Antimicrobial susceptibilities of clinical bacterial isolates from urinary tract infections to fosfomycin and comparator antibiotics determined by agar dilution method and automated micro broth dilution

Uncomplicated bacteremic urinary tract infections (bUTIs) are common, often caused by Escherichia coli , Klebsiella pneumoniae , and Enterococcus faecalis , with most encounters treated empirically. As rates of antimicrobial resistance increase, available antibiotic treatment options are dwindling. Novel antibiotics approved for treating bUTIs are limited, leading to a resurgence of interest in older antibiotics, including fosfomycin. Here, clinical urine samples from patients including military personnel, retirees, and their dependents diagnosed with bUTIs from a military hospital located in Bethesda, Maryland, were tested for susceptibility to fosfomycin and comparator antibiotics (levofloxacin, nitrofurantoin, and trimethoprim-sulfamethoxazole [TMS]). A total of 1,353 nonduplicate bacterial isolates were tested, including 605 non-ESBL and 285 ESBL E. coli , and 84 non-ESBL and 52 ESBL K. pneumoniae . Fosfomycin susceptibility rates were similar for non-ESBL and ESBL E. coli (95.9% vs 96.1%) and K. pneumoniae (38.1% vs 36.5%). Fosfomycin demonstrated high activity against other Enterobacterales and gram-positive organisms including Enterobacter faecalis and Staphylococcus aureus . Interestingly, most fosfomycin non-susceptible isolates were susceptible to other first-line bUTI treatment options, and most isolates that were non-susceptible to other first-line bUTI treatment option were susceptible to fosfomycin. ESBL K. pneumoniae isolates were the least susceptible to current first-line treatment options. Fosfomycin Etest demonstrated high sensitivity compared to agar dilution, making it a viable AST testing method especially in resource-limited areas. Overall, we demonstrated fosfomycin has high activity against common etiologies that cause bUTIs. Further clinical efficacy studies investigating the use of fosfomycin in treating non- E . coli bUTI pathogens, as single or combination therapy, are warranted.

IMPORTANCE

Uncomplicated bUTIs are often caused by Escherichia coli , Klebsiella pneumoniae , and Enterococcus faecalis . Fosfomycin is one of the recommended firstline antibiotics for the treatment of symptomatic, uncomplicated bUTIs. Fosfomycin susceptibility testing is complicated by the fact that although both CLSI and EUCAST recognize agar dilution (AD) as the reference method albeit being labor-intensive, breakpoints are different, and Etest is only approved by EUCAST. We investigated the susceptibility of bUTI clinical isolates to fosfomycin using AD and compared performance in a subset of isolates to Etest. Fosfomycin susceptibility profiles of bacterial isolates were compared to other firstline antibiotics. We found isolates were susceptible to fosfomycin at similar or higher rates compared to other firstline antibiotics. Importantly, fosfomycin was effective against isolates producing extended-spectrum beta-lactamases and those that were resistant to other firstline treatments. Furthermore, our data showed Etest was a viable option for susceptibility testing with 94% agreement to the AD.