Dissecting the Latest Super Bug

The report of a highly resistant E.coli bacterium isolated from a urinary tract infection that occurred in a 49 year old Pennsylvania woman (in April of 2016) has temporarily stolen the headlines from Zika. This colistin-resistant E.coli was uncovered via a Department of Defense program in which bacteria that meet certain criteria are automatically forwarded on for further study. While there has been much written about this event and its implications, there are a lot of misconceptions in the headlines.

A few facts about this phenomenon:

1. Plasmid-mediated colistin resistance is a very bad development.

Colistin resistance has existed before, but usually is conferred through changes in the genes of the bacterial chromosome delimiting spread to other bacteria. Indeed, I've seen many colistin resistant bacteria. When resistance is present on a plasmid, which is a mobile piece of genetic information, it can more easily disseminate to neighboring bacteria. The mcr-1 plasmid is such a mechanism for transmission of resistance. Colistin, a drug well known to infectious disease physicians, was a drug put on the shelf decades ago because of toxicity concerns. Today, it is often a drug of last resort and taken off the shelf in special situations in which resistance makes its use necsessary. Losing it through the dissemination of plasmid-resistance, first described in China, would be very problematic. Of note, the woman, who recovered from her infection, had no travel in the 5 months prior to the infection and it will be important to investigate her close contacts (animal and human) to attempt to pinpoint how the strain was acquired.

2. This E.coli isolate was, thankfully not totally drug resistant.

Though this bacterium deserves the "superbug" moniker, given it was both colistin-resistant and harbored an extended-spectrum beta-lactamase (ESBL), it was not resistant to all antibiotics known to man -- something I have battled against twice (Klebsiella pneumonia, Pseudomonas aeruginosa) not too successfully. Cabapenem (it's not a CRE), aminoglycoside, and nitrofurantoin (!) susceptibility was present in the strain leaving the patient with options. 

3. The isolation of an E.coli bearing the mcr-1 plasmid in a pig intestine sample is highly significant.

The aspect of the story -- which hasn't garnered as much attention with the notable exception  Maryn McKenna, one of the best infectious disease journalists -- is a puzzling development as colistin is not an antibiotic used in agriculture. Tracing the origin of the pig intestine to the farm in which the pig it belonged to resided will be important as will sampling other animals -- and humans -- on the farm.

Antibiotic resistance is the norm--it is what bacteria do naturally to survive. The discovery of this strain in the US is not surprising in the least. This event, however, should serve to underscore the need to treat antibiotics as the precious resources they are and not squander them through injudicious use whether in the hospital, the pediatrician's office, or the urgent care center. Additionally, infectious disease medicine must meet these challenges with less reliance on broad-spectrum non-specific antimicrobials and more with targeted therapies such as monoclonal antibodies, bacteriophages, lysins, and virulence factor disruptors and sophisticated and fast companion diagnostics.

GMO Mosquitoes: Will Zika Change the Equation?

As the Zika virus outbreak continues and mosquito season in this hemisphere approaches, there will be a ramp up in vector control activities. These activities are aimed at reducing mosquito populations and are practiced for several types of mosquitoes, most notably those that spread West Nile Fever. However, even prior to the Zika outbreak, because of the threat of dengue and chikungunya, aggressive campaigns against Aedes mosquitoes had taken place in certain areas such as Texas, Hawaii, and Florida.

Florida, which has had several instances of local transmission of both dengue and chikungunya, has been a national leader in mosquito control as exemplified by the Key West Mosquito Control District. Over the past years, faced with a continual threat of dengue, the use of Oxitec's sterile male genetically modified mosquitoes to reduce Aedes aegypti populations has been contemplated as a means to augment ordinary mosquito control operations. 

However, in today's context, "genetically modified" evokes an unjustified Frankenstein/Jurassic Park horror in many people and has stalled release of these mosquitoes in the US (they have been part of trial releases in the Cayman Islands, Panama, and Brazil).

Given this context, pre-Zika, my colleagues and I sought to understand how the public conceives of GMO mosquitoes and what their support or opposition is influenced on. To meet this aim we fielded surveys to residents of a Florida community in which the release of these mosquitoes is being contemplated. PLoS Currents Outbreaks just published the results of that work.

There were several findings that we found particularly striking:

• Being a female was significantly associated with being opposed to the use of GMO mosquitoes
• Having never known anyone with chikungunya or dengue was significantly associated with opposition to use of GMO mosquitoes

The 2nd finding is what I deem the most important, as it reflects the role of risk assessment on an individual level and will likely change as people's threat assessment changes. A headline-grabbing virus like Zika may be just the threat that will cause people to think differently about GMO mosquitoes -- something that is already happening.

We hope to follow this paper with a follow-up post-Zika study of the same area as well as explore the mechanics and public health communication strategies used in the Cayman Islands, Panama, and Brazil. Additionally, it will be important to put GMO mosquitoes firmly in the tradition of such endeavors as the eradication of the agricultural screwworm pest, irradiated sterile mosquitoes, and Wolbachia-infected mosquitoes.

It is the role of public health authorities and physicians to help calibrate the general public's analysis and our hope is that this paper can help move the discussion of GMO mosquitoes further forward.

Clandestine Diarrhea & Inadequate Chlorination: The Perfect Storm

Possibly lost amongst many other pressing infectious disease issues such as yellow fever, Zika, and antibiotic resistance was a report released by CDC assessing public swimming pools. The bombshell contained in the report is the finding that 80% of pools have been closed for safety violations. While I believe that many of these safety violations might be the result of bureaucratic intricacies and pose no danger, those that deal with diminished chlorine, for example, are likely serious as they potentially can allow dangerous microbes to pass from one swimmer to another. Rotavirus, E.coli O157, and cryptosporidium are pathogens that can find a poorly disinfected pool hospitable. 

While it is unequivocally important to highlight the appropriate disinfection procedures that must be followed for optimal safety, it is not a good state of affairs when people have to be warned not to swim in a public pool if they have diarrhea. A floating turd, which I have seen on multiple occasions (in fact it's how, as a child taking swimming lessons at the YMCA, I first learned what the word feces meant), is an identifiable hazard that can be easily seen, avoided, and remedied. Diarrhea, to unaware swimmers, to use threat analysis terms is an unknown unknown. 

Why people with diarrhea think it's OK to merge their "stream" with that of the pool's I will never know.

Will Dengue Unravel the Mystery of Zika?

One of the puzzles about Zika virus and its newly discovered penchant to cause fetal anomalies is understanding why these facts about Zika are being noticed now given relatively large outbreaks of the virus that occurred in Micronesia and French Polynesia. In those outbreaks, complications such as Guillain-Barre Syndrome were noted but not microcephaly was noted (French Polynesia recently reported 8 microcephaly cases from their outbreak).

One tantalizing hypothesis which is gaining evidence is the role of preexisting dengue antibodies. Dengue, a flavivirus like Zika, has the ability to cause severe disease by employing preexisting antibodies to one strain to enhance infection with another. This phenomenon is known as antibody-dependent enhancement and was discovered by Dr. Scott Halstead who, early on, thought this was playing a role with Zika.  

Now, evidence is beginning to be presented that shows that this may be more than a hypothesis. A pre-publication paper published by researchers at Florida Gulf Coast University illustrates that dengue monoclonal antibodies and immune sera both have the potential to enhance Zika infection in a cell culture model. 

These preliminary findings were pathbreaking in their own right but yesterday at the Cura Zika symposium at the University of Pittsburgh's School of Public Health a leading Zika researcher at the institute presenting some extremely important data on this phenomenon that deserve a wide audience.

Dr. Ernesto Marquez, working out of Recife, presented data illustrating that in Brazil -- as opposed to Southeast Asia and other other areas in which dengue and Zika co-circulate --monotypic infection is much more common. What this means is that Recife women are more likely to have been infected with just 1 (out of 4 strains) of dengue than in Thailand where multi-typic infection is the norm. DENV-3 is the 

What Marquez noted in his data was the almost unique association of DENV-3 to enhance infection. There is much more to this presentation and much nuance to how these antibodies work (for example, their quantity) so I suggest watching it online. It is a great example of how scientific analysis proceeds. 

The obvious policy question that comes to mind is how would the dengue vaccine, approved for use in Brazil, Mexico, and the Philippines, interact with Zika? Would it foster antibody dependent enhancement? Or would it be protective? Other questions to answer would involve looking at case-control data between dengue-naive and non-naive pregnant women who are infected and assessing how their clinical courses may differ. 

Nonetheless, science is advancing quite rapidly on this fascinating virus. 

Can I Check Your Inflammatory Reflex?

The realms of infectious disease and critical care medicine intersect at a place called sepsis. Sepsis is what our grandmothers called "blood poisoning" and what our ancestors before that believed was caused by evil "humors" in the body. As one of about 113 physicians with dual training in both infectious disease and critical care medicine, this disease entity is one I find extremely fascinating for obvious reasons. A good way to think of sepsis, is as the final common pathway for many infections as they increase in severity. 

Sepsis recently underwent a notable change in definition that improved the utility of the concept by reflecting state-of-the-art scientific principles. The fundamental basic definition of sepsis is dsyregulated host response to infection. When I first saw the new definition, which I found to have much more clarity than prior versions, I didn't parse every word out. However, after reading Clifford Deutschman's analysis, I am reminded of how important definitions are both for what they include and also for what they exclude.

The definition of sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. What Deutschman's piece highlights is the fact that the definition stipulates only a host response -- not which part of the host. Most people, rightly, think of the dysregulated response as largely immunologic but, like many physiological phenomenon, there's more to the story. He also goes on to point to the answer to the question of what other systems are involved. 

Tracking down his references one finds that it is the nervous system that is involved. A tantalizing aspect of this involvement is something known as "the inflammatory reflex" (sounds like a media term for an attribute of Donald Trump) as elucidated by Kevin Tracey.

This reflex involves the vagus nerve directly communicating with the immune system. This communication is two way with infection triggering "sickness behavior" such as anorexia, social withdrawal, and sleepiness. On the other side, T-cells of the immune system are influenced in order to diminish inflammation, which though essential can sometimes be overwhelming. 

The details of this interaction are endlessley fascinating and open up whole areas for intervention. Equally fascinating is understanding the evolutionary role of this pathway, which predates the immune system proper as it is present in the simple organism C.elegans which does not have immune cells. Sickness behavior is interesting in its own right and one can see how such behavior might delimit contagion and conserve metabolic resources needed to weather the infectious storm--a really cool thing to contemplate.