Controversies in Diagnosis and Therapy of Neonatal Sepsis

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Controversies in Diagnosis and Therapy of Neonatal Sepsis Sarah S. Long, M.D. Professor of Pediatrics Drexel University College of Medicine Chief, Section of Infectious Diseases St.

1 Controversies in Diagnosis and Therapy of Neonatal Sepsis Sarah S. Long, M.D. Professor of Pediatrics Drexel University College of Medicine Chief, Section of Infectious Diseases St. Christopher s Hospital for Children Philadelphia, Pennsylvania Dr. Long has no conflict of interest to disclose

Mother had fever on presentation in labor and was begun on antibiotics for presumed chorioamnionitis.

2 Evaluation of a newborn infant shows a normal examination. He was born at 38 weeks gestation by vaginal delivery after 8 hours of rupture of membranes. Mother had fever on presentation in labor and was begun on antibiotics for presumed chorioamnionitis. The most appropriate management of the newborn is: A. Observation B. CBC at 6-12 hrs with further management pending results C. Blood culture, CBC at 6-12 hrs with further management pending results D. Blood culture, CBC at 6-12 hrs, empiric antibiotics, further decision regarding management at 48 hrs

Perinatal GBS Guidelines and Resource Utilization Pediatrics 2014;133:196 Guidelines for intrapartum antibiotic prophylaxis 1996, 2002 and 2010 Management well neonate after inadequate IAP: 2002

3 Perinatal GBS Guidelines and Resource Utilization Pediatrics 2014;133:196 Guidelines for intrapartum antibiotic prophylaxis 1996, 2002 and 2010 Management well neonate after inadequate IAP: 2002 Guideline Evaluation 15% well-appearing > 35 weeks gestation Empiric antibiotics for 50% evaluated 2010 Guideline Change to evaluate only if additional risk factor present Retrospective cohort study Brigham and Women s of >15000 infants born >36 wks 1 year before and after the 2010 guideline change Results EOS evaluations because of inadequate IAP 31 to <1/1000 neonates Overall evaluations of well appearing neonates 25% No negative consequences/outcomes

Chorioamnionitis (CAM) complicates 1-10% of pregnancies Risk early onset neonatal sepsis Maternal Abx risk early onset sepsis Maternal Abx sensitivity neonatal blood cultures AAP CoFN 2012 recs: BC

4 Chorioamnionitis (CAM) complicates 1-10% of pregnancies Risk early onset neonatal sepsis Maternal Abx risk early onset sepsis Maternal Abx sensitivity neonatal blood cultures AAP CoFN 2012 recs: BC at birth + Empiric Antibiotics If infant remains well appearing Perform CBC + CRP at 6-12 hrs D/C Abx 48 hrs if normal labs & culture Meant to emphasize when to D/C Abx (well, BC, CBC) We would not treat a well appearing >48-72 hrs even if labs abnormal

had LP) Pediatrics 2014;133:1122 Can see how the combination of statements is

5 Study: Phila Retro 554 neonates > 35 wks CAM exposed 28% WBC had IT >.2 or CRP >1 (<1% BC+) 24% given prolonged Abx (Most only because of labs) (Most had LP) Pediatrics 2014;133:1122 Can see how the combination of statements is confusing. CoFN modified its recs in Authors Reply to Ltr to the Editor in 2012 But no new box..

6 2012 Recommendations Commentary 2014 Conundrums New Box

7 J Peds : 1070r Reappraisal of Guidelines Management Suspected EOS Benitz WE, Wynn JL, Polin RA. Commentary J Pediatr (In Press) Generations of CDC/AAP recs prevent/manage EOS since 1992 Inconsistent Clarifications are necessary Local adaptations are common Compliance rates are low Reasons for lack of consensus management re EOS 1) OB prevention strategies incidence EOS Strategy based on risk factors has validity All-cause 34 wks gest >2 in s <<1 in 2000s 2) New data relationships among risk factors and clinical signs Risk predictors may have different utilities in different groups

8 J Peds 2015 Benitz New Data Newborn with Clinical Signs of Illness Many with mild illness (esp. respiratory) become asymptomatic by 6 hrs manage with observation Most (80-100%) with positive blood culture have clinical signs illness <48 hrs Few (2%-5%) with clinical signs illness have EOS NNT with clinical signs to benefit 1 with EOS = Bottom line: Until new tests NPV EOS, evaluate and Rx ill Use serial normal lab test results to discontinue Rx early

9 J Peds 2015 Benitz New Data Newborn with Maternal Chorioamnionitis Guidelines recommend Rx neonate when Dx made Early studies linking Chorio & EOS used strict criteria (maternal fever clinical) Chorio found in 90% cases failure intrapartum abx to prevent EOS Strict criteria Chorio difficult in current practice Dx often based on maternal fever alone Maternal Dx Chorio = crux of reliability as predictor Currently Chorio present in <50% EOS after failed intrapartum abx Currently Chorio risk EOS is strongly dependent on gest age Rates EOS >35 wks if Chorio = <1% (NNT ) <35 wks if Chorio = 5%-17% (NNT 6-21) (Not stratified by clinical signs) Bottom lines: Rx of Chorio-exposed preterm infants is justified. Rx chorio-exp well-appearing >34 wks should be abandoned

10 New Data EOS Stratification Late Preterm/Term by Mat & Infant Risks Peds : ,000 infants >34 weeks gestation Model risk prediction EOS on mult maternal, IP & neonate s exam findings Findings: Optimal utilization of information fails accept strategy Acceptably low NNT ~100 captures only 50% EOS Hashavya PIDJ :840 F-Rimon ActaPaed :e540 Cantoni J Peds :568 G-Munoz PedNeo :381 Need an alternative strategy Multinational studies U.S., Israel, Italy since 2010s Eval incidence EOS >100,000 infants >35 weeks gestation & well-appearing Risk factors maternal +neonatal lab screening tests Findings: Risk EOS extremely low (1/100,000) Lab screening tests add little/no diagnostic info Bottom line: Rely on serial clinical examinations rather than risk factors and lab screening tests

11 Bottom of the Bottom Lines of Benitz, Wynn & Polin Obstetrical interventions to prevent EOS are effective Infant w persistent progressive mod severe signs = Empiric Rx Infant w mild-mod respiratory signs immed birth = Observe for resolution (~6h?) w/o Rx A rapid diagnostic test with sensitivity + NPV = Great but doesn t exist Preterm (<34 wks or <1500g) have risk EOS = Consider Until more data on value risk factors, use them (maternal, clinical & laboratory test in the neonate) Most with infection will have clin signs = Rx Preterm well and no risks = Consider serial monitoring/serial tests

12 Bottom of the Bottom Lines of Benitz, Wynn & Polin Well-appearing late-preterm and term w or w/o risk factors = Close clinical observation (because poor sensitivity risk factors for EOS) Most infants treated for EOS, even with selective strategy, are not infected. Serial normal lab test results = early stop Abx (<48h) In well-appearing with negative culture, Isolated abnormal result(s) should not prolong Abx > 48 hrs Implementation of novel strategies for ascertainment and Rx EOS in late preterm/term should be cautious

32 cases perinatally acquired HSV 2011;30:556 50% had

in 75% 75% had CNS HSV (40% HSV presenting with

with nonspecific S/S only) Age 21 days at onset S/S

13 32 cases perinatally acquired HSV 2011;30:556 50% had only nonspecific S/S at presentation, which was fever in 75% 75% had CNS HSV (40% HSV presenting with mucocutaneous only, 83% HSV with seizures, 94% HSV with nonspecific S/S only) Age 21 days at onset S/S captured 90% of all cases and 94% with nonspecific S/S only Shah. Pediatr 2011;128:1153 Delay acyclovir Rx perinatal HSV from Hosp Day 1 to Day 2/3 was assoc with OR death 2.63

Don t forget to look 2012;161:134 J Peds

Melvin AJ, Mohan KM, Schiffer JT et al 63

14 Don t forget to look 2012;161:134 J Peds 2015;1 66:827 Plasma and CSF herpes simplex virus levels at diagnosis and outcome of neonatal infection. Melvin AJ, Mohan KM, Schiffer JT et al 63 Seattle infants with HSV and quant. plasma PCR at diagnosis Dissem disease 100% DNAemia CNS disease 64% DNAemia Overall 83% DNAemia SEM disease 78% DNAemia

15 Kimberlin and NIAID CASG 2011;365:1284 Patients: CASG 103 CNS Rx acyclovir IV x3 wks CASG 104 SEM Rx acyclovir IV x 2 wks (Culture/PCR dx, <28d, >800g) Intervent: Acyclovir 300mg/m 2 /dose vs placebo tid x 6 mo or until 2 nd cutaneous recurrence Outcomes: 1 o = Bayley Scales of Infant 2 o = <2 cutaneous recurrences to 12 mo CSF PCR + during/post suppr to 12 mo 3 o = Toxic effects > grade 2 (WHO) Assess: 2 & 4 wks; then q mo on study drug; 12 mo

16 TIME TO DISCONTINUATION OF STUDY DRUG PER PROTOCOL DUE TO 2 RECURRENCES * Median time infants rec d study drug was 2.5 mos longer in acyclovir vs placebo groups (P=0.009) (4.1 mos longer if CNS; 1.7 mos longer if SEM)

17 NEURODEVELOPMENTAL OUTCOMES CASG 103 (CNS) 45 Acyclovir Placebo m 12 m Score = Score = P =.046* Bayley M-D scores ; 100 mean *Adjusted HC & Wt

18 NEURODEVELOPMENTAL OUTCOMES CASG Neurologic impairment CASG 103 Normal Mild Mod Severe Acyclovir 69% 6% 6% 19% Placebo 33% 8% 25% 33% Bayley scores incrementally higher w dur suppr Rx none =58, <6 mos = 70, 6 mos = 90 No significant differences in CASG 104 (SEM) in Bayley 12 months (8/15 acyclovir and 7/14 placebo recips studied) Neurologic outcome not different by HSV type

Bottom Lines Perinatal HSV, 2015 Can manifest nonspecifically as sepsis or less <21 days Plasma PCR should be included in diagnostic testing Treatment is acyclovir 20 mg/kg/dose

19 Bottom Lines Perinatal HSV, 2015 Can manifest nonspecifically as sepsis or less <21 days Plasma PCR should be included in diagnostic testing Treatment is acyclovir 20 mg/kg/dose q8h IV (SEM 2 weeks, CNS or Dissem 3 weeks) Suppressive therapy is indicated 6 mos age (Acyclovir 300 mg/m 2 /dose tid PO) Follow up needed re neutropenia, recurrences and outcome

Congenital CMV and Long Term Suppression Journal of Pediatrics 2003 JID 2011 *CASG I RDPCT of 6-wk ganciclovir IV for symptom CMV Showed benefit re best-ear hearing @ 6 mos Waning benefit @ 2 yrs?

21 Congenital CMV and Long Term Suppression Journal of Pediatrics 2003 JID 2011 *CASG I RDPCT of 6-wk ganciclovir IV for symptom CMV Showed benefit re best-ear 6 mos Waning 2 yrs? Probable improved neurodevelopmental outcome (poor F/U) *CASG II Valganciclovir PO drug expose ganciclovir IV NEJM 2015;372:933 Study: *CASG III RDPCT Valganciclovir PO 6 wks vs 6 mos for sympt CMV 1 o Outcome = Change best-ear hearing baseline 6 mos 2 o Outcomes = Change hearing baseline 12 & 24 mos Neurodevelopmental 12 & 24 mos

22 Findings 6 Weeks vs 6 Months Valganciclovir for ccmv 6-wk Therapy 6-mo Therapy 6 wks Hearing 24 mos Bayley 24 mos Best-ear 6 mos NS NS Total 12 mos* 57% 73% Total 24 mos 64% 77% Bayley 24 mos Superior ǂ Bayley 24 mos Superior ǂ Bayley cognitive & 24 mos Superior Grade 3-4 Neutropenia < 6 wks 19% 19% Grade 3-4 Neutropenia > 6 wk 6 mos 21% 27% Improved or still normal (one or both ears) P ǂ P

24 TREATMENT FOR SYMPTOMATIC CCMV Questions WHO INITIAL DRUG HOW LONG Comments and Suggestions Symptomatic ccmv infections Start treatment within first 4 weeks of life IV ganciclovir (6mg/kg/dose q 12hr Or PO valganciclovir (16mg/kg/dose q12hr Initial therapy 6 weeks Then consider PO valganciclovir (same dose, adj) to age 6 months? 1yr

25 CONGENITAL CMV TREATMENT DECISIONS Severe ccmv infections CNS ccmv infections Symptomatic ccmv infections YES YES YES Asymptomatic ccmv infections NO Treatment = until 6 months of age

26 MANAGEMENT CONSIDERATIONS Follow-up Infectious Diseases Ophthalmology Audiology Neurodevelopmental Evaluation Neurology Physical, Occupational, Speech Therapies Support for parents/caregivers Support for infant/child At least monthly while on treatment At least yearly until age 5 yrs Every 3-6 months until age 2-3 yrs Then yearly until age 7 yrs PMD at each visit Formal evaluation at 12 mos As needed depending on CNS involvement As appropriate, case-by-case Ongoing Ongoing community services Kadambari S, Williams EJ, Luck s, Griffiths PD, Sharland M. Evidence based management guidelines for the detection and treatment of congenital CMV. Early Human Develop. 2011;87:

27 Bottom Lines Congenital and Postnatal CMV, 2015 Definition of symptomatic ccmv for Rx is expanding Begin treatment of symptomatic ccmv early (<4 wks of age) Initial Rx ganciclovir IV vs valganciclovir PO should be discussed Suppressive Rx valganciclovir PO is indicated 6 mos of age Multispecialty follow up is required re Rx issues and outcomes We need to learn more about peri/postnatal CMV in preterm

Nationwide Children s-associated Neo Services, 2003 2013 CLABSI rate 6.0 0.

Yale-New Haven NICU, 2004 2013 Of 410 episodes sepsis, 90% late onset Cases late-onset sepsis in latter years

NICUs, 1997 2012 CoNS BSI if >2 blood cultures positive <4 days 4000+ cases in ~1 million infants 35% had

28 Nationwide Children s-associated Neo Services, CLABSI rate per 1000 catheter days for >5 years Each of 8 nurseries logged >1 year CLABSI free J Pediatr 2015;167:41 Yale-New Haven NICU, Of 410 episodes sepsis, 90% late onset Cases late-onset sepsis in latter years CoNS responsible 31% cases , none after 2011 J Pediatrr2015;166:1193 Duke University Ped Med Group 348 NICUs, CoNS BSI if >2 blood cultures positive <4 days cases in ~1 million infants 35% had delayed vancomycin (85% 1-2 day delay) Odds ratio 7 days, 30 days and discharge if delayed = (All 95% Cis <1 to <2) PIDJ 2015;34:371

PEDIATRIC INFECTIOUS DISEASES UPDATE. Neonatal HSV. Recognition, Diagnosis, and Management Coleen Cunningham MD

PEDIATRIC INFECTIOUS DISEASES UPDATE. Neonatal HSV. Recognition, Diagnosis, and Management Coleen Cunningham MD Neonatal HSV Recognition, Diagnosis, and Management Coleen Cunningham MD Important questions Who is at risk? When do you test? What tests do you perform? When do you treat? What is appropriate therapy?