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. 

Viral Cataloging ≠ Pandemic Preparedness

When my Johns Hopkins Center for Health Security colleagues and I were working on our pandemic pathogens project, the report of which has been released, one of the more contentious issues we had to face was separating the task of pandemic preparedness from viral discovery and cataloging. One of the participants in our round table meeting on the topic colorfully referred to viral cataloging as "stamp collecting"! 

On its face, it might seem very reasonable to believe that knowing all the viruses "out there" will by design lead us to new pathogens that have the capacity to cause pandemics, but that is not a foregone conclusion for two main reasons:

1. Most viruses on the planet are innocuous to humans and do not have the capacity to cause damage 
2. While it is most likely that pandemics in the modern age are exclusively the province of viruses, it is possible a non-viral agent could, under certain circumstances and in certain contexts, be the cause of a pandemic

For pandemic preparedness purposes, we proposed focusing on ensuring specific diagnosis and enhanced surveillance of infectious syndromes such as respiratory infections, sepsis, and central nervous system infections in all parts of the world. By focusing on what has unequivocally demonstrated the ability to infect humans -- what would be level 2 and 3 pathogens according to an insightful paper by Woolhouse, the yield of uncovering a potential pandemic pathogen will be much higher. Such activities will have salutary effects on other activities such as antibiotic and antiviral stewardship as well as improving the epidemiology around well-characterized pathogens.

It is undeniable that viral discovery will enormously advance our understanding of virology and is very valuable but it is not synonymous with pandemic preparedness -- it is distinct. 

A new commentary published in Nature by three eminent researchers in the field, Eddie Holmes, Andrew Rambaut, and Kristian Anderson, provides some additional validation for the above conclusion we drew. The piece, entitled "Pandemics: spend on surveillance, not prediction," makes the point that:

“Broad genomic surveys of animal viruses will almost certainly advance our understanding of virus diversity and evolution. In our view, they will be of little practical value when it comes to understanding and mitigating the emergence of disease.”

Pandemic preparedness is a daunting task with many facets and varied approaches. It is only in the modern era with the sharp tools of biology coupled to advances in information and communication technology that we are even able to truly prepare for pandemics. It is essential that these powerful tools be directed at the right task.

Nipah: A Dangerous Virus That Deserves A Lot of Respect

While infectious disease headlines are rightly focusing attention on the current Ebola outbreak in the DRC, those with an eye to how pandemics unfold are watching a less prominent one unfold in India. A Nipah virus outbreak, centered in the Indian state of Kerala, was first reported last month and has killed 17 of the 18 people it has infected -- a horrific fatality rate that hovers around 75%.

Nipah is not an unknown virus as it has been responsible for sporadic deadly outbreaks since the 1990s in countries such as Singapore, Malaysia and Bangladesh. It has also appeared in India before. It is actually a priority virus when it comes to vaccine development. The virus is zoonotic and spills from fruit bats (the natural host) to pigs and humans. Humans can be infected by direct contact with bats, by consuming date palm sap contaminated with bat urine, by pigs, and by other humans. The virus causes flu like symptoms that can progress to a fulminant infection of the brain (encephalitis). There are no standard treatments for it though the antiviral ribavirin may have some positive impact.

When it comes to pandemic pathogens, as my colleagues and I argued in our recently released report, RNA viruses (because of their mutability) and respiratory-borne microbes rise to the top of the list. Nipah is a paramyxovirus and, as such, has an RNA genome. Though early outbreaks of the disease did not revolve around respiratory transmission between humans, subsequent outbreaks have been augmented by human-to-human transmission, especially to those caring for patients who were likely exposed to oral and respiratory secretions known to harbor the virus. It appears that the current Indian outbreak has been enhanced by human-to-human transmission after originating from exposure to bats. 

The major fear is that Nipah might become more efficient at transmitting from human-to-human and cause a large outbreak that spreads to multiple countries (the fictional virus in the movie Contagion was a Nipah-like agent). Such a scenario would rapidly become difficult to contain as there is no vaccine and no standard antiviral regimen. Currently, Nipah transmits only inefficiently between humans (about 1 in 12 pass it on to another human). 

While the not-so-contagious Ebola may grab headlines like no other infectious disease, and this NIpah outbreak has not been deemed a global threat, ultimately, it is viruses with the potential for respiratory spread that merit the most attention. While this outbreak will likely be contained, it underscores the danger of this class of microorganisms, the need to understand their evolution, track their transmission, and to be prepared for their appearance with robust countermeasures.

Condoms as a Instrument of Crime ?!? Law Enforcement Becomes an Instrument of Disease Transmission

When a condom is labeled an "instrument of crime" by law enforcement, law enforcement becomes an instrument of disease transmission. The recent news that police in Allegheny County, in which the city of Pittsburgh is located, are adding charges to the arrests of commercial sex workers if they are found to possess condoms is almost incredible. It illustrates just how backward and misguided the Puritanical war on prostitution is. Such actions compound the injustice that occurs each time consenting adults are arrested for a crime in which there are no victims and no violations of individual rights -- except for the ones violated by the arresting officers. 

To penalize a commercial sex worker for possessing condoms -- a sign of mindfulness regarding risks inherent in the profession -- does nothing except discourage the use of condoms and facilitate the spread of sexually transmitted infections -- an incontrovertible fact. When sexually transmitted infections increase further in the area it will be important to see how much such insane policies as this one contributed. 

The Power of a Cell Line: A Review of The Vaccine Race

When most people think of the challenges of vaccine development, the first thing that enter their mind is the serial passaging of a microbe to weaken it, the search for a microbial protein to prime the immune system, or the large clinical trials needed to show efficacy. What is almost taken for granted, in the modern era, is the ability to find suitable cells to grow the microbe in (for viral vaccines) and produce the vaccine in. The Vaccine Race: Science, Politics, and the Human Costs of Defeating Disease, a new book by Dr. Meredith Wadman, provides an exciting narrative that describes the intricacies of the development of one such cell line that has been employed to vaccinate millions upon millions of humans and contribute to their flourishing.

The chief subject of Wadman's book is Leonard Hayflick, a scientist whose name is familiar to any student of biology as it was his work that demonstrated the limits of cell division -- their "Hayflick Limit" -- as their chromosomal telomeres shortened. However, that is just one thing Hayflick discovered. He is also responsible for identifying Mycoplasma as the cause of "walking pneumonia." However, the main thrust of this book is focused on understanding Hayflick's cell line WI-38, derived from an aborted Swedish fetus, that became the standard research cell line used in vaccines that range from measles to polio to rubella. Such a cell-line, because it was human derived, removed concerned with contamination with viruses such as the infamous tumor-virus SV-40 which was harbored by rhesus and cynomolgus monkey kidney cells. 

In telling this story, which if full of giants such as Hayflick, Stanley Plotkin, Joseph Smadel, and Hilliary Koprowski, the founding and development of the Wistar Institute is also explored in great detail as is the business of scientific research, interactions with pharmaceutical companies, controversial clinical trial design, the intellectual property rights of scientists, and controversies over using vaccines grown in fetal cells.

It is hard to encapsulate all the information contained in this notable book (and there is some controversy -- see Hayflick's list of inaccuracies he identified) but it is required reading for anyone who wants to understand the fight against infectious disease, the history of medicine, and the life-saving role of vaccines.