Time To Positivity of Blood Cultures in Neonatal Late-Onset Bacteraemia

Original research
Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2021-323416 on 10 March 2022. Downloaded from http://fn.bmj.com/ on October 28, 2022 at World Health
Time to positivity of blood cultures in neonatal late-
onset bacteraemia
Sagori Mukhopadhyay,1,2,3 Sara M Briker,1,4 Dustin D Flannery ‍ ‍,1,2,3
Miren B Dhudasia ‍ ‍,1,3 Sarah A Coggins ‍ ‍,1,2 Emily Woodford,1 Eileen M Walsh,5
Sherian Li,5 Karen M Puopolo,1,2,3 Michael W Kuzniewicz ‍ ‍5,6
► Additional supplemental ABSTRACT

material is published online Objective To determine the time to positivity (TTP) What is already known on this topic?
only. To view, please visit the
journal online (http://d x.doi. of blood cultures among infants with late-onset
⇒ The duration of empiric antibiotic therapy in
org/1 0.1136/a rchdischild- bacteraemia and predictors of TTP >36 hours.
sepsis evaluation is conventionally based on
2021-323416). Design Retrospective cohort study.
the time to positivity (TTP) for the majority of
Setting 16 birth centres in two healthcare systems.
1
Division of Neonatology, confirmed cases.
Patients Infants with positive blood cultures obtained
Children’s Hospital of ⇒ Automated blood culture detection systems can
Philadelphia, Philadelphia, >72 hours after birth.
shorten the time to detection of pathogens and
Pennsylvania, USA Outcome The main outcome was TTP, defined as
2 allow shorter empiric antibiotic durations in the
Department of Pediatrics, the time interval from specimen collection to when a
neonatal intensive care unit.
Organisation (HINARI) - Group A. Protected by copyright.

University of Pennsylvania neonatal provider was notified of culture growth. TTP
Perelman School of Medicine, ⇒ A 36-hour empiric duration is being used in
Philadelphia, Pennsylvania, USA analysis was restricted to the first positive culture per early-onset sepsis evaluations, but it is unclear
3
Center for Pediatric Clinical infant. Patient-specific and infection-specific factors were
Effectiveness, Children’s Hospital analysed for association with TTP >36 hours.
whether 36-hour empiric duration can be
of Philadelphia, Philadelphia, applied to late-onset sepsis evaluations.
Results Of 10 235 blood cultures obtained from 3808
Pennsylvania, USA
4 infants, 1082 (10.6%) were positive. Restricting to
University of Pennsylvania
Perelman School of Medicine, bacterial pathogens and the first positive culture, the
Philadelphia, Pennsylvania, USA median TTP (25th–75th percentile) for 428 cultures
5
Division of Research, Kaiser was 23.5 hours (18.4–29.9); 364 (85.0%) resulted in What this study adds?
Permanente Northern California, 36 hours. Excluding coagulase-negative staphylococci
San Francisco, California, USA ⇒ Among 428 infants with late-onset
6
Department of Pediatrics, (CoNS), 275 of 294 (93.5%) cultures were flagged
positive by 36 hours. In a multivariable model, CoNS bacteraemia, 85% of all cultures and 94% of
Kaiser Permanente Northern
California, San Francisco, isolation and antibiotic pretreatment were significantly non-coagulase-negative staphylococci (non-
California, USA associated with increased odds of TTP >36 hours. CoNS) pathogens were detected by 36 hours.
Projecting a 36-hour empiric duration at one site and ⇒ CoNS isolation and pretreatment with
Correspondence to assuming that all negative evaluations were associated antibiotics were significantly associated
Dr Sagori Mukhopadhyay, with TTP >36 hours in a multivariable model
Pediatrics, University of with an empiric course of antibiotics, we estimated
that 1164 doses of antibiotics would be avoided in adjusting for patient-specific and culture-
Pennsylvania, Philadelphia, PA
19146, USA; 629 infants over 10 years, while delaying a subsequent specific factors.
m
ukhopadhs@email.c hop.edu antibiotic dose in 13 infants with bacteraemia. ⇒ Empiric antibiotic coverage for late-onset
Conclusions Empiric antibiotic administration in late- sepsis evaluations not targeting CoNS (such
Received 22 October 2021 as regimens using oxacillin for Gram-positive
Accepted 21 February 2022 onset infection evaluations (not targeting CoNS) can be
Published Online First stopped at 36 hours. Longer durations (48 hours) should coverage) can be stopped at 36 hours.
10 March 2022 be considered when there is pretreatment or antibiotic
therapy is directed at CoNS.
In early-onset sepsis (EOS) evaluations, a 36-hour
empiric antibiotic duration has been proposed
to capture the majority of cases while minimising
INTRODUCTION antibiotics among the ultimately uninfected.6–8
Optimising antibiotic use in healthcare settings is National guidelines now suggest that a 36- hour
a key strategy to combat the global rise of antimi- empiric duration may be appropriate in EOS evalu-
crobial resistance.1 In neonatal intensive care units ations.9 10 However, it is unclear whether a 36-hour
(NICUs), empiric treatment for suspected infection empiric duration can also be applied to late-onset
is a large contributor of antibiotic use.2 The dura- sepsis evaluations. Prior studies report that TTP in
© Author(s) (or their
employer(s)) 2022. No tion of empiric antibiotic therapy should be based late-onset sepsis is longer than in EOS,6 11 but few
commercial re-use. See rights on the time to positivity (TTP) for the majority of studies have evaluated the impact of patient charac-
and permissions. Published confirmed cases. Traditionally, empiric antibiotic teristics or antibiotic pretreatment on TTP in late-
by BMJ. duration ranges from 48 to 72 hours.3 4 Widespread onset sepsis.
To cite: Mukhopadhyay S, use of automated blood culture detection systems The objectives of this study were to determine
Briker SM, Flannery DD, et al. has shortened the time in which most pathogens are TTP in late-onset bacteraemia cases and the factors
Arch Dis Child Fetal Neonatal reported,5 which could allow shorter empiric dura- associated with TTP >36 hours and to estimate the
Ed 2022;107:F583–F588. tions and reduce antibiotic utilisation in the NICU. probability of pathogen isolation after 36 hours. We
Mukhopadhyay S, et al. Arch Dis Child Fetal Neonatal Ed 2022;107:F583–F588. doi:10.1136/archdischild-2021-323416 F583
Original research
also estimated differences in antibiotic use with a 36-hour versus Analysis
a 48-hour empiric antibiotic duration. We compared the median TTP and IQR and the propor-
tion of positive bacterial cultures by 24, >24–36, >36–48
and >48 hours in the following groups: (1) pathogens versus
METHODS contaminants; (2) pathogens excluding CoNS versus CoNS
Study setting managed as pathogen; (3) Gram- positive (excluding CoNS)
This was a retrospective cohort study of infants admitted to versus Gram-negative pathogens; (4) cultures obtained prior to
NICUs in two healthcare systems who had a blood culture antibiotic administration versus pretreated cultures; (5) CLABSI
obtained >72 hours after birth. Study centres and time periods episodes versus non- line-
associated infections; and (6) PAH
included the following: Pennsylvania Hospital (PAH; infants
versus KPNC. We generated Kaplan-Meier curves for TTP in
born from 1 January 2009 to 31 December 2020, excluding
these groups to graphically present the differences. We deter-
infants born from 1 January 2015 to 30 September 2016 due to
mined the probability of a culture growing a bacterial pathogen
lack of available data) and 15 birth facilities affiliated with Kaiser
after 36 hours using the formula provided by Lambregts et al12:
Permanente Northern California (KPNC; infants born from 1 [ ( )
1−TTPe ∗X
]
January 2010 to 31 December 2020). Patient demographics, P = 1−(TTP ∗X) ∗ 100 , where TTPe is the proportion of positive
‍ e ‍
antibiotic information and blood culture results were obtained blood cultures growing ≤36 hours after birth and X is the rate
from electronic medical records. Assessments of contaminants, of positivity for blood cultures obtained >72 hours after birth.
TTP, incubation time and central line presence were determined In the subcohort with all variables available, we tested for
by chart review. Data on central line and incubation time were the associations between TTP >36 hours and gestational age
available for KPNC infants and a subset of PAH infants born at birth, postnatal age when culture was obtained, sex, pres-
after 1 October 2016. Analyses that included these variables ence of central line, pathogen type, study centre and antibiotic
were restricted to this subcohort. pretreatment. For the multivariable logistic regression model, we

included variables significantly associated with the outcome in
the bivariable analysis and forced study centre into the model.
Blood culture processing
To estimate the impact of a 36-hour versus a 48-hour empiric
All blood cultures obtained >72 hours after birth with detectable
antibiotic duration, we used PAH data that contained infor-
microbial growth were included in the analysis. At KPNC, 1 mL
mation on all sepsis evaluations, including those with negative
of blood was inoculated in an aerobic bottle, followed by incu-
blood culture results. A new evaluation was defined as a blood
bation at an off-site centralised microbiology laboratory using
culture obtained >2 days after completion of antibiotic course
BacT/Alert Pediatric FAN. PAH used an on-site microbiology
for a previous bacteraemia or >2 days after a previous negative
laboratory and the BD BACTEC system. Between 2009 and
culture. We assumed that all evaluations were associated with
2014 at PAH, 1 mL of blood was inoculated in an aerobic bottle.
empiric antibiotic initiation consisting of an 8-hourly dose for
After 1 October 2016, 2 mL of blood were inoculated, divided
Gram- positive coverage (eg, oxacillin) and a 24- hourly dose
equally between an aerobic and an anaerobic bottle. Microbi-
for Gram-negative coverage (eg, aminoglycoside). Further, we
ology staff at both sites call and inform the neonatal provider in
real time when the automated microbial detection system alarms assumed that these antibiotics would be discontinued after 48
to signal microbial growth. hours if cultures resulted as sterile at that time. We estimated
that a 36-hour empiric duration compared with 48-hour would
avoid one antibiotic dose for Gram-positive coverage at the 40th
Study definitions hour.
TTP was defined as the duration in hours from when the culture All analyses were performed using Stata V.16.
specimen was obtained to the time that laboratory staff reported
growth to a neonatal provider. Preanalytic time was defined
as the duration in hours from when the culture specimen was RESULTS
obtained to the time it was incubated in the automated detection A total of 10 235 blood cultures were obtained from 3808 infants
system. >72 hours after birth, with 77.9% of the cultures obtained at
Known commensal organisms such as diphtheroids, Micro- KPNC. Online supplemental figure delineates derivation of the
coccus species, etc were classified as contaminants. Coagulase- study population. A total of 1082 blood cultures were positive
negative staphylococci (CoNS) were classified as pathogens (10.6%). After excluding cultures that were repeat positive
when managed accordingly by the clinical team with ≥5 days due to persistent bacteraemia/fungaemia (n=441, 40.8%) and
of antibiotics. For infants with multiple positive blood cultures, contaminants (n=145, 13.4%), there were 496 unique episodes
a new bacteraemia episode was defined as isolation of a of late-
onset bacteraemia or fungaemia in 447 infants. The
different organism or isolation of the same organism >2 days median gestational age for the cohort was 26 weeks (IQR 24–29
after completion of antibiotic course for previous bacteraemia. weeks). The median postnatal age at the first episode was 14
Contaminants and fungi were excluded from the primary TTP days (IQR 9–24 days) (online supplemental table 1). Of 496
analysis. For all TTP analyses, only the first episode of bacter- episodes, antibiotic pretreatment was observed in 62 (12.5%)
aemia for each infant was used to avoid non-independence asso- episodes. Data on central line were available for 378 episodes,
ciated with repeated measures. All episodes of bacteraemia were and 252 (66.7%) of these were identified as CLABSI.
used to calculate rates of positivity. Of the 496 episodes of late-onset bacteraemia or fungaemia,
Pretreatment with antibiotics was defined as parenteral anti- Gram-positive organisms accounted for 58.1% of all pathogens
biotic administration 1–24 hours prior to drawing the culture isolated. CoNS was the predominant organism, representing
specimen. 28.8% of all pathogens. Gram- negative organisms were the
Central line-associated bloodstream infection (CLABSI) was second most common (33.3%), followed by fungi (6.1%) and
defined as pathogen isolation from a culture obtained with a polymicrobial infections (2.6%) (table 1). Organisms excluded
central line in place for ≥2 days or ≤2 days of its removal. as contaminants are shown in online supplemental table 2.
F584 Mukhopadhyay S, et al. Arch Dis Child Fetal Neonatal Ed 2022;107:F583–F588. doi:10.1136/archdischild-2021-323416
Original research
of positive cultures by 36 hours was similar between the two
Table 1 Blood culture pathogens isolated from all late-onset
centres (88.1% vs 83.4%, p=0.19).
infection evaluation episodes
Positive by
Pathogens isolated n=496 Median TTP (Q1, Q3) 36 hours* Factors associated with TTP >36 hours
Gram-positive, n (%) 288 (58.1)
In the bivariable analysis (table 3), central line presence, anti-
CoNS 143 30.4 (24.3, 39.2) 98 (68.5)
biotic pretreatment and CoNS were significantly associated
with TTP >36 hours. In the multivariable analysis, CoNS and

Staphylococcus aureus† 99 23.9 (19.5, 29.0) 89 (89.9)
pretreatment remained significantly associated with TTP >36,

Streptococcus agalactiae 27 15.0 (11.0, 19.0) 27 (100.0)
but central line presence did not.

Enterococcus sp 11 23.1 (18.3, 27.6) 10 (90.9)
Other Streptococcus sp 7 19.3 (9.6, 28.0) 7 (100.0)

Bacillus cereus 1 24.0 1 (100.0) Antibiotic use with empiric duration of 36 hours vs 48 hours
Gram-negative, n (%) 165 (33.3) At PAH, there were 174 episodes of late-onset bacteraemia in 152

Escherichia coli 82 19.8 (16.9, 23.1) 77 (93.9) infants and 1164 episodes of negative evaluations in 629 infants.

Klebsiella sp 38 17.4 (12.5, 21.0) 38 (100.0) Stopping antibiotics at 36 hours would have avoided 1164 anti-

Pseudomonas aeruginosa 18 24.1 (22.1, 28.8) 16 (88.9) biotic doses for Gram- positive coverage. It also would have

Enterobacter sp 11 17.6 (17.4, 22.7) 9 (81.8) resulted in an interruption of antibiotic therapy for <8 hours

Serratia sp 10 24.5 (17.1, 25.7) 10 (100.0) in seven infants and >8 hours in six infants with an eventual

Citrobacter sp 2 25.3 (23.2, 27.5) 2 (100.0)
positive culture. The longest TTP was for a culture growing E.

Morganella sp 2 19.8 (19.0, 20.5) 2 (100.0)
cloacae (83.6 hours). For this episode, a 36-hour empiric dura-

Proteus mirabilis 1 20.8 1 (100.0)
tion would have interrupted the 40th-hour antibiotic dose and

Stenotrophomonas 1 37.5 0
delayed subsequent dose by 44 hours, whereas a 48-hour empiric

maltophilia duration would have interrupted the 48th-hour antibiotic dose
Fungi, n (%) 30 (6.1) 38.0 (30.6, 47.1) 14 (46.7) and delayed subsequent dose by 36 hours. For every case with
Polymicrobial, n (%) 13 (2.6) 21.7 (15.0, 23.9) 13 (100.0) an interruption of antibiotic therapy of >8 hours, 194 antibiotic
*Row percentages shown.
doses would be avoided.
†Includes 16 methicillin-resistant Staphylococcus aureus.
CoNS, coagulase-negative staphylococci; Q1, first quartile; Q3, third quartile; TTP, time to
positivity. DISCUSSION
In a large cohort of infants admitted to NICUs in two health-
care systems, 85.1% of late-onset bacteraemia cases and 93.5%
Time to positivity of non-CoNS pathogens were identified by 36 hours. CoNS
Restricting to the first episode of pathogenic bacteraemia bacteraemia and antibiotic pretreatment were associated with
(n=428), the median TTP was 23.5 hours (IQR 18.4–29.9), with TTP >36 hours. We found a low probability (1.8%) for a culture
54.2% detected by 24 hours, 85.1% by 36 hours and 94.9% by that is negative at 36 hours to signal growth thereafter, and an
48 hours. The probability of detecting a bacterial pathogen after even lower probability (0.5%) that it will detect a non-CoNS
36 hours was 1.8% (95% CI 1.4 to 2.2) and the probability of organism.
detecting a non-CoNS pathogen after 36 hours was 0.5% (95% Based on TTP data, recent reports have proposed short-
CI 0.3 to 0.7). ening the empiric antibiotic duration for EOS evaluation from
Figure 1 shows the TTP curves by specific characteristics. 48–72 hours to 24–36 hours.7 11 13 Our study highlights some
Pathogens had a significantly shorter TTP compared with contam- additional considerations when contemplating similarly limiting
inants (figure 1A). CoNS had a longer TTP compared with other empiric antibiotic duration for late-onset infection evaluations.
pathogens (figure 1B). The median TTP of non-CoNS pathogens First, we found that a longer preanalytic time correlated with
was 21.2 hours (IQR 17.1–25.7), with 93.5% detected within a significant centre-specific difference in TTP. Studies reporting
36 hours (table 2). Excluding CoNS, the median TTP remained TTP in late- onset bacteraemia often calculate TTP from the
longer for other Gram-positive organisms compared with Gram- time of incubation6 14–17 to detection of bacterial growth by the
negative organisms. However, the proportion detected by 36 culture machine.11 16 17 In real-world practice, TTP determining
hours did not differ (91.9% vs 94.5%, p=0.38) (figure 1C). empiric antibiotic duration also includes the time from blood
CoNS accounted for 45 of 64 (70.3%) organisms detected collection to incubation, and the time from detection of growth
after 36 hours. The remaining 19 organisms included Staphy- to provider notification.3 TTP calculated from the time of incu-
lococcus aureus (n=10), Escherichia coli (n=4), Pseudomonas bation can give shorter durations both by excluding the preana-
aeruginosa (n=2), Enterobacter cloacae (n=1), Enterococcus lytic time and by not accounting for the growth that potentially
faecalis (n=1) and Stenotrophomonas maltophilia (n=1). Anti- occurred during that time. Samples from KPNC, processed at an
biotic pretreatment was observed in 5 of 19 (26.3%) of these off-site microbiology facility, had a significantly longer prean-
non-CoNS cultures. alytic time, which corresponded to longer median TTP and
While antibiotic pretreatment was not associated with a lower lower percentage of positive cultures at 24 hours. However, by
median TTP (figure 1D), pretreated cultures were less likely to 36 hours, a similar proportion were detected at both centres,
be positive by 36 hours compared with non-pretreated cultures suggesting a potentially generalisable 36-hour cut-off.
(64.7% vs 86.8%, p=0.001). Central line presence was associ- Second, we found that pretreated cultures had significantly
ated with a longer median TTP (figure 1E). PAH cultures (on- longer TTP compared with cultures drawn before antibiotic
site microbiology facility) had a significantly shorter median administration, a finding reported by others as well.18 Since only
TTP compared with KPNC cultures (centralised, off-site facility) 64.7% of eventual positive pretreated cultures resulted by 36
(figure 1F). The median preanalytic time was significantly higher hours, a shortened empiric duration may not be sufficient. These
for KPNC (8 hours, IQR 5–10 hours) compared with PAH cases highlight the role for culture-independent techniques such
(1 hour, IQR 0–2 hours; p<0.001). However, the proportion as PCR-based methods in supplementing culture-based methods.
Original research
Figure 1 Kaplan-Meier curves of TTP for late-onset bacteraemia: subgroup comparisons. The figure demonstrates the TTP of positive cultures among
the following subgroups: (A) pathogens versus contaminants; (B) pathogens excluding CoNS versus CoNS managed as pathogen; (C) Gram-positive
(excluding CoNS) versus Gram-negative pathogens; (D) cultures obtained prior to antibiotic administration versus pretreated cultures; (E) CLABSI
episodes versus non-line-associated infections; and (F) PAH versus KPNC. The p values shown demonstrate the difference in median TTP (by Mann-
Whitney U test) of the respective comparison groups. CLABSI, central line-associated bloodstream infections; CoNS, coagulase-negative staphylococci;
KPNC, Kaiser Permanente Northern California; PAH, Pennsylvania Hospital; TTP, time to positivity.
While blood cultures remain the best way to determine suscepti- 36 hours was low.6 11 12 In a study of over 700 late-onset blood
bility for a broad group of pathogens, culture-independent tech- cultures, most pathogens were detected by 24–36 hours,11 and
niques offer specific advantages in that they are less sensitive to almost all Gram-negative organisms were detected by 24 hours.
pretreatment19 and can detect organisms not easily cultured.20 The authors suggested that aminoglycoside coverage could be
While challenges remain with widespread availability and lack stopped at 24 hours. In our study, only 76.0% of Gram-negative
of guidance on how best to integrate them in clinical practice,21 pathogens were detected by 24 hours. These differences may be
these tests may allow both earlier identification of pathogens and due to differing patient characteristics or longer preanalytic time
increase clinician confidence in a sterile result. for some samples in our study.
Lastly, the positivity rate of blood cultures in suspected late- While the majority of late- onset bacteraemia cases were
onset infection evaluations can be as high as 30%,3 6 14 22–24 detected in 36 hours, many pretreated cultures and cases of
substantially greater than the 2%–4% positivity rates seen in EOS CoNS bacteraemia were not. If considering a 36-hour empiric
evaluation.6 7 23 This higher prior probability of detecting bacte- duration, these two scenarios could be resolved differently.
raemia may change how clinicians view the risks and benefits of Since pretreatment is known to the ordering provider, they
early antibiotic discontinuation. Consistent with other studies, may elect to choose a longer empiric antibiotic duration. For
we found that the probability of detecting bacteraemia after CoNS cases, a more general risk–benefit assessment is required.
Original research
Table 2 TTP for neonatal late-onset bacteraemia by culture characteristics
TTP†
Characteristics TTP, median (Q1, Q3) P value* 24 hours, n (%) >24–36 hours, n (%) >36–48 hours, n (%) ≥48 hours, n (%)
All bacterial pathogens (n=428) 23.5 (18.4, 29.9) – 232 (54.2) 132 (30.8) 42 (9.8) 22 (5.1)
Pathogens vs contaminants‡
Pathogens (n=428) 23.5 (18.4, 29.9) <0.001 232 (54.2) 132 (30.8) 42 (9.8) 22 (5.1)
Contaminants (n=142) 42.1 (34.1, 54.3) 6 (4.2) 39 (27.5) 41 (28.9) 56 (39.4)
CoNS (managed as pathogens) vs other pathogens
CoNS (n=134) 30.0 (24.6, 40.3) <0.001 29 (21.6) 60 (44.8) 33 (24.6) 12 (9.0)
Other pathogens (n=294) 21.2 (17.1, 25.7) 203 (69.1) 72 (24.5) 9 (3.1) 10 (3.4)
Gram-positive (excluding CoNS) vs Gram-negative
Gram-positive (n=136) 22.1 (17.7, 27.6) 0.02 83 (61.0) 42 (30.9) 4 (2.9) 7 (5.2)
Gram-negative (n=146) 20.4 (17.1, 23.9) 111 (76.0) 27 (18.5) 5 (3.4) 3 (2.1)
Pretreatment with antibiotics
Pretreated cultures (n=34) 25.8 (19.4, 38.6) 0.12 15 (44.1) 7 (20.6) 7 (20.6) 5 (14.7)
Cultures obtained prior to antibiotics (n=394) 23.3 (18.4, 29.4) 217 (55.1) 125 (31.7) 35 (8.9) 17 (4.3)
Central line§
Present (n=208) 23.8 (19.0, 31.7) 0.01 107 (51.4) 62 (29.8) 21 (10.1) 18 (8.7)
Absent (n=113) 22.1 (17.5, 27.6) 69 (61.1) 33 (29.2) 11 (9.7) 0
Study centre
KPNC (n=277) 24.0 (19.7, 31.1) <0.001 140 (50.5) 91 (32.9) 29 (10.5) 17 (6.1)

PAH (n=151) 21.3 (15.1, 27.3) 92 (60.9) 41 (27.2) 13 (8.6) 5 (3.3)
*P values demonstrate difference in median TTP (by Mann-Whitney U test) between the respective subgroups.
†Row percentages shown.
‡Excludes 3 cases (2 Staphylococcus aureus and 1 Candida albicans) managed as contaminants by the clinical team; infants remained well without antibiotic treatment.
§Only shown for infants with central line data available.
CoNS, coagulase-negative staphylococci; KPNC, Kaiser Permanente Northern California; PAH, Pennsylvania Hospital; Q1, first quartile; Q3, third quartile; TTP, time to positivity.
Table 3 Bivariable and multivariable associations between patient and culture characteristics and TTP >36 hours*
Bivariable Multivariable
Characteristics OR (95% CI) P value aOR (95% CI) P value
Gestational age (weeks) 0.96 (0.88 to 1.04) 0.35 – –
Sex (male vs female) 0.90 (0.49 to 1.66) 0.74 – –
Postnatal age (days) at positive culture 1.00 (0.98 to 1.01) 0.68 – –
Central line (present vs absent) 2.21 (1.08 to 4.51) 0.03 1.34 (0.60 to 3.02) 0.48
Pretreated vs not pretreated 6.07 (2.16 to 17.06) 0.001 5.31 (1.46 to 19.27) 0.01
CoNS vs other pathogens 14.34 (7.10 to 28.96) <0.001 14.60 (6.98 to 30.58) <0.001
Gram-positive vs Gram-negative† 1.67 (0.56 to 4.97) 0.36 – –
KPNC vs PAH 1.71 (0.58 to 5.04) 0.33 2.26 (0.68 to 7.55) 0.19
*Includes first positive episode of late-onset bacteraemia growing a pathogen (except fungus and polymicrobial) for infants who had data available for central line (n=313).
†Excludes CoNS (n=237).
aOR, adjusted OR; CoNS, coagulase-negative staphylococci; KPNC, Kaiser Permanente Northern California; PAH, Pennsylvania Hospital; TTP, time to positivity.
Management of CoNS bacteraemia is challenging as definitive of TTP. Lastly, our estimates of antibiotic doses reduced using a
criteria for excluding contamination are rarely met in neonates. 36-hour convention for ‘rule out sepsis’ would differ depending
It is also associated with lower mortality and it is unclear on what proportion of infants were ultimately treated in the face
whether a few hours’ interruption of antibiotic therapy impacts of sterile blood cultures for conditions such as necrotising entero-
morbidity.14 25 Studies on vancomycin reduction initiatives in colitis, urinary tract infection and cellulitis, and depending on
the NICU have previously discussed the risk–benefit of empiric centre practice regarding treatment for ‘culture-negative’ sepsis.
CoNS coverage.26 27 Many NICU providers conclude that the
benefits of using oxacillin/nafcillin (less nephrotoxic antibi- CONCLUSIONS
otic; superior activity towards methicillin-sensitive S. aureus; Empiric antibiotic coverage for late-onset infection evaluations
avoids selection pressure against vancomycin) outweigh the (not targeting CoNS) can be stopped at 36 hours. Longer dura-
risks of delaying CoNS coverage. Aligned with previous studies, tions (48 hours) should be considered when there is pretreat-
we conclude that empiric coverage not targeting CoNS can ment or antibiotic therapy is directed at CoNS.
be stopped at 36 hours.11 If antibiotics are targeted at CoNS,
empiric coverage for 48 hours may be warranted. Twitter Sagori Mukhopadhyay @sagori, Dustin D Flannery @dus10flan and Miren B
A strength of the study is the large sample size and inclusion Dhudasia @MDhudasia
of multiple study centres with differing microbiology processing Acknowledgements The authors would like to thank Suyi Zhu, RN, MSN for
systems, making the results more generalisable. Limitations assisting with data collection.
include the lack of information on clinical presentation, site of Contributors SM and MWK conceptualised and designed the study, contributed
blood draw and details of blood inoculant volume as a predictor to interpretation of results, drafted the initial manuscript, and reviewed and revised
Original research
the final manuscript. DDF and SMB contributed to study design, data acquisition, 6 Jardine L, Davies MW, Faoagali J. Incubation time required for neonatal blood cultures
interpretation of results, drafted the initial manuscript, critically reviewed the to become positive. J Paediatr Child Health 2006;42:797–802.
manuscript, and approved the final manuscript as submitted. MBD contributed to 7 Kuzniewicz MW, Mukhopadhyay S, Li S, et al. Time to positivity of neonatal blood
study design and data acquisition, performed statistical analyses, critically reviewed cultures for early-onset sepsis. Pediatr Infect Dis J 2020;39:634–40.
the manuscript, and approved the final manuscript as submitted. SAC and KMP 8 Meyers JM, Tulloch J, Brown K, et al. A quality improvement initiative to optimize
contributed to interpretation of results, critically reviewed the manuscript and antibiotic use in a level 4 NICU. Pediatrics 2020;146. doi:10.1542/peds.2019-3956.
approved the final manuscript as submitted. EW, EMW and SL contributed to data [Epub ahead of print: 14 10 2020].
collection and verification, critically reviewed the manuscript, and approved the 9 National Institute for Health and Care Excellence. Neonatal infection: antibiotics for
final manuscript as submitted. SM accepts full responsibility for the work and/or the prevention and treatment (NG195). Available: https://www.nice.org.uk/guidance/
conduct of the study, had access to the data, and controlled the decision to publish. ng195 [Accessed 21 Oct 2021].
10 Puopolo KM, Benitz WE, Zaoutis TE, et al. Management of Neonates Born at ≥35 0/7
Funding DDF receives funding from the Agency for Healthcare Research and
Weeks’ Gestation With Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics
Quality (K08HS027468). SM receives funding from the Eunice Kennedy Shriver
2018;142.
National Institute of Child Health and Human Development from the National
11 Ur Rehman Durrani N, Rochow N, Alghamdi J, et al. Minimum duration of antibiotic
Institutes of Health (grant K23HD088753). SAC receives funding from the National
treatment based on blood culture in rule out neonatal sepsis. Pediatr Infect Dis J
Heart, Lung, and Blood Institute of the National Institutes of Health (T32HL007891).
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Patient consent for publication Not required. cultures supports early re-evaluation of empiric broad-spectrum antimicrobial therapy.
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Provenance and peer review Not commissioned; externally peer reviewed. J Glob Infect Dis 2017;9:102–7.
15 Garcia-Prats JA, Cooper TR, Schneider VF, et al. Rapid detection of microorganisms
Supplemental material This content has been supplied by the author(s). It in blood cultures of newborn infants utilizing an automated blood culture system.
has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have Pediatrics 2000;105:523–7.

been peer-reviewed. Any opinions or recommendations discussed are solely those 16 Huggard D, Powell J, Kirkham C, et al. Time to positivity (TTP) of neonatal blood
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and cultures: a trend analysis over a decade from Ireland. J Matern Fetal Neonatal Med
responsibility arising from any reliance placed on the content. Where the content 2021;34:780–6.
includes any translated material, BMJ does not warrant the accuracy and reliability 17 Vamsi SR, Bhat RY, Lewis LE, et al. Time to positivity of blood cultures in neonates.
of the translations (including but not limited to local regulations, clinical guidelines, Pediatr Infect Dis J 2014;33:212–4.
terminology, drug names and drug dosages), and is not responsible for any error 18 Scheer CS, Fuchs C, Gründling M, et al. Impact of antibiotic administration on blood
and/or omissions arising from translation and adaptation or otherwise. culture positivity at the beginning of sepsis: a prospective clinical cohort study. Clin
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Supplemental material placed on this supplemental material which has been supplied by the author(s) Arch Dis Child Fetal Neonatal Ed
Supplemental Figure. Derivation of the Study Population
NICU, neonatal intensive care unit; TTP, time to positivity.
Mukhopadhyay S, et al. Arch Dis Child Fetal Neonatal Ed 2022;0:1–6. doi: 10.1136/archdischild-2021-323416
Supplemental Table 1. Demographics and Clinical Characteristics of Infants with Late-

Onset Bacteremia or Fungemia Episode
Characteristics N = 447
Gestational age (weeks), median (Q1, Q3) 26 (24, 29)
Birth weight (grams), median (Q1, Q3) 830 (660, 1250)
Sex (male), n (%) 258 (57.7)
Race/ethnicity, n (%)
Black/Non-Hispanic 70 (15.7)
White/Non-Hispanic 73 (16.3)
Asian 99 (22.2)
Hispanic 78 (17.5)
Other/Unknown 112 (25.1)
Study center, n (%)
KPNC 295 (66.0)
PAH 152 (34.0)
Age at 1st late-onset infection episode (days), median (Q1, Q3) 14 (9, 24)
Late-onset infection episodes per infant, n (%)
1 405 (90.6)
2 37 (8.3)
3+ 5 (1.1)
Footnotes: KPNC, Kaiser Permanente Northern California; PAH, Pennsylvania Hospital; Q1,
first quartile; Q3, third quartile.
Supplemental Table 2. Organisms Deemed as Contaminants
Organisms N = 145
CoNS 122
Streptococcus mitis 4
Bacillus sp. 3
Micrococcus sp. 2
Neisseria sp. 2
Staphylococcus aureus1 2
Alpha-Hemolytic Streptococcus sp. 1
Bifidobacterium sp. 1
Candida albicans 1
Diphtheroids 1
Gram-positive rods 1
Granulicatella sp. 1
Leuconostoc sp. 1
Propionibacterium sp. 1
Stomatococcus sp. 1
Wautersia paucula 1
Footnotes: 1Includes 1 methicillin-resistant Staphylococcus aureus. CoNS, coagulase-negative
Staphylococcus aureus; sp., species.

Time To Positivity of Blood Cultures in Neonatal Late-Onset Bacteraemia

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Organisation (HINARI) - Group A. Protected by copyright.

Organisation (HINARI) - Group A. Protected by copyright.

Organisation (HINARI) - Group A. Protected by copyright.

Organisation (HINARI) - Group A. Protected by copyright.

Supplemental Figure. Derivation of the Study Population

NICU, neonatal intensive care unit; TTP, time to positivity.

Supplemental Table 1. Demographics and Clinical Characteristics of Infants with Late-

Supplemental Table 2. Organisms Deemed as Contaminants

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