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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 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

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

Antibiotics influence this
balance…..What else tips the
balance????
(Tribute to Nancy Fawcett, MD)

Body  weight  -­‐  microflora  con#nued  
WT  and  obese  mouse  experiments  
Stool  calorimetry:    
energy  lost  from  similar  diets  

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)  

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

Bacterial succession in term
babies
Aerobes  

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

Obligate  anaerobes  
 Bacteroides  
 Clostridia  

Adulthood  

 
  **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.”  
• 
• 
• 
• 
• 
• 
• 
• 

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  
•  1/3rd  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

Before national prevention policy Transition

Universal screening

Source: Active Bacterial Core surveillance / Emerging Infections Program

Preterm  Infants  
•  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  medical  group,  by  way  of  P.  Brian  Smith  

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%

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  
•  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  

ALL  
Low  
Duke  
alone  

20  
15  
10  
5  
0  
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  

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

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

21  

Experiment  1A:  Intact  Innate  Immune  response  is  
important  to  Gut  Integrity  post  injury  
DSS  +  WT  Intact  immune  response:  
100%  survival  

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

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

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

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)

Clamoxyl  affects  intes#nal  gene  expression  
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  
Germ - Free

Ex germ-free
conventionalized

Ex germ free with B.
thetha

Green  marker  for  developing  endothelial  cells  

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

26  

Metagenome  

RNA  metabolism  
Virulence  
Phosphorous  metabolism  
Protein  metabolism  
DNA  metabolism  
Cell  wall  and  capsule  
Clustering-­‐based  subsystems  
Carbohydrates  
Amino  acids  and  deriva3ves  
Stress  response  
Respira3on  

Adult  

Baby  1  

Latuga  MS,  et  al.  2011  

Baby  2  

Results:  Scaffolds-­‐Baby  1    

Sequence  Size  Distribu3on  
(n=52  scaffolds)  

GC  (%)  Distribu3on)  

Virulence  

An3bio3c  resistance  

Cell  Cycle  
Amino  Acids  
Fa,y  Acids/Lipid  
Carbohydrate  

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  

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  

Sequence  Size  Distribu3on  
(n=56  scaffolds)  

GC  (%)  Distribu3on)  

virulence  
An3bio3c  resistance  

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

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

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.

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

Changes  in  propor#on  of  bacterial  phyla.  

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

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

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

Results
Median Duration of Empirical Initial Antibiotics
10
9

Median Days

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 Total
20

Centers
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%

% 5 or more days

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

DUKE
Now < 70%

FIGURE 1 Numbers of study infants according to duration of initial empirical 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)
p-value Odds ratio (95% CI) p-value
(each day)
NEC or
Death
NEC
Death

1.04 (1.02, 1.06)

< 0.01

1.30 (1.10, 1.55)

< 0.01

1.07 (1.04, 1.10)

<0.01

1.21 (0.98, 1.51)

0.08

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  

•  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.  

3rd  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  =  
365  

OR*  

CI  

NNH  

Late  onset  
sepsis    

76  (21%)  

2.45  

1.28-­‐4.67  

…  

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.  

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

Average Duration of Initial Course of Antibiotic Therapy (Days)

Monitoring  An#bio#c  Dura#on  
6

Target: Less than 5 days

5

4

3

2

1

0

2006

2007

2008

2009

2010

Years:

2011

 P  <0.001  

2012

Individual  Prac##oner  ABX  Dura#on  
1.0
Group
CC
EE
FF
GG
HH
II
JJ
KK
OO
QQ
Combined

Percentage of treated patients

0.9
0.8
0.7
0.6

Mean
3.94884
4.52657
4.09881
4.27485
4.56832
5.17241
4.29944
3.61658
4.04233
4.4006
4.30318

Std Error
0.18974
0.22577
0.17986
0.2131
0.17349
0.24473
0.20656
0.18201
0.20254
0.16811
0.06264

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)  

0.5
0.4
0.3
0.2
0.1
0
1

2

3

4

5

6

7

8

9

10

11 12

Duration of initial antibiotic course (days)

13

14

15

Average Duration of Initial Course of Antibiotic Therapy (Days)

Prac##oner  Modifies  Prac#ce  
7
6
5
4
3
2
1
0

2006

2007

2008

2009
Years

2010

2011

2012

An#bio#cs  for  >  5  days  1st  An#bio#c  Course  
100  
90  
80  
70  
ALL  

60  

DUKE  
High  

50  

Low  

40  
30  
20  
10  
0  

2001  

2002  

2003  

2004  

2005  

2006  

2007  

2008  

2009  

2010  

2011  

2012  

2013  

2014  

Pediatrix  Data  
An#bio#c  Dura#on  Nega#ve  Cultures  
0.6  

1997  

1998  

1999  

2000  

2001  

2002  

2003  

2005  

2006  

2007  

2008  

2009  

2010  

2011  

2011  

2004  

1997  
Peaks  in  an#bio#c  dura#on  are  
shiDing  “to  the  leD”  –  shorter  
dura#on  of  empiric  use  

0.5  
0.4  
0.3  
0.2  
0.1  
0  
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
70  

NICHD  NRN  ELBW:  Late  onset  sepsis  
ALL  
High  

60  

Low  
Duke  alone  

50  
40  
30  
20  

36%  
19%  

10  
0  
2001   2002   2003   2004   2005   2006   2007   2008   2009   2010   2011   2012   2013   2014   2015  

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  
2000  

2001  

2002  

2003  

2004  

2005  

2006  

2007  

2008  

2009  

2010  

2011  

2012  

2013  

2014  

2015  

Extreme  Preterm  Mortality    

70  

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

60  

NRN  GDB  High  Ctr  
NRN  GDB  Low  Ctr  

50  

40  

30  

20  

10  

0  
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  =  1896)  

Era  2  (2006-­‐11)  
(N  =  1728)  

P-­‐value  

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  
pneumoniae  

1  (0.1%)  

1  (0.1%)  

Group  A  Streptococcus  

0  (0%)  

6  (0.3%)  

 

Clostridia  spp.  

0  (0%)  

1  (0.1%)  

 

Possible  
contaminantsa  

34  (2%)  

22  (1%)  

Gram-­‐posi#ve,  N  (%)  

 

   

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  =  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.  

 Pseudomonas  
    spp.  

74  (4%)  

45  (3%)  

 

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  
maltophilia  

0  (0%)  

1  (0.1%)  

1  (0.1%)  

0  (0%)  

Possible  
contaminantsa  

 
 

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  
–  Candida  -­‐  73%  death  or  neurodevelopmental  impairment  

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

 

Variable

   

Gestational age

Thrombocytopenia
Cephalosporin or
Carbepenem

Category

OR

95% CI

28 wk

Referrent

-

25-27 wk

2.02

1.52 – 3.05

< 25 wk

4.15

3.12 – 6.12

Plt ct > 150
Value <150

Referrent
3.56

2.68–4.74

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.  

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  

•  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.  
 

An#bio#c  risks:  First  days  of  life    

Empirical  Ini3al  Broad  Spectrum  use  varies  by  center  

• 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.

Clark RH et al. Pediatrics 2006;117: 67-74

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

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

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.    

2016 Choosing Antibiotics Wisely

Candidiasis  is  decreasing  

Broad-­‐spectrum  an#bio#c  use  

Fluconazole  prophylaxis  

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  2  (2006-­‐11)  
(N  =  1728)  

P-­‐value  

188  (10%)  

111  (6%)  

<.001  

Candida  spp.b  

182  (9%)  

96  (6%)  

 

Other  fungic  

6  (0.3%)  

15  (0.9%)  

 

Fungus,  N  (%)  

 

   

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

NI C H D  

N EONATAL R ESEARCH N ETWORK

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)  
 

Background  
—  In  20092,  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)  

2Cotten

et al., Pediatrics 2009;123:58–66

50%
36%

Adjusted OR (95% CI) for birth year: 0.87 (0.85-90)

69%
First  report:  range    was  27  –  85%  

30%

Mul#variable  logis#c  regression  
Outcome
Death, N
Prolonged initial
therapy, n (%)
Death or NEC, N
Prolonged initial
therapy, n (%)
NEC, N
Prolonged initial
therapy, n (%)
Death, NEC, or LOS, N
Prolonged initial
therapy, N (%)
Fungal LOS, N
Prolonged initial
therapy, N (%)

No
4934

Yes
919

2105 (43%)

496 (54%)

4528

1325

1930 (43%)

670 (51%)

5196

668

2301 (44%)

303 (45%)

3457

2400

1447 (42%)

1155 (48%)

1531

120

681 (45%)

71 (59%)

Adjusted OR (95% CI) P-value

1.20 (1.02, 1.42)

0.030

1.10 (0.95, 1.26)

0.196

1.01 (0.84, 1.20)

0.955

0.99 (0.87, 1.12)

0.837

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

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  

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  

2016 Choosing Antibiotics Wisely

An#microbials  –  increase  in  use  

•  From  2005  report  to  2010  report,  all  NICU  
admits  
  • 
• 
• 
• 
• 
• 

70%  increase  in  use  of  cefepime  (4th  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  

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.

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.

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.    

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).

Revised leaves out the “continue
antibiotics if labs abnormal”
Polin R A et al. Pediatrics 2014;133:1122-1123

©2014 by American Academy of Pediatrics

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

Clinical Illness

1. Persistent need for CPAP / HFNC / IMV (outside the
delivery room)
2. Hemodynamic instability requiring vasoactive drugs
3. Neonatal encephalopathy /Perinatal depression
1.  Seizure
2.  Apgar Score @ 5 minutes < 5
4. Need for supplemental O2 > 2 hours to maintain oxygen
saturations > 90% (outside of the delivery room)

Equivocal

1. Persistent physiologic abnormality > 4 hrs
1.  Tachycardia (HR > 160)
2.  Tachypnea (RR > 60)
3.  Temperature instability (> 100.4˚F or < 97.5˚F)
4.  Respiratory distress (grunting, flaring, or
retracting) not requiring supplemental O2
2. Two or more physiologic abnormalities lasting for > 2 hrs
1.  Tachycardia (HR > 160)
2.  Tachypnea (RR > 60)
3.  Temperature instability (> 100.4˚F or < 97.5˚F)
4.  Respiratory distress (grunting, flaring, or
retracting) not requiring supplemental O2
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.  
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  
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.  
**CBC’s  commonly  obtained  with  hyperbilirubinemia  work  up  
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  
•  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  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. Published online January 09, 2017.e164396 doi:10.1001/jamapediatrics.2016.4396
Mortality

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 (90th percentile)
were better than best performers (10th
percentile) of 2005!!
ALSO SIMILAR RESULTS FOR MORTALITY

CLD

Late onset sepsis

Severe IVH

NEC

Severe ROP

Figure Legend:
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.
Copyright © 2017 American Medical Association. All
Date of download: 1/9/2017
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