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Editorial
Optimizing the management of Pseudomonas aeruginosa infections with tools for the detection of resistance mechanisms and pharmacokinetic/pharmacodynamic (PK/PD) analysis
Optimizando el manejo de las infecciones por Pseudomonas aeruginosa mediante la utilización de herramientas para la detección de mecanismos de resistencia y el análisis farmacocinético/farmacodinámico (PK/PD)
Carlos Juan
Servicio de Microbiología y Unidad de Investigación, Hospital Universitario Son Espases – Instituto de Investigación Sanitaria Illes Balears (IdISBa), Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> is one of the most important opportunistic pathogens&#44; being for instance the main cause of ventilator-associated pneumonia and burn wound infections in hospitalized patients&#46; It is also the first etiologic agent of chronic respiratory infections in patients with chronic underlying diseases such as cystic fibrosis or chronic obstructive pulmonary disease&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> The success of this species to develop this pathogenic lifestyle is supported by its great adaptability&#44; in turn based on its extensive genome&#46; It encodes a plethora of genes sustaining its notable metabolic versatility&#44; an outstanding set of virulence factors&#44; and finally&#44; a great potential for antibiotic resistance development&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a> This is probably the most striking feature of <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#44; which supports the worldwide growth on the prevalence of resistant isolates&#46; In fact&#44; the isolation of multidrug-resistant&#44; extensively drug-resistant and even pan-resistant strains of <span class="elsevierStyleItalic">P&#46; aeruginosa</span> is not exceptional but the contrary&#44; mainly in developing countries of Asia&#44; Middle East and Latin America&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">3</span></a> The <span class="elsevierStyleItalic">P&#46; aeruginosa</span> resistance can be achieved through mutations in chromosomal genes&#44; mainly driving to porins&#8217; loss&#44; hyperexpression of efflux pumps or of the chromosomal cephalosporinase AmpC&#44; or to the alteration of the antibiotics&#8217; targets&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4&#44;5</span></a> Besides&#44; <span class="elsevierStyleItalic">P&#46; aeruginosa</span> is very often reported to harbor horizontally-acquired resistance determinants usually encoded in class I integrons&#44; in turn located in transferable plasmids&#46; Among these transmitted determinants the most relevant is the almost endless array of acquired &#946;-lactamases&#44; including extended spectrum and&#47;or carbapenemases &#40;topic that will be addressed below&#41;&#44; so that virtually no &#946;-lactam escapes from their hydrolytic spectrum&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> This outstanding capacity for resistance development makes of <span class="elsevierStyleItalic">P&#46; aeruginosa</span> infection a clinical-epidemiological problem of paramount importance&#44; making the infections caused by this species highly life-threatening and increasing the length of hospital admissions&#44; which has obvious economic implications&#46; To curb down this growing menace of <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#44; research has been forced to play a prominent role in the last years&#46; Fortunately&#44; very substantial advances to understand the antibiotic resistance mechanisms of <span class="elsevierStyleItalic">P&#46; aeruginosa</span> have been achieved&#44; and for instance today we almost completely understand the genetics and molecular basis for the AmpC hyperproduction&#44; the most important resistance mechanism of this species&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a> An obvious consequence of this knowledge is the development of new antipseudomonal formulations usually including &#946;-lactamase inhibitors &#40;e&#46;g&#46; cefiderocol&#44; ceftazidime&#8211;avibactam&#44; ceftolozane&#8211;tazobactam&#44; meropenem&#8211;vaborbactam&#44; zidebactam&#44; etc&#46;&#41;&#44; that although show encouraging activity&#44; do not completely solve the problem of <span class="elsevierStyleItalic">P&#46; aeruginosa</span> resistance since it has been shown to be capable of becoming resistant also to them&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">6</span></a> But in parallel to all these advances achieved during the last decades&#44; the fight against <span class="elsevierStyleItalic">P&#46; aeruginosa</span> has been and needs to be approached from other points of view&#44; such as the epidemiological works of resistances&#8217; prevalence&#44; i&#46;e&#46; antimicrobial susceptibility surveillance studies&#46; Many of them have been published dealing with <span class="elsevierStyleItalic">P&#46; aeruginosa</span> since several years ago&#44; which shows once more the epidemiological threat that <span class="elsevierStyleItalic">P&#46; aeruginosa</span> resistance supposes&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">3</span></a> Of course&#44; these retrospective works have interest to look to the past&#44; but they will be always a need in future&#44; to see the evolution of resistance to the new compounds as those mentioned above&#46; They are also needed to assess if the measures in terms of antibiotic stewardship&#44; dissemination limitation strategies&#44; etc&#46; applied in a certain area and lapse of time are working&#46; In addition and obviously&#44; they provide a fast idea of the local epidemiology of resistance&#44; and thus&#44; they constitute an indispensable tool to determine the empirical treatments more suitable for each context&#46; However&#44; these studies gain considerable scope if they are complemented with molecular epidemiology &#40;i&#46;e&#46; clonal relatedness&#44; MLST typing&#44; etc&#46;&#41; and&#47;or resistance mechanisms characterization&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">7&#44;8</span></a> data obviously very helpful to draw more appropriate empirical treatments&#46; In fact&#44; thanks to this last kind of works it has been identified the existence of globally spread <span class="elsevierStyleItalic">P&#46; aeruginosa</span> successful clones &#40;also called high-risk clones&#41;&#44; characterized by several features mainly related with resistance mechanisms&#44; explaining their outstanding success and dissemination&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">9</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In this same context&#44; the combination of the local antimicrobial susceptibility data with other additional parameters&#44; namely pharmacokinetic&#47;pharmacodynamics &#40;PK&#47;PD&#41;&#44; is a novel perspective that has been scarcely approached in the past&#44;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">10&#8211;12</span></a> and that greatly enhances the potential of the studies on epidemiology of resistance and surveillance&#46; Since many years ago it is known that PK&#47;PD parameters &#91;e&#46;g&#46; the maximum concentration&#47;minimal inhibitory concentration &#40;MIC&#41;&#44; time above the MIC&#44; area under the time-concentration curve&#44; etc&#46;&#93; define the requirements of an antimicrobial to successfully clear a given infection&#46; In fact&#44; each group of antibiotics display a particular behavior regarding these parameters&#44; and for instance&#44; the aminoglycosides are concentration-dependent drugs&#44; whereas beta-lactams effectiveness rely on the time above the MIC&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">13&#8211;15</span></a> On its turn&#44; additional factors such as the location of the infection&#44; the half-life of the drug&#44; its binding capacity to the serum proteins&#44; etc&#46; are those which finally determine the PK&#47;PD values&#44; and thus&#44; have to be considered in order to evaluate the success&#8217; possibilities of a specific treatment&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Either way&#44; the work of Valero and colleagues included in the current number of EIMC<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> is an excellent example of study combining different approaches to manage <span class="elsevierStyleItalic">P&#46; aeruginosa</span> challenge&#44; because not only provides information regarding the raw susceptibility&#47;resistance&#44; but also introduces information of PK&#47;PD data from a retrospective analysis of 18 years from a tertiary Spanish Hospital &#40;excluding ICU patients&#41;&#46; The combination of the mentioned epidemiological and PK&#47;PD data together with Monte Carlo simulations to model the possible infection outcome without knowledge of the specific isolate&#39;s susceptibility&#44; through the determination of the so-called cumulative fraction of response &#40;CFR&#41;&#44; definitively provides great interest to this study&#46; It allows to see changes in the predicted drugs&#8217; effectiveness that would not be visible by only considering the local MIC distributions&#44; and besides&#44; it also displays the trends of these parameters during the last years in the specific geographic area&#46; In fact&#44; the work suggests that certain drugs with relatively low local susceptibility values&#44; such as carbapenems &#40;mainly meropenem&#41; could be more effective than suspected&#44; and thus their therapeutic value could be reconsidered&#46; Contrary results &#40;relatively high percentages of susceptibility but low CFRs&#41; for certain antibiotics such as cefepime are also shown by Valero and co-workers&#46; Thus&#44; this work indicates that the correlation between raw susceptibility and the predicted success probability &#40;estimated through CFR&#41; is not always clear and direct&#44; and hence&#44; they must be used as complementary tools&#44; in accordance with the work of Zelenitsky and colleagues in Canada&#58; the raw MICs data were shown to be overestimating the ciprofloxacin capacity&#44; for instance&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> Hence&#44; these results also support the previous work of Valero and colleagues with strains from critically ill patients&#44; in which the raw susceptibility data were shown to be insufficient to detect changes in CFR in certain cases&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a> The use of Monte Carlo simulations to determine the probabilities of target attainment in order to optimize the empiric treatments has been proposed before&#44;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> but its combination with such large amount of data of raw MICs &#40;18 years period&#41; is innovative&#44; enhancing the scope of the study of Valero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In parallel to these approaches&#44; the diagnosis of the resistance mechanisms in the laboratory routine is another essential point of the fight against <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#44; and is often closely related with the local epidemiology of resistance&#46; The diagnostic tools gain even more importance when referred to the detection of transferable mechanisms &#40;obviously because of their dissemination risk&#41;&#44; mostly if we have into account the growing prevalence of <span class="elsevierStyleItalic">P&#46; aeruginosa</span> strains harboring horizontally-acquired carbapenemases&#44; and the increasing diversification &#40;in terms of amino-acid variants&#41; of these enzymes&#46; In fact&#44; it has been reported in <span class="elsevierStyleItalic">P&#46; aeruginosa</span> the isolation of carbapenemases from classes A&#58; GES and KPC enzymes&#59; B&#58; also called Metallo-&#946;-lactamases&#44; from IMP&#44; VIM&#44; GIM&#44; NDM&#44; SIM&#44; SPM types and the recently described CAM-1&#59; and C&#58; OXA-40 and OXA-198&#46; Among these carbapenemases&#44; the IMP and VIM types are those more worldwide disseminated and displaying more variants by far&#58; more than 30 different IMP and 25 different VIM variants have been found in <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#44; although the number of different enzymes within each type is even greater &#40;almost double&#41; if we consider the rest of species&#46; Although several of the amino acid variants do not entail any advantage&#44; some of them have been described to provide significant changes in the hydrolytic spectrum of the enzyme&#44; which enforces the idea for the need of reliable detection tests&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">18&#8211;20</span></a> In the specific case of the featured study of Guti&#233;rrez and colleagues&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> who assess the validity of the carbapenem inactivation method &#40;CIM&#41; to detect the carbapenemase-producing <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#44; they used an extensive collection of carbapenem-resistant strains proceeding from Colombia&#44; a country in which the presence of transferable carbapenemases is not negligible at all&#46; In fact&#44; carbapenem-resistant <span class="elsevierStyleItalic">P&#46; aeruginosa</span> mediated by KPC- and&#47;or VIM-type enzymes is considered endemic in this country&#46; Besides&#44; Colombia was the first place in which a KPC-type carbapenemase &#40;very likely proceeding from the massive dissemination of these enzymes in Colombian <span class="elsevierStyleItalic">Klebsiella pneumoniae</span>&#41; was first detected in <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a> Thus&#44; although the percentages of carbapenem-resistant isolates in Colombia are significantly lower than in some other Latin America countries&#44;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">23&#44;24</span></a> the active and reliable detection of acquired carbapenemases in the daily practice is indispensable to improve the empiric treatments and to limit the horizontal dissemination of the strains and&#47;or determinants in this and other countries&#46; In their interesting work&#44; Guti&#233;rrez et al&#46; conclude that&#44; although limited by the relatively long time required to obtain results and the lack of capacity to identify the specific carbapenemase&#44; the use of imipenem instead of meropenem significantly improves the accuracy of the CIM test in terms of sensitivity and specificity &#40;reaching 99&#46;4 and 98&#46;9&#37; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> Although the CIM was first introduced to detect carbapenemases only in <span class="elsevierStyleItalic">Enterobacteriaceae</span>&#44; the further modifications introduced allowed to apply the test to <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#46; Some additional changes have been subsequently introduced&#44; in terms of incubation time and&#47;or mediums&#44; resulting in the so-called modified CIM &#40;mCIM&#41; and the CIMTris&#46; These modifications&#44; shown to increase the sensitivity &#40;reaching 100&#37;&#41; have the inconvenient of decreasing the specificity&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">25&#44;26</span></a> Of course&#44; other phenotypic diagnostic methods &#40;boronic acid&#44; modified Hodge test&#44; modified Carba NP test&#44; Epsilon test&#44; etc&#46;&#41;&#44; are widely used&#44; but since they usually require the use of specific&#47;expensive reagents that are not always available in the clinical laboratories in Latin America&#44; and more importantly&#44; since they have been shown to not clearly improve the performance of the carbapenemase detection&#44;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">26&#44;27</span></a> the use of CIM is envisaged as an inexpensive&#44; relatively quick and reliable test to be mainly used in laboratories with limited resources&#46; Mainly if having into account two additional points&#44; &#40;i&#41; the significant improvement that the use of imipenem supposes&#44; as shown by Guti&#233;rrez et al&#46;&#44; and &#40;ii&#41; in Colombia the diversity of carbapenemases is quite limited &#40;as told before&#44; the great majority of identified enzymes belong to VIM or KPC types&#41;&#44; and for this reason&#44; the identification of the specific type through the use of more expensive tests such as multiplex PCR could be expendable by now&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">28&#44;29</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Thus&#44; the works of Valero and colleagues and Guti&#233;rrez and coworkers published in the current number of EIMC<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">16&#44;21</span></a> are two excellent examples of the type of studies we need to combine with basic research&#44; in order to progressively gain ground in the fight against <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#46; Only departing from a multi-disciplinary attack including the maximum number of approaches as those presented here&#44; we will make steps in that direction against this fearsome adversary&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interest</span><p id="par0030" class="elsevierStylePara elsevierViewall">None to declare&#46;</p></span></span>"
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos