array:23 [ "pii" => "S2529993X18302600" "issn" => "2529993X" "doi" => "10.1016/j.eimce.2018.10.005" "estado" => "S300" "fechaPublicacion" => "2019-01-01" "aid" => "1927" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica" "copyrightAnyo" => "2018" "documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Enferm Infecc Microbiol Clin. 2019;37:1-3" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 253 "formatos" => array:2 [ "HTML" => 177 "PDF" => 76 ] ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S0213005X18302738" "issn" => "0213005X" "doi" => "10.1016/j.eimc.2018.10.002" "estado" => "S300" "fechaPublicacion" => "2019-01-01" "aid" => "1927" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica" "documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Enferm Infecc Microbiol Clin. 2019;37:1-3" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 1794 "formatos" => array:2 [ "HTML" => 1125 "PDF" => 669 ] ] "es" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Uso actual de la fosfomicina: del laboratorio a la práctica clínica" "tienePdf" => "es" "tieneTextoCompleto" => "es" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "1" "paginaFinal" => "3" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Current approach to fosfomycin: From bench to bedside" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Francisco Javier Candel, Rafael Cantón" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Francisco Javier" "apellidos" => "Candel" ] 1 => array:2 [ "nombre" => "Rafael" "apellidos" => "Cantón" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2529993X18302600" "doi" => "10.1016/j.eimce.2018.10.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2529993X18302600?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213005X18302738?idApp=UINPBA00004N" "url" => "/0213005X/0000003700000001/v1_201901030625/S0213005X18302738/v1_201901030625/es/main.assets" ] ] "itemSiguiente" => array:18 [ "pii" => "S2529993X18302776" "issn" => "2529993X" "doi" => "10.1016/j.eimce.2018.05.009" "estado" => "S300" "fechaPublicacion" => "2019-01-01" "aid" => "1864" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Enferm Infecc Microbiol Clin. 2019;37:4-10" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 114 "formatos" => array:2 [ "HTML" => 89 "PDF" => 25 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Clinical efficacy of fosfomycin combinations against a variety of gram-positive cocci" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "4" "paginaFinal" => "10" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Eficacia clínica de las combinaciones de fosfomicina contra una variedad de cocos grampositivos" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3992 "Ancho" => 3103 "Tamanyo" => 561478 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Time kill studies of two MSSA clinical strain <span class="elsevierStyleItalic">versus</span> daptomycin, levofloxacin, oxacillin, and vancomycin in combination with gentamycin and fosfomycin. (A) Daptomycin combinations. (B) Levofloxacin combinations. (C) Oxacillin combinations. (D) Vancomycin combinations. DAP1: daptomycin 1íMIC. DAP4: daptomycin 4íMIC. GM2: gentamycin 2íMIC. FOS2: fosfomycin 2íMIC. LEV1: levofloxacin 1íMIC. LEV4: levofloxacin 4íMIC. OX1: oxacillin 1íMIC. OX4: oxacillin 4íMIC. VAN1: vancomycin 1íMIC. VAN4: vancomycin 4íMIC.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Nieves M. Coronado-Álvarez, Diego Parra, Jorge Parra-Ruiz" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Nieves M." "apellidos" => "Coronado-Álvarez" ] 1 => array:2 [ "nombre" => "Diego" "apellidos" => "Parra" ] 2 => array:2 [ "nombre" => "Jorge" "apellidos" => "Parra-Ruiz" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2529993X18302776?idApp=UINPBA00004N" "url" => "/2529993X/0000003700000001/v1_201901050608/S2529993X18302776/v1_201901050608/en/main.assets" ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Current approach to fosfomycin: From bench to bedside" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "1" "paginaFinal" => "3" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Francisco Javier Candel, Rafael Cantón" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Francisco Javier" "apellidos" => "Candel" "email" => array:1 [ 0 => "fj.candel@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Rafael" "apellidos" => "Cantón" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Microbiología Clínica, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Microbiología, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Uso actual de la fosfomicina: del laboratorio a la práctica clínica" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The need to use effective antimicrobials to treat multidrug-resistant (MDR) infections has driven the pharmaceutical industry to design new molecules, as well as to rediscover molecules which were already known about, such as colistin and fosfomycin. Indeed, use of fosfomycin, which is only approved in some European and Latin American countries, has seen unprecedented growth in the last four years. Fosfomycin, which is only approved by the US Food and Drug Administration as fosfomycin trometamol for the treatment of uncomplicated cystitis, is currently pending approval in intravenous form as disodium salt. In 2013, a randomised, multi-centre, open-label, controlled phase <span class="elsevierStyleSmallCaps">3</span> clinical trial to evaluate the efficacy of fosfomycin <span class="elsevierStyleItalic">versus</span> meropenem in the targeted treatment of bacteriaemic urinary tract infection due to extended-spectrum beta-lactamase-producing <span class="elsevierStyleItalic">Escherichia coli (E. coli)</span> (FOREST study) began in Spain.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">1</span></a> In 2017, another multi-centre, randomised, double-blind, phase <span class="elsevierStyleSmallCaps">2</span>/<span class="elsevierStyleSmallCaps">3</span> non-inferiority study to evaluate the safety and efficacy of intravenous fosfomycin <span class="elsevierStyleItalic">versus</span> piperacillin-tazobactam in the treatment of adult hospitalised patients with complicated urinary tract infections (ZEUS study) began in the United States.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Fosfomycin was discovered in Spain by an integrated research team from the now defunct <span class="elsevierStyleItalic">Compañía Española de Penicilina y Antibióticos</span> [Spanish Company of Penicillin and Antibiotics] (CEPA) from an isolate of <span class="elsevierStyleItalic">Streptomyces fradiae</span> collected in 1966 in Jávea (Alicante). As a phosphoenolpyruvate (PEP) analogue, it irreversibly inhibits the cytosolic enzyme MurA (N-acetylglucosamine enolpyruvyl-transferase), which plays a key role in the formation of N-acetylmuramic acid found in the peptidoglycan layer of the cell wall. It also reduces the formation of penicillin-binding proteins (PBP).<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">3</span></a> Fosfomycin is water soluble, has a low molecular mass (138) and binds negligibly to proteins, which is why it has excellent tissue diffusion properties.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">4,5</span></a> It also penetrates and diffuses in biofilms in experimental models at concentrations equal to or higher than ciprofloxacin or co-trimoxazole.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">6</span></a> The pharmacokinetic-pharmacodynamic efficacy parameter to take into account to achieve the therapeutic target with fosfomycin is the ratio between the area under the curve at 24<span class="elsevierStyleHsp" style=""></span>h and the MIC. It also shows postantibiotic effect at lower concentrations.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">7</span></a> Some of the resistance mechanisms reported include reduced intracellular transport of the antibiotic (mutations in transporter genes and AMPc <span class="elsevierStyleItalic">glpT</span> or <span class="elsevierStyleItalic">uhpT</span> regulators), change of target caused by <span class="elsevierStyleItalic">murA</span> expression mutations or abnormalities and, finally, the direct inactivation of the antibiotic by metalloenzymes (FosA, FosB and FosX) or by kinases (FormA and FormB).<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The lack of consistency between the CLSI (≥64<span class="elsevierStyleHsp" style=""></span>mg/l) and EUCAST (≥32<span class="elsevierStyleHsp" style=""></span>mg/l) breakpoints, the fact that some microorganisms have a naturally higher MIC (<span class="elsevierStyleItalic">Klebsiella</span> spp., <span class="elsevierStyleItalic">Enterobacter</span> spp., <span class="elsevierStyleItalic">Serratia</span> spp., <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>) due to the expression of chromosomal genes homologous to <span class="elsevierStyleItalic">FosA</span> and <span class="elsevierStyleItalic">FosB</span> that interact with fosfomycin, and the varying effective concentrations of the drug for Gram-positive and Gram-negative bacteria explains why the dosage recommendations for the treatment of MDR infections range from 8 to 12<span class="elsevierStyleHsp" style=""></span>g/day when Gram-positive microorganisms are involved, and from 16 to 24<span class="elsevierStyleHsp" style=""></span>g/day when treating Gram-negative bacteria.<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">8,9</span></a> It has recently been established that <span class="elsevierStyleItalic">E. coli</span> colonies that grow in the inhibition halos of diffusion tests, and whose presence is not related to clinical failure, are mutants with loss of GlpT and UhpT transporter expression.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">10</span></a> Given that the selection frequency of mutants with higher fosfomycin MIC values than those obtained with a wild strain depends on the concentration of fosfomycin present in the medium (5.5<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">5</span><span class="elsevierStyleHsp" style=""></span>CFU/ml with concentrations 5 times the MIC and >1.2<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span><span class="elsevierStyleHsp" style=""></span>CFU/ml with concentrations 256 times the MIC), the use of high doses of the drug, particularly if prescribed in monotherapy, would avoid this selection window.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">11</span></a> Furthermore, most of these mutants, particularly those selected with a lower fosfomycin concentration, would not be stable in successive passages, impacting on the high MIC values.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">12</span></a> Finally, a recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">13</span></a> found just 3.4% onset of resistance (95% CI, 1.8%–5.1%) during treatment with fosfomycin in monotherapy, which would presumably be lower or non-existent with combination therapy.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Fosfomycin has at least an additive effect, or even a synergistic effect in combination with almost all the antimicrobials tested thanks to its high diffusion and unique mechanism of action. In this edition of the journal, Coronado-Alvarez et al.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">14</span></a> present an interesting study that highlights the synergistic activity <span class="elsevierStyleItalic">in vitro</span> of fosfomycin at suprainhibitory concentrations (above the MIC) in combination with other antimicrobials (daptomycin, vancomycin, imipenem or linezolid) against strains of methicillin-susceptible <span class="elsevierStyleItalic">Staphylococcus aureus</span> (MSSA) and methicillin-resistant <span class="elsevierStyleItalic">S. aureus</span> (MRSA). Previous studies had demonstrated an additive effect of fosfomycin at subinhibitory concentrations (below the MIC). Coronado-Alvarez et al.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">14</span></a> also show the clinical correlation of their observations <span class="elsevierStyleItalic">in vitro</span> in patients administered fosfomycin in combination to treat bacteraemia caused by MRSA and MSSA, as well as by <span class="elsevierStyleItalic">Enterococcus faecium</span>. The most active combinations <span class="elsevierStyleItalic">in vitro</span> were those containing daptomycin or imipenem, while those with vancomycin or linezolid were less effective. The clinical results also revealed greater efficacy with daptomycin (93% therapeutic success) when compared with vancomycin (47% therapeutic success). In all cases, sterilisation of blood cultures was observed 48<span class="elsevierStyleHsp" style=""></span>h after initiating combination therapy with fosfomycin. Although a variety of regimens were used, no significant differences were observed when the combination therapy was administered at baseline <span class="elsevierStyleItalic">versus</span> 72<span class="elsevierStyleHsp" style=""></span>h after the onset of bacteraemia.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The results published by Coronado-Alvarez et al.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">14</span></a> corroborate those already published by other authors with combinations of fosfomycin with daptomycin<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">15</span></a> or with imipenem.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">16</span></a> The current guidelines on the treatment of persistent infection, or infection complicated by MRSA, issued by the <span class="elsevierStyleItalic">Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica</span> [Spanish Society of Infectious Diseases and Clinical Microbiology], recommend the combination of fosfomycin and daptomycin.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">17</span></a> This recommendation is expected to be further reinforced when the results of an ongoing trial comparing the combined activity of fosfomycin and daptomycin <span class="elsevierStyleItalic">versus</span> daptomycin in monotherapy for the treatment of MRSA infection are published.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Furthermore, the combination of fosfomycin with other antimicrobials has also demonstrated synergy <span class="elsevierStyleItalic">in vitro</span> against multidrug-resistant Gram-negative microorganisms,<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">19</span></a> and there is published clinical evidence of its use at high doses and in combination with other agents in the treatment of carbapenemase-producing enterobacteriaceae<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">20–22</span></a> and extensively-drug resistant <span class="elsevierStyleItalic">Pseudomonas</span> spp.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">23</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Fosfomycin is considered to be a relatively safe and well-tolerated antimicrobial. Nevertheless, cases of intolerance caused by sodium overload have been reported in exceptional cases. One gram of fosfomycin sodium contains 0.33<span class="elsevierStyleHsp" style=""></span>g (14.4<span class="elsevierStyleHsp" style=""></span>meq) of sodium,<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">24</span></a> which means that treatment with 12–24<span class="elsevierStyleHsp" style=""></span>g of fosfomycin provides the extracellular compartment with 4–8<span class="elsevierStyleHsp" style=""></span>g of sodium. Cases of heart failure have been reported in patients being treated with fosfomycin, including patients with a normal ejection fraction, requiring the drug to be withdrawn.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">14,16,25</span></a> Monitoring sodium overload in patients treated with high doses of fosfomycin (16–24<span class="elsevierStyleHsp" style=""></span>g/day) could be complicated in comorbid patients with water retention (cirrhosis, heart or kidney failure) as the neurohormonal expression of soluble factors (norepinephrine, vasopressin, atrial natriuretic peptides, <span class="elsevierStyleItalic">etc.</span>) could trigger an episode of volume overload in the extracellular compartment.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">26</span></a> In standard practice, the stability of fosfomycin at room temperature has led to its use in continuous infusion, particularly to treat MDR infections, striving for relatively low doses (12–16<span class="elsevierStyleHsp" style=""></span>g/day) that guarantee plasma trough concentrations above 32<span class="elsevierStyleHsp" style=""></span>mg/l, thereby reducing the total salt overload that would require the administration of fractionated doses. This could be particularly beneficial for patients suffering from the water retention conditions referred to above.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In conclusion, although this molecule is not new, its positioning has yet to be fully defined. The more we find out about fosfomycin, the more potential benefits it seems to reveal. Given its safety and activity, the most attractive therapeutic model is probably that proposed by Coronado-Alvarez et al.,<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">14</span></a> featuring the synergistic combination with other antimicrobials to treat complicated MDR infections.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">FJC and RC have participated in training activities sponsored by Laboratorios ERN.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Candel FJ, Cantón R. Uso actual de la fosfomicina: del laboratorio a la práctica clínica. Enferm Infecc Microbiol Clin. 2019;37:1–3.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:26 [ 0 => array:3 [ "identificador" => "bib0135" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fosfomycin versus meropenem in bacteraemic urinary tract infections caused by extended-spectrum β-lactamase-producing <span class="elsevierStyleItalic">Escherichia coli</span> (FOREST): study protocol for an investigator-driven randomised controlled trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Rosso-Fernández" 1 => "J. Sojo-Dorado" 2 => "A. Barriga" 3 => "L. Lavín-Alconero" 4 => "Z. Palacios" 5 => "I. 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