I’m still stuck on the recent FDA meetings
where pathways to regulatory approval for pathogen-specific antibiotics were
discussed. The example chosen to illustrate the challenges in identifying a
pathway was a fictional drug called X-1 that was entirely specific for Pseudomonas aeruginosa. I suggested a
superiority design trial where patients with a high risk for Pseudomonas infection would be enrolled
and treated with a combination of a carbapenem, X-1 and, if desired, an
aminoglycoside. Controls would include those treated with only the carbapenem
plus (or not) aminoglycoside. As I noted, the centers would have to be those
where there was a rate of carbapenem-resistance among Pseudomonas but not at
such a high level that physicians would feel uncomfortable with empiric
carbapenem therapy. (Globally,
the rate for carbapenem resistance in this organism is in the range of 15-20%
range. In this range, most patients are
still treated empirically with a carbapenem, usually in combination with an
aminoglycoside). In my design, I
suggested that the evaluable population for analysis of superiority would, in
fact, be those with carbapenem-resistant infections.
The response I received was a horrified, “But the
aminoglycoside is an active drug. It
will confound your results. You will
never know what to attribute to X-1 vs. the aminoglycoside!” Some insisted this
would be true even if the aminoglycoside were only administered for the first
few days of therapy. I beg to differ (at least for serious infections outside the urinary tract).
There are a number of studies examining the effect of
aminoglycosides on Pseudomonas aeruginosa
infections. One, from Leibovici
et. al. in Israel. In their
prospective observational study, they were unable to demonstrate an advantage
of adding an aminoglycoside to B-lactam therapy outside of those patients who
were neutropenic and those with bacteremia. But more interesting was that for
patients where the aminoglycoside was the only “appropriate” drug based on
susceptibility testing, patients had a 40-100% higher mortality compared to appropriate
beta-lactam monotherapy.
Another study
looked at bacteremia caused by Pseudomonas
aeruginosa. In this study from Spain, it appeared as though a higher
mortality among those treated “appropriately” was mostly due to those who
received an aminoglycoside as the only active drug.
Several other studies confirm the lack of an advantage for
combination therapy of beta-lactam plus aminoglycoside compared to beta-lactam
alone in treating these infections. Several, like the two I noted here, suggest
that there is a treatment disadvantage when, in fact, an aminoglycoside is the
only active drug in the regimen. These
studies suggest to me that a few days of an aminoglycoside in the design I
suggested would be anything but confounding.
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