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Rational use of antimicrobials in the treatment of upper airway infections Please cite this article as: Miguélez SA, Garcia-Marcos L. Rational use of antimicrobials in the treatment of upper airway infections. J Pediatr (Rio J). 2020;96(S1):111-9.

Abstract

Objective

To analyze the main cause of the irresponsible use of antibiotics at the pediatric level in a very frequent, usually self-limited, and typically viral condition: upper airway respiratory infections.

Sources

Different databases were searched using specific terms related to resistance to antibiotics, upper airway respiratory infections, and pediatrics patients.

Summary of the findings

Effectiveness varies depending on the place, the form of intervention, and the resources used. Multiple interventions appear to be more effective. The foundations of treatment are training in technical aspects and in communication skills for the prescribers, and having enough time for each patient; and training through the health clinic and the media for patients/parents. Deferred prescription and the use of rapid diagnostic tests in the primary care setting have been shown to be effective. A fluid relationship based on trust between clinicians and parents/guardians is one of the keystones.

Conclusions

Any project that seeks to be totally effective must include a health authority, which in addition to helping implement these measures, has the firm intention of drastically reducing the use of antibiotics in animals and in the environment, as well as favoring research into new antimicrobials.

Keywords
Antibiotic resistance; Upper airway infections; Children

Resumo

Objetivo

Analisar a principal causa do uso irresponsável de antibióticos em nível pediátrico de doenças muito frequentes, normalmente autolimitadas e virais: infecções respiratórias das vias aéreas superiores.

Fontes

Diferentes bases de dados foram pesquisadas com termos específicos relacionados à resistência a antibióticos, infecções respiratórias das vias aéreas superiores e pacientes de pediatria.

Resumo dos achados

A eficácia varia, depende do local, da forma e dos recursos usados. As formas de múltiplas intervenções parecem mais eficazes. O treinamento em aspectos técnicos e habilidades de comunicação para médicos e tempo suficiente para cada paciente, além do treinamento por meio da clínica e da mídia para pacientes/pais, são a base da eficácia. Prescrições de uso posterior e testes de diagnóstico rápido no ambiente de cuidado primário mostraram ser eficazes. Uma relação de confiança entre médicos e pais ou responsáveis é uma das pedras angulares.

Conclusões

Qualquer projeto que busque ser completamente eficaz deve incluir uma autoridade em saúde, que, além de ajudar a implantar as medidas nos pacientes, tem a sólida intenção de reduzir drasticamente o uso de antibióticos em animais e no meio ambiente, além de favorecer a pesquisa sobre novos antimicrobianos.

Palavras-chave
Resistência antibiótica; Infecções das vias aéreas superiores; Crianças

Resistance to antibiotics has become one of the most important public health problems throughout the world in today’s society.11 Bosley H, Henshall C, Appleton JV, Jackson D. A systematic review to explore influences on parental attitudes towards antibiotic prescribing in children. J Clin Nurs. 2018;27:892-905.,22 OMS. Proyecto del 13º Programa General de Trabajo 2019-2023. Available from: https://www.who.int/es/emergencies/ten-threats-to-global-health-in-2019.
https://www.who.int/es/emergencies/ten-t...
This increase, which has been observed since at least the last years of the 20th century, has caused a movement, which has been generalized at a global level, with the aim of limiting the potentially catastrophic effects that have been forecast. The World Health Organization (WHO) defined antibiotic resistance as the resistance of a microorganism to an antibiotic which it had been previously sensitive to (WHO, 2016).

The golden age of antibiotics, when new molecules appeared every year, has reached its end and the industry is seen as being unable to develop new molecules that can overcome the appearance of new resistances.33 Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, et al. Antibiotic resistance: a rundown of a global crisis. Infect Drug Resist. 2018;11:1645-58.

4 Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:1-12.
-55 Sukkar E. Why are there so few antibiotics in the research and development pipeline? Pharma J. 2013;291:520.

The consequences of antibiotic resistance are difficult to forecast, but it is estimated that in 2050 it will be the cause of death of around ten million people and assume an enormous economic cost.66 O’Neill J. Antimicrobial resistance: tackling a crisis for the health and wealth of nations. London, UK: The Review on Antimicrobial Resistance; 2014. The European Centre for Disease Prevention Control (ECDC) calculates that it currently causes the death of 25,000 people in Europe every year and has a cost of 1.5 billion euros per year.77 European Centre for Disease Prevention and Control (ECDC). Antimicrobial resistance in focus. [Cited 2019 Oct 26]. Available from: http://ecdc.europa.eu/en/healthtopics/antimicrobialresistance/Pages/index.aspx.
http://ecdc.europa.eu/en/healthtopics/an...

The appearance of resistances to antibiotics is a complex problem which is affected by multiple factors:88 Castro-Sánchez E, Moore LS, Husson F, Holmes AH. What are the factors driving antimicrobial resistance? Perspectives from a public event in London, England. BMC Infect Dis. 2016;16:465. environmental factors, those of the microorganism itself, and those regarding the use of antibiotics in patients and also in animals, especially in the food production chain.33 Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, et al. Antibiotic resistance: a rundown of a global crisis. Infect Drug Resist. 2018;11:1645-58.,99 Cantarero-Arévalo L, Hallas MP, Kaae S. Parental knowledge of antibiotic use in children with respiratory infections: a systematic review. Int J Pharm Pract. 2017;25:31-49. Chokshi et al.1010 Chokshi A, Sifri Z, Cennimo D, Horng H. Global contributors to antibiotic resistance. J Global Infect Dis. 2019;11:36-42. analyzed the contribution to the development of antimicrobial resistances according to the socio-economic and political factors of different countries, extracted from the data of the countries’ own health agencies. Their conclusion is that there are many factors involved, and that these differ between developed and developing countries. It should be highlighted that research into new antibiotics is scarce, given the lack of incentives from public administrations.

In the light of the seriousness of this situation, important changes have been occurring in recent years, not only from the health institutions but also from the highest levels of politics.

In 2016, 193 world heads of state at a meeting in the General Assembly of the United Nations committed themselves to adopting a common strategy to tackle the fundamental causes of this problem from a focus of “One Health”1111 Roca I, Akova M, Baquero F, Carlet J, Cavaleri M, Coenen S, et al. The global threat of antimicrobial resistance: science for intervention. New Microbes New Infect. 2015;6:22-9. and the WHO included it, in 2019, in its five-year general strategic plan among the ten most important threats to health (https://www.who.int/es/emergencies/ten-threats-to-global-health-in-2019). A ray of hope has appeared, as some studies have communicated that there has been a change in the trend and that consumption has stabilized in recent years.1212 Littmann J, Buyx A, Cars O. Antibiotic resistance: an ethical challenge. Int J Antimicrob Agents. 2015;46:359-61. However, there is still a great deal more to be done and the current situation remains unsustainable.

Numerous factors intervene in antibiotic administration to humans, which ultimately condition their inappropriate use. The most important factors include those referring to clinicians, while others refer to the patients, parents/guardians, and even to society itself.33 Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, et al. Antibiotic resistance: a rundown of a global crisis. Infect Drug Resist. 2018;11:1645-58.,1313 Vaz LE, Kleinman KP, Raebel MA, Nordin JD, Lakoma MD, Dutta-Linn MM, et al. Recent trends in outpatient antibiotic use in children. Pediatrics. 2014;133:375-85.,1414 Szymczak JE, Feemster KA, Zaoutis TE, Gerber JS. Pediatrician perceptions of an outpatient antimicrobial stewardship intervention. Infect Control Hosp Epidemiol. 2014;35:S69-78. Moreover, when discussing inadequate antibiotic use, the present authors do not only refer to the use of antibiotics in unnecessary situations but also, when required, to the use of broad-spectrum antibiotics instead of the most suitable for each pathology and with a narrower spectrum, as well as the use of incorrect doses and treatment periods.1515 Tonkin-Crine S, Yardley L, Little P. Antibiotic prescribing for acute respiratory tract infections in primary care: a systematic review and meta-ethnography. J Antimicrob Chemother. 2011;66:2215-23. The latter two aspects have been identified as being of great importance in the development of bacterial resistances. The use of sub-doses, as occurs with the use of expired antibiotics or by incorrect prescription, is related to increased resistances.99 Cantarero-Arévalo L, Hallas MP, Kaae S. Parental knowledge of antibiotic use in children with respiratory infections: a systematic review. Int J Pharm Pract. 2017;25:31-49. A prolonged duration of antibiotic treatment gives a false security to the prescriber. However, during recent years it has been shown that, in frequent conditions, short courses of antibiotics are as efficacious, without any effect on the curing or recurrence rates. A short course improves adherence and diminishes side effects and bacterial resistances.1010 Chokshi A, Sifri Z, Cennimo D, Horng H. Global contributors to antibiotic resistance. J Global Infect Dis. 2019;11:36-42. The primary care setting accounts for between 70 and 80 % of prescriptions and the majority are for airway infections, in which a viral etiology is predominant.1515 Tonkin-Crine S, Yardley L, Little P. Antibiotic prescribing for acute respiratory tract infections in primary care: a systematic review and meta-ethnography. J Antimicrob Chemother. 2011;66:2215-23.

Among the causes regarding clinicians, the most important are the handling of uncertainty (such as fears, lack of knowledge, diagnostic errors), inadequate communication, undervaluing the disease with respect to that felt by the parents, or the demand perceived from the patients or parents/guardians.1313 Vaz LE, Kleinman KP, Raebel MA, Nordin JD, Lakoma MD, Dutta-Linn MM, et al. Recent trends in outpatient antibiotic use in children. Pediatrics. 2014;133:375-85.,1414 Szymczak JE, Feemster KA, Zaoutis TE, Gerber JS. Pediatrician perceptions of an outpatient antimicrobial stewardship intervention. Infect Control Hosp Epidemiol. 2014;35:S69-78.,1616 Goossens H, Ferech M, Vander Stichele R, Elseviers M. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet. 2005;365:579-87.

If we refer to the people as a population as well as when we act as patients, the behavior regarding antibiotics has been established depending on numerous interconnected variables: access to services, adequate medical services and access to medication, knowledge on antibiotics, and social attitudes. In the general population, knowledge on the topic may not be adequate in an important percentage of patients.11 Bosley H, Henshall C, Appleton JV, Jackson D. A systematic review to explore influences on parental attitudes towards antibiotic prescribing in children. J Clin Nurs. 2018;27:892-905.,33 Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, et al. Antibiotic resistance: a rundown of a global crisis. Infect Drug Resist. 2018;11:1645-58.,88 Castro-Sánchez E, Moore LS, Husson F, Holmes AH. What are the factors driving antimicrobial resistance? Perspectives from a public event in London, England. BMC Infect Dis. 2016;16:465. Some patients interrupt their treatment once they feel clinically better and self-medicate when faced with a similar clinical picture to another for which they had received antibiotics.1717 Lucas PJ, Cabral C, Hay AD, Horwood J. A systematic review of parent and clinician views and perceptions that influence prescribing decisions in relation to acute childhood infections in primary care. Scand J Prim Health Care. 2015;33:11-20.

This problem is especially relevant in pediatric ages. Antibiotics are the most used therapeutic agents in this population range,1818 Hersh AL, Shapiro DJ, Pavia AT, Shah SS. Antibiotic prescribing in ambulatory pediatrics in the United States. Pediatrics. 2011;128:1053-61. and also, as in the general population, above all in primary care,1919 Goldman JL, Newland JG. New Horizons for Pediatric Antibiotic Stewardship. Infect Dis Clin North Am. 2015;29:503-11.,2020 Yonts AB, Kronman MP, Hamdy RF. The burden and impact of antibiotic.prescribing in ambulatory pediatrics. Curr Probl Pediatr Adolesc Health Care. 2018;48:272-88. with those indicated in respiratory cases accounting for more than 70 % of the consultations in which antibiotics are prescribed. Upper respiratory tract infections are the most frequent pathologies, including the common cold, pharyngitis, otitis, and sinusitis. These processes are of a viral etiology or in many cases are self-limiting and therefore do not require antibiotic treatment.2020 Yonts AB, Kronman MP, Hamdy RF. The burden and impact of antibiotic.prescribing in ambulatory pediatrics. Curr Probl Pediatr Adolesc Health Care. 2018;48:272-88.,2121 Alzahrani MS, Maneno MK, Daftary MN, Wingate L, Ettienne EB. Factors associated with prescribing broad-spectrum antibiotics for children with upper respiratory tract infections in ambulatory care settings. Clin Med Insights Pediatr. 2018;12, 1179556518784300. eCollection 2018. Erratum in: Clin Med Insights Pediatr. 2018 Dec 27; 12:1179556518800765.

Many studies suggest that approximately half of the antibiotics used in pediatrics are incorrect in their indication, choice of molecule, and duration.33 Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, et al. Antibiotic resistance: a rundown of a global crisis. Infect Drug Resist. 2018;11:1645-58.,2222 Youngster I, Avorn J, Belleudi V, Cantarutti A, Díez-Domingo J, Kirchmayer U, et al. Antibiotic use in children - a cross-national analysis of 6 countries. J Pediatr. 2017;182:239-44, e1. Moreover, they are not innocuous and may provoke side effects such as diarrhea, exanthemas, and vomiting, leading to more than 140,000 visits to emergency services in 2008.2323 Shehab N, Patel PR, Srinivasan A, Budnitz DS. Emergency department visits for antibiotic-associated adverse events. Clin Infect Dis. 2008;47:735-43.

As has been stressed previously, this is particularly true for the first years of life, above all in infants under two years of age,2020 Yonts AB, Kronman MP, Hamdy RF. The burden and impact of antibiotic.prescribing in ambulatory pediatrics. Curr Probl Pediatr Adolesc Health Care. 2018;48:272-88. and in the primary care setting, in which the majority of upper airway infections (common cold, pharyngitis) have a viral aetiology.2424 Clavenna A, Bonati M. Differences in antibiotic prescribing in paediatric outpatients. Arch Dis Child. 2011;96:590-5. The viral etiology of these infections together with the knowledge that group A Streptococcus does not usually cause pharyngitis in patients under 3 years of age make it unnecessary in most cases to use antibiotics in the young infants in such infections. Acute otitis media (AOM), which is frequently diagnosed, is in many cases self-limiting.2525 Nash DR, Harman J, Wald ER, Kelleher KJ. Antibiotic prescribing by primary care physicians for children with upper respiratory tract infections. Arch Pediatr Adolesc Med. 2002;156:1114-9.

The diagnosis that is most associated with antibiotic use is for AOM. It is a disease that is difficult to diagnose, and more so in the first 2 years of life when the clinical data and the difficulty in viewing the timpani offer a great deal of help in some cases. Some authors believe it to be an over-diagnosed disease.2222 Youngster I, Avorn J, Belleudi V, Cantarutti A, Díez-Domingo J, Kirchmayer U, et al. Antibiotic use in children - a cross-national analysis of 6 countries. J Pediatr. 2017;182:239-44, e1.,2626 Pichichero ME. Acute Otitis Media: Part I. Improving diagnostic accuracy. Am Fam Physician. 2000;61:2051-6. A study carried out by Alzahrani et al.2121 Alzahrani MS, Maneno MK, Daftary MN, Wingate L, Ettienne EB. Factors associated with prescribing broad-spectrum antibiotics for children with upper respiratory tract infections in ambulatory care settings. Clin Med Insights Pediatr. 2018;12, 1179556518784300. eCollection 2018. Erratum in: Clin Med Insights Pediatr. 2018 Dec 27; 12:1179556518800765. examined the antibiotics used in AOM and found that broad-spectrum antibiotics were used in up to 41.2 % of cases - the main cause for prescribing them. These figures were similar to those found in another prior study, also conducted in the United States, ten years previously. A similar situation was found with sinusitis, and both diagnoses increased the risk of receiving antibiotics when compared to acute pharyngitis. All of these occurred without observing better clinical results.2727 Gerber JS, Ross RK, Bryan M, Localio AR, Szymczak JE, Wasserman R. Association of broad- vs narrow-spectrum antibiotics with treatment failure, adverse events, and quality of life in children with acute respiratory tract infections. JAMA. 2017;318:2325-36.

However, apart from enhancing the appearance of resistances, antibiotics have a great impact on microbiome. This is formed from birth and its most critical phases occur during childhood, especially during the first months of life. Changes in microbiome produce changes in vital functions and has been related with the appearance, in later stages, of metabolism problems such as obesity2828 Turta O, Rautava S. Antibiotics, obesity and the link to microbes - what are we doing to our children? BMC Med. 2016;14:57.; with autoimmune diseases such as diabetes, rheumatoid arthritis, and multiple sclerosis 2929 Vangay P, Ward T, Gerber JS, Knights D. Antibiotics, pediatric dysbiosis, and disease. Cell Host Microbe. 2015;17:553-64.; and with allergic diseases.3030 Obiakor CV, Tun HM, Bridgman SL, Arrieta MC, Kozyrskyj AL. The association between early life antibiotic use and allergic disease in young children: recent insights and their implications. Expert Rev Clin Immunol. 2018;14:841-55. The association grows closer with lower age and higher number of antibiotic doses.2020 Yonts AB, Kronman MP, Hamdy RF. The burden and impact of antibiotic.prescribing in ambulatory pediatrics. Curr Probl Pediatr Adolesc Health Care. 2018;48:272-88. Infancy is a critical period in the immunological and metabolic development; antibiotic use may alter these processes.

Another very important piece of data that shows the wide margin for improvement is the variability that exists among different countries, areas, and professionals when analyzing antibiotic prescription rates, taking into account that this cannot be justified by socio-sanitary factors alone.2020 Yonts AB, Kronman MP, Hamdy RF. The burden and impact of antibiotic.prescribing in ambulatory pediatrics. Curr Probl Pediatr Adolesc Health Care. 2018;48:272-88.,2222 Youngster I, Avorn J, Belleudi V, Cantarutti A, Díez-Domingo J, Kirchmayer U, et al. Antibiotic use in children - a cross-national analysis of 6 countries. J Pediatr. 2017;182:239-44, e1.,2424 Clavenna A, Bonati M. Differences in antibiotic prescribing in paediatric outpatients. Arch Dis Child. 2011;96:590-5.,2525 Nash DR, Harman J, Wald ER, Kelleher KJ. Antibiotic prescribing by primary care physicians for children with upper respiratory tract infections. Arch Pediatr Adolesc Med. 2002;156:1114-9.,3131 Schwartz KL, Brown KA, Etches J, Langford BJ, Daneman N, Tu K, et al. Predictors and variability of antibiotic prescribing amongst family physicians. J Antimicrob Chemother. 2019;74:2098-105. The cause of this variability may also be multiple, linked to different prescription polices, to different health systems, to the pharmaceutical market, to sociocultural and economic factors, but above all linked to the prescribers themselves,2424 Clavenna A, Bonati M. Differences in antibiotic prescribing in paediatric outpatients. Arch Dis Child. 2011;96:590-5. which is indeed unacceptable. Youngster et al.2222 Youngster I, Avorn J, Belleudi V, Cantarutti A, Díez-Domingo J, Kirchmayer U, et al. Antibiotic use in children - a cross-national analysis of 6 countries. J Pediatr. 2017;182:239-44, e1. found up to a 7.5-fold difference when referring to the 0-2 year-old group, in a study carried out in six countries in Europe, the United States, and Korea in children younger than 18 years, divided into four sub-groups. The present authors’ experience in a study performed in their region in 3 year-old children (unpublished data) showed up to a seven-fold difference among the prescribing clinicians, without it being possible to justify this by other factors and without the results being compromised in health terms. These differences are both qualitative and quantitative2424 Clavenna A, Bonati M. Differences in antibiotic prescribing in paediatric outpatients. Arch Dis Child. 2011;96:590-5. and usually coincide in lower antibiotic use coupled with a better use of those that are used and with a narrower spectrum.2222 Youngster I, Avorn J, Belleudi V, Cantarutti A, Díez-Domingo J, Kirchmayer U, et al. Antibiotic use in children - a cross-national analysis of 6 countries. J Pediatr. 2017;182:239-44, e1.,2424 Clavenna A, Bonati M. Differences in antibiotic prescribing in paediatric outpatients. Arch Dis Child. 2011;96:590-5.,3232 Yan J, Hawes L, Turner L, Mazza D, Pearce C, Buttery J. Antimicrobial prescribing for children in primary care. J Paediatr Child Health. 2019;55:54-8. For example, the United States is among the countries that use the most antibiotics in children, more than double that of countries such as Germany and the Netherlands; despite the existence of clinical guides published by the American Academy of Pediatrics (AAP) or the Infectious Disease Society of America (IDSA), the use of azithromycin is found in second place in certain pathologies in which its use should be far more restricted.2020 Yonts AB, Kronman MP, Hamdy RF. The burden and impact of antibiotic.prescribing in ambulatory pediatrics. Curr Probl Pediatr Adolesc Health Care. 2018;48:272-88. It is, therefore, an excellent marker of bad practice and appears as an important area for improvement.2424 Clavenna A, Bonati M. Differences in antibiotic prescribing in paediatric outpatients. Arch Dis Child. 2011;96:590-5.

Neutralizing and reverting this enormous and complex problem also requires complex intervention that covers all the factors that are involved, i.e., global access to tools for the prevention, diagnosis, and treatment; ensuring that responsible use is made of existing antibiotics; and favoring the research and development of new molecules.3333 Hoffman SJ, Outterson K, Røttingen JA, Cars O, Clift C, Rizvi Z, et al. An international legal framework to address antimicrobial resistance. Bull World Health Organ. 2015;93:66. Different entities, organisms, and states, led by the WHO, work to achieve global access to all the prevention, diagnosis, and treatment tools and to stimulate research into new antibiotics, vaccines, and other drugs.3434 Daulaire N, Bang A, Tomson G, Kalyango JN, Cars O. Universal access to effective antimicrobials: an essential feature of global collective action against antimi-crobial resistance. J Law Med Ethics. 2015;43:17-21.,3535 Laximinarayan R, Duse A, Wattal C, Zaidi AKM, Wertheim HFL, Sumpradit N, et al. Antibiotic resistance—the need for global solutions. Lancet Infect Dis. 2013;13:1057-98.

In recent years different interventions have been studied and put into practice to influence the most important agents involved in rational antibiotic use, the clinicians/prescribers, the patients, the parents/guardians, and society in general. Some interventions are carried out acting on a single factor while other do so on multiple factors simultaneously. Some of those that the present authors consider to be the most important are analyzed below.

On prescribers

Some degree of effectiveness has been shown by many strategies, but they are inconsistent over time and, moreover, lose their effectiveness when they are no longer applied.3636 Gerber JS, Prasad PA, Fiks AG, Localio AR, Bell LM, Keren R, et al. Durability of benefits of an outpatient antimicrobial stewardship intervention after discontinuation of audit and feedback. JAMA. 2014;312:2569-70.

Wei et al.3737 Wei X, Zhang Z, Walley JD, Hicks JP, Zeng J, Deng S, et al. Effect of a training and educational intervention for physicians and caregivers on antibiotic prescribing for upper respiratory tract infections in children at primary care facilities in rural China: a cluster-randomised controlled trial. Lancet Glob Health. 2017;5:e1258-67. performed a study in patients aged 2-14 years who attended several hospitals in a province as outpatients. The intervention consisted in educating the clinicians (reviewing guides and training in the prescription), monthly reviews, and brief education given to the care providers in the clinic and previously in the waiting room by means of videos in a group of hospitals, whereas another similar group received no intervention. They achieved a 29 % reduction in prescriptions in just three months in the intervention group compared to the control group.

Gerber et al.3838 Gerber JS, Prasad PA, Fiks AG, Localio AR, Grundmeier RW, Bell LM, et al. Effect of an outpatient antimicrobial stewardship intervention on broad-spectrum antibiotic prescribing by primary care pediatricians: a randomized trial. JAMA. 2013;309:2345-52. studied whether antimicrobial stewardship intervention could reduce the incorrect prescription of broad-spectrum antibiotics for bacterial and viral ARTIs during one year after the interventions. The interventions were carried out in 162 pediatricians and included education on the topic together with audit and feedback of their prescriptions. The main outcomes were changes in the behavior on broad-spectrum prescription for acute sinusitis, streptococcal pharyngitis, and pneumonia, and change in antibiotic use for viral infections. The proportion of children receiving antibiotics was importantly reduced after interventions. This reduction was statistically significant for pneumonia and the same trend (although without reaching statistical significance) was found for acute sinusitis.

Audit and feedback interventions require the least amount of resources to be implemented.3939 Hemkens LG, Saccilotto R, Reyes SL, Glinz D, Zumbrunn T, Grolimund O, et al. Personalized prescription feedback using routinely collected data to reduce antibiotic use in primary care: a randomized clinical trial. JAMA Intern Med. 2017;177:176-83. They produce a small but statistically significant benefit,3939 Hemkens LG, Saccilotto R, Reyes SL, Glinz D, Zumbrunn T, Grolimund O, et al. Personalized prescription feedback using routinely collected data to reduce antibiotic use in primary care: a randomized clinical trial. JAMA Intern Med. 2017;177:176-83.,4040 Ivers N, Jamtvedt G, Flottorp S, Young JM, Odgaard-Jensen J, French SD, et al. Audit and feedback: effects on professional practice and healthcare outcomes. Cochrane Database Syst Rev. 2012;6:CD000259. although with regard to the issue of reducing antibiotics, their benefit is not clear.

On prescribers and parents/guardians

The interaction and good relationship of trust between patient, parents, and clinicians is a basic foundation of the attempts to reduce inappropriate antibiotic use. Different studies have assessed parents’ attitudes and knowledge, and although it is true that some parents have the wrong concept regarding which diseases antibiotics are necessary for and in which they are not,11 Bosley H, Henshall C, Appleton JV, Jackson D. A systematic review to explore influences on parental attitudes towards antibiotic prescribing in children. J Clin Nurs. 2018;27:892-905.,1111 Roca I, Akova M, Baquero F, Carlet J, Cavaleri M, Coenen S, et al. The global threat of antimicrobial resistance: science for intervention. New Microbes New Infect. 2015;6:22-9. it is no less true that they only want them when they are really necessary.4141 Finkelstein JA, Dutta-Linn M, Meyer R, Goldman R. Childhood infections, antibiotics, and resistance: what are parents saying now? Clin Pediatr (Phila). 2014;53:145-50. However, they become unhappy when clinicians minimize the importance of their children’s symptoms, do not sympathize with the parents’ problems, and fail to offer an alternative.11 Bosley H, Henshall C, Appleton JV, Jackson D. A systematic review to explore influences on parental attitudes towards antibiotic prescribing in children. J Clin Nurs. 2018;27:892-905.,4242 Havens L, Schwartz M. Identification of parents’ perceptions of antibiotic use for individualized community education. Glob Pediatr Health. 2016;3:1-7.,4343 Cabral C, Horwood J, Hay AD, Lucas PJ. How communication affects prescription decisions in consultations for acute illness in children: a systematic review and meta-ethnography. BMC Fam Pract. 2014;15:63.

In the interaction between parents and prescribers, the latter perceive an unproven pressure from the parents to prescribe antibiotics, and the relationship between both sides deteriorates if this does not happen.1212 Littmann J, Buyx A, Cars O. Antibiotic resistance: an ethical challenge. Int J Antimicrob Agents. 2015;46:359-61.,1313 Vaz LE, Kleinman KP, Raebel MA, Nordin JD, Lakoma MD, Dutta-Linn MM, et al. Recent trends in outpatient antibiotic use in children. Pediatrics. 2014;133:375-85.,4444 Mangione-Smith R, Zhou C, Robinson JD, Taylor JA, Elliott MN, Heritage J. Communication practices and antibiotic use for acute respiratory tract infections in children. Ann Fam Med. 2015;13:221-7. In fact, parents’ satisfaction seems to be more related to the quality of the communication than with the fact of using or not using antibiotics in a specific case.1212 Littmann J, Buyx A, Cars O. Antibiotic resistance: an ethical challenge. Int J Antimicrob Agents. 2015;46:359-61.,1313 Vaz LE, Kleinman KP, Raebel MA, Nordin JD, Lakoma MD, Dutta-Linn MM, et al. Recent trends in outpatient antibiotic use in children. Pediatrics. 2014;133:375-85.,4444 Mangione-Smith R, Zhou C, Robinson JD, Taylor JA, Elliott MN, Heritage J. Communication practices and antibiotic use for acute respiratory tract infections in children. Ann Fam Med. 2015;13:221-7.

In the case of children, above all in the youngest, the parents’ attitude and their knowledge of antibiotics is one of the most important factors. Bosley et al.11 Bosley H, Henshall C, Appleton JV, Jackson D. A systematic review to explore influences on parental attitudes towards antibiotic prescribing in children. J Clin Nurs. 2018;27:892-905. carried out a systematic review to understand the factors that may influence the attitude of parents regarding antibiotic use in their children.

Those authors found a great variability in the amount and quality of the knowledge and in the relationship/communication with their pediatricians, and highlighted that a lack of knowledge on their use, the relationship between pediatricians and parents in general, and in each case in particular in the management of each disease and past experiences are very influential factors. A relationship based on trust, with clear messages that can be clearly understood, must exist and the parents must not perceive that their pediatrician undervalues their children’s disease.

The knowledge level was greater in developed countries, and antibiotic use was related to the education level received and to the age and anxiety of the parents.11 Bosley H, Henshall C, Appleton JV, Jackson D. A systematic review to explore influences on parental attitudes towards antibiotic prescribing in children. J Clin Nurs. 2018;27:892-905.

Mangione et al.4444 Mangione-Smith R, Zhou C, Robinson JD, Taylor JA, Elliott MN, Heritage J. Communication practices and antibiotic use for acute respiratory tract infections in children. Ann Fam Med. 2015;13:221-7. studied parent satisfaction depending on their communication with their pediatricians. The existence of positive messages (symptomatic medication), plus negative messages (why antibiotics were not used), plus the existence of a contingency plan (follow-up) notably increased the acceptance and satisfaction of parents and facilitated the reduction in unjustified antibiotic use.

Cantarero et al.99 Cantarero-Arévalo L, Hallas MP, Kaae S. Parental knowledge of antibiotic use in children with respiratory infections: a systematic review. Int J Pharm Pract. 2017;25:31-49. carried out a systematic review with the objective of describing the characteristics of parents’ knowledge about antibiotic use in respiratory infections, their attitude towards their pediatrician, and their behavior when their child suffers an infection. Its objective was to answer the questions as to whether there is a relationship between the degree of knowledge and judicious antibiotic use, and to analyze the sociodemographic factors linked to antibiotic use in these infections. They found that parental knowledge on antibiotics affects their attitudes and behavior, although said acceptable knowledge does not always impede antibiotic use, because few parents believe that their children receive too many antibiotics. The main problem detected was the lack of a complete physical examination and specific clarifications that could help the child in his/her recovery, more than merely prescribing antibiotics with no further explanation. Once again, good communication and not undervaluing the problem are shown to be instrumental in reducing inadequate antibiotic use.

Lucas et al.1515 Tonkin-Crine S, Yardley L, Little P. Antibiotic prescribing for acute respiratory tract infections in primary care: a systematic review and meta-ethnography. J Antimicrob Chemother. 2011;66:2215-23. conducted research into qualitative studies with the aim of describing the points of view, beliefs, and attitudes of parents, children, and pediatricians that may influence prescribing antibiotics for acute infections in the primary care setting. They highlighted certain points that the present authors’ consider to be of utmost importance in understanding this issue and seeking to find effective solutions. Clinicians frequently use antibiotics “just in case,” when they do not feel sure of the results at a clinical and social level or due to a supposed pressure from parents. On the contrary, this can be avoided when parents do not ask for them or resistance or intolerance problems exist. Parents ask for antibiotics when they believe that they will improve their child’s disease, but also wish to avoid the antibiotic’s side-effects. Finally, something as straightforward as paying careful attention, with a good examination, in itself transmits security to parents. This may create a conflict with clinicians, who seek to finish the consultation quickly on occasions. Parents’ anxiety coupled with green nasal mucus were clear indicators for antibiotic prescription. The confidence in the clinician-parent/patient relationship, educating the parents on the evolution of the process, and their satisfaction are essential in not prescribing antibiotics.

Hernández-Díaz et al.4545 Hernández-Díaz I, Ayala-Meléndez A, González-González E, Rosario-Calderón I, Figueroa-Ríos D, Melin K, et al. Knowledge and beliefs, behaviors, and adherence among Latino parents or legal guardians related to antibiotic use for upper respiratory tract infections in children under 6 years of age. J Am Pharm Assoc. 2003;2019(59):506-13. studied the beliefs, behavior, and adherence of parents/guardians of children of Latin origin, under the age of 6 years, in the United States with respect to antibiotic use in upper airway respiratory infections, concluding that the knowledge and erroneous beliefs of that group indicate a significant problem, and that this is more so the lower the educational level and age of the parents is.

Van Hecke et al.4646 Van Hecke O, Butler CC, Wang K, Tonkin-Crine S. Parents’ perceptions of antibiotic use and antibiotic resistance (PAUSE): a qualitative interview study. J Antimicrob Chemother. 2019;74:1741-7. carried out a qualitative study about the perception of parents on antibiotic use and resistance in children under the age of 5 years; they found them to be very optimistic because they believed that their families would not be affected by resistance since they used few antibiotics, and very few considered that resistance is a problem. Furthermore, they considered that the campaigns about this problem are in line with their behavior and thus they will not be affected, thus those authors concluded that they must be revised.

Kianmehr et al.4747 Kianmehr H, Sabounchi NS, Seyedzadeh Sabounchi S, Cosler LE. Patient expectation trends on receiving antibiotic prescriptions for respiratory tract infections: a systematic review and meta-regression analysis. Int J Clin Pract. 2019;73:e13360. carried out a systematic review on the expectations patients have when receiving antibiotics for airway infections and concluded that there is a trend to a lower perceived need over the years and that this was global, thus highlighting that this may be a point of support for the prescribers in order to improve antibiotic use.

On informative campaigns

Information campaigns are another of the possible interventions to reduce antibiotic use and, as with other strategies, have also produced contradictory results. Huttner et al.4848 Huttner B, Goossens H, Verheij T, Harbarth S. CHAMP consortium. Characteristics and outcomes of public campaigns aimed at improving the use of antibiotics in outpatients in high-income countries. Lancet Infect Dis. 2010;10:17-31. performed a review of campaigns carried out in developed countries which were driven and developed by health authorities at both national as well as regional level. Five of them were specifically directed at the pediatric population. The methods varied greatly: they used written formats such as pamphlets, posters, and notices, as well as audio-visual techniques. These interventions were part of a broader campaign that was usually directed at prescribing clinicians. Those authors concluded that the effects are difficult to assess, but that the data suggest that they may have a positive effect. However, Roope et al.,4949 Roope LS, Tonkin-Crine S, Butler CC, Crook D, Peto T, Peters M. Reducing demand for antibiotic prescriptions: evidence from an online survey of the general public on the interaction between preferences, beliefs and information, United Kingdom, 2015. Euro Surveill. 2018. doi: 2018.23.25.1700424.
https://doi.org/2018.23.25.1700424...
in a study carried out in the United Kingdom, found that these campaigns can have a paradoxical effect of actually producing an increase in antibiotic demand. Therefore, they recommend that such campaigns must be tested in small areas prior to being generalized. The messages must be clear, simple, impacting, highlighting all the positive aspects, but without omitting the drawbacks and even evoking fear.4848 Huttner B, Goossens H, Verheij T, Harbarth S. CHAMP consortium. Characteristics and outcomes of public campaigns aimed at improving the use of antibiotics in outpatients in high-income countries. Lancet Infect Dis. 2010;10:17-31. Authors such as Barriere5050 Barriere SL. Clinical, economic and societal impact of antibiotic resistance. Expert Opin Pharmacother. 2015;16:151-3. even believe that the dramatism of the means of communication when talking of the appearance of superbacteria is a positive element, which makes the public more aware of the problem.

A Cochrane review by O’Sullivan5151 O’Sullivan JW, Harvey RT, Glasziou PP, McCullough A. Written information for patients (or parents of child patients) to reduce the use of antibiotics for acute upper respiratory tract infections in primary care. Cochrane Database Syst Rev. 2016;11:CD011360. analyzed the effectiveness of written information on the reduction of antibiotics in upper airway respiratory infections in pediatric patients, concluding with moderate-to-low level of evidence that this strategy is effective in achieving a significant reduction in antibiotics, without finding significant changes in re-consultations nor in parental satisfaction.

On rapid tests that help in the diagnosis in the primary care setting

The use of rapid tests to detect group A beta-hemolytic Streptococcus is another of the tools that have been put forward to improve antibiotic use in primary health care. Many studies reflect a positive impact, but some studies have detected a high proportion of incorrectly performed tests, which may minimize that effect. The main cause for considering them inadequate was the presence of clinical data of two or more viral infections.5252 Norton LE, Lee BR, Harte L, Mann K, Newland JG, Grimes RA, et al. Improving guideline-based streptococcal pharyngitis testing: a quality improvement initiative. Pediatrics. 2018:142i:e20172033. Additionally, the use of rapid influenza diagnostic tests (RIDTs), which have a great sensitivity when used at the point of care, may be useful for improving the diagnosis, reducing the use of antibiotics when not indicated, and supporting antiviral treatment, if warranted.5353 van Esso DL, Valente AM, Vilà M, Casanovas JM, de Quixano M, Rodrigo C, et al. Rapid influenza testing in infants and children younger than 6 years in primary care: impact on antibiotic treatment and use of health services. Pediatr Infect Dis J. 2019;38:e187-9.

The use of C-reactive protein (CRP) has been studied with varied results. Some studies have shown a variable, but significant, reduction in the prescription of antibiotics to children with fever, while others, such as a study carried out in Norway in children who attended non-hospital emergency services with fever and respiratory symptoms, have not demonstrated effectiveness in reducing the number of antibiotics nor in the number of patients referred to hospital emergency services.5454 Rebnord IK, Sandvik H, Batman Mjelle A, Hunskaar S. Out-of-hours antibiotic prescription after screening with C reactive protein: a randomised controlled study. BMJ Open. 2016;6:e011231. In general, the impact of CRP on more correct antibiotic use is higher in developed countries, also depending on the cut-off point used.5555 Althaus T, Greer RC, Swe MM, Cohen J, Tun NN, Heaton J, et al. Effect of point-of-care C-reactive protein testing on antibiotic prescription in febrile patients attending primary care in Thailand and Myanmar: an open-label, randomised, controlled trial. Lancet Glob Health. 2019;7:e119-31.

On deferred prescription and shared prescription

Deferred prescription is a strategy that involves prescribing antibiotics to the patient that are only to be taken if certain situations arise, typically a worsening in the infection.

A Cochrane review concluded that, in deferred prescription, the patient’s satisfaction is similar to when antibiotic treatment is started immediately and far greater than if treatment is not started. Moreover, when the doctor was not sure whether to use antibiotics or not, deferred prescription significantly reduced antibiotic use.5656 Spurling GK, Del Mar CB, Dooley L, Foxlee R, Farley R. Delayed antibiotic prescriptions for respiratory infections. Cochrane Database Syst Rev. 2017;9:CD004417.

Couchman et al.5757 Couchman GR, Rascoe TG, Forjuoh SN. Back-up antibiotic prescriptions for common respiratory symptoms. Patient satisfaction and fill rates. J Fam Pract. 2000;49:907-13. found that deferred prescription may be a good method to achieve a reduction in antibiotic use without detriment to parental satisfaction.

Shared decision-making is an important component in patient-centered care. This requires good communication and clinical practice based on the best knowledge. Coxeter et al.5858 Coxeter P, Del Mar CB, McGregor L, Beller EM, Hoffmann TC. Interventions to facilitate shared decision making to address antibiotic use for acute respiratory infections in primary care. Cochrane Database Syst Rev. 2015;12:CD010907. carried out a systematic review on the topic of antibiotic use in upper airway infections, concluding that it is an effective strategy in the short term, without being able to conclude whether its effectiveness is maintained over time.

Multiple interventions

It is difficult to analyze this aspect given that within the multiple interventions there are very different degrees of complexity, but many authors identified them as being the most effective.4848 Huttner B, Goossens H, Verheij T, Harbarth S. CHAMP consortium. Characteristics and outcomes of public campaigns aimed at improving the use of antibiotics in outpatients in high-income countries. Lancet Infect Dis. 2010;10:17-31.

Clavenna and Bonati2424 Clavenna A, Bonati M. Differences in antibiotic prescribing in paediatric outpatients. Arch Dis Child. 2011;96:590-5. performed a review with the objective of analyzing and comparing the profile of antibiotic prescription in different countries and regions; they found major differences between countries and regions, and at the level of professionals. They concluded that monitoring the consumption and comparing it among different zones and professionals, and the elaboration of local guides, as well as training plans for professionals and educational training for parents, can be effective at reducing antibiotic use.

Lee et al.5959 Lee CR, Lee JH, Kang LW, Jeong BC, Lee SH. Educational effectiveness, target,and content for prudent antibiotic use. Biomed Res Int. 2015;2015:214021. performed a systematic review analyzing the importance of educating the prescribers and the public in general, including children, on prudent antibiotic use. Medical education programs (training, interactive seminars, mailings, working groups in evidence-based medicine, communication skills workshops, and support visits) achieved a mean 34 % reduction, although this figure is not uniform in the literature and some studies did not find significant reductions. The effectiveness of the combination of these strategies with others such as educating patients and their families, deferred prescription, audits, and feedback showed a greater reduction in antibiotic prescription. In recent years, WHO-supported learning programs have been started to include children from 7 years of age in the training; such initiatives have been shown to increase the knowledge level in that population group.

In a systematic review conducted in patients over the age of 13 years, Köchling et al.6060 Köchling A, Löffler C, Reinsch S, Hornung A, Böhmer F, Altiner A, et al. Reduction of antibiotic prescriptions for acute respiratory tract infections in primary care: a systematic review. Implement Sci. 2018;13:47. found that different actions have a greater impact depending on the characteristics of the country where they are applied: in countries that have a lower prescription rate the most successful actions were those actions directed at improving the communication skills; while in countries with a higher prescription rate, point-of-care testing (POCT) and computerized clinical decision support systems (CDSS) were most successful, although the different trials did show considerable variation. They also observed that an intervention directed at reducing the number of antibiotics prescribed had the collateral effect that those used were used more adequately (better fitting spectrum).

For Goldman and Newland,1919 Goldman JL, Newland JG. New Horizons for Pediatric Antibiotic Stewardship. Infect Dis Clin North Am. 2015;29:503-11. educating clinicians and adequate and personalized audit and feedback are effective at reducing antibiotic use. However, if the intervention is discontinued the effect disappears, returning to square one.

However, a multiple intervention that includes communication skills, deferred prescription, implementation of consensus protocols in electronic prescription databases, and quarterly feedback, carried out in the Netherlands by Vervloet et al.6161 Vervloet M, Meulepas MA, Cals JW, Eimers M, van der Hoek LS, van Dijk L. Reducing antibiotic prescriptions for respiratory tract infections in family practice: results of a cluster randomized controlled trial evaluating a multifaceted peer-group-based intervention. NPJ Prim Care Respir Med. 2016;26:15083. in primary care clinicians, achieved a reduction in the patients over the age of 12 years, but surprisingly, not in children under 12.

Bozzella et al.6262 Bozzella MJ, Harik N, Newland JG, Hamdy RF. From paper to practice: Strategies for improving antibiotic stewardship in the pediatric ambulatory setting. Curr Probl Pediatr Adolesc Health Care. 2018;48:289-305. analyzed the different interventions to reduce inadequate antibiotic use in a recent review, suggesting that all the interventions may be beneficial, but that multiple interventions obtain better results.

Conclusions

Clinicians are therefore facing a complex problem that requires complex and personalized interventions depending on the characteristics of the patient population and on the resources available.33 Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, et al. Antibiotic resistance: a rundown of a global crisis. Infect Drug Resist. 2018;11:1645-58. Multidisciplinary interventions are also necessary in other fields such as the environment and agriculture, not only in those involving people, and these interventions must be prolonged over time and at all levels.

The present authors believe that the first step is involving the corresponding administrations to regulate and minimize antibiotic use in agriculture with the impact that it has at environmental level and directly on humans through foodstuffs. They must also support industry in the research of new molecules and it is a moral obligation of the industry to intensify that research, which can help to resolve this serious problem.

In humans, no single intervention has been shown to be absolutely superior to others and their effectiveness is measured by the sociocultural, economic, and prescription-pattern conditions of each area. Nonetheless, improving antibiotic administration in children in the primary care setting is crucial.

Training and awareness campaigns are important at national or regional level. They must be campaigns delivering clear, direct messages, and they should be impactful. Training parents and guardians is a very important task and must be performed from the very beginning of the relationship with the pediatrician. The pregnancy period is seen as being vital. This is a particularly sensitive period in which messages regarding the health and disease of the unborn child are especially significant. The waiting room of the clinic is also an appropriate setting for health education by means of audio-visual or written messages. Training must cover not only the non-use of antibiotics in pathologies caused by viruses or which are self-limiting, but also in the adequate compliance with them when they are required, in addition to preventing self-medication.

As seen in different studies, good communication with the primary care pediatrician is essential.

A worthwhile option could be the inclusion of health topics in the education of schoolchildren from 7 to 8 years of age with the goal of having a society bearing greater knowledge, but it is essential that students of health professions and all the health professionals involved are fully aware of the seriousness of this issue.

However, ultimately, clinicians must not forget that prescription lies in their hands. Improving it will involve an important effort. There are different scenarios for improvement, namely: elaborating algorithms, protocols, or clinical guides through participation, consensus, and which fit the evidence and the local microbiology, as well as training seminars or sessions. Training in communication skills has been shown, on numerous occasions, to be an essential aspect; carrying out a thorough physical examination and not undervaluing the child’s disease have also been shown to be important in the studies performed. Perhaps pediatricians need to reject the idea that parents are pressuring them and that they leave happier if their child has been prescribed antibiotics, given that the studies do not uphold this idea.

Diagnostic tools based on molecular techniques and the application of these and other rapid techniques outside the hospital setting may help antibiotic use by identifying with greater certainty which patients need antibiotics. Some examples of these tests include the Group A beta-hemolytic Streptococcus antigen detection test, above all in infants over the age of 3 years, the CRP test and, in certain cases, the possible use of viral antigenic flu detection tests, etc. Additionally, deferred prescription or “wait and see” can have a positive impact. Interventions with audit-feedback and assistance by means of computer programs in dispensing may close this circle of help to the prescribing clinician. All these studies indicate that these interventions need to be continual in order to be efficient.

To conclude, it must be recognized that many countries have created tailor-made programs based on the socio-sanitary and economic realities in their countries with the objective of achieving “One Health” as called for by the WHO. These projects must include advances in all the fields of development in health, including the control and rational use of antibiotics.

The present authors agree with Barriere5050 Barriere SL. Clinical, economic and societal impact of antibiotic resistance. Expert Opin Pharmacother. 2015;16:151-3. when he expresses the opinion that it is a moral obligation of society and of health systems to ensure that these tools that were inherited are available for future generations.

Is there a ray of light at the end of the tunnel?

  • Please cite this article as: Miguélez SA, Garcia-Marcos L. Rational use of antimicrobials in the treatment of upper airway infections. J Pediatr (Rio J). 2020;96(S1):111-9.

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Publication Dates

  • Publication in this collection
    17 Apr 2020
  • Date of issue
    Mar-Apr 2020

History

  • Received
    18 Sept 2019
  • Accepted
    7 Nov 2019
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