Coverage gaps in empiric antibiotic regimens used to treat serious bacterial infections in neonates and children in Southeast Asia and the Pacific

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Summary

Background

High levels of antimicrobial resistance (AMR) are propagating deaths due to neonatal and paediatric infections globally. This is of particular concern in Southeast Asia and the Pacific, where healthcare resources are constrained and access to newer agents to treat multidrug-resistant pathogens is limited.

Methods

To assess the coverage provided by commonly prescribed empiric antibiotic regimens for children in low- and middle-income countries in Southeast Asia and the Pacific, we built a weighted incidence syndromic combination antibiogram (WISCA), parameterised using data obtained from a systematic review of published literature incorporating WHO-defined SEARO and WPRO regions in Ovid MEDLINE, EMBASE, Global Health and PubMed. Susceptibility data for bacterial pathogens were extracted to provide coverage estimates for pre-specified antibiotics (aminopenicillins, gentamicin, third-generation cephalosporins and carbapenems), reported at the regional level.

Findings

6648 bacterial isolates from 11 countries across 86 papers were included in the Bayesian WISCA model, which weighted bacterial incidence and antimicrobial susceptibility of relevant isolates. Coverage provided by aminopenicillins in neonatal sepsis/meningitis was 26% (80% credible interval: 16–49) whilst gentamicin coverage was 45% (29–62). Third-generation cephalosporin coverage was only 29% (16–49) in neonatal sepsis/meningitis, 51% (38–64) in paediatric sepsis and 65% (51–77) in paediatric meningitis. Carbapenems were estimated to provide the highest coverage: 81% (65–90) in neonatal sepsis/meningitis, 83% (72–90) in paediatric sepsis and 79% (62–91) in paediatric meningitis.

Interpretation

These findings reveal alarmingly high rates of resistance to commonly prescribed empirical therapies for neonatal and paediatric sepsis and meningitis in the Asia–Pacific region.

Funding

This research was funded in whole, or in part, by the doi 10.13039/100010269, Wellcome Trust; [220211]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. PCMW is supported by a doi 10.13039/501100000925, National Health and Medical Research Council; (NHMRC) Investigator Grant. NHMRC had no involvement in the design or conduct of the research.

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Most cited references 44

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Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis

(2022)

Summary Background Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estimated the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for specific pathogen–drug combinations in select locations. To our knowledge, this study presents the most comprehensive estimates of AMR burden to date. Methods We estimated deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 23 pathogens and 88 pathogen–drug combinations in 204 countries and territories in 2019. We obtained data from systematic literature reviews, hospital systems, surveillance systems, and other sources, covering 471 million individual records or isolates and 7585 study-location-years. We used predictive statistical modelling to produce estimates of AMR burden for all locations, including for locations with no data. Our approach can be divided into five broad components: number of deaths where infection played a role, proportion of infectious deaths attributable to a given infectious syndrome, proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antibiotic of interest, and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden based on two counterfactuals: deaths attributable to AMR (based on an alternative scenario in which all drug-resistant infections were replaced by drug-susceptible infections), and deaths associated with AMR (based on an alternative scenario in which all drug-resistant infections were replaced by no infection). We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. We present final estimates aggregated to the global and regional level. Findings On the basis of our predictive statistical models, there were an estimated 4·95 million (3·62–6·57) deaths associated with bacterial AMR in 2019, including 1·27 million (95% UI 0·911–1·71) deaths attributable to bacterial AMR. At the regional level, we estimated the all-age death rate attributable to resistance to be highest in western sub-Saharan Africa, at 27·3 deaths per 100 000 (20·9–35·3), and lowest in Australasia, at 6·5 deaths (4·3–9·4) per 100 000. Lower respiratory infections accounted for more than 1·5 million deaths associated with resistance in 2019, making it the most burdensome infectious syndrome. The six leading pathogens for deaths associated with resistance (Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) were responsible for 929 000 (660 000–1 270 000) deaths attributable to AMR and 3·57 million (2·62–4·78) deaths associated with AMR in 2019. One pathogen–drug combination, meticillin-resistant S aureus, caused more than 100 000 deaths attributable to AMR in 2019, while six more each caused 50 000–100 000 deaths: multidrug-resistant excluding extensively drug-resistant tuberculosis, third-generation cephalosporin-resistant E coli, carbapenem-resistant A baumannii, fluoroquinolone-resistant E coli, carbapenem-resistant K pneumoniae, and third-generation cephalosporin-resistant K pneumoniae. Interpretation To our knowledge, this study provides the first comprehensive assessment of the global burden of AMR, as well as an evaluation of the availability of data. AMR is a leading cause of death around the world, with the highest burdens in low-resource settings. Understanding the burden of AMR and the leading pathogen–drug combinations contributing to it is crucial to making informed and location-specific policy decisions, particularly about infection prevention and control programmes, access to essential antibiotics, and research and development of new vaccines and antibiotics. There are serious data gaps in many low-income settings, emphasising the need to expand microbiology laboratory capacity and data collection systems to improve our understanding of this important human health threat. Funding Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.

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GRADE guidelines: 3. Rating the quality of evidence.

Howard Balshem, Mark Helfand, Holger Schünemann … (2011)

This article introduces the approach of GRADE to rating quality of evidence. GRADE specifies four categories-high, moderate, low, and very low-that are applied to a body of evidence, not to individual studies. In the context of a systematic review, quality reflects our confidence that the estimates of the effect are correct. In the context of recommendations, quality reflects our confidence that the effect estimates are adequate to support a particular recommendation. Randomized trials begin as high-quality evidence, observational studies as low quality. "Quality" as used in GRADE means more than risk of bias and so may also be compromised by imprecision, inconsistency, indirectness of study results, and publication bias. In addition, several factors can increase our confidence in an estimate of effect. GRADE provides a systematic approach for considering and reporting each of these factors. GRADE separates the process of assessing quality of evidence from the process of making recommendations. Judgments about the strength of a recommendation depend on more than just the quality of evidence. Copyright © 2011 Elsevier Inc. All rights reserved.

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Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals

Li Liu, Shefali Oza, Dan Hogan … (2016)

Summary Background Despite remarkable progress in the improvement of child survival between 1990 and 2015, the Millennium Development Goal (MDG) 4 target of a two-thirds reduction of under-5 mortality rate (U5MR) was not achieved globally. In this paper, we updated our annual estimates of child mortality by cause to 2000–15 to reflect on progress toward the MDG 4 and consider implications for the Sustainable Development Goals (SDG) target for child survival. Methods We increased the estimation input data for causes of deaths by 43% among neonates and 23% among 1–59-month-olds, respectively. We used adequate vital registration (VR) data where available, and modelled cause-specific mortality fractions applying multinomial logistic regressions using adequate VR for low U5MR countries and verbal autopsy data for high U5MR countries. We updated the estimation to use Plasmodium falciparum parasite rate in place of malaria index in the modelling of malaria deaths; to use adjusted empirical estimates instead of modelled estimates for China; and to consider the effects of pneumococcal conjugate vaccine and rotavirus vaccine in the estimation. Findings In 2015, among the 5·9 million under-5 deaths, 2·7 million occurred in the neonatal period. The leading under-5 causes were preterm birth complications (1·055 million [95% uncertainty range (UR) 0·935–1·179]), pneumonia (0·921 million [0·812 −1·117]), and intrapartum-related events (0·691 million [0·598 −0·778]). In the two MDG regions with the most under-5 deaths, the leading cause was pneumonia in sub-Saharan Africa and preterm birth complications in southern Asia. Reductions in mortality rates for pneumonia, diarrhoea, neonatal intrapartum-related events, malaria, and measles were responsible for 61% of the total reduction of 35 per 1000 livebirths in U5MR in 2000–15. Stratified by U5MR, pneumonia was the leading cause in countries with very high U5MR. Preterm birth complications and pneumonia were both important in high, medium high, and medium child mortality countries; whereas congenital abnormalities was the most important cause in countries with low and very low U5MR. Interpretation In the SDG era, countries are advised to prioritise child survival policy and programmes based on their child cause-of-death composition. Continued and enhanced efforts to scale up proven life-saving interventions are needed to achieve the SDG child survival target. Funding Bill & Melinda Gates Foundation, WHO.

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Author and article information

Contributors

Phoebe C.M. Williams

Journal

Journal ID (nlm-ta): Lancet Reg Health Southeast Asia

Journal ID (iso-abbrev): Lancet Reg Health Southeast Asia

Title: The Lancet Regional Health - Southeast Asia

Publisher: Elsevier

ISSN (Electronic): 2772-3682

Publication date PMC-release: 31 October 2023

Publication date Collection: March 2024

Publication date (Electronic): 31 October 2023

Volume: 22

Electronic Location Identifier: 100291

Affiliations

[a ]Faculty of Medicine, School of Public Health, The University of Sydney, Sydney, NSW, Australia

[b ]Department of Infectious Diseases, Sydney Children's Hospital Network, Sydney, NSW, Australia

[c ]Sydney Institute of Infectious Diseases (Sydney ID), Sydney, NSW, Australia

[d ]Department of Infectious Diseases, Royal Darwin Hospital, Tiwi, Northern Territory, Australia

[e ]Department of Global Health, London School of Hygiene and Tropical Medicine, London, UK

[f ]Lao-Oxford Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Lao PDR

[g ]Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

[h ]Cambodia Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia

Author notes

[∗ ]Corresponding author. Faculty of Medicine, School of Public Health, The University of Sydney, Edward Ford Building, Camperdown, NSW, Australia. phoebe.williams@ 123456sydney.edu.au

Article

Publisher Item ID: S2772-3682(23)00151-8 Publisher ID: 100291

DOI: 10.1016/j.lansea.2023.100291

PMC ID: 10934317

PubMed ID: 38482147

SO-VID: f6234c60-4a0f-44ae-ae6e-fda45a303b8d

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

History

Date received : 2 April 2023

Date revision received : 25 August 2023

Date accepted : 21 September 2023

Coverage gaps in empiric antibiotic regimens used to treat serious bacterial infections in neonates and children in Southeast Asia and the Pacific

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Background

Methods

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Interpretation

Funding

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Pediatric Pulse: Advancing Neonatal and Child Health

Most cited references 44

Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis

GRADE guidelines: 3. Rating the quality of evidence.

Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals

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