Paediatrics and International Child Health

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Reviewing the WHO guidelines for antibiotic use

for sepsis in neonates and children

Aline Fuchs, Julia Bielicki, Shrey Mathur, Mike Sharland & Johannes N. Van
Den Anker

To cite this article: Aline Fuchs, Julia Bielicki, Shrey Mathur, Mike Sharland & Johannes
N. Van Den Anker (2018) Reviewing the WHO guidelines for antibiotic use for sepsis in
neonates and children, Paediatrics and International Child Health, 38:sup1, S3-S15, DOI:
10.1080/20469047.2017.1408738

To link to this article: https://doi.org/10.1080/20469047.2017.1408738

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Published online: 23 May 2018.

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Paediatrics and International Child Health, 2018
VOL. 38, NO. S1, S3–S15
https://doi.org/10.1080/20469047.2017.1408738

Reviewing the WHO guidelines for antibiotic use for sepsis in neonates and
children
Aline Fuchsa, Julia Bielickia,b, Shrey Mathurb  , Mike Sharlandb and Johannes N. Van Den Ankera,c
a
Paediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel, Basel, Switzerland; bPaediatric Infectious Disease
Research Group, Institute for Infection and Immunity, St George’s University of London, London, UK; cDivision of Clinical Pharmacology,
Children’s National Health System, Washington, DC, USA

ABSTRACT ARTICLE HISTORY

Background:  Guidelines from 2005 for treating suspected sepsis in low- and middle-income Received 29 September 2017
countries (LMIC) recommended hospitalisation and prophylactic intramuscular (IM) or Accepted 2 November 2017
intravenous (IV) ampicillin and gentamicin. In 2015, recommendations when referral to hospital KEYWORDS
is not possible suggest the administration of IM gentamicin and oral amoxicillin. In an era of Sepsis; antibiotics;
increasing antimicrobial resistance, an updated review of the appropriate empirical therapy for antimicrobial resistance;
treating sepsis (taking into account susceptibility patterns, cost and risk of adverse events) in treatment guidelines
neonates and children is necessary.
Methods:  Systematic literature review and international guidelines were used to identify
published evidence regarding the treatment of (suspected) sepsis.
Results: Five adequately designed and powered studies comparing antibiotic treatments in a
low-risk community in neonates and young infants in LMIC were identified. These addressed
potential simplifications of the current WHO treatment of reference for infants for whom
admission to inpatient care was not possible. Research is lacking regarding the treatment
of suspected sepsis in neonates and children with hospital-acquired sepsis, despite rising
antimicrobial resistance rates worldwide.
Conclusions:  Current WHO guidelines supporting the use of gentamicin and penicillin for
hospital-based patients or gentamicin (IM) and amoxicillin (oral) when referral to a hospital is not
possible are in accordance with currently available evidence and other international guidelines,
and there is no strong evidence to change this. The benefit of a cephalosporin alone or in
combination as a second-line therapy in regions with known high rates of non-susceptibility is
not well established. Further research into hospital-acquired sepsis in neonates and children is
required.

Introduction 72 h of life. As a result, neonatal sepsis in LMIC is often

classified as community- and hospital-acquired instead
Sepsis remains a leading cause of mortality and mor-
of early- and late-onset [4].
bidity, especially during the first five days of life and in
WHO provides guidelines for the management of
low- and middle-income countries (LMIC) [1]. In 2015,
common childhood illnesses, through the Pocket Book
of the 5.9 million deaths of children under the age of
of Hospital Care for Children published for the first
5 years, 45% were of neonates, and this figure exceeded
time in 2005 [5]. The second edition was published in
50% in several regions [2]. Neonatal sepsis is the third
2013 [6]. It is one of a series of documents and tools
most common cause of death in this age group with an
supporting the Integrated Management of Childhood
estimated 0.4 million deaths in 2015, the vast majority
Illness (IMCI). These guidelines focus on management
of which were in LMIC [3]. Beyond the neonatal period,
of the major causes of childhood mortality in coun-
the first year of life carries the highest risk of death from
tries with limited health care (and other) resources.
sepsis.
Recommendations for preventing neonatal infection
In high-income countries (HIC), early-onset neonatal
and for the management of possible serious bacterial
sepsis (EONS) is defined by occurring in the first 72 h after
infection remain the same in the second edition. It rec-
birth, as opposed to late-onset neonatal sepsis (LONS,
ommends providing prophylactic intramuscular (IM)
onset  ≥  72  h after birth). In LMIC, many neonates are
or intravenous (IV) ampicillin and gentamicin in neo-
born outside health care facilities, and might become
nates with documented risk factors for infection for at
infected with community-acquired pathogens even after

CONTACT  Aline Fuchs  [email protected]

© 2018 Informa UK Limited, trading as Taylor & Francis Group
S4   A. FUCHS ET AL.

least 2 days and then to reassess. Treatment should be Against this background, concerns are increasing regard-
continued only if there are signs of sepsis (or positive ing bacterial pathogens with reduced susceptibility to
blood culture). It recommends hospitalisation and IM or empirical medication with variations both between and
IV antibiotic therapy with a combination of gentamicin within LMIC [9].
and benzylpenicillin or ampicillin for at least 7–10 days The potential need to revise the existing WHO guide-
in infants aged <2 months who fulfil the case definition lines based on new antimicrobial resistance (AMR) data
of serious bacterial infection. If infants are deemed to or evidence relating to drug safety in neonates and chil-
be at risk of staphylococcal infection, IV cloxacillin and dren must be evaluated. This review collates evidence to
gentamicin are recommended. support current empirical antibiotic recommendations
In many LMIC, these parenteral treatments might for suspected or confirmed sepsis in neonates and chil-
only be available where inpatient neonatal and pae- dren according to the most recent (≥year 2012) relevant
diatric care can be provided, and access to these treat- studies.
ments is limited by transportation, financial and/or
cultural factors. In previous studies, even when these
Methods
constraints were addressed, a substantial proportion
of families still refused referral to hospital for young An iterative systematic literature search was undertaken
infants with possible serious bacterial infection (PSBI). to identify published clinical evidence relevant to the
A body of research undertaken in the past decade led review question. Searches were conducted in MEDLINE
to the development and publication in 2015 of the and Embase. Databases were searched using relevant
first guideline for Managing Possible Serious Bacterial medical subject headings, free-text terms and study-
Infection in Young Infants When Referral is not Possible type filters, where appropriate. Search terms included
[7] in infants aged <59 days. The guideline recommends variations of ‘anti-bacterial agents’, ‘antibiotic’, ‘sepsis’ and
(Table 1): ‘bacteraemia’. Limits were set for the appropriate popu-
Option 1: IM gentamicin 5–7.5  mg/kg (for low-birth- lation, i.e. ‘all child (0 to 18 years)’. Studies published in
weight infants gentamicin 3–4  mg/kg) once daily for languages other than English were not reviewed. The
7  days and twice daily oral amoxicillin, 50  mg/kg per search was undertaken for manuscripts published from
dose for 7 days. 2012 to cover the most recent WHO guidelines (WHO
Option 2: IM gentamicin 5–7.5  mg/kg (for low-birth- Pocket Book of Hospital Care for Children, 2013).
weight infants gentamicin 3–4  mg/kg) once daily for Potentially relevant studies were identified from
2  days and twice daily oral amoxicillin, 50  mg/kg per the search results by reviewing titles and abstracts.
dose for 7 days.
Full papers were then obtained and reviewed against
Thus, penicillin/gentamicin is recommended for pre-specified inclusion (antimicrobial choice, compar-
community neonatal sepsis, hospital neonatal sepsis isons between different antibiotics and/or antibiotic
and all sepsis in children. It is known, however, that in classes and/or comparisons with placebo, drug thera-
many countries, agents with a broader spectrum such peutic use, drug efficacy, drug safety and harm, drug
as third-generation cephalosporins (e.g. ceftriaxone) are resistance) and exclusion criteria (only bacterial sepsis
commonly used to treat neonatal and infant sepsis [8]. was considered, case reports were not considered) to

Table 1. Current WHO recommendation for antibiotic therapy in infants aged 0–59  days with signs of possible serious bacterial
infection or for prophylaxis.
Reference Conditions Antibiotics Dosing regimen
Pocket Book of Hospital Prophylaxis in neonates with IM or IV ampicillin and g
­ entamicin Gentamicin (IM/IV):
Care for Children, documented risk factors for at least 2 days First week of life
2013 Case definition PSBI IM or IV gentamicin and Low-birthweight infants: 3 mg/kg once a day; normal
­benzylpenicillin or ampicillin for birthweight: 5 mg/kg per dose once a day
at least 7–10 days Weeks 2–4 of life: 7.5 mg/kg once a day
Greater risk of staphylococcus IV cloxacillin and gentamicin for at Ampicillin (IM/IV):
infection least 7–10 days First week of life: 50 mg/kg every 12 h
Weeks 2–4 of life: 50 mg/kg every 8 h
Benzylpenicillin (penicillin G) (IM):
First week of life: 50,000 U/kg every 12 h; weeks 2–4 and
older: 50,000 U/kg every 6 h
Procaine benzylpenicillin (IM):
50,000 U/kg once a day
Cloxacillin (IV):
First week of life: 25–50 mg/kg every 12 h
Weeks 2–4 of life: 25–50 mg/kg every 8 h
Managing possible Referral to hospital for young Option 1: IM gentamicin once Gentamicin: IM 5–7.5 mg/kg (for low-birthweight infants
serious bacterial infants with PSBI is not daily for 7 days and oral gentamicin 3–4 mg/kg) once daily
infection in young possible ­amoxicillin twice daily for 7 days Amoxicillin: Oral 50 mg/kg twice daily
infants when referral Option 2: IM gentamicin once ­daily
is not possible, 2015 for 2 days and oral ­amoxicillin
twice daily for 7 days
 PAEDIATRICS AND INTERNATIONAL CHILD HEALTH   S5

identify studies that addressed the review question. between groups C and A was −1.7% (95% CI −4.5 to
Fungal and viral sepsis were not taken into account in 1.1). Non-fatal severe adverse events were rare. Three
this review, although invasive candidiasis is an important infants in group A, two in group B and three in group C
emerging cause of LONS. had severe diarrhoea [19]. In the SATT trial in Pakistan,
The Cochrane Database for Systematic Reviews was treatment failed within 7 days of enrolment in 90 (12%)
also searched using the terms ‘sepsis’ AND ‘antibiotic’. of infants in group A compared with 76 (10%) infants
Five international guidelines were reviewed: the in group B and 99 (13%) in group C. The risk difference
Surviving Sepsis Campaign endorsed by the Infectious between groups B and A was −1.9% (95% CI −5.1 to
Diseases Society of America (IDSA) [10], the National 1.3) and between groups C and A was −1.7% (−2.3 to
Institute for Health and Care Excellence (NICE) [11,12], 4.5) [20].
the American Academy of Pediatrics (AAP) [13–15], One of two large RCTs from the AFRINEST (AFRIcan
the British Medical Journal (BMJ) Clinical Evidence NEonatal Sepsis Trial) Group compared oral amoxicil-
[16] and the British National Formulary for Children lin with injectable procaine benzylpenicillin plus gen-
(BNFc) [17]. tamicin in five African centres in young infants (≤59 days
old, n = 2333) with fast breathing as a single sign of PSBI
Results illness when referral was not possible. In the procaine
benzylpenicillin–gentamicin group, 234 infants (22%)
Evidence for current WHO recommendations: penicillin
failed treatment compared with 221 (19%) infants in
and gentamicin in community-based neonatal sepsis
the oral amoxicillin group (risk difference 2.6%, 95%
A randomised controlled trial (RCT) undertaken in three CI −6.0 to 0.8). The results were taken to indicate that
low-income communities in Pakistan evaluated the fail- young infants with fast breathing alone can be effec-
ure rates of three clinic-based antibiotic regimens in tively treated with oral amoxicillin as outpatients when
young infants with clinical signs of PSBI (≤59 days old, referral to hospital is not possible [21].
n  =  434) whose families refused hospital referral [18]. The second large RCT from the AFRINEST Group,
Infants were randomly allocated to receive: (i) procaine undertaken in the same countries, compared the cur-
penicillin and gentamicin, reference arm, (ii) ceftriax- rent reference treatment for PSBI of injectable procaine
one or (iii) oral trimethoprim–sulfamethoxazole and benzylpenicillin–gentamicin for 7  days (group A) with
gentamicin for 7  days. Results showed that the effi- a simplified regimen in young infants (≤59  days old,
cacy of a procaine benzylpenicillin–gentamicin com- n  =  3564) when referral was not possible. The follow-
bination was much higher than that of trimethoprim/ ing simplified regimens were investigated: (i) injectable
sulfamethoxazole–gentamicin [treatment failure was gentamicin and oral amoxicillin for 7  days (group B),
significantly higher with trimethoprim/sulfamethoxaz- (ii) injectable procaine benzylpenicillin–gentamicin for
ole–gentamicin compared with penicillin–gentamicin 2 days, then oral amoxicillin for 5 days (group C), (iii) or
(relative risk 2.03, 95% confidence interval 1.09–3.79)]. injectable gentamicin for 2 days and oral amoxicillin for
Differences were not significant in the ceftriaxone versus 7 days (group D) [22]. Treatment failed in 67 (8%) infants
penicillin–gentamicin comparison (relative risk 1.69, 95% in group A compared with 51 (6%) in group B (risk dif-
CI 0.89 to 3.23). ference −1.9%, 95% CI −4.4 to 0.1), 65 (8%) in group C
The two SATTs (Simplified Antibiotic Therapy Trial) (risk difference −0.6%, 95% CI −3.1 to 2.0) and 46 (5%) in
were large RCTs, one of which was conducted in five group D (risk difference −2.7%, 95% CI −5.1 to 0.3). The
centres in Bangladesh (four urban hospitals and one results suggest that the three simplified regimens were
urban field) [19] and the other in five centres in Pakistan as effective as injectable procaine benzylpenicillin–gen-
[20]. It included young infants (≤59 days old, n = 2367 tamicin for 7 days on an outpatient basis in young infants
and ≤ 59 days old, n = 2251 per protocol, respectively) with clinical signs of severe infection, without signs of
for whom referral to hospital was not possible. The critical illness, and whose caregivers could not accept
trial compared the standard treatment of injecta- referral for hospital admission.
ble procaine benzylpenicillin–gentamicin for 7  days In these five aforementioned studies [18–22], the
(group A) with two alternative regimens: (i) injectable equivalence margin was predefined at 5%. Based on
gentamicin and oral amoxicillin for 7  days (group B), in vitro data from LMIC on a benzylpenicillin and gen-
and (ii) intramuscular procaine benzylpenicillin and tamicin regimen (~4000 blood culture isolates) [23], a
gentamicin for 2 days, then oral amoxicillin for 5 days significant proportion of bacteraemia is not covered:
(group C). The results suggested that the two alterna- 43% in neonates and 37% in infants of 1–12  months.
tive regimens were as efficacious as the standard regi- However, this was not confirmed by the SATT trial in
men when hospital admission was refused. In the SATT Pakistan which, of the five aforementioned studies, is the
trial in Bangladesh, treatment failed in 78 (10%) infants only one which obtained blood cultures in the majority
in group A compared with 65 (8%) infants in group B of patients (84%) [20]. Thirty-two (86%) of 37 pathogens
and 64 (8%) in group C. The risk difference between tested for antimicrobial susceptibility were sensitive to
groups B and A was −1.5% (95% CI −4.3 to 1.3) and amoxicillin and gentamicin [20]. Interestingly, of the
S6   A. FUCHS ET AL.

2067 blood cultures obtained, only 81 (4%) were posi- an aminoglycoside was not superior to monotherapy
tive for a micro-organism. Overall, mortality was low in with a β-lactam agent alone for managing enterobacte-
the SATT and AFRINEST studies: it was 2% in each group riaceae bacteraemia in children. But patients receiving
comparing the reference treatment of injectable pro- combination therapy had approximately twice the risk
caine benzylpenicillin–gentamicin for 7 days with two of nephrotoxicity compared with those receiving mono-
alternative regimens [19], <1% in each group compar- therapy (odds ratio 2.15, 95% CI 2.09 to 2.21) [29].
ing amoxicillin with benzylpenicillin–gentamicin [20,21] In a study of neonates and young infants (≤59 days
and ≤2% in each group comparing the reference treat- old, n = 265), based on in vitro susceptibilities from iso-
ment of injectable procaine benzylpenicillin–gentamicin lates, third-generation cephalosporins combined with
for 7 days with the three simplified dosing regimens [22]. ampicillin would have been effective for 98.5% of infants
but unnecessarily broad with a third-generation cepha-
losporin use for 83.8% of infants with suspected serious
Drug management in hospital-based neonatal sepsis
bacterial infection [27]. Because of the 20 Enterococcus
Two other studies in the Asian region were found. One, faecalis isolates (7.5% of identified pathogens), intrinsi-
a retrospective study in hospitalised neonates and chil- cally resistant to cephalosporins, third-generation ceph-
dren (≤59 months of age, n = 183) in Bangladesh, inves- alosporin monotherapy was less effective than either
tigated injected ampicillin and gentamicin as a first-line combination (p < 0.001).
combination for the management of sepsis [24]. Another In a retrospective study in which children receiving
single-centre prospective study in India of hospitalised empirical combination therapy were matched 1:1 with
neonates (≤59 months old, n = 90) compared two empir- children receiving empirical monotherapy [31], the
ical regimens: a cloxacillin and amikacin combination 10-day mortality was similar in children (aged > 2 months
(n = 40) versus a cefotaxime and gentamicin combina- to 14  years, n  =  452) receiving empirical combination
tion (n = 50) for at least 10 days in cases of late-onset sep- therapy versus empirical monotherapy (odds ratio 0.84,
sis [25]. The study analyses of these reports are unclear 95% CI 0.28 to 1.71). A survival benefit was observed
and either they do not address the stated primary out- when empirical combination therapy was prescribed
come (mortality between the two groups) or specify the for children growing multidrug-resistant Gram-negative
statistical methods used for analyses, or do not provide organisms (n = 46) in the bloodstream (odds ratio 0.70,
numerical values for non-significant results [24,25]. 95% CI 0.51 to 0.84).
All other studies retrieved since 2012 which compared A systematic review in 2013 assessed β-lactam mon-
the impact of different antibiotic regimens and/or routes otherapy versus β-lactam-aminoglycoside combination
of administration on outcome were undertaken in hospi- therapy in patients with sepsis. It included 69 randomised
talised patients in HIC, mainly in North America. Because and quasi-randomised trials but only four included chil-
of the considerable differences in pathogen spectrum, dren. In trials comparing the same β-lactam, there was no
resistance patterns, but also levels and types of underly- difference between study groups with regard to all-cause
ing diseases, it is unlikely that the results of these studies mortality (Relative Risk RR 0.97, 95% CI 0.73 to 1.30) and
are directly generalisable to LMIC [26,27]. clinical failure ((RR) 1.11, 95% CI 0.95 to 1.29). In studies
comparing different β-lactams, a trend for benefit with
monotherapy for all-cause mortality (RR 0.85, 95% CI 0.71
Third-generation cephalosporin monotherapy versus
to 1.01) and a significant advantage for clinical failure (RR
in combination with another antibiotic
0.75, 95% CI 0.67 to 0.84) was observed, but the studies
Historically, combination therapy has been used to included were generally classified as being of low quality.
increase coverage and because of its potential additive No significant disparities emerged from analyses of par-
clinical effect. While studies tend to show that there is ticipants with Gram-negative infection. Nephrotoxicity
no difference in clinical outcomes or mortality between was significantly less frequent with monotherapy (RR
mono- and combined therapy, increased toxicities with 0.30, 95% CI 0.23 to 0.39) [28].
combination therapy has been documented [28,29].
Four studies since 2012 were found which compared
Evidence for alternative antibiotic treatment options
β-lactam monotherapy with β-lactam combined with
aminoglycoside in hospitalised paediatric patients in One RCT conducted in India compared amikacin mon-
the USA [27,29–31]. otherapy with piperacillin/tazobactam monotherapy as
In the retrospective studies by Berkowitz et al. [30] empirical treatment for suspected EONS (n = 187) [32]. In
(n = 203) and Tama [29] (n = 879), there was no differ- this neonatal unit, amikacin or piperacillin–tazobactam
ence in 30-day mortality between the β-lactam mono- was the standard regimen since reported resistance rates
therapy and the combination therapy of aminoglycoside previously ranged between 86% and 89% for ampicillin,
and β-lactams for Gram-negative bacteria in children. gentamicin and cefotaxime. Treatment failure defined
Combination therapy consisting of a β-lactam agent and as a blood culture isolate resistant to the allocated
 PAEDIATRICS AND INTERNATIONAL CHILD HEALTH   S7

antibiotic or as a change of antibiotic was very low (n = 3 Although the incidence of ototoxicity detected fol-
and n = 2, respectively, p = 0.44). No increased risk or lowing aminoglycoside exposure remains low (1–3%)
significant difference between the two study groups in and less than that reported in adults, gentamicin appears
the incidence of secondary infection within 7  days of to be the least cochleotoxic. The specific association
stopping the study antibiotic was observed, nor any dif- between hearing loss and aminoglycoside exposure
ference in the incidence of fungal sepsis, nor a difference is complicated, mainly owing to the presence of many
in all-cause mortality at days 7 and 28. However, only five other confounding factors in this population, e.g. low
blood cultures were positive. gestational age and birthweight, intrauterine and post-
A retrospective single-centre study in neonates natal infections, neonatal asphyxia, requirement for
(5–37 days old, n = 10) with persistent CoNS bacteraemia prolonged oxygen therapy and respiratory support,
(LONS) investigated the addition of rifampicin to vanco- congenital malformations, family history of hearing
mycin for infection resolution [33]. Bacteraemia persisted impairment, genetic abnormalities [36]. An association
for a median of 9 days (range 6–19) until the initiation with high peak concentration has been suggested in the
of rifampicin. In all cases, the bacteraemia resolved with past but recent studies are not so categorical [35,36].
vancomycin–rifampicin without serious side effects and A recent systematic review considered the risk of gen-
in all patients the blood cultures became negative on tamicin toxicity in neonates treated for PBSI in LMIC with
vancomycin–rifampicin taken 24–72 h after the initiation the WHO recommended first-line antibiotics (gentamicin
of rifampicin. No serious side effects were observed. with penicillin) [37]:

• Six trials reported formal assessments of ototoxic-

Synopsis of international guidelines ity outcomes in neonates treated with gentamicin,
and the pooled estimate for hearing loss was 3%
Table 2 summarises recommendations by international
(95% CI 0 to 7%).
organisations. When selecting empirical treatment regi-
• Nephrotoxicity was assessed in 10 studies but
mens, most guidelines suggest relying on data on antibi-
could not be evaluated owing to variation in the
otic resistance patterns in locally prevalent pathogens at
case definitions used.
the institutional level but do not define how this should
• Estimates of the number of neonates potentially
be done. They recommend individualising empirical
affected by gentamicin toxicity were not under-
antibiotic recommendations according to local antibiotic
taken owing to insufficient data.
protocols and local pathogen susceptibility. There is little
if any detail on how such data are to be used to select The authors concluded that data were insufficient to
treatment regimens. For EONS, most guidelines are in assess the potential for harm in terms of toxicity associ-
line with WHO recommendations: NICE, AAP, BMJ and ated with gentamicin treatment.
BNFc recommend the use of benzylpenicillin or ampi- The volume of distribution of gentamicin is larger in
cillin combined with gentamicin as empirical treatment preterm neonates as a consequence of a higher percent-
and list third-generation cephalosporins as an alterna- age of body water compared with term neonates. Kidney
tive. Of note, guidelines often state that the aim is to function is reduced in preterm neonates owing to incom-
target the most common pathogens in EONS, i.e. group plete nephrogenesis. As a consequence, recent trends
B streptococcus (GBS) and Escherichia coli in HIC. More are in favour of higher doses (>4 mg/kg up to 5 mg/kg)
variability is seen in the suggested empirical treatment with extended dose intervals in preterm neonates (>24 h
for LONS. up to 48 h for the most preterm infants or more accord-
ing to some authors) [38–42] to achieve higher peak con-
centrations for improved efficacy while maintaining low
Dosing consideration
trough concentrations for safety. According to currently
International guidelines differ on dosing regimens for available knowledge, term infants should receive about
gentamicin, from 4 to 5 mg/kg every 24–36 h. Current 4.0–4.5 mg/kg every 24 h [43–45].
WHO guidelines recommend a once-daily dosing reg- However, rates of multidrug-resistant Gram-negative
imen, from 3 to 7.5  mg/kg/day according to age and (MRD GN) infections are increasing worldwide, particu-
birthweight. larly in LMIC. As a result, many enterobacteraciae gen-
Gentamicin has a narrow therapeutic index. Efficacy tamicin MIC are 4 or higher nowadays, compared with
of aminoglycosides has been associated with high peak 0.5 or 1 in the past when dosing recommendations were
concentrations relative to minimum inhibitory concen- developed, and so determining the appropriate dosing
tration (MIC) of the infecting micro-organism with a ratio recommendations has become very challenging. It might
peak concentration/MIC of >8–10, whereas low trough be possible that even higher doses are required to reach
concentrations appear to be associated with reduced risk effective exposure (10× MIC) with longer extended dos-
of nephro- and ototoxicity (at least <2 mg/L, but <1 mg/L ing interval periods (to prevent toxicity). Such question-
is also often advocated) [34,35]. ing emphasises the urgent need for further prospective
S8   A. FUCHS ET AL.

Table 2. Current international guidelines for the empirical treatment of suspected sepsis or blood infection.
Guideline Last update Recommendations
Surviving Sepsis 2012 • Administration of effective intravenous antimicrobials within the first hour of recognition of septic
Campaign(endorsed shock (grade 1B) and severe sepsis without septic shock (grade 1C) is the goal of therapy
by IDSA) • Initial empiric anti-infective therapy of one or more drugs which have activity against all likely
pathogens (bacterial and/or fungal or viral) and penetrate in adequate concentrations into tissues
presumed to be the source of sepsis (grade 1B)
• Combination empirical therapy for neutropenic patients with severe sepsis (grade 2B) and for
patients with difficult-to-treat, multidrug-resistant bacterial pathogens such as acinetobacter
and pseudomonas spp. (grade 2B). For patients with severe infections associated with respiratory
failure and septic shock, combination therapy with an extended spectrum beta-lactam and either
an aminoglycoside or a fluoroquinolone is recommended for P. aeruginosa bacteremia (grade 2B). A
combination of beta-lactam and macrolide for patients with septic shock from bacteraemic Strepto-
coccus pneumoniae infections (grade 2B) is recommended
• Empirical combination therapy should not be administered for more than 3–5 days (grade 2B)
• Duration of therapy typically 7–10 days; longer courses may be appropriate in patients with a slow
clinical response, undrainable foci of infection and bacteremia with S. aureus; also some fungal and
viral infections or immunologic deficiencies, including neutropenia (grade 2C)
• Special pediatric consideration:
• The empiric drug choice should be changed as epidemic and endemic ecologies dictate (grade 1D)
• Clindamycin and anti-toxin therapies for toxic shock syndromes with refractory hypotension (grade
2D)
• Clostridium difficile colitis should be treated with enteral antibiotics if tolerated. Oral vancomycin is
preferred for severe disease (grade 1A)
NICE 2016 • Neonates presenting in hospital with suspected sepsis in their first 72 h: IV benzylpenicillin 25 mg/
kg twice daily (increase to 3 times daily if clinically concerned) and gentamicin (starting dose 5 mg/
kg every 36 h). Minimum 7-day course of IV antibiotics for strong suspicion of sepsis or a positive
blood culture
• Neonates, community-acquired sepsis:
• >40 weeks corrected gestational AGE: ceftriaxone 50 mg/kg once daily unless already receiving an
intravenous calcium infusion at the time
•  ≤ 40 weeks corrected gestational age or receiving an intravenous calcium infusion: cefotaxime
50 mg/kg every 6–12 h, depending on the age of the neonate
• Up to 17 years, community acquired sepsis: ceftriaxone 80 mg/kg once a day with a maximum dose
of 4 g daily at any age
• Up to 17 years, hospital acquired sepsis or patients who are known to have previously been
infected with or colonised with ceftriaxone-resistant bacteria: consult local guidelines for choice of
antibiotic
• For children younger than 3 months, give an additional antibiotic active against listeria (for exam-
ple, ampicillin or amoxicillin)
AAP 2012, 2015 • Early-onset sepsis:
• Broadspectrum antimicrobial agents [ampicillin 150 mg/kg per dose intravenously (IV) every 12 h
and an aminoglycoside (usually gentamicin 4 mg/kg per dose IV every 24 h)]. Once a pathogen is
identified, antimicrobial therapy should be narrowed (unless synergism is needed)
• Third-generation cephalosporins (e.g. cefotaxime) represent a reasonable alternative to an amino-
glycoside. Bacteraemia without an identifiable focus of infection is generally treated for 10 days
Notes:
• Antimicrobial therapy should be discontinued at 48 h in clinical situations in which the probability
of sepsis is low (controversial)
• Risk of resistance to cefotaxime. Owing to excellent CSF penetration, suggest to restrict to infants
with meningitis attributable to Gram-negative organisms
• To cover group B streptococcus (GBS) and Escherichia coli
• Late-onset sepsis admitted from the community: ampicillin 75 mg/kg per dose IV every 6 h and
gentamicin 4 mg/kg per dose IV every 24 h
• Late-onset sepsis, hospitalised since birth: vancomycin: 10 to 20 mg/kg every 12 to 48 h according
serum creatinine level and gentamicin 4 mg/kg per dose IV every 24 h
BMJ Clinical Evidence 2016 Treatment should be initiated with broad-spectrum antibiotic cover appropriate for the prevalent
organisms for each age group and geographical area. This should be changed to an appropriate
narrow-spectrum antibiotic regimen once a causative pathogen is identified
• Early-onset sepsis: cited as example: benzylpenicillin plus gentamicin (from NICE guidelines) OR
ampicillin plus gentamicin or cefotaxime
Note: To cover group GBS and Gram-negative bacilli
Late-onset sepsis: (selective therapy for empirical antibiotics regimen):
• Cited as an example: ampicillin plus gentamicin OR cefotaxime, OR vancomycin plus gentamicin OR
cefotaxime
• Ceftazidime or piperacillin/tazobactam may be added to the empirical regimen if Pseudomonas is
suspected
• Metronidazole or clindamycin may be added to the empirical regimen to cover for anaerobes/ne-
crotising enterocolitis
• Infants and young infants, community-acquired infection:
• Third-generation cephalosporin (e.g. cefotaxime, ceftriaxone)
• Infants and young infants, hospital-acquired infection:
• Extended-spectrum penicillin (e.g. piperacillin/tazobactam) OR carbapenem (e.g. meropenem)
• Additional broadening of this cover (e.g. with gentamicin, ciprofloxacin, or vancomycin) may be
considered depending on case-specific factors. Clindamycin should be used for toxin-induced toxic
shock syndromes with refractory hypotension
 PAEDIATRICS AND INTERNATIONAL CHILD HEALTH   S9

Table 2. (Continued).
Guideline Last update Recommendations
BNFc 2015/16 • Septicaemia in neonates ≤72 h old:
• Benzylpenicillin sodium, 50 mg/kg in neonate under 7 days every 12 h, in neonate 7–28 days every
8 h
• AND
• Gentamicin 5 mg/kg in neonates up to 6 days every 36 h; in neonates 7–28 days: every 24 h
• If Gram-negative septicaemia suspected: ADD cefotaxime IM or IV 25 mg/kg in neonates under
7 days every 12 h, in neonates 7–21 days every 8 h; neonates 21–28 days every 6–8 h; dose is
doubled in severe infection and meningitis
AND stop benzylpenicillin sodium if Gram-negative infection confirmed
• Septicaemia in neonates >72 h old:
• Flucloxacillin, oral 25 mg/kg in neonate under 6 days twice daily; neonates 7–20 days 3 times daily;
neonates 21–28 days 4 times daily; IV 25 mg/kg in neonates under 6 days every 12 h; in neonates
7–20 days every 8 h; in neonates 21–28 days every 6 h; may be doubled in severe infection
• AND
• Gentamicin (see dose above)
• OR Amoxicillin IV 50 mg/kg in neonates under 7 days every 12 h; in neonates 7–28 days every 8 h,
• OR Ampicillin IV 50 mg/kg in neonates up to 6 days every 12 h; in neonates 7–20 days every 8 h; in
neonates 21–28 days every 6 h
• AND
• Cefotaxime (see dose above)
• For 7 days
• Child 1 month – 18 years, community-acquired sepsis:
• Aminoglycoside, e.g. gentamicin initially 7 mg/kg, then adjusted according to serum gentamicin
concentration or multiple daily dose regimen with child aged 1 month–12 years: 2.5 mg/kg every
8 h; child 12–18 years 2 mg/kg every 8 h
• AND
• Amoxicillin 50 mg/kg every 4–6 h (max. 2 g every 4 h)
• OR Ampicillin 50 mg/kg every 4–6 h (max. per dose 2 g every 4 h)
• OR Cefotaxime alone 50 mg/kg every 8–12 h; increase to every 6 h in very severe infections and
meningitis (max. 12 g daily) OR ceftriaxone alone IM or IV 1 g daily, increased to 2–4 g daily,
increased dose to be used in severe infections
• If pseudomonas or resistant micro-organism suspected: broad-spectrum anti-pseudomonal
beta-lactam [piperacillin–tazobactam: 90 mg/kg (max. 4.5 g) every 6 h]
• If anaerobic infection suspected, ADD metronidazole, oral in child 1–2 months 7.5 mg/kg every
12 h; in child 2 months–12 years 7.5 mg/kg (max. 400 mg) every 8 h; in child 12–18 years
400 mg every 8 h; rectal in child 1 month–1 year 125 mg 3 times daily for 3 days, then twice daily
thereafter; in child 1–5 years 250 mg 3 times daily for 3 days, then twice daily thereafter; in child
5–10 years 500 mg 3 times daily for 3 days then twice daily thereafter; in child 10–18 years 1 g
3 times daily for 3 days then twice daily thereafter; IV in child 1–2 months 15 mg/kg as a single
loading dose followed after 8 h by 7.5 mg/kg every 8 h; in child 2 months–18 years 7.5 mg/kg
(max. 500 mg) every 8 h
• If Gram-positive infection suspected, ADD glucloxacillin oral in child 1 month–1 year 62.5–125 mg
4 times daily; in child 2–9 years 125–250 mg 4 times daily; in child 10–17 years 250–500 mg 4
times daily; IM in child 1 month–18 years 12.5–25 mg/kg every 6 h (max. 500 mg every 6 h); IV in
child 1 month–18 years 12.5–25 mg/kg every 6 h (max. 1 g every 6 h); may be doubled in severe
infection
• OR Vancomycin 15 mg every 8 h (max. 2 g per day)
• OR Teicoplanin initially 10 mg/kg every 12 h (max. 400 mg per dose) for 3 doses, then (by IV infu-
sion or IM injection) 6 mg/kg once daily (max. 400 mg per dose); (After initial 3 doses subsequent
doses can be given by IM route, if necessary, although, IV is preferable). For severe infection:
Initially 10 mg/kg every 12 h for 3 doses, 10 mg/kg once daily for 5 days
• Child 1 month–18 years, hospital-acquired sepsis:
• Broadspectrum anti-pseudomonal beta-lactam: piperacillin-tazobactam 90 mg/kg (max. 4.5 g)
every 6 h OR ticarcillin/clavulanic acid, child under 40 kg: 80 mg/kg every 8 h (increased if neces-
sary to 80 mg/kg every 6 h, increased frequency used for more severe infections); child ≥40 kg:
3.2 g every 6–8 h (increased if necessary to 3.2 g every 4 h, increased frequency for more severe
infections)
• OR Imipenem/cilastatin, in child 1–2 months IV 20 mg/kg every 6 h; in child 3 months–17 years IV
15 mg/kg every 6 h (max. 500 mg per dose) (life-threatening infection: 25 mg/kg every 6 h, max.
1 g per dose)
• OR meropenem, in child 1 month–11 years (bodyweight ≥50 kg) 2 g every 8 h; in child 12–17 years
2 g every 8 h
• If pseudomonas or resistant micro-organism suspected ADD aminoglycoside (see dose above)
• If MRSA suspected ADD vancomycin OR teicoplanin (see dose above)
• If anaerobic infection suspected ADD metronidazole (see dose above) to a broadspectrum cepha-
losporin (see dose above for cefotaxime and ceftriaxone) for 5 days

Note: IDSA – Infectious Diseases Society of America.

studies in populations with MRD GN specifically collect- patients to the risk of toxicity, especially when treatment
ing PBSI isolates (there are few isolates to date) with MICs is prolonged (>48 h), because of the possibility of drug
to gentamicin, actual dosing and peak concentration/ accumulation. However, providing various dosing inter-
trough estimation, and both clinical outcomes (infection vals that stratify neonates may complicate feasibility and
resolution, toxicity). acceptability.
Using the 24-h dosing interval for all neonates Pharmacokinetics data for neonates are scarce and
suggested by WHO may expose a large proportion of so it is difficult to summarise current dosing regimens
S10   A. FUCHS ET AL.

Table 3. Safety data summary for empirical antibiotic treatment used in possible serious bacterial infection.
Antibiotic Adverse events and contraindications Relevant interactions
Natural penicillin: Serious toxicity is rare in association with penicillin therapy Concomitant use of bacteriostatic antibac-
Benzylpenicillin sodium • Diarrhoea is the most common terial agents (i.e. tetracyclines, sulfona-
Aminopenicillin: • Incidence is increased following use of amoxicillin/clavulanate (broad- mides, erythromycins, chloramphenicol)
Ampicillin spectrum therapy) compared with the use of amoxicillin should be avoided
Amoxicillin • There is some evidence that different ratios of the amoxicillin to Caution should also be exerted with the
Antistaphylococcal penicillin: clavulanic acid components may affect the proportion of children who use of certain other β-lactam antibiot-
Cloxacillin experience diarrhoea ics, namely cephalosporins (especially
• The incidence of diarrhoea following amoxicillin use was significantly 1st- and 2nd-generation, e.g. cefalex-
lower for b.i.d. than with t.i.d. regimen (6.7–9.6 vs. 10.3–26.7%, respec- in, cefaclor) and carbapenems (e.g.
tively) in one study meropenem) as cross-reactivity in the
• Drug-induced rash, hypersensitivity, anaphylaxis allergies between these classes can occur
• Penicillin allergy has been estimated to affect 1–10% of people given (but its importance has frequently been
penicillins. True incidence of penicillin allergy in patients who report overstated)
that they are allergic is actually <10%
• Very rarely, seizures
• Important consideration if higher than usual doses or dose frequencies,
or following rapid administration of high intravenous doses (therefore
should be infused over at least 30 min)
• Electrolyte imbalances (e.g. sodium salts)
• Hepatotoxicity, mild/moderate gastro-intestinal effects
3rd-generation cephalosporin: • Mainly hypersensitivity and gastro-intestinal effects (mostly diarrhoea) Concurrent use of cephalosporin with:
Cefotaxime • •Rarely causes nephrotoxicity or seizures in neonates • Nephrotoxic drugs (aminoglycosides)
increased risk of nephrotoxicity
• Warfarin may result in an increased risk
of bleeding
3rd-generation cephalosporin: • Mainly hypersensitivity and gastro-intestinal effects (mostly diarrhoea) Concurrent use of cephalosporin with:
Ceftriaxone • Hyperbilirubinemia (ability of ceftriaxone to displace bilirubin from • Nephrotoxic drugs (aminoglycosides)
serum albumin binding sites) increased risk of nephrotoxicity
• Cholestasis and pseudolithiasis owing to biliary sludging (with high • Warfarin may result in an increased risk
concentration of ceftriaxone in the system) of bleeding
• Concomitant administration of intravenous ceftriaxone and calci-
um-containing solutions is not recommended since concurrent ad-
ministration with calcium-containing solutions may produce insoluble
precipitates (ceftriaxone-calcium salts) leading to cardiorespiratory
complications
Broadspectrum antibiotics • Increased risk of invasive candidiasis and death
and prolonged duration of • Increased risks of necrotising enterocolitis (NEC), death and late-onset
antibiotic therapy sepsis

of β-lactams in this review. Antibacterial activity of main pathogens are CoNS, responsible for half of the
β-lactams is best characterised by time-dependent kill- episodes. Other important aetiological agents are E.
ing. The pharmacokinetic-pharmacodynamic parame- coli, klebsiella spp. and candida spp. Less common
ter that correlates with the clinical and bacteriological causes of LONS include S. aureus, enterococcus spp. and
efficacy of β-lactam antibiotics is the percentage of Pseudomonas aeruginosa [4,56].
time that the serum free drug concentration exceeds Aetiological data from LMIC, particularly from rural,
the MIC for the pathogen (time above the MIC). Overall, community-based studies, are very limited. In systematic
β-lactams present a favourable safety profile and most reviews on this topic, the commonest causes of neonatal
dosing recommendation suggested by WHO are in line bacteraemia in LMIC are S. aureus, E. coli and klebsiella
with current knowledge [45]. spp. and, in older infants, S. aureus, Streptococcus pneu-
moniae, klebsiella spp. and E. coli, and non-typhoidal
salmonella [23,57]. Although there are some similari-
Review of harm and toxicity – safety
ties between community- and hospital-acquired sepsis,
Safety and harm toxicity data for empirical antibi- available data are of insufficient quality to justify firm
otic treatment used in PSBI are summarised in Table 3 conclusions [4]. Acinetobacter spp., for example, appear
[37,46–55]. to be predominant in some regions [58,59], while the
incidence is very low in other regions. GBS is responsible
for only 2–8% of cases in LMIC. It is possible that infants
Pathogen distribution and antimicrobial resistance
with GBS infection are underreported, since this patho-
patterns
gen usually presents very early in life and infected new-
Pathogen distribution.  In HIC, the most common borns might die or be adequately treated before blood
causes of EONS are GBS and E. coli. The remaining cultures or other relevant microbiological samples are
cases of EONS are caused by Staphylococcus aureus, obtained. CoNS is responsible for a lower proportion
coagulase-negative staphylococci (CoNS), Listeria of hospital-acquired infections than in HIC [4], and this
monocytogenes and other Gram-negative bacteria [4]. may be related to the use of invasive medical devices,
In LONS (mainly in very low-birthweight infants), the e.g. central venous catheters. Interestingly, in the SATT
 PAEDIATRICS AND INTERNATIONAL CHILD HEALTH   S11

Figure 1. Pathogen distribution for studies conducted in a specific setting and reported after 2005 in neonates.
Notes: Staaur, S. aureus; stacoa, coagulase-negative staphylococci; strepspp, streptococci; straga, S. agalactiae; entcocspp, enterococci; other Gpos, other
Gram-positive pathogens; esccol, E. coli; klespp, klebsiella spp; psespp, pseudomonas spp; entbacspp, enterobacter spp; acispp, acinetobacter spp., other
Gneg: other Gram-negative pathogens.

Figure 2. Pathogen distribution for studies conducted in a specific setting and reported after 2005 in children.
Notes: Staaur, S. aureus; stacoa, coagulase-negative staphylococci; strpne, S. pneumonia; strepspp, streptococci; strpyo, S. pyogenes; entcocspp, enterococci;
other Gpos, other Gram-positive pathogens; esccol, E. coli; klespp, klebsiella spp; psespp, pseudomonas spp; entbacspp, enterobacter spp; acispp,
acinetobacter spp; salspp, salmonella spp; other Gneg, other Gram-negative pathogens.

in Pakistan which obtained blood cultures from 2067 Antimicrobial resistance patterns
(84%) infants, a high frequency of campylobacter was
Only very limited reliable data on antimicrobial suscepti-
found in the absence of diarrhoea (22% of the positive
bility are available from Asia, Latin America and Africa. It
blood cultures) [20].
is evident from existing summaries of the data that there
Regarding local variations, Figures 1 (neonates) and
is considerable antibiotic resistance to many commonly
2 (children) show the pathogen distribution for studies
used antibiotics with variations both between and within
conducted in specific LMIC reported after 2005. These
regions in LMIC [57,60].
data demonstrate the heterogeneity likely to be encoun-
According to a systematic review and meta-anal-
tered in settings for which the WHO essential medicines
ysis by Downie et al. [23], more than 40% of cases of
list is relevant. In particular, it is not presently possible
community-acquired neonatal bacteraemia in LMIC are
to definitively delineate the specific role played by bac-
resistant or have reduced susceptibility to a combina-
teria which are difficult to treat, e.g. Klebsiella spp. and
tion of penicillin and gentamicin and to third-generation
Acinetobacter spp. The relative incidence of these path-
cephalosporins, thus suggesting that third-generation
ogens may have a considerable impact on the probable
cephalosporins are no more effective in treating sep-
cover by different empirical regimens as certain bac-
sis than the currently recommended antibiotics, ben-
teria are intrinsically resistant or display high levels of
zylpenicillin and gentamicin. More than 35% of cases
acquired resistance to commonly used antibiotics, which
of community-acquired bacteraemia in infants aged
lowers their coverage.
S12   A. FUCHS ET AL.

1–12 months are resistant or have reduced susceptibility high doses of aminoglycoside to target high MIC, while
to the combination of penicillin and gentamicin and to preventing drug accumulation over days and thus poten-
third-generation cephalosporins. In neonates, the gaps tial toxicity (mostly nephrotoxicity) based on a once-daily
in antibiotic coverage with either benzylpenicillin/ampi- dosing regimen. However, these studies did not evaluate
cillin and gentamicin or third-generation cephalospor- regimens and/or agents outside of those currently on
ins regimens were mostly in infections owing to enteric the essential medicines list. Also, they were limited to a
Gram-negative bacilli, particularly klebsiella spp. [23]. specific subpopulation of infants and children (≤59 days
However, in the Pakistan SATT trial, it was reassuring that old, weight ≥ 1500 g) with suspected sepsis. Enrolment
the majority of micro-organisms tested (32/37) were sus- according to the diagnosis of PSBI was based on the
ceptible to gentamicin and amoxicillin [20]. presence of any sign of clinical severe infection except
Similar findings were reported in a 2015 systematic signs of critical illness (unconsciousness and convulsions)
review of studies which estimated AMR rates in Gram- [19–22]. As it was a community-based, low-risk study,
negative bloodstream infections in children in LMIC a considerable proportion of treated infants might not
[58]. Gram-negative bacteria accounted for 67% of all have had a bacterial infection. Indeed, in the single trial
episodes. The predominance of klebsiella spp. with that performed blood cultures (Pakistan SATT trial), only
a high prevalence of resistance to gentamicin in Asia 4% were positive for a pathogen [20]. It is also unclear
(69%, Interquartile Range (IQR) 19–95%) and Africa (54%, what the rates of antimicrobial resistance were in these
IQR 0–68%) and the overall level of resistance of Gram- settings, but sensitivities to the aminoglycoside-based
negative bacteria to third-generation cephalosporins regimens are likely to be higher than in facility-based
(Asia 84%, IQR 45–95%; Africa 50%, IQR 0–87%) were settings, and the results of susceptibility testing in the
very concerning. Pakistan SATT trial tend to confirm this, although the
All reviews published to date note the very low num- number of samples tested (37) was very low. In the
ber of studies with adequate data. In particular, many of Pakistan SATT, the presence of bacteraemia did not pre-
the studies reviewed had a high risk of bias with substan- dict treatment failure in per-protocol infants [10 (13%)
tial uncertainty about how representative the data are for of 75 children with bacteraemia and 227 (12%) of 1618
each setting. There are concerns that the data published without bacteraemia had treatment failure (risk differ-
are mainly from larger tertiary neonatal units, many of ence 1.03, 95% CI −6.8 to 8.9)]. Overall, studies assess-
which might have higher rates of resistance owing to ing the efficacy of specific antibiotic regimens in infants
a nosocomial outbreak. In addition, virtually no clinical and children with blood culture-proven sepsis and/or the
outcome data are reported (a finding confirmed by this effectiveness of different regimens in infants and chil-
review), particularly relating to the underlying disease, dren with nosocomial sepsis are virtually lacking. Given
pathogen phenotype, empirical antibiotic treatment the challenges of increasing levels of antibiotic resistance
and clinical outcome. This imposes major limitations to in LMIC (based on evaluation of blood cultures usually
selecting empirical regimens on the basis of their clinical collected from inpatients or at least on presentation at
impact. hospital) and the considerable variation in the patterns
of bacteria causing bacteraemia, for example, with the
predominance of klebsiella spp. and acinetobacter spp.,
Discussion
it might be expected that additional antibiotic options
Since 2012, only suspected community neonatal sepsis will be required. Closing the existing gaps in evidence
has been addressed and there have been no adequate must be made a priority so that any additions/changes
studies in other settings. Five adequately designed to the recommended regimens are based on robust data.
and powered studies which compared antibiotic treat- All the other trials addressing antibiotic regimens in neo-
ments in a low-risk community setting in neonates and natal and paediatric sepsis that were identified were
young infants (0–59 days) in LMICs were found [18–22]. disappointing in terms of design (often retrospective),
They addressed potential simplifications of the current power (low sample size) and outcomes (not performed in
WHO treatment of reference, particularly for infants for LMIC, method not always well-reported, drug dose often
whom admission to inpatient care was not acceptable not reported). In addition, it is essential to have more
or possible. In this group of infants, evidence suggests data on causative pathogens and their susceptibilities
that treatment regimens could potentially be simplified, in order to understand which treatment regimens could
for example, by using injectable gentamicin for 2 days be effective and should be prioritised for further inves-
and oral amoxicillin for 7 days for young infants [22]. We tigation. There are virtually no relevant studies with rig-
hypothesise that the regimen of injectable gentamicin orous methods to direct therapeutic options in children.
for 2  days and oral amoxicillin for 7  days would offer Fundamental concepts of effective antimicrobial therapy
advantages over others investigated by requiring fewer in critically ill children (proper culture techniques, timely
invasive procedures with only two injections, promoting initiation of therapy, selection of agents with a high
treatment adherence, and by allowing administration of likelihood of susceptibility and sufficient penetration
 PAEDIATRICS AND INTERNATIONAL CHILD HEALTH   S13

to the site of infection, adequate doses and intervals antimicrobials in children, developing the evidence base for
to enhance bactericidal activity) are often impractical paediatric antimicrobials and antimicrobial stewardship.
in LMIC owing to limited resources and infrastructure.
Johannes N. van den Anker is the Eckenstein-Geigy distin-
Overall, a recommendation to amend the current WHO guished Professor of Paediatric Pharmacology, University
antibiotic regimens for PSBI cannot be made. of Basel Children’s Hospital, Switzerland. His research
The utility of third-generation cephalosporins as sec- interests include developmental, neonatal and paediatric
ond-line treatment is under debate based on the sparse pharmacology.
microbiological surveillance data available. Additionally,
there is major concern about the widespread use of
third-generation cephalosporins and selection for ORCID
multidrug Gram-negative infections in neonatal units. Shrey Mathur   http://orcid.org/0000-0002-2809-8244
Further efforts are urgently needed to investigate alter-
native older off-patent therapeutic antimicrobials such
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