MERS as (another) messenger of prevention

It's hard for me to know how to interpret the MERS situation in South Korea. At a high level, a recently recognized viral respiratory pathogen has traveled halfway around the world and is causing morbidity and mortality in a small section of an immunologically naive population. It appears to be associated with hospitals. What do we take away from this? Lessons will be learned when the event subsides and people study what happened, but to me, MERS reminds us that outbreaks of pathogens for which there are no vaccines or drug therapies underscore the importance of prevention.

When possible, preventing pathogens from physically reaching or entering a host by respiratory, percutaneous, alimentary, blood et al pathways is preferable to relying on pharmaceutics. Drugs tend to be complex and costly to develop, can take a long time to enter the marketplace, and -- especially in the case of antibiotics and antivirals -- they can become obsolete over time. Moreover, drugs are often toxic to the patient. Prevention is applicable in situations when appropriate drugs don't exist (e.g., for newly emerged pathogens), when it isn't possible to administer drugs in a timely manner, or when patients cannot tolerate them. 

Consider two anecdotes related to the spread of MERS virus in South Korean hospitals. As described by Choe Sang-Hun, it appears that the index patient in the South Korean event had "coughed and wheezed his way through four hospitals before officials figured out, nine days later, that he had something far more serious and contagious." Furthermore, ED wait times in Korea can be extraordinarily long by US standards. Another patient, who waited two-and-a-half days in the emergency department before a hospital bed became available, infected 55 additional individuals during their wait. Apparently, 2.5 days isn't an unusually long waiting time in some Seoul hospitals. 

Applying effective prevention measures to patients suspected of infection is the only way of stopping the chain of transmission in such environments. Unfortunately, it is unclear how to achieve good infection control for MERS and a range of other pathogens. Eli Perencevich described the issue clearly, as usual, in the Controversies in Hospital Infection Prevention blog recently: 

. . . we don't actually know how to achieve good infection control for MERS and the other diseases he [Tom Frieden] mentioned [measles, DR-TB, SARS, Ebola]. If only we invested in studies to understand how to best implement PPE in these [hospital] settings. One could imagine improved PPE technology, refined PPE donning and doffing algorithms and enhanced environmental cleaning as potential targets for future studies examining optimal protection from MERS. Not coincidentally, many of these are the same targets that Mike, Dan and I mentioned in our Ebola+PPE editorial several months ago. If we invest in infection prevention technology and implementation research, our health care system will be safer regardless of the pathogen du jour.

And that's the point that MERS makes me think about. Yes we need antimicrobials and vaccines that work against specific pathogens, of course we do, but developing such drugs is a major effort. Biochemical pathways must be understood, pathogen life histories and survival strategies must be elucidated, and the host response must be characterized among many, many other things. Doesn't it make sense that research on pathogen-agnostic approaches to prevention, which don't require such specific and complex information, might be simpler and broadly applicable? 

Investing in research on infection prevention approaches, and how to implement them sustainably in realistic clinical environments, would pay benefits far beyond helping to thwart the spread of exotic and newly emerged pathogens. We may learn how to better control and prevent the usual suspects of hospital associated infection, which, afterall, are responsible for a tremendous burden of disease day in and day out.

(image source: Wikipedia)

New antibiotics: Prevention is important, too!

Losee Ling et al recently described a new antibiotic compound, called teixobactin, that kills pathogens without detectable resistance. The abstract of their study notes that

. . . We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

It's a beautiful study, and obviously everybody hopes these implications are realized, and soon; new drugs are very badly needed. Eli Perencevich, writing in the blog Controversies in Hospital Infection Prevention, summarizes some of the important results from the study and also offers an important perspective,

I agree with Dr. William Schaffner's comments in the NY Times as he called the study/method “ingenious” yet also cautioned that "it’s at the test-tube and the mouse level, and mice are not men or women, and so moving beyond that is a large step, and many compounds have failed.” I would add one additional caveat  -- teixobactin had little activity against most Gram-negative bacteria including E. coli, Klebsiella and Pseudomonas. . . . Since the real resistance crisis is in multi drug-resistant Gram-negatives (think CRE, NDM-1), we better get back to digging in the dirt.

Certainly, these and other Gram negatives are important. As I've mused before, it's critically important to research infection prevention approaches in addition to investing in new drug development. We must understand how to prevent infections from occurring and spreading in healthcare (and other) settings before new drugs are introduced. It is clear that we do not possess this understanding, at least on any significant scale or in any sustainable way, at present.

(image source: CDC)

Ebola and the cult of vitamin R

This week saw the appearance of Ebola virus disease in a Liberian visitor to the United States. Active transmission here is not expected and public health authorities have done extensive contract tracing. Fifty individuals who were potentially exposed to the virus are being monitored and a small number are in isolation. 

First, a brief description of the episode. A man who had direct contact on September 15th with a woman suffering from advanced Ebola virus disease in Monrovia, Liberia, traveled to Dallas, Texas, to visit relatives. He flew from Monrovia to Brussels on the 19th of September and took a connecting flight to Washington DC before catching a final flight to Dallas, arriving on the 20th. He was screened for fever and exposure at the airport before departing Liberia; apparently, his answers to a screening questionnaire were inaccurate. After arriving in Dallas he remained asymptomatic for several days and began suffering symptoms on the 24th. On the 26th he presented to the hospital. (Note: some news accounts report the date as the 25th.) At this first visit he was evaluated, prescribed antibiotics, and sent home to the relatives with whom he was staying in Dallas. He subsequently deteriorated and was transported to the ED by ambulance on the 28th. The positive test for Ebola virus was received on the 30th.

Many details about this event are unsettling. To me, especially disappointing is that the man's travel history was not a factor in the clinical diagnosis on the 26th, although a nurse was informed that he was visiting from Liberia. The nurse entered the information into the electronic health record (EHR), following protocol, but that didn't trigger suspicion. The hospital has since clarified why: There are separate physician and nursing workflows, and patient travel history did not automatically appear in the physician's standard workflow. The doctor never saw the information.

I think it's also interesting that the man was prescribed antibiotics for what turned out to be a viral illness. In a sense, this is a familiar story: change the name of the virus and it's a scene that occurs daily in many clinics and office visits. It seems ironic that, a week after the White House released its National Strategy for Combating Antibiotic-resistant Bacteria, this physician-patient encounter resulted in the apparent inappropriate prescription of antibiotics. As the National Strategy tells us, 

. . . a growing body of evidence demonstrates that programs dedicated to improving antibiotic use, known as "antibiotic stewardship" programs, can help slow the emergence of resistance while optimizing treatment and minimizing costs. These programs help providers prescribe the right antibiotic for the right amount of time and prevent prescription of antibiotics for non-bacterial infections. It is imperative that such programs become a routine and robust component of healthcare delivery in the United States. (emphasis added)

To be fair, the man may have had a bacterial infection at the first hospital visit, in addition to the unsuspected Ebola virus infection. We don't know; it's a matter of his private health record. However, I am reminded of how a physician colleague once described the pervasive inappropriate, and often rushed, use of antibiotics,

It's a common problem. Patients present with vague complaints that are plausibly due to bacterial infection and there is a very low threshold for prescribing antibiotics. The patients often request or insist on it, and it often seems harmless to acquiesce. In fact, many doctors view prescribing them as a protection mechanism in case there is an infection or one develops. It's so common that in many clinics and EDs ceftriaxone is referred to as "vitamin R".

Perhaps the antibiotic prescription dimension of the encounter on the 26th is all too understandable.

One can hope that a thorough, transparent investigation and analysis of this entire episode can produce helpful knowledge on how to harden healthcare systems for routine healthcare as well as extraordinary events like this one. In the meantime, the CDC has produced clear guidance for evaluating patients with a history of traveling to epidemic regions.

Acknowledgement: The title is inspired from a Medscape Connect item entitled "The cult of Vitamin R", which no longer appears to be available online.

(image source: Wikipedia)

The usual suspects: Fluffy can make you sick

Large scale livestock production in conjunction with the widespread use of antibiotics to promote animal growth has resulted in the emergence of antibiotic resistant bacteria in farm animals. People who work on and live near such farms are exposed to the resulting pathogens. Smith et al observed that both pigs and the farm workers who raise them in the American Midwest can become colonized with MRSA. Voss et al reported MRSA prevalence among pig farmers that was more than 760 times higher than that among patients admitted to Dutch hospitals. Moreover, a recent study by Carrel and coworkers shows an association between people's proximity to concentrated animal-feeding operations and colonization with MRSA.

These studies, along with many others, illustrate the point that if we blast animals with antibiotics, then we should expect that the environment and people inhabiting it will be exposed to antibiotic resistant pathogens. Recognizing the risks involved, in 2006 the European Union banned the use of antibiotics to fatten farm animals. Denmark went even further and eliminated their use for disease prevention in livestock. In the US, the FDA recently described steps aimed at reducing antibiotic use in agriculture. Hopefully the proposed rules will be adopted and result in decreased use.

I think of the farm and antibiotics issue as being part of a larger thing: the nexus of animal and human health. This idea is often described as "One Health", which recognizes that human, animal, and environmental health are all linked.

And by "animal" we don't only mean livestock. I don't ordinarily think of Staph as a zoonosis, but it is. In fact, several studies have observed human infection associated with companion animals. A review by Day et al highlighted the remarkable spectrum of infectious diseases of dogs and cats that are shared by humans (including Staphylococcus spp.). More recently, Vincze et al described an alarming rate of MRSA in wound samples taken from companion animals in Germany.

It's important to realize that pets get antibiotics, too. Lots, it appears. Writing in 2005, Heuer et al observed that

 . . . a comparatively small number of companion animals (550,000 dogs and 650,000 cats) consume approximately the same amount of fluoroquinolones and cephalosporins as consumed annually in the much larger population of food animals in Denmark (23 million slaughter pigs, 130 million broiler chickens, and 1.2 million cattle and dairy cows). We do not believe that antimicrobial drugs are more generously prescribed for companion animals in Denmark than in other industrialized countries.

This is something that needs to be borne in mind. Overuse of antibiotics in companion animals also carries risks to human health, especially when you think about the frequent contact owners have with their pets.

So the next time Fluffy is feeling down, think twice before asking the vet for antibiotics.

(image source: David Hartley)