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.

A Philosopher Looks at Antibiotic Resistance

The antibiotic crisis and its cascading impact is a well-characterized seemingly insoluble infectious disease problem. There is a large context of factors that impact antibiotic and exacerbate the problem which include: the ever present threat of evolved resistance and consequent antibiotic stewardship concerns, the low relative price of antibiotics (versus more lucrative pharmaceutical products), the outrage that accompanies any attempt to raise the price of an antimicrobial, the fact that one individual’s (or animal’s) use of an antibiotic can impact another individual’s future use, and the general societal undervaluing of infectious disease control, prevention, and treatment.

In recent years, one of the biggest legislative effort to incentivize antibiotic development has been The GAIN Act, which is “pull” incentive that provides an additional 5 years of market exclusivity for certain qualified infectious disease products (QIDPs) that is stacked upon other market exclusivity that may exist because of its novel chemical nature, its applicability to pediatric patients, or its niche in treating a rare (orphan) disease. Importantly this market exclusivity is not intellectual property based, but instead results from the FDA not allowing any generic versions to be marketed for that period of time. Other pull initiatives include special technology payments to hospitals that use certain “breakthrough” antibiotics that use them as well as proposals to reimburse hospitals higher for drug-resistant infections and to carve antibiotics out of bundled payments for hospitalization (removing the incentive to use cheaper antibiotics when more expensive and more effective ones may be indicated). There are also “push” initiatives that fund early development such as CARB-X.

Given this context, it is clear that there is a real problem to solve — one that is often blamed on markets. Gregory Salmieri — a philosopher and friend of mine dating back to when he was a graduate student at the University of Pittsburgh’s philosophy program — has recently published an innovative and creative solution in the George Mason University Law Review.

In his piece, Salmieri first presents the current situation in a very comprehensive manner addressing legislation and new proposed business models (such as decoupling/delinking revenues from sales volume). Next, he makes a convincing case that antibiotics suffer from a “tragedy of the commons” in which “a resource of immense value” is “being used myopically in a way that destroys existing stocks of the resource” with little “being done to find or develop new stocks of it.”

The proposal Salmieri advances is one premised upon enabling “creators of drugs to profitably exercise their rights over the drugs in a manner that preserves the drugs’ effectiveness over time—ideally into the indefinite future.” By tying patent life explicitly to resistance rates of target organisms to a predetermined threshold (e.g. remaining below 20%), a patent could exist in perpetuity (like a trademark). Such a mechanism incentives the judicious use of the antibiotic in order to preserve its profitability at higher patent-protected prices that could also reflect a premium placed on drugs-of-last resort, increasing return on investment over a longer term horizon.

Salmieri also addresses certain complications including cross resistance to drugs developing and issues related to how other countries steward antibiotics.

I think that this is an excellent paper to read — irrespective of whether you agree with the solution —because it offers a clearly reasoned solution that looks at this problem through a different lens and allows one to better conceptualize a problem that has been looming since the time of Alexander Fleming’s prescient warning. I hope it finds a large audience and sparks the debate it merits.

Why Did the Chicken Cross the Road? To Get Antibiotics : A Review of Big Chicken

One of the most pressing aspect of the antibiotic resistance crisis is the role of antibiotics in agriculture and the link with human infections. This is an aspect of the problem that has received mixed treatment in the past. It was clear that agricultural use of antibiotics was a problem but its impact on human infections was debated, not well known, and not conclusive though all doctors probably could recite the statistic that 80% of antibiotics sold in the US were for used in animals. Many people, myself included, focused heavily on the superbugs stalking our hospitals and ICU and thought almost exclusively about infection control and human antibiotic stewardship.

However, with the publication of Big Chicken: The Incredible Story of How Antibiotics Created Modern Agriculture and Changed the Way the World Eats, I suspect things will change. This book written by, in my opinion, the premier science journalist, Maryn McKenna, is something extraordinary. I read books in this genre continually and I can saw that McKenna’s ability to tell a compelling non-fiction story while weaving together history, politics, science, and medicine in a manner that teaches and leaves the reader completely captivated is unrivalled.

Big Chicken, which published in 2017, is much more than a book on unraveling antibiotic use in chickens, who are fed “routine doses of antibiotics on almost every day of their lives.” It is nothing short than a history of the chicken industry in the US — which breeds “for everything but flavor: for abundance, for consistency, for speed” — and it is only by understanding antibiotic use in that context that one can really grasp the issue. This is the book’s chief value.

The book teems with so much good information that it is impossible to capture in a short blog post. Some highlights include:

• How antibiotics facilitated the transformation of grain into muscle making an “active backyard bird into a fast-growing, slow-moving, docile block of protein”. Slaughter weights of chickens have doubled in the past 70 years and can be achieved in half the time due largely to the use of growth promoting antibiotics, which allowed chickens to become more than just egg-layers to most farmers.

• The story of the McNugget

• The use of antibiotic-laced harpoons to shoot whales!

• The questionable role of a Mississippi Democrat congressman

• The change in culture that sparked companies like Chick-fil-A and Perdue to revaluate antibiotic use

The book also has great anecdotes of disease outbreak investigations — one featuring a young Mike Osterholm — and scientific studies that increasingly linked antibiotic use in animals to huma infections. The book also discusses how policy evolved with respect to this issue.

For anyone interested in a great story that traces the roots of a major scientific/medical problem, I highly recommend this book. For those who work in infectious disease, it is required reading (as are all of Maryn McKenna’s books).

Antibiotic Resistant Infections Kill More than Car Accidents: A Review of Superbugs

I often say that the biggest infectious disease problem humans face is that of antimicrobial resistance. I am not alone in this assessment and today there are myriad books describing  this problem and its many facets. However, a recent book I read on this topic, Superbugs: An Arms Race Against Bacteria, provides a unique lens to view the problem: economics. Below I give a short overview of the prime value I took from this book.

Superbugs is a book that stems from a high level review of antimicrobial resistance commissioned by then UK prime minister David Cameron and is written, not by scientific subject matter experts, but by economists and policymakers (Jim O'Neill, William Hall, and Anthony McDonell).

I think it is not difficult for anyone to see that a drug-resistant infection will be, on average, more expensive to treat than a drug-sensitive one. This cost disparity exists for several reasons that include the expense of switching therapy to a an appropriate regimen, the expense of isolation of patients with drug resistant infections, and the increased severity of illness because time to appropriate antibiotic therapy is delayed. 

The book is divided into two parts that focus, respectively, on the problem and solutions to drug resistance. To me, the chief value of the book is the authors attempt to quantify the problem of antimicrobial resistance because as they note a whole different audience -- beyond the health one -- is more receptive to a quantitative analysis. Several of their estimates are worth noting.

• 1.5 million people die of antimicrobial resistant infections annually (more than die i automobile accidents)
• Total worldwide costs (direct and lost productivity) are approximately $864 billio

The book provides a comprehensive overview of the economic challenges inherent with antibiotics: namely, stewardship programs that diminish revenue from new antibiotics, low prices of antibiotics vs. other pharmaceuticals, and the ability to substitute antibiotics.

One of the most valuable portions of the book, to me, is their discussion of diagnostic tests. Much of inappropriate antibiotic prescribing is done for viral infections. It is thus obvious that by employing diagnostic tests to determine whether a patient's symptoms are caused by a virus or a bacteria and which virus it might be could curtail injudicious antibiotic prescribing (and provide valuable epidemiological information) however they are seldom employed despite their availability. Superbugs delves into the dilemma that has stifled the routine use of diagnostics for infectious disease contrasting it the use of advanced diagnostics tests that are standard of care for cancer. 

Chief amongst these obstacles, as they note and I have experienced first hand, is the hospital siloing of costs. Because a multiplex point-of-care molecular diagnostic test deployed during an office visit for bronchitis is more than the entire cost of the visit plus the inappropriate antibiotic prescription that will likely result, testing is foregone. But economics is not only about the seen, but also the unseen, and taking a wider perspective allows one to realize that the costs of antimicrobial resistance driven by the inappropriate prescribing outweighs the cost of running a diagnostic test. 

The book concludes with policy recommendations to solve what the authors believe to be a tractable problem that are informed by a thorough analysis of the problem that are familiar to those that follow this issue and include increasing awareness, increased R&D, and the inclusion of all relevant parties (including agriculture). 

I recommend Superbugs to those who would like an up-to-date holistic analysis of a pressing public-- and individual -- health threat. 

Don't Finish Your Antibiotics -- They Probably Weren't Necessary

It's a tale as old as time: when you're prescribed a course of antibiotics, finish it no matter if you feel better after a few doses. The implicit rationale behind that maxim was that if one is being prescribed antibiotics, it is because they have been accurately diagnosed with a bacterial infection in which antibiotic treatment will be helpful. 

Every antibiotic one takes has two aspects to its nature. Antibiotics, even narrow spectrum ones, impact not only the offending bacteria but also others who are bystanders. Those bystanders are reduced in population opening up space for more dangerous bacteria as well as putting pressure on bacterial populations to select for and evolve resistance (collateral selection). Broad spectrum antibiotics do this on a larger scale and that's why they should be used only when the clinical situation warrants it (i.e. wide uncertainty about the cause of a patient's symptoms). 

There is a risk benefit calculus that must occur with each dose of an antibiotic. Does the risk of antibiotic resistant bacteria developing and antibiotic side effects occurring outweigh the benefit of the antibiotic. Obviously, in a viral infection the risk strongly outweighs the benefit.

The other aspect of this issue is that often antibiotic courses, even when they are needed, are prescribed for arbitrary amounts of time. Courses of 7 days, 10 days, 14 days may have little to no rationale behind them. More and more studies are showing shorter course therapies are optimally effective and there has been a movement to shorten courses of antibiotics as much as possible. A new piece in the British Medical Journal is a tour de force  as is this excellent piece by Brad Spellberg. 

The point is that if an antibiotic is prescribed injudiciously -- as most are -- each unnecessary dose one takes is harmful. Also, each prolonged course of antibiotics that exceeds what is necessary confers unneeded risk. Of course, when a course is appropriately and rationally constructed to ameliorate the infection one should take the prescribed dose so as not to foster recrudescence of the infection with possibly resistant organisms (targeted selection).

Antibiotics are a precious resource that changed the face of medicine and improved human life immeasurably. The threat of antibiotic resistance is one of the most pressing problems medicine faces. Exploding arbitrary dogma to optimize antibiotic use will be essential.