Clinical Symptom Resolution Following PCR-Guided vs. Culture and Susceptibility-Guided Management of Complicated UTI: How Time-To-Antibiotic Start and Antibiotic Appropriateness Mediate the Benefit of Multiplex PCR—An Ad Hoc Analysis of NCT06996301

Background: Rapid multiplex PCR assays promise faster and broader detection of uropathogens and resistance markers than conventional quantitative urine culture and susceptibility testing (C treating investigators received and acted on randomized results from one diagnostic modality and remained blinded to the comparator. The modified intention-to-treat (Mod-ITT) cohort at end-of-study (EOS) included 362 participants (PCR n = 193; C IQR 12–36) than in the C IQR 30–66; p < 0. 001). Antibiotic appropriateness was higher after PCR-guided care (161/193; 83. 4%) versus C 62. 1%; p < 0. 001). Complete clinical cure occurred in 143/193 (74. 1%) PCR versus 106/169 (62. 7%) C partial cure in 161/193 (83. 4%) versus 121/169 (71. 6%; p = 0. 014). In a total-effect mixed model (no mediators), PCR assignment was associated with higher odds of cure (adjusted OR 1. 95; 95% CI 1. 12–3. 39; p = 0. 018). In the mechanistic model including mediators, antibiotic appropriateness (OR 2. 48; 95% CI 1. 45–4. 24; p = 0. 001), and time-to-antibiotic (per 1 h, OR 0. 95; 95% CI 0. 926–0. 975; p < 0. 001) were independently predictive, while the direct arm effect was attenuated (OR 1. 10; 95% CI 0. 33–3. 71). Mediation analysis estimated a statistically significant combined indirect effect (ACME) of 0. 0648 (95% CI 0. 0343–0. 0977), ADE 0. 0207 (95% CI −0. 0282–0. 0784), total effect 0. 0796 (95% CI 0. 0419–0. 1225), and proportion mediated ≈ 74%. Both time-to-antibiotic and appropriateness contributed, with ACMEₜime ≈ 0. 046 and ACMEₐppropriateness ≈ 0. 019. Exploratory analysis using partial cure as the outcome confirmed the robustness and internal validity of the complete-cure findings. Conclusions: In this ad hoc analysis of a randomized trial, PCR-guided management of cUTI improved patient-centered symptom outcomes compared with culture-guided care. Most of the benefit was mediated through faster initiation of antibiotics and, to a lesser extent, increased probability of an appropriate initial antibiotic. These results support stewardship-integrated, rapid molecular diagnostics (used alongside culture) to shorten time-to-effective therapy and improve clinical outcomes in cUTI.