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Pediatrics. Author manuscript; available in PMC 2018 October 15.
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Published in final edited form as:

Pediatrics. 2018 September ; 142(3): . doi:10.1542/peds.2018-0115.

Variations in Neonatal Antibiotic Use

Joseph Schulman, MD, MSa, Jochen Profit, MD, MPHb,c,d, Henry C. Lee, MD, MSb,c,d, Grace
Dueñas, MPHb,c,d, Mihoko V. Bennett, PhDb,c,d, Janella Parucha, BSd, Maria A.L. Jocson,
MD, MPHa, and Jeffrey B. Gould, MD, MPHb,c,d
aCalifornia Children’s Services, California Department of Health Care Services, Sacramento,
California;
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bPerinatal
Epidemiology and Health Outcomes Research Unit, Division of Neonatology,
Department of Pediatrics, School of Medicine, Stanford University, Stanford, California;
cLucile Packard Children’s Hospital, Palo Alto, California;
dCalifornia Perinatal Quality Care Collaborative, Stanford, California

Abstract
OBJECTIVES: We sought to identify whether and how the NICU antibiotic use rate (AUR),
clinical correlates, and practice variation changed between 2013 and 2016 and attempted to
identify AUR ranges that are consistent with objectively determined bacterial and/or fungal
disease burdens.

METHODS: In a retrospective cohort study of >54000 neonates annually at >130 California

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NICUs from 2013 to 2016, we computed nonparametric linear correlation and compared AURs
among years using a 2-sample test of proportions. We stratified by level of NICU care and
participation in externally organized stewardship efforts.

RESULTS: By 2016, the overall AUR declined 21.9% (95% confidence interval [CI] 21.9%–
22.0%), reflecting 42960 fewer antibiotic days. Among NICUs in externally organized antibiotic
stewardship efforts, the AUR declined 28.7% (95% CI 28.6%–28.8%) compared with 16.2% (95%
CI 16.1%–16.2%) among others. The intermediate NICU AUR range narrowed, but the
distribution of values did not shift toward lower values as it did for other levels of care. The 2016
AUR correlated neither with proven infection nor necrotizing enterocolitis. The 2016 regional
NICU AUR correlated with surgical volume (ρ = 0.53; P = .01), mortality rate (ρ = 0.57; P = .
004), and average length of stay (ρ = 0.62; P = .002) and was driven by 3 NICUs with the highest
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AUR values (30%–57%).

CONCLUSIONS: Unexplained antibiotic use has declined but continues. Currently measured
clinical correlates generally do not help explain AUR values that are above the lowest quartile
cutpoint of 14.4%.

Address correspondence to Joseph Schulman, MD, MS, California Department of Health Care Services, California Children’s
Services, 1501 Capitol Ave, MS 4502, PO Box 997437, Sacramento, CA 95899-7437. [email protected].
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
 Schulman et al. Page 2

Recent work reveals that a considerable portion of NICU antibiotic use is unwarranted., In a
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2013 sample of 52061 infants receiving 746051 patient-days of care, antibiotic use rates
(AURs) varied widely across NICUs and were unexplained by the corresponding burden of
proven infection or other clearly warranted indications for treatment. Antibiotic prescribing
practice variation apparently hinges on variation in how practitioners frame, interpret, and
respond to clinical situations that are ultimately considered unproven infection. NICU staff
differ in their indications for treatment, and conceptualizations of “culture-negative sepsis.”

Such practice variation plausibly may be mitigated with the aid of carefully conceived
antibiotic stewardship initiatives used to promote current evidence-based practice. During
the past 2 years, the Vermont Oxford Network partnered with the Centers for Disease
Control and Prevention in a collaborative involving 167 NICUs in 38 states, Puerto Rico,
and 6 countries. The California Perinatal Quality Care Collaborative (CPQCC), began a
collaborative involving 28 California NICUs along with an alternative entailing similar
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interventions minus facilitated access to the other centers participating in the collaborative or
its expert panel.

Accurately estimating the impact of such work requires understanding concurrent trends: are
changes in measured outcomes restricted to NICUs engaged with specified interventions, or
are outcomes changing more broadly? For example, 1 large NICU recently reported a 27%
decrease in days of therapy per 1000 patient-days after a local antibiotic stewardship
intervention. Recently published recommendations may also be driving practice changes., , –
Individual NICU improvement efforts may be informal and may not be reported in peer-
reviewed literature. Informed clinical, payer, and regulatory evaluations of resource use and
an unbiased interpretation of formal improvement efforts require measuring and
understanding such concurrent trends.
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Since 2013, the California Department of Health Care Services has tracked NICU antibiotic
use at all NICUs approved by California Children’s Services (CCS); additional NICUs have
also reported these data to the CPQCC. In the current study, we seek to identify (1) changes
over time in NICU antibiotic use and the range of practice variation, (2) whether concurrent
trends differed from performance at NICUs participating in known externally organized
antibiotic stewardship efforts (described above), and (3) whether clinical and resource use
correlations with AUR changed since 2013.

These insights are essential for estimating AUR ranges that are consistent with objectively
determined bacterial and/or fungal disease burdens, a topic that has not yet been addressed
in the literature. The stewardship initiatives and publications cited above reflect a broad-
based view that NICU AURs often are unnecessarily high, begging the question,”Which rate
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is right?”

METHODS
CCS confers state approval for 3 levels of NICU care: regional, community, and
intermediate. These generally correspond to American Academy of Pediatrics levels IV, III,
and II, respectively. CCS standards include required annual data reporting of specific

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variables. All CCS-approved NICUs submit their data to the CPQCC, which prepares an
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annual report for each NICU and submits an aggregate data set to CCS. The CPQCC collects
clinical data prospectively using an expanded version of the Vermont Oxford Dataset, and a
supplemental CCS form. All CCSapproved NICUs must complete the supplemental CCS
form; the CPQCC requires that other NICUs also do so. Non–CCS-approved NICUs may be
level II or III and typically choose not to apply for approval. The collected data constitute a
single overarching database.

Of the 148 NICUs in California, 137 currently belong to the CPQCC, and 122 are CCS
approved. Thus, the combined data set is used to describe NICU care and outcomes for most
neonates receiving NICU care in California. For the study analysis, we used CPQCC–CCS
data sets for calendar years 2013 to 2016. This study was approved by the Stanford
University Institutional Review Board.
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Study Population
All neonates receiving care at CPQCC–CCS NICUs in California reporting on data variables
used for this study were included. The number of NICUs varied from 131 to 137 by year
(Table 1).

Study Variable Definitions

The AUR is the number of patientdays that infants were exposed to ≥1 antibacterial or
antifungal agents administered intravenously or intramuscularly per 100 patientdays in the
reporting NICU expressed as a percentage. The early-onset sepsis (EOS) rate is the
percentage of infants with a bacterial or fungal infection diagnosed by blood culture within 2
days of birth. The central line–associated bloodstream infection rate is the number of
laboratory-confirmed bloodstream infections for which a central line was in place for 2 days
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on the date of the event per 1000 central line–days. The inborn admission rate is the
proportion of all live births at a hospital who were admitted to the NICU. The number of
surgical cases includes patients undergoing a surgical procedure, excluding circumcision,
extracorporeal membrane oxygenation cannulation and/or decannulation, peritoneal dialysis
catheter placement and/or removal, chest tube placement, and central line placement. The
NICU mortality rate is the ratio of NICU deaths to the number of NICU admissions. The
inborn admission rate is the proportion of live births at a hospital who were admitted to the
NICU expressed as a percent value. Twelve reporting hospitals were self-designated free-
standing NICUs that are organizationally independent of a maternal delivery service. Data
used to quantify the service birth population (located in the same building as the NICU)
were available for 8 of these and were used to compute inborn admission rates.
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Certain CPQCC–CCS variables are restricted to infants who were 401 g to 1500 g or 22 to
29 weeks’ gestation at birth. The rate of lateonset sepsis (LOS) is the percentage of infants
with a bacterial or fungal infection diagnosed by blood culture at ≥3 days after birth. The
fungal infection rate is the percentage of infants with a fungal infection diagnosed by blood
culture at ≥3 days after birth. The necrotizing enterocolitis (NEC) rate is the percentage of
infants diagnosed with NEC either at surgery, at postmortem examination, or by
radiographic pneumatosis intestinalis, hepatobiliary gas, and/or pneumoperitoneum

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accompanied by bilious gastric aspirate or emesis, abdominal distention, and/or gross or

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occult blood in stool with no apparent rectal fissure. The average length of stay is the
average NICU length of stay in days for patients discharged from the hospital.

Study variable values were computed by calendar year.

Statistical Methods
The unit of observation and analysis was the individual NICU. The primary outcome was the
AUR. Before the study began, we formulated hypotheses that were consistent with goals for
NICU antibiotic stewardship efforts: the AUR would correlate positively with the burden of
proven infection, with NEC, with the number of surgical cases, and with highest NICU level
of care. We examined post hoc (1) the correlation between the number of surgical cases and
NICU mortality rate; (2) 4-year differences in intermediate NICU admissions, patient-days,
and antibiotic use–days; (3) the mean clinical and resource correlate values for NICUs in
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AUR quartile 1 versus quartiles 2 to 4.

We estimated linear correlation by Spearman rank correlation to avoid reliance on specific

distributional assumptions and mitigate effects of extreme outlier values. We compared the
AUR for different time periods by 2-sample tests of proportions. We compared AUR
correlate sample means by analysis of variance; when variances were unequal by Bartlett’s
test, we used 2-sample t tests with unequal variances. We compared differences in
intermediate NICU admissions, patient-days, and antibiotic-days over 2, 3, and 4 years by
paired t tests. Hypothesis tests were 2-sided with a significance level at P ≤ .05. We used
stratified analyses to examine the NICU level of care or participation in known externally
organized antibiotic stewardship efforts. We used Stata 15 (Stata Corp, College Station, TX)
for analyses and graphical displays.
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RESULTS
As detailed in Table 1 and Fig 1, by 2016, the overall AUR declined by 21.9% (95%
confidence interval [CI] 21.9%–22.0%), and AUR variation narrowed among NICUs by
fivefold to 10-fold. Antibiotic-days declined by 42960 (from 214370 to 171410) despite
18469 additional patient-days (from 777194 to 795663). The 44 NICUs participating in
known externally organized antibiotic stewardship efforts accounted for 41% of NICU
admissions, 41% of antibiotic-days, and 45% of patient-days. The 2013 AUR among NICUs
later participating in known externally organized antibiotic stewardship efforts was 28.0%
and 27.2% among those that did not (difference of 0.8%; 95% CI 0.6%–1.0%). The 2016
AUR among NICUs in known externally organized antibiotic stewardship efforts declined to
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19.9% (28.7% decrease; 95% CI 28.6%–28.8%) compared with 22.8% (16.2% decrease;
95% CI 16.1%–16.2%) among NICUs that did not participate (19.9% vs 22.8%; 12.7%
relative difference; 95% CI 12.5%–12.7%).

Figure 2 illustrates the range of AUR values and relative frequency of occurrence stratified
by NICU level of care. For regional, community, and non-CCS NICUs, the AUR range
narrowed and the bulk of the distributions shifted toward lower values. The AUR distribution
pattern for intermediate NICUs noticeably differs: although the range narrowed, the bulk of

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the distribution of values did not shift toward lower values, as it did at other levels of care.
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Intermediate NICU admissions, patient-days, and antibiotic-days did not significantly differ
across years.

The 2016 AUR correlated neither with proven infection nor NEC, echoing our 2013 findings
(Table 2). Only among regional NICUs did the 2016 AUR correlate with surgical case
volume (ρ = 0.53; P = .01), NICU mortality rate (ρ = 0.57; P = .004), and average length of
stay (ρ = 0.62; P = .002). However, among regional NICUs in quartile 1 (≤14.4%), the AUR
did not correlate so. The AUR correlated with inborn admission rate across all NICUs (ρ =
0.23; P = .009) and community NICUs (ρ = 0.3; P = .006). The latter correlation did not
persist when examined for community NICUs in AUR quartile 1 (≤14.3%) or quartiles 2 to
4. Proven infection rates at NICUs in AUR quartiles 2 to 4 were statistically similar at
NICUs in quartile 1. The NEC rate was significantly higher among community NICUs in
AUR quartiles 2 to 4 compared with quartile 1 (absolute rate difference 1.11%; P = .03).
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Surgical volume was higher among regional NICUs in AUR quartiles 2 to 4 (mean 243.94;
SD 159.43) compared with quartile 1 (mean 76.80; SD 69.92; P = .03).

DISCUSSION
From 2013 to 2016, the overall AUR declined by 21.9%; antibiotic exposure–days declined
by ~43 000. The continuing lack of correlation between AURs and proven infection or NEC
reveals that at many NICUs, the AUR can decrease further. Among NICUs participating in
known externally organized antibiotic stewardship efforts, the AUR declined by 28.7%;
among the other NICUs, the AUR declined by 16.2%. These differences are statistically and
clinically highly significant (tens of thousands of antibiotic exposure–days avoided).
Although the 2013 baseline of 0.8% absolute AUR difference between these groups (Table
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1) was statistically significant (reflecting large numbers of patient- and antibiotic-days),

clinical significance may be debatable. By 2015, the overall AUR had already declined by
9.7% (95% CI 9.3%–10.1%). California NICUs began to receive AUR feedback in
mid-2014; 1 pertinent guideline reappraisal was published in 2015. We speculate that 2015
AUR values began to reflect new publications, , and the initiation of the antibiotic
stewardship efforts described above.

Our correlation analyses rest on 2 key assumptions: (1) antibiotic exposures should correlate
with objectively measured bacterial and/or fungal disease burden, and (2) the selected
correlates represent most of the objectively measured NICU bacterial disease burden.
Therefore, 2 possible explanations exist for the absence of AUR correlations: (1) ≥1
objectively determined bacterial diseases that are quantitatively important antibiotic use
drivers were omitted from the analysis, or (2) AUR variation across California NICUs is
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unrelated to the commonly occurring indications for treatment that are consistent with
antibiotic stewardship principles. Our data do not enable an estimate of a NICU’s burden of
blood culture–negative bacterial disease justifying antibiotic treatment (eg, meningitis,
omphalitis, osteomyelitis, tracheitis, and pneumonia). Although in our experience such
blood culture–negative conditions are not likely to be important AUR drivers at most
NICUs, we encourage NICUs to examine in detail this aspect of the AUR.

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Considered in isolation, the positive correlations at regional NICUs between the AUR and
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number of surgical cases (ρ = 0.53; P = .01), NICU mortality rate (ρ = 0.57; P = .004), and
average length of stay (ρ = 0.62; P = .002) might reveal that at regional NICUs, the AUR
represents a proxy measure of surgical case volume and illness severity. However, Fig 3A
illustrates a strong positive correlation between surgical volume and the NICU mortality rate
(ρ = 0.74; P < .001). Figures 3C and3D show that the correlation between the AUR and each
of these 2 variables does not scale linearly. The correlations are largely driven by only 3 of
23 NICUs, those with the highest AUR values (30%–57%). The data points indicating the
other 20 regional NICUs are contained within the dashed rectangles and show no significant
correlation. Interestingly, Fig 3B illustrates that the surgical case volume and mortality
relationship largely persists among the 20 regional NICUs with an AUR <30% (ρ = 0.68; P
= .001) as well as when the AUR and average length of stay are similarly evaluated (ρ =
0.47; P = .04). Overall, the evidence reveals that although surgical case volume and illness
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severity might sometimes drive the AUR, a relatively high AUR also may be used to
independently predict mortality and average length of stay. In a recent report, the Canadian
Neonatal Network found that higher AURs were associated with adverse neonatal outcomes
among infants without culture-proven sepsis or NEC, including a twofold increase in
mortality odds associated with a 10% AUR increase. A possible contributing factor is
dysbiosis associated with neonatal antibiotic exposure., It is thus particularly noteworthy that
regional NICU AURs did not correlate with cultureproven sepsis or NEC. Figure 3 thus
illustrates opportunities for antibiotic stewardship efforts used to target NICU surgical
practice.

When the 2013 data were initially reported, several NICUs reporting an AUR value <1%
were dropped from the analysis because the values were considered clinically implausible.
To explore the trajectory of these NICU values over time, no censoring was applied in the
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current study. NICU data accuracy may have improved with increasing AUR collection
experience and use of database technology. Since 2015, the lowest reported AUR was 5.6%.
In 2013, the cutpoint value for the lowest AUR quartile was 17.2%; in 2016, it was 14.4%.

Our findings can inform a framework for estimating AUR ranges that are consistent with
objectively determined bacterial and/or fungal disease burdens. The 2016 cutpoint value for
the lowest regional NICU AUR quartile was the same as for all NICUs combined: 14.4%.
Among these low-quartile regional NICUs, the AUR did not correlate with surgical volume,
NICU mortality rate, or any other variable, including proven infection or NEC. However,
these same low-quartile NICUs have an average lower surgical volume than all regional
NICUs. Thus, complex relationships remain to be disentangled, and not only for higher-
volume surgical centers. A correlation between the AUR and inborn admission rate for
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community-level NICUs may similarly reflect unaccounted bias and/or confounding; it

vanished when examined solely for community NICUs in AUR quartile 1 or for community
NICUs in quartiles 2 to 4. Interpretation of higher NEC rates at community NICUs (and not
at regional NICUs) in AUR quartiles 2 to 4 (Table 2) is constrained by a lack of patient-level
data, including exposure and/or outcome timing and transfer-in after NEC onset. The 1.11%
absolute difference in the NEC rate negligibly accounts for the higher AURs.

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Interestingly, some NICUs already in the lowest 2013 AUR quartile nonetheless believed
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there was further opportunity to improve, joining stewardship collaboratives in subsequent

years; their belief is confirmed by the even lower 2016 quartile 1 value and narrowed
variation (Fig 1). The distribution of AUR values among intermediate level NICUs thus
raises particular concern. The 2016 cutpoint value for the lowest AUR quartile among
intermediate NICUs was 17.5%, and the overall distribution shifts toward relatively higher
values. Why might intermediate NICUs operate with higher AURs than other NICUs (Fig
2)? All else remaining the same, if decision rules at intermediate NICUs changed over time
so that fewer neonates were admitted to rule out sepsis, then patient-days could decrease
disproportionately to antibiotic-days. Ironically, the AUR could rise. However, the numbers
of intermediate NICU admissions, patient-days, and antibiotic-days did not significantly
differ across years, nor were EOS rates higher than at other levels of NICUs (Table 2).
Therefore, antibiotic overuse is clearest at intermediate NICUs with both a relatively high
AUR and inborn admission rate, and this may support other observations, that reveal a
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component of supply-sensitive care., Supply-sensitive care has little evidence base, reflecting
instead available service capacity and payment systems that are used to incentivize resource
use. In other words, the availability of NICU beds becomes a determinant of NICU care.27

The AUR, as a single measure of NICU-level antibiotic use, necessarily entails imprecisely
answering, “Which rate is right?” A NICU’s AUR is used to summarize aggregated results
of several different care processes and subpopulations with varying risk profiles (eg,
asymptomatic term and nearterm neonates with suspected EOS, extremely preterm neonates
with suspected EOS or LOS, neonates undergoing surgical procedures [again, a
heterogeneous subpopulation], and [as already mentioned] neonates requiring antibiotic
treatment without a positive blood culture result, such as for meningitis or pneumonia).
Accounting for such complexity requires further analytical stratification and individual
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patient-level units of observation and analysis. Calibrating patient antibiotic exposures with
treatment indication could provide important complementary insight and requires collecting
additional data elements (eg, estimated number needed to treat for each case of EOS or
blood culture–negative meningitis).

CONCLUSIONS
The persistent lack of association between AURs and currently collected clinical correlates
signals a likely opportunity to continue decreasing antibiotic use and the need for a more
complete case-mix characterization. With the possible exception of high–surgical volume
NICUs, NICUs in AUR quartiles 2 to 4 generally serve populations with similar measured
clinical correlates as NICUs in quartile 1 at the same level of care. Thus, for most or all
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NICUs, currently available data elements reveal no explanation for AURs above the lowest
quartile cutpoint of 14.4%. We suggest that all NICUs, and especially those with an AUR
beyond quartile 1, interpret their AURs in light of answers to the following systematic
critical review: Are our numerator and denominator values accurate? What fraction of our
numerator reflects patients with objectively diagnosed bacterial disease not measured by the
currently collected data elements? Does our denominator reflect a relatively low inborn
admission rate; has it changed over time? And might there be genuine opportunities to

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improve antibiotic use (eg, a large portion of the numerator represents patients in whom
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objective bacterial disease cannot be established by current evidence-based methods)?

Acknowledgments
Dr Schulman conceptualized and designed the study, performed the analyses, drafted the initial manuscript, and
reviewed and revised the manuscript; Drs Profit, Lee, and Gould supervised data collection and critically reviewed
the manuscript; Ms Dueñas, Dr Bennett, and Ms Parucha coordinated and supervised data collection, aggregated
data, provided the aggregated data sets to California Children’s Services, and critically reviewed the manuscript; Dr
Jocson participated in the study design and interpretation of analyses and critically reviewed the manuscript; and all
authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No specific support was provided. Dr Profit was supported in part by grants from the Eunice Kennedy
Shriver National Institute of Child Health and Human Development (R01 HD083368–01 and R01 HD08467–01;
principal investigator: Dr Profit). The content is solely the responsibility of the authors and does not necessarily
represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human
Development or the National Institutes of Health. This funding source had no role in any of the following aspects of
this study: design and conduct of the study; collection, management, analysis, and interpretation of the data;
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preparation, review, or approval of the article; and decision to submit the article for publication.

ABBREVIATIONS
AUR antibiotic use rate

CCS California Children’s Services

CI confidence interval

CPQCC California Perinatal Quality Care Collaborative

EOS early-onset sepsis

LOS late-onset sepsis

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NEC necrotizing enterocolitis

REFERENCES
1. Schulman J, Dimand RJ, Lee HC, Duenas GV, Bennett MV, Gould JB. Neonatal intensive care unit
antibiotic use. Pediatrics. 2015; 135(5):826–833 [PubMed: 25896845]
2. Cantey JB, Baird SD. Ending the culture of culture-negative sepsis in the neonatal ICU. Pediatrics.
2017;140(4):e20170044 [PubMed: 28928289]
3. Benitz WE, Wynn JL, Polin RA. Reappraisal of guidelines for management of neonates with
suspected early-onset sepsis. J Pediatr. 2015;166(4):1070–1074 [PubMed: 25641240]
4. Kuzniewicz MW, Puopolo KM, Fischer A, et al. A quantitative, risk-based approach to the
management of neonatal early-onset sepsis. JAMA Pediatr. 2017;171(4):365–371 [PubMed:
28241253]
Author Manuscript

5. Soll RF, Edwards WH. Antibiotic use in neonatal intensive care. Pediatrics. 2015;135(5):928–929
[PubMed: 25896842]
6. Vermont Oxford Network. iNICQ 2018: choosing antibiotics wisely. 2018 Available at: https://
public.vtoxford.org/quality-education/inicq-2018/. Accessed September 9, 2017
7. California Perinatal Quality Care Collaborative. Antibiotic stewardship collaborative. 2017
Available at: https://www.cpqcc.org/qi-projects/cpqccccs-collaboratives/antiobiotic-stewardship-
collaborative-5. Accessed September 9, 2017
8. California Perinatal Quality Care Collaborative. NICU QI. 2017 Available at: https://
www.cpqcc.org/qi-projects/nicu-qi. Accessed September 9, 2017

Pediatrics. Author manuscript; available in PMC 2018 October 15.

 Schulman et al. Page 9

9. Cantey JB, Wozniak PS, Pruszynski JE, Sánchez PJ. Reducing unnecessary antibiotic use in the
neonatal intensive care unit (SCOUT): a prospective interrupted time-series study. Lancet Infect
Author Manuscript

Dis. 2016;16(10):1178–1184 [PubMed: 27452782]

10. Committee on Obstetric Practice. Committee opinion no. 712: intrapartum management of
intraamniotic infection. Obstet Gynecol. 2017;130(2):e95–e101 [PubMed: 28742677]
11. Hooven TA, Polin RA. Time to overhaul the “rule out sepsis” workup. Pediatrics.
2017;140(1):e20171155 [PubMed: 28759417]
12. Higgins RD, Saade G, Polin RA, et al.; Chorioamnionitis Workshop Participants. Evaluation and
management of women and newborns with a maternal diagnosis of chorioamnionitis: summary of
a workshop. Obstet Gynecol 2016;127(3):426–436 [PubMed: 26855098]
13. California Department of Health Care Services. Provider standards. 2014 Available at:
www.dhcs.ca.gov/services/ccs/Pages/ProviderStandards.aspx#nicu. Accessed July 17, 2014
14. American Academy of Pediatrics Committee on Fetus and Newborn. Levels of neonatal care.
Pediatrics. 2012;130(3):587–597 [PubMed: 22926177]
15. California Perinatal Quality Care Collaborative. California Perinatal Quality Care Collaborative
(CPQCC). Available at: https://www.cpqcc.org/. Accessed April 25, 2018
Author Manuscript

16. California Perinatal Quality Care Collaborative. CPQCC data center. 2018 Available at: https://
www.cpqcc.org/perinatal-programs/cpqcc-data-center. Accessed April 25, 2018
17. Vermont Oxford Network. Vermont Oxford Network database: manual of operations for infants
born in 2015. 2015 Available at: https://public.vtoxford.org/wp-content/uploads/2014/11/
Manual_of_Operations_Part2_v19.pdf. Accessed October 5, 2017
18. Bhatt DR, Adams M, Clearly J, et al. NICUs & Neonatologists in California. California
Association of Neonatologists, District IX Section on Neonatal-Perinatal Medicine, California
Perinatal Quality Care Collaborative, California Children’s Services; 2017
19. Stata Statistical Software [computer program]. Version 15. College Station, TX: Stata Press; 2017
20. Ting JY, Synnes A, Roberts A, et al.; Canadian Neonatal Network Investigators. Association
between antibiotic use and neonatal mortality and morbidities in very low-birth-weight infants
without culture-proven sepsis or necrotizing enterocolitis. JAMA Pediatr. 2016;170(12):1181–
1187 [PubMed: 27775765]
21. Mukhopadhyay S, Puopolo KM. Antibiotic use and mortality among premature infants without
Author Manuscript

confirmed infection-perpetrator or innocent bystander? JAMA Pediatr. 2016;170(12):1144–1146

[PubMed: 27775753]
22. Vangay P, Ward T, Gerber JS, Knights D. Antibiotics, pediatric dysbiosis, and disease. Cell Host
Microbe. 2015;17(5):553–564 [PubMed: 25974298]
23. Schulman J, Braun D, Lee HC, et al. Association between neonatal intensive care unit admission
rates and illness acuity. JAMA Pediatr. 2018;172(1):17–23 [PubMed: 29181499]
24. Harrison W, Goodman D. Epidemiologic trends in neonatal intensive care, 2007–2012. JAMA
Pediatr. 2015;169(9):855–862 [PubMed: 26214387]
25. Fisher ES, Wennberg JE. Health care quality, geographic variations, and the challenge of supply-
sensitive care. Perspect Biol Med. 2003;46(1):69–79 [PubMed: 12582271]
26. The Dartmouth Institute for Health Policy and Clinical Practice. Supply-sensitive care. 2017
Available at: www.dartmouthatlas.org/keyissues/issue.aspx?con=2937. Accessed May 4, 2017
27. Freedman S. Capacity and utilization in health care: the effect of empty beds on neonatal intensive
care admission. Am Econ J Econ Policy. 2016;8(2):154–185 [PubMed: 27942353]
Author Manuscript

28. Puopolo KM, Mukhopadhyay S, Hansen NI, et al.; NICHD Neonatal Research Network.
Identification of extremely premature infants at low risk for early-onset sepsis. Pediatrics.
2017;140(5):e20170925 [PubMed: 28982710]

Pediatrics. Author manuscript; available in PMC 2018 October 15.

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WHAT’S KNOWN ON THIS SUBJECT:

Neonatal antibiotic prescribing practice varies widely and is unexplained by the burden of
proven infection or other unambiguous clinical indications. Researchers in recent
publications and antibiotic stewardship efforts aim to reduce such variation.

WHAT THIS STUDY ADDS:

Antibiotic use rates are declining; practice variation is narrowing yet still largely
unexplained. Our findings help inform a framework for estimating antibiotic use rate
ranges that are consistent with objectively determined bacterial and/or fungal disease
burdens.
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FIGURE 1.
AUR ranges for all NICUs, those not participating in externally organized antibiotic
stewardship efforts, and those participating in externally organized antibiotic stewardship
efforts. Shaded rectangles indicate the interquartile range and median. Lines above or below
the box extend farther by 1.5 times the interquartile range. Dots indicate extreme outliers. A,
2013. B, 2014. C, 2015. D, 2016. AS, externally organized antibiotic stewardship efforts.
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FIGURE 2.
Distribution of AUR values by level of care for all NICUs from 2013 to 2016. The y-axis
displays kernel density, which is essentially a smoothed frequency distribution histogram
used to estimate the density of the distribution of values (the relative percent of NICUs at
each admission rate value). A, 2013. B, 2014. C, 2015. D, 2016.
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FIGURE 3.
A, Regional NICUs, all AUR values (ρ = 0.75; P < .001). B, Regional NICUs with AUR
<30% (ρ = 0.68; P = .001). C, Regional NICUs (ρ = 0.53; P = .01). D, Regional NICUs (ρ
= 0.57; P = .004). Centers within dashed rectangles have an AUR <30%. Straight lines
indicate fitted values.
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TABLE 1

NICU Patient Volume and Antibiotic Use Stratified by Participation in Externally Organized Antibiotic Stewardship Efforts

No. NICUs No. Admissions No. Patient d No. Antibiotic d Overall AUR, % AUR Median/Mean (SD) Range of AUR, Multiples of Lowest/Highest AUR
Lowest to Highest Value Value, %
Schulman et al.

2013
All NICUs 131 54181 777194 214370 27.6 24.2/28 (17.8) >100 0.01/97.1
Regional 22
Community 82
Intermediate 14
Non-CCS 13
Collaboratives 43 22936 355 839 99613 28.0 26.4/29.4 (17.9) >100 0.01/89.8
Nonparticipants 88 31245 421 355 114757 27.2 23.8/27.3 (17.8) >100 0.2/97.1
2014
All NICUs 131 56146 796 258 215355 27.0 23.8/27.2 (15.4) 78 1.1/84.9
Regional 23
Community 81
Intermediate 13
Non-CCS 14
Collaboratives 44 23 386 361102 98 782 27.4 26.2/28.6 (14.1) 13 6.3/80.4
Nonparticipants 87 32 760 435156 116573 26.8 22.3/26.5 (16.1) 77 1.1/85
2015
All NICUs 134 57 332 791 220 195679 24.7 21.4/24.4 (12.2) 9 7.3/66.7
Regional 23

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Community 81
Intermediate 14
Non-CCS 16
Collaboratives 42 23 294 341 260 80 389 23.6 21.9/24 (10.4) 7 7.3/52
Nonparticipants 92 34038 449 960 115290 25.6 21/24.6 (13) 8 8.2/66.7
2016
All NICUs 137 56 257 795 663 171410 21.6 19.7/21.8 (10) 10 5.6/57
Regional 23
Community 83
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No. NICUs No. Admissions No. Patient d No. Antibiotic d Overall AUR, % AUR Median/Mean (SD) Range of AUR, Multiples of Lowest/Highest AUR
Lowest to Highest Value Value, %
Intermediate 17
Non-CCS 14
Collaboratives 44 23127 356 822 71200 19.9 19/21.1 (8.2) 5 9.4/46.8
Schulman et al.

Nonparticipants 93 33130 438 841 100210 22.8 20.1/22.2 (10.7) 10 5.6/57

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TABLE 2

Estimated Correlations With AURs and Correlate Variable Sample Means for Quartiles 1 Versus Quartiles 2–4

Correlation Coefficient, ρ P AUR Quartile 1, Mean (SD) AUR Quartiles 2–4, Mean (SD) P
EOS
Schulman et al.

All NICUs 0.10 .29 0.59 (0.74) 0.61 (0.64) .86

Regional 0.02 .93 0.47 (0.46) 0.73 (0.81) .51
Community 0.11 .33 0.66 (0.83) 0.61 (0.57) .78
Intermediate 0.20 .47 0.25 (0.43) 0.45 (0.69) .64

Non-CCS —a N/A —b —b N/A

CLABSI
All NICUs −0.02 .81 0.81 (2.19) 0.98 (1.59) .69
Regional 0.27 .21 0.91 (0.96) 1.25 (0.68) .78
Community −0.08 .45 1.07 (2.71) 1.07 (1.83) .99

Intermediate —a N/A —a —a N/A

Non-CCS 0.40 .20 0(0) 1.38 (1.94) .19

LOS
All 0.03 .77 2.76 (2.94) 3.18 (2.98) .48
Regional 0.20 .37 3.14 (1.35) 3.98 (2.17) .43
Community −0.07 .50 3.40 (3.29) 3.19 (2.79) .79
Intermediate 0.33 .19 0 (0) 1.10 (2.49) .46
Non-CCS 0.36 .20 1.38 (2.19) 4.67 (4.68) .17
Fungal infection

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All 0.05 .60 0.08 (0.28) 0.19 (0.57) .14
Regional −0.18 .41 0.57 (0.56) 0.31 (0.46) .30
Community 0.15 .17 0 (0) 0.18 (0.57) .15

Intermediate —a N/A —a —a N/A

Non-CCS 0.31 .28 0 (0) 0.35 (1.04) .48

NEC
All NICUs 0.01 .88 1.47 (2.27) 2.23 (2.89) .16
Regional 0.04 .87 4.59 (1.77) 5.03 (3.02) .76
Community 0.11 .34 0.83 (1.71) 1.94 (2.64) .03
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Correlation Coefficient, ρ P AUR Quartile 1, Mean (SD) AUR Quartiles 2–4, Mean (SD) P

Intermediate —a N/A —a —a N/A

Non-CCS −0.003 .99 1.90 (2.93) 1.56 (2.33) .82

No. surgical cases
All NICUs −0.04 .67 14.97 (37.28) 50.07 (112.49) .007
Schulman et al.

Regional 0.53 .01 76.80 (69.92) 243.94 (159.43) .03

Community 0.07 .52 5.48 (13.75) 11.97 (24.44) .14
Intermediate −0.17 .51 1.33 (2.31) 0.14 (0.53) .47
Non-CCS −0.37 .19 1.20 (1.09) 2.44 (5.50) .53
NICU mortality rate
All NICUs −0.08 .34 0.01 (0.01) 0.01 (0.01) .69
Regional 0.57 .004 0.02 (0.01) 0.03 (0.02) .13
Community −0.13 .23 0.01 (0.01) 0.01 (0.01) .39
Intermediate 0.10 .70 0 (0) 0.001 (0.003) .66
Non-CCS 0.08 .78 0.002 (0.003) 0.005 (0.005) .28
Inborn admission rate
All NICUs 0.23 .009 11.20 (7.12) 13.03 (5.35) .18
Regional 0.26 .30 16.90 (15.32) 18.73 (7.30) .81
Community 0.30 .006 10.92 (4.92) 12.66 (4.72) .17
Intermediate 0.07 .79 9.54 (1.80) 11.45 (3.60) .23
Non-CCS 0.39 .16 7.68 (1.44) 9.85 (2.41) .06
Average length of stay
All NICUs 0.05 .56 55.06 (12.87) 58.69 (21.69) .25

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Regional 0.62 .002 66.84 (8.47) 82.87 (19.02) .08
Community 0.06 .56 56.81 (10.36) 59.89 (11.76) .30
Intermediate −0.29 .27 36.44 (11.74) 21.91 (13.95) .12
Non-CCS 0.53 .06 47.47 (12.42) 54.70 (16.03) .41

From the 2016 data set. CLABSI, central line–associated bloodstream infection; N/A, not available; —, not applicable.
a
NICUs reported a rate of 0.
b
Not reported.
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