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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The World Health Organization &#40;WHO&#41; defines that patients receive appropriate medications to their clinical needs if they are prescribed in doses that meet their own individual requirements&#44; for an adequate period of time&#44; and at the lowest cost to them and their community&#46; These general principles are obviously applicable to antimicrobial use in general and to the administration of antimicrobials in the critical care setting&#46; Many parameters of importance for optimal quality of antimicrobial therapy have already been defined&#46; Maximal efficacy of the treatment should be combined with minimal toxicity at the lowest cost&#46; Quality of antimicrobial drug use is dependent on knowledge of many aspects of infectious diseases and patient characteristics&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Inappropriate use of antimicrobial drugs is the major determinant of antimicrobial resistance development increasing the costs of care&#44; morbidity and mortality&#46; Critically ill patients are especially complex suffering profound pathophysiological changes that can affect PK&#47;PD properties of antibiotics&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Institutional programs aiming at reducing the inappropriate use of antibiotics have been launched worldwide&#46; These activities require accurate comparators of antibiotic consumption to benchmark antimicrobial drug use&#46; The three more common metrics for measuring aggregate antimicrobial use are the defined daily dose &#40;DDD&#41;&#44; the prescribed daily doses &#40;PDD&#41;&#44; and the days of therapy &#40;DOT&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The DDD is the measure endorsed by the WHO&#44; and nowadays&#44; the metric most widely used for comparisons of antibiotic use in primary care and in hospitals&#46; The consensus document of the Spanish programs for optimizing the use of antibiotics &#40;PROA&#41; in hospitals recommends DDD as the basic meter for monitoring antibiotic consumption considering DOT and DDP as metrics of excellence&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">However&#44; many studies have documented that DDD does not accurately reflect the antibiotic consumption and the quality of antibiotic prescription&#46; One of the major drawbacks of DDD measurement is that it underestimates antibiotic consumption when the WHO-consigned DDD is greater than the administered dose as occurs in patients with renal insufficiency or in pediatric populations&#46; Conversely&#44; DDD overestimates antibiotic consumption when reference DDD is lower than the administered dose as occurs very frequently in the critical care setting&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">In this issue&#44; the study by Vall&#232;s et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> has documented that DDD misjudges antibiotic use in adult critically ill patients overestimating the utilization of the majority of antibacterial and antifungal drugs&#46; Previous studies have shown discordant measurements between DDD and DOT&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">6&#8211;8</span></a> The measurement of DOT favors those situations where broad spectrum monotherapy is used&#44; independently of the dosages administered&#46; DOT punishes the use of combination therapy including those with narrow spectrum antimicrobials&#46; DOT is more difficult to measure requiring patient-level antibiotic use data&#44; but it has been demonstrated to be a superior measurement methodology than DDD&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">These differences may be even greater in burns or neurocritical care units&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">7</span></a> Severe burn injury results in a complex physiological derangement that significantly alters drug PK&#47;PD&#46; Burns patients require higher and more frequent dosing to reach and maintain therapeutic levels&#46; Similarly&#44; antibiotic doses are higher for central nervous system &#40;CNS&#41; infections than for other infections in order to achieve therapeutic levels in the CNS&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Nowadays&#44; high doses of antimicrobials are used appropriately in the ICUs&#46; The advent of therapeutic drug monitoring has revealed that up to 50&#37; of critically ill patients have suboptimal antibiotic plasma concentrations &#40;beta lactam&#44; aminoglycosides&#44; etc&#46;&#41;&#44; especially those with augmented renal clearance or high volume of distribution&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">10</span></a> The dramatic increase in bacterial resistance is the other factor that forces clinicians to increase antibiotic dosing to prevent therapeutic failure and death&#46; Therefore&#44; in this scenario&#44; DDD will not accurately reflect the quality of antibiotic prescription punishing hospital with routine use of TDM or those with outbreaks or endemics of multi-drug resistant bacteria&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In the study by Vall&#232;s and colleagues&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> discrepancies between DDDs and DOTs were major &#40;&#62;25&#37;&#41; in nine antibiotics and in three antifungals&#46; It is true that in 2019&#44; WHO has modified the DDD of several critical antibiotics to bring DDD closer to the usual dose of antibiotics&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">11</span></a> This modification affects only to four of the antimicrobials including in the list of &#8220;major differences&#8221; &#40;amoxicillin&#8211;clavulanic&#44; cefepime&#44; ciprofloxacin&#44; and meropenem&#41; and none of the antifungals&#46; Moreover&#44; these updated DDD are still lower than the doses used in many critically ill patients&#46; As examples&#44; 3<span class="elsevierStyleHsp" style=""></span>g a day of meropenem may be clearly insufficient in hyperdynamic critically ill patients as occurs with de new DDD of ampicillin &#40;6<span class="elsevierStyleHsp" style=""></span>g a day&#41; for the treatment of a bacteremia caused by <span class="elsevierStyleItalic">Enterococcus faecalis</span>&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The study by Vall&#232;s et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> is not absent of some limitations&#46; It is a single center study so their findings cannot be extrapolated to other Units with different levels of complexity&#46; However&#44; its compelling data should be taken into account to consider DOT as the standard measurement to monitor antibiotic use in the critical care setting&#46; In fact&#44; the new Infectious Diseases Society of America &#40;IDSA&#41; antibiotic stewardship guidelines suggests the use of DOT over the DDD for antibiotic consumption monitoring&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">12</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">There is room for improvement in antibiotic prescriptions in all hospitals and obviously in the ICUs&#46; However&#44; validated antibiotic use data are needed to provide correct feedback to clinicians&#46; The DOT method should be also used to carry out national and international comparisons among different Units&#46; In critical care units&#44; DOT&#44; undoubtfully with its limitations&#44; reflects more appropriately the quality of antibiotic prescription and ecological antibiotic pressure&#46;</p></span>"
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Editorial
Adequate antibiotic monitoring to improve what needs to be improved
Monitorización adecuada de antibióticos para mejorar lo que necesita mejorarse
R. Amaya-Villar
Jefa de Servicio, UGC Cuidados Intensivos, Hospital Universitario Virgen del Rocío, Avda. Manuel Siurot s/n, Sevilla 41013, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The World Health Organization &#40;WHO&#41; defines that patients receive appropriate medications to their clinical needs if they are prescribed in doses that meet their own individual requirements&#44; for an adequate period of time&#44; and at the lowest cost to them and their community&#46; These general principles are obviously applicable to antimicrobial use in general and to the administration of antimicrobials in the critical care setting&#46; Many parameters of importance for optimal quality of antimicrobial therapy have already been defined&#46; Maximal efficacy of the treatment should be combined with minimal toxicity at the lowest cost&#46; Quality of antimicrobial drug use is dependent on knowledge of many aspects of infectious diseases and patient characteristics&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Inappropriate use of antimicrobial drugs is the major determinant of antimicrobial resistance development increasing the costs of care&#44; morbidity and mortality&#46; Critically ill patients are especially complex suffering profound pathophysiological changes that can affect PK&#47;PD properties of antibiotics&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Institutional programs aiming at reducing the inappropriate use of antibiotics have been launched worldwide&#46; These activities require accurate comparators of antibiotic consumption to benchmark antimicrobial drug use&#46; The three more common metrics for measuring aggregate antimicrobial use are the defined daily dose &#40;DDD&#41;&#44; the prescribed daily doses &#40;PDD&#41;&#44; and the days of therapy &#40;DOT&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The DDD is the measure endorsed by the WHO&#44; and nowadays&#44; the metric most widely used for comparisons of antibiotic use in primary care and in hospitals&#46; The consensus document of the Spanish programs for optimizing the use of antibiotics &#40;PROA&#41; in hospitals recommends DDD as the basic meter for monitoring antibiotic consumption considering DOT and DDP as metrics of excellence&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">However&#44; many studies have documented that DDD does not accurately reflect the antibiotic consumption and the quality of antibiotic prescription&#46; One of the major drawbacks of DDD measurement is that it underestimates antibiotic consumption when the WHO-consigned DDD is greater than the administered dose as occurs in patients with renal insufficiency or in pediatric populations&#46; Conversely&#44; DDD overestimates antibiotic consumption when reference DDD is lower than the administered dose as occurs very frequently in the critical care setting&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">In this issue&#44; the study by Vall&#232;s et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> has documented that DDD misjudges antibiotic use in adult critically ill patients overestimating the utilization of the majority of antibacterial and antifungal drugs&#46; Previous studies have shown discordant measurements between DDD and DOT&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">6&#8211;8</span></a> The measurement of DOT favors those situations where broad spectrum monotherapy is used&#44; independently of the dosages administered&#46; DOT punishes the use of combination therapy including those with narrow spectrum antimicrobials&#46; DOT is more difficult to measure requiring patient-level antibiotic use data&#44; but it has been demonstrated to be a superior measurement methodology than DDD&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">These differences may be even greater in burns or neurocritical care units&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">7</span></a> Severe burn injury results in a complex physiological derangement that significantly alters drug PK&#47;PD&#46; Burns patients require higher and more frequent dosing to reach and maintain therapeutic levels&#46; Similarly&#44; antibiotic doses are higher for central nervous system &#40;CNS&#41; infections than for other infections in order to achieve therapeutic levels in the CNS&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Nowadays&#44; high doses of antimicrobials are used appropriately in the ICUs&#46; The advent of therapeutic drug monitoring has revealed that up to 50&#37; of critically ill patients have suboptimal antibiotic plasma concentrations &#40;beta lactam&#44; aminoglycosides&#44; etc&#46;&#41;&#44; especially those with augmented renal clearance or high volume of distribution&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">10</span></a> The dramatic increase in bacterial resistance is the other factor that forces clinicians to increase antibiotic dosing to prevent therapeutic failure and death&#46; Therefore&#44; in this scenario&#44; DDD will not accurately reflect the quality of antibiotic prescription punishing hospital with routine use of TDM or those with outbreaks or endemics of multi-drug resistant bacteria&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In the study by Vall&#232;s and colleagues&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> discrepancies between DDDs and DOTs were major &#40;&#62;25&#37;&#41; in nine antibiotics and in three antifungals&#46; It is true that in 2019&#44; WHO has modified the DDD of several critical antibiotics to bring DDD closer to the usual dose of antibiotics&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">11</span></a> This modification affects only to four of the antimicrobials including in the list of &#8220;major differences&#8221; &#40;amoxicillin&#8211;clavulanic&#44; cefepime&#44; ciprofloxacin&#44; and meropenem&#41; and none of the antifungals&#46; Moreover&#44; these updated DDD are still lower than the doses used in many critically ill patients&#46; As examples&#44; 3<span class="elsevierStyleHsp" style=""></span>g a day of meropenem may be clearly insufficient in hyperdynamic critically ill patients as occurs with de new DDD of ampicillin &#40;6<span class="elsevierStyleHsp" style=""></span>g a day&#41; for the treatment of a bacteremia caused by <span class="elsevierStyleItalic">Enterococcus faecalis</span>&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The study by Vall&#232;s et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> is not absent of some limitations&#46; It is a single center study so their findings cannot be extrapolated to other Units with different levels of complexity&#46; However&#44; its compelling data should be taken into account to consider DOT as the standard measurement to monitor antibiotic use in the critical care setting&#46; In fact&#44; the new Infectious Diseases Society of America &#40;IDSA&#41; antibiotic stewardship guidelines suggests the use of DOT over the DDD for antibiotic consumption monitoring&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">12</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">There is room for improvement in antibiotic prescriptions in all hospitals and obviously in the ICUs&#46; However&#44; validated antibiotic use data are needed to provide correct feedback to clinicians&#46; The DOT method should be also used to carry out national and international comparisons among different Units&#46; In critical care units&#44; DOT&#44; undoubtfully with its limitations&#44; reflects more appropriately the quality of antibiotic prescription and ecological antibiotic pressure&#46;</p></span>"
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