nRICH

N ewer R esearch and recommendations In Child H ealth

Lead Author
Sen Sarma M

Co-Author
Yachha S K

UNDER THE AUSPICES OF THE IAP ACTION PLAN 2023

Upendra Kinjawadekar
IAP President 2023
GV Basavaraja Remesh Kumar R
IAP President 2024 IAP President 2022
Vineet Saxena
IAP HSG 2022-23
Dear fellow IAPans,

nRICH
Newer Research and recommendations In Child Health-aims to bring you the abstracts
of some of the breakthrough developments in pediatrics, carefully selected from
reputed journals published worldwide.
Expert commentaries will evaluate the importance and relevance of the article and
discuss its application in Indian settings. nRICH will cover all the different
subspecialities of pediatrics from neonatology, gastroenterology, hematology,
adolescent medicine, allergy and immunology, to urology, neurology,vaccinology etc.
Each issue will begin with a concise abstract and will represent the main points and
ideas found in the originals. It will then be followed by the thoughtful and erudite
commentary of Indian experts from various subspecialties who will give an insight on
way to read and analyze these articles.
I’m sure students, practitioners and all those interested in knowing about the latest
research and recommendations in child health will be immensely benefitted by this
endeavor which will be published online on every Monday.

Happy reading!

Upendra Kinjawadekar
National President 2023
Indian Academy of Pediatrics
Chairperson
Upendra Kinjawadekar

Convenor
Vijay Yewale

IAP nRICH team

Arun Bansal
Vaman Khadilkar
Indu Khosla
Srinivas Murki
Nitin K Shah
Tanu Singhal
Rhishikesh Thakre
Prakash Vaidya
SK Yachha
Ceftriaxone and unconjugated hyperbilirubinemia: Friend or foe?
1 2
Sen Sarma M , Yachha S K

1
Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India ,
2
Department of Pediatric Gastroenterology, Hepatology and Liver Transplant, Sakra World Hospital, Bengaluru, India

BASED ON ARTICLE

Amin SB. Bilirubin-Displacing Effect of Ceftriaxone in Infants With Unconjugated

Hyperbilirubinemia Born at Term. J Pediatr. 2023 Mar;254:91-95. doi:10.1016/j.jpeds.2022.10.030.

SUMMARY
Ceftriaxone is usually contraindicated in unconjugated hyperbilirubinemia for the fear that it will
displace bilirubin from albumin and predispose to kernicterus. The author aimed to evaluate the effect
of intravenous (IV) ceftriaxone on free-bilirubin concentrations in infants with unconjugated
hyperbilirubinemia born at term. A prospective study was performed with the inclusion criteria: infants
born at term <7 days old with sepsis and receiving IV antibiotics for >3 days and resolving
hyperbilirubinemia with total serum bilirubin levels between 6 and 12 mg/dL by day 4 of life. Free-
bilirubin concentrations were measured by two types of peroxidase methods: conventional unbound
bilirubin (UB) analyser and the new Zone Fluidics device that minimizes dilution. Free-bilirubin was
assessed before (baseline) and 15 minutes after (follow-up) IV ceftriaxone administration on postnatal
days 4 to 6. The Ka (L/mmol) was measured as: total serum bilirubin - free bilirubin/ free-
bilirubin(albumin - total serum bilirubin + free bilirubin). In total, 27 infants were studied. An auditory
brainstem-evoked response was measured at follow-up. The mean gestational age and birth weight of
the 27 infants were 39.2 weeks and 3533 g, respectively. All infants were appropriate for gestational
age at birth. Ten subjects (37%) were delivered via cesarean delivery. All infants had an Apgar score >7
at 5 minutes. All infants had culture-negative sepsis. Ceftriaxone was administered on mean postnatal
day 5 (range 4-6). All infants had serum albumin >2.5 g/dL. The mean TSB at baseline was 9 (range 6-
11.6) mg/dL. The calculated bilirubin albumin molar ratio was <0.5 for each individual infant. When
measured by a UB analyzer, the mean serum free-bilirubin concentration (mg/dL) at follow-up was not
significantly different from baseline. However, the mean serum free-bilirubin concentration (mg/dL)
was significantly lower at follow-up compared with baseline when measured by the Zone Fluidics
device. The free-bilirubin after 2 ceftriaxone administration/free-bilirubin at baseline before initiating
the ceftriaxone ratio, an index of displacing effect, was 1.02 (95% CI 0.89-1.14) with the UB analyzer
and 0.58 (95% CI 0.30-0.86) with the Zone Fluidics device. There were no significant differences in the
bilirubin-albumin binding affinity (Ka) between follow-up and baseline when measured by the UB
analyzer or Zone Fluidics device. The mean difference between follow-up Ka and baseline Ka was 2.34
±28 L/mmol when measured with the UB analyzer and 19.7 ± 63 L/mmol when measured with the

1
Zone Fluidics device, suggesting no worsening of Ka after administration of ceftriaxone. All infants
passed the automated auditory brainstem-evoked response test performed within 6 hours of IV
ceftriaxone administration. All infants were discharged home on the same day they received IV
ceftriaxone to complete the antibiotic course with IM ceftriaxone administered once daily by a home
visiting nurse or in an outpatient pediatric clinic. The author concluded that cceftriaxone was not
associated with a bilirubin-displacing effect in infants with mild unconjugated hyperbilirubinemia.
Home therapy with once-daily intramuscular ceftriaxone may be an alternative option for management
of the sepsis in asymptomatic infants with a mild unconjugated hyperbilirubinemia born at term [1].

COMMENTARY
Ceftriaxone is an excellent antibiotic for primary care in neonates for multiple reasons: 1) Ceftriaxone
works principally against gram-positive and gram-negative organisms in neonatal sepsis. 2) it has
excellent cerebrospinal penetration and can hence be used in neonatal meningitis, 3) has a long half-life
and hence can be used as once daily parenteral administration and 4) intramuscular delivery has near
similar plasma and pathogen inhibitory concentration as intravenous administration [2]. However,
ceftriaxone is avoided in unconjugated hyperbilirubinemia as it is believed that bilirubin is displaced
from albumin, resulting in higher free -bilirubin and potential neurotoxicity. In yesteryears, this
information was mostly derived from in vitro studies of pooled umbilical cord samples [3,4]. From
older studies, this knowledge was thereafter extrapolated to clinical practice. Ceftriaxone, a potentially
useful drug was therefore deemed unsafe and underutilized. We are well aware that many in vitro and in
vivo experiences do not match. Ceftriaxone is also unpopular in neonates with liver dysfunction.
Ceftriaxone has a proclivity toward calcium precipitation, which leads to the formation of insoluble
crystals in bile secretions precipitating biliary sludge and resulting in gall bladder sludge or calculi.
Ceftriaxone >2 g/day may also result in impaired gall bladder contractility [5]. However, this
phenomenon is self-limiting and resolves spontaneously on discontinuation of the drug. There are
many ways to look at the literature on bilirubin-induced neurotoxicity. It has been shown earlier that if
the baseline free-bilirubin concentration is very low, to begin with (mild unconjugated
hyperbilirubinemia), the maximum displacement factor of up to 3 may not result in significant
elevations of free-bilirubin concentrations. It has also been seen that in term 3 infants, free-bilirubin
concentrations <2 mg/dL, as measured by the modified peroxidase method, are unlikely to be
associated with acute or chronic bilirubin-induced neurotoxicity. An indirect evidence of a clinically
non-significant displacing effect was provided by an in vitro study that demonstrated that a
bilirubin–albumin molar ratio of <0.4 was not associated with free-bilirubin concentrations >2.0
mg/dL when using ceftriaxone concentrations of 225-250 mmol/L. There is a paucity of in-vivo
studies. Martin et al studied the reserve albumin concentration as an estimation of displacement after
intravenous ceftriaxone administration 50 mg/ kg. The study reported a decrease in the reserve albumin
concentration by 58% at the end of infusion and by 37% at 90 minutes after infusion [6]. There are
many strengths to this study. The author selected a homogenous cohort. Sepsis, a common neonatal
problem was included in the study. Sepsis negatively influences the Ka. They compared two peroxidase
methods, the older conventional (42-fold dilution) versus a recent specialised (2-fold dilution) method.

2
The specialized method is deemed to have greater accuracy and better results. Finally, to strengthen the
proof of their hypothesis, they studied the auditory brainstem-evoked response. The author made a
reasonable plea that intramuscular ceftriaxone can still be used in resource-poor countries without
having to fear bilirubin-induced neurotoxicity. There are a few oddities that stand out as limitations. In
an era where multicentre studies are in vogue, this manuscript stands out as a single-author experience.
Such prospective studies need more validation. Only when similar results are reproduced from other
centres, it will stand the test of time. Serum ceftriaxone levels were not measured for correlation.
Neonates with liver dysfunction may have lower albumin. Does lower albumin predispose to greater
bilirubin displacement? More studies are needed on the same. In this study, the auditory
brainstemevoked response was performed only once after the first dose of ceftriaxone. One-time tests
in neonates have limitations in interpretation. Bilirubin neurotoxicity is far a greater problem in
preterms than term babies. The real dilemma of starting antibiotics arises actually in complicated
patients. This study was performed in a niche group with lesser events. For the time being, it should be
cautioned that the results from this study should not yet be extrapolated for preterms, term babies with
moderate-severe unconjugated hyperbilirubinemia and babies with systemic illness other than sepsis.

REFERENCES
1. Amin SB. Bilirubin-Displacing Effect of Ceftriaxone in Infants With Unconjugated Hyperbilirubinemia Born at Term. J
Pediatr. 2023 Mar;254:91-95. doi:10.1016/j.jpeds.2022.10.030.
2. Mulhall A, de Louvois J, James J. Pharmacokinetics and safety of ceftriaxone in the neonate. Eur J Pediatr. 1985
Nov;144(4):379-82. doi: 10.1007/BF00441782.
3. Fink S, Karp W, Robertson A. Ceftriaxone effect on bilirubin-albumin binding. Pediatrics. 1987 Dec;80(6):873-5. PMID:
3684399.
4. Robertson A, Fink S, Karp W. Effect of cephalosporins on bilirubin-albumin binding. J Pediatr. 1988 Feb;112(2):291-4. doi:
10.1016/s0022-3476(88)80072-6.
5. Shiffman ML, Keith FB, Moore EW. Pathogenesis of ceftriaxone-associated biliary sludge. In vitro studies of calcium-
ceftriaxone binding and solubility. Gastroenterology. 1990 Dec;99(6):1772-8. doi: 10.1016/0016-5085(90)90486-k..
6. Martin E, Fanconi S, Kälin P, Zwingelstein C, Crevoisier C, Ruch W, Brodersen R. Ceftriaxone--bilirubin-albumin interactions
in the neonate: an in vivo study. Eur J Pediatr. 1993 Jun;152(6):530-4. doi: 10.1007/BF01955067.