Oral Antibiotics For Neonatal Infections: A Systematic Review and Meta-Analysis
Oral Antibiotics For Neonatal Infections: A Systematic Review and Meta-Analysis
1
Department of Pediatrics, Division of Neonatology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands;
2
Department of Pediatrics, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands; 3Department of Development
and Regeneration, KU Leuven, Leuven, Belgium
*Corresponding author. Department of Pediatrics, Division of Neonatology, Erasmus MC-Sophia Children’s Hospital, dr. Molewaterplein,
40, 3015 CN Rotterdam, The Netherlands.
E-mail: [email protected]
Received 10 March 2019; returned 18 April 2019; revised 21 May 2019; accepted 21 May 2019
Background: Worldwide many neonates suffer from bacterial infections. Adequate treatment is important but
is associated with prolonged hospitalization for intravenous administration. In older children, oral switch therapy
has been proven effective and safe for several indications and is now standard care.
Objectives: To evaluate the currently available evidence on pharmacokinetics, safety and efficacy of oral antibi-
otics and oral switch therapy in neonates (0–28 days old).
Methods: We performed systematic searches in Medline, Embase.com, Cochrane, Google Scholar and Web of
Science. Studies were eligible if they described the use of oral antibiotics in neonates (0–28 days old), including
antibiotic switch studies and pharmacological studies.
Results: Thirty-one studies met the inclusion criteria. Compared with parenteral administration, oral antibiotics
generally reach their maximum concentration later and have a lower bioavailability, but in the majority of cases
adequate serum levels for bacterial killing are reached. Furthermore, studies on efficacy of oral antibiotics
showed equal relapse rates (OR 0.95; 95% CI 0.79–1.16; I2 0%) or mortality (OR 1.11; 95% CI 0.72–1.72; I2 0%).
Moreover, a reduction in hospital stay was observed.
Conclusions: Oral antibiotics administered to neonates are absorbed and result in adequate serum levels,
judged by MICs of relevant pathogens, over time. Efficacy studies are promising but robust evidence is lacking,
most importantly because in many cases clinical efficacy and safety are not properly addressed. Early oral anti-
biotic switch therapy in neonates could be beneficial for both families and healthcare systems. There is a need
for additional well-designed trials in different settings.
C The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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T.MIC. For vancomycin, efficacy depends on AUC/MIC and for Results
aminoglycosides it depends on Cmax. The MIC is pathogen specific
and cut-off values vary by antibiotic.9,10 From a total of 4559 studies, we reviewed the full text of 102 po-
To our knowledge, no systematic review evaluating the use of tential articles. Figure 1 shows the selection process. Additionally,
oral antibiotics in neonates has been performed. Together with the five articles were selected through screening of reference lists,
uncertainties regarding oral absorption in the first weeks of life, the leading to 31 selected publications for this review. The characteris-
lack of evidence may be a possible reason why oral switch therapy tics of included studies are described in Table 1.
is not yet standard care in neonates. The aim of this systematic re-
view is therefore to evaluate the currently available evidence on
Quality assessment
safety and efficacy of iv-to-oral switch therapy in neonates, and
to evaluate whether, following oral antibiotic administration, Risk of bias in seven out of nine RCTs was low; in the remaining two
adequate serum concentrations are attainable in neonates it was unclear (Figure S1).28,30 In all studies, blinding of patients
(0–28 days). and personnel was considered unethical [e.g. repeated intramus-
cular (im) placebo administration] and therefore not performed.
However, the independent outcome assessors were blinded for
Methods treatment allocation. Seven RCTs were registered in a public trial
Search strategy and study selection register.34–40 The quality of the six observational papers was ac-
ceptable (Table S4). With regard to the pharmacological studies,
We performed a systematic review in accordance with the Preferred
with focus on pharmacokinetics, overall, quality seems adequate
Reported Items for Systematic Reviews and Meta-analysis (PRISMA),11
taking into account available methods of analysis at that time.
searching Medline, Embase.com, Cochrane Central, Google Scholar and
Web of Science on 22 February 2019. The PRISMA statement and full search However, in some cases crucial information was missing, such as
strategies can be found in the Supplementary data (available at JAC gestational age (GA) or postnatal age (PNA), or the exact methods
Online). Titles and abstracts were screened and the full text of potential used (Table S3). The complete assessment is included in Table S1.
articles was reviewed independently by two reviewers (F. M. K. and G. A. T.-
S.). Disagreements were resolved by discussion or through consultation
with a third investigator (R. F. K.). Congress abstracts, reference lists and Study population
reviews were screened for additional studies. Eligible studies were limited As expected, the study population was quite heterogeneous,
to those performed in humans. Since we expected the amount of evidence including both term and preterm infants of different postnatal
to be small, we did not apply any restriction regarding year of publication or
ages. Four studies were performed in healthy newborns, admitted
language. We included randomized controlled trials (RCTs), intervention
for a non-infectious indication.17–20 The remaining 27 studies
studies and retrospective studies describing the use of oral antibiotics
including oral switch therapy and pharmacological studies in newborns 0– included subjects with a clinical condition requiring antibiotics,
28 days of age. ranging from prophylactic use to culture-proven infection. Two
The protocol was registered in PROSPERO (protocol number studies evaluated oral switch therapy in neonates with culture-
CRD42017070854). proven sepsis.31,41 Thirteen studies were performed in LMICs. In
these trials, antibiotic therapy indication was defined solely on clin-
ical symptoms.26,32,34–40,42,43,45,46
Data extraction
Three authors (F. M. K., G. A. T.-S. and K. A.) independently extracted the
data following a predefined extraction form (see Supplementary data). We Absorption of oral antibiotics
did not contact authors for additional information.
Pharmacokinetic analysis and interpretation
In 10 papers serum levels were determined using the agar plate dif-
Quality assessment
fusion method; the remaining and more recently published papers
Quality assessment was performed independently by two authors (F. M. K.
used HPLC. Most studies provided descriptive data on absorption,
and either K. A. or G. A. T.-S.) using the Cochrane Risk of Bias Tool for RCTs12
mainly Cmax without further pharmacokinetic estimates (e.g. V and
and the Newcastle–Ottawa Quality Assessment Scale (NOS) for non-
randomized trials.13 Since a tool for quality assessment of pharmacological CL). Three papers provided AUC estimates.21,23,28 Regarding inter-
papers is currently lacking, we used the ClinPK statement, a descriptive tool pretation, six papers reported MIC cut-off values28–33 with only one
without a grading system, to assess quality of pharmacokinetics papers study reporting a T.MIC.32 Extracted pharmacokinetic data and
(Table S2).14 administered doses are described in Table 2.
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Table 1. Characteristics of included studies
Assessment of pharmacokinetics
Healthy subjects
Huang and High USA non-RCT unknown healthy (pre)term newborns single dose of oral penicillin single dose of im comparison of absorp- (i) mean serum levels
(1953)17 antibiotics antibiotics tion rate
Systematic review
O’Connor et al. USA cohort study n"15 healthy newborns (PNA oral antibiotics nafcillin no comparison serum levels following (i) mean serum levels
(1965)18 0–2 days) oral therapy
Grossman and USA non-RCT n"171 healthy term newborns single dose of oral nafcillin, cloxa- single dose of im comparison of serum (i) mean serum levels
Ticknor (1965)19 (PNA 0–5 days) antibiotics cillin, antibiotics levels following
ampicillin oral/im
Weingärtner et al. Germany cohort study n"23 healthy preterm/term single dose of oral amoxicillin no comparison serum level (i) mean serum levels
(1977)20 newborns antibiotics determination
Neonates with clinical indication for antibiotic therapy
Silverio and Poole USA case–control n"10 term newborns (GA 40 weeks; single dose of oral ampicillin oral antibiotics in comparison of serum (i) mean serum levels
(1973)21 PNA 1–2 days), clinical antibiotics adults concentrations
indication
Cohen et al. (1975)22 Scotland non-RCT n"27 newborns (GA 28–40 weeks, oral antibiotics ampicillin, no comparison determination of (i) mean serum levels
PNA 1–6 days), prophylac- amoxicillin, serum concentra-
tics/UTI flucloxacillin tions of oral
antibiotics
Lönnerholm Sweden crossover trial n"14 newborns, suspected infec- iv-to-oral switch amoxicillin, no comparison determination of bio- (i) mean serum levels
(1982)23 tion, good clinical ampicillin availability of oral
condition antibiotics
Mulhall (1985)24 England non-RCT n"9 newborns (GA oral antibiotics chloramphenicol iv antibiotics comparison of oral/iv (i) mean
34.6+2 weeks, antibiotic therapy steady-state
PNA 14+3 days), concentration
sepsis
Herngren et al. Sweden cohort study n"9 newborns (GA 36.6 weeks; iv-to-oral switch flucloxacillin no comparison determination of kin- (i) pharmacokinetics of
(1987)25 PNA 7.2 days), suspected etics of flucloxacillin oral and iv
sepsis antibiotics
(ii) side effects
Weber et al. (1999)26 Philippines, non-RCT n"58 (n"34: newborns ,3 months, severe oral antibiotics chloramphenicol im pharmacokinetics of (i) mean serum levels
The PNA bacterial infection chloramphenicol
Gambia ,29 days)
Assessment of pharmacokinetics and clinical efficacy
Squinazi et al. France cohort study n"20 preterm/term newborns, sus- oral antibiotics amoxicillin – efficacy and tolerance (i) clinical course
(1983)27 pected sepsis, 1–8 days of oral therapy (ii) tolerance
PNA (iii) serum levels
Autret et al. (1988)28 France RCT n"21 full-term newborns (PNA oral antibiotics amoxicillin iv amoxicillin comparison of serum (i) serum levels .MIC
3 days), bacterial levels iv/oral with (ii) clinical course and
colonization MIC tolerance
Autret (1989)29 France cohort study n"10 full-term newborns (GA iv-to-oral antibiotic amoxicillin no comparison Cmax and steady-state (i) serum levels .MIC
39.8+1.8 weeks) bacterial switch after 48 h concentrations in (ii) accumulation
colonization, clinically well relation to MIC cut- (iii) clinical course and
off values tolerance
Giustardi and Italy RCT n"32 term newborns (GA 39– oral antibiotics amoxicillin iv amoxicillin comparison of serum (i) mean serum levels
Coppola (1992)30 40 weeks, PNA 2–3 days), levels (ii) clinical course
neonatal sepsis
Gras le Guen et al. France cohort study n"222 term newborns (GA iv-to-oral antibiotic amoxicillin no comparison reaching adequate (i) re-infection rate
(2007)31 39.2+1.5 weeks; PNA 2 switch after 48 h iv serum levels and within 3 months
days), possible or proven therapy tolerance of iv/oral (ii) tolerance
early-onset GBS sepsis switch therapy (iii) serum levels
Continued
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Table 1. Continued
32
Mir (2013) Pakistan pilot study of n"44 (n"29: newborns (GA 38 weeks), oral antibiotics amoxicillin no comparison pharmacokinetic effi- (i) dose–exposure pro-
larger RCT PNA 0– clinical signs of severe cacy targets (T.MIC) file, time–exposure
27 days) infection profile T.MIC 50%;
MIC 2.0 mg/L
Sicard et al. (2015)33 France retrospective n"16 preterm newborns (GA: oral antibiotics linezolid parenteral description of linezolid (i) disappearance of
study 28+3.5 weeks; PNA: antibiotics concentrations, clinical symptoms
20.9+11.7 days) with a clinical course and (ii) side effects
bacterial infection side effects in pre- (iii) plasma
mature infants concentrations
Assessment of clinical efficacy
Tikmani et al. Pakistan RCT n"970 term newborns oral antibiotics amoxicillin placebo equivalence of oral (i) treatment failure by
(2017)34 (n"754: (GA.37 weeks, PNA amoxicillin com- day 8 post-enrol-
0– 15.4+16.2 days), fast pared with placebo ment visit
28 days) breathing
Mir et al. (2017)35 Pakistan RCT n"2780 newborns, clinical signs of comparison of three (i) gentamicin ! procaine benzylpe- assessment of equiva- (i) treatment failure
(n"1083: severe infection regimens oral nicillin ! lence of two within 7 days after
0–6 years) amoxicillin gentamicin regimens enrolment
(ii) procaine ben-
zylpenicillin
! oral
amoxicillin
Degefie Haielgebriel Ethiopia RCT n"22 geo- newborns with possible signs regimen of im ! oral gentamicin im ! – feasibility and mortal- (i) post-day 1 neonatal
et al. (2017)36 graphical of serious infection antibiotics oral ity impact of a sim- mortality
clusters, amoxicillin plified antibiotic
n"11 regimen
interven-
tion,
n"11
control
Baqui et al. (2015)37 Bangladesh RCT n"2490 newborns, clinical signs of se- comparison of three (i) gentamicin im procaine benzylpe- identification of effect- (i) treatment failure
(n"253: vere infection regimens ! oral nicillin ! ive alternative anti- within 7 days after
0–6 days) amoxicillin. gentamicin biotic regimens enrolment
(ii) procaine ben-
zylpenicillin !
gentamicin
im ! oral
amoxicillin
Tshefu et al. DR Congo, RCT n"2333 newborns, fast breathing oral antibiotics amoxicillin injectable penicillin effectiveness of oral (i) treatment failure by
(2015)38 Kenya, (n"882: ! gentamicin amoxicillin com- day 8 post-enrol-
Nigeria 0–6 days) pared with inject- ment visit
able procaine
benzylpenicillin/
gentamicin
Tshefu et al. DR Congo, RCT n"3564 newborns, clinical signs of comparison of four (i) gentamicin ! procaine benzylpe- effectiveness of simpli- (i) treatment failure by
(2015)39 Kenya, (n"1160: bacterial infection regimens oral nicillin ! fied antibiotic regi- day 8 post-enrol-
Nigeria 0–6 days) amoxicillin gentamicin mens compared to ment visit
(ii) procaine ben- injectable procaine
zylpenicillin ! benzylpenicillin/
gentamicin ! gentamicin
oral
Systematic review
amoxicillin
(iii) gentamicin
! oral
amoxicillin
Zaidi et al. (2012)40 Pakistan RCT n"434 newborn, possible serious comparison of three (i) ceftriaxone im procaine benzylpe- comparison of failure (i) treatment failure
(n"333: bacterial infection regimens (ii) oral co- nicillin ! rates of three clinic- within 7 days after
0– trimoxazole gentamicin based antibiotic enrolment
28 days) regimens
Manzoni et al. Italy case–control n"108 (36/ full-term newborns, pre- iv-to-oral antibiotic cefpodoxime matched controls, efficacy, safety, toler- (i) clinical course (tim-
(2009)41 study 72) sumed/proven bacterial switch continuation of ability of switch ing of normalization
infection iv therapy therapy of laboratory data,
duration of hospi-
talization, type of
feeding)
Bang et al. (2005)42 India case–control n"39 inter- newborns, clinical signs of regimen of im ! oral gentamicin im ! – evaluation of feasibility (i) neonatal sepsis
from previ- vention possible infection antibiotics oral co- and effectiveness of related mortality
ous study villages, trimoxazole home-based man-
n"47 agement of neo-
control natal sepsis
villages
Bang et al. (1999)43 India case–control n"39 inter- newborns, clinical signs of regimen of im ! oral gentamicin im ! – reduction of neonatal (i) neonatal mortality
study vention possible infection. antibiotics oral co- mortality by intro- rate
villages, trimoxazole duction of neonatal
n"47 home packages
control including antibiotics
villages
Blond et al. (1990)44 France non-RCT n"119 term newborns ! 6 preterm, iv-to-oral antibiotic amoxicillin, – efficacy of oral (i) clinical course in first
bacterial colonization switch after 3 days amoxicillin/ treatment month of life
clavulanic
acid
Coffey et al. (2012)45 Nepal cohort study n"67 newborns with possible se- regimen of im ! oral gentamicin im ! – feasibility of gentami- (i) clinical course(ii)
vere bacterial infection antibiotics oral co- cin prefilled injec- local reaction to
trimoxazole tion system ! oral injection
antibiotics
Qamar et al. Pakistan descriptive n"1083 newborns, omphalitis oral antibiotics cefalexin injectable procaine description of clinical (i) decreased area of
(2013)46 study penicillin ! gen- profile and outcome redness/cellulitis or
tamicin, topical of home-based purulent discharge
gentian violet management (ii) complete resolution
of signs of sepsis
(iii) development of
signs of sepsis
Magı́n et al. (2007)47 Spain retrospective n"172 newborns (PNA 7–31 days), iv-to-oral switch amoxicillin/clav- no comparison examination of clinical (i) re-infection within
study UTI ulanic acid course, efficacy of 14 days after cessa-
short-term iv tion of therapy
therapy
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Table 2 Pharmacokinetic data on oral antibiotics
Timing between
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birth/admission and
Route (mode of first oral antibiotic Sampling schedule
Study Population Type of antibiotics administration) Dosea dose (h) Mean Cmax Mean Tmax (h) AUC (mgh/L)
Huang and High (i) term newborns procaine penicillin potas- oral vs im 22000 U/kg sd – 1=2, 2, 4, 6 2.5 U/mL (1.0–4.0) 2 –
(1953)17 sium penicillin G
potassium penicillin G 3.50 U/mL (0.5–8.0) 0.5 –
Systematic review
a
sd, single dose.
Systematic review JAC
probable bacterial infection, no relapse was reported after oral of treatment and no mortality after 1 month. Admission duration
treatment (80–150 mg/kg/day q12h). Moreover, no side effects was significantly lower and breastfeeding rate was significantly
occurred and all measured serum concentrations were reported to higher among neonates with an oral switch.41
be above the MICs of targeted pathogens.27,30 In a clinical study
on Escherichia coli urinary tract infection (UTI), four neonates Flucloxacillin
showed no re-infections in the next 2 years following a 14 day oral
treatment of 120 mg/kg/day (in an era with low E. coli amoxicillin In a small switch study, performed in 1987, neonates at risk of sep-
resistance).22 In an RCT including 21 neonates with suspected in- sis switched to oral flucloxacillin combined with oral amoxicillin
fection, 11 switched to oral amoxicillin (120 mg/kg q8h) after 48 h after severe bacterial infection had been ruled out. Plasma concen-
of iv therapy (ampicillin/netilmicin). The control group switched to trations following oral administration were all above the MIC cut-
amoxicillin iv. All patients included in the study had negative blood offs for Staphylococcus aureus.25
cultures and tolerated oral feeding well without any vomiting.
Concentrations remained above the MIC for E. coli for all but three Linezolid
patients (n"2 iv, n"1 oral).28 Dose optimization through increasing In a retrospective study, five preterm infants (GA 28+3.5 weeks),
the dosing frequency was suggested and subsequently evaluated treated for late-onset sepsis, who experienced renal failure,
in a second study. Ten infants switched to oral amoxicillin switched from iv vancomycin (30 mg/kg/day) to oral linezolid
(100 mg/kg/day q6h). All plasma concentrations were above the (30 mg/kg/day q8h). Cmax for all patients but one was above the
MIC for E. coli without substantial side effects or re-infections.29 measured MIC for the causative pathogen.33
An uncontrolled iv-to-oral switch trial was performed in 222
term neonates with probable or proven group B-streptococcal
(GBS) sepsis. Subjects switched to oral amoxicillin (300 mg/kg/day Larger efficacy studies including trials in LMIC settings
q6h) after 48 h of iv amoxicillin (100 mg/kg per day). All infants had Since there is a need for good outpatient-based management in
to be asymptomatic and enterally fed at the moment of switch. LMICs, several large trials have taken place evaluating regimens
Because of high serum concentrations, the dose was reduced (to including oral antibiotics. In a controlled trial in .80 villages in
200 mg/kg/day q6h) in the remaining 158 patients. Serum levels India, health workers in the intervention villages were trained in
were all above the MIC for GBS. Moreover, therapy was well toler- providing neonatal care.42,43 When clinical sepsis was suspected
ated without any side effects or reinfections and a reduction of but admission refused, neonates received home-based treatment
5 days in hospital admission was seen.31 including oral co-trimoxazole. Sepsis-related mortality decreased
from 16.6% to 6.9% compared with the period before introduction.
Amoxicillin/clavulanic acid Subsequently, several large RCTs comparing home-based antibiot-
ic regimens have been published. The evaluated regimens are
A retrospective study evaluated the clinical course and treatment described in Table 3.
of 172 newborns with a UTI. An increase in use of oral instead of iv Three regimens were compared in 434 Pakistani children 0–
therapy was seen over the years. In total, 119 patients switched to 59 days old (72% were 28 days old). Higher treatment failure
oral amoxicillin/clavulanic acid (dose not reported) as continuation rates were seen among patients treated with oral co-trimoxazole
therapy. None of the orally treated newborns experienced a re- plus gentamicin compared with other regimens.40 In a Nepalese
lapse in the 6 months after treatment.47 In another study, oral study, oral co-trimoxazole was administered in combination with
amoxicillin/clavulanic acid (80 mg/kg/day q12h) was administered im gentamicin to 67 newborns with a possible bacterial infection.45
successfully to neonates at risk of infection without any re- The authors reported a 100% completion rate of oral therapy with-
infections or treatment failure in the first month after treatment out any treatment failure. An Ethiopian trial evaluated the imple-
completion.44 mentation of im gentamicin and oral amoxicillin.36 When infection
was suspected, pre-referral medication was given and the patient
Cefalexin was referred to the hospital. If referral was not possible, the inter-
A study from Pakistan described the outcome of oral management vention group continued with home-based treatment; the control
in neonates with clinical omphalitis. Omphalitis was categorized group did not receive further treatment. Results seem promising,
based on severity; cases without sepsis were treated with cefalexin with a decline in mortality from 17.9 deaths per 1000 live births at
suspension (50 mg/kg/day q8h) with a success rate of 99.5%, baseline to 9.4 per 1000 in the intervention group. In the compari-
showing that outpatient treatment of clinically well neonates with son group, mortality rates declined to a lesser extent, from 14.4 to
omphalitis using oral therapy is feasible.46 11.2 per 1000. However, mortality rates were not significantly
lower in the intervention group compared with the control
(P " 0.33).
Cefpodoxime Three RCTs, with a total of 8834 subjects, compared regimens
Switching therapy from iv to oral was performed in 36 term neo- including oral amoxicillin with standard im regimens (penicillin/
nates with a probable or proven bacterial infection. After 72 h of iv gentamicin) in newborns at risk of severe infection. The first trial, in
treatment (ampicillin/sulbactam ! amikacin), patients who were Bangladesh, compared three regimens, including an oral switch
asymptomatic switched to oral cefpodoxime (10 mg/kg/day), a regimen, among 2490 children (10% aged 0–6 days)37 The second
third-generation cephalosporin. Seventy-two matched controls trial, in the Democratic Republic of the Congo, Kenya and Nigeria
continued on iv therapy. Outcomes were comparable for the two (AFRINEST study) included 3564 infants 0–59 days old (30% 0–
groups, with identical inflammatory parameters in the first week 6 days old)39 comparing four regimens including one oral switch to
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Systematic review
amoxicillin. The third study included 2453 infants (44% 0–6 days later after oral administration compared with other routes. Thus,
of age) evaluating similar regimens.35 Heterogeneity between as in older patients, initial therapy should consist of iv antibiotics to
studies was low. Primary outcome was treatment failure within quickly reach target concentrations, but can subsequently be
8 days, defined as death, clinical deterioration, hospital admission switched to oral therapy once the neonate is clinically well.
or treatment-related serious adverse events. The combined OR for The efficacy studies showed equal relapse rates and good toler-
the orally treated group was 0.95 (95% CI 0.79–1.16; I2 0%) ation of oral therapy compared with iv therapy without reporting
Mortality within 2 weeks after enrolment was comparable in both an increase in side effects. Moreover, in two studies oral adminis-
groups, with an OR of 1.11 (95% CI 0.72–1.72; I2 0%). Forest plots tration led to a shorter stay in hospital and more exclusively
are shown in Figure 2. breast-fed infants. In LMICs, mortality rates have decreased
Finally, two trials evaluated the use of oral amoxicillin in neo- through the introduction of home-based therapy when referral is
nates with tachypnoea as a single symptom of possible infection. not possible and simplified antibiotic regimens with an oral switch
The first, in which oral treatment was compared with placebo in have shown efficacy similar to that of standard im therapy.
849 infants (78% 0–28 days old; dropout: n"121), showed a higher The strength of this review is the fact that we provide a com-
mortality in the placebo group compared with the treatment plete overview of all retrieved studies on oral antibiotic use in neo-
group, underlining the potential benefits of antibiotic treatment in nates. Although this provides a great historical overview of an idea
infants with fast breathing alone.34 A second trial, including 2333 that has existed since the 1950s, the heterogeneity of the studies
neonates (38% 0–6 days old), showed equivalence of oral amoxi- found makes pooling and generalizability to current clinical prac-
cillin compared with an im regimen in newborns with fast breath- tice difficult. In an attempt to translate findings to contemporary
ing, with comparable treatment failure rates [22% (im regimen) practice, limitations will be discussed in the light of study design
versus 19% (oral regimen)] and mortality rates (,1% in both and setting, ethics, techniques used and analysis.
groups).38 First, study groups were small and without randomization, ex-
cept for a few large RCTs, introducing a possible selection bias with
Discussion exclusion of the sicker newborns. In most studies, clinical efficacy,
bacterial re-infection or treatment failure is used as the primary
In this systematic review, we collected the currently available evi- outcome. Given the fact that the bacterial re-infection rate is low, a
dence on oral antibiotics in neonates. While oral administration is much larger study sample is needed to show non-inferiority or effi-
not commonly considered at present in neonates, several pharma- cacy of oral treatment.49 Moreover, the clinical indication for anti-
cological and efficacy studies have been performed with different biotic treatment and infection severity is unclear in a number of
types of antibiotics. studies; therefore data cannot be translated to current practice.
In general, adequate serum levels according to the MICs of rele- The included studies were performed in both preterm and term
vant pathogens can be achieved after oral administration in neo- infants, sometimes without providing the GA or PNA of the sub-
nates. Inter-individual variation is observed, which has also been jects. Drug clearance differs between preterm and term infants
reported following iv administration and should therefore not be and improves with increasing postnatal age, thereby influencing
used as an argument for discarding oral therapy. Cmax is reached plasma concentrations.50 Finally it must be stressed that a great
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Systematic review JAC
(a)
iv-to-oral switch Injectable PEN/GEN Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Baqui et al. (2015) 64 790 78 795 33.5% 0.81 [0.57, 1.15]
Mir et al. (2017) 99 753 90 747 36.8% 1.11 [0.81, 1.50]
Tshefu et al. (2015) 65 862 67 828 29.7% 0.93 [0.65, 1.32]
(b)
iv-to-oral switch Injectable PEN/GEN Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Baqui et al. (2015) 12 790 14 795 35.7% 0.86 [0.40, 1.87]
Mir et al. (2017) 12 753 13 747 33.3% 0.91 [0.41, 2.02]
Tshefu et al. (2015) 20 862 12 828 31.0% 1.62 [0.78, 3.33]
Figure 2. (a) Forest plot comparing treatment failure of reference treatment (penicillin/gentamicin im for 7 days) with switch regimen (penicillin/gen-
tamicin im for 2 days followed by oral amoxicillin for 5 days). The regimens used are further described in Table 3. (b) Forest plot comparing mortality
of reference treatment (penicillin/gentamicin im for 7 days) with switch regimen (penicillin/gentamicin im for 2 days followed by oral amoxicillin for
5 days). The regimens used are further described in Table 3. PEN, penicillin; GEN, gentamicin.
variety of antibiotic regimens have been used, including single-dose Finally, for the interpretation of results and thus the evaluation
administration, and sometimes without mentioning the adminis- of efficacy, the pharmacological mode of action of the specific
tered dose. Some of the therapies and regimens are rarely prescribed antibiotic should be considered. The effect of b-lactam antibiotics
nowadays, partly due to increased concerns regarding antibiotic re- depends on T.MIC, whereas for aminoglycosides it depends on the
sistance and the availability of alternatives with fewer side effects. Cmax/MIC ratio. Although six papers do refer to MIC, only one
In LMICs, simplified regimens including oral antibiotics are al- reports T.MIC. Comparison of Cmax with a single MIC value in case
ready recommended by the WHO when referral is not possible.51 of b-lactam antibiotics has no clinical relevance and cannot be
Unfortunately, the setting differs greatly from HICs, with refusal of used as a relevant surrogate marker for therapy efficacy.
hospital admission still being common and accepted, especially in Moreover, MIC levels have increased in recent years, due to an in-
remote areas. In addition to the differences in setting, the majority crease in bacterial resistance. In 1992, Giustardi and Coppola30
of patients are solely diagnosed on clinical symptoms since diag- reported an amoxicillin MIC of 5 mg/L for E. coli, whereas now an
nostic tools are often lacking, possibly leading to an overestimation MIC of .8 mg/L is advised to properly treat an E. coli infection.
of the actual number of bacterial infections. Furthermore, the in- Given these limitations, the currently published studies cannot be
tensity of surveillance due to the execution of the study combined used as conclusive evidence to safely change our current guide-
with exclusion of the sicker neonates may have biased mortality lines on management of neonatal bacterial infection. However,
rate numbers. our findings do give the impression that such studies may be
Regarding the pharmacokinetic analysis, ethics requirements of undertaken safely.
studies have changed and the same holds true for the administra-
tion of antibiotics to healthy newborns. With regard to blood sam-
pling, it is no longer considered ethical to collect large volumes or Conclusion and future directions
many samples in neonates. Advanced population pharmacoki- Early switch to oral antibiotics after a short course of iv antibiot-
netic approaches should be applied in further research, using a ics could be promising in term neonates with a (probable) bac-
reduced number of samples per newborn.52 terial infection. This claim is partly supported by the available
Further, improved knowledge and better techniques have led to evidence retrieved in this systematic review. Unfortunately, the
novel antibiotic assays, replacing agar plate dilution methods. lack of large well-designed studies in a high-income setting,
Advanced analysis programs are available in order to develop evaluating the efficacy of oral antibiotics, together with the
pharmacokinetic models, used for prediction of exposure and drug uncertainties regarding pharmacokinetics has obstructed fur-
response, following different dosage regimens in a target popula- ther implementation. Future research should focus on the clinic-
tion. Those models take into account covariates such as gestation- al efficacy of oral therapy and the safety of iv-to-oral antibiotic
al and postnatal age or disease characteristics that possibly switch therapy in neonates using different types of antibiotics,
influence the pharmacokinetics and dynamics of a drug. Notably, taking into account the mode of action of the specific antibiotic.
none of the included papers reported covariates in their analysis. These studies should include pharmacokinetic analyses when
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Systematic review
possible, to properly evaluate currently used dosing regimens. 4 Polin RA, Committee on Fetus and Newborn. Management of neonates
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in neonates, its implementation may have a strong effect on 1006–15.
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Part of this work has been presented at the 36th Annual Meeting of the
7 Rutten NB, Rijkers GT, Meijssen CB et al. Intestinal microbiota composition
European Society for Pediatric Infectious Diseases (ESPID) Abstract
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Funding 10 EUCAST. Clinical Breakpoints and Dosing of Antibiotics. http://www.eucast.
This work was supported by The Netherlands Organisation for Health org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_9.0_
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been supported by the Fund for Scientific Research, Flanders (fundamental 11 PRISMA. Prisma Transparent Reporting of Systematic Reviews and Meta-
clinical investigatorship 1800214 N). The research activities are further Analyses. http://www.prisma-statement.org/.
facilitated by the agency for innovation by Science and Technology in
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