Sunday, November 19, 2017

Face to Face

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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