Background: Treatment of complicated urinary tract infections (cUTI), including acute pyelonephritis (AP) due to multi-drug resistant (MDR) Gram-negative uropathogens (e.g., extended-spectrum ß-lactamase (ESBL)-producing and fluoroquinolone-resistant strains) is associated with poor outcomes and increase costs of care. In the setting of limited alternative oral options, patients with cUTI/AP are commonly hospitalized to receive intravenous (IV) antibiotic therapy. Co-resistance also presents challenges in transitioning clinically stable patients from IV to oral antibiotics to facilitate discharge. Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is a novel, orally bioavailable carbapenem antibiotic in development for the treatment of cUTI/AP. The recently completed ADAPT-PO trial demonstrated the non-inferiority of oral TBP-PI-HBr versus IV ertapenem in patients with cUTI/AP. We sought to evaluate markers of clinical stability from ADAPT-PO to assess a potential timeframe for possible transition of care to the outpatient setting in hospitalized patients with cUTI or AP.
Methods: ADAPT-PO was a Phase 3, multinational, randomized, double-blind, double-dummy noninferiority trial evaluating the efficacy and safety of oral TBP-PI-HBr vs. IV ertapenem in hospitalized adults with cUTI/AP. Patients were randomized 1:1 to receive oral TBP-PI-HBr 600 mg every 8 hours or IV ertapenem 1 g every 24 hours for a duration of 7-10 days (up to 14 days in patients with bacteremia). In this subgroup analysis, daily measurements of both time to defervescence (temperature ≤38.0°C) and time to resolution or improvement (by ≥1 grade with no worsening) in baseline signs and symptoms (S/Sx) were assessed overall and across various patient characteristics (e.g., age, diagnosis, baseline bacteremia, etc.). Kaplan–Meier curves with a log rank test were utilized to compare treatment groups over time.
Results: Among the 1372 patients randomized, 868 (449, TBP-PI-HBr; 419 ertapenem) were included in the microbiological intent-to-treat (micro-ITT) population. Patient demographics and patient characteristics were well-balanced between treatment arms. In the micro-ITT population, mean time to defervescence in both treatment arms was 2.2 days at which point 65% of patients were afebrile (Figure). The median time to defervescence was 2 days in both treatment groups; no differences were found between groups (p=0.736). The mean time to improvement/resolution of S/Sx from baseline was ~4 days in both treatment groups, 4.1 days (75% of patients) for TBP-PI-HBr and 3.7 (78% of patients) for ertapenem (p=0.044), a difference that was considered non-clinically meaningful. The median time to improvement/resolution of S/Sx was 3 days for both groups.
Conclusions: In this time-to-event analysis from ADAPT-PO, markers of clinical stability appeared similar for patients treated with oral TBP-PI-HBr as compared with IV ertapenem. These indicators of early response to treatment for hospitalized patients with cUTI/AP suggest potential opportunities for early transition of care to the outpatient setting. TBP-PI-HBr may offer a feasible option for patients with limited oral alternatives.