Executive summary of the consensus document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) on the diagnosis and antimicrobial treatment of infections due to carbapenem-resistant Gram-negative bacteria / 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

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.(AU)

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.(AU)

Effectiveness of fosfomycin trometamol as oral step-down therapy for bacteraemic urinary tract infections due to MDR Escherichia coli: a post hoc analysis of the FOREST randomized trial.

BACKGROUND: Fosfomycin is a potentially attractive option as step-down therapy for bacteraemic urinary tract infections (BUTI), but available data are scarce. Our objective was to compare the effectiveness and safety of fosfomycin trometamol and other oral drugs as step-down therapy in patients with BUTI due to MDR Escherichia coli (MDR-Ec). METHODS: Participants in the FOREST trial (comparing IV fosfomycin with ceftriaxone or meropenem for BUTI caused by MDR-Ec in 22 Spanish hospitals from June 2014 to December 2018) who were stepped-down to oral fosfomycin (3 g q48h) or other drugs were included. The primary endpoint was clinical and microbiological cure (CMC) 5-7 days after finalization of treatment. A multivariate analysis was performed using logistic regression to estimate the association of oral step-down with fosfomycin with CMC adjusted for confounders. RESULTS: Overall, 61 patients switched to oral fosfomycin trometamol and 47 to other drugs (cefuroxime axetil, 28; amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole, 7 each; ciprofloxacin, 5) were included. CMC was reached by 48/61 patients (78.7%) treated with fosfomycin trometamol and 38/47 (80.9%) with other drugs (difference, -2.2; 95% CI: -17.5 to 13.1; P = 0.38). Subgroup analyses provided similar results. Relapses occurred in 9/61 (15.0%) and 2/47 (4.3%) of patients, respectively (P = 0.03). The adjusted OR for CMC was 1.11 (95% CI: 0.42-3.29, P = 0.75). No relevant differences in adverse events were seen. CONCLUSIONS: Fosfomycin trometamol might be a reasonable option as step-down therapy in patients with BUTI due to MDR-Ec but the higher rate of relapses would need further assessment.

Risk factors for infections caused by carbapenem-resistant Enterobacterales: an international matched case-control-control study (EURECA).

Background: Data on risk factors for carbapenem-resistant Enterobacterales (CRE) with wider applicability are needed to inform preventive measures and efficient design of randomised trials. Methods: An international matched case-control-control study was performed in 50 hospitals with high CRE incidence from March 2016 to November 2018 to investigate different aspects of infections caused by CRE (NCT02709408). Cases were patients with complicated urinary tract infection (cUTI), complicated intraabdominal (cIAI), pneumonia or bacteraemia from other sources (BSI-OS) due to CRE; control groups were patients with infection caused by carbapenem-susceptible Enterobacterales (CSE), and by non-infected patients, respectively. Matching criteria included type of infection for CSE group, ward and duration of hospital admission. Conditional logistic regression was used to identify risk factors. Findings: Overall, 235 CRE case patients, 235 CSE controls and 705 non-infected controls were included. The CRE infections were cUTI (133, 56.7%), pneumonia (44, 18.7%), cIAI and BSI-OS (29, 12.3% each). Carbapenemase genes were found in 228 isolates: OXA-48/like, 112 (47.6%), KPC, 84 (35.7%), and metallo-ß-lactamases, 44 (18.7%); 13 produced two. The risk factors for CRE infection in both type of controls were (adjusted OR for CSE controls; 95% CI; p value) previous colonisation/infection by CRE (6.94; 2.74-15.53; <0.001), urinary catheter (1.78; 1.03-3.07; 0.038) and exposure to broad spectrum antibiotics, as categorical (2.20; 1.25-3.88; 0.006) and time-dependent (1.04 per day; 1.00-1.07; 0.014); chronic renal failure (2.81; 1.40-5.64; 0.004) and admission from home (0.44; 0.23-0.85; 0.014) were significant only for CSE controls. Subgroup analyses provided similar results. Interpretation: The main risk factors for CRE infections in hospitals with high incidence included previous colonization, urinary catheter and exposure to broad spectrum antibiotics. Funding: The study was funded by the Innovative Medicines Initiative Joint Undertaking (https://www.imi.europa.eu/) under Grant Agreement No. 115620 (COMBACTE-CARE).

Executive summary of the consensus document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) on the diagnosis and antimicrobial treatment of infections due to carbapenem-resistant Gram-negative bacteria.

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.

A systematic literature review and expert consensus on risk factors associated to infection progression in adult patients with respiratory tract or rectal colonisation by carbapenem-resistant Gram-negative bacteria / Revisión sistemática de la literatura y consenso de expertos sobre los factores de riesgo asociados a la progresión de la infección en pacientes adultos con colonización del tracto respiratorio o rectal por bacterias gramnegativas resistentes a carbapenémicos

Objective. Risk factors (RFs) associated with infection progression in patients already colonised by carbapenem-resistant Gram-negative bacteria (CRGNB) have been addressed in few and disperse works. The aim of this study is to identify the relevant RFs associated to infection progression in patients with respiratory tract or rectal colonisation.Material and methods. A systematic literature review was developed to identify RFs associated with infectionprogression in patients with CRGNB respiratory tract or rectal colonisation. Identified RFs were then evaluated and discussed by the expert panel to identify those that are relevant according to the evidence and expert’s experience.Results. A total of 8 articles were included for the CRGNB respiratory tract colonisation and 21 for CRGNB rectal colonisation, identifying 19 RFs associated with pneumonia development and 44 RFs associated with infection progression, respectively. After discussion, the experts agreed on 13 RFs to be associated with pneumonia development after respiratory tract CRGNB colonisation and 33 RFs to be associated with infection progression after rectal CRGNB colonisation. Respiratory tract and rectal colonisation, previous stay in the ICU and longer stay in the ICU were classified as relevant RF independently of the pathogen and site of colonisation. Previous exposure to antibiotic therapy or previous carbapenem use were also common relevant RF for patients with CRGNB respiratory tract and rectal colonisation. (AU)

Objetivo. Los factores de riesgo (FR) asociados a la progresión de la infección en pacientes ya colonizados por bacterias gramnegativas resistentes a carbapenémicos (BGNRC) han sido abordados en pocos y dispersos trabajos. El objetivo de este estudio es identificar los factores de riesgo relevantes asociados a la progresión de la infección en pacientes con colonización del tracto respiratorio o rectal.Material y métodos. Se realizó una revisión sistemática de la literatura para identificar los FR asociados a la progresión de la infección en pacientes con colonización del tracto respiratorio o rectal por BGNRC. Los FR identificados fueron luego evaluados y discutidos por el panel de expertos para identificar aquellos que son relevantes según la evidencia disponible y la experiencia de los expertos.Resultados. Un total de 8 artículos fueron incluidos en el análisis de los FR en la colonización del tracto respiratorio y 21 para la colonización rectal, identificándose 19 FR asociados al desarrollo de neumonía y 44 FR asociados a la progresión de la infección respectivamente. Tras la sesión de discusión, los expertos acordaron que 13 FR se asociaban al desarrollo de neumonía tras la colonización del tracto respiratorio por BGNRC y 33 FR a la progresión de la infección tras la colonización rectal por BGNRC. La colonización del tracto respiratorio y rectal, la estancia previa en la UCI y una estancia prolongada en la UCI se clasificaron como FR relevantes independientemente del patógeno y del lugar de colonización. La exposición previa a antibióticos o el uso previo de carbapenémicos se clasificaron como FR relevantes para varios de los patógenos tanto en pacientes con colonización del tracto respiratorio como rectal. (AU)

Impact of ceftazidime/avibactam versus best available therapy on mortality from infections caused by carbapenemase-producing Enterobacterales (CAVICOR study).

BACKGROUND: Infections caused by carbapenemase-producing Enterobacterales (CPE) are not well represented in pivotal trials with ceftazidime/avibactam. The best strategy for the treatment of these infections is unknown. METHODS: We conducted a multicentre retrospective observational study of patients who received ≥48 h of ceftazidime/avibactam or best available therapy (BAT) for documented CPE infections. The primary outcome was 30 day crude mortality. Secondary outcomes were 21 day clinical response and microbiological response. A multivariate logistic regression model was used to identify factors predictive of 30 day crude mortality. A propensity score to receive treatment with ceftazidime/avibactam was used as a covariate in the analysis. RESULTS: The cohort included 339 patients with CPE infections. Ceftazidime/avibactam treatment was used in 189 (55.8%) patients and 150 (44.2%) received BAT at a median of 2 days after diagnosis of infection. In multivariate analysis, ceftazidime/avibactam treatment was associated with survival (OR 0.41, 95% CI 0.20-0.80; P = 0.01), whereas INCREMENT-CPE scores of >7 points (OR 2.57, 95% CI 1.18-1.5.58; P = 0.01) and SOFA score (OR 1.20, 95% CI 1.08-1.34; P = 0.001) were associated with higher mortality. In patients with INCREMENT-CPE scores of >7 points, ceftazidime/avibactam treatment was associated with lower mortality compared with BAT (16/73, 21.9% versus 23/49, 46.9%; P = 0.004). Ceftazidime/avibactam was also an independent factor of 21 day clinical response (OR 2.43, 95% CI 1.16-5.12; P = 0.02) and microbiological eradication (OR 0.40, 95% CI 0.18-0.85; P = 0.02). CONCLUSIONS: Ceftazidime/avibactam is an effective alternative for the treatment of CPE infections, especially in patients with INCREMENT-CPE scores of >7 points. A randomized controlled trial should confirm these findings.

Multicentre study of ceftazidime/avibactam for Gram-negative bacteria infections in critically ill patients.

This study aimed to assess the efficacy of ceftazidime/avibactam (C/A) in the treatment of infections due to Gram-negative bacteria (GNB) in critically ill patients. A multicentre, retrospective, observational study was conducted in critically ill patients receiving C/A for GNB infections. We evaluated demographic data, localisation and severity of infection, clinical and microbiological outcomes, and mortality. A total of 68 patients received C/A for serious GNB infections. The main infections were respiratory (33.8%), intra-abdominal (22.1%) and urinary tract infections (10.3%); bacteraemia was found in 22 cases (32.4%). Most infections were complicated by septic shock (58.8%) or sepsis (36.8%) and most of them required life-supporting therapies. Enterobacterales (79.4%) and Pseudomonas aeruginosa (19.1%) were the most frequently isolated bacteria; 84.2% of isolates were carbapenem-resistant. Thirty-four patients (50.0%) received C/A in combination with other antimicrobials. Fifty patients (73.5%) presented a favourable clinical response. Microbiological eradication was documented in 25 cases (36.8%). No significant differences were found in clinical response between patients treated with monotherapy or combined therapy (79.4% vs. 67.6%; P = 0.27). Overall intensive care unit (ICU) mortality was 41.2%. Univariate analysis showed that 30-day all-cause mortality was significantly (P < 0.05) associated with bacteraemia, previous corticosteroid use and the need of life-supporting therapies. C/A appears to be an effective therapy for severe infections due to GNB, including carbapenem-resistant isolates, in critically ill patients. C/A combination therapy was not associated with a higher clinical response. Mortality correlated significantly with the presence of bacteraemia, previous corticosteroid use and the need for life-supporting therapies.

Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections: A Randomized Clinical Trial.

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 parenteral 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 ∞ 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, -∞ 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. Trial Registration: ClinicalTrials.gov Identifier: NCT02142751.

Carbapenemase-producing Enterobacterales infections in COVID-19 patients.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) infections have been occasionally described in patients with coronavirus disease-19 (COVID-19). We assess the clinical features and outcome of these infections. METHODS: In this retrospective single-centre, case-control study, we included 54 patients with CPE infection: 30 case-patients (COVID-19) and 24 controls (non-COVID-19), collected between March and May 2020. We compared the epidemiological, clinical features, and outcome between cases and controls. RESULTS: CPE infection was more frequent in COVID-19 patients than in controls (1.1 vs. 0.5%, p = .005). COVID-19 patients were younger, had a lower frequency of underlying diseases (p = .01), and a lower median Charlson score (p = .002). Predisposing factors such as antimicrobial use, mechanical ventilation, or ICU admission, were more frequent in COVID-19 patients (p < .05). There were 73 episodes of infection (42 cases and 31 controls) that were more frequently hospital-acquired and diagnosed at the ICU in COVID-19 patients (p < .001). Urinary tract was the most common source of infection (47.9%), followed by pneumonia (23.3%). The frequency of severe sepsis or shock (p = .01) as well as the median SOFA score (p = .04) was higher in cases than in controls. Klebsiella pneumoniae (80.8%), Serratia marcescens (11%) and Enterobacter cloacae (4.1%) were the most common bacteria in both groups (KPC 56.2%, OXA-48 26% and VIM 17.8%). Overall 30-d mortality rate of COVID-19 patients and controls was 30 and 16.7%, respectively (p = .25). CONCLUSIONS: COVID-19 patients have an increased risk of CPE infections, which usually present as severe, nosocomial infections, appearing in critically-ill patients and associated with a high mortality.

A Large Multicenter Prospective Study of Community-Onset Healthcare Associated Bacteremic Urinary Tract Infections in the Era of Multidrug Resistance: Even Worse than Hospital Acquired Infections?

INTRODUCTION: Healthcare-associated (HCA) infections represent a growing public health problem. The aim of this study was to compare community-onset healthcare associated (CO-HCA) bacteremic urinary tract infections (BUTI) and hospital-acquired (HA)-BUTI with special focus on multidrug resistances (MDR) and outcomes. METHODS: ITUBRAS-project is a prospective multicenter cohort study of patients with HCA-BUTI. All consecutive hospitalized adult patients with CO-HCA-BUTI or HA-BUTI episode were included in the study. Exclusion criteria were: patients < 18 years old, non-hospitalized patients, bacteremia from another source or primary bacteremia, non-healthcare-related infections and infections caused by unusual pathogens of the urinary tract. The main outcome variable was 30-day all-cause mortality with day 1 as the first day of positive blood culture. Logistic regression was used to analyze factors associated with clinical cure at hospital discharge and with receiving inappropriate initial antibiotic treatment. Cox regression was used to evaluate 30-day all-cause mortality. RESULTS: Four hundred forty-three episodes were included, 223 CO-HCA-BUTI. Patients with CO-HCA-BUTI were older (p < 0.001) and had more underlying diseases (p = 0.029) than those with HA-BUTI. The severity of the acute illness (Pitt score) was also higher in CO-HCA-BUTI (p = 0.026). Overall, a very high rate of MDR profiles (271/443, 61.2%) was observed, with no statistical differences between groups. In multivariable analysis, inadequate empirical treatment was associated with MDR profile (aOR 3.35; 95% CI 1.77-6.35), Pseudomonas aeruginosa (aOR 2.86; 95% CI 1.27-6.44) and Charlson index (aOR 1.11; 95% CI 1.01-1.23). Mortality was not associated with the site of acquisition of the infection or the presence of MDR profile. However, in the logistic regression analyses patients with CO-HCA-BUTI (aOR 0.61; 95% CI 0.40-0.93) were less likely to present clinical cure. CONCLUSION: The rate of MDR infections was worryingly high in our study. No differences in MDR rates were found between CO-HCA-BUTI and HA-BUTI, in the probability of receiving inappropriate empirical treatment or in 30-day mortality. However, CO-HCA-BUTIs were associated with worse clinical cure.

Usefulness of Fecal Calprotectin in the Management of Patients with Toxigenic Clostridioides difficile.

The availability of highly sensitive molecular tests for the detection of Clostridioides difficile in feces leads to overtreatment of patients who are probably only colonized. In this prospective study, the usefulness of fecal calprotectin (fCP) is evaluated in a cohort of patients with detection of toxigenic C. difficile in feces. Patients were classified by an infectious diseases consultant blinded to fCP results into three groups-group I, presumed Clostridioides difficile infection (CDI); group II, doubtful but treated CDI; and group III, presumed C. difficile colonization or self-limited CDI not needing treatment. One hundred and thirty-four patients were included. The median fCP concentrations were 410 (138-815) µg/g in group I, 188 (57-524) µg/g in group II, and 51 (26-97) µg/g in group III (26 cases); p < 0.05 for all comparisons. In forty-five out of 134 cases (33.5%), the fCP concentrations were below 100 µg/g. In conclusion, fCP is low in most patients who do not need treatment against C. difficile, and should be investigated as a potentially useful test in the management of patients with detected toxigenic C. difficile.

Nosocomial infections associated to COVID-19 in the intensive care unit: clinical characteristics and outcome.

Bacterial and fungal co-infection has been reported in patients with COVID-19, but there is limited experience on these infections in critically ill patients. The objective of this study was to assess the characteristics and ouctome of ICU-acquired infections in COVID-19 patients. We conducted a retrospective single-centre, case-control study including 140 patients with severe COVID-19 admitted to the ICU between March and May 2020. We evaluated the epidemiological, clinical, and microbiological features, and outcome of ICU-acquired infections. Fifty-seven patients (40.7%) developed a bacterial or fungal nosocomial infection during ICU stay. Infection occurred after a median of 9 days (IQR 5-11) of admission and was significantly associated with the APACHE II score (p = 0.02). There were 91 episodes of infection: primary (31%) and catheter-related (25%) bloodstream infections were the most frequent, followed by pneumonia (23%), tracheobronchitis (10%), and urinary tract infection (8%) that were produced by a wide spectrum of Gram-positive (55%) and Gram-negative bacteria (30%) as well as fungi (15%). In 60% of cases, infection was associated with septic shock and a significant increase in SOFA score. Overall ICU mortality was 36% (51/140). Infection was significantly associated with death (OR 2.7, 95% CI 1.2-5.9, p = 0.015) and a longer ICU stay (p < 0.001). Bacterial and fungal nosocomial infection is a common complication of ICU admission in patients with COVID-19. It usually presents as a severe form of infection, and it is associated with a high mortality and longer course of ICU stay.

Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial.

BACKGROUND: We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis. METHODS: A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy. RESULTS: Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93-1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018). CONCLUSIONS: Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events. CLINICAL TRIALS REGISTRATION: NCT01898338.

Multicenter study of ceftolozane/tazobactam for treatment of Pseudomonas aeruginosa infections in critically ill patients.

BACKGROUND: This study aimed to assess the efficacy of ceftolozane-tazobactam (C/T) for treating infections due to Pseudomonas aeruginosa (P. aeruginosa) in critically ill patients. PATIENTS AND METHODS: A multicenter, retrospective and observational study was conducted in critically ill patients receiving different C/T dosages and antibiotic combinations for P. aeruginosa infections. Demographic data, localisation and severity of infection, clinical and microbiological outcome, and mortality were evaluated. RESULTS: Ninety-five patients received C/T for P. aeruginosa serious infections. The main infections were nosocomial pneumonia (56.2%), intra-abdominal infection (10.5%), tracheobronchitis (8.4%), and urinary tract infection (6.3%). Most infections were complicated with sepsis (49.5%) or septic shock (45.3%), and bacteraemia (10.5%). Forty-six episodes were treated with high-dose C/T (3 g every 8 hours) and 38 episodes were treated with standard dosage (1.5 g every 8 hours). Almost half (44.2%) of the patients were treated with C/T monotherapy, and the remaining group received combination therapy with other antibiotics. Sixty-eight (71.6%) patients presented a favourable clinical response. Microbiological eradication was documented in 42.1% (40/95) of the episodes. The global ICU mortality was 36.5%. Univariate analysis showed that 30-day mortality was significantly associated (P < 0.05) with Charlson Index at ICU admission and the need of life-supporting therapies. CONCLUSIONS: C/T appeared to be an effective therapy for severe infections due to P. aeruginosa in critically ill patients. Mortality was mainly related to the severity of the infection. No benefit was observed with high-dose C/T or combination therapy with other antibiotics.

Colistimethate sodium and acute kidney injury: Incidence, risk factors, outcome and prognosis of renal function / Fracaso renal agudo y colistimetato de sodio: incidencia, factores de riesgo, resultados y pronóstico de la función renal

BACKGROUND: Colistimethate sodium (CMS) treatment has increased over the last years, being acute kidney injury (AKI) its main drug-related adverse event. Therefore, this study aimed to evaluate the incidence and risk factors associated with AKI, as well as identifying the factors that determine renal function (RF) outcomes at six months after discharge. MATERIALS AND METHODS: This retrospective study included adult septic patients receiving intravenous CMS for at least 48 h (January 2007-December 2014). AKI was assessed using KDIGO criteria. The glomerular filtration rate (GFR) was estimated by the 4-variable MDRD equation. Logistic and linear models were performed to evaluate the risk factors for AKI and chronic kidney disease (CKD). RESULTS: Among 126 patients treated with CMS; the incidence of AKI was 48.4%. Sepsis-severe sepsis (OR 8.07, P = 0.001), sepsis-septic shock (OR 42.9, P < 0.001), and serum creatinine (SCr) at admission (OR 6.20, P = 0.009) were independent predictors. Eighty-four patients survived; the main factors for RF evolution at the 6-month follow-up was baseline eGFR (0.58, P < 0.001) and at discharge (0.34, P < 0.001). Fifty-six percent (34/61) of the patients that developed AKI survived. At six months, 32% had CKD. CONCLUSIONS: The development of AKI in septic patients with CMS treatment was associated with sepsis severity and SCr at admission. Baseline eGFR and eGFR at discharge were and important determinant of the RF at the 6-month follow-up. These predictors may assist in clinical decision making for this patient population

INTRODUCCIÓN: El tratamiento con colistimetato de sodio (CMS) se ha incrementado, siendo su principal complicación el fracaso renal agudo (FRA). El objetivo de este estudio fue determinar la incidencia de FRA y los factores de riesgo asociados, así como identificar los factores que determinan la función renal (FR) a los 6 meses del alta hospitalaria. MATERIALES Y MÉTODOS: Estudio retrospectivo que incluyó pacientes adultos sépticos que recibieron CMS intravenoso durante al menos 48 h (enero 2007-diciembre 2014). El diagnóstico de FRA se realizó según los criterios KDIGO. Se estimó el filtrado glomerular (FG) mediante la ecuación del MDRD-4. Se realizaron modelos logísticos y lineales para evaluar los factores de riesgo para el desarrollo de FRA y enfermedad renal crónica (ERC). RESULTADOS: Ciento veintiséis pacientes fueron incluidos; la incidencia de FRA fue del 48,4%. Sepsis-sepsis severa (OR: 8,07; p = 0,001), sepsis-shock séptico (OR: 42,9; p < 0,001) y la creatinina sérica (CRs) al ingreso (OR: 6,20; p = 0,009) fueron predictores independientes de FRA. Ochenta y cuatro pacientes sobrevivieron; el determinante principal de la evolución de la FR a los 6 meses de seguimiento fue el FGe basal (0,58; p < 0,001) y al alta (0,34; p < 0,001). El 56% (34/61) de los pacientes que desarrollaron FRA sobrevivieron. A los 6 meses, el 32% desarrollo ERC. CONCLUSIONES: El desarrollo de FRA asociado al tratamiento con CMS se asoció con el grado de severidad de la sepsis y la CRs al ingreso. El FGe basal y al alta hospitalaria fueron predictores independientes de la FR a los 6 meses de seguimiento

Linezolid for therapy of Staphylococcus aureus meningitis: a cohort study of 26 patients.

BACKGROUND: Linezolid has good penetration to the meninges and could be an alternative for treatment of Staphylococcus aureus meningitis. We assessed the efficacy and safety of linezolid therapy for this infection. METHODS: Retrospective multicenter cohort study of 26 adults treated with linezolid, derived from a cohort of 350 cases of S. aureus meningitis diagnosed at 11 university hospitals in Spain (1981-2015). RESULTS: There were 15 males (58%) and mean age was 47.3 years. Meningitis was postoperative in 21 (81%) patients. The infection was nosocomial in 23 (88%) cases, and caused by methicillin-resistant S. aureus in 15 cases and methicillin-susceptible S. aureus in 11. Linezolid was given as empirical therapy in 10 cases, as directed therapy in 10, and due to failure of vancomycin in 6. Monotherapy was given to 16 (62%) patients. Median duration of linezolid therapy was 17 days (IQR 12-22 days) with a daily dose of 1,200 mg in all cases. The clinical response rate to linezolid was 69% (18/26) and microbiological response was observed in 14 of 15 cases evaluated (93%). Overall 30-day mortality was 23% and was directly associated with infection in most cases. When compared with the patients of the cohort, no significant difference in mortality was observed between patients receiving linezolid or vancomycin for therapy of methicillin-resistant S. aureus meningitis (9% vs. 20%; p = .16) nor between patients receiving linezolid or cloxacillin for therapy of methicillin-susceptible S. aureus meningitis (20% vs 14%; p = .68). Adverse events appeared in 14% (3/22) of patients, but linezolid was discontinued in only one patient. CONCLUSIONS: Linezolid appears to be effective and safe for therapy of S. aureus meningitis. Our findings showed that linezolid may be considered an adequate alternative to other antimicrobials in meningitis caused by S. aureus.

Colistimethate sodium and acute kidney injury: Incidence, risk factors, outcome and prognosis of renal function.

BACKGROUND: Colistimethate sodium (CMS) treatment has increased over the last years, being acute kidney injury (AKI) its main drug-related adverse event. Therefore, this study aimed to evaluate the incidence and risk factors associated with AKI, as well as identifying the factors that determine renal function (RF) outcomes at six months after discharge. MATERIALS AND METHODS: This retrospective study included adult septic patients receiving intravenous CMS for at least 48h (January 2007-December 2014). AKI was assessed using KDIGO criteria. The glomerular filtration rate (GFR) was estimated by the 4-variable MDRD equation. Logistic and linear models were performed to evaluate the risk factors for AKI and chronic kidney disease (CKD). RESULTS: Among 126 patients treated with CMS; the incidence of AKI was 48.4%. Sepsis-severe sepsis (OR 8.07, P=0.001), sepsis-septic shock (OR 42.9, P<0.001), and serum creatinine (SCr) at admission (OR 6.20, P=0.009) were independent predictors. Eighty-four patients survived; the main factors for RF evolution at the 6-month follow-up was baseline eGFR (0.58, P<0.001) and at discharge (0.34, P<0.001). Fifty-six percent (34/61) of the patients that developed AKI survived. At six months, 32% had CKD. CONCLUSIONS: The development of AKI in septic patients with CMS treatment was associated with sepsis severity and SCr at admission. Baseline eGFR and eGFR at discharge were and important determinant of the RF at the 6-month follow-up. These predictors may assist in clinical decision making for this patient population.

Empiric Therapy With Carbapenem-Sparing Regimens for Bloodstream Infections due to Extended-Spectrum ß-Lactamase-Producing Enterobacteriaceae: Results From the INCREMENT Cohort.

BACKGROUND: There is little information about the efficacy of active alternative drugs to carbapenems except ß-lactam/ß-lactamase inhibitors for the treatment of bloodstream infections (BSIs) due to extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-E). The objective of this study was to assess the outcomes of patients with BSI due to ESBL-E who received empiric therapy with such drugs (other active drugs [OADs]) or carbapenems. METHODS: A multinational retrospective cohort study of patients with BSI due to ESBL-E who received empiric treatment with OADs or carbapenems was performed. Cox regression including a propensity score for receiving OADs was performed to analyze 30-day all-cause mortality as main outcome. Clinical failure and length of stay were also analyzed. RESULTS: Overall, 335 patients were included; 249 received empiric carbapenems and 86 OADs. The most frequent OADs were aminoglycosides (43 patients) and fluoroquinolones (20 patients). Empiric therapy with OADs was not associated with mortality (hazard ratio [HR], 0.75; 95% confidence interval [CI], .38-1.48) in the Cox regression analysis. Propensity score-matched pairs, subgroups, and sensitivity analyses did not show different trends; specifically, the adjusted HR for aminoglycosides was 1.05 (95% CI, .51-2.16). OADs were neither associated with 14-day clinical failure (adjusted odds ratio, 0.62; 95% CI, .29-1.36) nor length of hospital stay. CONCLUSIONS: We were unable to show that empiric treatment with OAD was associated with a worse outcome compared with carbapenems. This information allows more options to be considered for empiric therapy, at least for some patients, depending on local susceptibility patterns of ESBL-E.

Executive summary of the diagnosis and treatment of urinary tract infection: Guidelines of the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC) / Resumen ejecutivo del diagnóstico y tratamiento de las infecciones del tracto urinario. Guía de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC)

Most urinary tract infections (UTI) are uncomplicated infections occurring in young women. An extensive evaluation is not required in the majority of cases, and they can be safely managed as outpatients with oral antibiotics. Escherichia coli is by far the most common uropathogen, accounting for >80% of all cases. Other major clinical problems associated with UTI include asymptomatic bacteriuria, and patients with complicated UTI. Complicated UTIs are a heterogeneous group associated with conditions that increase the risk of acquiring infection or treatment failure. Distinguishing between complicated and uncomplicated UTI is important, as it influences the initial evaluation, choice, and duration of antimicrobial therapy. Diagnosis is especially challenging in the elderly and in patients with in-dwelling catheters. The increasing prevalence of resistant uropathogens, including extended-spectrum β-lactamases and carbapenemase-producing Enterobacteriaceae, and other multidrug-resistant Gram-negative organisms further compromises treatment of both complicated and uncomplicated UTIs. The aim of these Clinical Guidelines is to provide a set of recommendations for improving the diagnosis and treatment of UTI

La mayoría de infecciones del tracto urinario (ITU) son infecciones no complicadas que se presentan en mujeres jóvenes. En la mayoría de los casos no se requieren pruebas diagnósticas complementarias y se pueden tratar ambulatoriamente de forma segura con antibióticos por vía oral. Escherichia coli es el uropatógeno más frecuente causando más del 80% de estas infecciones. La bacteriuria asintomática (BA) y las ITUs complicadas son otras formas de presentación de la ITU. Las ITU complicadas son un grupo heterogéneo de condiciones que incrementan el riesgo de adquisición de la infección o de fracaso del tratamiento. La distinción entre ITU complicada y no complicada es fundamental para decidir la evaluación inicial del paciente, la elección del antimicrobiano y la duración del mismo. El diagnóstico es especialmente difícil en ancianos y en pacientes con sondaje permanente. El incremento de cepas resistentes a los antibióticos, especialmente Enterobacterías productoras de beta-lactamasas de espectro extendido y de carbapenemasas y de otros Gram negativos multirresistentes, dificultan la elección del tratamiento de las ITU complicadas y no complicadas. El objetivo de esta guía clínica es proporcionar recomendaciones basadas en la evidencia para mejorar el diagnóstico y tratamiento de las ITU