Smog: What Lurks Within

The planet teems with bacteria in all niches imaginable, including the air we breath. Integrate this fact with the fact of the ubiquity of antibiotic resistant bacteria and it is not surprising that the air itself contains antibiotic resistant bacteria. A recent study, that the popular press has been reporting on, reveals that the smog (an amalgam of fog and particulate matter) of Beijing contains many antimicrobial resistance genes. 

Before anyone suits up in a gas mask before going outside (as if the air inside one's house is sterile), it is important to put the finding into context.

While the finding itself doesn't strike me as surprising, it does illustrate the magnitude and full scope of antibiotic resistance. I often emphasize that antibiotic resistance is a unrelenting process in nature that humans have exacerbated with injudicious use of antibiotics. Antibiotic resistance is how bacteria struggle and fight with other microbial species and everywhere you look resistance is present -- even in caves in which no human has set foot. It will always be present at some levels and that is why antibiotic stewardship that accounts for this fact and minimizes the acceleration of the process is crucial

What the implications are of this latest piece of research? I wonder if some of the community-acquired drug-resistant infections and colonization might be the result of acquisition from the air. This study noted the presence of antibiotic resistant genes -- not the presence of viable bacteria --- so follow up studies could attempt to cultivate antibiotic resistant bacteria from the air.

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.

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.

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.

Be Specific: A Review of Pneumonia Before Antibiotics

When I lecture on existential infectious disease threats -- a subject I am writing a book on -- antimicrobial resistance is what I usually will list as #1, above influenza, above Ebola, above HIV, and definitely above Zika. To me, as a practicing infectious disease and critical care physician, treating infections with multiple-drug resistant organisms is something I do all day and all night. 

When I am asked how to reverse the trend of injudicious antibiotic prescribing which has driven antimicrobial resistance to new heights, I reply we have to be more specific. By being specific I mean that we have to not be satisfied with a generic diagnosis of upper respiratory tract infection, community-acquired pneumonia, or the like. Such non-specific diagnoses engender empiric broad-spectrum antimicrobial therapy when a narrower agent--or often no antibiotic at all--is actually indicated. It seems like it may have always been this way, but that is not the case.

In Pneumonia Before Antibiotics: Therapeutic Evolution and Evaluation in 20th Century America, Harvard's Dr. Scott Podolosky (someone who I have heard lecture before) provides the much needed history of how such a menace as the Captain of the Men of Death was handled prior to the advent of antimicrobials (first sulfa drugs and then penicillin). In a word therapy was specific.

The chief means community-acquired pneumococcal pneumonia -- still a major infectious disease killer--was treated was with type-specific serum. Typing individual patient's strain of pneumococcus might sound as extremely complex and delay-ridden to a modern physician, but it was neither in an era before antibiotics. Podolosky's book, which is ripe with historical detail, illustrates just how this was accomplished and how pneumonia was construed as a public health threat that spawned typing and serum centers nationwide to get the correct type-specific serum to the patient in hours!

The most interesting part of this book which is littered with mentions of such iconic figures in infectious disease as William Osler and Maxwell Finland (to me) is how once sulfa drugs -- cheap, easy to administer, and non-specific -- appeared, the clinical paradigm rocked and shifted as physicians contemplated which countermeasure to use and when combination therapy might be warranted. I expect this same debate to recur soon as the market in infectious disease therapeutics begins to expand to include such specific therapies as monoclonal antibodies, bacteriophages, lysins, and the like.

It will be essential for the forthcoming debates and research on the optimal treatment of infectious diseases to be informed by the important context Dr. Podolosky's work provides.