Proyecto ENDOKINETIC-CEF: tratamiento de la endocarditis infecciosa por Enterococcus faecalis en programas de tratamiento antibiótico endovenoso domiciliario

Esta tesis doctoral explora el tratamiento de la endocarditis infecciosa por Enterococcus faecalis para su utilización en los programas de tratamiento antibiótico endovenoso domiciliario (TADE), prestando especial atención a la adaptación a estos programas del tratamiento con la combinación de ampicilina y ceftriaxona. El objetivo de este trabajo ha sido aportar una visión amplia y crítica sobre las posibilidades de tratamiento antibiótico en este escenario e indagar en los aspectos más controvertidos de la adaptación del tratamiento con ampicilina y ceftriaxona a estos programas, como son la farmacocinética de ceftriaxona administrada a altas dosis y la estabilidad de soluciones antibióticas en las condiciones de uso habituales dentro de estos programas. Este trabajo se ha divido en cuatro estudios para abordar los diferentes objetivos. En primer lugar, se realizó un ensayo clínico para estudiar la farmacocinética de ceftriaxona administrada según la pauta propuesta para la adaptación del tratamiento combinado con ampicilina y ceftriaxona en el medio extrahospitalario, es decir, en una dosis única diaria de 4 gramos. La farmacocinética de esta nueva pauta se comparó con la de la pauta estándar cuya efectividad clínica ha sido avalada en estudios clínicos y que consiste en administrar 2 gramos de ceftriaxona cada 12 horas. En segundo lugar, se examinaron las alternativas terapéuticas estudiadas para el tratamiento de continuación de la endocarditis infecciosa por E. faecalis en el medio extrahospitalario mediante una revisión sistemática de la literatura. En tercer lugar, se ha determinado la estabilidad físico-química de dos soluciones antibióticas de ampicilina y ampicilina más ceftriaxona útiles para el tratamiento de esta entidad en programas de tratamiento antibiótico endovenoso domiciliario y en condiciones similares a las que encontramos en estos programas. Por último, se ha desarrollado un método analítico robusto, sencillo y versátil para la determinación de ceftriaxona en plasma mediante cromatografía líquida de alta resolución acoplada a espectrometría de masas. Este método ha sido utilizado para el análisis de los fármacos en los diferentes estudios. Los resultados del primer estudio han mostrado que la pauta de ceftriaxona propuesta para el tratamiento extrahospitalario con la combinación de ampicilina y ceftriaxona alcanzaba concentraciones valle significativamente menores que la pauta habitual, aunque con ninguna de las dos se alcanzó la concentración propuesta como objetivo para lograr la sinergia entre estos dos antibióticos. Por ello, su utilidad clínica queda supeditado al desarrollo de nuevos estudios que permitan definir un objetivo farmacocinético/farmacodinámico cuya relación con los resultados clínicos esté probada. En cuando al estudio de estabilidad, este aporta datos que permiten usar las soluciones estudiadas en los programas de tratamiento antibiótico endovenoso domiciliario. Esto supone un importante avance en la adaptación del tratamiento combinado con ampicilina y ceftriaxona al medio extrahospitalario y aumenta las opciones de tratamiento de la 9 endocarditis por E. faecalis en este ámbito. Además, aporta datos sobre la estabilidad de estas soluciones a temperaturas similares a las que se alcanzan en nuestro entorno, lo que aumenta su aplicabilidad en zonas con climas cálidos. El análisis de las alternativas terapéuticas llevado a cabo aporta una amplia visión de las mismas, destacando las fortalezas y debilidades de cada una de ellas y señalando aquellas que por sus buenos resultados de eficacia o por su fácil adaptación a los programas TADE parecen ser las opciones más atractivas. Por último, el método desarrollado para el análisis de fármacos cumplió todos los estándares exigidos por las guías internacionales y ha sido utilizado con éxito en los estudios que componen este trabajo. En conclusión, este estudio supone una aproximación integral al tratamiento de la endocarditis infecciosa por E. faecalis en el ámbito extrahospitalario, en la que se realizan grandes avances y se pone de manifiesto las áreas de conocimiento que requieren nuevos estudios en este ámbito

Stability of Ampicillin plus Ceftriaxone Combined in Elastomeric Infusion Devices for Outpatient Parenteral Antimicrobial Therapy

Ampicillin; Infective endocarditis; Outpatient parenteral antimicrobial therapyAmpicil·lina; Endocarditis infecciosa; Teràpia antimicrobiana parenteral ambulatòriaAmpicilina; Endocarditis infecciosa; Terapia antimicrobiana parenteral ambulatoriaCurrently, ampicillin plus ceftriaxone (AC) is one of the preferred treatments for Enterococcus faecalis infective endocarditis. However, there is a lack of stability data for the combination of both drugs in elastomeric devices, so the inclusion of AC in Outpatient Parenteral Antimicrobial Therapy (OPAT) programs is challenging. The objective of the study was to determine the stability of AC in elastomeric pumps when stored at 8 ± 2 °C, 25 ± 2 °C, 30 ± 2 °C and 37 ± 2 °C using LC-MS/MS. The combination was diluted in 0.9% sodium chloride and the final concentrations were ampicillin 24 g/L plus ceftriaxone 8 g/L. Physical and chemical stability were evaluated at 12, 20, 24, 36 and 48 h after preparation. Stability was met at each time point if the percentage of intact drug was ≥90% of its respective baseline concentration and color and clearness remained unchanged. The drug combination was stable for 48 h when it was kept at 8 ± 2 °C. At 25 ± 2 °C and 30 ± 2 °C, they were stable for 24 h of storage. At 37 ± 2 °C, the stability criterion was not met at any time point. These results prove that AC could be included in OPAT programs using elastomeric infusion devices for the treatment of E. faecalis infections.This work was supported by the Sociedad Española de Farmacia Hospitalaria and the AFinf Working Group for the project “Stability study of antimicrobials under conditions analogous to the outpatient parenteral antibiotic therapy program (OPAT)”. A.G.-V. was supported by the Instituto de Salud Carlos III, co-financed by the European Development Regional Fund (“A way to achieve Europe”), Subprograma Miguel Servet (grant CP19/00159). L.H.-H. was supported by the Instituto de Salud Carlos III, co-financed by the European Development Regional Fund (“A way to achieve Europe”), Subprograma Juan Rodés (grant JR22/00049)

Stability of Antimicrobials in Elastomeric Pumps: A Systematic Review

Antimicrobials; Elastomer; Systematic reviewAntimicrobianos; Elastómero; Revisión sistemáticaAntimicrobians; Elastòmer; Revisió sistemàticaOutpatient parenteral antimicrobial therapy (OPAThttp) programs have become an important healthcare tool around the world. Portable elastomeric infusion pumps are functional devices for ambulatory delivery of antimicrobial drugs, and their stability is an essential point to guarantee an appropriate infusion administration. We conducted a systematic review to provide a synthesis and a critical evaluation of the current evidence regarding antimicrobial stability in elastomeric pumps. Data sources were PubMed, EMBASE, and Web of Sciences. The review protocol was registered on the Center for Open Science, and it was carried out following the PRISMA guidelines. Studies were eligible if the aim was the evaluation of the physicochemical stability of an antimicrobial agent stored in an elastomeric device. Of the 613 papers identified, 33 met the inclusion criteria. The most studied group of antimicrobials was penicillins, followed by cephalosporins and carbapenems. In general, the stability results of the antimicrobials that have been studied in more than one article agree with each other, with the exception of ampicillin, flucloxacillin, and ceftazidime. The antibiotics that displayed a longer stability were glycopeptides and clindamycin. Regarding the stability of antifungals and antivirals, only caspofungin, voriconazole, and ganciclovir have been investigated. The information provided in this article should be considered in patient treatments within the OPAT setting. Further stability studies are needed to confirm the appropriate use of the antimicrobials included in this program to ensure optimal patient outcomes.This work was supported by the Sociedad Española de Farmacia Hospitalaria and the AFinf Working Group for the project “Stability study of antimicrobials under conditions analogous to the outpatient parenteral antibiotic therapy program (OPAT)”. A.G.-V. was supported by the Instituto de Salud Carlos III, co-financed by the European Development Regional Fund (“A way to achieve Europe”), Subprograma Miguel Servet (grant CP19/00159). L.H.-H. was supported by the Instituto de Salud Carlos III, Subprograma Rio Hortega (grant CM19/00152)

Stability Studies of Antipseudomonal Beta Lactam Agents for Outpatient Therapy

Pseudomonas aeruginosa; Beta lactams; Multidrug-resistant bacteriaPseudomonas aeruginosa; Betalactámicos; Bacterias resistentes a múltiples medicamentosPseudomonas aeruginosa; Betalactàms; Bacteris resistents a múltiples medicamentsOutpatient parenteral antimicrobial therapy (OPAT) is a useful treatment strategy against Pseudomonas aeruginosa and other multidrug-resistant bacteria. However, it is hindered by the lack of stability data for the administration of antibiotics under OPAT conditions. Our objective was to investigate the stability of nine antipseudomonal and broad-spectrum beta lactam antibiotics (aztreonam, cefepime, cefiderocol, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem, meropenem/vaborbactam, and piperacillin/tazobactam) to allow the spread of OPAT programs. All the antibiotics were diluted in 500 mL 0.9% sodium chloride and stored at 4, 25, 32, and 37 °C for 72 h in two different devices (infusion bags and elastomeric pumps). The solutions were considered stable if the color, clearness, and pH remained unchanged and if the percentage of intact drug was ≥90%. All the antimicrobials remained stable 72 h under refrigerated conditions and at least 30 h at 25 °C. At 32 °C, all the antibiotics except for meropenem and meropenem/vaborbactam remained stable for 24 h or more. At 37 °C, only aztreonam, piperacillin/tazobactam, cefepime, cefiderocol, and ceftolozane/tazobactam were stable for at least 24 h. The stability results were the same in the two devices tested. All the antibiotics studied are actual alternatives for the treatment of antipseudomonal or multidrug-resistant infections in OPAT programs, although the temperature of the devices is crucial to ensure antibiotic stability.This work was supported by the Sociedad Española de Farmacia Hospitalaria and the AFinf Working Group for the project “Stability study of antimicrobials under conditions analogous to the outpatient parenteral antibiotic therapy program (OPAT)”. A.G.-V. and L.H.-H. were supported by the Instituto de Salud Carlos III, co-financed by the European Development Regional Fund (“A way to 251 achieve Europe”). A.G.-V. received financial support from the Subprograma Miguel Servet (CP19/00159). L.H.-H. received financial support from the Subprograma Juan Rodés (JR22/00049)

Conventional Hospitalization versus Sequential Outpatient Parenteral Antibiotic Therapy for Staphylococcus aureus Bacteremia: Post-Hoc Analysis of a Multicenter Observational Cohort

Staphylococcus aureus; Bacteremia; Outpatient parenteral antimicrobial therapyStaphylococcus aureus; Bacterièmia; Teràpia antimicrobiana parenteral ambulatòriaStaphylococcus aureus; Bacteriemia; Terapia antimicrobiana parenteral ambulatoriaIt is not known whether sequential outpatient parenteral antimicrobial (OPAT) is as safe and effective as conventional hospitalization in patients with S. aureus bacteremia (SAB). A post-hoc analysis of the comparative effectiveness of conventional hospitalization versus sequential OPAT was performed in two prospective Spanish cohorts of patients with S. aureus bacteremia. The PROBAC cohort is a national, multicenter, prospective observational cohort of patients diagnosed in 22 Spanish hospitals between October 2016 and March 2017. The DOMUS OPAT cohort is a prospective observational cohort including patients from two university hospitals in Seville, Spain from 2012 to 2021. Multivariate regression was performed, including a propensity score (PS) for receiving OPAT, stratified analysis according to PS quartiles, and matched pair analyses based on PS. Four hundred and thirteen patients were included in the analysis: 150 in sequential OPAT and 263 in the full hospitalization therapy group. In multivariate analysis, including PS and center effect as covariates, 60-day treatment failure was lower in the OPAT group than in the full hospitalization group (p < 0.001; OR 0.275, 95%CI 0.129−0.584). In the PS-based matched analyses, sequential treatment under OPAT was not associated with higher 60-day treatment failure (p = 0.253; adjusted OR 0.660; % CI 0.324−1.345). OPAT is a safe and effective alternative to conventional in-patient therapy for completion of treatment in well-selected patients with SAB, mainly those associated with a low-risk source and without end-stage kidney disease

Clinical outcomes of an innovative cefazolin delivery program for MSSA infections in OPAT

Cefazolin is a recommended treatment for methicillin-susceptible Staphylococcus aureus (MSSA) infections that has been successfully used in outpatient parenteral antibiotic therapy (OPAT) programs. The aim of this study was to assess the clinical outcomes of cefazolin delivered each day (Group 24) vs. every two days (Group 48) for MSSA infections in OPAT programs. It was a prospective observational study with retrospective analysis of a cohort of MSSA infections attended in OPAT. The primary outcome was treatment success, defined as completing the antimicrobial regimen without death, treatment discontinuation, or readmission during treatment and follow-up. A univariate and multivariate logistic regression model was built. A two-sided p < 0.05 was considered statistically significant. Of the 149 MSSA infections treated with cefazolin 2 g/8 h in OPATs, 94 and 55 patients were included in the delivery Group 24 and Group 48, respectively. Treatment failure and unplanned readmission rates were similar in both groups (11.7% vs. 7.3% p = 0.752 and 8.5% vs. 5.5% p = 0.491). There was a significant increase in vascular access complications in Group 24 (33.0%) with respect to Group 48 (7.3%) (p < 0.001). Treating uncomplicated MSSA infection with cefazolin home-delivered every two days through an OPAT program is not associated with an increased risk of treatment failure and entails a significant reduction in resource consumption compared to daily delivery

Ampicillin plus ceftriaxone combined therapy for enterococcus faecalis infective endocarditis in opat

Ampicillin plus ceftriaxone (AC) is a well-recognized inpatient regimen for Enterococcus faecalis infective endocarditis (IE). In this regimen, ceftriaxone is usually administered 2 g every 2 h (AC12). The administration of AC in outpatient parenteral antibiotic treatment (OPAT) programs is challenging because multiple daily doses are required. AC regimens useful for OPAT programs include once-daily high-dose administration of ceftriaxone (AC24) or AC co-diluted and jointly administered in bolus every 4 h (ACjoined). In this retrospective analysis of prospectively collected cases, we aimed to assess the clinical effectivity and safety of three AC regimens for the treatment of E. faecalis IE. Fifty-nine patients were treated with AC combinations (AC12 n = 32, AC24 n = 17, and ACjoined n = 10). Six relapses occurred in the whole cohort: five (29.4%) treated with AC24 regimen and one (10.0%) with ACjoined. Patients were cured in 30 (93.3%), 16 (94.1%), and eight (80.0%) cases in the AC12, AC24 and ACjoined groups, respectively. Unplanned readmission occurred in eight (25.0%), six (35.3%), and two (20.0%) patients in the AC12, AC24 and ACjoined groups, respectively. The outcome of patients with E. faecalis IE treated with AC in OPAT programs relies on an optimization of the delivery of the combination. AC24 exhibit an unexpected rate of failures, however, ACjoined might be an effective alternative which clinical results should corroborate in further studies

Ampicillin Plus Ceftriaxone Combined Therapy for Enterococcus faecalis Infective Endocarditis in OPAT

Cardiovascular Infectious Study Group of the Andalusian Society of Infectious Diseases.Ampicillin plus ceftriaxone (AC) is a well-recognized inpatient regimen for Enterococcus faecalis infective endocarditis (IE). In this regimen, ceftriaxone is usually administered 2 g every 2 h (AC12). The administration of AC in outpatient parenteral antibiotic treatment (OPAT) programs is challenging because multiple daily doses are required. AC regimens useful for OPAT programs include once-daily high-dose administration of ceftriaxone (AC24) or AC co-diluted and jointly administered in bolus every 4 h (ACjoined). In this retrospective analysis of prospectively collected cases, we aimed to assess the clinical effectivity and safety of three AC regimens for the treatment of E. faecalis IE. Fifty-nine patients were treated with AC combinations (AC12 n = 32, AC24 n = 17, and ACjoined n = 10). Six relapses occurred in the whole cohort: five (29.4%) treated with AC24 regimen and one (10.0%) with ACjoined. Patients were cured in 30 (93.3%), 16 (94.1%), and eight (80.0%) cases in the AC12, AC24 and ACjoined groups, respectively. Unplanned readmission occurred in eight (25.0%), six (35.3%), and two (20.0%) patients in the AC12, AC24 and ACjoined groups, respectively. The outcome of patients with E. faecalis IE treated with AC in OPAT programs relies on an optimization of the delivery of the combination. AC24 exhibit an unexpected rate of failures, however, ACjoined might be an effective alternative which clinical results should corroborate in further studies.The authors received no financial support for the research, authorship, and/or publication of this article. GVA was supported by the Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund (“A way to achieve Europe”), Subprograma Miguel Servet (grant CP19/00159). HHL was supported by the Instituto de Salud Carlos III, Subprograma Rio Hortega (grant CM19/00152)

Extracellular vesicles from pristane-treated CD38-deficient mice express an antiinflammatory neutrophil protein signature, which reflects the mild lupus severity elicited in these mice

In CD38-deficient (Cd38-/-) mice intraperitoneal injection of pristane induces a lupus-like disease, which is milder than that induced in WT mice, showing significant differences in the inflammatory and autoimmune processes triggered by pristane. Extracellular vesicles (EV) are present in all body fluids. Shed by cells, their molecular make-up reflects that of their cell of origin and/or tissue pathological situation. The aim of this study was to analyze the protein composition, protein abundance, and functional clustering of EV released by peritoneal exudate cells (PECs) in the pristane experimental lupus model, to identify predictive or diagnostic biomarkers that might discriminate the autoimmune process in lupus from inflammatory reactions and/or normal physiological processes. In this study, thanks to an extensive proteomic analysis and powerful bioinformatics software, distinct EV subtypes were identified in the peritoneal exudates of pristane-treated mice: 1) small EV enriched in the tetraspanin CD63 and CD9, which are likely of exosomal origin; 2) small EV enriched in CD47 and CD9, which are also enriched in plasma-membrane, membrane-associated proteins, with an ectosomal origin; 3) small EV enriched in keratins, ECM proteins, complement/coagulation proteins, fibrin clot formation proteins, and endopetidase inhibitor proteins. This enrichment may have an inflammation-mediated mesothelial-tomesenchymal transition origin, representing a protein corona on the surface of peritoneal exudate EV; 4) HDL-enriched lipoprotein particles. Quantitative proteomic analysis allowed us to identify an anti-inflammatory, Annexin A1- enriched pro-resolving, neutrophil protein signature, which was more prominent in EV from pristane-treated Cd38-/- mice, and quantitative differences in the protein cargo of the ECM-enriched EV from Cd38-/- vs WT mice. These differences are likely to be related with the distinct inflammatory outcome shown by Cd38-/- vs WT mice in response to pristane treatment. Our results demonstrate the power of a hypothesis-free and data-driven approach to transform the heterogeneity of the peritoneal exudate EV from pristanetreated mice in valuable information about the relative proportion of different EV in a given sample and to identify potential protein markers specific for the different small EV subtypes, in particular those proteins defining EV involved in the resolution phase of chronic inflammation.Proyecto del plan estatal, Ministerio de Ciencia e Innovacion PT13/0001/011CSIC PT17/0019/0010 PID2020-119567RB-I0

Stability of temocillin in outpatient parenteral antimicrobial therapy: is it a real option?

[Background] Temocillin is an interesting alternative to carbapenems for susceptible Enterobacteriaceae. Although its use in outpatient parenteral antimicrobial therapy (OPAT) programmes has generated interest, this has been hampered by the lack of stability data.[Objectives] The purpose of the present study was to evaluate the physical and chemical stability of temocillin at the recommended dose for its use in OPAT programmes, contained in polypropylene infusion bags or polyisoprene elastomeric devices at different temperatures, and to describe a novel LC-MS/MS developed for the quantification of temocillin.[Methods] Temocillin daily dose (6 g) was diluted in 500 mL of 0.9% sodium chloride to obtain a final concentration of 12 g/L. This solution was stored at 4°C, 25°C, 32°C and 37°C for 72 h, both in polypropylene infusion bags and in polyisoprene elastomeric pumps. Physical and chemical stability were evaluated during 72 h after manufacturing. Solutions were considered stable if colour, clearness and pH remained unchanged and if the percentage of intact drug was ≥90%.[Results] Temocillin attained the chemical stability criterion of ≥90% of the original concentration for the whole experiment in both devices at 4°C, 25°C and 32°C. At 37°C, temocillin was stable for 24 h but its concentration dropped below 90% from that timepoint. No precipitation occurred and minor colour changes were observed.[Conclusions] Temocillin is stable under OPAT conditions and it would be an appropriate candidate for the treatment of patients who can be discharged to complete therapy in an OPAT programme. For this study, an LC-MS/MS method was developed.This work was supported by the Sociedad Española de Farmacia Hospitalaria and the AFinf Working Group for the project ‘Stability study of antimicrobials under conditions analogous to the outpatient parenteral antibiotic therapy program (OPAT)’. A.G.-V. and L.H.-H. were supported by the Instituto de Salud Carlos III, co-financed by the European Development Regional Fund (‘A way to 251 achieve Europe’). A.G.-V. received financial support from the Subprograma Miguel Servet (CP19/00159). L.H.-H. received financial support from the Subprograma Juan Rodés (JR22/00049).Peer reviewe