It Takes Two to TANGO With a Carbapenemase

Because of the global rise in antimicrobial resistance, meropenem-vaborbactam, the first carbapenem/β-lactamase combina­tion medication, is a welcome new antibac­terial—it could restore carbapenem’s utility in bacteria with carbapenemases. The vabor­bactam component renders the meropenem useful even against carbapenemase-pro­ducing bacteria.¹

Meropenem-vaborbactam was approved by the US Food and Drug Administration (FDA) for treating compli­cated urinary tract infection in 2017.¹ The TANGO I trial published in JAMA by Kaye et al was a phase 3 multicenter, multinational, randomized, active-control trial that compared treatment with meropenem-vaborbactam to piperacillin-tazobactam in patients with a complicated urinary tract infection (cUTI), including pyelonephritis.²

Patients who met the trial’s eligibility criteria were randomized to receive either 4.5 g of piperacillin-tazobactam or 2-g/2-g meropen­em-vaborbactam intravenously 3 times a day for at least 5 days. After 5 days, patients who met prespecified criteria for improvement were able to switch to an oral fluoroquinolone. The study had a primary FDA endpoint (a composite score of clinical and microbiologic cure) and a European Medicines Agency (EMA) primary end point (primarily microbiologic cure).

Using the FDA primary end point, mero­penem-vaborbactam was statistically superior for treatment of cUTI compared with pipera­cillin-tazobactam (98.4% vs. 94.0%). Using the EMA endpoint, meropenem-vaborbactam was noninferior to piperacillin-tazobactam. In both groups, adverse event rates were high—39% with meropenem-vaborbactam versus 35.5% with piperacillin-tazobactam.

This was a well-designed clinical trial that stayed true to its original protocol. However, the studied indication fills a narrow gap in the literature. Although the results from TANGO I are promising, the question lies in meropen­em-vaborbactam’s utility in other serious infections such as bloodstream infections. The group’s next study, TANGO II, garnered publicity because it was stopped early due to a signif­icant reduction in mortality when meropen­em-vaborbactam was used.³ Tango II was a phase 3, multicenter, randomized, open-label study that compared meropenem-vaborbactam with current best available therapy in patients with known or suspected carbapenem-resis­tant Enterobacteriaceae infections including cUTI, pneumonia, bacteremia, and compli­cated intra-abdominal infection. TANGO II may answer some substantial questions that remain, but TANGO I’s major takeaway is that there is now another viable treatment option for patients with a cUTI, particularly if the pathogen is suspected of being or known to be carbapen­emase-producing.²

References:

1. Cho JC, Zmarlicka MT, Shaeer KM, Pardo J. Meropenem/vaborbactam, the first carbapenem/β-lactamase inhibitor combination [published online March 1, 2018]. Ann Pharmacother. doi: 10.1177/1060028018763288.
2. Kaye KS, Bhowmick T, Metallidis S, et al. 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. JAMA. 2018;319(8):788—799. doi: 10.1001/jama.2018.0438.
3. Kaye KS, Vazquez J, Mathers A, et al. Clinical outcomes of serious infections due to carbapenem-resistant Enterobacteriaceae (CRE) in TANGO II, a phase 3, randomized, multi-national, open-label trial of meropenem-vaborbactam (M-V) versus best available therapy (BAT). Poster presented at: IDWeek; October 4-8, 2017; San Diego, CA. Poster 1862.