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An#bio#c Stewardship Why we do it and How we’ve done it

C. Michael Co,en MD MHS

An#bio#c Stewardship Why we do it and How we’ve done it C. Michael Co,en MD MHS

CM Cotten: Disclosures

Disclosures:

DSMB for rEVO pharmaceuticals (preeclampsia) Consultant Windtree Pharma (respiratory intervention) Advisory Board for GW Pharma (neuroprotection)

The use of antibiotics in neonates without infection is off-label.

Are an3bio3cs an inevitable part of NICU/ Neonatal life, especially for preterm infants? If they are, why should we care (microbiome?) and what can we do to use them most effec3vely and efficiently?

What is Our “Microbiome”?

•   Microbiota : Microbial community •   Microbiome : collective genomes and gene products

Microbiota: Microbial community Microbiome: collective genomes and gene products of resident microbes living within and on humans Metagenome: Collection of genomes within complex microbial communities and human DNA

WE ARE MOSTLY MICROBIAL

Human microbiome 1,000,000+ genes Human genome 23,000 genes
Human microbiome 1,000,000+ genes
Human microbiome
1,000,000+ genes
Human microbiome 1,000,000+ genes Human genome 23,000 genes

Human genome 23,000 genes

What do the microbes do for us?

Provide the ability to harvest nutrients Produce additional energy otherwise inaccessible to the host. Produce vitamins Metabolize xenobiotics (including drugs) Provide resistance to tumor and cancer leading neoplasms Assist in developing a mature immune system

EARLY LIFE LESSONS

Inflammation/Immunity

Tolerance

Inflammation/Immunity Tolerance Antibiotics influence this balance… balance???? (Tribute to Nancy Fawcett, MD) What
Inflammation/Immunity Tolerance Antibiotics influence this balance… balance???? (Tribute to Nancy Fawcett, MD) What

Antibiotics influence this

balance…

balance???? (Tribute to Nancy Fawcett, MD)

What

else tips the

Body weight - microflora con#nued WT and obese mouse experiments

Increase in body fat 2 wks aLer obese mouse flora is transplanted into germ free (clear bar) vs. increase when lean mouse flora transplanted into germ free (dark bar)

lean mouse flora transplanted into germ free (dark bar) Stool calorimetry: energy lost from similar diets

Stool calorimetry:

energy lost from similar diets

free (dark bar) Stool calorimetry: energy lost from similar diets Turnbaugh PJ et al Nature 2006
free (dark bar) Stool calorimetry: energy lost from similar diets Turnbaugh PJ et al Nature 2006

Turnbaugh PJ et al Nature 2006; 444: 1027-131

Bacterial succession in term

babies

Aerobes

Faculta3ve anaerobes Streptococci Staphylococci Coliforms Lactobacilli ** Obligate Anaerobes** Bifidobacteria* *

Obligate anaerobes

Bacteroides

Clostridia

* * Obligate anaerobes Bacteroides Clostridia Birth Wean Adulthood **In infants receiving breast milk
* * Obligate anaerobes Bacteroides Clostridia Birth Wean Adulthood **In infants receiving breast milk

Birth

Wean

Adulthood

anaerobes Bacteroides Clostridia Birth Wean Adulthood **In infants receiving breast milk Modified from Hooper,

**In infants receiving breast milk

Modified from Hooper, Trends in Microbiology, 2004

An#bio#cs

ADer Fleming and Penicillin (1928),,,, The word “an3bio3c” was coined by soil microbiologist Selman Waksman, the Nobel Prize-winning co-discoverer of streptomycin. He and his dis3nguished team (including Albert Schatz ) isolated hundreds of ac3nomycetes from different soils and subsequently iden3fied compounds with an3bio3c ac3vity in the laboratory (streptothricin-1943, neomycin, ac3nomycin D, etc.). Schatz demonstrated that streptomycin was ac3ve against the bacterium that causes tuberculosis. These discoveries were the genesis of the an3bio3c industry.

Waksman described an an#bio#c as “a compound produced by a microbe that kills or inhibits the growth of another microbe.”

that kills or inhibits the growth of another microbe.” • Penicillins : inhibit bacterial cell wall
that kills or inhibits the growth of another microbe.” • Penicillins : inhibit bacterial cell wall

Penicillins: inhibit bacterial cell wall synthesis and are bactericidal.

Aminoglycosides: bactericidal, inhibit protein synthesis and cell wall integrity through

binding to ribosomes. Cephalosporins: like penicillins, b-lactam antibiotics, bactericidal and interfere with

synthesis of the bacterial cell wall. Glycopeptides: bactericidal, inhibit bacterial cell wall synthesis.

Carbepenems: bactericidal, resistant to B-lactamases

de Hoog M, Mouton JW, van den Anker JN. New dosing strategies for an3bacterial agents in the neonate. Pediatrics. 2011;127:e367-74 Davies J, Davies D. Origins and Evolu3on of An3bio3c Resistance Microbiol Mol Biol Rev. 2010; 74: 417–433 .

h,p://urwebsrv.rutgers.edu/focus/ar3cle/Albert%20Schatz,%20co-discoverer%20of%20streptomycin,%20dies%20at%2084/1504

An#bio#c Use Prevalence

1/3 rd of U.S. Mothers receive intrapartum

an3bio3cs

10% of U.S. newborns receive an3bio3cs ̴100% of Very Low Birthweight (VLBW; < 1500 grams BWgt)/Extremely Low Gesta3onal Age (ELGANS; < 28 weeks), receive an3bio3cs during their hospital stay.

Van Dyke MK, Phares CR, Lynfield R, Thomas AR, Arnold KE, Craig AS, Mohle-Boetani J, Gershman K, Schaffner W, Pe3t S, Zansky SM, Morin CA, Spina NL, Wymore K, Harrison LH, Shu, KA, Bareta J, Bulens SN, Zell ER, Schuchat A, Schrag SJ. Evalua3on of universal antenatal screening for group B streptococcus. N Engl J Med. 2009 Jun 18;360(25):2626-36. Weston EJ, Pondo T, Lewis MM et al. The burden of invasive early-onset neonatal sepsis in the United States, 2005-2008. Pediatr Infect Dis J 2011; 30: 937-41.

An#microbials ARE Commonly Used in NICUs

1,425,992 records of 409 unique medica#ons covering 1/1996 – 4/2005. Among the top 10 most used:

Ampicillin #1 Gentamicin #2 Cefotaxime #5 Vanco #8

Clark RH et al. Pediatrics 2006; 117:1979-1987

Rate of Early- and Late-Onset GBS in the U.S.,

1990-2008

Early-onset GBS Late-onset GBS
Early-onset GBS
Late-onset GBS

Before national prevention policy Transition

Universal screening

Source: Active Bacterial Core surveillance / Emerging Infections Program

Preterm Infants

Preterm Infants •   Characteris3cs for risk of acquired infec3on –   Imperfect, leaky barriers –

Characteris3cs for risk of acquired infec3on

Imperfect, leaky barriers Rely heavily of innate immune mechanisms and neutrophil ac3vity Exposed to hospital environment for weeks Poor early nutri3on Dependence on intravenous access and mul3ple invasive procedures

Cuenca AG, Wynn JL, Moldawer LL, Levy O. Role of innate immunity in neonatal infec3on. Am J Perinatol 2013; 30:105–12.

Likelihood of Finding A Posi#ve Culture By Day It Was Drawn Data source: Mednax /Pediatrix

Likelihood of Finding A Posi#ve Culture By Day It Was Drawn

Data source: Mednax /Pediatrix medical group, by way of P. Brian Smith

of Finding A Posi#ve Culture By Day It Was Drawn Data source: Mednax /Pediatrix medical group,

Necrotizing Enterocolitis

7-10% of ELBW infants/1-5% of all neonates admits 20-50% mortality/leading cause of morbidity in survivors Quadruples risk of neurodevelopmental impairment 30% with positive cultures Surgical survival about 50%

in survivors Quadruples risk of neurodevelopmental impairment 30% with positive cultures Surgical survival about 50%
in survivors Quadruples risk of neurodevelopmental impairment 30% with positive cultures Surgical survival about 50%

Ancient Connec#on

NEC happens in the intes3ne, where microbes are at home, and necessary, and compete for space Humans did not invent an#bio#cs; we merely observed—oLen by accident—that bacteria and other microorganisms produced biological compounds capable of killing or suppressing growth and reproduc3on of other bacteria…. and we use them… a lot!!!

Choffnes ER, et al. An3bio3c Resistance: Implica3ons for Global Health and Novel Interven3on Strategies: Workshop Summary h,p://www.nap.edu/catalog/12925.html

Neonatal An#bio#cs and wheeze and asthma risk:

systema#c review and metaanalysis

wheeze and asthma risk: systema#c review and metaanalysis •   18 studies were eligible for meta-

18 studies were eligible for meta- analysis

pooled OR 1.27 (95% CI 1.12-1.43)

9 Studies without design bias

pooled OR 1.12 (95% CI 0.98-1.26).

3 studies focused on wheeze/ asthma beyond 5-6 yrs of age

pooled OR 1.08, 95% CI 0.93-1.23; dominated by one study

Penders J et al. Infant an3bio3c use and wheeze and asthma risk: a systema3c review and meta-analysis. Eur Respir J. 2011 Aug;38(2):295-302.

“A robust and dose-dependent associa#on was found between an#bio#c use in the first 2 yr of life and asthma at age 7.5 yr but did not appear to be mediated through an associa#on with

atopy.”

Hoskin -Parr L et al. An3bio3c exposure in the first two years of life and development of asthma and other allergic diseases by 7.5 yr: a dose-dependent rela3onship. Pediatr Allergy Immunol. 2013 ;24:762-71

Duke and Network Med+Surg NEC GDB/ELBW inborn

For our first four years in the NICHD Neonatal Research Network, Duke had the highest rate of medical+surgical NEC.

35

30

25

20

15

10

5

0

ALL Low Duke alone
ALL
Low
Duke
alone

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

# of Bacterial Species vs. # of days on an#bio#cs of the first 30 postnatal days

vs. # of days on an#bio#cs of the first 30 postnatal days Culture-based evaluation ; Lower

Culture-based evaluation; Lower diversity with higher number of antimicrobial days

Gewolb, I. H et al. Arch. Dis. Child. Fetal Neonatal Ed. 1999;80:167-F173

Innate Immunity and Commensal Bacteria

Innate Immunity and Commensal Bacteria Madara , J. N Engl J Med 2004 ;351:1685-1686 21

Madara, J. N Engl J Med 2004;351:1685-1686

Innate Immunity and Commensal Bacteria Madara , J. N Engl J Med 2004 ;351:1685-1686 21

21

Experiment 1A: Intact Innate Immune response is important to Gut Integrity post injury

Immune response is important to Gut Integrity post injury DSS + WT Intact immune response: 100%

DSS + WT Intact immune response:

100% survival

DSS + gene#cally deficient immune response, MyD88 -/-……0% survival

DSS + gene#cally deficient immune response, MyD88 -/-……0% survival Rakoff-Nahoum et al. Cell 2004;118:229-241.
DSS + gene#cally deficient immune response, MyD88 -/-……0% survival Rakoff-Nahoum et al. Cell 2004;118:229-241.

Rakoff-Nahoum et al. Cell 2004;118:229-241.

Experiment 1B: Remove microbes with An#bio#cs and screw up immune homeostasis

microbes with An#bio#cs and screw up immune homeostasis All 4 abx combined, no flora = No

All 4 abx combined, no flora = No survival. No produc#on of IL-6, TNF, or KC-1

Rakoff-Nahoum et al. Cell 2004;118:229-241

Slide courtesy of Patrick Seed ( peds ID Duke/now Northwestern)

Slide courtesy of Patrick Seed (peds ID Duke/now Northwestern)

Clamoxyl affects intes#nal gene expression

Clamoxyl affects intes#nal gene expression genes related to an#gen presenta#on downregulated , MHC class II and

genes related to an#gen presenta#on downregulated,

MHC class II and nonclassical class Ib genes. expression of CD1d, a gene associated with the presenta3on of lipid-containing an3gens, was significantly downregulated in the proximal small

intes3ne.

genes coding for an#-microbial products downregulated.

Genes associated with Paneth cell secre3on products were differen3ally regulated especially in proximal small intes3ne at D17, including an3-microbial pep3des such as defensins, lysozyme, and phospholipase A2.

upregulated expression of mast cell proteases

in the distal small intes3ne.

Schumann A et al. Phys Genomics 2005;23:235-245

Delayed Coloniza3on: Development of Intes3nal Angiogenesis with Microbes

Ex germ-free conventionalized

Ex germ free with B. thetha

Germ - Free

conventionalized Ex germ free with B. thetha Germ - Free Green marker for developing endothelial cells

Green marker for developing endothelial cells

Stapperbeck, et al. PNAS 99:154-51, 2002

Metagenome

Metagenome RNA metabolism Virulence Phosphorous metabolism Protein metabolism DNA metabolism Cell wall and capsule

RNA metabolismMetagenome Virulence Phosphorous metabolism Protein metabolism DNA metabolism Cell wall and capsule Clustering-based

VirulenceMetagenome RNA metabolism Phosphorous metabolism Protein metabolism DNA metabolism Cell wall and capsule Clustering-based

Phosphorous metabolismMetagenome RNA metabolism Virulence Protein metabolism DNA metabolism Cell wall and capsule Clustering-based subsystems

Protein metabolismMetagenome RNA metabolism Virulence Phosphorous metabolism DNA metabolism Cell wall and capsule Clustering-based

DNA metabolismVirulence Phosphorous metabolism Protein metabolism Cell wall and capsule Clustering-based subsystems

Cell wall and capsulePhosphorous metabolism Protein metabolism DNA metabolism Clustering-based subsystems Carbohydrates Amino acids and

Clustering-based subsystemsProtein metabolism DNA metabolism Cell wall and capsule Carbohydrates Amino acids and deriva3ves Stress response

Carbohydratesmetabolism Cell wall and capsule Clustering-based subsystems Amino acids and deriva3ves Stress response Respira3on Adult

Amino acids and deriva3veswall and capsule Clustering-based subsystems Carbohydrates Stress response Respira3on Adult B a b y 1 Latuga

Stress responsesubsystems Carbohydrates Amino acids and deriva3ves Respira3on Adult B a b y 1 Latuga MS, et

Respira3onsubsystems Carbohydrates Amino acids and deriva3ves Stress response Adult B a b y 1 Latuga MS,

Carbohydrates Amino acids and deriva3ves Stress response Respira3on Adult B a b y 1 Latuga MS,

Adult

Baby 1

Latuga MS, et al. 2011

Baby 2
Baby 2

Results: Scaffolds-Baby 1

Results: Scaffolds-Baby 1 Sequence Size Distribu3on (n=52 scaffolds) G C ( % ) D i s
Results: Scaffolds-Baby 1 Sequence Size Distribu3on (n=52 scaffolds) G C ( % ) D i s

Sequence Size Distribu3on (n=52 scaffolds)

GC (%) Distribu3on)

Virulence An3bio3c resistance Cell Cycle Amino Acids Fa,y Acids/Lipid Regula3on and Cell Signaling Virulence
Virulence
An3bio3c resistance
Cell Cycle
Amino Acids
Fa,y Acids/Lipid
Regula3on and Cell Signaling
Virulence
Cofactors, Vitamins, Pigments
Clustering-based subsystems
Stress Response
RNA Metabolism
Iron Scavenging
TIII,IV,ESAT Secre3on
An3bio3c Resist, Toxins
Prophage, Mobile Element
Methicillin Resistance
Teicoplanin Resistance
Mercuric Reductase
Carbohydrate
Latuga MS et al. Beyond bacteria: a study of the enteric microbial consor@um in extremely low
birth weight infants. PLoS One. 2011;6(12):e27858. doi : 10.1371/journal.pone.0027858.

Results: Scaffolds-Baby 2

Results: Scaffolds-Baby 2 Sequence Size Distribu3on (n=56 scaffolds) virulence Cell Cycle Amino Acids Fa,y

Sequence Size Distribu3on (n=56 scaffolds)

virulence
virulence

Cell Cycle Amino Acids Fa,y Acids-Lipids Phosph Metabol Carbohydrates

DNA Metabolism Cofactors, Vitamins, Pigments Virulence Clustering-based subsystems RNA Metabolism Protein Metabolism

GC (%) Distribu3on)

An3bio3c resistance Iron Scavenging An3bio3c Resist, Toxins Pathogenicity Islands Prophage, Mobile Element
An3bio3c resistance
Iron Scavenging
An3bio3c Resist, Toxins
Pathogenicity Islands
Prophage, Mobile Element
Methicillin Resistance
Teicoplanin Resistance
Fluoroquinolone Resistance
Beta-lactamase

Latuga MS et al. Beyond bacteria: a study of the enteric microbial consor@um in extremely low birth weight infants. PLoS One. 2011;6(12):e27858. doi : 10.1371/journal.pone.0027858

Microbiome NEC vs no NEC

Weekly stool specimens Gesta3onal ages ≤32 completed weeks or birth weights ≤ 1250 g. High throughput 16S rRNA sequencing Compare diversity of microbiota and prevalence of specific bacterial signatures in 9 NEC infants and 9 matched controls.

Same maturity/chronologic age 454 sequences Calculated diversity indices and rarefac3on curves. Opera3onal Taxonomic Units (OTUs)

Mai V, Young CM, Ukhanova M, Wang X, Sun Y, Casella G, Theriaque D, Li N, Sharma R, Hudak M, Neu J. Fecal microbiota in premature infants prior to necro3zing enterocoli3s. PLoS One. 2011;6(6):e20647

Microbiome NEC vs non NEC

Microbiota composi3on differed in the matched samples collected 1 week but not <72 hours prior to NEC. Detected a bloom (34% increase) of Proteobacteria and a decrease (32%) in Firmicutes in NEC cases between the 1 week and <72 hour samples. No significant change was iden3fied in the controls.

Mai V, Young CM, Ukhanova M, Wang X, Sun Y, Casella G, Theriaque D, Li N, Sharma R, Hudak M, Neu J. Fecal microbiota in premature infants prior to necro3zing enterocoli3s . PLoS One. 2011;6(6):e20647

Chao rarefaction diversity.

Chao rarefaction diversity. Mai V, Young CM, Ukhanova M, Wang X, et al. (2011) Fecal Microbiota

Mai V, Young CM, Ukhanova M, Wang X, et al. (2011) Fecal Microbiota in Premature Infants Prior to Necrotizing Enterocolitis. PLoS ONE 6(6): e20647. doi:10.1371/journal.pone.0020647

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020647

ONE 6(6): e20647. doi:10.1371/journal.pone.0020647 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020647

Changes in propor#on of bacterial phyla .

Proteobacteria Firmicutes Bacteroidetes Actinobacteria
Proteobacteria
Firmicutes
Bacteroidetes
Actinobacteria

Cases increase proteobacteria from 36% of microbiome to 70%

Mai V, Young CM, Ukhanova M, Wang X, et al. (2011) Fecal Microbiota in Premature Infants Prior to Necrotizing Enterocolitis. PLoS ONE 6(6): e20647. doi:10.1371/journal.pone.0020647

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020647

ONE 6(6): e20647. doi:10.1371/journal.pone.0020647 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020647

Early-onset Sepsis

We choose:

Who we treat What we use How long we treat

Early-onset Sepsis We choose: •   Who we treat •   What we use •  

Duration of Initial Antibiotic Course in Extremely Low Birthweight Infants:

Association with Necrotizing Enterocolitis and Death

of Initial Antibiotic Course in Extremely Low Birthweight Infants: Association with Necrotizing Enterocolitis and Death
of Initial Antibiotic Course in Extremely Low Birthweight Infants: Association with Necrotizing Enterocolitis and Death

Results

Median Duration of Empirical Initial Antibiotics

10 9 8 7 6 5 4 3 2 1 0 1 2 3 4
10
9
8
7
6
5
4
3
2
1
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19
20
Total
Centers
Median Days

Cotten CM et al. Prolonged Initial Empirical Antibiotics are Associated with Increased Necrotizing Enterocolitis and Mortality in Extremely Low Birthweight Infants. Pediatrics.2009; 123: 58-66.

Duke

Results

% with Prolonged Empirical Initial Antibiotics: > 5 days

90 80 Range 27 – 85% 70 60 50 40 30 20 10 0 1
90
80
Range 27 – 85%
70
60
50
40
30
20
10
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19
20
Total
Centers
%
5 or more days

DUKE Now < 70%

FIGURE 1 Numbers of study infants according to duration of initial empirical antibiotic treatment

to duration of initial empirical antibiotic treatment Cotten, C. M. et al. Pediatrics 2009;123:58-66 Copyright

Cotten, C. M. et al. Pediatrics 2009;123:58-66 Copyright ©2009 American Academy of Pediatrics

antibiotic treatment Cotten, C. M. et al. Pediatrics 2009;123:58-66 Copyright ©2009 American Academy of Pediatrics

Results

Risk factor adjusted associations between NEC or Death and

1. Duration of empirical initial antibiotics

2. Prolonged empirical initial antibiotics

Outcome

Duration empirical antibiotics

 

Prolonged empirical initial antibiotics (> 5 days)

Odds ratio (95% CI) (each day)

p-value

Odds ratio (95% CI)

p-value

NEC or

       

Death

1.04

(1.02, 1.06)

<

0.01

1.30

(1.10, 1.55)

<

0.01

NEC

1.07

(1.04, 1.10)

<0.01

1.21

(0.98, 1.51)

0.08

Death

1.18

(1.08, 1.28)

<

0.01

1.46

(1.19, 1.78)

<

0.01

Cotten CM et al. Prolonged Initial Empirical Antibiotics are Associated with Increased Necrotizing Enterocolitis and Mortality in Extremely Low Birthweight Infants. Pediatrics.2009; 123: 58-66.

Additional Finding: late onset sepsis

Both 4 and 5 days of initial empirical antibiotic treatment associated with increased risk of the combined outcome LOS caused by organisms other than CONS or death 4 days: OR: 1.32 [95% CI: 1.11–1.58] – 5 days: OR: 1.24 [95% CI: 1.06–1.44]

Cotten CM et al. Prolonged Initial Empirical Antibiotics are Associated with Increased Necrotizing Enterocolitis and Mortality in Extremely Low Birthweight Infants. Pediatrics.2009; 123: 58-66.

An#microbial Exposure and NEC

Yale cohort replicates NRN associa#on

Exposure and NEC Yale cohort replicates NRN associa#on •   2000 -2008 •   124 cases;

2000 -2008 124 cases; 248 controls (1:2) GA mean: 28 wk BW mean: 1100 g Total days on ABX, not just EOS empirical therapy Human milk was

protec3ve

Alexander VN, Northrup V, Bizzarro MJ. An3bio3c exposure in the newborn intensive care unit and the risk of necro3zing enterocoli3s . J Pediatr. 2011;159(3):392-7.

3 rd Ini#al Empirical An#microbial Study CCHMC

3 hospitals in Cincinna3; 2000 - 2004 < 32 weeks gesta3onal age < 1500 g birth weight Survived free of sepsis and NEC for 7 days. Mul3variable logis3c regression

Outcome variables: NEC, LOS, death + combina3ons

LOS: posi3ve blood, cerebrospinal fluid, urine, or sterile site culture aLer 3 postnatal days. NEC II/III

Prolonged ini3al an3bio3cs defined as abx > 5 days, beginning day 1

Almost universally Amp/Gent

Covariables :

birth weight, gesta3onal age, race, prolonged premature rupture of membranes, days HFV in 7 days, amount of breast milk received in the first 14 days of life.

Kuppala VS. Prolonged Initial Empirical Antibiotic Treatment is Associated with Adverse Outcomes in Premature Infants. J Pediatr 2011;159:720-5

Prolonged An#bio#cs (III)

Outcome

N (total =

OR*

CI

NNH

 

365

Late onset

76

(21%)

2.45

1.28-4.67

sepsis

 

NEC

17

(4.6%)

1.28

0.42-3.93

Death

20

(5.5%)

1.12

0.40-3.10

Composite

91

(25%)

2.66

1.12-6.30

3

LOS+NEC+Death

 

*Odds Ra#o for categorical variable, ini#al empirical an#bio#cs > 5 days

Kuppala VS. Prolonged Ini3al Empirical An3bio3c Treatment is Associated with Adverse Outcomes in Premature Infants. J Pediatr 2011;159:720-5

The Crisis in An#bio#c Resistance

The synthesis of large numbers of an#bio#cs over the past three decades has caused complacency about the threat of bacterial resistance. Bacteria have become resistant to an3microbial agents as a result of chromosomal changes or the exchange of gene3c material via plasmids and transposons. Streptococcus pneumoniae, Streptococcus pyogenes , and staphylococci, organisms that cause respiratory and cutaneous infec3ons, and members of the Enterobacteriaceae and Pseudomonas families, organisms that cause diarrhea, urinary infec3on, and sepsis, are now resistant to virtually all of the older an3bio3cs. The extensive use of an#bio#cs in the community and hospitals has fueled this crisis. Mechanisms such as an3bio3c control programs, be,er hygiene, and synthesis of agents with improved an3microbial ac3vity need to be adopted in order to limit bacterial resistance.

Harold Neu . The crisis in an3bio3c resistance. Science 1992;257:1064-1073

Pathophysiology of Necro#zing Enterocoli#s.

Pathophysiology of Necro#zing Enterocoli#s . Neu J, Walker WA. N Engl J Med 2011 ;364:255-264.

Neu J, Walker WA. N Engl J Med 2011;364:255-264.

Pathophysiology of Necro#zing Enterocoli#s . Neu J, Walker WA. N Engl J Med 2011 ;364:255-264.

Average Duration of Initial Course of Antibiotic Therapy (Days)

Average Duration of Initial Course of Antibiotic Therapy (Days)

Monitoring An#bio#c Dura#on

of Antibiotic Therapy (Days) Monitoring An#bio#c Dura#on 6 6 6 Target: Less than 5 days Target:
6 6 6 Target: Less than 5 days Target: Less than 5 days 5 5
6 6
6
Target: Less than 5 days
Target: Less than 5 days
5 5
5
4 4
4
3
3 3
2
2 2
1 1 1
0 0
0

2006

2006

2007

2007

2008

2008

2009

2009

2010

2010

2011

2011

Years:

P <0.001

2012

2012

Individual Prac##oner ABX Dura#on 1.0 1.0 Group Group Group Mean Mean Mean Std Error Std
Individual Prac##oner ABX Dura#on
1.0 1.0
Group
Group
Group
Mean
Mean
Mean
Std Error
Std Error
Std Error
CC
CC
CC
3.94884
3.94884
3.94884
0.18974
0.18974
0.18974
0.9 0.9
EE
EE
EE
4.52657
4.52657
4.52657
0.22577
0.22577
0.22577
FF
FF
FF
4.09881
4.09881
4.09881
0.17986
0.17986
0.17986
GG
GG
GG
4.27485
4.27485
4.27485
0.2131
0.2131
0.2131
0.8 0.8
HH
HH
HH
4.56832
4.56832
4.56832
0.17349
0.17349
0.17349
II
II
II
5.17241
5.17241
5.17241
0.24473
0.24473
0.24473
JJ
JJ
JJ
4.29944
4.29944
4.29944
0.20656
0.20656
0.20656
0.7 0.7
KK
KK
KK
3.61658
3.61658
3.61658
0.18201
0.18201
0.18201
OO
OO
OO
4.04233
4.04233
4.04233
0.20254
0.20254
0.20254
QQ
QQ
QQ
4.4006
4.4006
4.4006
0.16811
0.16811
0.16811
0.6 0.6
Combined
Combined
Combined
4.30318
4.30318
4.30318
0.06264
0.06264
0.06264
0.5 0.5
0.4 0.4
0.3 0.3
Over this period of 3me, one
provider (II) has a tendency to
treat for more than the five day
target. Provider-specific counseling
in 2011 has resulted in a reduc3on
of an3bio3c days in 2012 (see
following graphic)
0.2 0.2
0.1 0.1
0 0
1 1
2
2
3
3
4
4
5
5
6
6
7
7
8
8
9
9
10
10
11
11
12
12
13
13
14
14
15
15
Percentage of treated patients
Percentage of treated patients

Duration of initial antibiotic course (days)

Duration of initial antibiotic course (days)

Average Duration of Initial Course of Antibiotic Therapy (Days)

Average Duration of Initial Course of Antibiotic Therapy (Days)

Prac##oner Modifies Prac#ce

7

7

7

6

6

6

5

5

5

4

4

4

3

3

3

2

2

2

1 1 1

0

0

0

2006 2006 2007 2007 2008 2008 2009 2009 2010 2010 2011 2011 2012 2012 Years
2006 2006
2007
2007
2008
2008
2009
2009
2010
2010
2011
2011
2012
2012
Years
Years

An#bio#cs for > 5 days 1 st An#bio#c Course

100

90

80

70

60

50

40

30

20

10

0

80 70 60 50 40 30 20 10 0 ALL DUKE High Low 2001 2002 2003
ALL DUKE High Low
ALL
DUKE
High
Low
50 40 30 20 10 0 ALL DUKE High Low 2001 2002 2003 2004 2005 2006
50 40 30 20 10 0 ALL DUKE High Low 2001 2002 2003 2004 2005 2006
50 40 30 20 10 0 ALL DUKE High Low 2001 2002 2003 2004 2005 2006

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

Pediatrix Data An#bio#c Dura#on Nega#ve Cultures
Pediatrix Data
An#bio#c Dura#on Nega#ve Cultures

1997

19981997 1999 2000 2001   2002 2003 2004

19991997 1998 2000 2001   2002 2003 2004

20001997 1998 1999 2001   2002 2003 2004

1997 1998 1999 2000 2001   2002 2003 2004

2001

 

2002

2003

1997 1998 1999 2000 2001   2002 2003 2004

2004

2005

20062005 2007 2008 2009 2010 2011  

20072005 2006 2008 2009 2010 2011  

20082005 2006 2007 2009 2010 2011  

2009

2005 2006 2007 2008 2009 2010 2011  

2010

2011

2011

 

0.6

0.5

0.4

0.3

0.2

0.1

0

2011
2011

Peaks in an#bio#c dura#on are shiDing “to the leD” – shorter dura#on of empiric use

1997
1997
“to the leD” – shorter dura#on of empiric use 1997 0 1 2 3 4 5

0

1

2

3

4

5

6

7

Days

8

9

10

11

12

13

14

Pediatrix Slide courtesy of A. Spitzer

2016 Choosing Antibiotics Wisely NICHD NRN ELBW: Late onset sepsis ALL High Low Duke alone

2016 Choosing Antibiotics Wisely

NICHD NRN ELBW: Late onset sepsis

ALL High Low Duke alone 36% 19%
ALL
High
Low
Duke alone
36%
19%

70

60

50

40

30

20

10

0

2001 2002

2003

2004

2005 2006

2007

2008

2009

2010 2011

2012 2013

2014 2015

Duke alone 36% 19% 70 60 50 40 30 20 10 0 2001 2002 2003 2004

ELBW…All NEC

NRN overall, high, low, Duke site and Duke alone as of 9/30/2015

35 ALL High Low 30 Duke alone 25 20 15 10 5 0
35
ALL
High
Low
30
Duke alone
25
20
15
10
5
0

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

Extreme Preterm Mortality

Duke ELBW inborn infants and NICHD NRN GDB: all sites combined, and high and low site % mortality for GDB infants

70

60

50

40

30

20

10

0

Duke InbornNRN GDB NRN GDB High Ctr NRN GDB Low Ctr

NRN GDBDuke Inborn NRN GDB High Ctr NRN GDB Low Ctr

NRN GDB High Ctr NRN GDB Low Ctr

0 Duke Inborn NRN GDB NRN GDB High Ctr NRN GDB Low Ctr 1997 1998 1999
0 Duke Inborn NRN GDB NRN GDB High Ctr NRN GDB Low Ctr 1997 1998 1999

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

  NICHD NRN: Late Onset Sepsis: Gram Posi#ve Organisms   Era 1 (2000-05) (N =
 

NICHD NRN: Late Onset Sepsis: Gram Posi#ve Organisms

 

Era 1 (2000-05) (N = 1896)

Era 2 (2006-11) (N = 1728)

P

-value

Gram-posi#ve, N (%)

1504 (78%)

1386

(79%)

.55

 

CoNS

973 (50%)

1007

(57%)

 

Staphylococcus aureus

217 (11%)

212 (12%)

 

Staphylococcus spp. (unspecified)

136 (7%)

0

(0%)

 

Enterococcus spp.

61

(3%)

92

(5%)

 

Streptococcus spp. (unspecified)

52

(3%)

0

(0%)

 

Group B Streptococcus

30

(2%)

45

(3%)

 

Streptococcus

1 (0.1%)

1

(0.1%)

pneumoniae

 

Group A Streptococcus

0

(0%)

6

(0.3%)

 

Clostridia spp.

0

(0%)

1

(0.1%)

 

Possible contaminants a

34

(2%)

22

(1%)

Greenberg R. et al. Late-onset sepsis in extremely premature infants: trends over 3me and correla3on with mortality. EPAS2014:1540.641

  NICHD NRN: ELBW Late Onset Sepsis: Gram nega#ve organisms   Era 1 (2000-05) (N
 

NICHD NRN: ELBW Late Onset Sepsis: Gram nega#ve organisms

 

Era 1 (2000-05) (N = 1896)

Era 2 (2006-11) (N = 1728)

P

-value

Gram-nega#ve , N (%)

371 (19%)

329 (19%)

 

.74

Escherichia coli

103 (5%)

117 (7%)

 

Klebsiella spp.

92

(5%)

90

(5%)

 

Enterobacter spp.

74

(4%)

45

(3%)

 

Pseudomonas spp.

58

(3%)

30

(2%)

 

Serra@a spp.

30

(2%)

24

(1%)

 

Citrobacter spp.

7

(0.4%)

10 (0.6%)

 

Proteus spp.

4

(0.2%)

6

(0.3%)

 

Acinetobacter spp.

2

(0.1%)

6

(0.3%)

 

Stenotrophomonas

0 (0%)

1

(0.1%)

 

maltophilia

Possible contaminants a

1

(0.1%)

0 (0%)

 

Greenberg R. et al. Late-onset sepsis in extremely premature infants: trends over 3me and correla3on with mortality. EPAS2014:1540.641

2016 Choosing Antibiotics Wisely Candidiasis and An#bio#c Stewardship •   Infants <1000 g birth weight

2016 Choosing Antibiotics Wisely

Candidiasis and An#bio#c Stewardship

Infants <1000 g birth weight

Candida - 73% death or neurodevelopmental impairment

Pediatrix Cohort of infants <1250 g (N = 21,233 cultures; 6,172 babies) > 3 days old

Variable

Category

OR

95% CI

Gestational age

28 wk

Referrent

 

-

 

25-27 wk

2.02

1.52

– 3.05

 

< 25 wk

4.15

3.12

– 6.12

Thrombocytopenia

Plt ct > 150

Referrent

 
 

Value <150

3.56

2.68–4.74

Cephalosporin or Carbepenem

no

Referrent

 
 

yes

1.77

1.33

– 2.29

Benjamin DK Jr et al. Empirical therapy for neonatal candidemia in very low birth weight infants. Pediatrics. 2003;112:543-7.

DK Jr et al. Empirical therapy for neonatal candidemia in very low birth weight infants. Pediatrics.
DK Jr et al. Empirical therapy for neonatal candidemia in very low birth weight infants. Pediatrics.
2016 Choosing Antibiotics Wisely Mortality Following Posi#ve Blood Culture •   Pediatrix Database •  

2016 Choosing Antibiotics Wisely

Mortality Following Posi#ve Blood Culture

Pediatrix Database < 1250 g birth weight 6172 with blood culture aLer day of life 3 1299 had a posi3ve culture Candida and Pseudomonas mortality (33% vs. 13% other G neg) the worst

Pseudomonas mortality (33% vs. 13% other G neg ) the worst •   Benjamin, DK Jr

Benjamin, DK Jr et al. Mortality following blood culture in premature infants: increased with gram-nega3ve bacteremia and Candidemia, but not gram-posi3ve bacteremia. Journal of Perinatology 2004;24:175-180. Benjamin DK Jr et al. Postconcep3on age and other risk factors associated with mortality following Gram-nega3ve rod bacteremia. J Perinatol. 2004;24:169-74.

age and other risk factors associated with mortality following Gram-nega3ve rod bacteremia. J Perinatol. 2004;24:169-74.
age and other risk factors associated with mortality following Gram-nega3ve rod bacteremia. J Perinatol. 2004;24:169-74.
age and other risk factors associated with mortality following Gram-nega3ve rod bacteremia. J Perinatol. 2004;24:169-74.
age and other risk factors associated with mortality following Gram-nega3ve rod bacteremia. J Perinatol. 2004;24:169-74.

An#bio#c risks: First days of life

Empirical Ini3al Broad Spectrum use varies by center

of life Empirical Ini3al Broad Spectrum use varies by center •   15 % of 165

15 % of 165 sites that reported data for >100 patients administered amp and cefotaxime concurrently for >50% of their patients • Proxies for selection bias may not reflect adequately the true severity of illness or the therapeutic approach.

Adjusted Mortality Odds Ratios within gestational-age groups Cefotaxime use associated odds of death

groups Cefotaxime use associated odds of death adjusted for: need for assisted ventilation, anomalies,

adjusted for: need for assisted ventilation, anomalies, birth depression, and estimated gestational age [EGA] within each estimated gestational-age group)

Clark, R. H. et al. Pediatrics 2006;117:67-74

Copyright ©2006 American Academy of Pediatrics

gestational-age group) Clark, R. H. et al. Pediatrics 2006;117:67-74 Copyright ©2006 American Academy of Pediatrics
2016 Choosing Antibiotics Wisely Candidiasis and An#bio#c Stewardship •   NICHD NRN cohort study: 2,888

2016 Choosing Antibiotics Wisely

Candidiasis and An#bio#c Stewardship

NICHD NRN cohort study: 2,888 inborn ELBWs; 1998-2001

Variable

Correlation with Candidiasis Correlation coefficient (p-value)

Candida Rate Center Range: 2.4% - 20.4%

1

N/A

Average Days of Broad Spectrum Antibiotics (BSAs) per infant Range: 0.9 – 15.42 days

0.6925

(0.0126)

Average Days of BSA’s with negative cultures per infant Range: 0.86 – 13.66 days

0.7048

(0.0105)

Co,en CM et al. The associa3on of third-genera3on cephalosporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics 2006;118:717-22.

cephalosporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics 2006;118:717-22.
cephalosporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics 2006;118:717-22.
2016 Choosing Antibiotics Wisely Candidiasis is decreasing Broad-spectrum an#bio#c use Fluconazole prophylaxis Aliaga S et

2016 Choosing Antibiotics Wisely

Candidiasis is decreasing

2016 Choosing Antibiotics Wisely Candidiasis is decreasing Broad-spectrum an#bio#c use Fluconazole prophylaxis Aliaga S et

Broad-spectrum an#bio#c use

Wisely Candidiasis is decreasing Broad-spectrum an#bio#c use Fluconazole prophylaxis Aliaga S et al. Changes in the

Fluconazole prophylaxis

Broad-spectrum an#bio#c use Fluconazole prophylaxis Aliaga S et al. Changes in the incidence of candidiasis in
Broad-spectrum an#bio#c use Fluconazole prophylaxis Aliaga S et al. Changes in the incidence of candidiasis in
Broad-spectrum an#bio#c use Fluconazole prophylaxis Aliaga S et al. Changes in the incidence of candidiasis in
Broad-spectrum an#bio#c use Fluconazole prophylaxis Aliaga S et al. Changes in the incidence of candidiasis in
Broad-spectrum an#bio#c use Fluconazole prophylaxis Aliaga S et al. Changes in the incidence of candidiasis in
Broad-spectrum an#bio#c use Fluconazole prophylaxis Aliaga S et al. Changes in the incidence of candidiasis in

Aliaga S et al. Changes in the incidence of candidiasis in neonatal intensive care units. Pediatrics. 2014 Feb;133(2):236-42.

NICHD NRN: Late onset sepsis: Fungal Infec#ons   Era 1 (2000-05) (N = 1896) Era

NICHD NRN: Late onset sepsis: Fungal Infec#ons

 

Era 1 (2000-05) (N = 1896)

Era 2 (2006-11) (N = 1728)

P

-value

Fungus, N (%)

188 (10%)

111 (6%)

 

<.001

Candida spp. b

182 (9%)

96 (6%)

 

Other fungi c

6 (0.3%)

15 (0.9%)

 

Greenberg R. et al. Late-onset sepsis in extremely premature infants: trends over 3me and correla3on with mortality.

EPAS2014:1540.641

NICHD N EONATAL R ESEARCH N ETWORK RG Greenberg, PB Smith, D Chowdhury, NI Hansen,

NICHD

NEONATAL RESEARCH NETWORK

NICHD N EONATAL R ESEARCH N ETWORK RG Greenberg, PB Smith, D Chowdhury, NI Hansen, PJ

RG Greenberg, PB Smith, D Chowdhury, NI Hansen, PJ Sanchez, BJ Stoll, RD Higgins, CM Co,en, and the GDB Subcommi,ee, on behalf of the Eunice Kennedy Shriver NICHD Neonatal Research Network (NRN)

Higgins, CM Co,en, and the GDB Subcommi,ee, on behalf of the Eunice Kennedy Shriver NICHD Neonatal
Higgins, CM Co,en, and the GDB Subcommi,ee, on behalf of the Eunice Kennedy Shriver NICHD Neonatal

Background

— In 2009 2 , the NICHD NRN reported that 53% of infants (1998-2001) had empiric an3bio3c therapy con3nued for ≥5 days for “culture-nega3ve” early-onset sepsis — Associated with:

 

OR (95% CI)

Death

1.46

(1.19-1.78)

Necro#zing enterocoli#s (NEC) or death

1.30

(1.10-1.54)

Late-onset sepsis or death

1.24

(1.06-1.44)

2 Cotten et al., Pediatrics 2009;123:58–66

(1.10-1.54) Late-onset sepsis or death 1.24 (1.06-1.44) 2 Cotten et al., Pediatrics 2009;123:58–66
(1.10-1.54) Late-onset sepsis or death 1.24 (1.06-1.44) 2 Cotten et al., Pediatrics 2009;123:58–66
50% 36% Adjusted OR (95% CI) for birth year: 0.87 (0.85-90)
50%
36%
Adjusted OR (95% CI) for birth year: 0.87 (0.85-90)
50% 36% Adjusted OR (95% CI) for birth year: 0.87 (0.85-90)
50% 36% Adjusted OR (95% CI) for birth year: 0.87 (0.85-90)
69% First report: range was 27 – 85% 30%
69%
First report: range was 27 – 85%
30%
69% First report: range was 27 – 85% 30%
69% First report: range was 27 – 85% 30%

Mul#variable logis#c regression

   

Outcome

     

No

Yes

Adjusted OR (95% CI)

P-value

Death, N

4934

 

919

   

Prolonged initial therapy, n (%)

2105 (43%)

496 (54%)

1.20 (1.02, 1.42)

0.030

Death or NEC, N

4528

1325

   

Prolonged initial therapy, n (%)

1930

(43%)

670

(51%)

1.10

(0.95, 1.26)

0.196

NEC, N

5196

 

668

   

Prolonged initial therapy, n (%)

2301

(44%)

303

(45%)

1.01

(0.84, 1.20)

0.955

Death, NEC, or LOS, N

3457

2400

   

Prolonged initial therapy, N (%)

1447

(42%)

1155 (48%)

0.99

(0.87, 1.12)

0.837

Fungal LOS, N

1531

 

120

   

Prolonged initial therapy, N (%)

681 (45%)

71 (59%)

1.50

(0.99, 2.26)

0.054

43% of survivors had prolonged abx compared with 54% of those that died 43 % of survivors without NEC had prolonged abx compared with 51% of those that died or had NEC 45% of those that did not have fungal sepsis had prolonged abx compared with 59% of those that had fungal infections

45% of those that did not have fungal sepsis had prolonged abx compared with 59% of
45% of those that did not have fungal sepsis had prolonged abx compared with 59% of

Conclusions

— The propor3on of infants receiving prolonged ini3al empiric an3bio3c therapy — Varied greatly by center — Decreased over 3me — The associa3on of this prac3ce with adverse outcome remains somewhat consistent with previous reports — These findings support the con3nued need for emphasis on an3bio3c stewardship in the NICU

with previous reports —   These findings support the con3nued need for emphasis on an3bio3c stewardship
with previous reports —   These findings support the con3nued need for emphasis on an3bio3c stewardship
2016 Choosing Antibiotics Wisely An#microbials: Commonly Used in NICUs •   1,425,992 records: 1996 –2005.

2016 Choosing Antibiotics Wisely

An#microbials: Commonly Used in NICUs

1,425,992 records: 1996 –2005.

Ampicillin #1 Gentamicin #2 Cefotaxime #5 Vanco #8

450,000 NICU records: 2005 – 2010

Ampicillin #1 Gentamicin #2 Vancomycin #4 Cefotaxime #15 Fluconazole #27 CeDaz #38 Pip/ Tazo #41

ELBW Infants 2005 - 2010 Gent #1 Amp #2 Vanc # 4 Cefotax #14 Flucon #18

Clark RH et al. Pediatrics 2006; 117:1979-1987 Hsieh EM et al. Am J Perinatology 2014;31:811-2

#18 •   Clark RH et al. Pediatrics 2006; 117:1979-1987 •   Hsieh EM et al.
2016 Choosing Antibiotics Wisely An#microbials – increase in use •   From 2005 report to

2016 Choosing Antibiotics Wisely

An#microbials – increase in use

From 2005 report to 2010 report, all NICU admits

70% increase in use of cefepime (4 th gen) 97% increase in use of piperacillin-tazobactam 100% increase in use of meropenem 350% increase in use of cefoxi3n 500% increase in use of linezolid 2900% increase in use of azithromycin

Clark RH et al. Pediatrics 2006; 117:1979-1987 Hsieh EM et al. Am J Perinatology 2014;31:811-2

in use of azithromycin Clark RH et al. Pediatrics 2006; 117:1979-1987 Hsieh EM et al. Am
in use of azithromycin Clark RH et al. Pediatrics 2006; 117:1979-1987 Hsieh EM et al. Am

How can we limit how many we treat?

Management of neonates with suspected or proven early-onset neonatal sepsis

Evaluation of asymptomatic infants <37 weeks’ gestation with risk factors for sepsis.

The diagnosis of chorioamnionitis is problematic and has important implications for the management of the newborn infant.

implications for the management of the newborn infant. Polin R A , and the COMMITTEE ON
implications for the management of the newborn infant. Polin R A , and the COMMITTEE ON

Polin R A , and the COMMITTEE ON FETUS AND NEWBORN Pediatrics 2012;129:1006-1015

©2012 by American Academy of Pediatrics

Management of neonates with suspected or proven early-onset neonatal sepsis

Evaluation of asymptomatic infants 37 weeks’ gestation with risk factors for sepsis. The diagnosis of chorioamnionitis is problematic and has important implications for the management of the newborn infant.

implications for the management of the newborn infant. Polin R A , and the COMMITTEE ON
implications for the management of the newborn infant. Polin R A , and the COMMITTEE ON

Polin R A , and the COMMITTEE ON FETUS AND NEWBORN Pediatrics 2012;129:1006-1015

©2012 by American Academy of Pediatrics

On the basis of the available data, Polin et al conclude the following:

Symptoma3c neonates without risk factors for infec3on (who improve over the first 6 hours of life) may not require treatment, but must be monitored closely. Chorioamnioni#s significantly increases the risk of early-onset sepsis; however, the likelihood of sepsis in an infant who appears well at birth is low. The risk of sepsis is reduced in infants born to mothers with chorioamnioni3s who receive intrapartum an3bio3cs, but an3bio3cs may be less effec3ve once chorioamnioni3s is established. The intrapartum use of an3bio3cs decreases the sensi3vity of postnatal blood cultures. Commonly used laboratory tests have a limited posi3ve predic3ve accuracy and should never be used as a ra3onale to con3nue treatment in an otherwise healthy term infant at 48 to 72 hours of life. Physical examina#on is as good or bever than most laboratory tests in “ruling in or ruling out” sepsis.

•   Physical examina#on is as good or bever than most laboratory tests in “ruling in
•   Physical examina#on is as good or bever than most laboratory tests in “ruling in

Polin et al. suggest:

An3bio3cs may be discon3nued in well-appearing term newborn infants born to women with chorioamnioni3s by 48 hours of life; treatment of 72 hours might be considered for infants with greater degrees of prematurity or abnormal screening studies A lumbar puncture should be performed in

(1) infants with a posi3ve blood culture, (2) infants with a high probability of sepsis on the basis of clinical signs or abnormal laboratory data, (3) infants who do not clinically improve when treated with appropriate an3microbial therapy

Conundrum of Early – Onset Sepsis: NEW ALGORITHM, Labs, what labs

Evaluation of asymptomatic infants (any gestational age).

Evaluation of asymptomatic infants (any gestational age). Polin R A et al. Pediatrics 2014;133:1122-1123 ©2014 by

Polin R A et al. Pediatrics 2014;133:1122-1123

©2014 by American Academy of Pediatrics

Revised leaves out the “continue antibiotics if labs abnormal”

©2014 by American Academy of Pediatrics Revised leaves out the “continue antibiotics if labs abnormal”

Escobar GJ, Puopolo KM, Wi S et al. Stra#fica#on of risk of early-onset sepsis in newborns >/= 34 weeks' gesta#on. Pediatrics 2014;133(1):30-36.

“It is possible to combine objec3ve maternal data with evolving objecCve neonatal clinical findings to define more efficient strategies for the evalua3on and treatment of EOS in term and late preterm infants. Judicious applica3on of our scheme could result in decreased an3bio3c treatment in 80,000 to 240,000 US newborns each year”

Slide from Reese Clark

Escobar GJ, Puopolo KM, Wi S et al. Stra#fica#on of risk of early-onset sepsis in newborns >/= 34 weeks' gesta#on. Pediatrics 2014;133(1):30-36.

OBJECTIVE: To define a quan3ta3ve stra3fica3on algorithm for the risk of early-onset sepsis (EOS) in newborns >/= 34 weeks' gesta3on. A retrospec3ve nested case-control study that used split valida3on. Using a combina3on of recursive par33oning and logis3c regression, we developed a risk classifica3on scheme for EOS on the deriva3on dataset. This scheme was then applied to the valida3on dataset.

Neonatal Sepsis Calculator

Results are quan#ta#ve:

EOS risk at birth Risks different per clinical appearance Well appearing Equivocal Clinical Illness Clinical recommenda#on for each clinical exam scenario

Recommenda#ons include Culture y/n An3bio3cs y/n Vital sign schedule

Clinical Exam

 

Description

 

1.Persistent need for CPAP / HFNC / IMV (outside the delivery room) 2.Hemodynamic instability requiring vasoactive drugs 3.Neonatal encephalopathy /Perinatal depression

Clinical Illness

1.

Seizure Apgar Score @ 5 minutes < 5

2.

4.Need for supplemental O 2 > 2 hours to maintain oxygen saturations > 90% (outside of the delivery room)

 

1.Persistent physiologic abnormality > 4 hrs

1.

Tachycardia (HR > 160) Tachypnea (RR > 60) Temperature instability (> 100.4˚F or < 97.5˚F) Respiratory distress (grunting, flaring, or

2.

3.

4.

Equivocal

retracting) not requiring supplemental O 2 2.Two or more physiologic abnormalities lasting for > 2 hrs

1.

Tachycardia (HR > 160)

2.

Tachypnea (RR > 60) Temperature instability (> 100.4˚F or < 97.5˚F)

3.

4.

Respiratory distress (grunting, flaring, or retracting) not requiring supplemental O 2

Note: abnormality can be intermittent

Well Appearing

No persistent physiologic abnormalities

hvp://www.dor.kaiser.org/external/DORExternal/research/Infec#onProbabilityCalculator.aspx

Reducing Reliance on Diagnos#c Tests

Swiss Health System//U of Lausanne Lab guided tests leads to lots of false posi3ves treated with ABX. Vast majority of infants with EOS develop signs in first 24 postnatal hours GBS moms all got CDC guided prophylaxis.

hours •   GBS moms all got CDC guided prophylaxis. Duvoisin G, Fischer C, Maucort-Boulch D,

Duvoisin G, Fischer C, Maucort-Boulch D, Giannoni E. Reduc3on in the use of diagnos3c tests in infants with risk factors for early-onset neonatal sepsis does not delay an3bio3c treatment. Swiss Med Wkly. 2014 Jun

Reducing Reliance on Diagnos#c Tests

Old Guideline: December 2006 – September 2009 CBC w/ manual diff and CRP in all infants born to mothers with at least one risk factor for neonatal infec3on:

inadequate GBS prophylaxis, rupture of membranes >18 hours [PROM], maternal fever, prematurity <37 weeks of gesta3on

No specific instruc3ons regarding the 3ming of diagnos3c tests. Vital signs were checked by midwives every 4 hours during the first 24 hours and every 8 hours during the next 24 hours in all infants with risk factors for EOS.

Duvoisin G, Fischer C, Maucort-Boulch D, Giannoni E. Reduc3on in the use of diagnos3c tests in infants with risk factors for early-onset neonatal sepsis does not delay an3bio3c treatment. Swiss Med Wkly. 2014 Jun 25;144:w13981.

Reducing Reliance on Diagnos#c Tests

“New” Guideline: October 2009 – December 2011 Monitoring of vital signs by midwives as before, Plus:

Infants with risk factors for EOS were examined by paediatric residents every 8 hours during the first 24 hours. A CBC was performed only in infants exposed to maternal chorioamnioni3s ,

Chorio : defined as maternal fever > 38 °C plus at least two of the following signs:

maternal heart rate >100/min, fetal heart rate >160/min, uterine tenderness, purulent amnio3c fluid, maternal leucocytosis 15,000/mL

Duvoisin G, Fischer C, Maucort-Boulch D, Giannoni E. Reduc3on in the use of diagnos3c tests in infants with risk factors for early-onset neonatal sepsis does not delay an3bio3c treatment. Swiss Med Wkly. 2014 Jun 25;144:w13981.

Reducing Reliance on Diagnos#c Tests

Neonatal infec#on was defined as:

(A) culture-proven infec3on (posi3ve blood and/or cerebrospinal fluid culture) or (B) probable infec3on with ≥2 signs of sepsis within the first 7 postnatal days

temperature instability, irritability or lethargy, feeding difficul3es, capillary refill >2 seconds, apnoea, tachycardia and/or tachypnoea), and elevated CRP >20 mg/l, and the decision of the avending neonatologist to treat for at least 7 days with intravenous an#bio#cs.

Duvoisin G, Fischer C, Maucort-Boulch D, Giannoni E. Reduc3on in the use of diagnos3c tests in infants with risk factors for early-onset neonatal sepsis does not delay an3bio3c treatment. Swiss Med Wkly. 2014 Jun 25;144:w13981.

Reducing Reliance on Diagnos#c Tests

Common to both:

Decision for ABX y/n up to clinician Blood cultures only in treated pa3ents CBC and CRP measurements performed during both study periods in all treated pa@ents to assist clinicians in determining the dura3on of an3bio3c treatment. Lumbar punctures were performed on an individual basis

Duvoisin G, Fischer C, Maucort-Boulch D, Giannoni E. Reduc3on in the use of diagnos3c tests in infants with risk factors for early- onset neonatal sepsis does not delay an3bio3c treatment. Swiss Med Wkly. 2014 Jun 25;144:w13981.

Reducing Reliance on Diagnos#c Tests

N = 11,613 ≥ 35 weeks (6183 period 1; 5320 period 2) Maternal characteris3cs in periods 1 and 2 similar. CRP measurements and CBCs ** performed :

26.8 (CRP) and 51.3 (CBC) per 100 live births during Period 1 2. 3 (CRP) and 36.1 (CBC) per 100 live births during Period 2 (p

<0.0001).

222 total infants total treated for suspected EOS.

2.1% (132/6183) treated in Period 1 1.7% (90/5,320) treated in Period 2.

27% (36/132) treated longer for infec#on in Period 1 18% (16/90) treated longer for infec#on in Period 2 Period 1: three w/ posi3ve blood cultures, 1 w/ CSF Period 2: 0 with posi3ve blood or CSF culture.

Reducing Reliance on Diagnos#c Tests

Time between birth and first dose shorter in Period 2, (Figure)

median 4.5 hours; Q1–Q3 2.6–10.9 hours) compared with Period 1 (median 10.7 hours; Q1–Q3 4.1–26.9 hours; table 2).

Dura#on of ABX in non-infected pa#ents shorter in Period 2 than Period 1

(median 66.6 hours; Q1–Q3 62.4–127.1 during Period 1 and 64.0 hours; Q1–Q3 60.6–66.8 during Period 2, p = 0.003),

all infants treated for suspected EOS Full line: period 1 all infants with signs of
all infants treated for
suspected EOS
Full line: period 1
all infants with
signs of infec#on
Full line: period 1

Duvoisin G, Fischer C, Maucort-Boulch D, Giannoni E. Reduc3on in the use of diagnos3c tests in infants with risk factors for early-onset neonatal sepsis does not delay an3bio3c treatment. Swiss Med Wkly. 2014 Jun 25;144:w13981.

Summary

More than 95% of the pa3ents we treat with an3bio3cs have nega3ve cultures,,, even in “high risk pa3ents” We use lots of an3bio3cs for lots of days and lots of doses. With every extra day and every extra dose there is the poten3al for error Accumula3ng evidence from several different sources suggest prolonged exposure to an3bio3cs is associated with NEC, mortality, and a higher likelihood of subsequent development of infec3ons with resistant organisms Some hopeful strategies to reduce exposures

From: Variation in Performance of Neonatal Intensive Care Units in the United States JAMA Pediatr.

From: Variation in Performance of Neonatal Intensive Care Units in the United States

JAMA Pediatr. Published online January 09, 2017.e164396 doi:10.1001/jamapediatrics.2016.4396

LOS in VLBWS Drops from unadjusted rate of 22% to 10% 678 of 695 NICUs (97.6%; 95% CI, 95.8%-99.6%) achieved shrunken adjusted rates of late-onset infection as low as or lower than the rate of the best quartile in 2005 Worst performers in 2014 (90 th percentile) were better than best performers (10 th percentile) of 2005!!

ALSO SIMILAR RESULTS FOR MORTALITY

Figure Legend:

Mortality CLD Late onset sepsis NEC Severe IVH Severe ROP
Mortality
CLD
Late onset sepsis
NEC
Severe IVH
Severe ROP

Risk-Adjusted Rates of Outcomes in the Neonatal Intensive Care Unit at the 10th, 25th, 50th, 75th, and 90th Percentiles, 2005-2014These charts illustrate percentiles of risk-adjusted rates for mortality and neonatal morbidities by year. A, Mortality. B, Chronic lung disease. C, Late-onset infection. D, Necrotizing enterocolitis . E, Severe intraventricular hemorrhage. F, Severe retinopathy of prematurity.

Date of download: 1/9/2017

Copyright © 2017 American Medical Association. All rights reserved.

Closing thoughts

An3bio3cs save lives Preven3ng infec3ons is most effec3ve way to avoid consequences of bacterial overuse An3bio3c exposures are unavoidable Follow local epidemiology, but look for best

prac3ces

Con3nue learning to use the EHR and your clinical skills

QC for prac3ce Epidemiology of infec3ons Combining mul3center data to iden3fy highest risk infants

Thanks!

PQCNC Teams and Leaders Duke colleagues

Ron Goldberg Patrick Seed (now a W-cat) Brian Smith Danny Benjamin Susan Latuga (now in NYC) Noelle Younge Rachel Greenberg Eric Benner Jim Wynn (now a Gator)

NRN colleagues and mentors

Barbara Stoll Pablo Sanchez Rich Polin

Non-NRN colleague and mentors

Joe Neu

Study team at Duke

Kim Fisher BSN PhD Joanne Finkle BSN JD Mandy Marion