MedicalResearch.com Interview with:
Keith S. Kaye, MD, MPH
Professor of Medicine, Division of Infectious Diseases
University of Michigan Medical School
Ann Arbor MI
MedicalResearch.com: What is the background for this study?
Response: Complicated complicated urinary tract infections (cUTI), including acute pyelonephritis, are a major cause of hospital admissions, and are associated with significant morbidity and mortality and can be difficult to treat. While the most common pathogen is Escherichia coli, the more problematic pathogens are multidrug-resistant (MDR) gram-negative organisms including other Enterobacteriaceae species. The prevalence of cUTI due to MDR gram-negative bacteria has risen. In some instances, MDR gram-negative bacteria isolated from the urinary tract can cause bacteremia.
Vabomere was approved by the U.S. Food and Drug Administration (FDA) in August 2017 for the treatment of adult patients with cUTI, including pyelonephritis, caused by designated susceptible Enterobacteriaceae: Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae species complex. Vabomere is a fixed-dose (2g/2g) combination product of a carbapenem and a β-lactamase inhibitor with potent in vitro activity against Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae (CRE), an important MDR organism associated with serious infections.
The Targeting Antibiotic Non-susceptible Gram-negative Organisms (TANGO I) trial was the pivotal Phase 3 study that compared the efficacy and safety of Vabomere to piperacillin-tazobactam in the treatment of patients with cUTI and acute pyelonephritis.
MedicalResearch.com: What are the main findings?
Response: The results of TANGO I demonstrated that VABOMERE was non-inferior to piperacillin-tazobactam with overall success in 98.4% of treated patients compared with 94.0% following treatment with piperacillin-tazobactam (p<0.001 for noninferiority) using the FDA primary endpoint of clinical cure plus microbiological eradication at the end of IV treatment. The study also met the European Medicines Association endpoint by demonstrating 66.7% microbial eradication at the test of cure visit following VABOMERE treatment compared with 57.7% following piperacillin-tazobactam treatment (p<0.001 for noninferiority).
In TANGO I, the incidence of adverse events (AEs) and severe AEs was similar in the VABOMERE and piperacillin-tazobactam groups. The most frequent AEs (greater than 2%) reported in this study included headache (8.8% VABOMERE vs 4.4% piperacillin- tazobactam), diarrhea (3.3% vs 4.4%), vaginal infection (0.4% vs 2.2%), and infusion site phlebitis (2.2% vs 0.7%). Additionally, there were fewer discontinuations due to AEs with VABOMERE vs piperacillin/tazobactam (2.9% vs. 5.1%, respectively).
MedicalResearch.com: What should readers take away from your report?
Response: In this study that compared the efficacy and safety of Vabomere to piperacillin-tazobactam in the treatment of patients with cUTI and acute pyelonephritis Vabomere demonstrated a greater numerical overall success rate vs piperacillin-tazobactam. Additionally, its safety profile was comparable to piperacillin-tazobactam.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Further research is needed to understand the spectrum of patients in whom Vabomere offers a clinical advantage. A major advantage of meropenem-vabomere is its activity against CRE, in particular, KPC-producing enterobacteriaceae. TANGO-I excluded patients with infections due to CRE. However, TANGO-2 is a study that specifically targeted inclusion of patients with infections due to CRE, comparing merorpnem-vaborbactam to best available therapy. Preliminary results presented at IDWeek were very favorable. The final results have not yet been published, but hopefully will be published soon.
MedicalResearch.com: Is there anything else you would like to add?
Response: Complicated UTIs, especially those caused by CRE Infections, can be extremely difficult to treat due in part, to a lack of effective therapeutic options. It is important that products such as Vabomere continue to be developed and brought to market help address the growing challenge of treating infections due to resistant Gram-negative bacteria. It is also critically important that newer antibiotics, such as meropenem-vabomere is only used when indicated, so as to limit the likelihood of emergence of resistance. Vabomere is an important addition to the current armamentarium of antimicrobial agents with activity against KPC producing CRE.
Keith S. Kaye, MD, MPH is professor of internal medicine at the University of Michigan Medical School at Ann Arbor, director of research for the Infectious Diseases division at the University of Michigan and president of the Society for Healthcare Epidemiology of America (SHEA). Dr. Kaye was also the primary investigator of TANGO-I and is the paid consultant for Melinta Therapeutics.
Kaye KS, Bhowmick T, Metallidis S, Bleasdale SC, Sagan OS, Stus V, Vazquez J, Zaitsev V, Bidair M, Chorvat E, Dragoescu PO, Fedosiuk E, Horcajada JP, Murta C, Sarychev Y, Stoev V, Morgan E, Fusaro K, Griffith D, Lomovskaya O, Alexander EL, Loutit J, Dudley MN, Giamarellos-Bourboulis EJ. Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract InfectionThe TANGO I Randomized Clinical Trial. JAMA. 2018;319(8):788–799. doi:10.1001/jama.2018.0438
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