Oral linezolid compared with benzathine penicillin G for treatment of early syphilis in adults (Trep-AB Study) in Spain: a prospective, open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Management of syphilis, a sexually transmitted infection (STI) with increasing incidence, is challenged by drug shortages, scarcity of randomised trial data, an absence of non-penicillin alternatives for pregnant women with penicillin allergy (other than desensitisation), extended parenteral administration for neurosyphilis and congenital syphilis, and macrolide resistance. Linezolid was shown to be active against Treponema pallidum, the causative agent of syphilis, in vitro and in the rabbit model. We aimed to assess the efficacy of linezolid for treating early syphilis in adults compared with the standard of care benzathine penicillin G (BPG). METHODS: We did a multicentre, open-label, non-inferiority, randomised controlled trial to assess the efficacy of linezolid for treating early syphilis compared with BPG. We recruited participants with serological or molecular confirmation of syphilis (either primary, secondary, or early latent) at one STI unit in a public hospital and two STI community clinics in Catalonia (Spain). Participants were randomly allocated in a 1:1 ratio using a computer-generated block randomisation list with six participants per block, to receive either oral linezolid (600 mg once per day for 5 days) or intramuscular BPG (single dose of 2·4 million international units) and were assessed for signs and symptoms (once per week until week 6 and at week 12, week 24, and week 48) and reagin titres of non-treponemal antibodies (week 12, week 24, and week 48). The primary endpoint was treatment response, assessed using a composite endpoint that included clinical response, serological response, and absence of relapse. Clinical response was assessed at 2 weeks for primary syphilis and at 6 weeks for secondary syphilis following treatment initiation. Serological cure was defined as a four-fold decline in rapid plasma reagin titre or seroreversion at any of the 12-week, 24-week, or 48-week timepoints. The absence of relapse was defined as the presence of different molecular sequence types of T pallidum in recurrent syphilis. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference in rates of treatment response was higher than -10%. The primary analysis was done in the per-protocol population. The trial is registered at ClinicalTrials.gov (NCT05069974) and was stopped for futility after interim analysis. FINDINGS: Between Oct 20, 2021, and Sept 15, 2022, 62 patients were assessed for eligibility, and 59 were randomly assigned to linezolid (n=29) or BPG (n=30). In the per-protocol population, after 48 weeks' follow-up, 19 (70%) of 27 participants (95% CI 49·8 to 86·2) in the linezolid group had responded to treatment and 28 (100%) of 28 participants (87·7 to 100·0) in the BPG group (treatment difference -29·6, 95% CI -50·5 to -8·8), which did not meet the non-inferiority criterion. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (five [17%] of 29, 95% CI 5·8 to 35·8 in the linezolid group vs five [17%] of 30, 5·6 to 34·7, in the BPG group). No serious adverse events were reported during follow-up. INTERPRETATION: The efficacy of linezolid at a daily dose of 600 mg for 5 days did not meet the non-inferiority criteria compared with BPG and, as a result, this treatment regimen should not be used to treat patients with early syphilis. FUNDING: European Research Council and Fondo de Investigaciones Sanitarias.

Virulence genotype and phenotype of two clinical isolates of Arcobacter butzleri obtained from patients with different pathologies.

The surge in human arcobacteriosis has increased interest in determining the mechanisms involved in the pathogenesis of Arcobacter butzleri. Here, genomic analyses and in vitro Caco-2 infection, motility, urease and antimicrobial susceptibility testing (AST) assays were used to characterise the virulence and antimicrobial resistance (AMR) determinants of strains HC-1, isolated from a patient with travellers' diarrhoea, and HC-2, isolated from another with pruritus. AMR determinants conferring resistance to tetracycline (tetO, present in both genomes) and to ampicillin and amoxicillin-clavulanic acid (bla3, present in HC-2) were identified. The same determinants associated with flagellum, chemotaxis, adhesion and invasion were detected in both, but HC-1 lacked eight flagellar genes. The urease cluster was only present in HC-1. Motility and urease tests confirmed the genetic differences between strains, but no genetic marker related to the inability of HC-2 to adhere and invade was identified. This inability could be conditioning the patient's pathology.

Antimicrobial susceptibility of Treponema pallidum subspecies pallidum: an in-vitro study.

BACKGROUND: The increasing incidence of syphilis and the limitations of first-line treatment with penicillin, particularly in neurosyphilis, neonatal syphilis, and pregnancy, highlight the need to expand the therapeutic repertoire for effective management of this disease. We assessed the in-vitro efficacy of 18 antibiotics from several classes on Treponema pallidum subspecies pallidum (T pallidum), the syphilis bacteria. METHODS: Using the in-vitro culture system for T pallidum, we exposed the pathogen to a concentration range of each tested antibiotic. After a 7-day incubation, the treponemal burden was evaluated by quantitative PCR targeting the T pallidum tp0574 gene. The primary outcome was the minimum inhibitory concentration (MIC) at which the quantitative PCR values were not significantly higher than the inoculum wells. We also investigated the susceptibility of macrolide-resistant strains to high concentrations of azithromycin, and the possibility of developing resistance to linezolid, a proposed candidate for syphilis treatment. FINDINGS: Amoxicillin, ceftriaxone, several oral cephalosporins, tedizolid, and dalbavancin exhibited anti-treponemal activity at concentrations achievable in human plasma following regular dosing regimens. The experiments revealed a MIC for amoxicillin at 0·02 mg/L, ceftriaxone at 0·0025 mg/L, cephalexin at 0·25 mg/L, cefetamet and cefixime at 0·0313 mg/L, cefuroxime at 0·0156 mg/L, tedizolid at 0·0625 mg/L, spectinomycin at 0·1 mg/L, and dalbavancin at 0·125 mg/L. The MIC for zoliflodacin and balofloxacin was 2 mg/L. Ertapenem, isoniazid, pyrazinamide, and metronidazole had either a poor or no effect. Azithromycin concentrations up to 2 mg/L (64 times the MIC) were ineffective against strains carrying mutations associated to macrolide resistance. Exposure to subtherapeutic doses of linezolid for 10 weeks did not induce phenotypic or genotypic resistance. INTERPRETATION: Cephalosporins and oxazolidinones are potential candidates for expanding the current therapeutic repertoire for syphilis. Our findings warrant testing efficacy in animal models and, if successful, clinical assessment of efficacy. FUNDING: European Research Council.

Validation of an expanded, in-house library and an optimized preparation method for the identification of fungal isolates using MALDI-TOF mass spectrometry.

The goal of this study was to validate an optimized sample preparation method for filamentous fungal isolates coupled with the use of an in-house library for the identification of moulds using Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) in a multicenter context. For that purpose, three Spanish microbiology laboratories participated in the identification of 97 fungal isolates using MALDI-TOF MS coupled with the Filamentous Fungi library 3.0 (Bruker Daltonics) and an in-house library containing 314 unique fungal references. The isolates analyzed belonged to 25 species from the genus Aspergillus, Fusarium, Scedosporium/Lomentospora, the Mucorales order and the Dermatophytes group. MALDI-TOF MS identification was carried out from hyphae resuspended in water and ethanol. After a high-speed centrifugation step, the supernatant was discarded and the pellet submitted to a standard protein extraction step. The protein extract was analyzed with the MBT Smart MALDI Biotyper system (Bruker Daltonics). The rate of accurate, species-level identification obtained ranged between 84.5% and 94.8% and the score values were 1.8 for 72.2-94.9% of the cases. Two laboratories failed to identify only one isolate of Syncephalastrum sp. and Trichophyton rubrum, respectively and three isolates could not be identified in the third center (F. proliferatum, n = 1; T.interdigitale, n = 2). In conclusion, the availability of an effective sample preparation method and an extended database allowed high rates of correct identification of fungal species using MALDI-TOF MS. Some species, such as Trichophyton spp. are still difficult to identify. Although further improvements are still required, the developed methodology allowed the reliable identification of most fungal species.

MALDI-TOF mass spectrometry has been improved as a diagnostic method for the rapid and reliable identification of filamentous fungi by means of the creation of an expanded database containing reference protein spectra of the most clinically impacting fungal species.

Pharmacokinetic/Pharmacodynamic Analysis of Oral Calcium Fosfomycin: Are Urine Levels Sufficient to Ensure Efficacy for Urinary Tract Infections?

Urinary tract infections (UTIs) are extremely common and a major driver for the use of antimicrobials. Calcium fosfomycin is an old antibiotic indicated for the treatment of UTIs; however, data about its urine pharmacokinetic profile are scarce. In this work, we have evaluated the pharmacokinetics of fosfomycin from urine concentrations after oral administration of calcium fosfomycin to healthy women. Moreover, we have assessed, by pharmacokinetic/pharmacodynamic (PK/PD) analysis and Monte Carlo simulations, its effectiveness considering the susceptibility profile of Escherichia coli, the main pathogen involved in UTIs. The accumulated fraction of fosfomycin excreted in urine was around 18%, consistent with its low oral bioavailability and its almost exclusively renal clearance by glomerular filtration as unchanged drug. PK/PD breakpoints resulted to be 8, 16, and 32 mg/L for a single dose of 500 mg, a single dose of 1000 mg, and 1000 mg q8h for 3 days, respectively. For empiric treatment, the estimated probability of treatment success was very high (>95%) with the three dose regimens, considering the susceptibility profile of E. coli reported by EUCAST. Our results show that oral calcium fosfomycin at a dose level of 1000 mg every 8 h provides urine concentrations sufficient to ensure efficacy for the treatment of UTIs in women.

Pseudomonas aeruginosa Susceptibility in Spain: Antimicrobial Activity and Resistance Suppression Evaluation by PK/PD Analysis.

Pseudomonas aeruginosa remains one of the major causes of healthcare-associated infection in Europe; in 2019, 12.5% of invasive isolates of P. aeruginosa in Spain presented combined resistance to ≥3 antimicrobial groups. The Spanish nationwide survey on P. aeruginosa antimicrobial resistance mechanisms and molecular epidemiology was published in 2019. Based on the information from this survey, the objective of this work was to analyze the overall antimicrobial activity of the antipseudomonal antibiotics considering pharmacokinetic/pharmacodynamic (PK/PD) analysis. The role of PK/PD to prevent or minimize resistance emergence was also evaluated. A 10,000-subject Monte Carlo simulation was executed to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) considering the minimum inhibitory concentration (MIC) distribution of bacteria isolated in ICU or medical wards, and distinguishing between sample types (respiratory and non-respiratory). Ceftazidime/avibactam followed by ceftolozane/tazobactam and colistin, categorized as the Reserve by the Access, Watch, Reserve (AWaRe) classification of the World Health Organization, were the most active antimicrobials, with differences depending on the admission service, sample type, and dose regimen. Discrepancies between EUCAST-susceptibility breakpoints for P. aeruginosa and those estimated by PK/PD analysis were detected. Only standard doses of ceftazidime/avibactam and ceftolozane/tazobactam provided drug concentrations associated with resistance suppression.

Molecular Epidemiology, Antimicrobial Surveillance, and PK/PD Analysis to Guide the Treatment of Neisseria gonorrhoeae Infections.

The aim of this study was to apply molecular epidemiology, antimicrobial surveillance, and PK/PD analysis to guide the antimicrobial treatment of gonococci infections in a region of the north of Spain. Antibiotic susceptibility testing was performed on all isolates (2017 to 2019, n = 202). A subset of 35 isolates intermediate or resistant to at least two antimicrobials were selected to search for resistance genes and genotyping through WGS. By Monte Carlo simulation, we estimated the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the antimicrobials used to treat gonorrhea, both indicative of the probability of treatment success. In total, 2.0%, 6.4%, 5.4%, and 48.2% of the isolates were resistant to ceftriaxone, cefixime, azithromycin, and ciprofloxacin, respectively. Twenty sequence types were identified. Detected mutations were related to antibiotic resistance. PK/PD analysis showed high probability of treatment success of the cephalosporins. In conclusion, multiple populations of N. gonorrhoeae were identified. We can confirm that ceftriaxone (even at the lowest dose: 250 mg) and oral cefixime are good candidates to treat gonorrhea. For patients allergic to cephalosporins, ciprofloxacin should be only used if the MIC is known and ≤0.125 mg/L; this antimicrobial is not recommended for empirical treatment.

Haemophilus influenzae Type a Sequence Type 23, Northern Spain.

Two consecutive cases of Haemophilus influenzae type a sequence type 23 invasive infection in 2 children attending the same daycare in 2019 triggered epidemiologic surveillance of H. influenzae infections in northern Spain. Despite the invasiveness potential of this virus strain, we detected no additional cases for 2013-2020.

Pharmacokinetic/pharmacodynamic evaluation of the antimicrobial therapy of pneumococcal invasive disease in adults in post-PCV13 vaccine period in Madrid, Spain.

The objective of our study was to evaluate by pharmacokinetic/pharmacodynamic (PK/PD) analysis, if the antimicrobials used for the treatment of invasive pneumococcal disease (IPD) in adults, including meningitis, are adequate considering the susceptibility profile of S. pneumoniae in Spain after the implantation of PVC13 vaccine. Pharmacokinetic parameters of benzylpenicillin and cefotaxime were obtained from the literature, and susceptibility data of invasive S. pneumoniae strains recovered in 2017 (post-PCV13 vaccination period) were provided by the Public Health Regional Laboratory of Madrid. We have also studied levofloxacin because it is used to treat pneumococcal pneumonia previously to be diagnosed as bacteremic pneumonia. Monte Carlo simulation was used to estimate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). All doses of benzylpenicillin except 2 mU q6h provide a high probability of treatment success for MIC values ≤ 1 mg/L; 4 mU q4h is even useful for MIC values up to 4 mg/L. This high dose, used for the treatment of meningitis, also provides high probability of treatment success for MIC ≤ 0.5 mg/L. At the susceptibility EUCAST breakpoint (≤ 0.5 mg/L), cefotaxime provides a high rate of PD target achievement, even at the lowest dose (1 g q8h). For meningitis, 2 g q6h ensures probabilities of target attainment ≥90% for MIC up to 1 mg/L. Our study confirms that after the implementation of PCV13 vaccine, the treatment with benzylpenicillin and cefotaxime provides high probability of the therapy success of IPD, including meningitis.

Recommendations of the Spanish Antibiogram Committee (COESANT) for selecting antimicrobial agents and concentrations for in vitro susceptibility studies using automated systems / Recomendaciones del Comité Español del Antibiograma (COESANT) para la selección de antimicrobianos y sus concentraciones en el estudio in vitro de la sensibilidad con métodos automáticos

Automated antimicrobial susceptibility testing devices are widely implemented in clinical microbiology laboratories in Spain, mainly using EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints. In 2007, a group of experts published recommendations for including antimicrobial agents and selecting concentrations in these systems. Under the patronage of the Spanish Antibiogram Committee (Comité Español del Antibiograma, COESANT) and the Study Group on Mechanisms of Action and Resistance to Antimicrobial Agents (GEMARA) from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), and aligned with the Spanish National Plan against Antimicrobial Resistance (PRAN), a group of experts have updated this document. The main modifications from the previous version comprise the inclusion of new antimicrobial agents, adaptation of the ranges of concentrations to cover the EUCAST breakpoints and epidemiological cut-off values (ECOFFs), and the inference of new resistance mechanisms. This proposal should be considered by different manufacturers and users when designing new panels or cards. In addition, recommendations for selective reporting are also included. With this approach, the implementation of EUCAST breakpoints will be easier, increasing the quality of antimicrobial susceptibility testing data and their microbiological interpretation. It will also benefit epidemiological surveillance studies as well as the clinical use of antimicrobials aligned with antimicrobial stewardship programs

Los sistemas automáticos utilizados en el estudio de la sensibilidad a los antimicrobianos están introducidos en la mayoría de los laboratorios de Microbiología Clínica en España, utilizando principalmente los puntos de corte del European Committee on Antimicrobial Susceptibility Testing (EUCAST). En 2007, un grupo de expertos publicó unas recomendaciones para incluir antimicrobianos y seleccionar concentraciones en estos sistemas. Bajo el auspicio del Comité Español del Antibiograma (COESANT) y del Grupo de Estudio de los Mecanismos de Acción y Resistencia a los Antimicrobianos (GEMARA) de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) y alineado con el Plan Nacional frente a la Resistencia a los Antibióticos (PRAN), un grupo de expertos ha actualizado dicho documento. Las principales modificaciones realizadas sobre la versión anterior comprenden la inclusión de nuevos agentes antimicrobianos, la adaptación de los rangos de concentraciones para cubrir los puntos de corte clínicos y los puntos de corte epidemiológicos (ECOFF) definidos por el EUCAST, y para la inferencia de nuevos mecanismos de resistencia. Esta propuesta debería ser considerada por los diferentes fabricantes y los usuarios cuando se diseñen nuevos paneles o tarjetas. Además, se incluyen recomendaciones para realizar informes selectivos. Con este enfoque, la implementación de los puntos de corte del EUCAST será más fácil, aumentando la calidad de los datos del antibiograma y su interpretación microbiológica. También será de utilidad para los estudios de vigilancia epidemiológica, así como para el uso clínico de los antimicrobianos, de acuerdo con los programas de optimización de uso de antimicrobianos (PROA)

Del CLSI al EUCAST, una transición necesaria en los laboratorios españoles / From CLSI to EUCAST, a necessary step in Spanish laboratories

El Comité Español del Antibiograma (COESANT) presenta en este documento una sencilla «hoja de ruta» en forma de decálogo de recomendaciones cuya finalidad es facilitar la transición de la normativa del Clinical and Laboratory Standards Institute (CLSI) a la del European Committee on Antimirobial Susceptibility Testing (EUCAST) en los Servicios y Unidades de Microbiología Clínica que aún emplean los criterios del CLSI. Su objetivo es adaptar las directrices europeas, más próximas a la realidad clínico-epidemiológica española, y conseguir una implantación de los criterios del EUCAST en la totalidad de los laboratorios de Microbiología en España

The Spanish Antibiogram Committee (Comité Español del Antibiograma, COESANT) presents in this document a simple "roadmap" or decalogue of recommendations, with a view to facilitating the transition from the Clinical and Laboratory Standards Institute (CLSI) to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) antimicrobial susceptibility testing regulations to the Clinical Microbiology Spanish laboratories that still use the CLSI guidelines. The objectives are to adapt the closer European regulations to the Spanish clinical and epidemiological reality and to fully implement the EUCAST recommendations in all microbiology laboratories in Spain

From CLSI to EUCAST, a necessary step in Spanish laboratories. / Del CLSI al EUCAST, una transición necesaria en los laboratorios españoles.

The Spanish Antibiogram Committee (Comité Español del Antibiograma, COESANT) presents in this document a simple "roadmap" or decalogue of recommendations, with a view to facilitating the transition from the Clinical and Laboratory Standards Institute (CLSI) to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) antimicrobial susceptibility testing regulations to the Clinical Microbiology Spanish laboratories that still use the CLSI guidelines. The objectives are to adapt the closer European regulations to the Spanish clinical and epidemiological reality and to fully implement the EUCAST recommendations in all microbiology laboratories in Spain.

Recommendations of the Spanish Antibiogram Committee (COESANT) for selecting antimicrobial agents and concentrations for in vitro susceptibility studies using automated systems.

Automated antimicrobial susceptibility testing devices are widely implemented in clinical microbiology laboratories in Spain, mainly using EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints. In 2007, a group of experts published recommendations for including antimicrobial agents and selecting concentrations in these systems. Under the patronage of the Spanish Antibiogram Committee (Comité Español del Antibiograma, COESANT) and the Study Group on Mechanisms of Action and Resistance to Antimicrobial Agents (GEMARA) from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), and aligned with the Spanish National Plan against Antimicrobial Resistance (PRAN), a group of experts have updated this document. The main modifications from the previous version comprise the inclusion of new antimicrobial agents, adaptation of the ranges of concentrations to cover the EUCAST breakpoints and epidemiological cut-off values (ECOFFs), and the inference of new resistance mechanisms. This proposal should be considered by different manufacturers and users when designing new panels or cards. In addition, recommendations for selective reporting are also included. With this approach, the implementation of EUCAST breakpoints will be easier, increasing the quality of antimicrobial susceptibility testing data and their microbiological interpretation. It will also benefit epidemiological surveillance studies as well as the clinical use of antimicrobials aligned with antimicrobial stewardship programs.

Susceptibility of Pseudomonas aeruginosa and antimicrobial activity using PK/PD analysis: an 18-year surveillance study / Sensibilidad de Pseudomonas aeruginosa y análisis PK/PD de su actividad antimicrobiana: estudio de vigilancia de 18 años

INTRODUCTION: We analysed the changes in the susceptibility of Pseudomonas aeruginosa to antimicrobials over an 18-year period (2000-2017) in order to evaluate the adequacy of the antimicrobial therapy against this organism in patients admitted in a tertiary Spanish hospital (excluding the intensive care unit). In addition, the antimicrobial activity was evaluated using pharmacokinetic/pharmacodynamic (PK/PD) criteria as a microbiological surveillance tool. METHODS: Susceptibility was studied according to the Clinical and Laboratory Standards Institute breakpoints. Monte Carlo simulations were conducted to calculate the cumulative fraction of response (CFR). Linear regression analysis was applied to determine the trends in susceptibility and in the CFR. RESULTS: In 2017, susceptibility rates were: amikacin, penicillins and cephalosporins ≥ 85%, tobramycin 76%, meropenem 75% and gentamicin, imipenem and fluoroquinolones < 70%. PK/PD analyses was able to identify changes in antimicrobial activity not detected by only assessing MICs; meropenem administered in extended infusion attained a CFR > 90%, ceftazidime, piperacillin/tazobactam and imipenem provided CFRs between 80-90%, all of them administered at the highest doses. CONCLUSIONS: Analysis of susceptibility and PK/PD modelling, should be considered together to select the most appropriate antimicrobial drug and dosage regimen. Empirical antipseudomonal therapy would vary considerably if both microbiological surveillance tools were considered. In this study, the PK/PD analysis made it possible to preserve the therapeutic value of antimicrobials with low susceptibility rates, such as carbapenems, and the selection of the most effective antimicrobials among those with high rates of susceptibility

INTRODUCCIÓN: Para evaluar la terapia antimicrobiana frente a Pseudomonas aeruginosa (P. aeruginosa) en pacientes ingresados en un hospital terciario español (excluida Unidad de Cuidados Intensivos), se analizaron los cambios en la sensibilidad a los antimicrobianos durante 18 años (2000-2017). También se evaluó la actividad antimicrobiana utilizando criterios farmacocinéticos/farmacodinámicos (PK/PD) como herramienta de vigilancia microbiológica. MÉTODOS: La sensibilidad se estudió utilizando los puntos de corte del CLSI. Se realizaron simulaciones de Monte Carlo para calcular la fracción de respuesta acumulada (CFR). Se llevó a cabo un análisis de tendencia de sensibilidad y CFR mediante regresión lineal. RESULTADOS: En 2017, la sensibilidad a amikacina, penicilinas y cefalosporinas fue ≥ 85%; tobramicina 76%, meropenem 75% y para gentamicina, imipenem y fluoroquinolonas < 70%. El análisis PK/PD fue capaz de identificar cambios en la actividad antimicrobiana no detectados mediante la evaluación únicamente de las concentraciones mínimas inhibitorias; meropenem administrado en forma de infusión extendida alcanzó una CFR > 90%, ceftazidima, piperacilina/tazobactam e imipenem proporcionaron CFR entre 80 y 90%, todos ellos administrados a las dosis más altas. CONCLUSIÓN: La evaluación de la sensibilidad y el análisis PK/PD deben considerarse conjuntamente para seleccionar el tratamiento antimicrobiano más apropiado: fármaco y régimen de dosificación. La terapia empírica frente a P. aeruginosa variaría considerablemente si se consideraran ambas herramientas de vigilancia microbiológica. En este estudio, el análisis PK/PD ha permitido preservar el valor terapéutico de antimicrobianos con bajos valores de sensibilidad, como los carbapenems, y la selección de los antimicrobianos de mayor eficacia, entre aquellos que presentaban altos valores de sensibilidad

Pharmacokinetic/pharmacodynamic analysis as a tool for surveillance of the activity of antimicrobials against Pseudomonas aeruginosa strains isolated in critically ill patients / Análisis farmacocinético/farmacodinámico como herramienta para la vigilancia de la actividad de los antimicrobianos frente a Pseudomonas aeruginosa en pacientes críticos

INTRODUCTION: To evaluate the changes in the susceptibility of Pseudomonas aeruginosa over time (2000-2017) against antimicrobials used in an intensive care unit of a Spanish tertiary hospital, and to compare them with the antimicrobial activity considering theoretical pharmacokinetic/pharmacodynamic (PK/PD) criteria. The influence of the method for handling duplicate isolates to quantify susceptibility rates was also evaluated. METHODS: The susceptibility was studied considering the Clinical and Laboratory Standards Institute (CLSI) breakpoints. Monte Carlo simulations were conducted to calculate the cumulative fraction of response (CFR). Linear regression analysis was applied to determine the trends in susceptibility and in the CFR. RESULTS: A significant decrease in the susceptibility to gentamicin and imipenem was observed, and more recently the highest percentages of susceptible strains were found for amikacin, cephalosporins and piperacillin/tazobactam ( > 80%). The probability of success of an empiric treatment or CFR for most of the evaluated antimicrobials was lower than 70% during the last two-year period. Only meropenem provided high probabilities ( > 90%) to achieve the PK/PD target. Cephalosporins provided moderate probabilities ( > 80%) although for ceftazidime, the highest dose (2g/8h) was required. Moreover, a significant decrease in the CFR trend for ciprofloxacin, imipenem and levofloxacin was observed. CONCLUSIONS: Both susceptibility rates and CFR values have to be considered together to optimize the antimicrobial dose regimen for clinical making-decisions. They are complementary tools and, they should be used jointly in surveillance programmes. In fact, susceptibility data are not always useful to detect changes in the CFR. No relevant differences were observed among the methods for handling repeated isolates

INTRODUCCIÓN: Evaluar los cambios en la sensibilidad de Pseudomonas aeruginosa (2000-2017) a los antimicrobianos utilizados en una unidad de cuidados intensivos en España, y compararlos con la actividad antimicrobiana considerando criterios f armacocinéticos/farmacodinámicos (PK/PD) teóricos. También se comparan los diferentes métodos para el manejo de aislados duplicados utilizados para cuantificar la sensibilidad. MÉTODOS: La sensibilidad se determinó siguiendo los puntos de corte del Clinical and Laboratory Standards Institute (CLSI). Se realizaron simulaciones de Monte Carlo para calcular la fracción de respuesta acumulada (CFR). Se analizó la tendencia en la sensibilidad microbiana y la CFR a lo largo del tiempo mediante regresión lineal. RESULTADOS: En el análisis de tendencias se observó un descenso significativo en la sensibilidad a gentamicina e imipenem, y una disminución significativa de la CFR para ciprofloxacino, imipenem y levofloxacino. En los últimos años, amikacina, cefalosporinas y piperacilina/tazobactam presentaron los mayores valores de sensibilidad (>80%). La CFR para la mayoría de los antimicrobianos fue inferior al 70% durante el último periodo estudiado. Solo meropenem proporcionó altas probabilidades (> 90%) de alcanzar el objetivo PK/PD. Las cefalosporinas proporcionaron probabilidades moderadas (> 80%), siendo necesarias dosis elevadas de ceftazidima (2 g/8 h). CONCLUSIONES: Los datos de sensibilidad antimicrobiana y los valores de CFR deben considerarse herramientas complementarias y, por tanto, evaluarse conjuntamente tanto en actividades de vigilancia como en la evaluación de la eficacia terapéutica de los regímenes de dosificación. De hecho, los datos de sensibilidad no siempre son útiles para detectar cambios en la CFR. Finalmente, no se observaron diferencias relevantes entre los métodos para el manejo de aislados duplicados empleados

Antibiotic susceptibility trend before and after long-term use of selective digestive decontamination: a 16 year ecological study.

OBJECTIVES: The aim of this study was to compare antimicrobial susceptibility rates in a Spanish ICU before and after the introduction of selective digestive decontamination (SDD) and also to compare these with susceptibility data from other Spanish ICUs without SDD. METHODS: We performed a retrospective study in the ICU of the University Hospital of Alava, where SDD was implemented in 2002. The SDD protocol consisted of a 2% mixture of gentamicin, colistin and amphotericin B applied on the buccal mucosa and a suspension of the same drugs in the gastrointestinal tract; additionally, for the first 3 days, systemic ceftriaxone was administered. From 1998 to 2013 we analysed the susceptibility rates for 48 antimicrobial/organism combinations. Interrupted time series using a linear dynamic model with SDD as an intervention was used. Data from other ICUs were obtained from the ENVIN-HELICS national registry. RESULTS: Only amoxicillin/clavulanic acid against Escherichia coli and Proteus mirabilis, and a high concentration of gentamicin against Enterococcus faecalis, resulted in a significant decrease in the susceptibility rate after the implementation of SDD, with a drop of 20%, 27% and 32%, respectively. Compared with other Spanish ICUs without SDD, the susceptibility rate was higher in the ICU of our hospital in most cases. When it was lower, differences were <10%, except for a high concentration of streptomycin against Enterococcus faecium, for which the difference was 19%. CONCLUSIONS: No relevant changes in the overall susceptibility rate after the implementation of SDD were detected. Susceptibility rates were not lower than those in the Spanish ICUs without SDD.

Susceptibility of Pseudomonas aeruginosa and antimicrobial activity using PK/PD analysis: an 18-year surveillance study.

INTRODUCTION: We analysed the changes in the susceptibility of Pseudomonas aeruginosa to antimicrobials over an 18-year period (2000-2017) in order to evaluate the adequacy of the antimicrobial therapy against this organism in patients admitted in a tertiary Spanish hospital (excluding the intensive care unit). In addition, the antimicrobial activity was evaluated using pharmacokinetic/pharmacodynamic (PK/PD) criteria as a microbiological surveillance tool. METHODS: Susceptibility was studied according to the Clinical and Laboratory Standards Institute breakpoints. Monte Carlo simulations were conducted to calculate the cumulative fraction of response (CFR). Linear regression analysis was applied to determine the trends in susceptibility and in the CFR. RESULTS: In 2017, susceptibility rates were: amikacin, penicillins and cephalosporins ≥85%, tobramycin 76%, meropenem 75% and gentamicin, imipenem and fluoroquinolones <70%. PK/PD analyses was able to identify changes in antimicrobial activity not detected by only assessing MICs; meropenem administered in extended infusion attained a CFR >90%, ceftazidime, piperacillin/tazobactam and imipenem provided CFRs between 80-90%, all of them administered at the highest doses. CONCLUSIONS: Analysis of susceptibility and PK/PD modelling, should be considered together to select the most appropriate antimicrobial drug and dosage regimen. Empirical antipseudomonal therapy would vary considerably if both microbiological surveillance tools were considered. In this study, the PK/PD analysis made it possible to preserve the therapeutic value of antimicrobials with low susceptibility rates, such as carbapenems, and the selection of the most effective antimicrobials among those with high rates of susceptibility.

Ciprofloxacin resistance in nontypable Haemophilus influenzae clinical isolates / Resistencia a la ciprofloxacina en aislados clínicos de Haemophilus influenzae no tipificables

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Pharmacokinetics of linezolid in critically ill patients on continuous renal replacement therapy: Influence of residual renal function on PK/PD target attainment.

PURPOSE: To assess the pharmacokinetics of linezolid in septic patients undergoing continuous renal replacement therapy (CRRT) and investigate whether residual renal function affects the probability of attaining the pharmacokinetic/pharmacodynamic (PK/PD) target. MATERIAL AND METHODS: Prospective study conducted in three Spanish hospitals. Linezolid concentrations were measured in plasma and effluent samples and pharmacokinetic parameters were calculated. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) were calculated considering AUC24/MIC>80 and %T>MIC > 85% as the PK/PD indexes related to efficacy. RESULTS: In anuric patients (CrCl<10 mL/min), the contribution of extracorporeal Cl to total Cl was higher (47% vs 16%) than in patients with residual renal function (CrCl≥10 mL/min). For an MIC of 2 mg/L, AUC24/MIC>80 was achieved in >85% of the anuric patients, but in <15% of the patients with residual renal function. CONCLUSIONS: The standard dose (600 mg q12h) ensures a moderately high probability of treatment success in anuric patients when the infection is due to microorganisms with MIC≤2 mg/L; although higher doses increase the probability of treatment success, the safety is compromised. In patients with residual renal function, the standard dose is insufficient, but 900 mg q8h provide higher probability of treatment success without compromising the safety.

Pharmacokinetic/pharmacodynamic analysis as a tool for surveillance of the activity of antimicrobials against Pseudomonas aeruginosa strains isolated in critically ill patients.

INTRODUCTION: To evaluate the changes in the susceptibility of Pseudomonas aeruginosa over time (2000-2017) against antimicrobials used in an intensive care unit of a Spanish tertiary hospital, and to compare them with the antimicrobial activity considering theoretical pharmacokinetic/pharmacodynamic (PK/PD) criteria. The influence of the method for handling duplicate isolates to quantify susceptibility rates was also evaluated. METHODS: The susceptibility was studied considering the Clinical and Laboratory Standards Institute (CLSI) breakpoints. Monte Carlo simulations were conducted to calculate the cumulative fraction of response (CFR). Linear regression analysis was applied to determine the trends in susceptibility and in the CFR. RESULTS: A significant decrease in the susceptibility to gentamicin and imipenem was observed, and more recently the highest percentages of susceptible strains were found for amikacin, cephalosporins and piperacillin/tazobactam (>80%). The probability of success of an empiric treatment or CFR for most of the evaluated antimicrobials was lower than 70% during the last two-year period. Only meropenem provided high probabilities (>90%) to achieve the PK/PD target. Cephalosporins provided moderate probabilities (>80%) although for ceftazidime, the highest dose (2g/8h) was required. Moreover, a significant decrease in the CFR trend for ciprofloxacin, imipenem and levofloxacin was observed. CONCLUSIONS: Both susceptibility rates and CFR values have to be considered together to optimize the antimicrobial dose regimen for clinical making-decisions. They are complementary tools and, they should be used jointly in surveillance programmes. In fact, susceptibility data are not always useful to detect changes in the CFR. No relevant differences were observed among the methods for handling repeated isolates.