Threats of Antimicrobial Resistance (AMR) in Pediatrics

By Jimmy Nkaiwuatei & Janice Odhiambo

For correspondence: odhiamboosumba001@gmail.com (Janice) & jimmynkaiwuatei@gmail.com (Jimmy)

Background

Antimicrobial resistance (AMR) is a severe worldwide health problem that needs immediate attention and action, and it has frequently been linked to a lack of public knowledge1. The goal of this article is to provide an in-depth overview of the danger of AMR, its consequences on children, and possible preventative strategies. AMR and the issues it poses must be understood in order to design suitable and effective AMR preventive methods. To promote AMR education among the general public, healthcare providers, and other key stakeholders, it is also necessary to develop sectoral and group-specific AMR education models.

AMR is one of the primary roadblocks to achieving the Sustainable Development Goals of the United Nations2. AMR has resulted in the deaths of numerous people throughout the world, not to mention animals. It happens when germs gain the capacity to fight antimicrobial medications (drugs used to treat illnesses) by changing into new forms that these treatments can no longer cure, and this can occur as a result of incorrect antimicrobial usage. Bacteria, viruses, fungi, and mycobacteria are among these germs. Pediatrics include delicate age groups such as newborns, infants and children that are particularly vulnerable to illness3.

Risks for pediatric infections and septicemia

Because of the low amounts, impaired qualitative functioning in the first few weeks of life, and fast depletion of neutrophils, infants, and particularly newborns, are at a significant risk for fungal and bacterial infections4. This lowered physiological function puts them at a higher risk of bacterial infections, which can lead to bacteremia. This can certainly lead to an increase in newborn mortality when bacteria acquire resistance to antibiotics, which is compounded by the fact that neonates and especially premature newborns have a weak defense mechanism owing to their underdeveloped immune systems4.

Neutrophils are a kind of leukocyte that fight infections like bacterial and fungal infections by phagocytosing them5, and neutropenia is defined as a reduction in neutrophil numbers. Neutropenia is common in newborns, and it can hasten the development of bacterial septicemia after neonatal bacterial infections4.

Septicemia is a life-threatening infection that can lead to sepsis, which is a leading cause of infant death across the world6. Approximately 1.3 million cases are reported each year, with an estimated 203,000 fatalities. Global data estimate that, in a population of 100,000 live births, roughly 2,202 neonates have neonatal sepsis, with a mortality rate of 11–19 percent, although these data (242–418 fatalities per 100,000 live births) largely come from high-income countries6. In a study of 200 pediatric patients conducted at Nobel Medical and Teaching Hospital in Nepal, bacterial sepsis was suspected in 88 percent (177) of the patients, and 52 cases were found to be resistant to the World Health Organization’s (WHO) Access and Watch class of antibiotics, including the reserved group such as linezolid and imipenem6. Data from low and middle-income countries (LMICs) are sparse, but what is available suggests that these nations have a high prevalence of infections and death due to a lack of access to excellent healthcare and poor infection prevention and control strategies which create more opportunities for drug-resistant infections6.The rising threat of AMR, particularly in children, is alarming, necessitating immediate preventive and eradication efforts.

Antimicrobial resistance in pediatric infections

AMR has posed a serious health threat to patients of all ages around the world. The World Health Organization (WHO) estimates that 700,000 people die each year from infections caused by multi-drug resistant bacteria, with 200,000 of those deaths occurring in newborns7. Multidrug-resistant illnesses account for over 30% of all infections in Europe’s pediatric population8. Antibiotic-resistant bacterial illnesses are on the rise in the Middle East, with drug-resistant germs found in 90 percent of babies suffering from sepsis and admitted to the Intensive Care Unit (ICU) 9. Antibiotic-resistant Escherichia coli is found in around 83 percent of children in Southeast Asia and about 66 percent of meningitis and neonatal sepsis infections are caused by antibiotic-resistant bacteria in Sub-Saharan Africa10. AMR has been a major concern for pediatricians all around the world. In the United States, for example, colistin-resistant gram-negative infections have been reported, with roughly 20% of pediatric patients having multi-drug resistant infections11.

Because of their underdeveloped immunity, children are vulnerable to infections, according to Sally Ellis et al, the project leader for the GARDP’s children’s antibiotics study. The absence of better treatment choices is a major reason for children’s’ deaths12. In a study involving approximately 3,200 neonates with suspected sepsis, it was discovered that approximately 11 percent of babies succumbed to sepsis across healthcare facilities, with the number rising to 18 percent when a pathogen was detected and confirmed. This is strong evidence that AMR is wreaking havoc among children. Furthermore, there was a significant difference in mortality amongst the institutions, ranging from 1% to 27%12.

Nearly all of the 84,534 neonatal infections studied in 151 studies from 26 countries were nosocomial, and insufficient information was reported in line with the STROBE-NI (Strengthening the Reporting of Observational Studies in Epidemiology for Newborn Infection) guidelines in 82 studies conducted between 2008 and 201813. Klebsiella spp, Staphylococcus aureus, and Escherichia coli were found in 21 percent (16–27), 25 percent (95 percent CI 21–29), and 10 percent (8–10) of culture-positive bacterial sepsis patients, respectively. The most common causes of meningitis were Group B Streptococcus, which accounted for 25% (16–33), Staphylococcus aureus, which accounted for 12% (3–25), and Streptococcus pneumoniae, which accounted for 17% (9–6). AMR to the WHO-recommended beta-lactam antibiotics was discovered in 614 (68%) of the 904 cases, while resistance to aminoglycosides was found in 317 (27%) of the 1,176 cases. In Africa, hospital-acquired newborn infections and AMR are huge problems13. This necessitates advancements in clinical care for infection prevention in hospital settings.

Challenges associated with treatment of pediatric infections

Because of the scarcity of effective antimicrobials, pediatric illnesses are particularly difficult to treat14. Because of their tiny bodies and fidgety disposition, obtaining a specimen for testing from pediatric patients might be difficult15, driving empirical treatment of infections, which can lead to suboptimal medication administration16. Pediatric infections are also difficult to diagnose accurately. The lack of adequate diagnosis processes, along with the existence of non-infectious health problems and frequent fevers in neonates that are comparable to sepsis, make neonatal infection detection more difficult17. As a result, doctors are obligated to provide antibiotics to neonates who have sepsis symptoms or are suspected of having sepsis. Unfortunately, long-term empirical antibiotic therapy and broad-spectrum antibiotics can cause unwanted side effects and AMR17.

Because of the differences in body physiology and pharmacodynamics, vaccination studies for some diseases, such as tuberculosis (TB), are primarily focused on adult populations16. The same cannot be trusted to work for juvenile patients18.  Due to a lack of standard operating procedures and evidence-based therapeutic regimens for the management of pediatric infections, novel treatment regimens are not produced on a regular basis19.

Because of the large age range of the pediatric population, pharmacokinetic characteristics vary, making it hard to come up with an optimum dosing regimen for infections7. There is still a knowledge gap about the most effective antibiotic regimen for children with co-morbidities and underlying diseases7. Because of the serious side effects of certain antibiotics, such as fluoroquinolones and tetracyclines, which prevent cartilage formation and cause tooth dis-colouration, treatment choices are restricted7.

Notably, sepsis may strike fully formed newborns as well. In the United States, a study using 4,255 bacterial cultures from a sample size of 160,818 infants found a positive rate of 0.57 per 1000 newborns. The most prevalent pathogen was Escherichia coli, and urinary tract infection was the primary cause of infection in these children20. Antibiotic resistance testing, especially in E.coli, is useful for monitoring and preventing antibiotic-resistant illnesses in children.

Recommendations for preventing antibiotic-resistant illnesses in children

  • Improved antibiotic resistance surveillance and monitoring, as well as greater study on pediatric illnesses in populations.
  • Involvement of healthcare professionals such as pediatricians and clinical pharmacists in pediatric Antimicrobial Stewardship (AMS) programs is also beneficial in ensuring the appropriate usage and movement of antimicrobials in and out of hospitals21.
  • Improved clinical and healthcare access for all children, particularly those in low-resource settings, to ensure sufficient treatment, as well as Infection Prevention and Control (IPC) to combat nosocomial infections in pediatric patients and pregnant people admitted to health-care institutions. To combat the spread of resistant superbugs, the WHO has released evidence-based treatments for IPC with eight key competencies concentrating on facility and national level22. To prevent the spread of frequently dangerous bacteria to the still growing kids, the same strategy should be used in birthing wards. A WASH (Water, sanitation, and hygiene) committee should be established at healthcare institutions to ensure that IPC principles are followed.
  • More studies on antibiotic adjuvants to increase antimicrobial medication therapeutic efficacy by lowering microbial pathogenicity. For example, clavulanic acid has been used together with beta-lactamase inhibitors to treat a variety of bacterial illnesses.
  • Raising awareness among important stakeholders, such as the Ministry of Health and the African Union on an international level, to redirect resources and efforts towards drug surveillance and epidemiology, with a specific focus on pediatrics. This will guarantee that medication regimens tailored to them are devised, resulting in improved treatment outcomes.
  • Develop a comprehensive health-systems management strategy and combat antibiotic resistance in children.

Conclusion

The problem of AMR among children was typically neglected until it was discovered that they are carriers of resistant microorganisms and significant antibiotic users. Newborn sepsis is a severe health risk in children, resulting in a high rate of neonatal death that can be increased by antibiotic resistance. Because of their weak defensive system, this specific group is particularly prone to diseases. This situation, however, may be rescued if the appropriate energy and resources are channeled. Pediatric research on alternatives to antibacterial treatments is critical for the development of effective therapies with minimum side effects. Furthermore, to combat antibiotic resistance in children, Antimicrobial Stewardship (AMS) focusing on pediatrics is essential.

References

(1) Appiah, Bernard, Lucy Asamoah-Akuoko, Elfreda Samman, Augustina Koduah, Irene Akwo Kretchy, Julius Yaw Ludu, Gloria Odonkor, Su Hyun Nam, and Martha Gyansa-Luterrodt. “The Impact of Antimicrobial Resistance Awareness Interventions Involving School children, Development of an Animation and Parents Engagements: A Pilot Study.” Antimicrobial Resistance and Infection Control. 2022, 11 (1): 1–10. https://doi.org/10.1186/S13756-022-01062-6/TABLES/2.

(2)“Antimicrobial Resistance Threatens Development, SDGs: Tripartite Report | News | SDG Knowledge Hub | IISD.” n.d. Accessed. https://sdg.iisd.org/news/antimicrobial-resistance-threatens-development-sdgs-tripartite-report/. 2022.

(3) “Neonate: MedlinePlus Medical Encyclopedia.” n.d. Accessed May 2, 2022. https://medlineplus.gov/ency/article/002271.htm.

(4) Johnson, Ken B., Travis Bailey, and Elizabeth Thackeray. “Physiology and Pharmacology of Obesity, Pediatrics, and the Elderly.” Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application, January. 2018, 91–112. https://doi.org/10.1016/B978-0-323-48110-6.00005-3.

(5) Melvan, John Nicholas, Gregory J. Bagby, David A. Welsh, Steve Nelson, and Ping Zhang. “Neonatal Sepsis and Neutrophil Insufficiencies.” International Reviews of Immunology. 2010,  29 (3): 315. https://doi.org/10.3109/08830181003792803.

(6) Yadav, S. K., S. K. Agrawal, S. K. Singh, A. Giri, G. K. Singh, R. Ghimire, A. G. Stewart, K. L. Show, and F. L. Moses. “Antimicrobial Resistance in Neonates with Suspected Sepsis.” Public Health Action. 2021, 11 (Suppl 1): 6. https://doi.org/10.5588/PHA.21.0038.

(7) Romandini, Alessandra, Arianna Pani, Paolo Andrea Schenardi, Giulia Angela, Carla Pattarino, Costantino De Giacomo, Francesco Scaglione. “Antibiotic Resistance in Pediatric Infections: Global Emerging Threats, Predicting the Near Future.” Antibiotics. 2021,393 10 (4): 393. https://doi.org/10.3390/ANTIBIOTICS10040393.

(8) Cassini, Alessandro, Liselotte Diaz Högberg, Diamantis Plachouras, Annalisa Quattrocchi, Ana Hoxha, Gunnar Skov Simonsen, Mélanie Colomb-Cotinat. “Attributable Deaths and Disability-Adjusted Life-Years Caused by Infections with Antibiotic-Resistant Bacteria in the EU and the European Economic Area in 2015: A Population-Level Modelling Analysis.” The Lancet. Infectious Diseases. 2019 (1): 56–66. https://doi.org/10.1016/S1473-3099(18)30605-4.

(9) Jarousha, Abdel Moati Kh Al, Abdel Hakeem N.El Jadba, Ahmed S.Al Afifi, and Iyad A.El Qouqa. “Nosocomial Multidrug-Resistant Acinetobacter Baumannii in the Neonatal Intensive Care Unit in Gaza City, Palestine.” International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases. 2009, 13 (5): 623–28. https://doi.org/10.1016/J.IJID.2008.08.029.

(10) Doare, Kirsty Le, Charlotte I.S. Barker, Adam Irwin, and Mike Sharland. “Improving Antibiotic Prescribing for Children in the Resource-Poor Setting.” British Journal of Clinical Pharmacology.2015, 79 (3): 446–55. https://doi.org/10.1111/BCP.12320.

 (11) Tamma, Pranita D., Jason G. Newland, Pia S. Pannaraj, Talene A. Metjian, Ritu Banerjee, Jeffrey S. Gerber, Scott J. Weissman, Susan E. Beekmann, Philip M. Polgreen, and Adam L. Hersh. “The Use of Intravenous Colistin among Children in the United States: Results from a Multicenter, Case Series.” The Pediatric Infectious Disease Journal. 2013 32 (1): 17–22. https://doi.org/10.1097/INF.0B013E3182703790.

(12) “GARDP Study Reveals That Babies Are Increasingly Dying of Neonatal Sepsis Caused by Drug-Resistant Bacterial Infections – GARDP.” n.d. Accessed May 21, 2022. https://gardp.org/news-resources/gardp-study-reveals-that-babies-are-increasingly-dying-of-neonatal-sepsis-caused-by-drug-resistant-bacterial-infections/.

(13) Okomo, Uduak, Edem N.K. Akpalu, Kirsty Le Doare, Anna Roca, Simon Cousens, Alexander Jarde, Mike Sharland, Beate Kampmann, and Joy E. Lawn. “Aetiology of Invasive Bacterial Infection and Antimicrobial Resistance in Neonates in Sub-Saharan Africa: A Systematic Review and Meta-Analysis in Line with the STROBE-NI Reporting Guidelines.” The Lancet Infectious Diseases. 2019, (11): 1219–34. https://doi.org/10.1016/S1473-3099(19)30414-1.

 (14) Folgori, Laura, and Julia Bielicki. “Future Challenges in Pediatric and Neonatal Sepsis: Emerging Pathogens and Antimicrobial Resistance.” Journal of Pediatric Intensive Care. 2019, 08 (01): 017–024. https://doi.org/10.1055/S-0038-1677535.

(15) Yumoto, Yuko. “[The Procedures for Sampling Specimens in Pediatrics].” Rinsho Byori. The Japanese Journal of Clinical Pathology. 2104, 62 (8): 766–74.

(16) Reuter, Anja, Jennifer Hughes, and Jennifer Furin. “Challenges and Controversies in Childhood Tuberculosis.” The Lancet. 2019, 394 (10202): 967–78. https://doi.org/10.1016/S0140-6736(19)32045-8.

(17) Zea-Vera, Alonso, and Theresa J. Ochoa. “Challenges in the Diagnosis and Management of Neonatal Sepsis.” Journal of Tropical Pediatrics. 2015, 61 (1): 1–13. https://doi.org/10.1093/tropej/fmu079.

(18) Stephenson, Terence. “How Children’s Responses to Drugs Differ from Adults.” British Journal of Clinical Pharmacology. 2005, 59 (6): 670. https://doi.org/10.1111/J.1365-2125.2005.02445.X.

(19) Årdal, Christine, Manica Balasegaram, Ramanan Laxminarayan, David McAdams, Kevin Outterson, John H. Rex, and Nithima Sumpradit. “Antibiotic Development — Economic, Regulatory and Societal Challenges.” Nature Reviews Microbiology. 2019, 18:5 18 (5): 267–74. https://doi.org/10.1038/s41579-019-0293-3.

20) Procianoy, Renato Soibelmann, and Rita C. Silveira. “The Challenges of Neonatal Sepsis Management.” Jornal de Pediatria. 2020, 96 (xx): 80–86. https://doi.org/10.1016/j.jped.2019.10.004.

(21) Hyun, David Y., Adam L. Hersh, Katie Namtu, Debra L. Palazzi, Holly D. Maples, Jason G. Newland, and Lisa Saiman. “Antimicrobial Stewardship in Pediatrics: How Every Pediatrician Can Be a Steward.” JAMA Pediatrics. 2013, 167 (9): 859–66. https://doi.org/10.1001/JAMAPEDIATRICS.2013.2241.

(22) Storr, Julie, Anthony Twyman, Walter Zingg, Nizam Damani, Claire Kilpatrick, Jacqui Reilly, Lesley Price. “Core Components for Effective Infection Prevention and Control Programmes: New WHO Evidence-Based Recommendations.” Antimicrobial Resistance & Infection Control. 2017, 6:1 6 (1): 1–18. https://doi.org/10.1186/S13756-016-0149-9.

Acknowledgement: Background Image copyright by Richard A. Chance

About the Authors: Jimmy is a finalist with a Bachelors in Biochemistry from Jomo Kenyatta University of Agriculture and Technology and Janice is a pharmacy student at the University of Nairobi. Both hail from Kenya and are very passionate and active AMR champions locally and regionally.

Leave a Comment

Your email address will not be published. Required fields are marked *