Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection: The TANGO I Randomized Clinical Trial

Abstract

Importance: Meropenem-vaborbactam is a combination carbapenem/beta-lactamase inhibitor and a potential treatment for severe drug-resistant gram-negative infections.

Objective: To evaluate efficacy and adverse events of meropenem-vaborbactam in complicated urinary tract infection (UTI), including acute pyelonephritis.

Design, setting, and participants: Phase 3, multicenter, multinational, randomized clinical trial (TANGO I) conducted November 2014 to April 2016 and enrolling patients (≥18 years) with complicated UTI, stratified by infection type and geographic region.

Interventions: Eligible patients were randomized 1:1 to receive meropenem-vaborbactam (2g/2g over 3 hours; n = 274) or piperacillin-tazobactam (4g/0.5g over 30 minutes; n = 276) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, to complete 10 days of total treatment.

Main outcomes and measures: Primary end point for FDA criteria was overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-to-treat (ITT) population. Primary end point for European Medicines Agency (EMA) criteria was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. Prespecified noninferiority margin was -15%. Because the protocol prespecified superiority testing in the event of noninferiority, 2-sided 95% CIs were calculated.

Results: Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%] women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-tazobactam (difference, 4.5% [95% CI, 0.7% to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenem-vaborbactam vs 105 of 182 (57.7%) with piperacillin-tazobactam (difference, 9.0% [95% CI, -0.9% to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9% [95% CI, -4.2% to 16.0%]; P < .001 for noninferiority). Adverse events were reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-tazobactam.

Conclusions and relevance: Among patients with complicated UTI, including acute pyelonephritis and growth of a baseline pathogen, meropenem-vaborbactam vs piperacillin-tazobactam resulted in a composite outcome of complete resolution or improvement of symptoms along with microbial eradication that met the noninferiority criterion. Further research is needed to understand the spectrum of patients in whom meropenem-vaborbactam offers a clinical advantage.

Trial registration: clinicaltrials.gov Identifier: NCT02166476.

Figure 1.. Flow of Patients in TANGO I Randomized Clinical Trial

MITT indicates modified intent-to-treat. ^aSpecific reasons and numbers for patient inclusion and exclusion not collected. ^bA patient could discontinue study treatment but remain in the study, discontinue study treatment but discontinue study at a later date, or discontinue study treatment and discontinue study at the same time. ^cPatients could have been excluded from microbiologic evaluable population for more than 1 reason. ^dKey inclusion criteria include documented or suspected complicated urinary tract infection (UTI) or acute pyelonephritis and removal/replacement of indwelling catheter before or within 12 hours of randomization. Key exclusion criteria included presence of perinephric abscess; renal corticomedullary abscess; uncomplicated UTI; polycystic kidney disease; chronic vesicoureteral reflux; previous or planned renal transplantation; hemodialysis; previous or planned cystectomy or ileal loop surgery, or known candiduria; presence of suspected/confirmed acute bacterial prostatitis, orchitis, epidymitis, or chronic bacterial prostatitis by history/physical examination; urinary tract surgery 7 days prior to or within randomization; estimated creatinine clearance less than 30 mL/min (Cockcroft-Gault); known nonrenal source of infection within 7 days of randomization; signs of severe sepsis; receipt of antibiotic agent with 48 hours of randomization; presence of immunodeficiency, immunocompromised condition, or immunosuppressive therapy; or neutropenia (less than 1000 polymorphonuclear leukocytes/µL). Detailed inclusion and exclusion criteria are reported in Supplement 1. ^eIf a patient met multiple criteria, the patient was counted only once when counting the total number of patients excluded from the clinical evaluable and microbiologic evaluable populations.

Figure 2.. Primary and Secondary Study End Points

For microbiologic outcome, eradication was defined as baseline bacterial pathogens reduced to less than 10⁴ colony-forming units (CFU)/mL on urine culture (US Food and Drug Administration [FDA] criteria) or less than 10³ CFU/mL (European Medicines Agency [EMA] criteria) AND negative blood culture for an organism that was identified as a uropathogen (if repeated after positive at baseline blood culture). In panel A, blue dashed line at x = −15 indicates the noninferiority margin. MITT indicates modified intent-to-treat; SIRS, systemic inflammatory response syndrome; UTI, urinary tract infection. ^aAt end of intravenous treatment, overall success represents patients with clinical cure or improvement and microbial eradication. At test of cure, overall success represents patients with clinical cure and microbial eradication. ^bThe microbiologic MITT population included all patients in the MITT population with bacterial pathogens of 10⁵ CFU/mL or greater in the baseline urine culture or the same bacterial pathogen present in concurrent blood and urine cultures. ^cIncludes urinary catheter or removable kidney stones. ^dAt end of intravenous treatment, clinical cure represents patients with complete resolution or significant improvement of baseline signs and symptoms of complicated UTI or acute pyelonephritis.

Figure 3.. Overall Success at End of Intravenous Treatment, by Subgroup (Microbiologic Modified Intent-to-Treat Analysis)

SI conversion factor: To convert creatinine clearance values to mL/s/m², multiply by 0.0167. ^aNumbers of patients too small to permit calculation of 95% CIs. ^bUsed to categorize comorbidities of patients based on the International Classification of Diseases diagnosis codes. Each comorbidity category has an associated weight ranging from 1 to 6, based on the adjusted risk of mortality or resource use. The sum of all the weights results in a comorbidity score. A higher score indicates a higher likelihood that the predicted outcome will result in mortality or higher resource use.