Abstract
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. 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. 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. 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. The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. 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). 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. ClinicalTrials.gov Identifier: NCT02142751.
Highlights
Escherichia coli is one of the most frequently occurring human pathogens
While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators, 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)
Summary
Escherichia coli is one of the most frequently occurring human pathogens. After a massive use of cephalosporins and fluoroquinolones, multidrug-resistant (MDR) isolates have spread dramatically worldwide.[1,2] As a consequence, the consumption of last-resort drugs, such as carbapenems, increased over the last 20 years,[3] which in turn is facilitating the dramatic spread of carbapenem-resistance.[4]. Fosfomycin, discovered more than 40 years ago, is active against a wide range of pathogens, including MDR Enterobacterales.[5,6] This drug is available for intravenous use as fosfomycin disodium in some countries ( not in the United States) and as an oral formulation (ie, fosfomycin trometamol). High-quality studies with fosfomycin are scarce.[5,7] Recently, it was shown to be noninferior to piperacillin-tazobactam for treatment of complicated urinary tract infections (cUTI).[8] Because cUTI includes highly heterogeneous infection types and considering that fosfomycin may be less efficacious against Enterobacterales than against other than E coli,[9,10] we conducted this study to test the hypothesis that fosfomycin is not inferior to ceftriaxone or meropenem for the targeted treatment of bacteremic UTI (bUTI) caused by MDR E coli
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