Paediatric drug

optimization
for antibiotics
Meeting report

30 NOVEMBER, 5-7 DECEMBER 2022

Paediatric drug
optimization
for antibiotics
Meeting report

30 NOVEMBER, 5-7 DECEMBER 2022

Paediatric drug optimization for antibiotics: meeting report, 30 November,
5-7 December 2022
ISBN 978-92-4-006893-3 (electronic version)
ISBN 978-92-4-006894-0 (print version)
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Contents

Acknowledgments iv
The need for paediatric drug optimization 1
Paediatric drug optimization for antibiotics 2
Objectives 4
Method 5
Summary of discussion 7
Moving forward and next steps 14
References 15
Annex 1. Meeting agenda 17
Annex 2. List of meeting participants 19

iii
 Acknowledgments

The writing of this meeting report was led by

Brian Jonat, with contributions from Alasdair
Bamford, Jennifer Cohn, Valeria Gigante, Benedikt
Huttner, Tiziana Masini, Martina Penazzato, Hatim
Sati, Michael Sharland and Wilson Were. WHO
acknowledges all speakers and participants who
joined and contributed to the paediatric drug
optimization for antibiotics meeting.

iv
The need for paediatric
drug optimization
The development of medicines for Paediatric drug optimization (PADO) exercises
children lags unacceptably behind to identify key priority products and their
preferred product characteristics for research
that for adults by nearly a decade (1).
and development have been successfully
Following the resolution at the 69th undertaken for HIV, hepatitis C and tuberculosis,
World Health Assembly on promoting demonstrating their potential and impact
innovation and access to quality, safe, to accelerate access to optimal formulations
in the context of fragmented, small markets
efficacious and affordable medicines
for medicines for children. To provide further
for children, WHO and partners have guidance to support similar processes for
increased their efforts to deliver on this optimizing drugs for children in other disease
global commitment and have scaled up areas, GAP-f has published a guidance
activities to ensure that age-appropriate document that is intended for all WHO technical
units and all stakeholders involved describing
formulations are available for children (2).
how to undertake a PADO process and adapt it
The Global Accelerator for Paediatric to the specific needs of each disease area (4).
Formulations Network (GAP-f), a WHO-hosted
network, works across the life cycle of drug
development to give priority to, evaluate,
develop and deliver optimal formulations for
children (3). Priority-setting is the first step to
enable a targeted approach to research and
development. Developing a prioritized drug
portfolio of the most needed formulations for
children is essential to streamline researchers’
and supplier’s efforts and resources around
specific dosage forms and formulations that
address most urgent needs for children. This
is particularly important given that the market
for medicines for children is often small and/or
fragmented, resulting in limited volumes with
potential market failures.

1
 Paediatric drug optimization
for antibiotics
Bacterial infections, especially
pneumonia, neonatal sepsis and
gastrointestinal infections, are the
leading cause of infectious mortality
among children younger than five
years worldwide (5).
Despite the existence of many different
classes of antibiotics, multiple challenges exist
in treating people with bacterial infections,
including lack of access to existing medicines
and to high-quality microbiology laboratory
services, especially in low- and middle-income
countries. This is all complicated by the rise
of development and spread of antibiotic
resistance and the inadequate pipeline of new
antibiotics as well as the lack of age-appropriate
formulations. WHO has developed multiple
avenues to provide guidance for public health
organizations and practitioners on developing
and using antibiotics for children.
2
ANTIBIOTICS WITH AN EXISTING
LICENCE FOR CHILDREN
Every two years, WHO publishes the WHO
Model List of Essential Medicines (WHO EML)
and the WHO Model List of Essential Medicines
for Children (WHO EMLc) (6,7). The medicines
included in these lists are selected with “due
regard to disease prevalence and public health
relevance, evidence of efficacy and safety and
comparative cost–effectiveness” (8). The WHO
EMLc was first published in 2007 and has been
updated every two years since then and includes
medicines that satisfy the priority health care
needs of children and young adolescents aged
up to 12 years globally.
To assist in developing tools for antibiotic
stewardship at the local, national and global
levels and to limit the spread of and reduce
antimicrobial resistance, WHO developed the
Access, Watch, Reserve (AWaRe) classification
of antibiotics (9). In this system, antibiotics are
classified into groups according to their potential
for resistance to emphasize the importance of
their appropriate use.
• The Access group includes antibiotics
that have activity against a wide range
of commonly encountered susceptible
pathogens while also showing lower
resistance potential than antibiotics in
the other groups.
• The Watch group includes antibiotic classes
that have higher resistance potential and
includes most of the highest-priority agents
among the critically important antimicrobials
for human medicine and/or antibiotics that
are at relatively high risk of selection of
bacterial resistance.
• The Reserve group includes antibiotics and
antibiotic classes that should be reserved for
treating infections confirmed or suspected
of being caused by multidrug-resistant
organisms. The Reserve group should be
treated as last-resort options.
The WHO EML and WHO EMLc alongside PIPELINE ANTIBIOTICS
the AWaRe classification have provided global
guidance on setting priorities for using available WHO has already undertaken extensive work
antibiotics. to identify priority bacterial pathogens for
which new antibiotics are urgently needed (13).
Alongside the WHO EML and WHO EMLc, WHO
Most of the pathogens on the WHO Bacterial
has also published the WHO AWaRe antibiotic
Priority Pathogens List, including those that are
book, which provides short, clinical guidance
listed in the “critical” category, are of concern
on managing more than 30 common infections
for neonates and other children.1 Moreover, the
among newborns and children in the hospital
WHO antibacterial pipeline analyses published
and primary care setting, including the optimal
annually since 2017 provide in-depth overviews
choice of antibiotic, dose and duration (10).
of the current antibacterial agents in preclinical
In 2021–2022, a comprehensive analysis of the and clinical development (14).
2021 WHO EMLc was conducted in conjunction
When considering antibiotics in the pipeline
with GAP-f partners to systematically assess
to be prioritized for their development in the
the age-appropriateness of formulations of
paediatric population, it is essential to consider
listed medicines to inform the 2023 update of
the potential public health impact for treating
the WHO EMLc (11). Numerous formulations for
key clinical infections with the highest mortality
potential addition to or removal from the WHO
and morbidity among neonates and other
EMLc were identified, and recommendations
children, along with the most likely causative
for proposed changes have been submitted
pathogens among neonates and other children
for consideration by the next WHO EML expert
as well as the most common phenotypic
committee (12). In addition, formulation gaps,
and genotypic resistance patterns. Other
including among antibiotics, were identified
considerations include whether intravenous
during the project (where an age-appropriate
and/or oral administration is required and
formulation does not appear to be available or
whether unique children-specific toxicities have
exist). This work has informed the existing PADO
been identified or the toxicity profile already
antibiotics exercise.
defined in the adult population is of concern
for children. The epidemiology and disease
burden associated with antimicrobial resistance
among children varies between high- and low-
income settings as well as within settings, and
considering this variation is also fundamental.

To address the remaining research gaps that hinder availability

of appropriate therapeutics for children with bacterial infections,
WHO convened and facilitated a PADO exercise for antibiotics
to ensure that research and development efforts in this field
target a priority list of medicines, ensuring that children with
bacterial infections can also rapidly benefit from safe, effective
and accessible treatment options.

1 “Critical” pathogens are the highest priority for new drug development based on a composite of mortality, health-care burden, 3
resistance, transmissibility, preventability, treatability and current pipeline.
 Objectives

The purpose of the paediatric drug optimization for

antibiotics founding meetings was:
• to identify antibiotics with an approved indication for
children for which age-appropriate formulations are
missing that need to be given priority for development;
• to identify pipeline or approved antibiotics without
indication for children to be given priority for further
investigation and development for children; and
• to develop a clear research agenda to support and
enable future antibiotics optimization work for children,
with the goal of ensuring that the unique needs of
children are effectively addressed.

More specifically, the goal of the paediatric drug

optimization for antibiotics exercise was to develop:
• A PADO priority list – including formulations to
be investigated and developed with a time horizon
of 3-5 years
• A PADO watch list – containing promising candidates
for investigation and development for children with
a time horizon of 5-10 years
This will enable alignment between funders, procurers,
market-coordination entities, researchers, academics,
product development partnerships and regulators on
priority products to be investigated and developed.

4
Method
SCOPE
Available resources published by WHO for
managing infectious diseases in children
were reviewed (including Integrated
Community Case Management (iCCM),
integrated management of childhood illness
(IMCI), hospital pocket book, the WHO EML
and the WHO AWaRe classification).
The priority-setting exercise for antibiotics
for children was undertaken separately for
antibiotics with an existing licence for children
and for antibiotics in clinical development.
For the first category, antibiotics listed on the
WHO EMLc were considered, for which a gap in
the availability of age-appropriate formulations
had been identified in the context of previous
work undertaken by WHO. The priority-setting
exercise for antibiotics for children in clinical
development considered both antibiotics that
have received a marketing authorization for
adults in the past 10 years but are not authorized
for children and those under development
(in Phase 2 and 3) for adults with or without
paediatric investigation plans already defined.
For this second category of antibiotics, the WHO
antibacterial pipeline analysis was considered as
a reference document (14).
PREPARATORY WORK
Before the meeting, two dedicated frameworks
(Table 1) were developed with the input of
meeting participants, who were invited to rank
the attributes in each framework to facilitate
priority-setting decisions.
The frameworks were populated with
information collected from relevant WHO
documents and available product labels and
shared with meeting participants before the
meeting.
MEETING PROCEEDINGS
The PADO for antibiotics meeting was held
virtually on 30 November 2022 (introductory
meeting), 5 December 2022 (antibiotics with
existing licence for children) and 7 December
2022 (pipeline antibiotics) and brought together
academics, researchers, clinical experts,
paediatricians, regulators, funders and other
key stakeholders involved in research and
development related to antibiotics. Conflict-
of-interest declarations were collected for all
participants and closely reviewed. Participants
with relevant conflicts were asked to
participate as observers or resource persons.
Consensus on priority antibiotics to be further
investigated and/or developed for infants,
children and adolescents was reached through
working group discussions informed by the
pre-populated framework. The final PADO
priority and watch lists for antibiotics, as well
as corresponding research agendas, were
developed during a final, plenary session.
5
 Table 1: attributes included in the prioritization framework of PADO for antibiotics
ANTIBIOTICS WITH AN EXISTING
LICENCE FOR CHILDREN
Public health relevance
Flexibility of indication and activity across
anatomic sites
Activity against resistant bacteria
(including anticipated impact on usability
in different regions)
Cross-resistance to other antibiotics used
Barriers to developing resistance
Drug–drug interactions
Patient acceptability of available formulations
Age-appropriateness of available formulations
Additional aspects (such as issues with storage
of available formulations)
6
PIPELINE ANTIBIOTICS
Efficacy
Safety and toxicity (including: signals from
preclinical studies, in vitro and animal models;
side-effects; tolerability and effect of organ
impairment on drug metabolism and excretion;
used in children before (for other indications))
Activity against bacteria with difficult to treat
resistance profiles
Public health relevance
Patient acceptability
Effective across anatomic sites
(eg, central nervous system, lungs)
Cross resistance to other available antibiotics
Variety of conditions and pathogens targeted
Need for clinical or laboratory monitoring for
signs of efficacy or toxicity
Required screening before initiating treatment
Drug-drug interactions
Summary of discussion
OVERVIEW OF EPIDEMIOLOGY
AND CLINICAL MANAGEMENT
The current epidemiological background and
WHO clinical guidelines for antibiotic use were
reviewed. Neonatal sepsis, pneumonia and
gastrointestinal infections were identified as
bacterial infections that contribute greatly to
worldwide mortality for children younger than
five years (15). Overall, communicable diseases
are responsible for many deaths and much
disability among children worldwide. Many of
the resources and guidance from WHO seek
to mitigate the significant effect of infectious
pathology on children (16,17).
Antibiotic resistance is also a major threat to
preventing and managing communicable
diseases among adults and children. Second-
and third-line antibiotic use has increased in
recent years, as has the subsequent potential for
antibiotic and multidrug resistance (18). Based
on available evidence and experts’ input, WHO
has included and ranked several bacteria in
the first ever published WHO Bacterial Priority
Pathogens List in 2017, which is going to be
updated in 2023. These bacteria should be the
priority targets for antibiotics in development
due to their resistance profiles and public
health burden, especially for children (13,19).
One example is bacterial infections caused
by multidrug-resistant Enterobacterales. The
WHO priority-setting of bacterial pathogens in
the WHO Bacterial Priority Pathogens List has
shown to be effective in informing research and
development as well as public health policy.
Both public and private entities use the WHO
Bacterial Priority Pathogens List to inform their
research and development investment decisions
in new antibacterial agents as well as public
health programme work.
Many low- and middle-income countries do
not have national or regional guidelines on
managing bacterial infections, underlying the
importance of global tools such as the AWaRe
antibiotic book. The recommended antibiotics
include oral and parenteral formulations and are
often age-dependent. Medications are classified
based on resistance potential and effectiveness.
Overall, guidance to clinical care is based on
infectious indication, severity of illness, patient
risk factors and local resistance patterns.
The documents reviewed provide guidance
related to several conditions relevant to children,
including pneumonia and empyema, otitis
media and mastoiditis, meningitis, dysentery
and sepsis.
Although existing antibiotics, as a precondition
to marketing authorization, demonstrate a
favourable benefit–risk ratio accounting for
an acceptable safety profile, efficacy against
common infections and public health relevance,
many antibiotics are not indicated for use in
children and do not exist in optimal formulations
for children. When suitable formulations for
children are designed, several factors should be
considered, including patient tolerability, ease
of administration by the caregiver or health-
care providers, frequency of dosing, the need
for special conditions during the compounding
process and the need for time-sensitive
preparatory steps at the time of administration.
Certain formulations can face logistical barriers
to use. For example, the need for reconstitution
or refrigeration may be a significant barrier to
widespread use in low- and middle-income
countries. Parenteral medications require
intravenous access and health-care worker
expertise in administration. Excipients used for
oral liquid or syrup formulation stability may
be unsuitable for children. Optimizing these
aspects of drug formulation is essential to
ensure appropriate use of effective antibiotics
for children. In addition, existing antibiotics
may not have sufficient activity against certain
pathogens or resistance mechanisms that are
more commonly found in low- and middle-
income countries. 7
 PAEDIATRIC DRUG PAEDIATRIC DRUG OPTIMIZATION
PRIORITY LIST AND RATIONALE
OPTIMIZATION PRIORITY
The priority drugs for PADO antibiotics were:
AND WATCH LISTS
• amoxicillin-clavulanic acid
The priority-setting process was conducted for
both authorized antibiotics with indications for • nitrofurantoin
children and antibiotics under development that • azithromycin
have not received marketing authorization for • cefiderocol.
children and/or adults.
Amoxicillin-clavulanic acid is a combination of a
For the first, a subset of those included beta-lactam with a beta-lactamase inhibitor. It
in the WHO EMLc with appropriateness has widespread use among children and is the
gaps was considered. The authorized WHO EMLc first choice for community acquired
antibiotics reviewed, which have a licence pneumonia (severe), complicated intraabdominal
for children, included: infections (mild to moderate), hospital acquired
pneumonia, low-risk febrile neutropenia, lower
• amoxicillin-clavulanic acid
urinary tract infections, sinusitis, skin and
• clindamycin soft tissue infections, highlighting its public
• cloxacillin health importance. It has an acceptable safety
• nitrofurantoin and toxicity profile, with minimal side-effects
(most common: diarrhoea or loose stool) and
• sulfamethoxazole-trimethoprim
drug–drug interactions. The combination is
• trimethoprim available as oral and parenteral formulations, and
• azithromycin dispersible tablets are in current production (20).
• ciprofloxacin Downsides to this medication include lack of
consistent activity against extended-spectrum
• clarithromycin
beta-lactamase-producing strains and frequent
• vancomycin (oral). cross- resistance with other antibiotics, such
The pipeline antibiotics (including as cephalosporins and other beta-lactams.
antibiotics under development in Phase 2 However, for most common community-acquired
and 3 or recently authorized in adults but infections, amoxicillin-clavulanic acid maintains
not in children) reviewed included: activity. More data are needed to refine specific
renal dosing for children. Additionally, not all
• cefiderocol a–c
formulations are interchangeable, resulting in
• meropenem-vaborbactam a–c inaccuracies in dosing ratios (subtherapeutic
• plazomicin c or supratherapeutic concentrations), especially in
• zidebactam-cefepime d settings with limited training and guidelines.

• XNW4107-imipenem-cilastin d Nitrofurantoin is a nitrofuran-class antibiotic.

• durlobactam-sulbactam d It is the WHO EMLc first choice for urinary tract
infections, one of the most common types of
• taniborbactam-cefepime d
bacterial infections in children. Given its unique
• enmetazobactam-cefepime d class, there is limited cross-resistance to this
• aztreonam-avibactam d. medication from other antibiotics. It has good
activity against most Enterobacterales species
that cause urinary tract infections, including
a Included in the WHO List of Essential Medicines.
most strains producing extended spectrum
b Approved for adults by the European Medicines Agency.
beta-lactamases as well as Enterococcus,
c Approved for adults by the United States Food and
Drug Administration. although resistance is seen in some multidrug-
d Pipeline antibiotics. resistant pathogens. Nitrofurantoin’s safety
profile for adults is acceptable (most common
adverse events: nausea and headache), but it
is contraindicated for children younger than
one month (because of the risk of haemolytic
anaemia) and has not been studied extensively
8
among children younger than 12 years.
In addition, nitrofurantoin may be associated
with haemolytic anaemia among people
with glucose-6-phosphate dehydrogenase
(G6PD) deficiency, promoting caution in use
in regions where this condition is prevalent
(21). Drug–drug interactions include oral
contraceptives, oral typhoid vaccine, antacids,
uricosuric drugs and barbiturates. At present,
dispersible tablets do not exist, and authorized
liquid formulations have excipients of concern,
indicating the importance of developing a
better formulation for children. Downsides to
this medication include its limited indication –
it is useful for lower urinary tract infections but
not pyelonephritis or other types of bacterial
infection due to its concentration in urine and
insufficient systemic levels (22).
Azithromycin is a macrolide antibiotic. It is the
WHO EMLc first choice for cholera, enteric fever,
trachoma and yaws and the second choice for
acute invasive bacterial diarrhoea, all major
public health concerns. Further studies are
ongoing for children that may expand
azithromycin’s indication. Currently, dispersible
tablets do not exist, and current liquid
formulations have excipients of some concern,
indicating the importance of developing an
optimized formulation for children. Azithromycin
has overall a good safety profile (most common
adverse events: diarrhoea or loose stool and
vomiting), although there is some concern for
drug–drug interactions including those leading
to increased risk of cardiovascular events
and arrhythmia (especially if concurrent use
of other QT-prolonging medications). Drug–
drug interactions also potentially exist with
cyclosporins, antacids, ergots, coumadin and
P-glycoprotein substrates. Exposure to oral
azithromycin in the newborn period increases
the risk of developing pyloric stenosis. Although
this risk is highest if the exposure occurred in
the first two weeks of life, the risk extends to six
weeks of age.
One important concern about this medication
is the low barrier to selection of resistance
even when dosed correctly. Concerns around
exacerbation of the development of resistance
have been raised also when the medicine is
used in the context of mass drug administration,
which involves administering the treatment
to an entire population or every person in a
geographical area. During trachoma and yaws
outbreaks, for example, azithromycin is used for
mass drug administration.
Cefiderocol is a siderophore cephalosporin
antibiotic. It has been included in the WHO EML
since 2021 as a Reserve antibiotic for resistant
gram-negative organisms, notably carbapenem-
resistant Enterobacterales, including Klebsiella
species. It has demonstrated in vitro and in vivo
efficacy against multiple organisms on the WHO
Bacterial Priority Pathogens List. It maintains
activity against Enterobacterales isolates that
produce metallo-beta lactamases for which few
other options exist, which is the most prevalent
genotypic type of carbapenem resistance in
many regions (such as India). Its safety profile is
similar to other cephalosporins (most common
adverse events: diarrhoea or loose stool and
vomiting). Clinical trials involving children are
ongoing. Cefiderocol induces cytochrome P450
and drug–drug interactions are therefore likely
(for example, oral contraceptives). Notably, in
one clinical trial with critically ill patients with
carbapenem-resistant organisms, all-cause
mortality was higher among subjects who
received cefiderocol versus the best available
therapy, although this did not achieve statistical
significance (23). This difference appeared to
be primarily driven by individuals infected with
Acinetobacter spp.
9
 PAEDIATRIC DRUG OPTIMIZATION
WATCH LIST AND RATIONALE
The watch list drugs of choice for PADO
antibiotics, among those that are under
development or do not have an indication
for children, were:
• cefepime-taniborbactam
• sulbactam-durlobactam.
In addition, two medications were indicated as
noteworthy compounds that may be of interest
for formulations for children in the future:
• cefepime-zidebactam
• aztreonam-avibactam.
Cefepime-taniborbactam is a beta-lactamase
inhibitor and fourth-generation cephalosporin
combination. This medication was specifically
designed to have enhanced in vitro activity
against carbapenem-resistant Enterobacterales
and carbapenem-resistant Pseudomonas
aeruginosa. It has demonstrated in vitro and
in vivo efficacy against multiple organisms
included in the WHO Bacterial Priority
Pathogens List and has activity against
metallo‑beta lactamase-producing isolates.
The overall safety profile based on clinical trials
from adult clinical studies presents a similar rate
and severity of adverse events in the study and
in the control group. There is an opportunity
to expedite planned studies involving children
for this compound.
Sulbactam-durlobactam is a combination
of two beta-lactamase inhibitors. When used
in combination with a carbapenem (such as
imipenem), it prevents degradation of the
carbapenem and results in improved antibiotic
efficacy against carbapenem-resistant
Acinetobacter baumanii, a key bacterium listed
on the WHO Bacterial Priority Pathogens List
and an important pathogen globally for children.
In clinical studies, where it is being testing in
combination with imipenem, there were few
treatment-related adverse events, indicating
an acceptable safety profile but more data are
needed. Downsides include a relatively narrow
therapeutic effect limited to Acinetobacter
which may make it difficult to use in settings
with limited access to diagnostics or long
turnaround times for test results.
10
Cefepime-zidebactam is a combination of
an “old” fourth-generation cephalosporin
with a novel beta-lactamase inhibitor. It has
demonstrated in vitro and in vivo efficacy
against multiple organisms included in the
WHO Bacterial Priority Pathogens List, including
metallo-beta lactamase-producing isolates. In
clinical studies, there were few treatment-related
adverse events, indicating a reassuring safety
profile. However, there are no completed clinical
trials of efficacy for this medication. Given its
early stage of development but promising
potential, cefepime-zidebactam is included in
the noteworthy category of reviewed antibiotics.
Aztreonam-avibactam is a monobactam and
beta-lactamase inhibitor combination. Although
this medication is currently under development,
both components are well established and
are authorized as individual agents by the
European Medicines Agency and United States
Food and Drug Administration and are used
in other combination regimens (avibactam as
beta-lactamase inhibitor in combination with
ceftazidime). The combination of avibactam
with aztreonam restores the in vitro activity and
in vivo efficacy of aztreonam against metallo-
beta lactamase-producing pathogens, making
the medication a potentially useful tool to
treat organisms included in the WHO Bacterial
Priority Pathogens List. The well-established
use of its individual components for children
makes safety less of a concern, although rates
of transaminitis may be higher with aztreonam-
avibactam than other medications considered.
Overall safety is supported by a complete Phase
1 and 2a clinical trials in adults. Phase 3 clinical
trials have been completed but their benefit in
clinical practice is still unclear. In addition, dosing
of this medication with loading and frequency
of infusion may make administration complex
in resource-limited settings and represents a
potential drawback.
FIG.1. PADO PRIORITY LIST

• Multiple therapeutic indications

Amoxicillin-clavulanic acid
• Minimal side-effects and drug–drug interactions
• Dispersible tablets are under development

• First choice in WHO EML for urinary tract infections

Nitrofurantoin
• Acceptable resistance and cross-resistance profile
• Opportunity to improve available formulations

• Multiple therapeutic indications

Azithromycin
• Ongoing studies that may expand indications
for children
• Opportunity to improve available formulations

• Efficacy against multiple pathogens in WHO

Cefiderocol
Bacterial Priority Pathogens List
• Favourable resistance and cross-resistance profile
• Ongoing clinical trials involving children

FIG.2. PADO WATCH LIST

• Efficacy against multiple pathogens in

Cefepime-taniborbactam
WHO priority list
• Acceptable safety profile
• Potential to expedite studies involving children

• Excellent efficacy against Acinetobacter baumanii

Sulbactam-durlobactam
• Reassuring safety profile

FIG. 3. PADO ANTIBIOTICS NOTEWORTHY PIPELINE AGENTS

• Efficacy against multiple pathogens in WHO Bacterial

Cefepime-zidebactam
Priority Pathogens List
• Acceptable safety profile
• Earlier stage of development

• Broad activity against multiple WHO priority pathogens

Aztreonam-avibactam
• Both components studied individually and approved by
the United States Food and Drug Administration and
European Medicines Agency as an individual component
• Possible risk of transaminitis

11
 PHASE 1 CANDIDATES
Given the lack of safety and efficacy data
on compounds still in Phase 1 development,
these drugs were not formally considered in
the PADO process. However, data on regional
and country-specific antimicrobial resistance
through Global Research on Antimicrobial
Resistance can inform the clinical priorities
for new drug and regimen development.
Proposed public health priorities for neonates,
infants and young children to be addressed by
Phase 1 compounds include:
• compounds active against multidrug-resistant
Klebsiella species, particularly carbapenem-
resistant strains (especially metallo-beta
lactamase and OXA-48 like carbapenemase
producing producing strains);
• carbapenem-sparing regimens for
extended spectrum beta lactamase-
producing Enterobacterales infections,
although Staphylococcus aureus causes
significant disease, there are still effective
treatment options for multidrug-resistant
and methicillin-sensitive S. aureus, so it
should not be given higher priority than
the other mentioned pathogens.
12
Antibiotics targeting specific single-pathogen
may be challenging to use in low- and
middle‑income countries, particularly in
terms of implementation because of the
lack of microbiologic laboratory capacities.
Therefore, there is an urgent need for large
multinational (including low- and middle-
income countries) pragmatic randomized
controlled trials evaluating combinations of
existing (both generic and patented) antibiotics
to treat multidrug-resistant sepsis among
neonates and other children. It is important
to review early-phase agents for their potential
relevance to neonates and other children,
and this evaluation ideally will be included
in future pipeline evaluation.
RESEARCH GAPS
Following the priority-setting exercise,
the group considered some of the research
gaps for antibiotics for children and noted
among other challenges the lack of alignment
between United States Food and Drug
Administration and European Medicines
Agency on study design, inclusion criteria
and regulatory requirements for studies
to obtain indication for use in children.
BOX 1. RESEARCH PRIORITIES IDENTIFIED BY THE PADO ANTIBIOTICS MEETING
PK AND SAFETY STUDIES
• Safety and pharmacokinetics studies
in different age groups
• Studies of agents in combination
• Investigating novel combinations
of existing antibiotics and oral agents
for treatment of extended spectrum
beta‑lactamase infections, especially
in neonatal sepsis, to enable treatment
in lower-level health facilities (such as
combinations including fosfomycin
and/or flomoxef)
• Research gaps to inform the development
and use of priority therapeutics for
bacterial infections
• Expansion of indications of use for
priority formulations
DIAGNOSTICS AND STEWARDSHIP
• Diagnostics in parallel with efficacy studies
(especially with narrow-range antibiotics
for specific pathogens)
• Counteracting resistance development
• Impact of antibiotic use outside of human
health and its effect on children’s health
OPTIMIZING CLINICAL USE
• Administration regimens that avoid
prolonged infusions (shorter infusions,
bolus and intramuscular)
• Creation of acceptable or optimal
formulations (dispersible tablets)
• Stability data for adult parenteral vials
to provide multiple doses to young children
and neonates
• Promoting the use of existing
optimal formulations
STUDY DESIGN AND REGULATION
• Ways to harmonize different regulatory
environments to facilitate the development
of new formulations of existing antibiotics
OTHERS
• Significance of the heterogeneity
of metallo‑beta lactamases
• Role of antibiotics in community-acquired
versus hospital-acquired infections
• Tissue penetration of pipeline antibiotics
(cerebrospinal fluid penetration)
13
 Moving forward
and next steps
Paediatric drug optimization antibiotics outcomes
will be widely disseminated with appropriate
stakeholders and shared with GAP-f partners to target
actions to ensure acceleration through the product
life cycle of the products given priority.

In particular, the GAP-f clinical research working

group will review opportunities for accelerating
ongoing programmes and discuss how to address
the research priorities identified. These priorities
will also feed into a broader research priority-setting
effort led by WHO’s antimicrobial resistance division,
which is currently ongoing to ensure synergy with
broader efforts to clarify research agenda and facilitate
the implementation of appropriate studies.

The GAP-f product development and regulatory affair

working group will examine opportunities to facilitate
the development and regulatory approval of antibiotics
that already have indication for children and will work
with industry to speed up investigation of those included
in the watch list. To ensure appropriate dissemination
and promote the alignment of key stakeholders, a policy
brief and a peer‑reviewed manuscript will be developed.

14
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PPL.pdf, accessed 30 January 2023).
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tablets, accessed 30 January 2023).
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EA. Nitrofurantoin and glucose-6-phosphate
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16
Annex 1. Meeting agenda

DAY 1 WEDNESDAY, 30 NOVEMBER 2022, 13:00–14:30 CET

INTRODUCTORY MEETING
CHAIR: RAJIV KSHIRSAGAR (UNICEF)

TOPIC SPEAKER TIME

Welcome John Reeder (WHO) 13:00–13:10

Meeting objectives Martina Penazzato (WHO) 13:10–13:20

Epidemiological background Wilson Were and Yasir Nisar (WHO) 13:20–13:35

and WHO guidelines on
antibiotics

The AWaRe antibiotic book Benedikt Huttner (WHO) 13:35–13:50

The WHO priority pathogen list Hatim Sati (WHO) 13:50–14:05

Q&A All 14:05–14:15

PADO for antibiotics – an Tiziana Masini (WHO) 14:15–14:25

overview

Wrap-up Martina Penazzato (WHO) 14:25–14:30

DAY 2 MONDAY, 5 DECEMBER 2022, 13:00–17:00 CET

EXISTING ANTIBIOTICS
CHAIR: SHABINA ARIFF (AGA KHAN UNIVERSITY HOSPITAL, KARACHI, PAKISTAN)

TOPIC SPEAKER TIME

Welcomes and review day Martina Penazzato (WHO) 13:00–13:05

1 objectives

Summary of background work Bernadette Cappello (WHO) 13:05–13:25

to inform the PADO exercise

Method of PADO for existing Tiziana Masini (WHO) 13:25–13:35

antibiotics

Breakout sessions (three Facilitated by Wilson Were, Yasir Nisar 13:35–15:15

groups) (Priority-setting and and Yaqub Nuhu (WHO)
research agenda)

17
 DAY 2 CONTINUED...

BREAK 15:15-15:30

Report back Rapporteurs: Jay Berkley (University of Oxford, 15:30–16:00

United Kingdom and KEMRI/Wellcome Trust
Research Programme), Pablo Rojo (Hospital
12 de Octubre, Madrid, Spain), Victor Musiime
(Makerere University, Kampala, Uganda)

Plenary discussion Facilitated by Julia Bielicki (SGUL, University 16:00–16:45

Children Hospital Basel, Switzerland)

Wrap-up Benedikt Huttner (WHO) 16:45–17:00

DAY 3 WEDNESDAY, 7 DECEMBER 2022, 13:00–17:00 CET

PIPELINE ANTIBIOTICS
CHAIR: ROBINSON WAMMANDA (AHMADU BELLO UNIVERSITY, ZARIA, NIGERIA)

TOPIC SPEAKER TIME

Welcomes and review day Martina Penazzato (WHO) 13:00–13:05

2 objectives

Overview of the WHO Valeria Gigante (WHO) 13:05–13:15

clinical pipeline

Method of PADO for Alasdair Bamford (WHO) 13:15–13:30

pipeline antibiotics

Breakout sessions (3 groups) Facilitated by Valeria Gigante, Hatim Sati 13:35–15:00

(Priority-setting and research and Alasdair Bamford (WHO)
agenda)

BREAK 15:00-15:15

Report back Rapporteurs: Adrie Bekker (Stellenbosch 15:15–15:30

University, South Africa), Phoebe Williams
(Sydney Children’s Hospital, University of
Sydney, Australia) and Irja Lutsar (University of
Tartu, Estonia)

Plenary discussion Facilitated by Mike Sharland (SGUL, University 15:30–16:15

Children Hospital Basel, Switzerland) and Jen
Cohn (GARDP, Geneva, Switzerland)

Review of overall Wilson Were and Yasir Nisar (WHO) 16:15–16:45

PADO outcomes

Wrap-up and next steps Martina Penazzato (WHO) 16:45–17:00

18
Annex 2.
List of meeting participants

NAME AFFILIATION
Narendra Arora INCLEN Trust International, New Delhi, India
Shabina Ariff Aga Khan University Hospital, Karachi, Pakistan
Adrie Bekker Stellenbosch University, Cape Town, South Africa
Jay Berkley University of Oxford, United Kingdom and KEMRI
& Wellcome Trust Research Programme, Kenya
Julia Bielicki St George’s University of London, United Kingdom
Radu Botgros European Medicines Agency, Amsterdam, Netherlands
Marta Busana European Medicines Agency, Amsterdam, Netherlands
Jennifer Cohn GARDP, Geneva, Switzerland
Alysha Croker Health Canada, Ottawa, Canada
Eric Decloedt Stellenbosch University and Tygerberg Hospital, Cape Town,
South Africa
Devika Dixit University of Saskatchewan and University of Calgary, Saskatoon
and Calgary, Canada
Laura Durno Health Canada, Ottawa, Canada
Herb Harwell Clinton Health Access Initiative, Boston, USA
Katy Hayward Clinton Health Access Initiative, Boston, USA
Yingfen Hsia St George’s University of London, United Kingdom
Fyezah Jehan Aga Khan University, Karachi, Pakistan
Dyness Kasungami Child Health Task Force Secretariat, Arlington, VA, USA
Rajiv Kshirsagar UNICEF
Janice Lee DNDi, Geneva, Switzerland
Irja Lutsar University of Tartu, Estonia
Karim Manji Muhimbili University of Health and Allied Sciences, Dar es Salaam,
United Republic of Tanzania
Amha Mekasha Addis Ababa University, Ethiopia
Anita Melnyk Health Canada, Ottawa, Canada
Hilda Mujuru University of Zimbabwe, Harare, Zimbabwe
Veronica Mulenga University of Lusaka and University Teaching Hospital,
Lusaka, Zambia
Victor Musiime Makarere University, Kampala, Uganda
Damalie Nalwanga Makarere University, Kampala, Uganda
Anthony Nunn Tony Nunn Consulting, Liverpool, United Kingdom

19
 NAME AFFILIATION
Christina Obiero KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
& Global Health, Academic Medical Center of the University of
Amsterdam, Netherlands
Seamus O’Brian GARDP, Geneva, Switzerland
Mary Ojoo UNICEF
Anna Ong-Lim Department of Health, Philippines
Manuele Piccolis Medicines Patent Pool, Geneva, Switzerland
Shamim Qazi Independent Consultant, Switzerland
Shalini Sri Ranganathan University of Colombo, Sri Lanka
Stephen Robinson DNDi, Geneva, Switzerland
Emmanuel Roilides Aristotle University School of Medicine, Thessaloniki, Greece
Pablo Rojo Hospital 12 de Octubre, Madrid, Spain
Jeeva Sankar All India Institute of Medical Sciences, New Delhi, India
Michael Sharland St George’s University of London, United Kingdom
Joe Standing University College London, United Kingdom
Sithembiso Velaphi University of the Witwatersrand, Johannesburg, South Africa
Robinson Wammanda Ahmadu Bello University, Zaria, Nigeria
Phoebe Williams Sydney Children’s Hospital and University of Sidney, Australia
Mei Zeng Children’s Hospital of Fudan University, Shanghai, China

20
WHO STAFF AND CONSULTANTS

WHO HEADQUARTERS
Alasdair Bamford
Silvia Bertagnolio
Bernadette Capello
Chad Centner
Stephen Osborne Nurse‑Findlay
Valeria Gigante
Benedikt Huttner
Brian Jonat
Farihah Malik
Tiziana Masini
Lorenzo Moja
Yasir Nisar
Yaqub Nuhu Omeiza
Martina Penazzato
John Reeder
Hatim Sati
Anjali Srivastava
Marie Valentin
Wilson Were

WHO REGIONAL OFFICE FOR AFRICA

Walter Fuller
Janet Kayita
Aissatou Sougou

WHO REGIONAL OFFICE FOR THE AMERICAS

Jose-Luis Castro

WHO REGIONAL OFFICE FOR THE EASTERN MEDITERRANEAN

Adi Al-Nuseirat
Elizabeth Tayler

WHO REGIONAL OFFICE FOR EUROPE

Sarah Garner
Kotoji Iwamoto
Martin Willi Weber

WHO REGIONAL OFFICE FOR SOUTH-EAST ASIA

Terence Fusire

WHO REGIONAL OFFICE FOR THE WESTERN PACIFIC

Socorro Escalante

21
World Health Organization
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