Point of care v/s central lab automated blood culture system in decreasing antibiotic usage in NICU: A randomized controlled trial

Abstract

Background

Antibiotic usage is rampant in NICUs. The time of stoppage of antibiotics depends predominantly on clinical condition of the neonate and final blood culture report. Delay in availability of report due to lab logistics might delay the stoppage of antibiotic. Hence, we hypothesized that having a point of care BACTEC system in NICU premises might reduce the delay, allowing earlier stoppage of antibiotics when no more warranted.

Objective

To compare the antibiotic usage (number of antibiotic doses) in neonates warranting antibiotics for suspected sepsis (both early onset and late onset sepsis) when the point of care blood culture system (BACTEC) has been used as compared to the central lab system.

Design, Setting, and Participants

This open labelled randomized controlled trial was conducted in a tertiary care NICU from November 2021 to April 2023. Inborn neonates with suspected sepsis in whom antibiotics were considered first time were participants.

Interventions

First blood cultures in neonates with suspected sepsis were placed in NICU BACTEC or sent to the central lab as per randomization.

Main Outcome Measures

Both the groups were compared for number of antibiotic doses.

Results

268 eligible neonates were randomized, 132 in point of care and 136 in central lab arm. Median antibiotic doses in neonates with suspected sepsis were 13 (7,25) versus 12 (8,29) in NICU versus central lab BACTEC arm (p = 0.501). Antibiotics were stopped in ≤48 hours in 25% neonates and 19.9% in NICU and central lab BACTEC, respectively. The mean antibiotic doses of the neonates whose antibiotics were stopped before 48 hours is 5.6 +/− 0.9 versus 6.3 +/− 1.5 in NICU versus central lab BACTEC arm (p = 0.042). There was no significant difference in mortality, necrotizing enterocolitis (NEC), subsequent culture-positive sepsis, fungal sepsis, and duration of hospital stay in both groups. In the central lab group, the mean time taken for the final report to be uploaded was 131 +/− 43 hours.

Conclusions

There was no significant difference in number of antibiotic doses among NICU and central lab arms. However, antibiotics were stopped early (<48 hours) in more neonates when point of care BACTEC was used. Establishing the effect of point of care blood culture system in reducing antibiotic use requires further studies with a larger sample size.

Keywords

point of care neonates BACTEC antibiotic usage

Introduction

Background

Sepsis accounts for nearly one-third of neonatal deaths globally and nearly two-thirds in India.¹ Antibiotic usage is therefore rampant in neonates. Especially, there are challenges in the recognition of early onset neonatal sepsis in initial 48 hours, as the signs and symptoms are non-specific, particularly at extreme gestational ages and closely mimic non-infectious etiologies. To add on, the currently available diagnostic tests are neither sensitive nor specific to diagnose sepsis. As missing sepsis might be detrimental to the neonate, many episodes of clinical neonatal sepsis are managed empirically with antibiotics despite having no pathogen being isolated.

Decision to stop antibiotics in such cases is usually based on blood culture report. Using the current automated blood culture systems (BACTEC/BACT Alert), where time to positivity (TTP) was ≤24 hours in 85.3% of episodes² and ≤48 hours in 95.36% of blood cultures,³ it is possible to stop antibiotics between 24 and 48 hours. Practically it was observed that, in most centers, antibiotics could not be stopped at an anticipated 24–48 hour period due to delay in logistics of the lab. Delay is more significant in low-resource settings where good microbiological lab facilities and transportation facilities are inaccessible. We hypothesized that having a point of care BACTEC system in such NICU premises, significantly reduces the time for processing, allowing early decision making in the stoppage of antibiotics when they are no more warranted. Apart from one study by Bruins et al⁴ in adult emergency setting, none such studies are available in neonatal set-ups where time to stoppage of antibiotics is always a talking point due to the excessive antibiotic use.

Objective

The objective of this study was to compare the antibiotic usage (number of antibiotic doses) in neonates warranting antibiotics for suspected sepsis (both early onset and late onset sepsis) when the point of care blood culture system (BACTEC) has been used as compared to the central lab system.

Methods

Trial design

The trail design was open labelled randomized controlled trial with an allocation ratio of 1.

Participants

All inborn neonates admitted in NICU with suspected sepsis (both early onset and late onset sepsis) in whom blood culture was taken and antibiotics initiated for the first time were screened. Those with surgical conditions requiring protocol based empirical antibiotics or joint infections requiring prolonged antibiotics and inability to collect blood culture before starting antibiotics have been excluded. AAP guidelines were considered for initiation of antibiotics in neonates with suspected early onset sepsis, which take into consideration clinical condition of the baby, gestational age, indication for delivery, maternal fever, leukocytosis, duration of rupture of membranes, fetal tachycardia, foul smelling liquor, and intrapartum antibiotic therapy. Neonates were enrolled only with the written informed consent of their parents. They were provided detailed information about the nature and purpose of study prior to enrollment. A patient information sheet was handed over to each attendant. Confidentiality of the records was maintained.

Interventions

1 mL of blood was collected in pediatric blood culture bottle following aseptic precautions. After collection, the sample was labelled and transported to either point of care BACTEC placed in NICU premises (Figure 1), or BACTEC in the central lab based on randomization. Any culture bottle flagged positive in NICU was transferred immediately to the central lab for plating and further processing. Red alert could be recognized by easily audible continuous beeping and red glow on the door of BACTEC unit. The final decision to stop antibiotics was made as per the antibiotic policy of the unit (36–48 hours) as well as the treating clinician’s decision.

Figure 1.

NICU BACTEC unit BD BACTEC FX-40.

Outcomes

Primary outcome was to compare number of antibiotic doses among the groups. Both the groups were also compared for the number of antibiotic days, length of therapy, and the percentage in which antibiotics were stopped ≤48 hours. The effects of prolonged antibiotic use, like mortality, incidence of stage 2/3 NEC, and HAIs, that is, subsequent sepsis and subsequent fungal sepsis, were also compared. The time to reach the central lab, blood cultures flagged positive, time to positivity, and time taken for final results were also noted.

Sample size

Based on our unit data, the mean number of doses received was 20 ± 3.5. Assuming a mean difference of 1 dose, power of 80%, alpha error of 0.05, culture positivity rate of 15%, and attrition of 5% due to breakage or misplacement of bottles, the final sample size was calculated to be 242 episodes of sepsis, 121 in each group.

Randomization

Stratified variable block randomization was done by computed generated random numbers. Allocation concealment was done by sequentially numbered opaque sealed envelopes (SNOSE) kept in NICU. Blinding was not possible.

Ethics

The trial was commenced after getting approval from Institutional Ethics Committee.

Statistical analysis

The study groups were analyzed for cumulative number of antibiotic doses received, length of therapy, antibiotic days, and total doses received in neonates in whom antibiotics were stopped in <48 hours, by an unpaired T test for statistical significance when the data is normally distributed or the Mann–Whitney U test when it is skewed distribution. The number of patients in which antibiotics were stopped at 48 hours was analyzed with the chi-square test with Pearson’s coefficient or Fisher’s exact based on the data. These were done using updated version IBM SPSS statistics 22 software.

Results

A total of 268 out of 734 inborn neonates admitted to NICU during a study period of 18 months (November 2021 to April 2023), in whom antibiotics were started for the first time, were randomized (132 in NICU BACTEC and 136 in central lab BACTEC arm). Flow chart of participants is mentioned in Figure 2. Baseline characteristics are depicted in Table 1.

Figure 2.

Flowchart of participants in the study.

Table 1.

Baseline characteristics of cohort.

Characteristics	Point of care BACTEC (n = 132)	Central lab BACTEC (n = 136)	p value
Mean gestational age (weeks)	35 +/− 4	35 +/− 4	0.619
≥35 weeks	62 (47%)	64 (47%)	0.988
28-34+6 weeks	59 (44.7%)	61 (44.9%)	0.980
<28 weeks	11 (8.3%)	11 (8.1%)	0.942
Birth weight (gram)	2121 +/− 878	2175 +/− 929	0.403
Female sex	59 (44.7%)	59 (43.4%)	0.828
SGA	37 (28%)	22 (16.2%)	0.019
Median age of randomization (hours)^a	11 (1,60)	12 (2,50)	0.852
Mode of delivery (caesarean)	61 (46.2%)	73 (53.7%)	0.222
Maternal fever^a	6 (4.5%)	7 (5.1%)	0.819
Preterm premature rupture of membranes (PPROM)**	32 (24.2%)	24 (17.6%)	0.184
Duration of rupture of membranes ≥18 hours	32 (24.2%)	22 (16.2%)	0.100
Foul smelling liquor	5 (3.8%)	3 (2.2%)	0.496
Unexplained PTOL	17 (12.9%)	24 (17.6%)	0.278
Bleeding PV	6 (4.5%)	9 (6.6%)	0.461
Maternal leukocytosis***	5 (3.8%)	4 (2.9%)	0.362
Suspected Triple I^	2 (1.5%)	1 (0.7%)	0.544
Confirmed Triple I^ (placental culture positive)	2 (1.5%)	0 (0%)	0.242
Positive CRP^$	37/95 (38.9%)	43/105 (40.9%)	0.773
Median CRP mg/l	n = 95	n = 105	0.574
Median CRP mg/l	6.6 (2,20.2)	7.5 (1.9,23.8)	0.574

Data are represented as n (%), mean+/−S.D.

n (%) denotes the number of total neonates with their percentage in brackets.

^aMedian (25th, 75th); interquartile range is represented.

$ Positive CRP (>10 mg/l).

The bolded value represents p-value <0.05 and is considered significant.

The primary purpose and outcome of this study is to limit the use of antibiotics at the earliest opportunity, that is, less than 48 hours among those neonates whose cultures were negative and the clinical course was not compatible with sepsis; however, antibiotics have been started initially based on suspicion of sepsis. Subsequently next opportunity to stop antibiotics in such group is 48–72 hours and then finally between 72 and 120 hours. So we have analyzed the neonates on the basis of time period at which antibiotics were stopped. The distribution of neonates with suspected sepsis whose antibiotics were stopped at various time periods is given in Figure 3. The proportion of neonates in which antibiotics were stopped in ≤48 hours was high in NICU BACTEC (25%) as compared to central lab BACTEC (19.9%). However, this difference was statistically insignificant. The difference between mean antibiotic doses of the neonates whose antibiotics were stopped at or before 48 hours is 5.6 +/− 0.9 in the NICU BACTEC arm versus 6.3 +/− 1.5 in the central lab BACTEC arm was significant with a p-value of 0.042 (in Table 2).

Figure 3.

Distribution of neonates with suspected sepsis whose antibiotics were stopped at various time periods.

Table 2.

Comparison of antibiotic doses in neonates with suspected sepsis whose antibiotics were stopped between 24 and 48 hours.

Category	NICU BACTEC n = 26	Central lab BACTEC n = 19	p value
Antibiotic doses	5.6+/−0.9	6.3+/−1.5	0.042

The bolded value represents p-value <0.05 and is considered significant.

The median antibiotic doses in neonates with suspected sepsis were 13 (7,25) in the NICU BACTEC arm versus 12 (8,29) in the central lab BACTEC arm (Table 3). The difference was insignificant with p value of 0.501. The median antibiotic doses [14 (7,26) versus 14 (8,33)], antibiotic days [9 days (5,17) versus 10 days (6,20)] and length of therapy [5 days (2,8) versus 5 days (3,11)] in total cohort between NICU BACTEC versus central lab BACTEC arms were insignificant. There was no significant difference in outcomes like mortality (7.5% vs 13.2%), the incidence of stage 2/3 NEC (0 vs 2.2%), HAIs, that is, subsequent culture-positive sepsis (12.1% vs 14%), subsequent fungal sepsis (4.5% vs 2.9%) and duration of hospital stay [13 days (8,24) versus 13 days (8,24)] in both the groups (Table 4).

Table 3.

Total number of antibiotic doses in suspected sepsis along with gestation wise analysis.

Primary outcome	NICU BACTEC n = 128	Central lab BACTEC n = 123	p value
Antibiotics doses in suspected sepsis^a	13 (7,25)	12 (8,29)	0.501
Strata analysis of antibiotic doses in suspected sepsis
≥35 week median	n = 62	n = 59	0.636
≥35 week median	13 (6,19)	11 (7,17)	0.636
28-34+6 week median	n = 55	n = 56	0.041
28-34+6 week median	12 (7,28)	21 (9,41)	0.041
<28 week median	n = 11	n = 8	0.109
<28 week median	30 (16,79)	14 (4,27)	0.109

Median (25th, 75th); interquartile range is represented.

p value is calculated by the Mann–Whitney test.

^aSuspected sepsis: Neonates having any sign or symptoms suggestive of sepsis with blood, CSF, or other body fluid culture being sterile.

Table 4.

Secondary outcomes in total cohort.

Outcomes	NICU	Central lab BACTEC n = 136	p value
Outcomes	BACTEC n = 132	Central lab BACTEC n = 136	p value
Total number of antibiotics doses in total cohort	14 (7,26)	14 (8,33)	0.298
Length of therapy (days) in total cohort	5 (2, 8)	5 (3,11)	0.280
Antibiotic days (days) in total cohort	9 (5,17)	10 (6,20)	0.304
Antibiotics stopped in <48 hours in total cohort	33/132 (25%)	27/136 (19.9%)	0.312
Mortality incidence	10 (7.5%)	18 (13.2%)	0.130
NEC incidence	0 (0%)	3 (2.2%)	0.247
Subsequent culture-positive sepsis incidence	16 (12.1%)	19 (14%)	0.653
Subsequent fungal sepsis incidence	6 (4.5%)	4 (2.9%)	0.536
Duration of hospital stay in days	13 (8,24)	13 (8,24)	0.732*
Blood culture positivity	4 (3%)	13 (9.6%)	0.002
Time to culture positivity in hours	n = 4	n = 13	0.477
Time to culture positivity in hours	16 (14,18)	13 (8,21)	0.477
Time taken for final report in hours (both sterile and first red alert report without sensitivity)	—	131 +/− 43
Time taken for blood culture to reach lab in hours	—	2 (1.5,3)
Time taken to change antibiotics if blood culture report is positive in hours (sensitivity report)	n = 3	n = 12	0.136
	91 (84,91)	66 (52,91)	0.136

n (%) denotes the number of total subjects with their percentage in brackets, mean+/−S.D.

Median (25th, 75th); interquartile range is represented p value is calculated by the chi-square test/Fisher’s exact test and Mann–Whitney test.

The time taken for culture positivity (TTP) was similar in both groups [16 hours (14,18) in NICU BACTEC versus 13 hours (8,21) in central lab BACTEC]. All the blood cultures flagged below 24 hours except for E. coli (55 hours) and Candida (67 hours). The median time taken to reach the central lab was 2 hours (1.5,3). The sensitivity report was available by day 3 or 4 in both groups. Though the blood culture status was found telephonically in the central lab group, the mean time taken for the final report to be uploaded was 131 +/− 43 hours (in Table 4).

Discussion

Nearly 37% of inborn neonates admitted to NICU during the study period of 18 months were started on antibiotics. The median antibiotic doses in neonates with suspected sepsis is 13 (7,25) in the NICU BACTEC arm versus 12 (8,29) in the central lab BACTEC arm. The difference was insignificant, with p value of 0.501. Though it is expected that antibiotics would be stopped early in the NICU arm due to early incubation in BACTEC and easier access to confirmation of negative reports, the outcomes showed insignificant differences. This could be due to a well-established sample transportation system in a tertiary care center (median time to reach the central lab was only 2 hours), 24 × 7 centralized microbiology lab facilities for receiving samples, adequate manpower, and availability of negative culture report round the clock telephonically on calling on duty resident that avoided a significant delay in availability of provisional report from the lab. The statistical significance among the 28-34+6 week stratum could be because it included those neonates whose clinical symptoms did not resolve early due to prematurity-related non-septic issues, and the antibiotics could be stopped only based on blood culture report.

As most of the blood cultures flag within 24 hours in automated blood cultures systems, antibiotics started empirically with suspicion of sepsis can be stopped if the blood culture remains sterile for 24 hours. In that case, the antibiotics should ideally be stopped between 24 and 48 hours. If the availability of the report takes some time due to computer logistics, the next best at which antibiotics could be stopped is 48–72 hours. The difference between mean antibiotic doses of the neonates whose antibiotics were stopped between 24 and 48 hours is 5.6 +/− 0.9 in the NICU BACTEC arm versus 6.3 +/− 1.5 in central lab BACTEC arm was significant with a p-value of 0.042. This difference of 0.7 could be more evident when larger studies were conducted.

The antibiotics given for >48 hours in most of the neonates in the study in spite of cultures being sterile depict that the clinician’s belief in culture reports is less, especially in countries like India where neonatal sepsis is rampant. The decision to continue antibiotics was predominantly based on clinical condition of the neonate. Though CRP was sent in 200 neonates enrolled in the study, it was positive in only 40%. Also, an inverse relation between birthweight and antibiotic duration is found, that is, the smaller the birthweight, the more the duration of antibiotics even when the cultures remained negative. This is in spite of having a lower threshold to start and continue antibiotics than other units.

The length of antibiotic therapy in both groups of our study was still less than a point prevalence study of 81 NICUs worldwide. Overall length of antibiotic therapy was found to be often prolonged (i.e., >72 h) (4). 80% (325/405) of the infants received for a median of 7 days and in presumed or culture-positive infection for a median of 10 days.⁵

The proportion of neonates in which antibiotics were stopped early was definitely higher in the NICU arm but the results were statistically insignificant with the present sample size. It is also observed that in spite of best efforts and having good microbiology lab support, practically antibiotics could be stopped in only 20–25% before 48 hours. This could be because the cohort included suspected EONS (where antibiotics were started based on antenatal risk factors), suspected LONS, and culture-negative sepsis where in the latter two, the antibiotics would be given for at least 5 days and 7–10 days, respectively. Also there was some variation in individual clinician’s decisions with respect to the stoppage of antibiotics. In some quality control studies, the proportion of culture-negative and screen-negative neonates where antibiotics were stopped within 48 hours could be increased up to 54% from a baseline of 16% with multiple interventions.⁶ 48% (129 out of 268) of the neonates enrolled in our study had no sepsis but received antibiotics. This data shows overuse of antibiotics in enrolled neonates.

Excessive antibiotic usage was theoretically associated with necrotizing enterocolitis (NEC), and subsequent sepsis, including fungal sepsis, thus leading to an increase in mortality.^7,8 In our study, it is shown that the incidence of mortality, NEC, subsequent culture-positive sepsis, and fungal sepsis in NICU BACTEC and central lab BACTEC arms are 7.5% versus 13.2%, 0% versus 2.2%, 12.1% versus 14%, and 4.5% versus 2.9%, respectively. All the outcomes except for fungal sepsis were slightly higher in the central lab arm though the difference is not of any statistical significance.

Allowing easy 24-hour access to BACTEC systems improves the time to incubation hence the time to give the result. In a study published in 2020 by Orellana et al., they allowed automated loading of bottles on the BACT/ALERT VIRTUO round the clock in opposition to regular 8.00 am to 10.00 pm allowing processing of blood cultures during the night shift, leading to a significant reduction of elapsed time 10.52 ± 5.23 h to 1.00 ± 4.40 h.⁹ The percentage of positivity also improved from 9.03% to 11.18% (p = 0.0003) and the average time to result significantly reduced from 24.78 ± 15.9 h to 16.85 ± 14.13 h (p < 0.0001) (9). Our study setting was a tertiary center that had good timely transportation facilities to the central lab round the clock. In spite of that, we found that the median time taken to reach the central lab from NICU was 2 hours (1.5,3) and the bottles were incubated to BACTEC within 1 hour of reaching the central lab. In one Canada-based study, the mean pre-incubation time for samples collected within the city limits was 3.94 hours versus 9.49–18.89 hours for other client sites outside city limits.¹⁰ This time taken might significantly increase in periphery settings, thus increasing the time to positivity in case of culture-positive sepsis and time for incubation, thereby giving additional doses. The time to positivity of all organisms in 21 cultures is less than 24 hours except for Candida parapsilosis (67 hours) and Escherichia coli (55 hours).

The time for availability of culture report was 9 hrs (84, 91) vs 66 hrs (52,91) in NICU vs central lab arms. The number is too small, and the difference is insignificant.

Practical experience and difficulties

All the residents found it easy to use the equipment after a single-time demonstration of use and also using a pictorial representation chart placed near the equipment. It was easy to interpret that in case of no red flag, the culture remained sterile and antibiotics could be stopped safely. Also, it alerted the clinicians whenever there was a red flag to follow up on the sensitivity report and optimize antibiotics accordingly. We have been using point of care BACTEC in all babies in our unit as routine practice from the time the enrollment to the study was ceased. One time during the study period, the change in temperature in BACTEC raised alarms, which were resolved immediately after restarting the equipment after consulting the BACTEC engineer. Another time failure in detecting the bottle occurred, raising an alarm, which was resolved after a software update. Such circumstances occurred rarely, even after regular service from the company.

Limitations of the study

• In this study, a very wide range of antibiotic doses (2–412) were received by the neonates making generalization of the results difficult.

• There was a significant difference in culture positivity between central lab BACTEC and NICU BACTEC (13 vs 4) in spite of having the same model (BACTEC FX) at both places. This could be attributed to machine maintenance issues in spite of intermittent quality checks of the BACTEC unit being performed before and at mid-way of the study by comparing time to positivity of fixed E. coli inoculum with that placed in the central lab. Though number of positive cultures is very small to comment on the difference, more frequent and stringent quality checks may be suggested in future studies. There was no deterioration in any neonate noted due to possible false negative blood culture results.

• Variation in individual decisions of three clinicians caused variation in the duration of stopping antibiotics at different time points in spite of final culture reports being available.

Implications of the study

Point of care automated blood culture system is a user-friendly system in which the residents place the bottles into the system themselves after a minimal amount of training. This has the advantage of being able to use and get results in any odd hours, thus bypassing the digital limitations where internet connectivity can be an issue. It also reduces the workload on the microbiology lab by sending only the positively flagged culture bottles for culture plating instead of a whole lot of culture bottles. The percentage of neonates in which antibiotics were stopped within 48 hours was definitely more in the NICU arm though it was statistically insignificant. The reasons for such results, particularly in a center with well-established transport and 24 × 7 lab facilities, were discussed above. But this kind of study would have much more implications in low-resource settings where round-the-clock microbiology lab facilities are unavailable. The procedure of incubation into BACTEC and reading the results—positive or negative—needs no significant amount of training with the cost of equipment as mentioned above. Investment in such equipment in low-resource SNCU settings would significantly reduce antibiotic usage. It also reduces the sample load and burden on the central lab, whose facilities can be utilized for processing of positive samples by advanced plating and sensitivity reporting. Hence, in the future, more studies with larger sample sizes could give better outcomes. Cost-effective analysis of such automated blood culture systems like BACTEC as a point of care equipment in low-resource settings could be studied.

Conclusions

There was no significant difference in number of antibiotic doses among NICU and central lab arms. However, antibiotics were stopped early (<48 hours) in more neonates when point of care BACTEC was used as compared to central lab BACTEC. Establishing the effect of point of care blood culture system in reducing antibiotic use requires further studies with a larger sample size.

Statements and declarations

Footnotes

Acknowledgements

I would like to convey my heartfelt gratitude to Dr Thanigainathan for tremendous support and assistance in conducting this trial.

Conflicting interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Trial registration

CTRI/2021/12/038372.

Disclaimer

Becton, Dickinson and Company had no role in protocol development, implementation, or interpretation of the trial.

ORCID iD

S. K. Choudhary

Appendix

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