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      Antibiotic selection in the treatment of acute invasive infections by Pseudomonas aeruginosa: Guidelines by the Spanish Society of Chemotherapy Translated title: Elección del tratamiento antibiótico en la infección invasiva aguda por Pseudomonas aeruginosa: Guía de la Sociedad Española de Quimioterapia

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          Pseudomonas aeruginosa is characterized by a notable intrinsic resistance to antibiotics, mainly mediated by the expression of inducible chromosomic β-lactamases and the production of constitutive or inducible efflux pumps. Apart from this intrinsic resistance, P. aeruginosa possess an extraordinary ability to develop resistance to nearly all available antimicrobials through selection of mutations. The progressive increase in resistance rates in P. aeruginosa has led to the emergence of strains which, based on their degree of resistance to common antibiotics, have been defined as multidrug resistant, extended-resistant and panresistant strains. These strains are increasingly disseminated worldwide, progressively complicating the treatment of P. aeruginosa infections. In this scenario, the objective of the present guidelines was to review and update published evidence for the treatment of patients with acute, invasive and severe infections caused by P. aeruginosa. To this end, mechanisms of intrinsic resistance, factors favoring development of resistance during antibiotic exposure, prevalence of resistance in Spain, classical and recently appeared new antibiotics active against P. aeruginosa, pharmacodynamic principles predicting efficacy, clinical experience with monotherapy and combination therapy, and principles for antibiotic treatment were reviewed to elaborate recommendations by the panel of experts for empirical and directed treatment of P. aeruginosa invasive infections.


          Pseudomonas aeruginosa se caracteriza por una notable resistencia intrínseca a los antibióticos mediada fundamentalmente por la expresión de β-lactamasas cromosómicas inducibles y la producción constitutiva o inducible de bombas de expulsión. Además de esta resistencia intrínseca, P. aeruginosa posee una extraordinaria capacidad para desarrollar resistencia a prácticamente todos los antimicrobianos disponibles a través de la selección de mutaciones. El aumento progresivo de la resistencia en P. aeruginosa ha llevado a la aparición de cepas que, de acuerdo con el grado de resistencia frente a los antibióticos habituales, se han definido como multirresistentes, extensamente resistentes y panresistentes. Estas cepas se están diseminando mundialmente, complicando progresivamente el tratamiento de las infecciones por P. aeruginosa. En este escenario, el objetivo de las presentes recomendaciones es la revisión y puesta al día de la evidencia publicada para el tratamiento de pacientes con infección aguda, invasiva y grave por P. aeruginosa. Con este fin, se han revisado los mecanismos de resistencia intrínseca, factores que favorecen el desarrollo de resistencia durante la exposición a anti-bióticos, prevalencia de la resistencia en España, antibióticos clásicos así como los de reciente introducción activos frente a P. aeruginosa, principios farmacodinámicos predictores de eficacia, experiencia clínica con tratamientos en monoterapia o terapia combinada y principios del tratamiento antibiótico para elaborar por un panel de expertos recomendaciones para el tratamiento empírico o dirigido de infecciones invasivas por P. aeruginosa.

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          Most cited references 220

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          Pseudomonas aeruginosa: all roads lead to resistance.

          Pseudomonas aeruginosa is often resistant to multiple antibiotics and consequently has joined the ranks of 'superbugs' due to its enormous capacity to engender resistance. It demonstrates decreased susceptibility to most antibiotics due to low outer membrane permeability coupled to adaptive mechanisms and can readily achieve clinical resistance. Newer research, using mutant library screens, microarray technologies and mutation frequency analysis, has identified very large collections of genes (the resistome) that when mutated lead to resistance as well as new forms of adaptive resistance that can be triggered by antibiotics themselves, in in vivo growth conditions or complex adaptations such as biofilm growth or swarming motility. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Pseudomonas Aeruginosa: Resistance to the Max

             Keith Poole (2011)
            Pseudomonas aeruginosa is intrinsically resistant to a variety of antimicrobials and can develop resistance during anti-pseudomonal chemotherapy both of which compromise treatment of infections caused by this organism. Resistance to multiple classes of antimicrobials (multidrug resistance) in particular is increasingly common in P. aeruginosa, with a number of reports of pan-resistant isolates treatable with a single agent, colistin. Acquired resistance in this organism is multifactorial and attributable to chromosomal mutations and the acquisition of resistance genes via horizontal gene transfer. Mutational changes impacting resistance include upregulation of multidrug efflux systems to promote antimicrobial expulsion, derepression of ampC, AmpC alterations that expand the enzyme's substrate specificity (i.e., extended-spectrum AmpC), alterations to outer membrane permeability to limit antimicrobial entry and alterations to antimicrobial targets. Acquired mechanisms contributing to resistance in P. aeruginosa include β-lactamases, notably the extended-spectrum β-lactamases and the carbapenemases that hydrolyze most β-lactams, aminoglycoside-modifying enzymes, and 16S rRNA methylases that provide high-level pan-aminoglycoside resistance. The organism's propensity to grow in vivo as antimicrobial-tolerant biofilms and the occurrence of hypermutator strains that yield antimicrobial resistant mutants at higher frequency also compromise anti-pseudomonal chemotherapy. With limited therapeutic options and increasing resistance will the untreatable P. aeruginosa infection soon be upon us?
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              Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance.

              The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates the impact of porins and efflux pumps on two major types of resistance, namely, mutational and adaptive types of resistance, both of which are regarded as key phenomena in the global rise of antibiotic resistance among pathogenic microorganisms. In particular, we explain how adaptive and mutational events can dramatically influence the outcome of antibiotic therapy by altering the mechanisms of influx and efflux of antibiotics. The identification of porins and pumps as major resistance markers has opened new possibilities for the development of novel therapeutic strategies directed specifically against these mechanisms.

                Author and article information

                Rev Esp Quimioter
                Rev Esp Quimioter
                Sociedad Española de Quimioterapia
                Revista Española de Quimioterapia
                Sociedad Española de Quimioterapia
                23 March 2018
                February 2018
                : 31
                : 1
                : 78-100
                [1 ]Servicio de Enfermedades Infecciosas, Hospital Clinic, Barcelona, Spain
                [2 ]Servicio de Medicina Enfermedades infecciosas, Hospital Universitario HM Montepríncipe, Universidad San Pablo CEU. Madrid, Spain
                [3 ]Unidad de Enfermedades Infecciosas, Complejo Hospitalario Universitario A Coruña, Spain
                [4 ]Servicio de Microbiología, Hospital Clinic, Barcelona, Spain
                [5 ]Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS). Madrid, Spain
                [6 ]Servicio de Microbiología, Complejo Hospitalario Universitario A Coruña, Spain
                [7 ]Servicio de Urgencias, Hospital Clínico San Carlos, Madrid, Spain
                [8 ]Servicio de Anestesiología, Hospital Universitario La Paz, Madrid, Spain
                [9 ]Servicio de Farmacología, Clínica Universitaria de Navarra, Pamplona, Spain
                [10 ]Servicio de Enfermedades Infecciosas, Hospital Universitario Virgen de la Nieves, Granada, Spain
                [11 ]Servicio de Enfermedades Infecciosas, Hospital Universitario Carlos Haya, Málaga, Spain
                [12 ]Servicio de Enfermedades Infecciosas, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
                [13 ]Servicio de Enfermedades Infecciosas, Hospital Universitario Cruces, Bilbao, Spain
                [14 ]Servicio de Medicina Intensiva, Hospital Son Llátzer, Palma de Mallorca, Spain
                [15 ]Departamento de Neumología, Hospital Clinic, Barcelona, Spain
                [16 ]Servicio de Medicina Intensiva, Hospital del Mar, Barcelona, Spain
                [17 ]Unidad de Enfermedades Infecciosas. Hospital Univeristario la Fe, Valencia, Spain
                [18 ]Servicio de Medicina Intensiva, Hospital Universitario Dr. Peset, Valencia, Spain
                [19 ]Servicio de Microbiología, Hospital Universitari Son Espases, Instituto de Investigación Sanitaria Illes Balears (idISBa), Palma de Mallorca, Spain
                Author notes
                Correspondence: José Mensa, Servicio de Enfermedades Infecciosas, Hospital Clinic, Barcelona, Spain. E-mail: jmensa@ 123456clinic.cat
                © The Author 2018

                The article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) ( https://creativecommons.org/licenses/by-nc/4.0/)

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