The death of polymyxins for KPC producers - parts 2 and 3

I recently posted news from Pittsburgh in which outcomes for patients with KPC producers treated with ceftazidime-avibactam were superior to those in which polymyxins were used. This data was observational, not from an RCT, and so requires confirmation from larger, better designed studies.

This week, results from the TANGO-2 study, were released in which a randomized trial comparing meropenem-vaborbactam with "best available therapy" (BAT) was stopped early by its DSMB because of the risk to patients in the BAT arm.

The press release describing these results can be found here:

http://www.themedicinescompany.com/investors/news/medicines-company-announces-tango-2-trial-meropenem-vaborbactam-formerly-carbavance

Only 72 patients were enrolled, of which 43 had CRE infections. Clinical cure was significantly higher in patients treated with meropenem-vaborbactam. These patients also had lower mortality and lower rates of renal adverse events.

This data has not yet been published, and further details are eagerly awaited. In particular, the number of "BAT" patients treated with polymyxins has not been specified in the press release.

These results echo those of an RCT comparing plazomicin with colistin in which plazomicin use was associated with lower mortality compared to colistin use. 

Details of the trial results are reproduced below:

"The Phase 3 CARE clinical trial compared plazomicin to colistin combination therapy on measures of efficacy and safety in bloodstream infection (BSI) or hospital acquired or ventilator associated bacterial pneumonia (HABP/VABP) due to CRE. Plazomicin demonstrated a lower rate of mortality at Day 28 or serious disease-related complications compared to colistin therapy. Among the 29 patients with BSI included in the microbiological modified intent-to-treat (mMITT) population, the mortality benefit of plazomicin vs. colistin was pronounced (7.1% all-cause mortality in the plazomicin group vs. 40.0% in the colistin group at Day 28, which represents an 82.3% relative reduction) and was maintained through Day 60 (63% reduction in the rate of death through Day 60).

Further analyses highlighted that plazomicin was associated with a higher microbiological response rate compared to colistin and, in terms of key safety outcomes, was associated with a lower incidence and magnitude of serum creatinine increases compared to colistin:

• In patients with BSI, a favorable microbiological response at the test of cure visit of 92.9% was observed in the plazomicin group vs. 53.3% in the colistin group;
• The incidence of serum creatinine increases ≥0.5 mg/dL above baseline at any time on study was 16.7% in the plazomicin group vs. 50.0% in the colistin group (the serum creatinine elevations in the plazomicin arm of Cohort 1 were all <1.0 mg/dL while the majority (6/8) of serum creatinine elevations in the colistin arm were ≥1.0 mg/dL)."

Again, these results have not yet appeared in peer-reviewed literature and so need closer examination.

However, the weight of evidence is certainly in favor of "new antibiotics" for KPC producers and the days of polymyxin use for KPC are clearly numbered.

Disclosure: I have participated on an advisory board for Achaogen, the manufacturer of plazomicin.