The Antibiotic Era: Required Reading

In the last few weeks antimicrobial resistance has been in the headlines with a frequency that has rarely been seen. The likely explanation is the unprecedented high level meeting convened by the United Nations that focused the world's attention on this public health crisis. To many, antimicrobial resistance seems to be a strictly modern problem with solutions only recently proffered. However, that is far from the truth and Harvard's Dr. Scott Podolsky's latest book The Antibiotic Era: Reform, Resistance, and the Pursuit of a Rational Therapeutics provides a comprehensive historical overview of a medical community grappling with a nascent technology that transformed medicine, the pharmaceutical industry, and the FDA.

This book, which should be required reading for anyone in the field, is the result of meticulous research that not only shows how antibiotics rippled through medicine but also how the entire medical subspecialty of infectious disease developed. The book is full of legendary figures in infectious disease such as Max Finland, Harry Dowling, Ed Kass and many others. 

One of the most valuable aspects of the book, to me, is that I know have a better understanding of how my field developed. I often wonder how physicians, who were once deluged with infections, lost their expertise and the need for a sub-specialty occurred. As Podolosky illustrates, in the post WWII era, civilization caused infectious diseases to recede in the US at the same time scores of new treatments (i.e. antibiotics) were coming to the market and experts who knew the (now rare) bug and the drugs used to treat them were valuable. This scenario culminated in the founding of the Infectious Diseases Society of America in 1963 and subspecialty certification in 1972. 

These early infectious disease physicians were on the vanguard in warning against antibiotic excess, the evolution of resistance, bacterial vs. viral diagnostic dilemmas, and the lure of shotgun empirical treatment approaches to cover all possibilities. Also detailed was the chasm between academic and community medicine ("town vs. gown", which still exists today) in which academic medical centers are ably equipped to use antibiotics judiciously but community hospitals are woefully behind. 

The book has many pearls of historical insight that are too numerous to list. A few of my favorite quotes I think will be sufficient to close with:

The “end” of antibiotics was envisioned almost from the beginning.

Patients are not born into this world with the view that antibiotics are required for common colds. It is learned from their friends who learned it from their doctors when they went, and so forth.

The Philosophy of Microbiology

I like to approach infectious disease and the related field of microbiological from a philosophical perspective by paying special attention to the guiding principles of the science, its axioms, and the standards of inference.  This may make me an odd type of physician, but, to me, it makes the field much more rewarding, fun, intellectually stimulating, and never boring.

Infectious disease and microbiology, like all fields of science and medicine, have an underlying philosophical approach. This approach, in many ways, is decidedly Aristotelian with the evidence of the senses, reason, logic, and valid inductive methodology at their centers. This philosophical framework is relied upon implicitly by practitioners  and seldom is made explicit or discussed in clinical settings.

In my own practice, I have thought a lot about the philosophy of infectious disease medicine and tried to be very mindful of the underlying rationale for the decisions I make when treating patients. When teaching students I overtly devote time to these topics. I was, therefore, excited to read a fascinating new paper from University of Bordeaux philosopher Maureen O'Malley entitled "Microbiology, philosophy and education."

This important paper explores the philosophical issues that are active in the field of microbiology. For example, O'Malley delves into such historical issues that arose with the first intimations of a microbial world such as whether, since dependent on microscopes, observations of microbes were just a technological artifact rather than the observation of actual entities. She also explores the  classification problems posed by the changing microbiological morphology of the same organism and how pure culture techniques helped solve that problem.

O'Malley also juxtaposes the Humean view of causality in which actual causes are discarded in favor of mere regular observances with the Aristotelian view of causes where the nature of entities that are 'difference makers' is responsible for the causal effect. This struggle between Humean correlation and Aristotelian causation is very active today in research involving the microbiome, for example. The transition the Zika virus made from association with microcephaly to definitive cause is another important example. 

O'Malley, who also wrote a book on this topic I am looking forward to reading, makes an argument in this paper that I agree with: that highlighting the philosophical aspects of microbiology works as, in her words, "glue to connect different aspects of microbiology."

Corruption in the Time of Ebola: A Review of Amy Maxmen's Ebola's Unpaid Heroes

Though Ebola has largely slipped from the headlines in favor of Zika, the infectious disease du jour, there is still much to learn from history's largest outbreak of this deadly disease. Currently, all three of the major countries that the virus ravaged are free from transmission and it will be vitally important for their surveillance systems to be vigilant for any recrudescence that may occur.

Several books have been written on the outbreak by now and I am sure many more will be written. The latest that I have read is a small book by Newsweek's Amy Maxmen entitled Ebola's unpaid heroes: How billions in aid skipped those at the frontline.

In this book Maxmen takes the reader through the experience of healthcare workers dealing with Ebola in Sierra Leone. In the midst of widespread death, chaos, and societal unrest she details these workers struggles to be paid for the work they were heroically performing. Not only were these individuals not being paid the hazard pay they were due but overt fraud was occurring. As Maxmen writes:

Yet almost immediately, the World Bank— a far larger contributor of funds— noticed signs of corruption in Sierra Leone’s health system. When they looked at the pay lists of frontline staff created by officials in the Ministry of Health, they discovered “ghostworkers”— aliases, family members, and mistakes in enumeration— all of which meant certain people might be collecting more money than they deserved.

This scenario caused the World Bank to innovate and use electronic payments directly to workers. The use of text messaging in the process led to the system becoming known as "mobile-money". Such a process stopped skimming by corrupt local officials.

I recommend this short book to all who are interested in Ebola, global health, and international funding mechanisms. That corruption exists and money vanishes before it reaches its intended target was something I knew occurred with regularity but I never really understand the mechanics of how it happens. Ms. Maxmen's work concretizes how, during what was an existential crisis caused by a parasitical virus, certain parasitical looting humans--in a nation in which individual rights and the rule of law are empty concepts--made the battle much more difficult. 

Eight is Not Enough: New Antibiotics Since 2010

A fascinating paper in the Annals of Internal Medicine, fittingly published in the lead up to the UN's High Level Meeting on Antimicrobial Resistance, is devoted to understanding how the fight against the pantheon of drug-resistant bacteria has went over the last 10 years. The scorecard being used is the number of antibiotics that the FDA approved between 2010-2015. 

That number is 8. 

While that number may seem to paint a rosy picture for our fight against superbugs, it really is not. While some members of the 8 have clearly had a major impact on the treatment of high priority drug resistant infections (e.g. ceftolozane-tazobactam, ceftazidime-avibactim, and bedaquiline), some have a limited role.

The summary statistics that are provided for the 8 provide important insight:

• 6 were developed outside of large pharmaceutical companies and now 7 are marketed by one of three major companies
• Only 1 drug showed superiority (as opposed to non-inferiority)
• The median time spent in clinical development was 6.2 years
• 7 of the 8 were from established drug classes
• Only 1 is indicated specifically for a drug resistant organism
• 3 of the 8 have activity against the high value targets known as the ESKAPE pathogens

There are a few implications that I draw from this very informative paper.

1. Development of a new class of antibiotic is difficult
2. The prospect of just having a drug indicated for resistant pathogens is one that is not so enticing financially and would require modification of clinical trials to include only those with drug-resistant pathogens
3. Superiority in the absence of trials only using drug-resistant pathogens is difficult to prove as comparator drugs are also highly effective antibiotics

As the world's eyes turn to the fight against antimicrobial resistant bacteria, it is important to know where we stand and this paper provides an important glimpse of the frontlines of the battle.

Rediscovering TB: A Review of Discovering Tuberculosis

The single microbe that kills the most humans in 2016 is not Ebola, not Zika, not brain-eating amoebas. It is not an infection that continually grabs headlines. It is Mycobacterium tuberculosis, a profligate killer that has menaced humans since our appearance on the planet. In 2014, tuberculosis felled 1.5 million humans.

There are many books about very aspects of tuberculosis that I have read but none of them have really attempted, in my recollection, to tell the story of tuberculosis with an aim to make the history of our species' battles with disease relevant to the present. That lack of present-centrism is no more with UVA History professor Christian McMillen's Discovering Tuberculosis: A Global History 1900 to the Present.

Discovering Tuberculosis is a scholarly work that takes the reader through several important phases in the control of tuberculosis with attention to the principles at play in each of them. From efforts to control TB on Native American reservations to the global fight against HIV/TB coinfection, McMillen skillfully makes the past not just come alive but completely inform how we presently face this infection.

Some important highlights of the book include the failure of the BCG vaccine and how this vaccine may have stymied vaccine development more generally; the early harbingers of the threat of drug resistant TB in 1960s Kenya; the vicissitudes of the approach to HIV/TB coinfection, and the not often mentioned negative effects of directly observed therapy.

One of the most important aspects of this book is that it relies on Professor McMillen's extensive review of the actual communications between programmatic leaders and health agencies. Such a level of granularity grounds his analysis in the actual medical debates that were occurring, allowing almost direct application to current efforts.

Discovering Tuberculosis allowed me to gain a better understanding of today's global anti-tuberculosis effort and grasp how difficult it will be to rid our race of its most astute infectious disease killer. I highly recommend it.