Editorial
Prudent use of antimicrobial agents: Revisiting concepts and estimating perspectives in a global world
Uso prudente de los antibióticos: revisión de los conceptos y análisis de las perspectivas en un mundo globalizado
a Servicio de Microbiología, CIBER en Epidemiología y Salud Pública (CIBERESP), Hospital Universitario Ramón y Cajal e Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
b Unidad Asociada al Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Resistencia a los antibióticos y virulencia bacteriana, Hospital Universitario Ramón y Cajal, Madrid, Spain
c Departamento de Medicina, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain
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Accordingly with this view, medical and veterinary practitioners were frequently acting in a non-prudent or irresponsible way when prescribing antimicrobials.<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a> The term “prudent use” acquired international relevance as an educational slogan aiming at contributing to the reduction of resistance rates in pathogenic microorganisms, as there was growing evidence of a correlation between levels of antibiotic consumption and levels of antibiotic resistance. In this context, the “imprudent use” meant the use of antibiotics considering <span class="elsevierStyleItalic">only</span> the real or potential benefits of prescription on the presumed infected patient, disregarding its potential negative effects on the society (including economic costs) or the environment. In contrast, the “prudent use” meant educated appropriate prescription, using antimicrobials only in cases in which their administration was fully justified on objective grounds.</p><p id="p0010" class="elsevierStylePara elsevierViewall">The time has arrived to refine those notions. First, imprudent use should not be considered as equivalent to “minimal use”. Because of the simplicity of the concept and its favourable economical consequences, conventional health managers are prone to consider,for instance, that countries or regions with a low antibiotic consumption <span class="elsevierStyleItalic">per capita</span> have a better policy of antibiotic use. However, in the absence of reliable statistics on the local prevalence of infections requiring antibiotic therapy, it is simply impossible to know if the consumption is appropriate or not.<a class="elsevierStyleCrossRef" href="#bib2"><span class="elsevierStyleSup">2</span></a> Second, we should accept that we are very far from knowing with certainty the circumstances in which antibiotic therapy should be considered as inappropriate. The NNTB index (number of individuals needed to treat for a benefit in one of them) does not cast any more light on the topic.<a class="elsevierStyleCrossRef" href="#bib3"><span class="elsevierStyleSup">3</span></a> Note, that in the case of a total absence of risk of antibiotic over-usage, a policy of extended use could be beneficial, particularly if the targeted infection is an important one. How many cases of bacteremic pneumonia in the elderly, or acute bacterial meningitis in children, are indeed prevented (treated before clinical symptoms) by “unjustified” use of antibiotics? What are the deleterious consequences of an excess of restriction in use? We are only now beginning to understand the downstream consequences of restricting antibiotics on outcomes and costs. We are hampered by the lack of a universal ethical framework and information on outcomes.<a class="elsevierStyleCrossRef" href="#bib4"><span class="elsevierStyleSup">4</span></a> Only in recent years we have started to extend databases and the required bioinformatic analytic tools able to address these questions. In reality, we are still awaiting rigorous scientific study about the risks and benefits of antibiotic use.<a class="elsevierStyleCrossRef" href="#bib5"><span class="elsevierStyleSup">5</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">The main ecological effect of antibiotics is promoting the emergence, spread, and diversification of antibiotic resistance genetic determinants, and consequently of the bacterial organisms carrying them, and is widely considered as the greatest risk associated to the imprudent extended use of these drugs. Although we do not have any major objection to adhere to this statement, we should also refine some common beliefs on this matter. First, the expected (stoichiometric) proportionality between the levels of antibiotic use and antibiotic resistance does not always occur. For instance, epidemics of fully-susceptible bacteria might reduce resistance in a region with high use; conversely, epidemics of resistant bacteria or resistance plasmids might occur in regions with appropriate levels of usage, unexpectedly increasing resistance.<a class="elsevierStyleCrossRefs" href="#bib6"><span class="elsevierStyleSup">6,7</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">The decrease in antibiotic usage might not have consequences on antibiotic resistance rates, frequently because the resistance determinants are harboured by bacteria at very low biological cost.<a class="elsevierStyleCrossRefs" href="#bib8"><span class="elsevierStyleSup">8,9</span></a> Second, and more importantly, we should be ashamed of confessing that, after three-quarters of a century from the discovery of antibiotic resistance, we still lack solid data about the true impact of antibiotic resistance in the morbidity and mortality of most bacterial infections. Not every infection produced by bacteria carrying antibiotic resistance determinants is refractory to therapy, nor are all infections caused by antibiotic susceptible organisms responsive to antibiotics. Finally, resistance might help to keep the synergistic interactions with our intestinal microbiota.<a class="elsevierStyleCrossRef" href="#bib10"><span class="elsevierStyleSup">10</span></a> But, in general, what we want to stress here is that the prudent use of antibiotics should be placed in a global ecological dimension.</p><p id="p0025" class="elsevierStylePara elsevierViewall">The yearly total production of antibiotics can be estimated between 100,000–200,000 tons annually, and about one-half of it is used in outside humans.<a class="elsevierStyleCrossRef" href="#bib11"><span class="elsevierStyleSup">11</span></a> Considering that most antibiotics exert their action at concentrations close to 1<span class="elsevierStyleHsp" style=""></span>ug/ml, that amount of antimicrobials is enough to cover the entire surface of the Earth with inhibitory concentrations, in other words, able to alter the populational genetic structure of microbes. Indeed the environment near to antibiotic producing factories might be heavily polluted: more than 20<span class="elsevierStyleHsp" style=""></span>ug/ml of oxytetracycline was detected in the treated effluent from a drug producing industry in China.<a class="elsevierStyleCrossRef" href="#bib12"><span class="elsevierStyleSup">12</span></a> Moreover, antibiotics are not easily removed from the environment, and some families of them might remain active for extended periods of time. Resistance is present in environmental locations without a history of antibiotic pollution.<a class="elsevierStyleCrossRef" href="#bib13"><span class="elsevierStyleSup">13</span></a> Nevertheless, the study of historical soils has demonstrated that the introduction of antibiotics has produced the increase in the prevalence of specific resistance determinants in environmental, non-clinical ecosystems.<a class="elsevierStyleCrossRef" href="#bib14"><span class="elsevierStyleSup">14</span></a></p><p id="p0030" class="elsevierStylePara elsevierViewall">Antibiotic release is probably one of the major anthropogenic effects on the Microbiosphere, altering the microbial systems. Of course part of this alteration is predictable as antibiotic resistance, but unpredictable effects are most likely to occur, such as changes in the interactions between microbes or with animals, plants, or influencing basic cycles of life in the common Earth environment.<a class="elsevierStyleCrossRefs" href="#bib15"><span class="elsevierStyleSup">15–17</span></a> Therefore, the use of industrial antibiotics in agriculture, farming, and human or veterinary medicine converges to a single, cooperative effect, changing bacterial ecology, not only in different environments, but in the common environment. The main problem is the existing connectivity between all environments, human, farming, and agricultural, so that the antibiotic-imposed effect in one of them has consequences in all the others. As regards the undesirable consequences of antibiotic resistance, connection between the different environments occurs essentially in two ways, and will be considered in the following paragraphs. First, dispersal and migration of biological units involved in antibiotic resistance, as bacterial communities (metacommunities), bacterial clones, mobile genetic elements, and, in general, gene dispersal.<a class="elsevierStyleCrossRef" href="#bib18"><span class="elsevierStyleSup">18</span></a> Second, there is dispersal of antimicrobial eco-toxic agents, which results in the production of selective gradients and stressor effects, and in the increase of microbial evolutionary rates. Combined migration of antibiotics and antibiotic-resistance biological units results in evolutionary-active interactions that occur in four main eco-genetic reactors: i) the intestinal microbiota of humans and animals; ii) the highly antibiotic-exposed areas with high rates of bacterial transmission, like hospitals (particularly newborn wards and intensive care units), iii) waste water, effluents, and sewage treatment plants, and iv) soil, sediments, surface and ground water,<a class="elsevierStyleCrossRef" href="#bib19"><span class="elsevierStyleSup">19</span></a> which contribute to the escalation of the emergence and spread of antimicrobial resistance.</p><p id="p0035" class="elsevierStylePara elsevierViewall">In the short term, the prudent use of antibiotics has a major beneficiary effect that justifies all measures: the severely ill patient whose health depends on the maintenance of antibiotic control of infections. If antibiotic-resistance were surpassing a threshold-limit, the consequences on the current standards of hospital-based medicine (including long-term-care facilities for elderly people) could be severely compromised. Albeit rare, there are already examples of resistant organisms to all available antimicrobials causing disease and death in the intense care setting. In the long term, the effect that the anthropogenic release of antibiotics has already caused in the genetic structure of bacterial populations is probably irreversible, and will influence the evolutionary future of microbes on the Earth.<a class="elsevierStyleCrossRef" href="#bib16"><span class="elsevierStyleSup">16</span></a> Social norms should be established in a context of Conservation Medicine,<a class="elsevierStyleCrossRef" href="#bib20"><span class="elsevierStyleSup">20</span></a> widening the limited scope of “prudent use” to be able to provide new equilibriums between humans and the Microbiosphere.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bb0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antibiotic resistance in Spain: what can be done? 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 0 | 4 |
| 2024 October | 13 | 18 | 31 |
| 2024 September | 9 | 12 | 21 |
| 2024 August | 9 | 2 | 11 |
| 2024 July | 17 | 13 | 30 |
| 2024 June | 11 | 28 | 39 |
| 2024 May | 15 | 41 | 56 |
| 2024 April | 14 | 16 | 30 |
| 2024 March | 29 | 52 | 81 |
| 2024 February | 15 | 28 | 43 |
| 2024 January | 21 | 30 | 51 |
| 2023 December | 24 | 30 | 54 |
| 2023 November | 23 | 60 | 83 |
| 2023 October | 25 | 43 | 68 |
| 2023 September | 8 | 13 | 21 |
| 2023 August | 9 | 20 | 29 |
| 2023 July | 16 | 29 | 45 |
| 2023 June | 28 | 6 | 34 |
| 2023 May | 36 | 2 | 38 |
| 2023 April | 30 | 7 | 37 |
| 2023 March | 28 | 5 | 33 |
| 2023 February | 19 | 9 | 28 |
| 2023 January | 11 | 12 | 23 |
| 2022 December | 19 | 16 | 35 |
| 2022 November | 48 | 11 | 59 |
| 2022 October | 23 | 19 | 42 |
| 2022 September | 33 | 67 | 100 |
| 2022 August | 18 | 24 | 42 |
| 2022 July | 22 | 5 | 27 |
| 2022 June | 21 | 19 | 40 |
| 2022 May | 38 | 22 | 60 |
| 2022 April | 28 | 16 | 44 |
| 2022 March | 35 | 14 | 49 |
| 2022 February | 49 | 5 | 54 |
| 2022 January | 46 | 7 | 53 |
| 2021 December | 38 | 22 | 60 |
| 2021 November | 36 | 26 | 62 |
| 2021 October | 40 | 24 | 64 |
| 2021 September | 38 | 11 | 49 |
| 2021 August | 37 | 9 | 46 |
| 2021 July | 46 | 27 | 73 |
| 2021 June | 42 | 10 | 52 |
| 2021 May | 56 | 17 | 73 |
| 2021 April | 96 | 37 | 133 |
| 2021 March | 46 | 7 | 53 |
| 2021 February | 33 | 10 | 43 |
| 2021 January | 39 | 13 | 52 |
| 2020 December | 38 | 17 | 55 |
| 2020 November | 11 | 10 | 21 |
| 2020 October | 54 | 6 | 60 |
| 2020 September | 38 | 13 | 51 |
| 2020 August | 30 | 11 | 41 |
| 2020 July | 34 | 8 | 42 |
| 2020 June | 16 | 5 | 21 |
| 2020 May | 33 | 8 | 41 |
| 2020 April | 30 | 8 | 38 |
| 2020 March | 30 | 10 | 40 |
| 2020 February | 40 | 11 | 51 |
| 2020 January | 18 | 32 | 50 |
| 2019 December | 29 | 14 | 43 |
| 2019 November | 26 | 8 | 34 |
| 2019 October | 14 | 11 | 25 |
| 2019 September | 19 | 22 | 41 |
| 2019 August | 18 | 15 | 33 |
| 2019 July | 12 | 16 | 28 |
| 2019 June | 18 | 40 | 58 |
| 2019 May | 78 | 85 | 163 |
| 2019 April | 41 | 21 | 62 |
| 2019 March | 18 | 6 | 24 |
| 2019 February | 8 | 11 | 19 |
| 2019 January | 10 | 5 | 15 |
| 2018 December | 5 | 8 | 13 |
| 2018 November | 6 | 8 | 14 |
| 2018 October | 10 | 20 | 30 |
| 2018 September | 6 | 2 | 8 |
| 2018 August | 1 | 4 | 5 |
| 2018 July | 11 | 2 | 13 |
| 2018 June | 0 | 2 | 2 |
| 2018 May | 8 | 9 | 17 |
| 2018 April | 3 | 2 | 5 |
| 2018 March | 11 | 2 | 13 |
| 2018 February | 7 | 1 | 8 |
| 2018 January | 5 | 1 | 6 |
| 2017 December | 8 | 1 | 9 |
| 2017 November | 3 | 5 | 8 |
| 2017 October | 12 | 1 | 13 |
| 2017 September | 11 | 3 | 14 |
| 2017 August | 14 | 9 | 23 |
| 2017 July | 14 | 7 | 21 |
| 2017 June | 6 | 14 | 20 |
| 2017 May | 19 | 19 | 38 |
| 2017 April | 29 | 15 | 44 |
| 2017 March | 33 | 6 | 39 |
| 2017 February | 19 | 8 | 27 |
| 2017 January | 19 | 7 | 26 |
| 2016 December | 22 | 15 | 37 |
| 2016 November | 35 | 9 | 44 |
| 2016 October | 50 | 7 | 57 |
| 2016 September | 23 | 10 | 33 |
| 2016 August | 20 | 6 | 26 |
| 2016 July | 18 | 5 | 23 |
| 2016 June | 36 | 10 | 46 |
| 2016 May | 31 | 1 | 32 |
| 2016 April | 23 | 11 | 34 |
| 2016 March | 25 | 24 | 49 |
| 2016 February | 21 | 17 | 38 |
| 2016 January | 27 | 18 | 45 |
| 2015 December | 19 | 13 | 32 |
| 2015 November | 24 | 17 | 41 |
| 2015 October | 46 | 20 | 66 |
| 2015 September | 19 | 11 | 30 |
| 2015 August | 11 | 11 | 22 |
| 2015 July | 23 | 3 | 26 |
| 2015 June | 16 | 4 | 20 |
| 2015 May | 10 | 6 | 16 |
| 2015 April | 14 | 11 | 25 |
| 2015 March | 22 | 14 | 36 |
| 2015 February | 42 | 2 | 44 |
| 2015 January | 44 | 9 | 53 |
| 2014 December | 62 | 6 | 68 |
| 2014 November | 31 | 4 | 35 |
| 2014 October | 50 | 9 | 59 |
| 2014 September | 33 | 5 | 38 |
| 2014 August | 31 | 7 | 38 |
| 2014 July | 30 | 7 | 37 |
| 2014 June | 27 | 3 | 30 |
| 2014 May | 16 | 0 | 16 |
| 2014 April | 26 | 3 | 29 |
| 2014 March | 42 | 13 | 55 |
| 2014 February | 35 | 8 | 43 |
| 2014 January | 31 | 8 | 39 |
| 2013 December | 35 | 9 | 44 |
| 2013 November | 93 | 10 | 103 |
| 2013 October | 94 | 17 | 111 |
| 2013 September | 43 | 9 | 52 |
| 2013 August | 53 | 16 | 69 |
| 2013 July | 39 | 9 | 48 |
| 2013 June | 6 | 7 | 13 |
| 2013 May | 19 | 6 | 25 |
| 2013 April | 13 | 8 | 21 |
| 2013 March | 11 | 11 | 22 |
| 2013 February | 5 | 2 | 7 |
| 2013 January | 2 | 2 | 4 |
| 2012 December | 5 | 2 | 7 |
| 2012 November | 0 | 2 | 2 |
| 2012 October | 2 | 1 | 3 |
| 2010 September | 888 | 0 | 888 |
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