Editor’s note:
Carbapenem-resistant Enterobacteriaceae (CRE) and extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) have been designated as “urgent priorities” in antibiotic research and development by the WHO. Besides accelerating the development of new drugs, emphasizing the “repurposing” of existing drugs under antimicrobial stewardship (AMS) can help alleviate the threat of resistant bacteria. At the 2023 IDWeek congress, There is a study using oral fosfomycin as a step-down therapy for ESBL-E complicated urinary tract infections (cUTI), as an alternative to intravenous beta-lactam/beta-lactamase inhibitor (BL/BLIS) therapy, achieving non-inferiority results. Dr. Chun-hui Li from Xiangya Hospital, Central South University, introduces and comments on the study as follows.
Introduction to the Study
Widespread use of carbapenem antibiotics in treating urinary tract infections caused by ESBL-producing Enterobacteriaceae has led to the emergence of carbapenem-resistant Enterobacteriaceae (CRE). This randomized controlled trial aims to determine whether oral fosfomycin treatment for cUTI caused by ESBL-producing Enterobacteriaceae is non-inferior to carbapenems or beta-lactamase inhibitor (BL/BLIS).
This multicenter, randomized, controlled, open-label, non-inferiority trial was conducted in four tertiary hospitals in South Korea. Patients who had received empirical treatment with carbapenems or BL/BLIS for 3-7 days before randomization, and showed symptom relief, were randomly assigned in a 1:1 ratio during the step-down treatment phase to either continue with carbapenems or BL/BLIS or switch to oral fosfomycin. The antibiotic course was set at a total of 10 days. The primary endpoint was the clinical success rate of urinary tract infection within 4 days after the end of treatment, including clinical cure and relief of relevant symptoms and signs.
Between November 1, 2022, and April 30, 2023, a total of 223 patients were screened, and ultimately, 199 patients were randomly assigned to receive oral fosfomycin (n=95, with 1 dropout) or continue empirical treatment with carbapenems or BL/BLIS (n=104). Most demographic and baseline characteristics did not show significant differences between the two groups.
In the oral fosfomycin group, 4.2% (4/95) experienced treatment failure, while in the carbapenem or BL/BLIS group, 2.9% (3/104) did, demonstrating non-inferiority (risk difference: -1.33, 95% CI: -6.49 to 3.84, P=0.612). Subgroup analysis results showed no significant statistical differences in the clinical success rates among all subgroups between the two groups.
The oral fosfomycin group achieved a urine microbiological cure rate of 91% (86/94), while the carbapenem or BL/BLIS group had an 87% (90/104) cure rate. No patients died in either group. Both groups experienced side effects during treatment, but no serious adverse events were observed.
Dr. Chun-hui Li Commentary
Enterobacteriaceae is the most common pathogen in urinary tract infections, and carbapenem-resistant Enterobacteriaceae (CRE) and ESBL-producing Enterobacteriaceae (ESBL-E) have increased the clinical difficulty of treatment, being designated as “urgent priorities” in antibiotic research and development by the WHO[2]. Currently, carbapenems and BL/BLIS remain the main clinical drugs for treating ESBL-E infections, but prolonged treatment may increase the risk of resistance. In clinical practice, “old drugs” like fosfomycin are often overlooked, but monitoring data show that fosfomycin still maintains some sensitivity to ESBL-E or CRE[3]. It is recommended in domestic and international guidelines for treating resistant bacterial infections[4-6] and is included in the WHO Essential Medicines List for the treatment of resistant bacteria[7].
Fosfomycin is available in both intravenous and oral formulations, with oral fosfomycin commonly used for uncomplicated cystitis or prophylactic UTI treatment. This study aimed to evaluate whether oral fosfomycin is non-inferior to continued intravenous carbapenems and BL/BLIS in the step-down treatment of cUTI patients. Previous studies were mostly retrospective, with a low level of evidence. Only one randomized controlled trial (RCT) showed that oral fosfomycin was non-inferior to ciprofloxacin treatment but focused mainly on febrile urinary tract infections in female patients rather than complicated urinary tract infections[8]. Complicated urinary tract infections often involve anatomical or functional abnormalities in the urinary system or extrarenal diseases, with repeated or persistent infections, making treatment challenging.
This prospective, multicenter RCT from Korea has a relatively reasonable study design with strict disease definitions and inclusion criteria. First, cUTI has a clear definition: (1) presence of ≥2 symptoms or signs (chills, myalgia, fever, and related symptoms; at least one temperature ≥38℃ within 24 hours; lower urinary tract symptoms); (2) presence of pyuria or bacteriuria; (3) at least one high-risk medical history (urogenital anatomical or functional abnormalities, underlying diseases, catheter-related infections, resistant bacterial infections, male gender, history of pyelonephritis, repeated use of antibiotics, hospital-acquired infections). Second, enrolled patients had a clear ESBL-E infection and sensitivity to fosfomycin (MIC≤32 mg/L), and after 3-7 days of empirical treatment, they met the step-down criteria, satisfying at least 3 criteria: stable vital signs, defervescence, improvement in UTI-related symptoms, WBC and CRP, and a trend toward improvement in pyuria/bacteriuria (negative leukocyte esterase, decreased or negative urine WBC, negative nitrites, bacteria in midstream urine culture <105/mL, bacteria in catheter urine culture <102/mL). Third, the study excluded patients with uncomplicated UTI, those who underwent surgery before or after the study period (excluding procedures to relieve obstruction, such as nephrostomy and ureteral stent placement), renal abscess/emphysematous pyelonephritis, non-renal infections, patients with liver or kidney dysfunction or other contraindications to treatment. These disease definitions and inclusion/exclusion criteria made the population for step-down therapy relatively clear, increasing the possibility of the study achieving the predetermined non-inferiority level (FDA-agreed non-inferiority margin is 15%, and the treatment success rate in this study needed to be above 70%).
The primary endpoint results showed success rates of 95.8% in the oral fosfomycin group and 97.1% in the intravenous carbapenem or BL/BLIS group, with a risk difference of only -1.33%, meeting the non-inferiority level. The treatment benefits were consistent across all subgroups. The results of secondary endpoints were also excellent, with a urine microbiological cure rate of 91% in the oral fosfomycin group, a nearly 5% improvement compared to the control group (87%), indicating that oral fosfomycin has a more persistent urine bactericidal concentration. There were no deaths in either group. It is worth noting that the incidence of diarrhea and nausea with fosfomycin (both at 12.9% vs. 6.7%) was higher, although not significantly different. This aligns with previous studies and clinical practice, where gastrointestinal reactions, including nausea, gastric burning, and diarrhea, are common with oral fosfomycin.
In summary, this is a prospective, multicenter, randomized controlled study with high credibility, achieving positive results supporting the use of oral fosfomycin in step-down therapy for cUTI. In the past, oral antimicrobial treatment was mainly used for uncomplicated urinary tract infections, and this study suggests that oral treatment can also be extended to complicated urinary tract infections. This step-down treatment strategy with an old drug has positive implications for the rational use of antibiotics, reducing the occurrence of multidrug-resistant (MDR) bacterial infections, and preventing disturbances in gut microbiota. We look forward to more such RCTs or real-world studies for validation.
Infection Control Center, Xiangya Hospital, Central South University
