BACKGROUND:The relative efficacy of antibiotic classes for pyelonephritis and complicated UTI (cUTI) remains unclear, as different antibiotic classes vary in antimicrobial activity, pharmacodynamics and pharmacokinetics.
METHODS:Systematic review and meta-analysis. We searched PubMed, Cochrane CENTRAL, clinical-trial registries and conference abstracts through 30 November 2025. Randomised controlled trials comparing antibiotic classes in adults with pyelonephritis/complicated UTI (cUTI) were eligible (PROSPERO CRD42023448020). Five comparisons were analysed: quinolones vs β-lactams, cephalosporins vs penicillins, aminoglycosides vs quinolones or beta-lactams, trimethoprim-sulfamethoxazole vs quinolones or beta-lactams and ESBL-active agents vs non-ESBL-active antibiotics. The primary outcome was clinical cure by day 7. We compiled risk ratios (RRs) with 95% confidence intervals (CI) using fixed-effect meta-analyses. Risk of bias was assessed with ROB 2.0 and evidence certainty using GRADE.
RESULTS:Thirty-seven RCTs were included, comprising 7,904 mainly hospitalized participants (62.7% women). Most had some risk-of-bias concerns. No significant difference in clinical cure was observed with moderate evidence certainty, across all comparisons. Relapse increased significantly with TMP/SMX compared to quinolones or beta-lactams (RR 2.34 [1.29, 4.24]) and microbiological cure improved with ESBL-active antibiotics (RR 1.07 [1.02, 1.13], very low certainty evidence). TMP/SMX increased adverse events and aminoglycosides increased nephrotoxicity and resistance acquisition.
CONCLUSIONS:Clinical cure was comparable across all comparisons. This supports basing antibiotic selection on local resistance patterns, patient factors and toxicity profiles rather than presumed class superiority.