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Implementation of an Automatic Stop Order and Initial Antibiotic Exposure in

Very Low Birth Weight Infants

Article  in  American Journal of Perinatology · June 2016

DOI: 10.1055/s-0036-1584522

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 Original Article 105

Implementation of an Automatic Stop Order and

Initial Antibiotic Exposure in Very Low Birth
Weight Infants
Veeral N. Tolia, MD1 Sujata Desai, PhD1 Huanying Qin, MS2 Polli D. Rayburn, NNP-BC1
Grace Poon, Pharm D3 Karna Murthy, MD, MSc4 Dan L. Ellsbury, MD5,6 Arpitha Chiruvolu, MD1

1 Division of Neonatology, Department of Pediatrics, Baylor University Address for correspondence Veeral N. Tolia, MD, Division of
Medical Center and Pediatrix Medical Group, Dallas, Texas Neonatology, Department of Pediatrics, Baylor University Medical
2 Department of Quantitative Sciences, Baylor Scott & White Health Center, 3500 Gaston Avenue, 3 Hoblitzelle, Dallas, TX 75246
Care System, Dallas, Texas (e-mail: veeral.tolia@bswhealth.org).
3 Department of Pharmacy, Baylor Hamilton Heart and Vascular
Hospital, Dallas, Texas
4 Division of Neonatology, Department of Pediatrics, Feinberg School
of Medicine, Northwestern University, and the Ann and Robert H.
Lurie Children’s Hospital of Chicago, Chicago, Illinois
5 Center for Research, Education and Quality, MEDNAX Services–Pediatrix

Downloaded by: Baylor Health Science Library. Copyrighted material.

Medical Group, Sunrise, Florida
6 Mercy Children’s Hospitals and Clinics, Des Moines, Iowa

Am J Perinatol 2017;34:105–110.

Abstract Objective To evaluate if an antibiotic automatic stop order (ASO) changed early
antibiotic exposure (use in the first 7 days of life) or clinical outcomes in very low birth
weight (VLBW) infants.
Study Design We compared birth characteristics, early antibiotic exposure, morbidity,
and mortality data in VLBW infants (with birth weight <¼ 1500 g) born 2 years before
(pre-ASO group, n ¼ 313) to infants born in the 2 years after (post-ASO, n ¼ 361)
implementation of an ASO guideline. Early antibiotic exposure was quantified by days of
therapy (DOT) and antibiotic use > 48 hours. Secondary outcomes included mortality,
early mortality, early onset sepsis (EOS), and necrotizing enterocolitis.
Results Birth characteristics were similar between the two groups. We observed
reduced median antibiotic exposure (pre-ASO: 6.5 DOT vs. Post-ASO: 4 DOT;
Keywords p < 0.001), and a lower percentage of infants with antibiotic use > 48 hours (63.4
► antibiotic stewardship vs. 41.3%; p < 0.001). There were no differences in mortality (12.1 vs 10.2%; p ¼ 0.44),
► very low birth weight early mortality, or other reported morbidities. EOS accounted for less than 10% of early
infants antibiotic use.
► automatic stop order Conclusion Early antibiotic exposure was reduced after the implementation of an ASO
► NICU without changes in observed outcomes.

Although antibiotics are the most commonly prescribed low birth weight (VLBW) infants, exposure to antibiotics
medications in the neonatal intensive care unit (NICU),1 increases the risk of mortality, necrotizing enterocolitis
recent data suggest that prolonged or unnecessary use of (NEC), and, paradoxically, future episodes of infection.2–8
antibiotics is associated with significant morbidities. In very Unfortunately, traditional antibiotic stewardship strategies

received Copyright © 2017 by Thieme Medical DOI http://dx.doi.org/

December 2, 2015 Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0036-1584522.
accepted after revision New York, NY 10001, USA. ISSN 0735-1631.
May 11, 2016 Tel: +1(212) 584-4662.
published online
June 10, 2016
106 Implementation of ASO and Initial Antibiotic Exposure
can be limited in the NICU because much of the antibiotic
exposure is either with unmonitored agents or used in cases
where the infants’ cultures remain sterile.9–12
Recent work has identified the use of antibiotic medi-
cations for more than 48 hours in infants with negative
cultures to be potentially unnecessary and thus an impor-
tant target to reduce both drug exposure and excessive
utilization.13–16 The Centers for Disease Control and Pre-
vention has recommended an antibiotic time-out of 48
hours after initiation as a part of the “Get Smart for Health-
care” program to reduce unnecessary use.17 However, the
impact of this type of change in practice remains uncertain
with regard to specific value and possible unintended
clinical consequences, particularly among very preterm
infants early in postnatal life.
In December 2011, we implemented an automatic stop
order (ASO) at 48 hours for antibiotics started on admission in
VLBW infants in our NICU. The purpose of this study was to
quantify the impact of this change. We hypothesized that
implementing this ASO would reduce early antibiotic expo-
sure (antibiotic use in the first 7 days of life) without a
concurrent increase in mortality or adverse events related
to infection.
Methods
Cohort Identification and Setting
We conducted a retrospective before–after cohort study
utilizing chart review of VLBW infants comparing infants
born in the 2-year period before implementation of the
ASO (pre-ASO group) to those infants born in the 2-year
period after implementation (post-ASO group). We included
all VLBW infants (birth weight  1500 g) born at or trans-
ferred to our hospital within 24 hours of birth from an
affiliated hospital during this 4-year period. We omitted
infants if they were transferred to another institution in
the first week of life.
Prior to implementation, there were no formal guidelines
on the initiation or continuation of antibiotics, and ampicillin
and gentamicin were used for empiric therapy. Starting on
December 11, 2011, we implemented guidelines recom-
mending the use of an ASO for antibiotics started on admis-
sion to the NICU.
The rationale for implementing the ASO was that bacterial
cultures likely to be representative of infection are typically
positive by 48 hours and that the ASO could reduce unneces-
sary antibiotic doses beyond this 48-hour period. This guide-
line specified that providers’ admission orders for ampicillin
(50 mg/kg) be limited to four doses and gentamicin (5 mg/kg)
be limited to one or two doses, depending on birth weight-
based dosing interval of every 48 for infants < 1200 g or
every 36 hours for infants > 1200 g.18 These dose limitations
were applied via written provider orders as computerized
provider order management was not installed in our hospital
system until June 2014. With this ASO, these drugs would be
automatically discontinued after the prespecified “end dose”
unless actively reordered by the clinician, which would
require an entirely new order. There was no provider alert
American Journal of Perinatology Vol. 34 No. 2/2017
Tolia et al.
or notification that the antibiotic order was expiring. These
changes were recommended for all antibiotics started on
admission and providers could modify these written orders
based on their discretion. Approximately 1 month prior to
implementation, the medical providers discussed and agreed
with these changes after a 1-hour lecture on antibiotic
stewardship and the use of an ASO. No auditing process
was utilized to measure adherence to the ASO due to lack
of resources.
During this study, there were no additional prescribed
changes in practice with either the threshold to evaluate for
suspected infection, choice of antibiotic medications, or
provider order entry process. Nor were there changes in
other routine practices, including feeding human donor
milk for infants < 32 weeks’ gestation when mother’s milk
was unavailable, obtaining a single blood culture as part of
any indicated sepsis evaluation, and using enteral prophylac-
tic nystatin in infants with central venous lines that were not
umbilical lines.19 Probiotics were not available during the
Downloaded by: Baylor Health Science Library. Copyrighted material.
study period.
Data Collection and Analyses
We analyzed birth characteristics from electronic infant
medical records including birth weight, gestational age
(as best estimate from infant provider), gender, maternal
race/ethnicity, and multiple gestations. We also reported on
factors that traditionally have been related to risk of infection,
including premature labor, preterm rupture of membranes
(ROM) > 18 hours, history of chorioamnionitis (as defined by
the obstetrician), maternal intrapartum antibiotic therapy,
and administration of maternal antenatal corticosteroids
within 7 days of delivery.
Primary Outcome Measures
To evaluate antibiotic exposure, we collected electronic phar-
macy records of drug administration (including dosage, num-
ber of doses, and dosing interval) for all antibiotics used
during the first 7 days of life. From these records, we
calculated antibiotic days of therapy (DOT) and days of
therapy per 1,000 patient-days (DOT/1,000 PD) as suggested
in the recent Centers for Disease Control and Prevention
module17,20,21 and used in a recent report of antibiotic
exposure in the NICU.22 DOT is the aggregate sum of the
number of days for each unique antibiotic medication and is
determined by multiplying the number of antibiotic doses by
the dosing interval and then dividing by 24 hours. For
example, if an infant is given ampicillin every 12 hours for
4 doses and gentamicin every 48 hours for 1 dose, the infant’s
DOT would be 4 as the infant received 2 days of ampicillin and
2 days of gentamicin. DOT/1,000 PD, which normalizes the
DOT sum over the total number of patient-days to reduce
variance,20 was calculated by dividing the summed DOT for all
infants by the summed total of hospital days for all infants. As
DOT and DOT/1,000 PD are measures of aggregate whole-
NICU antibiotic use, we also reported on the percentage of
individual infants with any antibiotic doses > 48 hours in the
absence of positive cultures. This measure was also calculated
from pharmacy drug administration data.
 Implementation of ASO and Initial Antibiotic Exposure Tolia et al. 107

We evaluated several other measures of antibiotic utiliza-
tion. We determined if a blood culture was obtained and if
antibiotics were started at admission. We also measured early
treatment with negative cultures (ETNC), which we defined
as any infant in whom antibiotic treatment was started in the
first week of life and continued for 7 consecutive days without
a positive blood, cerebrospinal (CSF) or urine culture. Infants
who died in the first 7 days of life were not assigned an ETNC
status. To determine if measured changes in DOT were related
to the ASO as opposed to other practice changes, we repeated
the analysis of the primary measures in a subgroup of those
infants who had early antibiotic exposure. In addition, we
categorized the indication for all antibiotic use in the cohort.
Antibiotic indication, quantified in DOT, was assigned based
on use in infants with early onset sepsis (EOS), infants with
ETNC, or empiric antibiotic use, which included the infants
who received either a “rule-out” sepsis evaluation and/or
antibiotic treatment for less than 7 days.
spontaneous intestinal perforation were not included in
either NEC group unless surgical pathology suggested coex-
isting NEC.
Statistical Analyses
Data were analyzed using SAS Enterprise Guide 6.1 (SAS).
Characteristics of infants, primary outcome, and secondary
outcome measures were compared between the pre-ASO and
post-ASO groups using t-test for continuous variables, chi-
square test for categorical variables, and multivariate logistic
regression for composite measures. As a test of a single
change, pre- and postmeasurement comparisons were
utilized versus other methods that test multiple quality
interventions. This study was approved by the Institutional
Review Board at the Baylor Research Institute and this article
was written to conform to the STROBE (Strengthening the
Reporting of Observational studies in Epidemiology) guide-
lines for reporting of cohort studies.

Downloaded by: Baylor Health Science Library. Copyrighted material.

Secondary Outcome Measures
With this planned practice change, we observed several
secondary outcomes including mortality prior to discharge
and early mortality (death in the first 7 days of life). EOS was
defined in infants with recovery of any bacteria from a sterile
body location (blood, CSF, urine) in their first 7 days of life that
was treated with antibiotics for at least 7 consecutive days.
Infants were classified as having medical NEC if they had
radiographic evidence of pneumatosis and surgical NEC if
they required laparotomy or peritoneal drain for suspected
NEC irrespective of radiographs or pathology. Infants with
Results
Overall, there were 677 VLBW infants eligible for the study.
After the exclusion of 3 infants who were transferred to
another facility within 7 days of birth, 313 remained in the
pre-ASO group and 361 in the post-ASO group. There were no
significant differences between the groups with regard to
infant birth characteristics, including gestational age, birth
weight, gender, and maternal risk factors (►Table 1), except
for slightly more infants in the post-ASO group with ROM
> 18 hours.

Table 1 Infant birth characteristics by group

Birth characteristic Pre-ASO Post-ASO P-Value

n ¼ 313 n ¼ 361
Birth weight (grams), mean (std) 1006 (316) 995 (304) 0.66
Gestational age (weeks), mean (std) 28.0 (3.1) 27.9 (3.0) 0.37
26 weeks EGA (%) 101 (32.3) 114 (31.6) 0.85
Female gender (%) 153 (48.9) 191 (52.9) 0.30
a
Maternal race/ethnicity (%)
White 112 (36.5) 122 (33.9) 0.61
Black 131 (42.7) 162 (45.0)
Hispanic 51 (16.6) 66 (18.3)
Asian or other 13 (4.2) 10 (2.8)
Multiple gestations (%) 78 (25.0) 101(28.1) 0.37
Premature labor (%) 151 (48.2) 202 (56.1) 0.08
ROM > 18 hour (%) 59 (19.6) 89 (26.0) 0.054
Chorioamnionitis (%) 16 (5.1) 15 (4.2) 0.56
Intrapartum antibiotics (%) 132 (42.4) 173 (48.2) 0.14
Antenatal steroids > 1 dose in 7 days (%) 166 (54.6) 203 (56.7) 0.59
Cesarean delivery (%) 252 (81) 270 (75.8) 0.10

Abbreviations: ASO, automatic stop order; EGA, estimated gestational age at birth; ROM, rupture of membranes.
a
Maternal race/ethnicity out of the 667 reported.

American Journal of Perinatology Vol. 34 No. 2/2017

108 Implementation of ASO and Initial Antibiotic Exposure Tolia et al.

Downloaded by: Baylor Health Science Library. Copyrighted material.

Fig. 1 Median antibiotic days of therapy in the first week of life over the study period (brackets represent interquartile range, Q ¼ quarter of
year). Implementation of the automatic stop order occurred during Q4 2011.

There were significant reductions in early antibiotic expo-
sure after the intervention. From the pre-ASO group to the
post-ASO group, the median DOT decreased from 6.5 to 4
(p < 0.001), a 38% reduction, and the DOT/1,000 PD de-
creased from 99.5 to 71.7 (p < 0.001), a 28% reduction. The
percentage of infants with antibiotic use > 48 hours was also
significantly lower, from 63.4% (pre-ASO) to 41.3% (post-ASO,
p < 0.001). Time-related changes in DOT in the cohort are
shown in ►Fig. 1. With regard to other primary outcomes,
fewer infants in the post-ASO group had a blood culture
obtained at birth, were started on antibiotics immediately
postpartum, or were treated for ETNC in the first week of life
compared with the pre-ASO. Primary outcome measures are
reported in ►Table 2.
To determine if these measured changes in early antibiotic
exposure were more likely due to the ASO as opposed to a
reduction in antibiotic initiation, we also analyzed a subgroup
of only those infants with exposure to early antibiotics
(►Table 3). In this subgroup of 477 infants, both DOT and
DOT/1,000 PD were lower in the post-ASO group. In addition,
the percentage of infants with antibiotic use > 48 hours was
reduced from 87.8% in the pre-ASO group to 64.0% in the post-
ASO group (p < 0.001) in this subgroup. When evaluating the
distribution of antibiotic DOT by indication, we found that the
most common indication for antibiotics was empiric antibi-
otic use followed by ETNC with a slight increase in the
distribution of EOS antibiotic use in the post-ASO group.
When comparing secondary outcome measures, the two
groups had similar rates of death (pre-ASO: 12.1% vs. post-
ASO: 10.2%; p ¼ 0.44), early death (6.4 vs. 4.4%; p ¼ 0.30),
NEC (7.7 vs. 5.3%; p ¼ 0.20), and combined death or NEC (18.8
vs. 13.8%; p ¼ 0.10). The post-ASO group had nonsignificant

Table 2 Primary outcome measures for infants in the cohort

Outcome measure Pre-ASO Post-ASO P-Value

n ¼ 313 n ¼ 361
DOT the first week of life, median (IQR) 6.5 (0–8.5) 4 (0–6.5) <0.001
Antibiotic DOT per 1,000 patient-days 99.5 71.7 <0.001
Infants with antibiotic use > 48 hoursa (%) 193 (63.4) 143 (41.3) <0.001
Blood culture obtained on admission (%) 259 (83.0) 271 (75.1) 0.01
Antibiotics started on admission (%) 222 (71.2) 239 (66.2) 0.17
ETNC (%) 54 (18.5) 49 (14.2) 0.14

Abbreviations: ASO, automatic stop order; DOT, Days of therapy; ETNC, early treatment with negative cultures; IQR, interquartile range.
a
Infants with EOS excluded from this measure.

American Journal of Perinatology Vol. 34 No. 2/2017

 Implementation of ASO and Initial Antibiotic Exposure
Table 3 Primary outcomes in a subgroup of infants with any antibiotic exposure
Outcome measure
DOT in the first week of life, median (IQR)
Antibiotic DOT per 1000 patient-days
Infants with antibiotic use > 48 hoursa (%)
ETNC (%)
Distribution of DOT by indication (%)
Empiric use
ETNC
EOS
Abbreviations: ASO, automatic stop order; DOT, days of therapy; EOS, early onset sepsis; ETNC, early treatment with negative cultures; IQR,
interquartile range.
a
Infants with EOS excluded from this measure.
slight increase in the incidence of EOS (4.2 vs. 2.9%; p ¼ 0.37).
Of the 27 infants with EOS in the entire cohort, 26 were
diagnosed with sepsis from a blood culture obtained on
admission that grew in the first 24 hours, while 1 other infant
(from the post-ASO group) had a positive blood culture that
was obtained at 6 days of life. There were no reports of any
infants whose antibiotics were discontinued inadvertently
despite provider preference to continue them.
Discussion
There is wide variability in reported NICU antibiotic expo-
sure, with a recent study documenting a 40-fold difference in
antibiotic use between centers with no apparent impact on
clinical outcomes.23 One of the targets in the “Choosing
Wisely” initiative is a reduction of unnecessary antibiotic
use past 48 hours to reduce waste in the NICU.16
In our cohort, implementation of an ASO was associated
with a significant reduction in early antibiotic exposure of
VLBW infants without an increase in adverse events. We found
this in both unit-level measurements (DOT and DOT/1,000 PD)
and infant measurements (infants with antibiotic exposure
> 48 hours). Although this approximate 38% reduction in
antibiotic use during the first week of life was modest, multiple
authors have demonstrated that even small changes in early
antibiotic exposure have differential effects on the infant’s
microbiome.24,25 Infants in the post-ASO group were less likely
to be started on antibiotics and experience ETNC despite a
higher incidence of EOS, suggesting that the education com-
ponent of the ASO implementation likely also influenced
behaviors of antibiotic administration. However, we also
observed a reduction in early antibiotic exposure in the
subgroup of infants who were started on antibiotics, an
analysis meant to minimize the effect of decreased antibiotic
initiation.
The use of an ASO is predicated on the observation that
EOS is uncommon and that bacterial blood cultures will be
positive by 24 to 36 hours. Correspondingly, only 5 to 7% of
early antibiotic use was indicated for EOS. In this light, and
until more sensitive and specific diagnostic algorithms26 are
Tolia et al. 109
Pre-ASO Post-ASO P-value
n ¼ 231 n ¼ 246
7 (6–12.5) 5 (4–10.5) 0.003
126.8 98.7 <0.001
194 (87.8) 148 (64.0) <0.001
54 (23.4) 49 (19.9) 0.41
1145 (55.5) 1013 (54.1) <0.001
814 (39.5) 717 (38.3)
104 (5.0) 141 (7.5)
validated, the question is how much to empirically treat this
Downloaded by: Baylor Health Science Library. Copyrighted material.
population of infants given the existing risk:benefit ratio. In
both groups of this cohort, the majority of antibiotic DOT
occurred in infants with empiric antibiotic use. This suggests
that the threshold to start antibiotics continues to represent a
critical target for further efforts to manage exposure.
We found that the other main category of antibiotic expo-
sure was ETNC. In this population, the diagnosis and exclusion
of infectious sepsis syndromes are fraught with issues. Blood
cultures remain the gold standard, but challenges with ade-
quate timing, volume, or contaminated sampling can decrease
diagnostic certainty.27 As culture negative sepsis and neonatal
pneumonia have varied clinical definitions and are subject to
provider interpretation, we chose to define ETNC using an
objective, easily obtainable metric. Although this measure has
not been prospectively validated, we support the further
development of this type of NICU-specific measurement that
allows meaningful tracking of antibiotic exposure.11 Although
there are situations where antibiotics are necessary with
sterile cultures, ETNC is likely another important target for
antibiotic stewardship programs because it represents such a
large part of early antibiotic exposure.
One of the main concerns with an ASO is the potential for
an unwanted discontinuation of antibiotics in an infant with a
proven infection. In this study, all infants with EOS were
diagnosed with a blood culture drawn within several hours of
birth, except for one infant who developed EOS at 6 days of
life. Importantly, there were no differences in early or overall
mortality, in spite of the overall reduction in antibiotic use.
This suggests that reducing antibiotic exposure can be
achieved safely and without increases in mortality.
Our study has several limitations. First, we have not estab-
lished a causal link between the ASO and the reported
decreased in antibiotic exposure. This decrease may also be
due to national trends in reduced antibiotic use in this
population or solely due to the education component of our
implementation. We cannot provide a control group for either
scenario. However, at a minimum, this study demonstrates
that reduction in antibiotic use did not result in a significant
increase in adverse events and that an ASO may be safely
American Journal of Perinatology Vol. 34 No. 2/2017
110 Implementation of ASO and Initial Antibiotic Exposure
implemented. Additional possible confounding factors include
the Hawthorne effect on clinicians28 and unreported changes
in the composition of our two groups. Although pharmacy
records were used for the primary outcomes, we only reported
on early antibiotic exposure and were not able to collect all
inpatient antibiotic use for these infants. As such, the effect of
this early ASO on later antibiotic usage and other clinical
outcomes remains uncertain. Finally, the single-center sample
limits the generalizability of these results. However, this study
reflects our implementation of this intervention.
In conclusion, the implementation of an ASO was associ-
ated with a reduction in antibiotic exposure in our VLBW
infants without observed adverse effects. An ASO may be a
useful tool to reduce unnecessary antibiotics, but multiple
approaches, including raising the threshold at which pro-
viders start these medications, will likely be necessary to
further lower exposure in these high-risk infants.
Conflict of Interest
None.
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