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.

Fidaxomicin monotherapy versus standard therapy combined with bezlotoxumab for treating patients with Clostridioides difficile infection at high risk of recurrence: a matched cohort study.

BACKGROUND: Both fidaxomicin and bezlotoxumab (used in combination with an antibiotic against Clostridioides difficile) achieve reductions in recurrence rates of C. difficile infection (CDI). However, the two strategies have never been compared. METHODS: Data from two retrospective cohorts of 'real-life' use of fidaxomicin and bezlotoxumab in combination with a standard anti-C. difficile antibiotic were used to compare the rates of recurrence of both strategies. Since the two cohorts were not identical, we used a propensity score analysis. RESULTS: Three hundred and two patients were included: 244 in the fidaxomicin cohort and 78 in the bezlotoxumab cohort. A history of renal failure or immunosuppression was more frequent in patients receiving bezlotoxumab (39.7% and 66.7% versus 26.6% and 38.9%; P = 0.03 and P < 0.001, respectively), but the severity and number of previous CDI episodes were similar in both cohorts. We observed that 19.3% of the patients in the fidaxomicin cohort experienced recurrence, compared with 14.1% in the bezlotoxumab cohort (OR 1.45; 95% CI 0.71-2.96; P = 0.29) but the difference remained non-significant after propensity score matching using previously defined variables (OR 1.24; 95% CI 0.50-3.07; P = 0.64). Moreover, the multivariate analysis did not show differences depending on the drug used. CONCLUSIONS: We observed that fidaxomicin and bezlotoxumab are prescribed in similar clinical scenarios, although those treated with bezlotoxumab have greater comorbidity. The proportion of recurrences was numerically lower in those treated with bezlotoxumab, although the propensity analysis did not find significant differences between the two drugs.

Real-life experience with fidaxomicin in Clostridioides difficile infection: a multicentre cohort study on 244 episodes.

The high cost of fidaxomicin has restricted its use despite the benefit of a lower Clostridioides difficile infection (CDI) recurrence rate at 4 weeks of follow-up. This short follow-up represents the main limitation of pivotal clinical trials of fidaxomicin, and some recent studies question its benefits over vancomycin. Moreover, the main risk factors of recurrence after treatment with fidaxomicin remain unknown. We designed a multicentre retrospective cohort study among four Spanish hospitals to assess the efficacy of fidaxomicin in real life and to investigate risk factors of fidaxomicin failure at weeks 8 and 12. Two-hundred forty-four patients were included. Fidaxomicin was used in 96 patients (39.3%) for a first episode of CDI, in 95 patients (38.9%) for a second episode, and in 53 patients (21.7%) for a third or subsequent episode. Patients treated with fidaxomicin in a first episode were younger (59.9 years vs 73.5 years), but they had more severe episodes (52.1% vs. 32.4%). The recurrence rates for patients treated in the first episode were 6.5% and 9.7% at weeks 8 and 12, respectively. Recurrence rates increased for patients treated at second or ulterior episodes (16.3% and 26.4% at week 8, respectively). Age greater than or equal to 85 years and having had a previous episode of CDI were identified as recurrence risk factors at weeks 8 and 12. We conclude that the outcomes with fidaxomicin in real life are at least as good as those observed in clinical trials despite a more demanding evaluation. Be it 85 years of age or older, and the use after a first episode appears to be independent factors of CDI recurrence after treatment with fidaxomicin.

Factors associated with malaria and arboviral disease in patients with imported febrile syndrome: a retrospective cohort study. / Factores asociados con malaria y arboviriasis en pacientes con síndrome febril importado: estudio de cohortes retrospectivo.

OBJECTIVES: To identify predictors of malaria and arboviral disease in patients with febrile syndrome who seek care after traveling from tropical or subtropical locations. MATERIAL AND METHODS: Observational retrospective cohort study. We collected demographic, epidemiologic, and clinical data; laboratory findings; and the clinical and final microbiologic diagnoses. Multivariate analysis was used to calculate indices of diagnostic accuracy (sensitivity, specificity, and predictive values) and coefficients of probability of combinations of variables. RESULTS: Data for 291 patients with febrile syndrome were included; 108 had malaria (37.1%), 28 had an arboviral disease (9.6%), and 155 had other causes of fever (53.3%). Multivariate analysis showed patients most likely to have malaria were those from sub-Saharan Africa, adjusted odds ratio (aOR) of 45.85 (95% CI, 9.45-222.49); immigrants who returned to visit friends and relatives (VFR), aOR of 3.55 (95% CI, 1.21-10.46); or had platelet concentrations 150 000/mm3, aORa of 16.47 (95% CI, 5.46-49.70) or headache, aOR of 10.62 (95% CI, 3.20-35.28). The combination of these 4 variables gave a positive probability coefficient (PPC) of 23.72 (95% CI, 5.76-97.62). Patients with febrile syndrome most likely to have an arboviral disease were those from Central or South America, OR 5.07 (95% CI, 1.73-14.92), and those who had exanthems, OR 5.10 (95% CI, 1.72-17.02) or joint pain, OR 14.50 (95% CI, 3.05-68.80). The combination of these 3 variables gave a PPC of 20.66 (95% CI, 7.74-55.21). CONCLUSION: Patients with febrile syndrome with the greatest probability of having malaria are those from sub-Saharan Africa, those who are VFR, and those with platelet concentrations under 150.000/µL or headache. Arboviral disease was more likely in patients from Central and South America who had exanthems or joint pain.

OBJETIVO: Definir variables predictoras de malaria y arboviriasis en pacientes que consultan por síndrome febril tras la vuelta de un viaje a zonas tropicales/subtropicales. METODO: Estudio de cohortes retrospectivo. Se incluyeron variables demográficas, epidemiológicas, clínicas, analíticas y el diagnóstico final clínico y microbiológico. Se realizó un análisis multivariante y se calcularon los índices de exactitud diagnóstica (sensibilidad, especificidad, valores predictivos) y cocientes de probabilidad de la combinación de dichasvariables. RESULTADOS: Se incluyeron 291 pacientes con síndrome febril, 108 tenían malaria (37,1%), 28 arboviriasis (9,6%) y 155 otras causas de fiebre (53,3%). En el análisis multivariante, los pacientes con síndrome febril con más riesgo de padecer malaria fueron los que procedían de África subsahariana [odds ratio ajustado (ORa): 45,85; IC 95%: 9,45- 222,49], eran inmigrantes que visitan a familiares y amigos (VFA) (ORa = 3,55; IC 95%: 1,21-10,46), presentaban cifras de plaquetas 150.000/mm3 (ORa = 16,47; IC 95%: 5,46-49,70) o cefalea (ORa = 10,62; IC 95%: 3,20-35,28). La combinación de estas cuatro variables tiene un cociente de probabilidad positivo (CPP) de 23,72 (IC 95%: 5,76- 97,62). Los pacientes con síndrome febril que tienen más riesgo de padecer arboviriasis eran los que procedían de Centroamérica y Sudamérica (OR = 5,07; IC 95%: 1,73-14,92), presentaban exantema (OR = 5,10; IC 95%: 1,72- 17,02) o artromialgias (OR = 14,50; IC 95%: 3,05-68,80). La combinación de estas tres variables tiene un CPP de 20,66 (IC 95%: 7,74-55,21). CONCLUSIONES: Los pacientes con síndrome febril que tienen más riesgo de padecer malaria son los que procedían de África subsahariana, eran VFA, presentaban cifras de plaquetas 150.000/µl o cefalea, y tenían mayor riesgo de padecer arboviriasis si procedían de Centroamérica y Sudamérica, presentaban exantema o artromialgias.

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

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

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.

Pseudomonas aeruginosa Community-Onset Bloodstream Infections: Characterization, Diagnostic Predictors, and Predictive Score Development-Results from the PRO-BAC Cohort.

Community-onset bloodstream infections (CO-BSI) caused by gram-negative bacilli are common and associated with significant mortality; those caused by Pseudomonas aeruginosa are associated with worse prognosis and higher rates of inadequateempirical antibiotic treatment. The aims of this study were to describe the characteristics of patients with CO-BSI caused by P. aeruginosa, to identify predictors, and to develop a predictive score for P. aeruginosa CO-BSI. Materials/methods: PROBAC is a prospective cohort including patients >14 years with BSI from 26 Spanish hospitals between October 2016 and May 2017. Patients with monomicrobial P. aeruginosa CO-BSI and monomicrobial Enterobacterales CO-BSI were included. Variables of interest were collected. Independent predictors of Pseudomonas aeruginosa CO-BSI were identified by logistic regression and a prediction score was developed. Results: A total of 78patients with P. aeruginosa CO-BSI and 2572 with Enterobacterales CO-BSI were included. Patients with P. aeruginosa had a median age of 70 years (IQR 60−79), 68.8% were male, median Charlson score was 5 (IQR 3−7), and 30-daymortality was 18.5%. Multivariate analysis identified the following predictors of CO-BSI-PA [adjusted OR (95% CI)]: male gender [1.89 (1.14−3.12)], haematological malignancy [2.45 (1.20−4.99)], obstructive uropathy [2.86 (1.13−3.02)], source of infection other than urinary tract, biliary tract or intra-abdominal [6.69 (4.10−10.92)] and healthcare-associated BSI [1.85 (1.13−3.02)]. Anindex predictive of CO-BSI-PA was developed; scores ≥ 3.5 showed a negative predictive value of 89% and an area under the receiver operator curve (ROC) of 0.66. Conclusions: We did not find a good predictive score of P. aeruginosa CO-BSI due to its relatively low incidence in the overall population. Our model includes variables that are easy to collect in real clinical practice and could be useful to detect patients with very low risk of P. aeruginosa CO-BSI.

[Application of validated severity scores for pneumonia caused by SARS-CoV-2]. / Aplicación de escalas pronósticas de gravedad en la neumonía por SARS-CoV-2.

OBJECTIVES: Compare the accuracy of PSI, CURB-65, MuLBSTA and COVID-GRAM prognostic scores to predict mortality, the need for invasive mechanical ventilation in patients with pneumonia caused by SARS-CoV-2 and assess the coexistence of bacterial respiratory tract infection during admission. METHODS: Retrospective observational study that included hospitalized adults with pneumonia caused by SARS-CoV-2 from 15/03 to 15/05/2020. We excluded immunocompromised patients, nursing home residents and those admitted in the previous 14 days for another reasons. Analysis of ROC curves was performed, calculating the area under the curve for the different scales, as well as sensitivity, specificity and predictive values. RESULTS: A total of 208 patients were enrolled, aged 63±17 years, 57,7% were men; 38 patients were admitted to ICU (23,5%), of these patients 33 required invasive mechanical ventilation (86,8%), with an overall mortality of 12,5%. Area under the ROC curves for mortality of the scores were: PSI 0,82 (95% CI: 0,73-0,91), CURB-65 0,82 (0,73-0,91), MuLBSTA 0,72 (0,62-0,81) and COVID-GRAM 0,86 (0,70-1). Area under the curve for needing invasive mechanical ventilation was: PSI 0,73 (95% CI: 0,64-0,82), CURB-65 0,66 (0,55-0,77), MuLBSTA 0,78 (0,69-0,86) and COVID-GRAM 0,76 (0,67-0,85), respectively. Patients with bacterial co-infections of the respiratory tract were 20 (9,6%), the most frequent strains being Pseudomonas aeruginosa and Klebsiella pneumoniae. CONCLUSIONS: In our study, the COVID-GRAM score was the most accurate to identify patients with higher mortality with pneumonia caused by SARS-CoV-2; however, none of these scores accurately predicts the need for invasive mechanical ventilation with ICU admission. The 10% of patients admitted presented bacterial respiratory co-infection.

Application of validated severity scores for pneumonia caused by SARS-CoV-2.

OBJECTIVES: Compare the accuracy of PSI, CURB-65, MuLBSTA and COVID-GRAM prognostic scores to predict mortality, the need for invasive mechanical ventilation (IMV) in patients with pneumonia caused by SARS-CoV-2 and assess the coexistence of bacterial respiratory tract infection during admission. METHODS: Retrospective observational study that included hospitalized adults with pneumonia caused by SARS-CoV-2 from 15/03 to 15/05/2020. We excluded immunocompromised patients, nursing home residents and those admitted in the previous 14 days for another reasons. Analysis of ROC curves was performed, calculating the area under the curve for the different scales, as well as sensitivity, specificity and predictive values. RESULTS: 208 patients were enrolled, aged 63 ± 17 years, 577% were men. 38 patients were admitted to ICU (235%), of these patients 33 required IMV (868%), with an overall mortality of 125%. Area under the ROC curves for mortality of the scores were: PSI 082 (95% CI 073-091), CURB-65 082 (073-091), MuLBSTA 072 (062-081) and COVID-GRAM 086 (070-1). Area under the curve for needing IMV was: PSI 073 (95% CI 064-082), CURB-65 066 (055-077), MuLBSTA 078 (069-086) and COVID-GRAM 076 (067-085), respectively. Patients with bacterial co-infections of the respiratory tract were 20 (9,6%), the most frequent strains being Pseudomonas aeruginosa and Klebsiella pneumoniae. CONCLUSIONS: In our study, the COVID-GRAM score was the most accurate to identify patients with higher mortality with pneumonia caused by SARS-CoV-2; however, none of these scores accurately predicts the need for IMV with ICU admission. 10% of patients admitted presented bacterial respiratory co-infection.

OBJETIVOS: Comparar el rendimiento de las escalas pronósticas PSI, CURB-65, MuLBSTA y COVID-GRAM para predecir mortalidad y necesidad de ventilación mecánica invasiva (VMI) en pacientes con neumonía por SARS-CoV-2. Valorar la existencia de coinfección bacteriana respiratoria durante el ingreso. MÉTODO: Estudio observacional retrospectivo que incluyó adultos hospitalizados con neumonía por SARS-CoV-2 del 15/03 al 15/05/2020. Se excluyeron aquellos inmunodeprimidos, institucionalizados e ingresados en los 14 días previos por otro motivo. Se realizó un análisis de curvas ROC, calculando el área bajo la curva para las diferentes escalas, así como sensibilidad, especificidad y valores predictivos. RESULTADOS: Se incluyeron 208 pacientes, con edad de 63 ± 17 años; el 57,7% eran hombres. Ingresaron en UCI 38 (23,5%), precisando de estos VMI 33 (86,8%), con una mortalidad global del 12,5%. Las áreas bajo las curvas ROC para mortalidad de los scores fueron: PSI 0,82 (95% IC 0,73­0,91), CURB-65 0,82 (0,73­0,91), MuLBSTA 0,72 (0,62­0,81) y COVID-GRAM 0,86 (0,70­1). Las áreas para necesidad de VMI fueron: PSI 0,73 (95% IC 0,64­0,82), CURB-65 0,66 (0,55­0,77), MuLBSTA 0,78 (0,69­0,86) y COVID-GRAM 0,76 (0,67­0,85), respectivamente. Los pacientes que presentaron coinfección bacteriana respiratoria fueron 20 (9.6%) siendo los gérmenes más frecuentes Pseudomonas aeruginosa y Klebsiella pneumoniae. CONCLUSIONES: En nuestro estudio el score COVID-GRAM fue el más preciso para identificar los pacientes con mayor mortalidad ingresados con neumonía por SARS-CoV-2, no obstante, ninguno de estos scores predice de forma precisa la necesidad de VMI con ingreso en UCI. El 10% de los pacientes presentó coinfección bacteriana respiratoria.

Revisiting the epidemiology of bloodstream infections and healthcare-associated episodes: results from a multicentre prospective cohort in Spain (PRO-BAC Study).

The epidemiology of bloodstream infections (BSIs) is dynamic as it depends on microbiological, host and healthcare system factors. The aim of this study was to update the information regarding the epidemiology of BSIs in Spain considering the type of acquisition. An observational, prospective cohort study in 26 Spanish hospitals from October 2016 through March 2017 including all episodes of BSI in adults was performed. Bivariate analyses stratified by type of acquisition were performed. Multivariate analyses were performed by logistic regression. Overall, 6345 BSI episodes were included; 2510 (39.8%) were community-acquired (CA), 1661 (26.3%) were healthcare-associated (HCA) and 2056 (32.6%) hospital-acquired (HA). The 30-day mortality rates were 11.6%, 19.5% and 22.0%, respectively. The median age of patients was 71 years (interquartile range 60-81 years) and 3656 (58.3%; 95% confidence interval 57.1-59.6%) occurred in males. The proportions according to patient sex varied according to age strata. Escherichia coli (43.8%), Klebsiella spp. (8.9%), Staphylococcus aureus (8.9%) and coagulase-negative staphylococci (7.4%) were the most frequent pathogens. Multivariate analyses confirmed important differences between CA and HCA episodes, but also between HCA and HA episodes, in demographics, underlying conditions and aetiology. In conclusion, we have updated the epidemiological information regarding patients' profiles, underlying conditions, frequency of acquisition types and aetiological agents of BSI in Spain. HCA is confirmed as a distinct type of acquisition.

Real-World Experience with Bezlotoxumab for Prevention of Recurrence of Clostridioides difficile Infection.

Bezlotoxumab is marketed for the prevention of recurrent Clostridioides difficile infection (rCDI). Its high cost could be determining its prescription to a different population than that represented in clinical trials. The objective of the study was to verify the effectiveness and safety of bezlotoxumab in preventing rCDI and to investigate factors related to bezlotoxumab failure in the real world. A retrospective, multicentre cohort study of patients treated with bezlotoxumab in Spain was conducted. We compared the characteristics of cohort patients with those of patients treated with bezlotoxumab in the pivotal MODIFY trials. We assessed recurrence rates 12 weeks after completion of treatment against C. difficile, and we analysed the factors associated with bezlotoxumab failure. Ninety-one patients were included in the study. The cohort presented with more risk factors for rCDI than the patients included in the MODIFY trials. Thirteen (14.2%) developed rCDI at 12 weeks of follow-up, and rCDI rates were numerically higher in patients with two or more previous episodes (25%) than in those who had fewer than two previous episodes of C. difficile infection (CDI) (10.4%); p = 0.09. There were no adverse effects attributable to bezlotoxumab. Despite being used in a more compromised population than that represented in clinical trials, we confirm the effectiveness of bezlotoxumab for the prevention of rCDI.