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The recent GRAM report on the global impact of antimicrobial resistance highlights the ongoing challenges to antibiotic stewardship¹. Considering global assessments of antibiotic use patterns, it is essential to note that children are likely to have an approximately three times higher consumption of antibiotics than adults in most settings, regardless of country income level². Incorporating evidence on optimal use of antibiotics in this group or generating such evidence when it is lacking is likely to play an important role in global antimicrobial stewardship.

High proportion of antibiotic use in the community

Most antibiotic use occurs in the community setting, although it has been difficult to estimate this accurately. Sweden’s annual report on Antibiotic Sales and Resistance for 2020, a year influenced by COVID-19, details that 86% of total antibiotic sales are generated in outpatient care³. It is likely that in settings with more informal and poorly regulated sales channels, such as many low and middle-income countries (LMICs), the proportion of antibiotic use in the community is even higher.

WHO has classified antibiotics into four groups: low-cost, generally safe Access antibiotics that have a targeted spectrum of activity and low resistance potential; broader-spectrum Watch antibiotics recommended only in specific indications and situations; reserve antibiotics considered to be treatments of last resort for multidrug-resistant infections; antibiotics that are not recommended because similar agents are already part of the AWaRe classification⁴. This classification underpins the draft WHO Essential Medicines List Antibiotic Book offering guidance for treating typical infections resulting in consultation with a healthcare provider, including for children⁴.

A considerable investment in surveillance of antibiotic use patterns among neonates and children globally is needed.

Data on the patterns of Access, Watch and Reserve antibiotic use among young children in 70 middle-income and high-income countries suggest that Access antibiotics already dominate in most included countries⁴. However, amoxicillin, which generally accounts for most antibiotic use in under-fives, accounts for a low proportion of use in many of these countries⁵. General consumption patterns vary between countries but without clear differences between middle- and high-income settings.

Increased antibiotics exposure in children

In young children, individual exposures to antibiotics are frequently very high, especially in LMICs. It is estimated that up to 27, 30 and 59 prescriptions have been issued for antibiotics between birth and five years of age in Nepal, Malawi and Uganda, respectively⁶. Furthermore, LMICs are seeing increasing antibiotic use among sick under-fives, particularly in low-income countries⁷. This observation underlines the importance of strengthening antibiotic stewardship activities alongside improved access in all settings to avoid tipping from a lack of access to antibiotics to excessive use.

Antibiotic use for mild diseases for which little evidence suggests benefits from antibiotics is common in the community setting. Children followed up prospectively in eight LMICs across Asia, Africa and Latin America were treated with antibiotics in 75% and 44% of bloody and non-bloody diarrhea episodes, 61% of healthcare workers confirmed acute episodes involving the lower airways and 40% of episodes involving the upper airways⁸. The authors noted that treatments were frequently inconsistent with international guidelines and resulted in a cumulative antibiotic exposure of up to 4 months in the first 24 months of life.

Antibiotics are also frequently prescribed to children in high-income countries presenting with febrile illness. Of more than 4500 otherwise healthy children presenting acutely with fever to 28 emergency departments in 11 European countries, every third child received an antibiotic⁹. This antibiotic use was driven by treatment for upper and lower airway infections. It was highly variable between hospitals, demonstrating the need for considering and addressing local drivers of suboptimal antibiotic use in children.

In young children, individual exposures to antibiotics are frequently very high, especially in LMICs. It is estimated that up to 27, 30 and 59 prescriptions have been issued for antibiotics between birth and five years of age in Nepal, Malawi and Uganda, respectively.

Antibiotic exposures are also frequent for children who are in hospital. Similar variations in patterns of Access, Watch and Reserve antibiotics as for community use can be observed. A few interesting general observations include: A relatively limited range of antibiotics prescribed to neonates compared to older children (e.g. 22 drugs contributing to 90% of antibiotic utilization for children in Africa compared with 12 drugs for neonates in the same region)¹⁰; Watch antibiotics representing a considerable proportion of antibiotic use in many world regions for neonates and children (around a third for both neonates and children in Africa)¹⁰; Prophylactic antibiotic use accounting for a quarter or more of prescriptions in neonates and children¹¹.

Arguably, neonates and children treated with antibiotics in the hospital setting are more likely to suffer from severe infections than in the community. Moreover, healthcare-associated infections are frequent in such children, resulting in a pathogen spectrum more typical of the hospital environment¹².

Excessive antibiotic use and rising antimicrobial resistance

This tendency to excessive use of antibiotics can lead to widespread antimicrobial resistance. Especially neonates with sepsis are increasingly impacted by rising antimicrobial resistance, with extended-spectrum beta (β)-lactamase-expressing and carbapenem-resistant Gram-negative bacteria becoming dominant in some Asian countries and parts of Africa^13,14. This increase in antimicrobial resistance presents obvious challenges for judicious use of antibiotics, including Watch and Reserve agents, in treating neonatal sepsis, with shifts towards such broader-spectrum options observed despite this contradicting current guidance^15,16.

So, what can be done?

A considerable investment in surveillance of antibiotic use patterns among neonates and children globally is needed. This need not be complex, as demonstrated by previous repeated point prevalence assessments, and could include extensions to existing child health surveys.

A two-pronged approach is likely necessary to support judicious antibiotic use: On the one hand, better evidence to inform which antibiotics should be used, at what dose and for how long for severe infections is urgently needed with few relevant studies underway¹⁷. Robust, pragmatic trials related to everyday challenges faced by prescribing clinicians can inform trusted guidelines. On the other hand, support needs to be offered to multiple stakeholders to ensure that antibiotics are used with great care when infections are mild, and children are unlikely to benefit from this precious resource. Additionally, digital advances may support safety-netting strategies for families to stay connected to healthcare providers and ensure responsiveness when symptoms are worsening.

References

1. Murray CJL, Ikuta KS, Sharara F, Swetschinski L, Aguilar GR, Gray A et al. (2022) Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet. 399(10325):629 – 655
2. Jackson C, Hsia Y, Bielicki JA, Ellis S, Stephens P, Wong ICK, et al. (2019) Estimating global trends in total and childhood antibiotic consumption, 2011-2015. BMJ Global Health. 4(1):e001241.
3. Public Health Agency of Sweden, National Veterinary Institute. (2020) Sales of antibiotics and occurrence of antibiotic resistance in Sweden. 
4. World Health Organization (2021) The WHO Essential Medicines List Antibiotic Book: improving antibiotic AWaReness. 
5. Hsia Y, Sharland M, Jackson C, Wong ICK, Magrini N, Bielicki JA. (2019) Consumption of oral antibiotic formulations for young children according to the WHO Access, Watch, Reserve (AWaRe) antibiotic groups: an analysis of sales data from 70 middle-income and high-income countries. The Lancet Infectious Diseases. 19(1):67-75.
6. Fink G, D’Acremont V, Leslie HH, Cohen J. (2020) Antibiotic exposure among children younger than 5 years in low-income and middle-income countries: a cross-sectional study of nationally representative facility-based and household-based surveys. The Lancet Infectious Diseases. 20(2):179-87.
7. Allwell-Brown G, Hussain-Alkhateeb L, Kitutu FE, Strömdahl S, Mårtensson A, Johansson EW. (2020) Trends in reported antibiotic use among children under 5 years of age with fever, diarrhoea, or cough with fast or difficult breathing across low-income and middle-income countries in 2005-2017: a systematic analysis of 132 national surveys from 73 countries. The Lancet Global Health. 8(6):e799-e807.
8. Rogawski ET, Platts-Mills JA, Seidman JC, John S, Mahfuz M, Ulak M, et al. (2017) Use of antibiotics in children younger than two years in eight countries: a prospective cohort study. The Bulletin of the World Health Organization. 95(1):49-61.
9. van de Maat J, van de Voort E, Mintegi S, Gervaix A, Nieboer D, Moll H, et al. (2019) Antibiotic prescription for febrile children in European emergency departments: a cross-sectional, observational study. The Lancet Infectious Diseases. 19(4):382-91.
10. Hsia Y, Lee BR, Versporten A, Yang Y, Bielicki J, Jackson C, et al. (2019) Use of the WHO Access, Watch, and Reserve classification to define patterns of hospital antibiotic use (AWaRe): an analysis of paediatric survey data from 56 countries. The Lancet Global Health. 7(7):e861-e71.
11. Versporten A, Bielicki J, Drapier N, Sharland M, Goossens H. (2016) The Worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) point prevalence survey: developing hospital-quality indicators of antibiotic prescribing for children. Journal of Antimicrobial Chemotherapy. 71(4):1106-17.
12. Zingg W, Hopkins S, Gayet-Ageron A, Holmes A, Sharland M, Suetens C. (2017) Health-care-associated infections in neonates, children, and adolescents: an analysis of paediatric data from the European Centre for Disease Prevention and Control point-prevalence survey. The Lancet Infectious Diseases. 17(4):381-9.
13. Chaurasia S, Sivanandan S, Agarwal R, Ellis S, Sharland M, Sankar MJ. (2019) Neonatal sepsis in South Asia: huge burden and spiralling antimicrobial resistance. BMJ. 364:k5314.
14. Williams PCM, Isaacs D, Berkley JA. (2018) Antimicrobial resistance among children in sub-Saharan Africa. The Lancet Infectious Diseases. 18(2):e33-e44.
15. Bielicki JA, Sharland M, Heath PT, Walker AS, Agarwal R, Turner P, et al. (2020) Evaluation of the Coverage of 3 Antibiotic Regimens for Neonatal Sepsis in the Hospital Setting Across Asian Countries. JAMA Network Open. 3(2):e1921124.
16. Jackson C, Hsia Y, Basmaci R, Bielicki J, Heath PT, Versporten A, et al. (2019) Global Divergence From World Health Organization Treatment Guidelines for Neonatal and Pediatric Sepsis. Pediatric Infectious Dissease Journal. 38(11):1104-6.
17. Thompson G, Barker CI, Folgori L, Bielicki JA, Bradley JS, Lutsar I, et al. (2017) Global shortage of neonatal and paediatric antibiotic trials: rapid review. BMJ Open. 7(10):e016293.