Due to a significantly higher rate of treatment discontinuation caused by adverse events, treatment with fosfomycin for bacteremic urinary tract infections (UTIs) caused by multidrug-resistant Escherichia coli was not noninferior to drugs such as ceftriaxone and meropenem.
However, researchers of the Fosfomycin vs Meropenem or Ceftriaxone in Bacteremic Infections Caused by Multidrug Resistance in E. Coli (FOREST) randomized clinical trial still have hope that fosfomycin may be effective in selected patients, notably those without previous heart disease and with low risk of sodium overload-related adverse effects. The findings were published in JAMA Network Open.
“In this randomized clinical trial, fosfomycin did not reach the noninferiority criteria in the treatment of [bacteremic] bUTI due to [multidrug-resistant] MDR E. coli. However, this was not due to lack of efficacy; in fact, the clinical and microbiological failure rate was numerically lower with fosfomycin in the MITT, for which the 1-sided 95% CI of the difference was the below the −7% noninferiority margin,” explained Jesús Sojo-Dorado, MD, PhD, of the Universidad de Sevilla, Spain, and fellow researchers.
For the multicenter, randomized, pragmatic, open-label FOREST clinical trial, conducted in 22 Spanish hospitals from June 2014 to December 2018, Sojo-Dorado and colleagues included 143 adults (median age: 72 years; 51.0% women) with bacteremic UTIs caused by multidrug-resistant E. coli, who were screened, randomized, and followed for 60 days. Their goal was to assess the noninferiority of fosfomycin to ceftriaxone or meropenem for targeted treatment of these infections.
They randomized patients 1:1 to either fosfomycin disodium (4 g every 6 hours intravenously; n=70) or a comparator (ceftriaxone or meropenem; n=73). After 4 days, patients treated with fosfomycin had the option of switching to oral fosfomycin trometamol, and those in the comparator group had the option to switch to an active oral drug or parenteral ertapenem.
The primary outcome of the study was clinical and microbiological cure 5-7 days after treatment finalization, with a noninferiority margin set at 7%.
Clinical and microbiological cure occurred in 68.6% of fosfomycin patients, compared with 78.1% of comparators (risk difference: −9.4 percentage points; 1-sided 95% CI: −21.5 to ∞ percentage points; P=0.10). Clinical or microbiological failure occurred in 14.3% versus 19.7%, respectively (risk difference: −5.4 percentage points; 1-sided 95% CI: −∞ to 4.9 percentage points; P=0.19).
In patients treated with fosfomycin, there was an increased rate of adverse event-related treatment discontinuations compared with comparators (8.5% versus 0%, respectively; P=0.006). Adverse events occurred in 62.9% versus 56.2%, respectively; serious adverse events occurred in 18.6% versus 13.7% (P=0.42).
Importantly, 8.6% of patients treated with fosfomycin developed heart failure. All were aged ≥81 years, two had chronic heart failure, and three chronic kidney insufficiency. Heart failure was deemed serious in five of these patients, and fosfomycin was discontinued in four.
Sojo-Dorado and colleagues also did an exploratory analysis among 38 patients undergoing rectal colonization studies, and found that those treated with fosfomycin acquired new ceftriaxone- or meropenem-resistant gram-negative bacteria at a lower rate than those treated with comparator therapies (0% versus 23.5%, respectively; 1-sided P=0.01).
“To the best of our knowledge, this is the first trial to include fosfomycin trometamol as an oral switch among patients with bacteremic infections; its concentrations are high in urine but low in plasma. However, bacteremia in [bacteremic] bUTI is an epiphenomenon, and once the parenchymal component of the infection is controlled, urine concentrations may be more important. The outcome data from the subgroup analyses among patients who were switched were encouraging. The investigation of the ecologic impact of the study drugs was exploratory. Overall, the data obtained support the idea that fosfomycin may cause less ecological damage than ceftriaxone and meropenem, and the findings may open the door to further studies,” they concluded.
In their interestingly entitled accompanying editorial, interestingly entitled “The Role of Intravenous Fosfomycin: Finding Our Way Out of Dante’s Forest Dark,” Robert A. Bonomo, MD, of the Louis B. Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, and colleagues applauded Sojo-Dorado et all for their “impressive” study.
Before detailing both the limitations and strengths of it, however, Bonomo and colleagues provided an overview of fosfomycin.
“Fosfomycin is the only commercially available member of the phosphonic acid class of antibiotics. This unique antibiotic was discovered in the 1960s and inhibits a critical first step in bacterial cell wall synthesis. As is the case with other agents whose availability preceded the contemporary rigorous regulatory environment, important gaps in knowledge regarding the safety and efficacy of fosfomycin remain. Interestingly, along with its antibacterial properties, fosfomycin alters leukocyte function, penetrates biofilms, and demonstrates intracellular bactericidal killing,” they wrote.
Bonomo et al also stressed that “[f]indings from the primary outcome were largely influenced by the inclusion of a notable number of patients with adverse event-related discontinuations in the fosfomycin group.” Indeed, of the six discontinuations, four were related to heart failure. They added that when Sojo-Dorado and colleagues studied only those patients who completed the course of treatment, the clinical failure rate was 14.3%, compared with 19.7% in the comparator group.
These findings from Sojo-Dorado et al suggest several things, according to the editorialists. First, in separating clinical outcomes from safety results, “this study indicates that IV fosfomycin may be a reasonable treatment option for patients with E. coli bacteremia from a urinary source,” they wrote.
Secondly, they continued, these results indicate that IV fosfomycin is to be used with caution or avoided altogether in older patients and those with risk factors for heart failure.
“Third, although this study provides important insights into our understanding of potential roles for IV fosfomycin, it does not provide sufficient support for the use of oral fosfomycin to treat invasive infections,” they added.
And finally, further studies on the ecological impact of fosfomycin on bacterial flora are needed.
“We applaud Sojo-Dorado and colleagues for their thought-provoking clinical trial investigating the role of IV fosfomycin for the treatment of E. coli bloodstream infections from urinary sources. Although several alternative agents exist for relatively susceptible E. coli bloodstream infections, the potential for the use of IV fosfomycin as a carbapenem-sparing alternative for ESBL-producing E. coli infections is intriguing. The ’forest dark’ of antimicrobial resistance is further illuminated,” concluded Bonomo et al.
Limitations of the study include that the calculated sample size was not reached and that a “highly exigent noninferiority margin was chosen.” Researchers also noted that a lack of blinding may have influenced delayed hospital discharge and Fosfomycin withdrawal, the diversity of treatment changes in the comparator group to mimic standard practice, and the small subset in which rectal colonization was studied.
The study was funded by grants from Plan Nacional de Investigación, Desarrollo e Innovación (I+D+i) 2013 to 2016 and the Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI); the Spanish Clinical Research and Clinical Trials Platform (SCReN); and co-financed by the European Development Regional Fund “A Way to Achieve Europe” and Operative Program Intelligence Growth 2014 to 2020.
Sojo-Dorado reported no conflicts of interest.
Bonomo reported receiving grants from Venatorx Pharmaceuticals, Merck, Shionogi, and Entasis Therapeutics.
Liz Meszaros, Deputy Managing Editor, BreakingMED™
Kaiser Health News
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