Last week I was honored to give the Philip Lerner Memorial
Lecture at Case Western Reserve University School of Medicine, my alma mater. I
talked about the economics of antibiotics and the broken antibiotic
market. Surprised? But I want to talk to
you today about another aspect of my visit.
I went to their infectious diseases case conference where fellows training
in infectious diseases and attending infectious diseases physicians discuss
difficult cases as a way of educating themselves and to find solutions for
patients.
One case was a patient with a particularly serious lung
infection caused by a carbapenem-resistant Enterobacter
cloacae and a carbapenem-resistant Stenotrophomonas
maltophilia. Aspergilus fumigatus was also identified as part of the mix. By the
time the case conference was meeting, the patient had already passed away from
his underlying disease and this polymicrobic lung infection. But the physicians
present discussed his treatment to show how they were able to piece together a
therapy that at least offered some hope for the patient and his family.
The Enterobacter
was shown not to produce a carbapenemase.
It was in fact, probably a strain with reduced expression of porins
combined with a high level of expression of its chromosomal B-lactamase. It was
susceptible to sulfamethoxazole-trimethoprim (Bactrim) and to
ceftazidime-avibactam. The results for colisitin were not even mentioned. The Stenotrophomonas was typical and was
susceptible to sulfamethoxazole-trimethoprim and to aztreonam. This result is because the carbapenem
resistance in this isolate was caused by the normal, chromosomally encoded
metallo-carbapenemase, L1. Aztreonam is resistant to hydrolysis by L1. The
patient was treated with a combination of ceftazidime-avibactam, aztreonam and
voriconazle (for the Aspergillus), but the family rapidly withdrew therapy
agreeing with their physicians that further therapy would be futile given the
disease underlying this terrible infection.
Even though this patient could not be saved, his physicians
were able to construct a potentially life-saving therapy for him. Without
ceftazidime-avibactam, it is unlikely that other therapies would have even been
effective. Sulfamethoxazole-trimethoprim
has no real track record in the treatment of serious lung infections with
Gram-negative pathogens like those infecting this patient. The other
alternative would have been colistin or polymyxin, which, as we know,
is both toxic and not very efficacious.
Of course, the combination of aztreonam plus
ceftazidime-avibactam, like so many antibiotic combinations we put together for
desperately ill patients, is a construct for which there is no good data. We don’t really know if the dosage chosen
based on current FDA labels for the individual components of this combination
are optimized. But aztreonam-avibactam is in the late stage pipeline and would
have been adequate based on careful PK/PD modeling of the dose being studied. A
PK study in seriously ill hospitalized adults has been completed and an
efficacy trial in such patients is about to start recruiting (finally!!). Lets
get a move on, Pfizer!
The physicians at the case conference asked me a difficult
question. Why, they asked, was
ceftazidime chosen as the partner for avibactam and not aztreonam. In fact, we
struggled with this question back at Novexel because we knew that both drugs
would have been good partners on a scientific basis. We hesitated about
aztreonam mainly because it simply was not used clinically outside the realm of
clinical trials. Its main advantage over ceftazidime, as demonstrated by our
patient, is that it resists hydrolysis by the metallo-B-lactamases such as L1.
At Novexel we thought that these infections were still rare in most areas of
the world and we didn’t know whether they would increase in frequency or
not. So we divised a strategy to develop
both ceftazidime-avibactam and, shortly thereafter, aztreonam-avibactam. In
fact, one of the constant arguments against pursuing aztreonam-avibactam was
that physicians would simply use the very combination utilized for our patient.
We thought that we needed a strong dosage rationale that would optimize therapy
compared to the dosing physicians might randomly choose in administering this
combination for which there is precious little data. Our strategy was ultimately
taken over by AstraZeneca (now at Pfizer) and Forest (now Allergan) and the rest is history.
Without ceftazidime-avibactam, and hopefully in the not too
distant future, aztreonam-avibactam, and other therapies to come, patients and
physicians will be left with few options for patients like this one. There are probably thousands of patients
around the globe with infections like this one where, unlike our case, patients
have a real chance at full recovery from their infection – given that we have
effective antibiotics with which to treat them. Our hope lies in the continuing
availability of new antibiotics (and maybe other antibacterial therapies). That hope is not going to be realized given today’s
paltry pipeline.
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