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 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) © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https:// creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization (http://www.wipo.int/amc/en/mediation/rules/). Suggested citation. Paediatric drug optimization for antibiotics: meeting report, 30 November, 5-7 December 2022. Geneva: World Health Organization; 2023. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see https://www.who.int/ publications/book-orders. To submit requests for commercial use and queries on rights and licensing, see https://www.who.int/copyright. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party- owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Design and layout by 400 Communications Limited. 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 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. Acknowledgments iv The development of medicines for children lags unacceptably behind that for adults by nearly a decade (1). Following the resolution at the 69th World Health Assembly on promoting innovation and access to quality, safe, efficacious and affordable medicines for children, WHO and partners have increased their efforts to deliver on this global commitment and have scaled up activities to ensure that age-appropriate formulations are available for children (2). The Global Accelerator for Paediatric 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. Paediatric drug optimization (PADO) exercises to identify key priority products and their preferred product characteristics for research and development have been successfully undertaken for HIV, hepatitis C and tuberculosis, demonstrating their potential and impact to accelerate access to optimal formulations in the context of fragmented, small markets for medicines for children. To provide further guidance to support similar processes for optimizing drugs for children in other disease areas, GAP-f has published a guidance document that is intended for all WHO technical units and all stakeholders involved describing how to undertake a PADO process and adapt it to the specific needs of each disease area (4). The need for paediatric drug optimization 1 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. 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. Paediatric drug optimization for antibiotics 2 The WHO EML and WHO EMLc alongside the AWaRe classification have provided global guidance on setting priorities for using available antibiotics. Alongside the WHO EML and WHO EMLc, WHO has also published the WHO AWaRe antibiotic book, which provides short, clinical guidance on managing more than 30 common infections among newborns and children in the hospital and primary care setting, including the optimal choice of antibiotic, dose and duration (10). In 2021–2022, a comprehensive analysis of the 2021 WHO EMLc was conducted in conjunction with GAP-f partners to systematically assess the age-appropriateness of formulations of listed medicines to inform the 2023 update of the WHO EMLc (11). Numerous formulations for potential addition to or removal from the WHO EMLc were identified, and recommendations for proposed changes have been submitted for consideration by the next WHO EML expert committee (12). In addition, formulation gaps, including among antibiotics, were identified during the project (where an age-appropriate formulation does not appear to be available or exist). This work has informed the existing PADO antibiotics exercise. 1 “Critical” pathogens are the highest priority for new drug development based on a composite of mortality, health-care burden, resistance, transmissibility, preventability, treatability and current pipeline. PIPELINE ANTIBIOTICS WHO has already undertaken extensive work to identify priority bacterial pathogens for which new antibiotics are urgently needed (13). Most of the pathogens on the WHO Bacterial Priority Pathogens List, including those that are listed in the “critical” category, are of concern for neonates and other children.1 Moreover, the WHO antibacterial pipeline analyses published annually since 2017 provide in-depth overviews of the current antibacterial agents in preclinical and clinical development (14). When considering antibiotics in the pipeline to be prioritized for their development in the paediatric population, it is essential to consider the potential public health impact for treating key clinical infections with the highest mortality and morbidity among neonates and other children, along with the most likely causative pathogens among neonates and other children as well as the most common phenotypic and genotypic resistance patterns. Other considerations include whether intravenous and/or oral administration is required and whether unique children-specific toxicities have been identified or the toxicity profile already 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. 3 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. Objectives 4 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. Method 5 Table 1: attributes included in the prioritization framework of PADO for antibiotics ANTIBIOTICS WITH AN EXISTING LICENCE FOR CHILDREN PIPELINE ANTIBIOTICS Public health relevance Efficacy Flexibility of indication and activity across anatomic sites 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 resistant bacteria (including anticipated impact on usability in different regions) Activity against bacteria with difficult to treat resistance profiles Cross-resistance to other antibiotics used Public health relevance Barriers to developing resistance Patient acceptability Drug–drug interactions Effective across anatomic sites (eg, central nervous system, lungs) Patient acceptability of available formulations Cross resistance to other available antibiotics Age-appropriateness of available formulations Variety of conditions and pathogens targeted Additional aspects (such as issues with storage of available formulations) Need for clinical or laboratory monitoring for signs of efficacy or toxicity Required screening before initiating treatment Drug-drug interactions 6 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. Summary of discussion 7 PAEDIATRIC DRUG OPTIMIZATION PRIORITY AND WATCH LISTS The priority-setting process was conducted for both authorized antibiotics with indications for children and antibiotics under development that have not received marketing authorization for children and/or adults. For the first, a subset of those included in the WHO EMLc with appropriateness gaps was considered. The authorized antibiotics reviewed, which have a licence for children, included: • amoxicillin-clavulanic acid • clindamycin • cloxacillin • nitrofurantoin • sulfamethoxazole-trimethoprim • trimethoprim • azithromycin • ciprofloxacin • clarithromycin • vancomycin (oral). The pipeline antibiotics (including antibiotics under development in Phase 2 and 3 or recently authorized in adults but not in children) reviewed included: • cefiderocol a–c • meropenem-vaborbactam a–c • plazomicin c • zidebactam-cefepime d • XNW4107-imipenem-cilastin d • durlobactam-sulbactam d • taniborbactam-cefepime d • enmetazobactam-cefepime d • aztreonam-avibactam d. a Included in the WHO List of Essential Medicines. b Approved for adults by the European Medicines Agency. c Approved for adults by the United States Food and Drug Administration. d Pipeline antibiotics. PAEDIATRIC DRUG OPTIMIZATION PRIORITY LIST AND RATIONALE The priority drugs for PADO antibiotics were: • amoxicillin-clavulanic acid • nitrofurantoin • azithromycin • cefiderocol. Amoxicillin-clavulanic acid is a combination of a beta-lactam with a beta-lactamase inhibitor. It has widespread use among children and is the WHO EMLc first choice for community acquired pneumonia (severe), complicated intraabdominal infections (mild to moderate), hospital acquired pneumonia, low-risk febrile neutropenia, lower urinary tract infections, sinusitis, skin and soft tissue infections, highlighting its public health importance. It has an acceptable safety and toxicity profile, with minimal side-effects (most common: diarrhoea or loose stool) and drug–drug interactions. The combination is available as oral and parenteral formulations, and dispersible tablets are in current production (20). Downsides to this medication include lack of consistent activity against extended-spectrum beta-lactamase-producing strains and frequent cross- resistance with other antibiotics, such as cephalosporins and other beta-lactams. However, for most common community-acquired infections, amoxicillin-clavulanic acid maintains activity. More data are needed to refine specific renal dosing for children. Additionally, not all formulations are interchangeable, resulting in inaccuracies in dosing ratios (subtherapeutic or supratherapeutic concentrations), especially in settings with limited training and guidelines. Nitrofurantoin is a nitrofuran-class antibiotic. It is the WHO EMLc first choice for urinary tract infections, one of the most common types of bacterial infections in children. Given its unique class, there is limited cross-resistance to this medication from other antibiotics. It has good activity against most Enterobacterales species that cause urinary tract infections, including most strains producing extended spectrum beta-lactamases as well as Enterococcus, although resistance is seen in some multidrug- 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 among children younger than 12 years. 8 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. 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. 10 FIG.1. PADO PRIORITY LIST FIG.2. PADO WATCH LIST FIG. 3. PADO ANTIBIOTICS NOTEWORTHY PIPELINE AGENTS • Excellent efficacy against Acinetobacter baumanii • Reassuring safety profile • Efficacy against multiple pathogens in  WHO priority list • Acceptable safety profile • Potential to expedite studies involving children Sulbactam-durlobactam Cefepime-taniborbactam • Efficacy against multiple pathogens in WHO Bacterial Priority Pathogens List • Acceptable safety profile • Earlier stage of development Cefepime-zidebactam • Broad activity against multiple WHO priority pathogens • 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 Aztreonam-avibactam • Multiple therapeutic indications • Minimal side-effects and drug–drug interactions • Dispersible tablets are under development • First choice in WHO EML for urinary tract infections • Acceptable resistance and cross-resistance profile • Opportunity to improve available formulations Nitrofurantoin • Multiple therapeutic indications • Ongoing studies that may expand indications for children • Opportunity to improve available formulations Azithromycin • Efficacy against multiple pathogens in WHO Bacterial Priority Pathogens List • Favourable resistance and cross-resistance profile • Ongoing clinical trials involving children Cefiderocol Amoxicillin-clavulanic acid 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. 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. 12 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 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. Moving forward and next steps 14 References 1. Shaping the global innovation and access landscape for better paediatric medicines. Geneva: World Health Organization; 2022 (https:// apps.who.int/iris/handle/10665/352200, accessed 30 January 2023). 2. Resolution WHA69.20. Promoting innovation and access to quality, safe, efficacious and affordable medicines for children. Geneva: World Health Organization; 2016 (https://apps.who.int/ iris/handle/10665/252800, accessed 30 January 2023). 3. Global Accelerator for Paediatric Formulations Network (GAP-f) [website]. Geneva: World Health Organization; 2023 (https://www.who.int/ initiatives/gap-f, accessed 30 January 2023). 4. Paediatric drug optimization standard procedure. Geneva: World Health Organization; 2021 (https://apps.who.int/iris/ handle/10665/349315, accessed 30 January 2023). 5. Global burden of disease study 2019. Seattle: Institute for Health Metrics and Evaluation; 2019 (https://ghdx.healthdata.org/gbd-2019, accessed 30 January 2023). 6. WHO Model List of Essential Medicines – 22nd list, 2021. Geneva: World Health Organization; 2021 (https://www.who.int/publications/i/item/ WHO-MHP-HPS-EML-2021.02, accessed 30 January 2023). 7. WHO Model List of Essential Medicines for Children – 8th list, 2021. Geneva: World Health Organization; 2021 (https://www.who. int/publications/i/item/WHO-MHP-HPS- EML-2021.03, accessed 30 January 2023). 8. Executive Board. Revised procedures for updating the WHO Model List of Essential Drugs: a summary of proposals and process. Geneva: World Health Organization; 2001 (https://apps. who.int/iris/handle/10665/78913, accessed 30 January 2023). 9. WHO access, watch, reserve (AWaRe) classification of antibiotics for evaluation and monitoring of use, 2021. Geneva: World Health Organization; 2021 (https://apps.who.int/iris/ handle/10665/345555, accessed 30 January 2023). 10. The WHO essential medicines list antibiotic book: improving antibiotic AWaReness (draft for public comment). Geneva: World Health Organization; 2021 (https://cdn.who. int/media/docs/default-source/essential- medicines/eml-antibiotic-book-draft. pdf?sfvrsn=cb6cb7c2_6&download=true, accessed 30 January 2023). 11. Walsh J, Masini T, Huttner BD, Moja L, Penazzato M, Cappello B. Assessing the appropriateness of formulations on the WHO Model List of Essential Medicines for Children: development of a paediatric quality target product profile tool. Pharmaceutics. 2022;14:473 (https://www.who.int/groups/expert- committee-on-selection-and-use-of-essential- medicines/24th-eml-expert-committee/ r1-review-of-age-appropriateness-of- formulations-of-essential-medicines-for-children- --emlc, accessed 00 Month 2023). 12. EML Secretariat proposal for changes to listings and reviews of medicines on the Model List of Essential Medicines for Children (EMLc), 2021 (https://www.who.int/groups/expert- committee-on-selection-and-use-of-essential- medicines/24th-eml-expert-committee/r1- review-of-age-appropriateness-of-formulations- of-essential-medicines-for-children---emlc, accessed 9 March 2023). 13. WHO publishes list of bacteria for which new antibiotics are urgently needed. Geneva: World Health Organization; 2017 (https://www. who.int/news/item/27-02-2017-who-publishes- list-of-bacteria-for-which-new-antibiotics-are- urgently-needed#:~:text=WHO%20today%20 published%20its%20first,greatest%20threat%20 to%20human%20health, accessed 30 January 2023) 14. 2021 antibacterial agents in clinical and preclinical development: an overview and analysis. Geneva: World Health Organization; 2022 (https://apps.who.int/iris/ handle/10665/354545, accessed 30 January 2023). 15 15. WHO global health estimate 2019. Geneva: World Health Organization; 2019 (https://www. who.int/data/gho/data/indicators/indicator- details/GHO/number-of-deaths, accessed 30 January 2023). 16. WHO, UNICEF. Institutionalizing integrated community case management (iCCM) to end preventable child deaths: a technical consultation and country action planning, 22–26 July 2019, Addis Ababa. Geneva: World Health Organization; 2020 (https://apps.who.int/iris/ handle/10665/333541, accessed 30 January 2023). 17. Pocket book of hospital care for children: guidelines for the management of common childhood illnesses. 2nd ed. Geneva: World Health Organization; 2013 (https://apps.who.int/ iris/handle/10665/81170, accessed 30 January 2023). 18. Klein EY, Milkowska-Shibata M, Tseng KK, Sharland M, Gandra S, Pulcini C et al. Assessment of WHO antibiotic consumption and access targets in 76 countries, 2000–15: an analysis of pharmaceutical sales data. Lancet Infect Dis. 2021;21:107–15. 19. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Geneva: World Health Organization; 2017 (https://revive.gardp. org/wp-content/uploads/2023/01/WHO-global- PPL.pdf, accessed 30 January 2023). 20. Cledomox 312.5 DT: amoxicillin 250mg with potassium clavulanate 62.5mg tablets. Tamilnadu: Medopharm; 2021 (https://www. medopharm.com/radiant/cledomox-312-dt- amoxicillin-potassium-clavulanate-dispersible- tablets, accessed 30 January 2023). 21. Recht J, Chansamouth V, White NJ, Ashley EA. Nitrofurantoin and glucose-6-phosphate dehydrogenase deficiency: a safety review. JAC Antimicrob Resist. 2022;4:dlac045. 22. Squadrito FJ, del Portal D. Nitrofurantoin. Treasure Island (FL): StatPearls Publishing; 2022. 23. Bassetti M, Echols R, Matsunaga Y, Ariyasu M, Doi Y, Ferrer R et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, Phase 3 trial. Lancet Infect Dis. 2021;21:226–40. 16 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 and WHO guidelines on antibiotics Wilson Were and Yasir Nisar (WHO) 13:20–13:35 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 overview Tiziana Masini (WHO) 14:15–14:25 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 1 objectives Martina Penazzato (WHO) 13:00–13:05 Summary of background work to inform the PADO exercise Bernadette Cappello (WHO) 13:05–13:25 Method of PADO for existing antibiotics Tiziana Masini (WHO) 13:25–13:35 Breakout sessions (three groups) (Priority-setting and research agenda) Facilitated by Wilson Were, Yasir Nisar and Yaqub Nuhu (WHO) 13:35–15:15 Annex 1. Meeting agenda 17 DAY 2 CONTINUED... BREAK 15:15-15:30 Report back Rapporteurs: Jay Berkley (University of Oxford, United Kingdom and KEMRI/Wellcome Trust Research Programme), Pablo Rojo (Hospital 12 de Octubre, Madrid, Spain), Victor Musiime (Makerere University, Kampala, Uganda) 15:30–16:00 Plenary discussion Facilitated by Julia Bielicki (SGUL, University Children Hospital Basel, Switzerland) 16:00–16:45 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 2 objectives Martina Penazzato (WHO) 13:00–13:05 Overview of the WHO clinical pipeline Valeria Gigante (WHO) 13:05–13:15 Method of PADO for pipeline antibiotics Alasdair Bamford (WHO) 13:15–13:30 Breakout sessions (3 groups) (Priority-setting and research agenda) Facilitated by Valeria Gigante, Hatim Sati and Alasdair Bamford (WHO) 13:35–15:00 BREAK 15:00-15:15 Report back Rapporteurs: Adrie Bekker (Stellenbosch University, South Africa), Phoebe Williams (Sydney Children’s Hospital, University of Sydney, Australia) and Irja Lutsar (University of Tartu, Estonia) 15:15–15:30 Plenary discussion Facilitated by Mike Sharland (SGUL, University Children Hospital Basel, Switzerland) and Jen Cohn (GARDP, Geneva, Switzerland) 15:30–16:15 Review of overall PADO outcomes Wilson Were and Yasir Nisar (WHO) 16:15–16:45 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 20 Avenue Appia 1211 Geneva 27 Switzerland