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New Drug Combo Succeeds in Tx-Resistant UTI, Kidney Infection

— Carbavance outperforms Zosyn in phase III trial

Ƶ MedicalToday

This article is a collaboration between Ƶ and:

NEW ORLEANS -- An investigational antibiotic combination outperformed a standard combination in treating carbapenem-resistant urinary tract infection (UTI) or kidney infection, an investigator reported here.

In a phase III trial, the combination of meropenem and vaborbactam (Carbavance) led to treatment success in 98.4% of patients with either complicated UTIs or acute pyelonephritis caused by carbapenem-resistant enterobacteriaceae (CRE), according to Jeff Loutit, MBChB, of of Parsippany, N.J., which is developing the drug.

Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

The standard combination of piperacillin/tazobactam (Zosyn) led to treatment success at the end of intravenous treatment -- the FDA-mandated endpoint of the study -- in 94% of patients, Loutit said at IDWeek, a joint meeting of the (IDSA), the (SHEA), the (HIVMA), and the (PIDS).

The difference in success rates met a pre-specified benchmark for noninferiority of the investigational combination, Loutit told a late-breaker session, and was also sufficient to establish superiority over the older drugs.

Results were comparable in a key secondary endpoint, the proportion of patients with treatment success at the so-called test-of-cure visit -- at 74.5% and 70.3%, respectively -- but the difference only established noninferiority, Loutit said.

Both combinations include a carbapenem antibiotic -- meropenem and piperacillin -- that is often rendered important by resistance. The addition of the beta-lactamase inhibitors vaborbactam and tazobactam is intended to overcome such resistance.

The novel element in the mix is the investigational beta-lactamase inhibitor vaborbactam, which Loutit said is part of a new class that is especially potent against resistance caused by the Klebsiella pneumonia carbapenemase.

The vaborbactam combination is being developed in a public-private partnership by Loutit's company and the U.S. Department of Health and Human Services' (HHS BARDA).

The findings are good news, commented , of Children's National Health System in Washington, who was not involved in the study but who co-moderated the session at which it was presented.

"We definitely need more drugs against CRE," she told Ƶ, "so I think any additional information is helpful."

But DeBiasi said she was less impressed with the test-of-cure success rates, which were both "similarly not too great. "I think we need other classes of drug that get away completely from the beta-lactamase inhibitors."

The TANGO I trial included 500 patients who were sick enough to require at least 5 days of intravenous therapy. They were randomly assigned, in a double-blind, double-dummy fashion, to get one of the drug combinations.

The study had two primary endpoints -- the FDA's treatment success at the end of therapy and one mandated by the European Medicines Agency that calls for microbiologic eradication of the pathogen involved at the test-of-cure visit in two slightly different subsets of patients.

The endpoints were evaluated first for noninferiority, which would be established if the lower limit of the two sided 95% confidence interval of the treatment difference were greater than minus 15%. Superiority would be established, Loutit said, if the lower limit were greater than zero.

For the European endpoint, the investigational combination succeeded in eradication in 66.7% and 66.3%, depending on which study population was analyzed. The older combination had rates of 57.7% and 60.4%.

In both populations, the treatment differences were enough to establish noninferiority but not superiority, Loutit reported.

The combinations had similar safety profiles, with comparable rates of treatment-emergent adverse events (whether drug-related or not), discontinuations owing to adverse events, serious adverse events, and deaths.

Disclosures

The study was supported by HHS BARDA and the Office of the Assistant Secretary for Preparedness and Response.

Primary Source

IDWeek

Loutit J, et al "Meropenem-Vaborbactam (M-V) compared with Piperacillin-Tazobactam (P/T) in the treatment of adults with complicated urinary tract infections (cUTI), including acute pyelonephritis (AP) in a phase 3 randomized, double blind, double-dummy trial (TANGO I)" IDWeek 2016.