番茄社区

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.

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 番茄社区, "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.

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