Wednesday, December 21, 2016

Aminoglycosides in the News

The title of this blog almost sounds like an oxymoron.  Aminoglycosides are boring, aren’t they? And they’re old! But with the onward march of antibiotic-resistant infections, could it be that the aminoglycosides are going to become not only news but clinically relevant as well? Well . . . . .maybe.

Achaogen has announced the top line results from their pivotal trials of plazomicin, a (not so) new aminoglycoside with activity against highly resistant Gram-negative pathogens. They ran two trials.  The first was a non-inferiority trail using plazomicin compared to meropenem to treat complicated urinary tract infections. The results are shown here.
Results for FDA pre-specified composite endpoint of clinical cure and microbiological eradication in the microbiological modified intent-to-treat (mMITT) population were as follows:
   Day 5: 88.0% plazomicin vs. 91.4% meropenem (difference -3.4%, 95% CI: -10.0, 3.1%), indicating statistical non-inferiority
   Test-of-Cure: 81.7% plazomicin vs. 70.1% meropenem (difference 11.6%, 95% CI: 2.7, 20.3%), indicating statistical superiority
Results for EMA-specified endpoints of microbiological eradication at the test-of-cure visit were as follows:
   mMITT: 87.4% plazomicin vs. 72.1% meropenem (difference 15.4%, 95% CI: 7.5, 23.2%), indicating statistical superiority
   ME: 90.5% plazomicin vs. 76.6% meropenem (difference 13.9%, 95% CI: 6.3, 21.7%), indicating statistical superiority.
  These data indcaite that plazomicin is at least as effective as meropnem and may even be superior for cUTI. The trial excluded meropenem-resistant pathogens so it is hard to see why this would be so – but the data are the data.

 The other trial that Achaogen ran was the CARE trail that they discussed at the recent FDA workshop that was the subject of a previous blog. The results they reported were from patients with (apparently) known carbapenem-resistant infections treated with either plazomicin + meropenem or tigecycline vs. colistin + meropenem or tigecycline.  Thus it was a comparison of combination therapy where the aminoglycoside plazomicin was used as one part of the combination vs. using colistin. The infections treated were either nosocomial pneumonia or bacteremia. No breakdown as to the source of the bacteremia was reported and in an email response to my questions, Achaogen replied that they were still analyzing the data and had no further information to share as yet. This is a crucial question (see below).  The results are shown below. 

Plazomicin Colistin
28 day all cause mortality 4/17 (23.5%) 10/20 (50%)
or significant complications
28 day all cause mortality 2/17 (11.8%) 8/20 (40%)

Clearly the numbers here are very small. My quick statistical analysis suggests that on the first endpoint there would be a P value of around 0.07 – a clear trend towards superiority of plazomicin.  But on the second endpoint, the P value would be closer to 0.2. Yet these are the kind of data that the regulatory agencies will have to try to interpret as they get into these small and extraordinarily difficult trials. That an aminoglycoside would be superior to colistin is not surprising.  And I’m sure these clinical data will be buttressed by strong PK/PD justifications for the activity of the drug.  Finally, when seen in the light of the large trial in urinary tract infection, the case for plazomicin becomes stronger.

At the same time, Sanofi has announced that they are taking over further progression of Warp Drive’s aminoglycoside program. It seems like 2016 is the year of the aminoglycosides.  What the Warp Drive compounds look like – I have no idea.

The remaining question for clinicians is, do we really need or want new aminoglycosides? Aminoglycosides are useful in the treatment of TB and serious Enterococcal infections - but our current aminoglycosides are probably adequate there. Among Gram-negative infections, one  area where combination therapy with aminoglycosides might be important is in the treatment of Pseudomonas infections in severely immunocompromised patients. Aminoglycosides are clearly effective in cUTI caused by Gram-negative pathogens. Otherwise, the data suggesting that these compounds work as well as other classes of antibiotics in Gram-negative infections remains controversial. I reviewed some of these data in a recent blog. My own clinical experience plus data from several studies where my lab participated suggested that combination therapy of Gram-negative infections with aminoglycosides did not prevent emergence of resistance and did not reduce mortality compared to treatment with beta-lactam antibiotics alone. Yet, in these days of increasing numbers of infections with highly resistant pathogens where colistin is the only available therapy, an active aminoglycoside might be a welcome alternative. Opposing this inclination is the market entry of other beta-lactam antibiotics active against highly resistant pathogens such as Avicaz and others in the late stage pipeline might that make these new aminoglycosides somewhat less relevant. Analysts have estimated a $340 million peak year sales for plazomicin.

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