Impacto de la monitorización de los niveles plasmáticos de colistina en la práctica clínica diaria

El rápido incremento de la resistencia antibiótica, junto con la falta de nuevos antibióticos en desarrollo, representa un problema médico de primera magnitud. En este escenario, las polimixinas en general y la colistina en particular en nuestro medio, constituyen en muchas ocasiones la última opción terapéutica. Las polimixinas hicieron su aparición en la práctica clínica en los años 50. Sin embargo, pronto fueron relegadas a un segundo plano en favor de los "menos tóxicos" aminoglucósidos y otros antipseudomónicos no nefrotóxicos. Este hecho provocó que tanto su desarrollo pre-clínico como su posterior proceso regulador no se realizaran de acuerdo a los estándares actuales. Como consecuencia de esto, y a pesar de los muchos avances realizados en los últimos años en el campo de la farmacología preclínica y clínica de las polimixinas, la información disponible en el momento actual resulta insuficiente para dar recomendaciones firmes que guíen su uso en la práctica clínica diaria. Los objetivos del presente trabajo fueron: 1.Valorar mediante un trabajo prospectivo observacional, la posible relación entre los niveles plasmáticos de colistina y el desarrollo de nefrotoxicidad durante el tratamiento. 2.Valorar en una cohorte de pacientes con infecciones causadas por Pseudomonas aeruginosa extremadamente resistente, la posible relación entre los niveles plasmáticos de colistina y la curación clínica y la mortalidad cruda a día 30. 3.Valorar mediante un estudio multicéntrico, aleatorizado no enmascarado, el posible impacto de una monitorización terapéutica de colistina en la práctica clínica diaria. Las conclusiones del presente trabajo fueron: 1.La colistina es un fármaco con un estrecho margen terapéutico siendo la nefrotoxicidad el efecto secundario limitante más frecuente. 2.Los niveles plasmáticos de colistina se relacionan de forma independiente con la aparición de nefrotoxicidad durante el tratamiento. Los valores que mejor predicen la aparición de nefrotoxicidad a día 7 de tratamiento y al final del mismo fueron 3,33 mg/L y 2, 42 mg/L respectivamente. 3.Con las dosis utilizadas en la práctica clínica habitual, incluyendo aquellos regímenes que utilizan dosis máximas (9 millones de UI/día), y en pacientes sin insuficiencia renal, es difícil alcanzar concentraciones plasmáticas de colistina en la fase de equilibrio estacionario consideradas óptimas (2,5 mg/L). 4.Los niveles plasmáticos de colistina no se asociaron con la curación clínica ni con la mortalidad cruda a día 30 de los pacientes con infecciones por Pseudomonas aeruginosa extremadamente resistente. 5.La monitorización terapéutica de la colistina no tuvo impacto sobre la curación ni la mortalidad cruda a día 30. 6.La monitorización de los niveles plasmáticos de colistina podría ser útil en la prevención de la nefrotoxicidad durante el tratamiento de colistina.In an era of increasing rates of multidrug resistance and a dry drug-development pipeline for new antimicrobial agents, the polymyxin antibiotics-colistin and polymyxin B-have had a substantial resurgence in their use for treatment of infections caused by Gram-negative bacteria. Polymyxins became clinically available in the 1950s, however, they soon fell out of favour in favor of "less toxic" aminoglycosides and other antipseudomonic drugs. For this reason, the polymyxins were not subjected to the drug development procedures and regulatory scrutiny needed for modern drugs. Despite substantial progress has been made in the study of preclinical and clinical pharmacology of polymyxins, information to guide their clinical use is scarce. In this scenario, the aims of this study were: 1. To determine in a cohort of patients treated with colistin, the incidence and the potential risk factors of colistin-associated nephrotoxicity including colistin plasma levels. 2. To assess the risk factors of 30-day all cause mortality including colistin plasma levels, in a cohort of patients infected by colistin-susceptible extremely drug-resistant (XDR) P. aeruginosa. 3. To assess the impact of colistin therapeutic drug monitoring (TDM) in daily clinical practice. A prospective, non-blinded multicenter study was designed to compare clinical outcomes in patients randomized to standard dosing vs. TDM (dose adjusted based on levels and renal function). The conclusions of the study were: 1. Colistin has a narrow therapeutic window being colistin-induced nephrotoxicity the major dose-limiting adverse effect. 2. Colistin plasma levels are predictive of acute kidney injury (AKI) during treatment. The breakpoints that better predicted AKI were 3.33 mg/L (P 0.001) on day 7 and 2.42 mg/L (P 0.001) at the end of treatment. 3. If we accept the target of colistin concentration is 2.5 mg/L, it becomes apparent that this is likely to be unachievable in certain patient populations, specifically in patients with a good renal function. 4. In XDR P. aeruginosa infections, colistin plasma levels were not related to 30-day all case mortality or clinical outcome. 5. Colistin TDM was not related to clinical cure or mortality. 6. In view of the narrow therapeutic window of polymyxins and the relationship between colistin plasma levels and the development of nephrotoxicity, there is a strong rationale for TDM in order to maximize clinical benefits while diminish adverse effects. However, the benefit of this approach should be evaluated in new appropriate prospective research studies

Adherence to a reliable PJI diagnostic protocol minimizes unsuspected positive cultures rate

The aim of the present study was to evaluate the incidence of unsuspected PJI when prosthetic revisions are thoroughly evaluated by PJI dedicated orthopedic surgeon before surgery. The hypothesis is that the incidence of unsuspected PJI is reduced by applying this protocol. This is a historical cohort study carried out in one university hospital. The prosthetic revision assessment was carried out in January 2019. From that date on, all patients that were programmed for hip or knee revision (either by an orthopedic surgeon specialized or not in septic revisions) were scheduled for a preoperative visit with the same orthopedic surgeon specialized in septic revisions. The diagnostic algorithm applied was based on the Pro-Implant Foundation diagnostic criteria. Prior to the revision assessment, the indication for joint aspiration was done at the surgeons' discretion (non-specialized in septic revisions) and the preoperative identification of PJI was also done by a hip or knee surgeon (not specialized in septic surgery). Based on the PIF criteria, there were 15 infections among the revisions in group 1 and 18 PJI in group 2 (p > 0.05). The most interesting finding was that there were 7 patients with unsuspected positive cultures in group 1. That represents 11% of all revisions. No patient in group 2 was found with unsuspected positive cultures (p < 0.001). A thorough PJI diagnostic algorithm should be implemented before prosthetic revision to avoid unsuspected positive cultures

Acute Hematogenous Periprosthetic Hip Infection by Gemella morbillorum, Successfully Treated with Debridement, Antibiotics and Implant Retention : A Case Report and Literature Review of Osteoarticular Gemella morbillorum Infections

Gemella morbillorum is a facultative anaerobic, catalase-negative and non-spore forming Gram-positive cocci. It can be found as part of the normal oropharyngeal flora, in the gastrointestinal tract and the female genital tract. However, it can be a causal agent of infections such as endocarditis, meningitis or brain abscesses, and very rarely can cause osteoarticular infections. Herein, a case report of an acute hematogenous prosthetic hip infection caused by Gemella morbillorum, successfully treated with a DAIR and beta-lactam antibiotic therapy, is presented. We provide a literature review of the other orthopedic-related infections caused by this microorganism

Clinical and Economic Impact of Community-Onset Urinary Tract Infections Caused by ESBL-Producing Klebsiella pneumoniae Requiring Hospitalization in Spain : An Observational Cohort Study

Objective : To analyze the clinical and economic impact of community-onset urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae requiring hospitalization. Methods : A retrospective cohort study that included all adults with a UTI caused by K. pneumoniae that were admitted to a tertiary care hospital in Barcelona, Spain, between 2011 and 2015. Demographic, clinical, and economic data were analyzed. Results : One hundred and seventy-three episodes of UTIs caused by K. pneumoniae were studied; 112 were non-ESBL-producing and 61 were ESBL-producing. Multivariate analysis identified ESBL production, acute confusional state associated with UTI, shock, and the time taken to obtain adequate treatment as risk factors for clinical failure during the first seven days. An economic analysis showed differences between ESBL-producing and non-ESBL-producing K. pneumoniae for the total cost of hospitalization per episode (mean EUR 6718 vs EUR 3688, respectively). Multivariate analysis of the higher costs of UTI episodes found statistically significant differences for ESBL production and the time taken to obtain adequate treatment. Conclusion : UTIs caused by ESBL-producing K. pneumoniae requiring hospitalization and the time taken to obtain adequate antimicrobial therapy are associated with worse clinical and economic outcomes

Resumen ejecutivo del documento de consenso de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) sobre el diagnóstico y tratamiento antimicrobiano de las infecciones por bacterias gramnegativas resistentes a carbapenémicos

[EN] Infections caused by multidrug resistant Gram-negative bacteria are becoming a worldwide problem due to their increasing incidence and associated high mortality. Carbapenem-resistant bacteria such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii are the most important in clinical practice. The objective of these guidelines is to update the recommendations for the diagnosis and treatment of infections caused by these multidrug resistant bacteria. Although ‘old’ antibiotics such as aminoglycosides, colistin, or tigecycline are frequently used for therapy of these bacteria, the ‘new’ beta-lactams such as ceftazidime–avibactam, ceftolozane–tazobactam, meropenem–vaborbactam, imipenem–cilastatin–relebactam or cefiderocol are progressively becoming the first-line therapy for most of these microorganisms. The Spanish Society of Infectious Diseases and Clinical Microbiology (Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica) designated a panel of experts in the field to provide evidence-based recommendations in response to common clinical questions. This document is primarily focused on microbiological diagnosis, clinical management, and targeted antimicrobial therapy of these infections, with special attention to defining the role of the new antimicrobials in the treatment of these bacteria.[ES] Las infecciones causadas por bacterias gramnegativas multirresistentes se han convertido en un problema mundial debido a su creciente incidencia y alta mortalidad asociada. Las bacterias resistentes a carbapenémicos como Klebsiella pneumoniae, Pseudomonas aeruginosa y Acinetobacter baumannii son las más importantes en la práctica clínica. El objetivo de este documento de consenso es actualizar las recomendaciones sobre diagnóstico y tratamiento de las infecciones causadas por estas bacterias multirresistentes. Aunque los antibióticos ‘antiguos’ como aminoglucósidos, colistina o tigeciclina se utilizan con frecuencia en el tratamiento de estas bacterias, los ‘nuevos’ betalactámicos como ceftazidima-avibactam, ceftolozano-tazobactam, meropenem-vaborbactam, imipenem-cilastatina-relebactam o cefiderocol se están convirtiendo de forma progresiva en el tratamiento de primera elección para la mayoría de estos microorganismos. La Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica ha designado un grupo de expertos en la materia para elaborar una guía de recomendaciones basadas en la evidencia sobre las cuestiones clínicas más habituales. Este documento está principalmente centrado en el diagnóstico microbiológico, el manejo clínico y el tratamiento dirigido de estas infecciones, con especial referencia a definir el papel de los nuevos antimicrobianos en el tratamiento de estas bacterias.Peer reviewe

Rates and Predictors of Treatment Failure in Staphylococcus aureus Prosthetic Joint Infections According to Different Management Strategies: A Multinational Cohort Study—The ARTHR-IS Study Group

Introduction: Guidelines have improved the management of prosthetic joint infections (PJI). However, it is necessary to reassess the incidence and risk factors for treatment failure (TF) of Staphylococcus aureus PJI (SA-PJI) including functional loss, which has so far been neglected as an outcome. Methods: A retrospective cohort study of SA-PJI was performed in 19 European hospitals between 2014 and 2016. The outcome variable was TF, including related mortality, clinical failure and functional loss both after the initial surgical procedure and after all procedures at 18 months. Predictors of TF were identified by logistic regression. Landmark analysis was used to avoid immortal time bias with rifampicin when debridement, antibiotics and implant retention (DAIR) was performed. Results: One hundred twenty cases of SA-PJI were included. TF rates after the first and all surgical procedures performed were 32.8% and 24.2%, respectively. After all procedures, functional loss was 6.0% for DAIR and 17.2% for prosthesis removal. Variables independently associated with TF for the first procedure were Charlson >= 2, haemoglobin 30 kg/m(2) and delay of DAIR, while rifampicin use was protective. For all procedures, the variables associated with TF were haemoglobin < 10 g/dL, hip fracture and additional joint surgery not related to persistent infection. Conclusions: TF remains common in SA-PJI. Functional loss accounted for a substantial proportion of treatment failures, particularly after prosthesis removal. Use of rifampicin after DAIR was associated with a protective effect. Among the risk factors identified, anaemia and obesity have not frequently been reported in previous studies. [GRAPHICS]

Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections

IMPORTANCE The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option. OBJECTIVE To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021. INTERVENTIONS Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or pa renteral ertapenem for the comparator group after 4 days. MAIN OUTCOMES AND MEASURES The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. RESULTS Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to infinity percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI. -infinity to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01). CONCLUSIONS AND RELEVANCE This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections

One- and two-stage surgical revision of peri-prosthetic joint infection of the hip: a pooled individual participant data analysis of 44 cohort studies.

One-stage and two-stage revision strategies are the two main options for treating established chronic peri-prosthetic joint infection (PJI) of the hip; however, there is uncertainty regarding which is the best treatment option. We aimed to compare the risk of re-infection between the two revision strategies using pooled individual participant data (IPD). Observational cohort studies with PJI of the hip treated exclusively by one- or two-stage revision and reporting re-infection outcomes were retrieved by searching MEDLINE, EMBASE, Web of Science, The Cochrane Library, and the WHO International Clinical Trials Registry Platform; as well as email contact with investigators. We analysed IPD of 1856 participants with PJI of the hip from 44 cohorts across four continents. The primary outcome was re-infection (recurrence of infection by the same organism(s) and/or re-infection with a new organism(s)). Hazard ratios (HRs) for re-infection were calculated using Cox proportional frailty hazards models. After a median follow-up of 3.7 years, 222 re-infections were recorded. Re-infection rates per 1000 person-years of follow-up were 16.8 (95% CI 13.6-20.7) and 32.3 (95% CI 27.3-38.3) for one-stage and two-stage strategies respectively. The age- and sex-adjusted HR of re-infection for two-stage revision was 1.70 (0.58-5.00) when compared with one-stage revision. The association remained consistently absent after further adjustment for potential confounders. The HRs did not vary importantly in clinically relevant subgroups. Analysis of pooled individual patient data suggest that a one-stage revision strategy may be as effective as a two-stage revision strategy in treating PJI of the hip

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Impacto de la monitorización de los niveles plasmáticos de colistina en la práctica clínica diaria

El rápido incremento de la resistencia antibiótica, junto con la falta de nuevos antibióticos en desarrollo, representa un problema médico de primera magnitud. En este escenario, las polimixinas en general y la colistina en particular en nuestro medio, constituyen en muchas ocasiones la última opción terapéutica. Las polimixinas hicieron su aparición en la práctica clínica en los años 50. Sin embargo, pronto fueron relegadas a un segundo plano en favor de los “menos tóxicos” aminoglucósidos y otros antipseudomónicos no nefrotóxicos. Este hecho provocó que tanto su desarrollo pre-clínico como su posterior proceso regulador no se realizaran de acuerdo a los estándares actuales. Como consecuencia de esto, y a pesar de los muchos avances realizados en los últimos años en el campo de la farmacología preclínica y clínica de las polimixinas, la información disponible en el momento actual resulta insuficiente para dar recomendaciones firmes que guíen su uso en la práctica clínica diaria. Los objetivos del presente trabajo fueron: 1. Valorar mediante un trabajo prospectivo observacional, la posible relación entre los niveles plasmáticos de colistina y el desarrollo de nefrotoxicidad durante el tratamiento. 2. Valorar en una cohorte de pacientes con infecciones causadas por Pseudomonas aeruginosa extremadamente resistente, la posible relación entre los niveles plasmáticos de colistina y la curación clínica y la mortalidad cruda a día 30. 3. Valorar mediante un estudio multicéntrico, aleatorizado no enmascarado, el posible impacto de una monitorización terapéutica de colistina en la práctica clínica diaria. Las conclusiones del presente trabajo fueron: 1. La colistina es un fármaco con un estrecho margen terapéutico siendo la nefrotoxicidad el efecto secundario limitante más frecuente. 2. Los niveles plasmáticos de colistina se relacionan de forma independiente con la aparición de nefrotoxicidad durante el tratamiento. Los valores que mejor predicen la aparición de nefrotoxicidad a día 7 de tratamiento y al final del mismo fueron 3,33 mg/L y 2, 42 mg/L respectivamente. 3. Con las dosis utilizadas en la práctica clínica habitual, incluyendo aquellos regímenes que utilizan dosis máximas (9 millones de UI/día), y en pacientes sin insuficiencia renal, es difícil alcanzar concentraciones plasmáticas de colistina en la fase de equilibrio estacionario consideradas óptimas (2,5 mg/L). 4. Los niveles plasmáticos de colistina no se asociaron con la curación clínica ni con la mortalidad cruda a día 30 de los pacientes con infecciones por Pseudomonas aeruginosa extremadamente resistente. 5. La monitorización terapéutica de la colistina no tuvo impacto sobre la curación ni la mortalidad cruda a día 30. 6. La monitorización de los niveles plasmáticos de colistina podría ser útil en la prevención de la nefrotoxicidad durante el tratamiento de colistina.In an era of increasing rates of multidrug resistance and a dry drug-development pipeline for new antimicrobial agents, the polymyxin antibiotics—colistin and polymyxin B—have had a substantial resurgence in their use for treatment of infections caused by Gram-negative bacteria. Polymyxins became clinically available in the 1950s, however, they soon fell out of favour in favor of “less toxic” aminoglycosides and other antipseudomonic drugs. For this reason, the polymyxins were not subjected to the drug development procedures and regulatory scrutiny needed for modern drugs. Despite substantial progress has been made in the study of preclinical and clinical pharmacology of polymyxins, information to guide their clinical use is scarce. In this scenario, the aims of this study were: 1. To determine in a cohort of patients treated with colistin, the incidence and the potential risk factors of colistin-associated nephrotoxicity including colistin plasma levels. 2. To assess the risk factors of 30-day all cause mortality including colistin plasma levels, in a cohort of patients infected by colistin-susceptible extremely drug-resistant (XDR) P. aeruginosa. 3. To assess the impact of colistin therapeutic drug monitoring (TDM) in daily clinical practice. A prospective, non-blinded multicenter study was designed to compare clinical outcomes in patients randomized to standard dosing vs. TDM (dose adjusted based on levels and renal function). The conclusions of the study were: 1. Colistin has a narrow therapeutic window being colistin-induced nephrotoxicity the major dose-limiting adverse effect. 2. Colistin plasma levels are predictive of acute kidney injury (AKI) during treatment. The breakpoints that better predicted AKI were 3.33 mg/L (P < 0.001) on day 7 and 2.42 mg/L (P < 0.001) at the end of treatment. 3. If we accept the target of colistin concentration is 2.5 mg/L, it becomes apparent that this is likely to be unachievable in certain patient populations, specifically in patients with a good renal function. 4. In XDR P. aeruginosa infections, colistin plasma levels were not related to 30-day all case mortality or clinical outcome. 5. Colistin TDM was not related to clinical cure or mortality. 6. In view of the narrow therapeutic window of polymyxins and the relationship between colistin plasma levels and the development of nephrotoxicity, there is a strong rationale for TDM in order to maximize clinical benefits while diminish adverse effects. However, the benefit of this approach should be evaluated in new appropriate prospective research studies