Sunday, November 24, 2019

Antibiotics - Innovation or Clinical Utility?

Lately I have become intrigued with the word, innovation. Innovation is used a criterion for funding grants, for status in reviews of our antibiotic pipeline, for intelligence, imagination and many other great things. I want to explore the meaning and utility of innovation in the particular context of antibiotic discovery and development and of our antibiotic pipeline.

A story I tell frequently comes from my days as a practicing infectious diseases physician at the Cleveland VA Medical Center. In the early 1980s our surgical ICU suffered an outbreak of bacteremia and pneumonia caused by Serratia marcescens resistant to all the antibiotics we tested at the time (colistin was not on that list). But imipenem was undergoing its phase 3 testing and I was able to obtain some under a compassionate use protol that Merck had established. I am sure that we saved lives. But imipenem is really just a B-lactam – albeit a very special one.  Is it innovative? I think so.  But more importantly, its clinical utility was infinite for the care team and our patients. 

To me, innovation stands for imagination, daring, intelligence and the ability to see things beyond what we know and think we understand. To innovate is to navigate to where we have not gone before, and, hopefully, to see a way to get there. So, yes, innovation can be a good thing. In the context of antibacterial discovery, Theuretzbacher et. al. note that for many, innovation connotes a novel target or novel chemistry or novel mode of action. In the end, Theuretzbacher et. al. end up defining innovation as simply meaning that the therapy shares no cross resistance with existing therapies. 

I would like to introduce a more useful concept – clinical utility. Clinical utility clearly would include a lack of cross-resistance, but also may include other advantages.  A new therapy might avoid the need for monitoring drug levels, it might be more safe than existing treatments, it might reduce the numbers of doses required, it might be orally bioavailable, or it might avoid the need for new, experimental diagnostic tests. All of these speak to the utility of any new therapy to the physicians who prescribe it and the patients they treat. 

In my world, innovation also means risk. And risk in the pursuit of new and important therapies is fine as long as everyone understands that this is the case. Therapies directed at novel targets, those that use novel chemistry and those that exploit new modes of action all are subject to increased risk.  The risks include the risk of scientific failure early in the discovery process, the risk of failure from non-clinical safety studies and the risk of clinical failure either because of safety or efficacy issues. 

On the other hand, the use of known targets, known chemistries and known modes of action reduces risk. Sometimes, this lack of “innovation” might also lead to a lack of clinical utility.  But, historically, while this does occur, there have been many very useful but not so innovative therapies to come forward over the last several decades. The B-lactamase inhibitors recently introduced to market (avibactam, vaborbactam) have a much broader spectrum of inhibition than their predecessors. They are innovative in that they utilize new chemistries to achieve their improved spectrum. Of greater importance to me, they have increased clinical utility based on this broad spectrum of activity and still avoid most cross-resistance. A major addition to our clinical armamentarium will be aztreonam-avibactam that will have activity against Class B B-lactamases, a group of enzymes that have so far eluded the BLI-BLA strategy. At this point, one could argue that this combination is not so novel or innovative and that would be true.  But look at how clinically useful it might be. Another pipeline combination that achieves this goal is VNRX5133-cefepime from VenatoRx. In this case, the inhibitor is still based on boron chemistry like vaborbactam, but is able to assume different binding modes to inhibit class A and B B-lactamases – an innovative mode of action.

When I look at drug discovery and development plans and proposals, although I consider “innovation,” what I truly evaluate and value is potential clinical utility. These two characteristics do not always go together. I suggest that we all prioritize providing better (but not necessarily innovative) therapies to our patients with unmet medical needs as our ultimate goal.

Wednesday, November 20, 2019

The CDC's Report on Antibiotic Resistant Threats in the US

This is Antibiotic Awareness week. The US Centers for Disease Control just released their new report, Antibiotic Resistant Threats in the United States, 2019. They used “new” methodologies to both retrospectively reconstruct their 2013 report and to carry out the studies used for the 2019 report.  In that way, the numbers are directly comparable. This report is extremely valuable and I recommend it as required reading for everyone interested in infectious diseases and antibiotics. 

While this new report is very welcome and while I (and everyone else) appreciate(s) all the efforts by the CDC to address resistance, there are still limits to the report and areas that I would have liked them to address differently. First, the numbers cited by the CDC must be considered an underestimate since they are derived almost exclusively from hospital data.  There are probably many infections arising in the community that do not present to acute care hospitals including those in long term care facilities. Second, I would have preferred that the CDC emphasize more that in spite of all of our efforts, no matter how successful, at antimicrobial stewardship and infection control, resistance will still emerge and we will still need to rely on new antibiotics to control these resistant infections. As such, additional discussion as to the factors combining to deprive us of these needed new antibiotics and suggested approaches to resolving this dilemma would have been helpful.

If you add the numbers for C. difficile infections to those for other resistant infections together, the CDC reports that there are ~ 3 million such infections per year in the US.  These are associated with almost 48,000 deaths every year.  These deaths approach that endured by the US military for the entire Vietnam war (58,000) and are greater than the numbers of Americans killed in traffic accidents every year (37,000).  The CDC provides data for certain resistant infections (see report) showing that they place an important economic burden on US healthcare. The CDC appropriately notes that antibiotic resistance threatens our ability to provide adequate care for surgery, chronic conditions like diabetes, organ transplant recipients, kidney dialysis patients and those with cancer.

In its report, the CDC emphasizes that they are leading the fight against resistance and, in some cases, we are making progress. For example, infections caused by carbapenem-resistant Acinetobacter have decreased since 2013.  But infections caused by carbapenem resistant and ESBL Enterobacteriaceae have increased.  In long term care, C. difficile infections may be decreasing, but we have not yet seen that in US hospitals. 

While the CDC emphasizes approaches like vaccination, infection control, antibiotic stewardship in hospitals, in the community and on our farms, and while they note that antibiotic resistance is a one health problem, they shy away from the economics of antibiotics. They do not deal with the important role that expert societies can play in guidance on all of these issues, but, importantly, a discussion of their role in assuring appropriate therapy is not really explored. 

The report outlines some of the difficulties in the development of antibiotics and diagnostics and it also decries the poor pipeline for many of the resistant infections considered as threats in the report. They believe that there is not enough “innovation” in the pipeline. 

In terms of innovation, I note that the WHO and others also see this as a problem in the antibiotic pipeline.  I strongly disagree with the concept that innovation is the most important criterion by which to judge the pipeline.  The most important criterion should be clinical utility.  Does the compound address resistant infections?  Is it safe?  Does it offer dosing or other advantages over other available therapies? (This will be the subject of a subsequent blog).

One area that CDC ignores is the economic barriers to the study and marketing of new antibiotics. The report sticks with the steps that we should all be taking to preserve the antibiotics that we have as long as possible.  And I agree that this is an important effort that we all should support. But, if the CDC leads the fight against resistance, they can hardly step back from dealing with the single major impediment to providing the robust pipeline they so clearly desire. To me, this is a singular omission in this otherwise complete and important document.