Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant <i>Escherichia coli</i> Bacteremic Urinary Tract Infections
Jesús Sojo-Dorado, Inmaculada López-Hernández, Clara Rosso-Fernández, Isabel Morales, Zaira R. Palacios‐Baena, Alicia Hernández‐Torres, Esperanza Merino de Lucas, Laura Escolà‐Vergé, Elena Bereciartúa, Elisa García‐Vázquez, Vicente Pintado, Lucía Boix-Palop, Clara Natera-Kindelán, Luisa Sorlí, Núria Borrell, Livia Giner, Concha Amador-Prous, Evelyn Shaw, A Jover, José Molina, Rosa Martínez-Álvarez, Carlos Dueñas, Jorge Calvo, Jose T. Silva, Miguel Ángel Cárdenes, María Lecuona, Virginia Pomar, Lucía Valiente de Santis, Genoveva Yagüe‐Guirao, María Ángeles Lobo-Acosta, Vicente Merino‐Bohórquez, Álvaro Pascual, Jesús Rodríguez‐Baño, REIPI-GEIRAS-FOREST group, Benito Almirante, Mario Fernández, José Ramón Paño‐Pardo, Marina de Cueto, Pilar Retamar, Luis Eduardo López-Cortés, Belén Gutiérrez‐Gutiérrez, Fernando Docobo-Pérez, Irene Borreguero, Manuel Cameán, Encarnación Moral‐Escudero, Ana Pareja-Rodríguez de Vera, María del Carmen Martínez-Toldos, Ana Blázquez-Abellán, Alba Bellés Bellés, María Fernanda Ramírez-Hidalgo, Beatriz Mirelis, Esther Calbo, Mariona Xercavins, Irene Gracia-Ahufinger, Angela M. Cano-Yuste, Laura Guío Carrión, Jose Luis Hernández‐Davó, Carlos Pigrau-Serrallach, Belen Viñado-Pérez, Mireia Puig Asensio, Carmen Ardanuy, Miquel Pujol, Dácil García-Rosado, Concepción Gil-Anguita, Ana Siverio, Adelina Gimeno, Vicente Boix-Martínez, Sergio Reus, Iván Agea-Durán, Carmen Fariñas, Begoña Palop, Helem Vílchez, José Antonio Lepe, María Victoria Gil-Navarro, Rafael San-Juan, Fernando Cháves, Rosa Escudero, Francesca Gioia, Ana María Sánchez‐Díaz, Ana María Cañas-Pedrosa, Nayra Sangil-Monroy, Carla Toyas-Miazza
Abstract
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.