents early-onset disease. The incidence of early-onset GBS disease in the United States since 1993 has declined 84% (from 1.7 cases per 1,000 live births in 1993 to 0.28 cases per 1,000 live births in 2008) , coinciding with increased prevention activities. These data are from Active Bacterial Core surveillance, part of the CDC’s Emerging Infections Program. Before national prevention policy Transition Universal screening Source: Active Bacterial Core surveillance / Emerging Infections Program

Antibiotics for IAP Penicillin the first-line agent for IAP Dosage: 5 million IU IV then 2.5-3.0 million IU IV every 4 hours Revised dose (2.5-3.0 million IU) consistent with available penicillin formulations Ampicillin an acceptable alternative Antibiotics for intrapartum antibiotic prophylaxis Penicillin is the first-line agent for IAP. Recommended dose is 5 million IU IV then 2.5-3.0 million IU IV every 4 hours Revised dose to be consistent with commercially available penicillin formulations and avoid need for pharmacies to specially mix doses Ampicillin is an acceptable alternative.

Data on Antibiotics for Intrapartum GBS Prophylaxis Data from clinical trials, observational studies, and pharmacokinetics studies indicate that penicillin and ampicillin given as intrapartum prophylaxis are effective in preventing early-onset GBS disease. Data from observational and pharmacokinetics studies indicate that cefazolin is probably effective as GBS intrapartum prophylaxis. In contrast, there are no similar data available for clindamycin, erythromycin, or vancomycin.

Antibiotics for IAP in Women Allergic to Penicillin Cefazolin best option for a woman allergic to penicillin but not at high risk for anaphylaxis Drugs with less evidence for effectiveness (e.g. clindamycin, vancomycin) only for women at high risk of anaphylaxis High risk for anaphylaxis defined as history of anaphylaxis, angioedema, respiratory distress or urticaria following penicillin Erythromycin no longer included as option Antibiotics for intrapartum antibiotic prophylaxis in penicillin-allergic women Ampicillin is an acceptable alternative. For women who are allergic to penicillin, cefazolin is the best option for a woman who is not at high risk for anaphylaxis Drugs with less evidence for effectiveness as GBS IAP, such as clindamycin and vancomycin, should only be used if a woman has a high risk of anaphylaxis to penicillin High risk for anaphylaxis is defined as a history of anaphylaxis, angioedema, respiratory distress, or urticaria following administration of a penicillin or a cephalosporin. Erythromycin is no longer included as an option in the 2010 GBS gudielines

Newborn Management in the 2010 GBS Guidelines This section will cover newborn management in the 2010 GBS guidelines.

This slide shows an algorithm for the secondary prevention of early-onset GBS disease among newborns.

Diagnosing Chorioamnionitis (2010 CDC Guidelines) On the basis of signs and symptoms: fever (which might be low-grade) uterine tenderness fetal tachycardia maternal tachycardia foul-smelling or purulent amniotic fluid Fever alone in labor may be used as a sign of chorioamnionitis and hence indication for antibiotic treatment

Infants Born to Mothers with Chorioamnionitis Show Symptoms Quickly In Manroe’s 1977 study all 45 infants had clinical signs of sepsis by 14 hours Time to onset of symptoms is not delayed by maternal antibiotics: CDC surveillance (GBS) 208 no abx 60 min prior to delivery; median illness 2 hours of life range 0-144 hours 33 got abx > 60 min prior to delivery; median illness 0 hours of life range 0-19

Risk Factors in Asymptomatic Infants and Likelihood of Proven Sepsis PROM >18 hours 1% Maternal + GBS (preprophylaxis era) 0.5-1% Maternal + GBS (in prophylaxis era) 0.2-0.4% Maternal + GBS + PROM, fever or preterm 4-7% Chorioamnionitis 3-8%* +GBS and chorioamnionitis 6-20% PROM + preterm 4-6% PROM + low Apgar score 3-4% Prematurity. The risk of sepsis from any cause starts and continues to rise at any gestation < 36 weeks. *Escobar, Pediatrics, 2000

Informal Poll of Neonatologists 25% would start antibiotics for asymptomatic chorioamnionitis without other evidence 75% wanted screening tests first

Screening Tests Gerdes, Ped Clin 2004; Gerdes and Polin, Ped Inf Dis J, 1987 Adjunctive test Sensitivity (%) PPV (%) NPV (%) ANC <= 1750 38-96 20-77 96-99 I/T >= 0.2 90-100 11-51 99-100 I/T >= 0.25 45 6 98 I/T >= 0.3 35 7 CRP > 1.0 mg/dL 70-93 7-43 97-99.5 *WBC <= 5000 100 27 * 2/3 tests positive

CRP-Benitz Pediatrics 1998 Two CRP levels <1 mg/dL obtained 24 hours apart, 8 to 48 hours after presentation, indicate that bacterial infection is unlikely. The sensitivity of a normal CRP at the initial evaluation is not sufficient to justify withholding antibiotic therapy. CRP elevation begins 4-6 hours after the onset of sepsis (or other stimulus) and peaks at 24-48 hours. The positive predictive value of elevated CRP levels is low.

Blood Cultures Aren’t Perfect Fastidious organisms, maternal antibiotic treatment and small volumes (<1ml) decrease sensitivity Contamination with skin organisms Molecular methods may eventually improve detection in less time

I:T Manroe J Peds, 1977 Purpose was to differentiate “wet lung” from GBS pneumonia No sensitivities or predictive values were calculated Upper limits of normal for I:T ratios were “designated”

Likelihood Ratios (LR) Combine sensitivity and specificity (probability that person with disease has positive test) sensitivity (probability that person without disease has positive test) 1-specificity A person with disease A is “___” more times likely to have a positive test than someone without the disease

Bayes Theorem “Pre-test probability” is estimated based on personal experience, prevalence data, published reports, etc. The test is used to modify pre-test probability to “post-test probability” Post-test odds= pre-test odds x LR

Fagan’s Nomogram

Maternal Risk Factor Assessment Using a Multivariate Model (Puopolo et al, Pediatrics, Nov 2011) 34 weeks and up, 350 cases (culture-confirmed bacterial sepsis at <72 hours) from 608,014 births Combining cutoff methods (ROM>x, T>x, GA<x) flags 17% of population at risk but only identifies 47% of sepsis cases

Maternal Variables and Risk for sepsis: Pre-test Probability 37-40wk ref GBS - REF 34-36wk 2.56 GBS + 1.14 41wk- 1.62 GBS -/UNK ROM < 12hr 1.38 12-17.9 hr 3.65 No intrapartum abx Ref 18-23.9 hr 2.81 Any antibiotic 1.91 24 hr- 14.8 GBS IAP 1.77 <100.5 Broad spectrum abx 6.25 100.5-101.4 4.53 Abx < 4 hr prior to del 101.5-102.4 20.08 Abx > 4 hr prior to del .34 102.5- 103.37

Interpretation of CBCs in Newborns at Risk for Sepsis (Newman et al, Pediatrics, 2010) 67,623 34 week and up infants, 245 positive blood cultures GBS 56%(decreasing over time) Ecoli 22% Enterococcus 4% Other 18%

LR for WBC, ANC, I/T Test <1 hour 1-3.99 hours 4+ hours WBC x 103/ul LR 0.4.99 n/a 27.6 80.5 5-9.99 1.4 2.4 6.4 10-14.99 1.1 0.65 1.0 15-19.99 0.73 0.64 0.41 20- 1.2 0.77 0.16 ANC x 103/ul 0-0.99 7.5 33.5 115 1-1.99 2.3 9.3 51.7 2-4.99 1 6.9 0.89 0.92 10- 0.93 0.55 0.31 I/T 0-0.14 0.45 0.46 0.25 0.15-0.29 1.3 0.3-0.449 2.9 3.1 0.45-0.599 4.8 3.3 8.8 0.6- 6.1 8.4 10.7 LR for WBC, ANC, I/T

Case 1: 38 week infant, asymptomatic, mother diagnosed with chorioamnionitis Temp 101.5, GBS+ antibiotics >4 hours prior, ampicillin. ROM 28 hours What is pretest risk based on experience? Based on Escobar’s paper? (0.23%)

Case 1: Additional Risk Based on Screening CBC WBC count 22.5K (LR1.2, .77, .06) I/T ratio of 0.3 (LR 1.4, 2.9, 3.1) ANC 6000 (LR .89, .82, .64)

Fagan’s Nomogram

Case 2: 38 week infant, asymptomatic, mother diagnosed with chorioamnionitis Temp 103, GBS+ antibiotics >4 hours prior, ampicillin. ROM 24 hours What is pretest risk based on experience? Based on Escobar’s paper? (2.21%)

Case 2: Additional Risk Based on Screening CBC WBC count 4K (N/A, 27, 80) I/T ratio of .6 (LR 6, 8.4, 10.7) ANC 750 (LR 7.5, 33.5, 115)

Fagan’s Nomogram

Case 3: 40 week infant, asymptomatic, mother diagnosed with chorioamnionitis (no question) No prenatal information What is pretest risk based on experience? (5%?)

Case 3: Additional Risk Based on Screening CBC WBC count 4K (N/A, 27, 80) I/T ratio of .6 (LR 6, 8.4, 10.7) ANC 750 (LR 7.5, 33.5, 115)

Fagan’s Nomogram 5% baseline risk I/T ratio .3 I/T ratio .6 ANC < 1000

Fagan’s Nomogram 1% baseline risk I/T ratio .3 I/T ratio .6 ANC < 1000