Tuesday, May 26, 2020

Back to the Future

I want to return to my favorite topic, antibiotics, viewed through the lens of the covid-19 pandemic. Of course, as is probably true for all of us, my perspective is colored by my own history and experience. I want to share that with you before proceeding further. 

Back when I was working as a microbiologist and infectious diseases specialist at the VA Medical Center in Cleveland, the head of the pulmonary department asked me if I would attend (supervise) on our medical intensive care unit for one month a year. I thought this was because he admired my ability to diagnose infections combined with the fact that I also understood blood gas data. In retrospect, I wonder if it wasn’t that he couldn’t find anyone else to take the job. This was before there was a recognized specialty in critical care medicine in the US (boards were established in 1985). Luckily, I was supported by pulmonologists so that I had backup on decisions involving the proper use of mechanical ventilators among other issues. The work was . . . .intense. Often, on arriving in the morning, I could tell which patients had gotten into trouble the previous night by the number of antibiotic orders written for them. There seemed to be a correlation between the number of antibacterial, antifungal, and, for those truly desperate, antiviral drug prescriptions and the severity of their acute illness. I spent a great deal of time trying to hone the diagnosis of infection, if there was one, and, in the light of day, to “adjust” therapy to something more appropriate. 

The US CDC estimates that about 50% of hospitalized patients receive at least one antibiotic during their hospital stay. A study from New York hospitals treating seriously ill covid-19 patients showed that 89% received antibiotics. A recent review showed that about 8% of patients hospitalized with covid-19 infections had a complicating bacterial or fungal infection during their hospital stay, but that a striking 72% of all hospitalized covid-19 patients received antibacterial or antifungal therapy.  This reminded me of my own ICU experience. Given the numbers of such patients overwhelming our hospitals, this could represent up to a 50% increase in hospital antimicrobial use.

One thing that we know for sure is that the “you use it, you lose it” law of antimicrobial resistance rules. This means that the use of antibiotics, whether appropriate or not, will select for the emergence of resistant pathogens. Therefore, we can expect an increase in bacterial resistance in our hospitals – globally. The CDC recently reported that there about 3 million antibiotic resistant infections occurred every year in the US resulting in 48,000 deaths. Several years ago, the Review on Antimicrobial Resistance (I call it the O’Neill Commission since it was led by Jim O’Neill ex of Goldman-Sachs) estimated that there were 700,000 deaths worldwide annually due to resistant infections.  They predicted that given the trajectory of resistance, by 2050, 10 million lives will be at risk annually along with a $100 trillion-dollar loss to world GDP. No one imagined, I guess, that this might be accelerated by a global pandemic – but here we are. 

This unexpected acceleration of resistance will occur at a time when our 95% of our completely inadequate new antibiotic pipeline is supported by small and fragile biotechs. Will it occur during a time when we have learned at least one key lesson from covid-19 – to invest in our future health? Will we finally realize that we have to support the antibiotic marketplace to prevent further bankruptcies of antibiotic biotechs?  Will we find a way to encourage investment in our antibiotic pipeline again? Or will we ignore the counsel of untold experts and just wait for the next disaster to strike?

Tuesday, May 12, 2020

The Keystone Cops vs. Coronavirus

It sounds like the US Department of Health and Human Services has become completely dysfunctional. The Secretary, Dr. Azar (ex-lobbyist and President of Eli Lilly), apparently can’t get along with his administrator of Medicare, Seema Verma. He led the FDA and CDC (HHS agencies) as they failed to protect the US population because of their disastrous early approach to coronavirus testing. And on and on . . . .

BARDA (an HHS agency) director Rick Bright was transferred to NIH after warning in January about the potential of a pandemic hitting the US and then hesitating to release large supplies of chloroquine and hydroxychloroquine without more evidence that this treatment for coronavirus infection was safe and effective. He accuses the HHS of a disregard for science and for cronyism in the award of BARDA contracts.  He states that his transfer to NIH was retaliation.

Some of the CDC guidelines on dealing with coronavirus defy logic and science. A good example is the guideline on essential workers stating that they should be allowed to work after a known covid exposure unless they are symptomatic.  This in spite of our knowledge that at least 25% of transmissions occur via presymptomatic or asymptomatic individuals. 

The CDC’s most recent detailed guidelines for re-opening the economy were rejected by the administration for being “too prescriptive.” There are guidelines on criteria for re-opening from the CDC posted on the Whitehouse and CDC websites. Many states that are re-opening are ignoring them. 

The federal government planned to screen airport travelers for fever to instill confidence that flying was safe again.  The CDC refused to participate saying the effort required was too costly and that the screening was ineffective anyway. 

The Whitehouse eschewed masks even though they were recommended by the CDC only to reverse course after several positive cases among their staff.  The President and Vice President were, of course, to be excepted from the requirement to wear masks in the West Wing. 

Dr. Deborah Birx, the White House Coronavirus Response Coordinator, recently said that she had no confidence in the coronavirus case and death statistics being provided by the CDC. While she (apparently) was complaining that the numbers were inflated, I (along with many experts) believe that the CDC was significantly undercounting both for lack of testing and because our methods of attributing deaths to the virus are antiquated. 

The NIH recently revoked a grant, renewed under the Trump administration, that supported a research collaboration between a US non-profit called Eco-Health Alliance and laboratory studying bat viruses in Wuhan, China. Apparently, the cancellation of funding was related to a debunked conspiracy theory that the Wuhan lab was the source of the covid-19.  This has been disproven many times over by now. The head of Eco-Health, Peter Daszac, had warned of the coming SARS pandemic back in 2003 and researches the animal origins of human viral infections. His collaboration with the Wuhan lab was key to identifying the anti-coronavirus activity of remdesivir – currently the only specific anti-viral therapy approved by the FDA for treatment of the disease. 

This is a living nightmare.  Who could have imagined what is happening to US science during the worst pandemic since the 1918-1919 influenza? 

If anyone is still optimistic that the US will be funding the incentives that we need to restore our antibiotic pipeline in the near future, just look around you. 


Sunday, May 3, 2020

What Have We Learned?

Those who cannot remember the past are condemned to repeat it. (George Santayana).

Never let a good crisis go to waste. (Churchill?, Emanuel?).

It’s tough to make predictions, especially about the future.  (Y. Berra).

We are still at the beginning of a tragic, horrible pandemic that is both robbing us of lives, of our livelihoods, and disrupting the very fabric of daily life. Sometime, hopefully in the not too distant future, we will need to look at how this tragedy unfolded and come to grips with what we could have done to make it, at least, somewhat less tragic. The fact that several countries and societies were able to escape the worst of the pandemic provides us with opportunities to learn and to act. So does our long history of scientific warnings that just such a thing could occur along with years of guidance on how to prepare – all of which were ignored – for decades.

So, it is with something less than optimism that I try and understand whether we, as a national or even global society, are capable of changing in a way that will alter our approach to public health. The problem I see is not new.  Its old.  Its usually green. And it’s made of paper (and cloth). We need to invest money now to prevent or manage a public health threat that might occur sometime in the future. Our history in this regard is not encouraging. 

My lack of optimism is fed by our recent experience with the problem of emerging antibiotic resistance and our failure to provide the financial incentives required to address this public health threat. Anyone who has been reading this blog for the last several years will be familiar with the issues.  Ditto for anyone who follows John Rex’s publications and blog. Mainstream media even picks up the topic from time to time. But to summarize – bacterial resistance to antibiotics is a growing problem worldwide. While relatively small numbers of patients have infections that are so resistant they are difficult to treat, these numbers are growing.  At the same time, our antibiotic pipeline is dismally inadequate to provide for new therapies for these resistant infections. One major reason for this situation is the fact that there is no real market for new antibiotics because, luckily, the numbers of patients with highly resistant infections are too low to support sufficient revenues from new therapies.  This has discouraged both large pharma and investors from research and development of new antibiotics.  Our meager pipeline today is provided almost entirely by small biotechs.  So far, almost all of those who have successfully developed a new antibiotic active against resistant infections have gone bankrupt (or the equivalent) shortly after commercialization. 

Why do I bring this up in the context of learning from the covid pandemic? Last week the Government Accountability Office released another report on antibiotics and antibiotic resistance. This government watchdog group has written a number of these in the past looking at the FDA and its role in the use of antibiotics in animal husbandry and our lack of ability to adequately monitor antibiotic use in human populations.  The latest report, similar to previous efforts, focused on the federal approach to addressing antibiotic resistance.  They covered a number of areas including surveillance of emerging resistance, the potential role for diagnostics in detecting and treating resistant infections, efforts to improve antibiotic use, and, most importantly for me, the insufficiency of federal efforts to incentivize antibiotic research and development.  For this latter point, they highlighted the need for the very incentives we have been discussing for years – market entry rewards, transferable exclusivity vouchers, or even value-based reimbursements (as an appropriately lower priority). The GAO faults the Department of Health and Human Services essentially for failing to lead and failing to provide a strategy to achieve the needed incentives. The response from HHS - HHS did not concur with the recommendation that it develop a strategy that includes the use of postmarket financial incentives to encourage the development of new treatments for antibiotic-resistant infections, citing its ongoing analysis to understand whether postmarket incentives should be included in such a strategy. This does not inspire confidence since these incentives and the need for such incentives have been the subject of innumerable conferences, reports and peer-reviewed publications. 

Will we have learned that our hospitals must be prepared?  That they must have sufficient surge capacity? Have we learned the potential importance of our Strategic National Stockpile?  Have we learned that the ability to rapidly design and deploy diagnostic testing is critical to success for the next pandemic? Have we learned that early testing and contact tracing is essential to avoiding the kind of mitigation by social distancing that has paralyzed the global economy? 

We can only hope that the recent GAO report and the HHS response will not exemplify our willingness to learn from the covid pandemic. If we do not act, the pronoun “we” is the key.  Our government is, in fact, us. If we do not force our representatives to act, they may well ignore our history and force us to re-live it.