MANAGEMENT OF EARLY-ONSET AND LATE ONSET SEPSIS IN THE NEONATE

Theoklis Zaoutis, MD, PhD

Chief, Division of Infectious Diseases

Children’s Hospital of Philadelphia

Professor of Pediatrics and Epidemiology

University of Pennsylvania School of Medicine

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OVERVIEW - NEONATAL INFECTIONS

• Early Onset Sepsis/Infections • Bacterial

• Intrapartum Prophylaxis

• Identifying at Risk Babies to Treat with Antibiotics

• Late onset Sepsis/Infections • Majority are healthcare-acquired

• Bacterial – Hand Hygiene and Prevention of Catheter-Associated Infections

• Antimicrobial Stewardship

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WHY SHOULD WE CARE ABOUT NEONATAL INFECTIONS?

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RISK OF ADVERSE NEURODEVELOPMENTAL OUTCOMES IN ELBW INFANTS WITH INFECTIONS

Stoll et al JAMA 292: 2357, 2004

Clinical infection (n=1538)

Sepsis (n=1922)

Sepsis + NEC (n=279)

MDI* <70 1.3 (1.1, 1.5) 1.3 (1.1, 1.6) 1.6 (1.2, 2.2)

PDI* < 70 1.5 (1.3, 2.0) 1.5 (1.2, 1.9) 2.4 (1.7, 3.4)

Cerebral palsy 1.3 (1.0, 1.6) 1.4 (1.1, 1.8) 1.7 (1.2, 2.5)

Microcephaly 1.3 ( 1.1, 1.6) 1.5 (1.2, 1.7) 2.0 (1.5, 2.6)

•Prospective multicenter study of 6093 ELBW infants (<1000 gms)

•65% had > 1 nosocomial infection

•Neurodevelopmental outcome assessed at 18-22 months (corrected gestational age)

MDI: mental developmental index PDI: psychomotor developmental index

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MORTALITY FROM EARLY-ONSET SEPSIS

[Stoll, et al. (2011) Pediatrics 127(5): 821-26] [Puopolo & Eichenwald (2010)

Pediatrics 125(5):e1031-8]

0

10

20

30

40

50

60

22-24 25-28 29-33 34-36 37+

Gestational Age (weeks)

Per

cen

t

0

5

10

15

20

25

30

35

All <1500 >1500

Birth Weight (grams)

Per

cen

t

7

• GBS prophylaxis strategy: reduces EOS by > 70%

• Chorioamnionitis treatment: reduces EOS by > 80%

• Latency antibiotics (PPROM): reduces EOS by ≈35%

• CLABSI bundle: reduces LOS by > 70%

These interventions work! Keep doing them!

Preventing Neonatal Infections

Targeting Antibiotic Therapy in the Neonate

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Benitz 1999b; Ting 2013

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PREVENTION OF NEONATAL EARLY-ONSET GROUP B STREPTOCOCCAL (GBS) DISEASE

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CONCEPT OF NEONATAL GBS PREVENTION

• Concept that neonatal GBS infection can be prevented came from recognition that maternal colonization predicted neonatal infection

• And not all pregnant women are colonized

• SO: eliminate maternal colonization and you eliminate neonatal infection!

• In some ways, this was refinement of practice (established by early 1980’s) of administering intrapartum antibiotics to febrile laboring women to prevent all-cause neonatal EOS

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STRATEGIES TO PREVENT GBS EOS

• Antepartum maternal culture/antibiotics • complicated by high incidence of recolonization

• Postpartum infant IM penicillin • no effect on overall mortality

• higher mortality from pen-resistant infection

• Intrapartum treatment effective

• Correlation of antepartum culture with labor status best when performed late in 3rd trimester

Hall RT, et al. Am J Obstet Gynecol 1976:124:630–4; Gardner SE, et al. Am J Obstet Gynecol

1979:135:1062–5; Siegel, J et al. N Engl J Med 1980:303(14):769-775; Boyer KM, et al. J Infect Dis.

1983:148(5):802-9.

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INTRAPARTUM ANTIBIOTIC ADMINISTRATION TO PREVENT GBS EOS

• Randomized non-febrile, high-risk GBS+ mothers in labor to ampicillin or no antibiotic

• Risk factors ROM > 12 hrs or GA < 37 weeks

• Febrile women were excluded on ethical grounds

Boyer and Gotoff, New England Journal of Medicine 1986

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NO GBS INFECTION AMONG INFANTS BORN TO MOTHERS TREATED WITH AMPICILLIN

0

10

20

30

40

50

60

Colonized Infected

Per

cen

t o

f In

fan

ts

Control

Ampicillin

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GBS INFECTION RATES PER 100 INFANTS

0.42

13

6.3

0

2

4

6

8

10

12

14

No risk factors Febrile Study

Per

cen

t o

f In

fan

ts

In all categories, there were no infections

if mothers received intrapartum ampicillin

(5/1170)

(3/23)

(5/79)

CDC 2010 Guidelines: Maternal Screening

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Targeting Antibiotic Therapy in the Neonate

Impact of Early Onset GBS Prevention Strategies

Schrag 2000; Active Bacterial Surveillance Reports 1999-2015

Cas

es p

er 1

00

0 L

ive

Bir

ths ACOG and AAP statements

CDC draft guidelines

CDC consensus guidelines

Revised guidelines Revised

guidelines

Early-Onset (0-6 days) Late-Onset (7-89 days)

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PREVENTION OF NEONATAL LATE ONSET SEPSIS/INFECTION

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Global burden: 1.4 million people have an HAI at any given time

(WHO)

How big is the problem in Europe? ◦ Prevalence 3.5 – 14.8% (average 7.1%)

Annual burden in Europe ◦ 4.1million patients experience 4.5 million HAI ◦ Cause 37,000 deaths (contribute to an additional

110,000 deaths) ◦ 16 million extra hospital days ◦ Costs 7 billion euros (direct costs only)

HAI IN EUROPE

ECDC, Comm Dis Report 2008

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HAI IN GREECE

• Estimated 10% of patients hospitalized in Greek hospitals will experience a health-acquired infection

• 3000 deaths annually

• Cost of 1.2 billion euros annually

• Majority are due to antibiotic-resistant organisms

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EPIDEMIOLOGY OF HEALTHCARE-ACQUIRED INFECTIONS (HAI)

• Central line associated bloodstream infection (CLABSI)

• Ventilator-associated pneumonia (VAP)

• Surgical site infection (SSI)

• Foley-associated urinary tract infection (F-UTI)

• C. difficile

• Nosocomial viral infections

CATHETER INFECTIONS

• Most common nosocomial infection in children

• Required to support critically ill children

• A single lines can be accessed > 100 x each day

• Simultaneous use of > 5 vascular devices

Gravel, AJIC, 2007

“As many as 65-70% of CABSI…may be preventable with current evidence-based

strategies.”

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IMPACT OF HAND HYGEINE ON HAI

PATHOGENESIS

Four Major

Mechanisms

1) Extraluminal contamination

2) Intraluminal contamination

3) Hematogenous

4) Contaminated

infusate

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SURVEILLANCE – IT ALL BEGINS WITH DATA!

• Important way to provide quality outcome indicators and identify key measures in order to reduce the burden of HAIs

• Surveillance is defined as ‘the ongoing systematic collection, collation, analysis and interpretation of health data essential to the planning, implementation and evaluation of public health practice, closely integrated with the timely dissemination of these data to those who need to know

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PREVENTING CLABSI BY STANDARDIZING CARE….

Evidence-based guidelines exist

(O’Grady et al. CID, 2011).

Challenge of implementation

Role of “bundles” of practices

Achieve “synergy” through simultaneous

implementation of multiple interventions

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WHAT IS A BUNDLE?

• As defined by the Institute for Healthcare Improvement (IHI)

“a group of best practices that individually improve care, but when applied together result in substantially greater improvement.”

PEDIATRIC CENTRAL LINE “INSERTION BUNDLE”

• Hand hygiene prior to procedure

• Appropriate skin antisepsis 2% chlorhexidine gluconate 70%

isopropyl alcohol Iodine containing solution (<2 months)

• Maximal sterile barrier precautions for insertion Gown, gloves, masks for inserter and

assistant Complete coverage (except for insertion

site) of patient with sterile drape

• Use catheter insertion kit or cart

Maintenance Practices

• Daily review of necessity

• Hand hygiene before and after ANY contact

• 15 second hub scrub and dry

• Keep all lines “closed” (needleless connectors or med lines)

• Restricted access of CVL; minimize breaks for blood sampling, bolus meds

• Rigorous aseptic technique for CVL dressing changes

PEDIATRIC CENTRAL LINE “MAINTENANCE BUNDLE”

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DAILY ASSESSMENT OF LINE NECESSITY/USE

• Establish goals for removal of catheters

• Daily review of progress toward goals (incorporate into morning rounds)

• Work with nursing to consolidate and/or eliminate catheter entries (blood draws, flushes, meds, etc.)

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CLABSI PREVENTION BUNDLES WORK!

Rinke, Pediatr, 2012.

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ANTIBIOTIC STEWARDSHIP IN THE NICU

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ADVERSE EFFECTS OF NICU ANTIBIOTIC USE?

• Invasive Candidiasis in ELBW receiving 3GC (Cotten Pediatrics 2006)

• NEC and death in ELBW after early life Abx (Cotten Pediatrics 2009)

• BPD in VLBW after early life Abx (Cantey J Peds 2017)

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• early life colonization coincides with a potentially time-limited period during which the immune system is permissive to microbial instruction

• immune influences induced by the microbiota might be durable, creating a “window of opportunity” for proper immune education to occur and resistance to disease later in life

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• Systematic review of 48 studies

• Prolonged antimicrobial therapy associated with:

• reduced gut microbial diversity

• Reduced abundance of protective commensal anaerobes

• Increased risk of antibiotic resistance development, including ESBL and other MDR pathogens

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POTENTIAL BEST PRACTICES FOR NICU ANTIBIOTIC STEWARDSHIP

1. Look at prescribing data

• which antibiotics are used most, for what conditions?

• prioritize interventions based on this.

2. Know your local antibiogram

3. Trust your blood cultures

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• Obtain blood cultures appropriately • Timing

• Volume

• Trust them • Modern culture technology is very sensitive

• Don’t get unnecessary cultures

Cantey JB and Baird SD. Pediatrics. 2017;140(4).

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Targeting Antibiotic Therapy in the Neonate

Blood Cultures are Very Reliable for Detection of Bacteremia • Modern culture methods have excellent reliability for

detection of organisms in blood at concentrations < 10 cfu/ml.

• Quantitative blood cultures in neonates with sepsis demonstrate bacteremia at ≥ 10 cfu/ml in 90% and ≥ 100 cfu/ml in 80%.

• There is a 98% probability that 1 ml of blood will contain at least one bacterium if the bacteremia density is at least 4 cfu/ml.

• A negative culture is very unlikely if a 1 ml blood inoculum blood is provided and the infant is bacteremic.

Dunne 2005; Nanua 2009; Sabui 1999; Schelonka 1996

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Targeting Antibiotic Therapy in the Neonate

Culture-Negative Neonatal Sepsis

Cantey 2017

• Blood culture sensitivity is essentially 100% for bacteremia at ≥ 4 cfu/ml. • Ultralow-density bacteremia is of dubious significance, and might be

adequately treated with a 36 hour course of antibiotics. • Recrudescent sepsis after stopping antibiotics at 36-48 hours is an

extremely rare event. • Negative cultures after intrapartum antibiotic exposure reflect either

absence of or adequate treatment of infection, and therefore support discontinuation of treatment.

• Clinical findings and ancillary tests are very poor predictors of bacterial infection, and cannot justify continuing treatment in the face of negative culture results.

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Targeting Antibiotic Therapy in the Neonate

Culture-Negative Neonatal Sepsis

Cantey 2017

“We must train ourselves to trust our cultures and discontinue empirical therapy if they remain

sterile at 36 to 48 hours of incubation.” – Cantey & Baird, 2017

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POTENTIAL BEST PRACTICES FOR NICU ANTIBIOTIC STEWARDSHIP

1. Look at prescribing data

• which antibiotics are used most, for what conditions?

• prioritize interventions based on this.

2. Know your local antibiogram

3. Trust your blood cultures

4. Don’t treat all babies the same

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SEPSIS RULE-OUTS AS AN EXAMPLE

• Most antibiotics are used for this

• 10x more antibiotics for culture negative than culture positive

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ANTIBIOTIC STEWARDSHIP IN EARLY ONSET SEPSIS (EOS)

• Newborns may be exposed to antibiotics: • before birth in the form of GBS IAP

• maternal surgical prophylaxis in cesarean deliveries

• intrapartum antibiotic therapy administered because of suspected or confirmed maternal infection

• 32-45% of all infants exposed to antibiotics

• Antibiotic administration in infancy increases health problems (wheezing, asthma, food allergy, IBD and obesity).

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ANTIBIOTIC STEWARDSHIP IN EARLY ONSET SEPSIS (EOS)

• Neonatal antibiotics alter gut microbiome

• Associated with changes in stool bacterial composition at 1 week, 3 months, and 12 months of age.

• The impact of breastfeeding on gut dysbiosis may be important given that mother-infant separation for EOS treatment

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RISK ASSESSMENT STRATEGIES TO IDENTIFY INFANTS AT RISK FOR EOS

• Categorical Risk Assessment • Example is CDC GBS Guidelines

• Unclear impact on antibiotic use

• Risk Assessment Based on Clinical Condition • Reliance on clinical signs of illness to identify infants with EOS.

• Regardless of neonatal or maternal risk factors for EOS

• Significant decreases in the use of laboratory tests, blood cultures, and empirical antibiotic agents

• Multivariate Risk Assessment – Sepsis Calculator

Escobar GJ, Puopolo KM, Wi S, Turk BJ, Kuzniewicz MW, Walsh EM, Newman TB, Zupancic J, Lieberman E, Draper D. Stratification of risk of early-onset sepsis in newborns ≥ 34 weeks' gestation. Pediatrics. 2014 Jan;133(1):30-6.

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Quantitative Risk Stratification for EOS. Quantitative risk stratification schema for newborns >34

weeks’ gestation developed in this study.

Escobar G J et al. Pediatrics 2014;133:30-36

©2014 by American Academy of Pediatrics

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SEPSIS CALCULATOR OUTCOMES

• A prospective validation in 204 685 infants: • Blood culture testing declined by 66%

• Empirical antibiotic administration by 48%

• Compared with categorical risk algorithms based on recommendations CDC.

• No adverse effects were noted during birth hospitalization.

• Readmissions for culture-confirmed infection during the week after discharge hospital were rare (5 in 100,000)and did not differ by approach

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EOS TREATMENT

• Ampicillin and gentamicin, in combination, is the first choice for empirical therapy for EOS.

• Among term newborn infants who are critically ill, the empirical addition of broader-spectrum therapy should be considered until culture results are available

• Antibiotics should be discontinued when blood cultures are sterile at 36 to 48 hours unless there is evidence of site-specific infection.

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EOS TREATMENT

• Continuing empirical antibiotic therapy in response to laboratory test abnormalities alone is rarely justified, particularly among well- appearing term infants.

• Serial abnormal CRP values alone should not be used to decide whether to administer antibiotics in the absence of culture confirmed infection.

• Duration of therapy should be guided by RED BOOK.

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SEPSIS STEWARDSHIP

• Don’t always start

• sepsis risk calculators

• Don’t start too broadly

• vancomycin typically not needed • MRSA

• CONS (after it grows, and w/ f/u culture)

• redundant coverage

• Don’t continue too long

• 48h/36h/24h rule outs?

• perioperative prophylaxis

THANK YOU

ZAOUTIS@EMAIL.CHOP.EDU