Effect of oral fosfomycin compared to the intravenous beta lactam/beta-lactamase inhibitor or carbapenem in step-down treatment of patients with complicated urinary tract infection
Presenter: Professor Jun-won Seo, PhD, Chosun University Hospital, Gwangju, Kwangju-jikhalsi, Republic of Korea.
Effect of oral fosfomycin compared to the intravenous beta lactam/beta-lactamase inhibitor or carbapenem in step-down treatment of patients with complicated urinary tract infection due to ESBL-producing Enterobacteriaceae; a multicenter, randomized, prospective, open-label, noninferiority trial.
For the strategy of changing to early oral antibiotics in the step-down treatment of complicated urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, oral fosfomycin is not inferior to carbapenem or intravenous beta-lactam/beta-lactamase inhibitors (BL/BLIs), according to findings presented in an oral session at ID Week 2023.
“Multidrug resistant strains of carbapenem-resistant Enterobacteriaceae pose a serious threat to public health, and there is a shortage of medications to treat them,” stated Professor Jun-won Seo, PhD, Chosun University Hospital, Gwangju, Kwangju-jikhalsi, Republic of Korea. The emergence of carbapenem-resistant Enterobacteriaceae, Seo stated, has been a consequence of the widespread use of carbapenem for treating UTIs caused by ESBL-producing Enterobacteriaceae. He added that among alternatives being explored such as colistin, aminoglycoside, and nitrofurantoin, concerns persist over potential for reduced treatment efficacy, and medication side effects. A new paradigm is needed, Seo urged, to reduce the use of broad-spectrum antibiotics for these ESBL-producing Enterobacteriaceae.
While interest is increasing in the efficacy of fosfomycin as an alternative to broad-spectrum antibiotics, most fosfomycin studies to date have focused on lower urinary tract or uncomplicated urinary tract infections, and have been retrospective.
Seo and colleagues, to determine whether oral fosfomycin was inferior to carbapenems or beta-lactam/beta-lactamase inhibitors in treatment of complicated UTIs caused by ESBL-producing Enterobacteriaceae, conducted a multicenter, randomized, controlled, open-label, noninferiority trial at 4 tertiary hospitals in South Korea. The noninferiority margin was set at 15%.
Investigators randomly allocated 199 patients 1:1 at the time of step-down therapy to 10 days of continued carbapenem or beta-lactam drugs already in use (n = 104) or to a switch to oral fosfomycin (n = 95). Clinical resolution of UTI-related symptoms and signs within 4 days after the end of treatment was the primary endpoint. Symptom improvement was defined by resolved fever (< 37.5 °C), and improved dysuria, frequency, urgency, suprapubic pain, and costovertebral angle tenderness. Improved signs included negative conversion of pyuria or bacteriuria in urinalysis and urine culture with normalization of inflammatory markers (white blood cell count, C-reactive protein).
Reporting an interim analysis of the primary endpoint, Seo stated that in the oral fosfomycin group, resolution of UTI-related symptoms and signs was observed in all but 4 of 95 (4.2%) patients versus 3 of 104 (2.9%) in the carbapenem or beta-lactam group. The –1.33% (–6.49 to 3.84) difference was not significant (P = .612). Subgroup analysis, as well, including age (above and below age 65 years), sex, clinical diagnosis (complicated UTI with or without pyelonephritis, with or without bacteremia) revealed no statistically significant differences between the 2 groups. Also, the secondary endpoint of microbiological cure within 4 days after the end of treatment assessed via urine specimens was similar for both groups and was achieved in 86 (91%) patients assigned to oral fosfomycin and in 90 (87%) assigned to carbapenem or beta-lactam drugs. Among other secondary endpoints, the rates of UTI-related hospital readmissions within 30 days were similar at 7% and 4% for oral fosfomycin and carbapenem or beta-lactam drugs, respectively, as were emergency room or outpatient clinic visits within 30 days at 7% and 5% for oral fosfomycin and carbapenem or beta-lactam drugs, respectively.
No serious adverse events were reported in either of the treatment groups, Seo said, and no patients discontinued because of adverse effects. The most common, diarrhea and nausea, occurred at rates of 12.8% (for both) in the oral fosfomycin group and 6.7% (for both) in the intravenous carbapenem and beta-lactam groups (P = .150).
The analysis, Seo stated, demonstrated that oral fosfomycin is not inferior to carbapenem or beta-lactam drugs for step-down treatment of complicated UTIs caused by ESBL-producing Enterobacteriaceae. “Therefore, it is one of the optimal treatment options applicable to the strategy of changing to early oral antibiotics,” Seo concluded.
Dr. Seo reported no disclosures.
Supported by National Institute of Health, Korea Disease Control and Prevention Agency.