A Book by Any Other Name Would Be as Sweet a Read: A Review of Superbugs

Of the many books written on the topic of “superbugs” many focus on listing the greatest threats faced by infectious disease physicians, difficult patient anecdotes, warnings, and proposed solutions. The other type of infectious disease books involve exotic locales and explosive outbreaks. The latest book I read is different from these and, in my estimation, is a worthy addition to the shelves or ipads of those who like this topic. Superbugs: The Race to Stop an Epidemic by Cornell infectious disease physician Matt McCarthy is a book ostensibly about a clinical trial but has a lot more of value in it.

McCarthy begins the book’s prologue with a patient anecdote but quickly moves to what I see as the essential focus of the book: the ins and outs of an antibiotic trial. Along with this trial McCarthy peppers in a lot of interesting aspects regarding infectious diseases and the day-to-day of an academic infectious disease physician. Besides himself, the chief protagonist is his mentor, the renowned mycologist Thomas Walsh, and their interactions provide a really enjoyable perk of the narration.

The book does cover the initial development of antibiotics — the stories of Domagk and Fleming — but adds an often neglected aspect: the crucial and undervalued role of pharmaceutical companies. He quotes Tony Fauci to make this point:

You don’t want the federal government to be a pharmaceutical company because you’d have to build an entire industry...If the federal government tried to re-create Merck it would cost billions of dollars. The expertise of production, filling, packaging, and lot consistency. People take that for granted, but that’s an art form that has been perfected by these companies, not the government

He also notes that, contrary to what those who villainize antibiotic manufacturers may say, the net present value (NPV) of an antibiotic is just $42 million compared to the $1 billion for other pharmaceutical products. He later points to another analysis showing the NPV may be negative $50 million.

The focus of McCarthy’s clinical trial is on dalbavancin, an interesting long acting gram positive injectable antibiotic. The drug had a little bit of a tortured history being passed from Pfizer to Durata to Actavis to Allergan (Durata was acquired by Actavis which bought Allergan and kept the name). At that time, Allergan was one of a few remaining major pharmaceutical companies involved in antibiotic development (it has since tried to sell its infectious disease unit). While dalbavancin isn’t a breakthrough antibiotic on par with some others, it has an important niche in treating MRSA infections, avoiding hospitalization, and avoiding the use of long term intravenous lines. The book uses this trial as backdrop to discuss topics such as institutional review boards (IRBs), informed consent, FDA oversight, and patient recruitment. All of this makes for worthwhile reading.

He also discusses fungal infections, which often get short shrift to our detriment, one of the passions of his mentor. He tells of the discovery the first antifungal, nystatin, by two female researchers, which I had never heard before and recounts that it was named for the New York State (NYS) Department of Health. He also covers the emergence of Candida auris and the quest for new treatment options.

I found the book very enjoyable to read and think it is an important contribution because it demonstrates what it is to be an infectious disease physician in the modern era, concretizing the daily battles, the insoluble and endless puzzles, and the exhilarating rush one gets from figuring things out.

Concretizing Influenza Then & Now With the Help of A Mütter Museum Exhibit

This year’s flu season is well into effect though somehow I have yet to diagnose a case myself. This season is marked by an early dominance of influenza B which will be interesting to see, from a virological standpoint, remains sustained. The last time a season was dominated by influenza B was my senior year of high school (I didn’t miss any days). Markers of severity are all below epidemic thresholds.

With this year’s flu season in mind, I recently visited an exhibit that detailed a very cataclysmic event: the 1918 pandemic the Mütter Museum in Philadelphia (maintained by The College of Physicians in Philadelphia) currently has two exhibits devoted to infectious disease. One is entitled Going Viral: Infections Through the Ages. This exhibit importantly takes the viewer through the various explanatory stages for infectious diseases: from the humoral stage to miasmas to the culmination of the germ theory of disease. This progression is really crucial to understanding the history of infectious disease and how science progresses.

The other is Spit Spreads Death, a special project that details the experience of Philadelphia during the 1918 pandemic. Interactive displays demonstrating the spread of the flu, newspaper headlines, photographs , and personal anecdotes are included.

As people forget about how dangerous a virus influenza is, exhibits like these help concretize the power of this infectious disease and are well-worth visiting for both the general public and infectious disease experts alike.

Rage Against The Machine: A Brief Review of Randall's Black Death at the Golden Gate

Several weeks ago news headlines carried stories of a spattering of plague cases in China. To those who follow infectious disease, it was not surprising as parts of Asia is considered the home of plague and cases occur there with regularity. But despite these facts, media headlines invoked the Black Death. The Black Death, which occurred over 500 years ago, was a calamitous outbreak of plague that likely killed one-third of Europe’s population.

The news stories about these latest cases almost universally left out the context of the Black Death — no supportive care, no antibiotics, and malnutrition. They also did not mention that though person-to-person spread of plague involving the lungs — pneumonic — is possible, it is rare (and the cases reported were bubonic which should prompt little in the way of special measures).

While this was all happening, i was in the middle of a new book on the topic of plague entitled Black Death at The Golden Gate: The Race to Save America from the Bubonic Plague. This book, published in 2019, by David Randall tells the story of the turn-of-the-century outbreak of bubonic plague in San Francisco. This subject has been told before in books but Randall’s approach, to me, appeared fresh and full of details that I hadn’t quite recalled from prior reading on the subject.

In brief outline, the story of plague in San Francisco is one that is familiar to anyone who knows the history of infectious disease: a cycle of denial, overreaction, and bureaucratic interference. The backdrop of the events that occurred in San Francisco occurred in the midst of a power struggle between the US Surgeon General Walter Wyman and rising public health luminary Joseph Kinyoun who was exiled to the Angel Island quarantine station. At the time, plague had just raged in Hawaii leading to the literal burning of Honolulu’s Chinatown — an ominous development that Kinyoun did not want to occur in San Francisco

Plague first appeared in San Francisco as a single case in Chinatown prompting a draconian quarantine of the entire region and then, when tests were not fully completed, a reversal and then another quarantine. Randall also details the baffling stories of how plague deaths were hidden from authorities (which including propping dead bodies up to make them look alive). The book details the bureaucratic machinations that Kinyoun faced — including interference from President McKinley and the California governor (Gage) — and ultimately how he was replaced.

In the end, plague established itself in the US after public health measures failed to contain it and the book illustrates how failing to heed the warnings of public health authorities can prove disastrous. I think these themes are timeless and have been repeated countless times in outbreaks small and large from HIV, to hepatitis A, to SARS, to Ebola. I was struck by the lone brilliance of those like Kinyoun who were, instead of being rewarded, were punished for their foresight.

Randall also weaves in a great deal of the history of California, San Francisco, and the Chinese Six Companies into the narrative. He also highlights some of the anti-Chinese immigrant sentiment that permeated area even prior to the outbreak including mayoral candidates campaigning to keep California “white” and threats of violence against those that employed Chinese immigrants.

I highly recommend this book as a great introduction to the history of plague in the modern era but even more so as a great case study of how public health and infectious disease authorities face not only the microbe but often a hostile public and government leadership that must also be navigated with equal precaution.

EEE: Rare, Deadly, and Headline-grabbing

With the recent news that the Eastern Equine Encephalitis (EEE) virus has been identified in Pennsylvania birds, has prompted me to get a few inquiries about this deadly mosquito-borne virus. (Here is a link to a television interview I did on the topic and a print interview is here). A recent summary published in STAT really provides a great primer for what you need to know about EEE and I have little to add to it. However, I wanted to emphasize several points.

1. EEE is a rare infection: Though headlines are announcing what sounds like a lot of EEE cases it is important to remember that it is rare. The average number of cases that occurs is about 7 and this clearly has seen an uptick with 28 cases in 7 states (there are no human cases in Pennsylvania this year — one did occur between 2009-2018) with 8 deaths. When it comes to mosquito borne infections, it is important to remember that West Nile is, by far, more common.

2. Not everyone who acquires the virus will have symptoms. In fact, only about 20% have a flu-like illness and of these, half will develop brain infection. If one develops encephalitis, the fatality rate can reach 33% and those that survive may be left with permanent disability. The mechanism of how EEE evades immune responses to get to the brain is fascinating and involves the silencing of host miRNAs. There is no human vaccine or antiviral treatment.

3. The virus is spread of mosquitoes that thrive in swampy areas and operates in a cycle between birds and mosquitoes. Eastern and Gulf coast states are where human cases are most commonly reported. Horses, for whom there is a vaccine for, can enter this cycle and become infected (the virus was first identified in horses in the 1930s). when other types of mosquitoes, which are less ornithophilic (e.g. Aedes, Culex, Coquillettidia) serve as “bridging vectors”. These mosquitoes can allow the virus to find its way to humans, swine, and other animals such as dogs.

4. In the absence of a vaccine, the best defense against this virus — like other mosquito-borne viruses — is to avoid mosquitoes, wear repellents, wear appropriate clothing, and remove mosquito breeding grounds from one’s property (e.g. standing water).

It is unclear, to me, what is behind the increased incidence this year. Some possibilities include: better detection/awareness, a change in the behavior of the virus causing more encephalitis cases, a change in the behavior of the vector or the bridging vector, or some other explanation. Understanding what is behind this rise will an important task (which the US Senate is interested in). Also, the heightened case burden may spur EEE vaccine development which, thus far, has been pursued virtually exclusively because of the potential for its use as a biological weapon.

The risk of EEE should trigger vigilance, not panic.

5 Questions for DA Henderson 3 Years After His Death

It’s been 3 years since DA Henderson died. As I’ve done each year since, I try to remember this giant of infectious disease and public health by thinking about how much worse off our field is without his towering presence and all the wisdom he so easily imparted. For those that don’t know, DA was the architect of the smallpox eradication campaign — arguably one of mankind’s greatest achievements — and a pioneer in myriad other public health campaigns, the dean of the premier school of public health, and eventually founded what became the Center for Health Security, where I met him and was mentored by him.

One way to acutely concretize the gap in the field, is to pose 10 questions to DA about current infectious diseases problems and try and ask yourself “What would DA do?” Here are 5 I came up with for this year:

1. How would you manage the current Ebola outbreak? This outbreak, the 2nd largest in history, is particularly challenging not because the virus has changed but because of the security situation and distrust of health authorities has made control impossible, despite the use of a very effective vaccine. I remember during 2014, how we offered the idea of focusing on the most contagious individuals — those with severe symptoms, emanating body fluids. However, in this outbreak some of the cases are not showing up at treatment centers (where experimental treatments are seeing great success) and a shadow outbreak is occurring. What would you do? Get aggressive like with smallpox eradication, finding the cases and treating them.

2. What do you think about the US on the cusp of losing its measles elimination status? This one is embarrassing and I suspect you would be furious as all the hard work you did in building expanding programs for immunization is being squandered. When elimination status passes, what do we do next? Should the US try to eliminate it again or is the anti-vaccine movement to strong and our voices in favor of vaccines too weak to win back the country from measles?

3. Is polio eradication feasible any longer? I know this is something that you had strong opinions on — when didn’t you have a strong opinion? — and things have only gotten worse. Wild polio is still spreading in Afghanistan and Pakistan with numbers increased this year over last. It doesn’t seem like the Taliban is every going to be in support of this program which is costing more and more money. People are still chasing vaccine-derived polio — something which you convinced me should be a separate task from wild polio.

4. How would you gauge recent activities with Russia and North Korea? Your prescient warnings about biological weapons and the expertise you leveraged to build US biosecurity programs are unmatched. You debriefing Soviet defectors and changed the way the world approached this threat. Now, we face belligerent actions with Russia using Novichok agents on British soil (a word that was classified when you were alive) and North Korea using VX in plain daylight. Syria has employed chemical weapons in war as. This use of chemical weapons so brazenly likely means that biological weapons are not necessarily a taboo for state-actors and indeed there are reports of increased interest in their use. What should we do to prepare? How would you augment activities??

5. Is HIV transmission elimination possible in the US? You worked on the early days of HIV when it was an incurable death sentence and saw it become an eminently treatable infection. Now with the concepts of U=U and PrEP, there is the prospect of halting transmission. How would you direct this program? Right now, it appears the HIV epidemic in the US is non-homogenous with certain counties accounting for the majority of new transmission. Would this be the thrust of the best approach ? How do we increase PrEP use? Make it over the counter?

These were just a selection of 5 questions I would desperately want to know DA’s thoughts on. It’s been 3 years since I could just walk several feet to his office, gaze at all his presidential citations and awards, and see that giant sitting there eagerly answering question after question that occurred to me.

His portrait looms large at the Center, but his spirit looms even larger.