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.

Asociación entre marcadores inflamatorios y traslocación bacteriana en pacientes con infección por el virus de la inmunodeficiencia humana en tratamiento antirretroviral / Association between inflammatory markers and microbial translocation in patients with human immunodeficiency virus infection taking antiretroviral treatment

Fundamento y objetivo: Ciertos marcadores inflamatorios están elevados en pacientes con infección por el virus de la inmunodeficiencia humana (VIH). El tratamiento antirretroviral (TAR) mejora algunos de estos parámetros, pero no suele normalizarlos. El objetivo de este estudio es determinar los factores, incluida la traslocación bacteriana, asociados a una mayor actividad inflamatoria en pacientes con infección por VIH en tratamiento. Pacientes y métodos: Estudio observacional transversal. Se incluyeron pacientes con infección por VIH que recibían TAR y tenían carga viral plasmática del VIH (CVP-VIH) < 400 copias/ml. Se seleccionaron pacientes consecutivos entre noviembre de 2011 y enero de 2012. Las variables de resultado fueron los valores séricos de interleucina 6 (IL-6) y de tumour necrosis factor α (TNF-α, «factor de necrosis tumoral α»). La variable explicativa principal fueron los marcadores de traslocación bacteriana (ADN ribosomal 16S y sCD14). Los pacientes con valores de IL-6 o TNF-α por encima del percentil 75 (grupo 1) se compararon con el resto de pacientes (grupo 2), y se calcularon las odds ratio (OR) brutas y ajustadas (análisis multivariante). Resultados: Se incluyeron 81 pacientes (73% varones, edad mediana 45 años, 48% en estadio C). El 26% tenía hepatitis crónica C. La mediana de linfocitos CD4 era de 493 cél/mm3 y el 30% tenía CVP-VIH detectable. Se detectó ADN ribosomal en el 21% de los pacientes. Los integrantes del grupo 1 presentaron con mayor frecuencia ADN ribosomal (OR 77, p < 0,0001), valores altos de sCD14 (p < 0,0001) y antecedentes de enfermedad cardiovascular (OR 15, p < 0,01). En el análisis multivariante la asociación se mantuvo para la presencia de ADN ribosomal (OR 62, p < 0,0001) y antecedentes cardiovasculares (OR 25, p < 0,01). Conclusiones: En pacientes con infección por VIH en tratamiento, los mayores valores de marcadores inflamatorios se observan en aquellos casos con traslocación bacteriana y antecedentes de enfermedad cardiovascular (AU)

Background and objective: Inflammatory biomarkers are increased in patients with human immunodeficiency virus (HIV) infection. Antiretroviral treatment (ART) improves some parameters but do not normalize them. The aim of this study is to determine those factors (including microbial translocation) associated with higher inflammation in HIV treated patients. Patients and methods: Transversal observational study. Inclusion criteria: HIV patients receiving ART with an HIV viral load (VL) < 400 copies/mL. Selection of patients: consecutively between November 2011 and January 2012. Main variable: plasma levels of interleukin 6 (IL-6) and tumour necrosis factor α (TNF-α). Main explanatory variable: microbial translocation markers (16S ribosomal DNA and sCD14). Patients with IL-6 or TNF-α levels above percentile 75 (group 1) were compared with the rest of patients (group 2). Odds ratio (OR) were determined. Results: Eighty-one patients were included (73% male, median age 45 years, 48% stage C). Twenty-six percent had chronic hepatitis C. Median CD4 cell was 493/mm3 and 30% had detectable HIV VL. 16S ribosomal DNA was detected in 21% of patients. Factors associated with the higher levels of inflammatory markers were 16S ribosomal DNA (OR 77, P < .0001), sCD14 levels (P < .0001) and history of cardiovascular disease (OR 15, P < .01). In multivariate analysis, associations remained for 16S ribosomal DNA (OR 62, P < .0001) and previous cardiovascular disease (OR 25, P < .01). Conclusions: In patients with HIV infection receiving treatment, the higher levels of inflammatory markers are associated with microbial translocation and past cardiovascular events (AU)

[Association between inflammatory markers and microbial translocation in patients with human immunodeficiency virus infection taking antiretroviral treatment]. / Asociación entre marcadores inflamatorios y traslocación bacteriana en pacientes con infección por el virus de la inmunodeficiencia humana en tratamiento antirretroviral.

BACKGROUND AND OBJECTIVE: Inflammatory biomarkers are increased in patients with human immunodeficiency virus (HIV) infection. Antiretroviral treatment (ART) improves some parameters but do not normalize them. The aim of this study is to determine those factors (including microbial translocation) associated with higher inflammation in HIV treated patients. PATIENTS AND METHODS: Transversal observational study. INCLUSION CRITERIA: HIV patients receiving ART with an HIV viral load (VL)<400 copies/mL. Selection of patients: consecutively between November 2011 and January 2012. Main variable: plasma levels of interleukin 6 (IL-6) and tumour necrosis factor α (TNF-α). Main explanatory variable: microbial translocation markers (16S ribosomal DNA and sCD14). Patients with IL-6 or TNF-α levels above percentile 75 (group 1) were compared with the rest of patients (group 2). Odds ratio (OR) were determined. RESULTS: Eighty-one patients were included (73% male, median age 45 years, 48% stage C). Twenty-six percent had chronic hepatitis C. Median CD4 cell was 493/mm(3) and 30% had detectable HIV VL. 16S ribosomal DNA was detected in 21% of patients. Factors associated with the higher levels of inflammatory markers were 16S ribosomal DNA (OR 77, P<.0001), sCD14 levels (P<.0001) and history of cardiovascular disease (OR 15, P<.01). In multivariate analysis, associations remained for 16S ribosomal DNA (OR 62, P<.0001) and previous cardiovascular disease (OR 25, P<.01). CONCLUSIONS: In patients with HIV infection receiving treatment, the higher levels of inflammatory markers are associated with microbial translocation and past cardiovascular events.