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.

A Pilgrim, A Saracen, and a Biothreat: A Review of I Am Pilgrim

If you were to get in the mind of someone in the biodefense field and amalgamate every horrible bioterrorist scenario that exists there you might come up with something like that envisaged by Terry Hayes in I Am Pilgrim. This 2013 book expertly weaves together standard espionage and law enforcement motifs with the possibility of bioterrorism. The bioterrorism act contemplated by the antagonist of the novel is no ordinary act, but one that would be positively cataclysmic, but not in an artificial way. The nefarious plan devised by Hayes's villain, known throughout most of the novel as The Saracen, is plucked right from real biosecurity concerns that derive from real scientific knowledge and experiments. In fact, Hayes integrates threats from synthetic biology, vaccine strategies, with weak pharmaceutical supply chains -- all topics of real concern in the field.

The plot of the novel is centered on a retired covert agent called back into action to stop an adversary to whom the "thinking enemy" label so often used in biosecurity discussions is a gross understatement. Overcoming his own personal conflicts, The Pilgrim, an expert forensic investigator, pieces together scattered clues in a methodical manner in order to zero in on his target. Throughout, and this may be the theme Hayes constructed his plot around, family ties between villains, minor characters, the protagonist's allies, and the protagonist are given strong emphasis and shown to be strengths and weaknesses depending on the context. 

I enjoyed, and was entertained, by the book for many reasons that went beyond the biosecurity setting of the novel. It is an exciting read. However, I do take issue with the ability of the protagonist's prowess with synthetic biology which he employs to synthesize a virus from scratch and endow it with vaccine-resistant traits. As has been thoroughly analyzed by Kathleen Vogel such feats are much more involved than just simply following a recipe. Tacit knowledge is not something easily obtained and, in fact, may preclude laboratory feats accomplished in one laboratory from being replicated in another with equivalent technology. That is not to diminish the very real simplification that has occurred in the realm, but science is still hard.

The book is soon to become a film and I am sure I won't be the only one in my profession seeing how biosecurity plays in Hollywood.

Repurposing Drugs to Fight Zika: Putting it into Context

Bursting through the almost continual parade of negative Zika headlines was news that 3 drugs -- one of which (niclosamide) was once FDA approved for another indication have the potential to combat this virus and its severe complications. This study was done in vitro in a laboratory setting and is unequivocally promising. The discoveries center on two drugs with antiviral effects and one which acts as a neuroprotectant. However, as I elaborated on in this interview with Healthday, there several important questions and caveats needed to put this finding in the proper context, two of which I discuss below.

1. In vitro needs to become in vivo: The most obvious next step to be taken with this finding is to see if it holds up--and provides a clinically meaningful benefit--in animal models. Can effective doses be achieved? How robust is the response in an animal model? Do they cross the placenta? Are they safe in pregnancy (at least niclosamide is)? These are the types of questions that would be pursued with an animal model and provide an ability to gauge the feasibility of these drugs as actual treatment options.

2. Concept of Operations: Anytime a new countermeasure is being evaluated for its use in the treatment, prevention, or control of an infectious disease the use case for how it is to optimally used must be part of the discussion. With Zika, an antiviral strategy is difficult for several reasons including, chiefly, the fact that the vast majority of people do not know they are infected and therefore wouldn't be prompted to seek treatment. Secondly, Zika is largely a fleeting virus that comes and goes and in that short process, in certain circumstances, causes fetal harm in pregnant women. Can pharmaceutical intervention occur quickly enough?  Can these compounds make an actual impact on complications? 

If I were to think of a possible concept of operations it would have to center around using these drugs prophylactically to prevent or blunt infection -- if the drugs have that ability in vivo. For only with high drug levels in one's body pre-infection could one have a good chance at preventing the virus from taking hold, spreading to the fetus, or causing other complications like Guillain-Barre Syndrome.

Overall, the repurposing of existing drugs in the face of an emerging infectious disease outbreak is a major effort that provides the fastest path forward to developing new countermeasures. This is especially true if the drug being repurposed has already been FDA approved for another indication such as niclosamide was. When an already approved drug can be used "off label" for a new clinical problem, the burden of funding large clinical trials and complying with FDA regulations is substantially lower.

Until a vaccine is available for Zika, it will be worthwhile to explore potential uses of antiviral therapy but building a concept of operations in which these compounds can be used optimally is essential.

The Red Queen & Pneumococcus

What does Alice in Wonderland have to do with infectious disease? It's not the risk of contracting tularemia from the rabbit but it's a very important quote from the Red Queen. Her statement below to Alice provided the basis for an important hypothesis.

"Now, here, you see, it takes all the running you can do, to keep in the same place."

This statement about Wonderland was taken up evolutionary biologist Leigh Van Halen to formulate the "Red Queen Hypothesis". According to this hypothesis, species constantly evolve to adapt to a world teeming with other evolving species just to keep up and survive, let alone reproduce.

Important evidence that illustrates that the Red Queen Hypothesis is more than a hypothesis was recently published in Clinical Infectious Diseases and revolves around the introduction of pneumococcal vaccines for children. Pneumococcus causes many important infections including those of the ears and sinuses as well as pneumonia. In 2000, the 7-valent version of the pneumococcal (Streptococcus pneumoniae) conjugate vaccine was released and became a universal vaccine recommendation in the US. The 13-valent version supplanted the 7-valent formulation 10 years later (Prevnar). Shortly, thereafter infections from non-vaccine types began to become more frequent, i.e. serotype replacement occurred.

This phenomenon led to discussion focused on whether "Red Queen dynamics" were at play. A new study provides fascinating evidence of the Red Queen's insight at work. In this study, conducted in Utah, specimens from 641 children who were hospitalized with invasive pneumococcal disease (IPD) between 1997 and 2014 were studied.

The results are striking. Not surprisingly, once the vaccines were introduced serotype diversity increased as serotypes that were, pre-vaccine, outcompeted by other serotypes got a chance to cause infection as the big 7 (and the big 13) were rendered obsolete, alone in a world that was too vaccinated for them to flourish.

However, after a period of time, that diversity decreased as certain serotypes began to dominate others and became the main causes of IPD in the post-Prevnar era. What transpired was the establishment of a new evolutionary paradigm in response to changing world conditions that came in the form of potent vaccines that brought about a great culling of the pneumococcal species. Ever resilient, the pneumococcus quickly adapted, on the species levels, to this new normal.

Serotype replacement and Red Queen dynamics make vaccine development a very difficult proposition when there is a pathogen swarm waiting for their turn to wreak havoc.