Comparison of oral third- versus first-/ second-generation cephalosporins for acute uncomplicated cystitis: a nationwide retrospective cohort study

PURPOSE: Oral cephalosporins are frequently prescribed for uncomplicated cystitis. Although cephalexin and cefaclor (first- and second-generation oral cephalosporins) exhibit favorable pharmacokinetic properties, third-generation agents demonstrate lower and more variable bioavailability, potentially resulting in reduced clinical effectiveness. This study compared oral third-generation cephalosporins with cephalexin and cefaclor in treating uncomplicated cystitis. METHODS: We conducted a retrospective cohort study using a nationwide claims database in Japan (2006-2022). We included adult women aged ≥ 18 years who newly received oral third-generation (cefdinir, cefpodoxime proxetil, cefditoren pivoxil, or cefcapene pivoxil) or first-/second-generation cephalosporins (cephalexin or cefaclor) for acute uncomplicated cystitis, with a prescription duration of 5-7 days. The primary outcome was a composite of pyelonephritis diagnosis or additional antibiotic use within 7 days. Secondary outcomes included the individual primary outcome components, all-cause hospitalization, and adverse events. We conducted propensity-score overlap weighting to adjust for possible confounders and stratified analyses by age (< 50 or ≥ 50 years). RESULTS: Among 40,003 eligible patients, 90.7% received third-generation cephalosporins. The proportion of the primary outcome was significantly higher in the third-generation group than in the first-/second-generation group (8.4% vs. 6.5%; risk difference, 1.9%; 95% confidence interval, 1.0%-2.7%). Among the secondary outcomes, additional antibiotic treatment was more frequent in the third-generation group, whereas the proportions of pyelonephritis diagnosis and other outcomes were similar between the groups. Subgroup analyses showed consistent results across age strata. CONCLUSIONS: Oral third-generation cephalosporins may be associated with more frequent additional antibiotic treatment compared with cephalexin or cefaclor in the management of uncomplicated cystitis.