ISSN: 0048-2706 (Print), ISSN: 2227-9199 (Online) PakHeart J2023;56(03)

A systematic review of the efficacy of antibiotics switch therapy in neonates

Siraj DAA Khan1, Mohammed Hamad DawoodAlyami2, AlaaSulimanAlsuhaibani3,
SameerHumaidi Al-Harbi4, Mmayada Mohammed Albarakati5,Mohammed Munif
Alharbi6
1
Supervisor, PhD, Pediatric Dentistry, Faculty of Dentistry, Najran University, Najran, Saudi Arabia(Corresponding Author)
2
College of Pharmacy, Najran University, Najran, Saudi Arabia,
3
Dentist Resident, AlBadaye General Hospital, Qassim, Saudi Arabia
4
Pharmacy Services Department, Johns Hopkins Aramco Healthcare (JHAH), Dhahran, Saudi Arabia
5
Pharmacy Services Department, Saudi German Hospital (SGH), Jeddah, Saudi Arabia
6
College of Pharmacy, Qassim University, Buraydah, Saudi Arabia

ABSTRACT

Aim: The Switch from intravenous antibiotic treatment to oral antibiotic therapy for neonates is not currently
common in high-income regions, primarily due to concerns regarding safety and adequate exposure. The objective
of this systematic review is to evaluate the effectiveness and safety of early transitioning from intravenous to oral
antibiotics in neonates with suspected bacterial infections, as compared to a complete course of intravenous
antibiotics. Material and Methods: A search was carried out using different terms i.e. switch therapy, antibiotics in
neonates, iv to oral switch to find the related articles. A total of 9 studies were used that described antibiotic switch
therapy in neonates. Results: The findings from selected studies indicated that transitioning to antibiotic switch
therapy had a notable impact on decreasing the length of hospital stays and the recurrence of infections in neonates.
Discussion: Oral switch therapy is not a widespread practice in neonates yet. Antibiotic therapy is started
immediately in case of maternal factors-based or clinical symptoms-based suspicion of infection. Antibiotic therapy
can be stopped 36-48 hours after the disappearance of symptoms, reassurance of inflammatory parameters, and
negative cultures in the best-case scenario.
Keywords: intravenous, neonates, effectiveness, bacterial infection

INTRODUCTION antibiotics are prescribed for at least 7 days when there

is a provenor probable bacterial infection [5]. Parent-
Proved bacterial infection in the first 72 hours of life,
child bonding is affected by prolonged hospital stay
also known as early-onset sepsis, has a ratio of 1 in
which is necessary for IV antibiotic therapy and there is
1000 live births which further increases in low birth
an increased risk of hospital-related infections and costs
weight and premature infants [1]. Infection is the main
of treatment are also increased [6]. Once the patient is
cause of mortality and morbidity in newborns [2].Forty-
clinically well, switch to oral antibiotics within the
five percent of childhood deaths under 5 years of age
course of treatment also known as, oral switch therapy,
occur in neonatal age and the main cause of death in
is now a part of standard practice in older children and
this group (22%) is neonatal bacterial infection [3].
it has been proven to be safe and effective for several
Non-specific clinical symptoms and laboratory findings
infections and indications [7]. The choice of antibiotic
make early diagnosis challenging in this group [4]. IV

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is based on a probabilistic approach and those drugs are at:www.nice.org.uk/guidance/ng139). The achievement
considered which are active against most of the of effective antibiotic concentration rapidly after IV
common bacteria cultured in infected neonates, as well administration makes this approach justified. A switch
as have better safety and tolerability, as there is no from IV to oral therapy should be considered in patients
availability of microbiological data and also there is with good clinical response and normal functioning of
increased risk of rapidly worsening bacterial the gastrointestinal tract after initial IV treatment for 48
diseases[8]. To reach therapeutic serum levels quickly to 72 hours as there is an increasing amount of recent
and prevent the development of complicated and more evidence in this favor(Available
severe infections, antibiotics are administered at:www.nice.org.uk/guidance/ng139).To our
intravenously in newborns with suspected bacterial knowledge, there have been limited systematic reviews
infections [9]. According to NICEguidelines, IV route conducted to assess the utilization of oral antibiotics in
of antibiotic administration is recommended for the neonates. Given the uncertainties surrounding oral
treatment of severe infections like hospital-acquired absorption during the initial weeks of life, the absence
pneumonia especially in those patients who are at high of substantial evidence could be a potential explanation
risk of antimicrobial resistance (Available for the non-standardization of oral switch therapy in
at:www.nice.org.uk/guidance/ng139). Infection, neonatal care. Consequently, the objective of this
increased risk of phlebitis, excess administration of systematic review is to assess the existing body of
sodium and fluid, high cost of treatment, and longer evidence regarding the safety and effectiveness of
stay at the hospital are important disadvantages of transitioning from intravenous (IV) to oral therapy in
prolonged IV administration of antibiotics [10]. neonates.
Common barriers preventing clinicians from an early
Material and Methods
IV to oral switch have been investigated in multiple
Search strategy:We conducted a comprehensive
studies [11]. There may be circumstances where reliable
literature search following the guidelines outlined in the
achievement of therapeutic concentrations of antibiotic
Preferred Reporting Items for Systematic Reviews and
after oral administration is uncertain due to
Meta-Analyses (PRISMA) (Available at:
gastrointestinal irregularities influencing drug
http://www.prisma-statement.org/). Our search
absorption, nausea/vomiting, swallowing dysfunction,
encompassed various reputable databases, including
and non-compliance in adhering to oral regimen due to
PubMed, Medline, ScienceDirect, Embase.com, Web of
altered mental state as in dementia and decreased
Science, Cochrane Central, and Google Scholar.
consciousness, and multiple other factors [12]. The
Initially, we screened titles and abstracts, and
misconception of clinician that IV administered
subsequently, three independent reviewers thoroughly
antibiotic is stronger and more effective in obtaining
examined the full texts of potentially relevant articles.
therapeutic concentration and has better tissue
Any disagreements were resolved through discussion or
penetration as compared to orally given antibiotic is
consultation with a third investigator. Additionally, we
another inappropriatereason [11]. When administration
screened congress abstracts, reference lists, and review
of antibiotics is decided in severe infections, it is better
articles for potential studies.
to start with IV antibiotics(Available

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Inclusion and exclusion criteria:Our inclusion criteria RESULTS

were limited to research involving human subjects, A total of 253 studies from all the databases were
including randomized controlled trials (RCTs), identified. After the removal of duplicates, we reviewed
intervention studies, and retrospective studies that the full text of 92 potential articles.Those studies
explored the use of oral antibiotics, including oral excluded who answered the focus questions. Further
switch therapy, as well as pharmacological assessment was performed by the author. Finally, 35
investigations in neonates.Articles written other than in articles were chosen for full reading. A total of 7
the English language were not included in this articles were selected after reading by all the authors
systematic review. independently. Figure 1 shows the selection process.
Data extraction:Two authors independently extracted Additionally, 2 articles were selected through screening
the following data from selected articles i.e. Author of reference lists, leading to 9 selected publications for
name, study type, sample size, intervention, antibiotics this review. The characteristics of the included studies
used, and outcomes. are described in Table 1.

In a multicenter, randomized clinical trial, the subsequent 11 days. Our findings suggest that oral
effectiveness of oral therapy versus initial intravenous cefixime can be considered a safe and efficacious
treatment was assessed in a group of 306 children aged treatment option for children presenting with fever and
1 to 24 months. These children were divided into two urinary tract infections. The use of cefixime has the
groups: one received oral cefixime for a duration of 14 potential to result in significant reductions in healthcare
days (with a double dose on the first day), while the costs [13].
other group received initial intravenous cefotaxime An uncontrolled iv-to-oral switch trial was performed in
treatment for 3 days, followed by oral cefixime for the 222term neonates with probable or proven group B-

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streptococcal (GBS) sepsis. Subjects switched to oral Group I received intravenous ampicillin at a dose of
amoxicillin (300mg/kg/day q6h) after 48 h of IV 200 mg/Kg/day every 6 hours, while Group II switched
amoxicillin (100mg/kg per day). Serum levels were all to oral amoxicillin at a dose of 40 mg/Kg/day every 8
above the minimal inhibitory concentration (MIC) for hours after two days of intravenous ampicillin treatment
GBS. Moreover, therapy was well tolerated without any at the same dose as Group I. The hospital stay duration
side effects or reinfections, and a reduction of 5 days in for children who underwent the switch to oral
hospital admission was seen [14]. Another retrospective antibiotics was significantly reduced. Additionally,
study evaluated the efficacy of iv to oral switch therapy there was a notable decrease in complications, including
in 172 newborns with a UTI. In total, 119 patients edema/extravasation, inflammation, and abscess
switched to oral amoxicillin/clavulanic acid as formation at the cannula site, among children who
continuation therapy. None of the orally treated switched to oral antibiotics [18]. Keij et al. (2019)
newborns experienced similar signs and symptomsin performed a multicenter randomized control trial
the 6months after treatment [15].Manzoni et al. (2009) involving 550 neonates with probable bacterial
performed antibiotic switch therapy from IV to oral in infection in which one group continued on IV treatment
36 term neonates with a probable or proven bacterial (penicillin and gentamicin) while the other group was
infection. After 72 h of IV treatment switched from IV to oral (Amoxicillin/clavulanic acid).
(Ampicillin/sulbactamAmikacin), patients who were It reduced the risks of hospital-related complications
asymptomatic switched to oral cefpodoxime such as nosocomial infections andimprovement in
(10mg/kg/day), a third-generation cephalosporin. quality of life (QOL) and better mother-child bonding
Seventy-two matched controls continued on IV therapy. was observed [19]. The study assessed the efficacy of
Admission duration was significantly lower and switching 478 clinically stable neonates with early
breastfeeding rate was significantly higher among onset infection from intravenous to oral antibiotics.
neonates with an oral switch [16].In a randomized trial None of the neonates required readmission due to
study switch therapy (IM to oral) was done on 82 infection. The median hospitalization duration was 3.0
neonates with bacterial infection and showed no days (IQR 2.5-3.5) for the switch group and 7.4 days
significant effect as compared to the control group (only (IQR 7.0-7.5) for the intravenous therapy group.
IM) [17].In a prospective study evaluating the efficacy Despite the convenience of oral administration, the
of antibiotic switch therapy in pneumonia patients, adoption of switch therapy did not lead to a higher
participants were randomly allocated into two groups: overall antibiotic usage [20].

Table 1: Efficacy of switch therapy in neonates

Reference Study Size Age Type of Intervention Antibiotic Results
design infection group
Oral cefixime
was effective
Hoberman Randomize Group I= Oral Oral=Cefixime treatment to
1 to 24 UTI and
et al 1999 d clinical 306 Group II= IV= reduce UTI and
months fever
[13] trial Switch IV to oral Cefotaxime reduction in
hospital
expenditure

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1 No re-infection
within 3 months
2 serum level
Gras le Early Switch to oral above MIC for
Cohort Newborns
Guen et al 222 onset GBS after 48 hours of Amoxicillin GBS
study 2 days
2007 [14] sepsis iv antibiotics 3 Well tolerated
4 Reduction of 5
days in hospital
stay
Magin et No relapse within
Retrospecti PNA 7-31 N=119, iv-to- Amoxicillin/Cl 6 months of
al 2007 172 UTI
ve study dys oral switch avulanic acid treatment
[15]
1 reduction in
Presumed/ N=36, Iv-to-oral
Manzoni Case hospital stay
Full term proven antibiotic switch
et al 2009 control 108 Cefpodoxime 2 significantly
newborn bacterial N=72,
[16] study higher
infection completely iv
breastfeeding
Bacterial Benzyl Results were
infection penicillin and same for control
Abdullah Randomize
with one gentamicin for group and switch
baqui et al d trial 82 0-6 days Im-to-oral switch
or more 2 days from im-to-oral
2015 [17] study
clinical Amoxicillin for group
signs 5 days
1 Significant
reduction of
Group I=IV hospital stay in
ampicillin group II
Prospective
Sharma D Group II=Switch 2 Reduction in
and 2-to-59 Pneumoni Ampicillin and
et al 2016 40 to oral edema,
observation months a Amoxicillin
[18] amoxicillin after inflammation,
al
2 days of IV extravasation and
ampicillin abscess at site of
cannula in group
II
reduce the risks
of hospital-related
Group I= IV for complications
IV= penicillin
multicentre 7 days such as
Probable and gentamicin
Keij et al., randomised Group II= nosocomial
550 0-28 days bacterial Oral=
2019 [19] controlled switched to oral infections and
infection Amoxicillin/cla
trial after 48 hours of improvement in
vulanic acid
iv QOL and better
mother-child
bonding
1 No readmission
Carlsen et All term Early
Cohort due to infection
al 2023 478 born onset IV-to-oral switch Amoxicillin
study 2 Reduction in
[20] neonates infection
hospital stay
Mohamme Randomise Group I= IV No Bacterial
d d open- Probable Amoxicillin/clav reinfection within
0-to-28 Amoxicillin/cla
Abdalhad label, non- 510 bacterial ulanic acid 28 days
days vulanic acid
y et al inferiority infection Group II=IV-to-
2023 [21] trial oral switch

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1 No readmission
Carlsen et All term Early
Cohort due to infection
al 2023 478 born onset IV-to-oral switch Amoxicillin
study 2 Reduction in
[22] neonates infection
hospital stay
Mohamme Randomise Group I= IV No Bacterial
d d open- Probable Amoxicillin/clav reinfection within
0-to-28 Amoxicillin/cla
Abdalhad label, non- 510 bacterial ulanic acid 28 days
days vulanic acid
y et al inferiority infection Group II=IV-to-
2023 [23] trial oral switch
In a randomized open-label non-inferiority trial, 510
infants aged 0 to 28 days, receiving a 7-day course of
antibiotics for suspected bacterial infection, were
randomly assigned to either switch to oral antibiotics received treatment for 7 days, and no bacterial
after 48–72 hours (intervention group) or continue reinfections were reported within 28 days [21].
intravenous antibiotics (control group). Both groups
DISCUSSION bacteremic and non-bacteremic urinary tract infections
Many advantages including a reduction in hospital stay has a growing body of evidence in a recent review [29].
and a reduction in associated health costs are obtained It is confirmed by these findings that the possibility of
from the early intravenous-to-oral antibiotic switch switch therapy can be used by all neonatologists who
which is described in several current guidelines [22]. aim to avoid unnecessary pain and other harmful effects
However, oral switch therapy is not a widespread in full-term neonates. Oral antibiotics used should be
practice in neonates yet. Antibiotic therapy is started effective against suspected bacteria causing infection
immediately in case of maternal factors-based or and also they should be well tolerated and safe.
clinical symptoms-based suspicion of infection. Furthermore, there should be a minimal effect of the
Antibiotic therapy can be stopped 36-48 hours after the pharmacokinetics of antibiotics on their absorption from
disappearance of symptoms, reassurance of intestines in the first days of life when administered to
inflammatory parameters, and negative cultures in the neonates. It is a known fact that physiological factors
best-case scenario [23]. Special value and importance like gastric pH, intestinal absorption, gastric emptying
should be given to the culture of “prolonged antibiotic time, the composition of meals, frequency of food
therapy is not safe at all” [24,25].Switching from IV to intake, and bacterial composition of the gut may have
oral antibiotics in pediatric patients is according to negative effects on the pharmacokinetics of antibiotics
general proposed principles about the need and time of in neonates [30,31].
switch in a number of different infections [26,27].
Generally, there is no recommendation for IV-to-oral CONCLUSION
switch in neonates aged less than 28 days, however, it is
shown in an open-label, randomized, multicenter, non- Encouraging the transition from intravenous to oral
inferiority trial that an early IV-to-oral switch with antimicrobial therapy management can enhance patient
amoxicillin-clavulanic acid is non-inferior to IV course convenience and reduce costs. It's important to note that
in probable neonatal bacterial infection [28]. Early IV- while this switch is beneficial in many cases, it may not
to-oral switch in infants aged less than 90 days with be suitable for all infections. Further clinical studies are

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necessary to establish its applicability across various 2. Switch Drug Therapy: Transitioning from one
infection types and patient profiles, where evidence oral drug to another within the same class,
remains limited. having similar antimicrobial MIC potency,
While the concept of transitioning has been discussed protein binding, and related properties.
and successfully implemented at numerous institutions 3. Step-Down Therapy: Adjusting the dose size
over decades, there's an urgency to adopt it on a broader and/or frequency of oral dosing, with the
scale globally. This can be achieved through various switch occurring either within the same class
strategies, including: or between different classes of drugs.
1. Direct Sequential Therapy: Switching from
intravenous to oral administration of the same
drug at the same dose.
streptococcal and E. coli disease continues.
Scientific Responsibility Statement Pediatrics. 2011; 127(5):817–6.
The authors declare that they are responsible for the
2. Liu L, Johnson HL, Cousens S, Perin J, Scott
article’s scientific content including study design, data
S, Lawn JE et al. Global, regional, and national
collection, analysis and interpretation, writing, some of
causes of child mortality: an updated
the main line, or all of the preparation and scientific
systematic analysis for 2010 with time trends
review of the contents and approval of the final version
since 2000. Lancet. 2012; 379(9832): 2151–1.
of the article.
3. Liu L, Oza S, Hogan D, Chu Y, Perin J, Zhu J
et al. Global, regional, and national causes of
Animal and human rights statement
under-5 mortality in 2000-15: an updated
All procedures performed in this study were in
systematic analysis with implications for the
accordance with the ethical standards of the institutional
Sustainable Development Goals. Lancet. 2016;
and/or national research committee and with the 1964
388(10063): 3027–5.
Helsinki declaration and its later amendments or
4. Polin RA, Committee on Fetus and Newborn.
comparable ethical standards. No animal or human
Management of neonates with suspected or
studies were carried out by the authors of this article.
proven early-onset bacterial sepsis. Pediatrics.
Funding: None
2012; 129(5): 1006–5.
5. Shane AL, Sanchez PJ, Stoll BJ. Neonatal
Conflict of interest
No financialsupport received that could be considered a sepsis. Lancet. 2017; 390(10104): 1770–80.
potential conflict of interest regarding the manuscript or 6. Rutten NB, Rijkers GT, Meijssen CB, Crijns
its submission. CE, Oudshoorn JH, van der Ent CK et al.
Intestinal microbiota composition after
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