Indian Journal of Pediatrics

https://doi.org/10.1007/s12098-021-03794-6

ORIGINAL ARTICLE

Ten Versus 14 Days of Antibiotic Therapy in Culture-Proven Neonatal

Sepsis: A Randomized, Controlled Trial
Asha Reddy 1 & Veeraraja Sathenahalli 1 & Niranjan Shivanna 1 & Naveen Benakappa 1 & Prathik Bandiya 2

Received: 2 December 2020 / Accepted: 28 April 2021

# Dr. K C Chaudhuri Foundation 2021

Abstract
Objectives To compare the efficacy of 10 d versus 14 d of antibiotic therapy in neonates with culture-positive sepsis.
Methods Neonates with culture-positive sepsis were randomized to either 10-d or 14-d antibiotic therapy. These neonates were
followed up to 28 d after discharge for treatment failure. Primary outcome of the study was treatment failure which was defined as
readmission to the NICU within 4 wk of discharge with blood culture growing same organism with similar antibiogram or any
readmission with signs of sepsis with negative blood culture.
Results A total of 70 neonates were randomized to receive either 10 d (n = 35) or 14 d (n = 35) of antibiotic therapy. Gram-negative
infections were encountered in majority of the neonates. Treatment failure occurred in 1 neonate in 10-d group and none in 14-d
group. The duration of hospital stay was significantly less in 10-d group as compared to 14-d group (16 d vs. 23 d, p < 0.01).
Conclusions Ten days of antibiotics in neonates with culture-positive sepsis, who have achieved clinical and microbiologic
remission at day 7, is noninferior to 14 d of therapy. Larger adequately powered trials will address this issue with certainty.

Keywords Neonate . Sepsis . Antibiotic

Introduction objective to compare 10 d of intravenous antibiotics with 14

Neonatal sepsis is one of the common causes of neonatal
mortality all over the world [1]. The highest burden of
sepsis-related deaths occurs in low- and middle-income coun-
tries [2]. Most of these are due to multidrug-resistant organ-
isms [3]. One of the important reason for development of
antibiotic resistance is irrational and prolonged use of antibi-
otics [4]. There is also increased risk of secondary bacterial
and fungal infections, change in the microbiome and
prolonged hospital stay due to prolonged use of antibiotics
[5]. There are no evidence-based guidelines for optimal dura-
tion of antibiotics in neonatal sepsis and most are consensus
based. There are few studies that have evaluated shorter
courses of antibiotic regimens in neonatal sepsis with varying
results [5–7]. Hence, this study was conducted with the
* Veeraraja Sathenahalli
virajbs.hb@gmail.com
1
Department of Pediatrics, Indira Gandhi Institute of Child Health,
Karnataka 560029 Bangalore, India
2
Department of Neonatology, Indira Gandhi Institute of Child Health,
Bangalore, Karnataka, India
d in neonates with culture-positive sepsis.
Material and Methods
This was a pilot randomized, controlled trial (RCT) conducted
between April 2018 and September 2019 in a level III neona-
tal unit of a tertiary care pediatric hospital in South India. All
neonates who presented with signs and symptoms of sepsis
with positive blood culture were assessed for eligibility.
Inclusion criteria for the study included all of the following:
gestational age > 32 wk and/or birth weight > 1.5 kg, neonates
with positive blood culture who had received 7 d of appropri-
ate antibiotics, no clinical signs of sepsis on day 7 and sterile
blood culture and negative sepsis screen sent on 7th day of
antibiotics. Neonates with major congenital malformations,
deep-seated infection, like meningitis and septic arthritis, fun-
gal sepsis, Staphylococcus aureus sepsis and severe birth as-
phyxia were excluded from the study. The study was ap-
proved by the institutional ethics committee and informed
parental consent was obtained from all the parents.
All the eligible neonates who met all the inclusion criteria and
none of the exclusion criteria were randomized at the end of 10th
day of antibiotics. Randomization sequence was generated and
 Indian J Pediatr

treatment assignments were placed in identical, serially num-
bered, opaque and sealed envelopes to ensure allocation conceal-
ment. Due to the nature of intervention, blinding of primary
caregivers was not possible. No placebo was used in the study.
Neonates in the 10-d group received no further antibiotics and
neonates in 14-d group received antibiotics for 4 more days i.e.,
for a total of 14 d. Clinical, demographic, and baseline data of all
the neonates were recorded in a predesigned proforma.
Complete blood count, blood culture, C-reactive protein
(CRP), microESR, peripheral smear and any other relevant in-
vestigations were sent in all eligible neonates at admission. CRP
was measured by immunoturbidimetry and value more than
10 mg/L was considered as significant. Lumbar puncture was
done in all cases of culture-positive sepsis to rule out meningitis.
Blood culture was done using BACTEC PedsPlus™ (Becton
Dickinson, Ireland) and antibiotic susceptibility testing was done
using the VITEK method. Peripheral venous blood sample (at
least 1 mL) for culture was drawn prior to starting antibiotics and
also on 7th day of antibiotics in case of culture-positive cases.
In both the groups, neonates were observed for a period of
48 h in the hospital for any clinical signs of sepsis. The neo-
nates were followed up telephonically on a weekly basis for
first 3 wk and were called to the hospital at the end of 4th wk.
The parents were also instructed to call the chief investigator
for any clinical signs of illness within 4 wk of discharge.
Treatment failure within 4 wk of discharge was considered
as the primary outcome. Treatment failure was defined as
readmission to the NICU within 4 wk of discharge with blood
culture growing same organism with similar antibiogram or
any readmission with signs of sepsis with negative blood cul-
ture. Duration of hospital stay and mortality were considered
as secondary outcomes.
Since this was a pilot study, a sample of 60 neonates was
decided. Assuming a loss to follow-up rate of 15%, 70 neo-
nates were recruited.
Statistical Analysis Patient information was collected in a
predesigned proforma. Data entry and analysis were done
using SPSS version 18. The standard statistical tests were
applied. Mean (SD) was used for continuous variables.
Paired data were analyzed using student t-test and proportions
were analyzed using chi-square test. The results were consid-
ered significant at 5% level of significance (p < 0.05).
Results
A total of 122 neonates were assessed for the eligibility during
the study period of which, 52 neonates did not meet the inclusion
criteria for various reasons. Seventy neonates were enrolled, of

Fig. 1 Flow diagram of the trial Assessed for Did not meet inclusion criteria (n =
Enrollment

eligibility (n = 122) 37)

Excluded (n = 15)

Meningitis = 5
Staph sepsis = 5
Randomized
(n = 70)

Allocated to 10-d group (n = 35) Allocated to 14-d group (n = 35)

Allocation

Received allocated intervention (n = 35) Received allocated intervention (n = 35)

Did not receive allocated intervention (n Did not receive allocated intervention
= 0) (n = 0)
Follow-up

Lost to follow-up (n = 1) Lost to follow-up (n = 1)

Discontinued intervention (n = 0) Discontinued intervention (n = 0)

Analysis

Analyzed (n = 34) Analyzed (n = 34)

Excluded from analysis (n = 0) Excluded from analysis (n = 0)

Indian J Pediatr

which, 35 neonates were randomized to 10-d group and 35 ne- Table 2 Organism profile in blood culture
onates to 14-d group (Fig. 1). The baseline demographic, clinical Bacteria 10-d group* 14-d group* Total p value
and laboratory characteristics were comparable between both the (n =35) (n=35) (n =70)
groups (Tables 1 and 2). Late-onset sepsis was present in major-
ity of the cases (74%) with poor feeding, respiratory distress and Gram +ve 5 (14.28) 2 (5.71) 7 (10) 0.23
Gram –ve 30 (85.71) 33 (94.28) 63 (90)
poor cry being the common presenting complaints. Gram-
negative sepsis (90%) accounted for most of the infections. *
n (%)
Klebsiella species was the most common organism isolated
(51.42%) followed by acinetobacter (15.71%), and E. coli
(11.42%) (Table 3). Among the gram-positive bacteria, infections accounted for majority of the infections which is
coagulase-negative staphylococci (CoNS) was the most com- in similarity to other studies from India [2, 5]. Since the au-
mon isolated in about 10% of all cases. There was one treatment thors’ center is an exclusive outborn unit, the incidence of late-
failure in 10-d group where the neonate was readmitted to the onset sepsis was more than early-onset sepsis. The authors
hospital 12 d after discharge in view of community-acquired included relatively stable neonates in the present study, who
pneumonia and blood culture was sterile in this baby. The mean were randomized after 10 d of antibiotic therapy after achiev-
duration of hospital stay was significantly lower in 10-d group as ing clinical remission. These neonates probably had cleared
compared to in 14-d group (16 vs. 23 d) (p < 0.001). There was 1 bacteria from their blood and additional days of antibiotic
lost to follow-up in each group (Table 4). would not have been beneficial. Other similar studies have
also included babies who were blood culture negative with
clinical remission and no laboratory markers suggestive of
Discussion active infection [5–7]. These studies also showed no major
difference in treatment failure between the groups.
In this pilot RCT, it was found that 10 d of antibiotic therapy is There was no difference in the primary outcome i.e.,
feasible in neonates with culture-positive sepsis, who have treatment-failure rate between the two groups and was similar
achieved clinical remission. In this study, gram-negative to results of other similar studies [6–8]. One of the reasons

Table 1 Demographic, clinical,

and laboratory characteristics Parameter 10-d group (n =35) 14-d group (n=35) p value

Male* 24 (68.6) 21(60) 0.454

Birth weight** 2594 (784) 2226 (777) 0.052
Gestation (wk)** 37.1 (3.4) 36.09 (3.8) 0.241
NVD* 17 (48.6) 21 (60.0) 0.328
Risk factors for sepsis* 4 (11.4) 2 (5.7) 0.392
Early-onset sepsis* 9 (25.7) 13 (37.1) 0.303
Late-onset sepsis* 26 (74.3) 22 (62.9)
Clinical features*
Respiratory distress 20 (57.1) 15 (42.9) 0.232
Poor feeding 18 (51.4) 20 (57.1) 0.631
Poor cry 11 (31.4) 16 (45.7) 0.220
Hypotonia 10 (28.6) 14 (40) 0.314
Shock 2 (5.7) 5 (14.3) 0.232
Hypo/Hyperthermia 3 (8.6) 3 (8.6) 1.000
Hypo/Hyperglycemia 2 (5.7) 4 (11.4) 0.393
Need for ventilation 5 (14.3) 6 (17.1) 0.743
Laboratory features
TLC (per mm3)** 15,359 (5459) 17,961 (10888) 0.211
ANC (per mm3)** 9399 (5384) 12,161 (8353) 0.105
CRP (mg/dL)# 12.6 (5–36) 19.4 (5–54) 0.734
Platelet count (per mm3)** 188,485 (117527) 178,228 (128637) 0.729
**
Mean (SD), # Median (IQR), * n (%)
ANC Absolute neutrophil count; CRP C-reactive protein; NVD Normal vaginal delivery; TLC Total leukocyte
count
 Indian J Pediatr

Table 3 Bacteriological profile in blood culture causes among gram-positive infections. Hence, the findings of
Organism 10-d group *
14-d group *
Total the present study cannot be generalized to all the culture-
(n =35) (n=35) n (%) positive sepsis.

Acinetobacter 6 (17.14) 5 (14.28) 11 (15.71)

CONS 6(17.18) 2 (5.7) 8 (11.42) Conclusion
E. coli 3 (8.57) 5 (14.28) 8 (11.42)
Enterobacter 0 (0.0) 1 (2.9) 1 (1.42) In conclusion, 10-d antibiotic course is as effective as 14-d
Klebsiella 17 (48.57) 19 (54.28) 36 (51.42) course in neonates with culture-positive sepsis.
NFGNB 2 (5.7) 0 (0.0) 2 (2.85)
Pseudomonas 1 (2.9) 0 (0.0) 1 (1.42)
Salmonella typhi 0 (0.0) 1 (2.9) 1 (1.42) Acknowledgments The authors thank Dr. Netra G for statistical analysis.
Serratia marcescens 0 (0.0) 2 (5.7) 2 (2.85)
Authors’ Contribution AR collected the data; VS analyzed the data and
*
n (%) wrote the manuscript; NS, NB conceptualized the idea and wrote the
manuscript; PB conceptualized the idea, analyzed the data, and wrote
CoNS Coagulase-negative staphylococci; NFGNB Nonfermenting gram-
the manuscript. NS is the guarantor for this paper.
negative bacilli

could be due to inclusion of slightly more mature babies,
exclusion of S. aureus and including neonates who had
achieved both clinical and laboratory remission [5, 7].
The mean duration of hospital stay was also significantly
less in 10-d group without any increase in failure rate. A recent
study by Rohatgi et al. also reported similar findings. This has
implication in reduced cost of health care, decreased chances
of hospital acquired infections, lesser side effects and less
chances of developing drug resistance [5].
The preliminary data from this pilot study will help in plan-
ning large meaningful RCTs on this aspect. However, the
present study is not without limitations. Since it was a pilot
study, the sample size was small. The number of babies who
were randomized were nearly 60% of the total enrollment.
This, in turn, means that some proportion of neonates would
not have achieved clinical remission or would still have cer-
tain laboratory features of sepsis. The results may not be valid
in this cohort of babies. The authors have also not included
neonates with S. aureus sepsis which is one of the common
Table 4 Outcome in both the groups
Outcome 10-d group 14-d group
(n=35) (n=35)
Treatment failure* 1 (2.8) 0 (0)
Lost to follow-up* 1 (2.8) 1 (2.8)
Death* 0 0
Duration of hospital stay** (d) 16 ± 5.3 23 ± 8.6
Declarations
Conflict of Interest None.
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*
n(%), ** Mean(SD)