Today’s blog is inspired by recent grant proposals,
discussions, publications and the promise of our antibacterial pipeline today.
I see many proposals where the concept of a better polymyxin is envisioned or
where the structure of polymyxin is used as a lead to generate a drug that will
attack the bacterial membrane to allow penetration of other, more effective
antibiotics. But my view is that we should relegate polymyxin and its relative,
colistin, to the trash heap of unused drugs – the sooner the better. And I believe that we are near the threshold
of being able to do just that.
My strong feelings come from an experience I had during my
training. I’ve recounted this in both of
the books I’ve written. I was working in a county hospital as an infectious
diseases fellow. The hospital was a
trauma center and had a large burn unit. Burn patients were regular users of
the infectious diseases service. Even
today about 70% of severely burned patients will experience a burn wound
infection and these infections are a common cause of mortality in this group of
patients. I was called to the burn unit to see such a patient with Pseudomonas aeruginosa bacteremia. I
began treatment with carbencillin and gentamicin (you see how long ago this
was). But the next day the lab reported that the isolate was resistant to all
antibiotics tested except colistin. And
they told me that a second patient on the unit was now also growing
Gram-negative rods in blood cultures. In all, we treated maybe six or seven
patients for this infection with colistin.
All but one (as I remember it) died with continuing positive blood
cultures in spite of adequate (above MIC) levels of colistin in plasma
(measured by bioassay). All showed evidence of kidney damage during therapy. I
was never forced to use colistin again because a robust antibiotic pipeline
made that unnecessary for the most part.
For those rare patients where their infections seemed resistant to all available
antibiotics except colistin, since they were all urinary tract infections, I
was able to devise combination therapy to get those patients through their
infection without having to resort to colistin.
Today we now have ceftazidime-avibactam (caz-avi). A recent
prospective observational study of caz-avi demonstrated a 9% mortality in the
caz-avi group vs 32% in the colistin group – a 23% reduction in mortality when
caz-avi was used as compared to colistin. Most infections treated were
pneumonia or bloodstream infections. Renal failure was significantly more
common the the colistin group and overall, there was a 64% chance that caz-avi
treatment would lead to a better outcome compared to colistin.
We are also about to have plazomicin – a new aminoglycoside
antibiotic. In their prospective randomized clinical trials they demonstrated an
all cause 30 day mortality of 11.8% for plazo treated patients vs 40% for those
treated with colistin. The difference in the subset of aptients with
bloodstream infections was even more dramatic in favor of plazo. 11% of plazo treated patients and 29% of
colistin treated patients suffered a serious adverse event related to decreased
kidney function. 
Vabormere (OK – it sounds like a body of water from the
Tolkien novels), a combination of meropenem plus the broad spectrum
beta-lactamase inhibitor vaborbactam, was just approved by the FDA based on
data in the treatment of complicated urinary tract infections where it was non-inferior
to piperacillin-tazobactam. Vabormere
seems to specifically target Gram-negative infections where the pathogen
carries a carbapenem hydrolyzing enzyme of a particular type such as KPC that
is widespread in the US. As a side note, it was approved based on a single
trial and yet its label did not restrict its use to those patients without
other alternatives. Would anyone like to guess whether vabormere will be
superior to colistin in its ongoing trial of treatment of carbapenem-resistant
infections? 
Then there is cefiderocol – a novel cephalosporin antibiotic developed by Shionogi that uses a siderophore to get into Gram-negative bacteria. It has completed a
trial in complicated urinary tract infections where it was non-inferior to
imipenem, a carbapenem antibiotic. In
vitro, the compound is active against many carbapenem resistant strains
including those not covered by caz-avi or vabormere. A competitor for
cefiderocol would be aztreonam-avibactam that seems stuck in early clinical
development. But both of these drugs should also be superior to
colistin/polymyxin.
For now, for most infections, even drug-resistant
infections, there is no reason to use colistin/polymyxin. Over the next year, we will be able to treat
even more resistant infections without using these ineffective and toxic
drugs. The only reason to continue their use is the cost of the new drug
therapies. But when compared to the cost
of kidney failure and mortality, what are we talking about?
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