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Aiding & Abetting Disease

 

We’ve got to stop focusing solely on the bugs. Decisions we make individually and collectively; for example, through legislation, strongly shape the risk of disease.

Exhibit A: Next week members of the House Energy and Commerce committee will vote to amend the Animal Drug User Fee Act (ADUFA) in a way that will greatly expand the use of antibiotic drugs in cattle, pigs, and poultry. That step, says the National Resources Defense Council, a U.S.-based environmental legal group, would be “rash, unforgivable, and will hasten the spread of antibiotic resistance.”

How increased use of antibiotics hastens the spread of resistant infections was explained by infectious disease expert, Brad Spelberg, MD, to an international audience via webinar this past February. Referring to our overuse of the drugs as an “ecological tidal wave of antibiotics,” he said:

But boy I’ll tell ya, we sure do our damnedest to educate them [bugs] to be resistant.

The amount of antibiotics that we put into the environment every year in this country is absolutely staggering: 21,000 tons every year in just the United States. And the rate of use in agriculture is not going down it is going up. It is continuing to increase despite our clarion calls that we have a resistance crisis. We truly have a problem, Washington.

Yet Washington’s response, according to the NRDC analysis, is to pour more antibiotics into the environment and do so with improper motive: “The Food and Drug Administration loves ADUFA because it requires pharmaceutical companies to pay tens of millions of dollars in fees that pay salaries and maintain FDA budgets. Pharmaceutical companies love ADUFA because it has greatly reduced the time needed for FDA to approve new animal drugs, meaning increased product sales and profits.”

In essence, the NRDC says the proposed amendments accomplish this by reducing the regulatory reach of the FDA over the use of antibiotics:

Since 1962, FDA’s primary job has been to make sure that human and animal drugs are both safe and effective. In 2004, Congress allowed “conditional approvals” which allowed companies to sell certain new animal drugs without submitting all the data showing that those products are effective. Congress intentionally limited these conditional approvals to minor animal species (like goats and rabbits) or to minor uses in major species (intended for small numbers of dogs, cats, pigs, cattle, turkeys, or chickens). They rationalized that because the markets for these products were so small, pharmaceutical companies needed lower costs to bother making them.

The problem is that now these same companies want Congress to expand conditional approvals to major uses in major animal species like cattle, pigs and poultry. These markets are enormous. If this provision passes, companies won’t have to submit all the data needed to approve drugs (including antibiotics) used in tens of millions of animals. [Emphasis in original.]

This ploy is dangerous to public health. It is laser focused on increasing the use and sales of drugs, including animal antibiotics. And that increase will speed up the development and spread of superbugs.

As bugs evolve so must our notions of what drives disease. A growing literature says “profit-driven diseases” are giving rise to pandemics. And thus we have, for example, a special report in next month’s Scientific American that shifts the focus from the bugs to us. They say that resurgent outbreaks of infectious diseases in the U.S. are sickening thousands, and the causes are societal, countering the “conventional wisdom that says that infections are caused solely by germs.”

 

 

 

 

How fast can bugs develop resistance?

Bugs can develop resistance to antibiotics during treatment and probably because of that treatment. As infectious disease specialist, Brad Spellberg, MD, told Frontline:

I have watched some of these pathogens develop new resistance in the middle of a course of therapy.

Just within days?

Within days.

That means that that antibiotic has basically stopped working while you’re treating the patient.

The way you know that the resistance has emerged in the middle of a course of therapy is the patient is very sick. You start the antibiotic; they get better. On day three or four, all of a sudden they get sick again, and back comes the same bacteria that you thought you eradicated. And now when you sent it to the lab, instead of “S” for “susceptible,” it says “R” for “resistance.”

So what do you do, switch to another and another?

If you have another, you switch to another.

But sometimes you don’t have another. Here’s Dr. Spellberg explaining what that’s like:

Good things happen when judges and doctors are rested and well fed

When we’re tired we take the easy way out. Psychologists call this “decision fatigue,” the idea that the quality of our decisions deteriorate over time as our brains get tired. No surprise there. The interesting bit, however, is that it applies not just to you and me, but also to judges and doctors acing in their professional capacity.

For example, a well-reported study of judicial decision making found that as court sessions wore on judges were far more likely to deny parole. The reason? Denying parole is what’s normally done. Thus as each case comes before the court, denying an application for release is the safe, easy option. To buck that trend and grant parole takes intellectual energy. Therefore, the study found, if you want out of jail your chances are “greater at the very beginning of the work day or after a food break than later in the sequence of cases.”

Similarly, with doctors, researchers asked the question whether decision fatigue would increase the likelihood of inappropriately prescribing antibiotics as the day wore on. And sure enough, in a study called Time of Day and the Decision to Prescribe Antibiotics, they found that inappropriate antibiotic prescribing “increased throughout the morning and afternoon clinic sessions … consistent with the hypothesis that decision fatigue progressively impairs clinicians’ ability to resist ordering inappropriate treatments.” (Chart below.)

The reason: Issuing the prescription is “again, the easy, safe, practice” because it conforms to a “perceived or explicit patient demand, a desire to do something meaningful for patients, a desire to conclude visits quickly, or an unrealistic fear of complications.”

The remedy involves doctor and patient. The physicians job, the authors suggest, is to modify their schedules, take mandatory breaks, or snack more frequently. Our job, as patients, is to stop asking for antibiotics and realize that they’ll be prescribed when appropriate.

And perhaps bring to the appointment, along with our insurance card, an apple for the doctor.

What do microbes look like? And how do they compare to various microcomponents of the human body?

Here are two helpful resources that let you into the world of the microcosmos so you can see for yourself what things look like.

The video begins by comparing the size and shapes of viruses to the much bigger bacteria, including Staphlococcus.

But the more detailed resource is this one from the University of Utah (sorry, it can’t be embedded). It takes you from a coffee bean all the way down to a carbon atom. Click on the cursor below the graphic and drag it to the right. It shows you not just the microbes, but how they compare to various well-known components of the human body. For example, you’ll see how bugs are smaller than a red blood cell or X chromosome, but larger than – in descending order – an antibody, or a molecule of hemoglobin, methionine (an amino acid), glucose, and water.

The unaided eye can just make out the human egg; for anything smaller you need a magnifying glass or microscope.

So, about that rubber duck …

 

Folks over at The New England Journal of Medicine aren’t too impressed with all the media attention devoted to a recent paper in Nature about the bacteria they found inside your kid’s rubber duck.

Nor are they impressed by similar media stories reporting bacterial counts on, well, pretty much anything: the coffee maker, the kitchen sponge, TV remote control, the playground sandbox, your flight’s tray table, your doctor’s necktie, lab coat, and stethoscope, and so on …

The reason the NEJM isn’t amused is captured by the title of their story: News Flash – The World Isn’t Sterile. Indeed, if you look hard enough, they say, bacteria can be found literally everywhere. And thus:

What’s missing from all these studies, of course, is a correlation between identification of these bugs and any subsequent diseases. It’s not as if kids with rubber ducks were coming down with more infections than kids who don’t have them …

In summary, bacteria on common household, work, and travel items are ubiquitous; furthermore we lack any clinical data that this is important in any way.

In other words, all these news stories are unfair to the duck. It’s just a kid’s toy – it’s not R. Ducktococcus aureus.  

 

 

Spot the Urban Legend

“Sigh. This urban legend about taking every last dose must stop. Who is spreading this malarkey?”

That was the response yesterday of @BradSpellberg, Chief Medical Officer of the Los Angeles County-University of Southern California Medical Center, to the NBC News headline, below, concerning a countrywide outbreak of a drug-resistant bug.

 

 

The problem, of course, isn’t with the hand washing. It’s with the idea that you must take every antibiotic pill in your prescription. Dr. Spellberg is one of the leading proponents of the new thinking that “shorter is better.” He explains:

“Every randomized clinical trial that has ever compared short-course therapy with longer-course therapy … has found that shorter-course therapies are just as effective … This myth needs to be replaced by a new antibiotic mantra: ‘Shorter is better!’ Patients should be told that if they feel substantially better, with resolution of symptoms of infection, they should call the clinician to determine whether antibiotics can be stopped early. Clinicians should be receptive to this concept, and not fear customizing the duration of therapy.”

This new thinking is predicated on the understanding that antibiotics, while sometimes necessary and even lifesaving, come with serious side effects. Spellberg:

“Antibiotics are harmful. They’re not this thing that magically cures disease and has no unfortunate side effects – that’s not real. Antibiotics have lots of problems associated with them: They breed out resistance. They breed out superinfections like C. diff [an antibiotic-driven bacterial infection] and Candida [a fungal infection]. They cause side effects.”

For further information on adverse side effects associated with antibiotic use, see here and here.

 

 

Zombie Genes, Slurpee Machines and Disease X

 

The story doesn’t always end after you kill a microbe. That death, in fact, can mark the beginning of a whole new life – for the organism’s genes.

According to MIT geneticist Eric Lander (below video), it works like this. Most bacteria carry, in addition to a regular set of chromosomes, an extra set of gene-carrying chromosomes called plasmids. And these genes often encode a protein that confers resistance to a range of antibiotics.

The reason for the presence of genes on plasmids is because plasmids are mobile, they move between living bacteria, conferring resistance along the way. But their movement isn’t confined to living bacteria: “It turns out that when bacteria die their cells crack open and their guts spill out – these little circles of DNA, these little plasmids.” At which point other bacteria will “slurp them up.”

Dr. Lander says this ability to slurp up zombie genes “is a little scary…. Because if we start using antibiotics willy-nilly, it’s pretty easy [to see] that if one species of bacteria had a … plasmid with a resistance gene, another species entirely can pick it up by horizontal transfer. [I]n fact, we are seeing an epidemic of antibiotic-resistant bacteria. Because as we use more antibiotics … [we’ve] selected for the bacteria that have picked up these things…. Not good, not good. And we’re seeing a huge spread of antibiotic resistance.“ (Emphasis added.)

This huge spread of drug-resistant microbes might be nearing critical mass. Last month, for example, the World Health Organization issued a list of disease-causing pathogens that have the potential to spread and kill worldwide and for which there are currently no, or insufficient, countermeasures available:

  • Crimean-Congo haemorrhagic fever (CCHF)
  • Ebola virus disease and Marburg virus disease
  • Lassa fever
  • Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS)
  • Nipah and henipaviral diseases
  • Rift Valley fever (RVF)
  • Zika
  • Disease X

The ominous sounding Disease X “represents the knowledge that a serious international epidemic could be caused by a pathogen currently unknown to cause human disease.” A “pathogen currently unknown” includes an existing microbe that, say, gains the ability to jump from animals to humans, for airborne transmission (imagine if HIV could do that), or mutates to become more virulent or more resistant to our drugs.

Experts in the field such as Dr. Michael Osterholm, founding director of the Infectious Disease Center for Research & Policy at the University of Minnesota, have been predicting a serious international epidemic, saying it’s not a question of if, but when. In his book Deadliest Enemy: Our War Against Killer Germs, Osterholm narrows the threat to antibiotic-resistant bacteria and the influenza virus, whose pathogenic potential relies in good part on their ability to mutate rapidly:

[T]here are only two microbial threats that … fit this description for pandemic potential. One is antimicrobial resistance and the very real threat of moving ever closer to a post-antibiotic era … a world more like that of our great-grandparents where deaths due to infectious diseases we now consider treatable are once again commonplace. The other is influenza, the one respiratory-transmitted infection that can spread around the world in short order and strike with lethal force.

 

One way microbes mutate rapidly is by the aforementioned plasma-mediated horizontal gene transfer. Here’s the engaging Eric Lander, former co-chair of President Obama’s Task Force on Combating Antibiotic-Resistant Bacteria, explaining to his first year MIT biology students how zombie genes and slurpee machines combine to yield Disease X potential. (The relevant bit runs from 2:40 – Why do cells have plasmids? – to 7:10.)

 

A severe flu can cause MRSA Pneumonia – but you can avoid all that

 

As the flu season mercifully winds down, a final lesson on the value of vaccination comes to us from Paul Auwaerter, MD, at the Johns Hopkins School of Medicine.

Having just finished a few weeks in the hospital doing infectious disease consultation, a number of the physician residents asked him why Staph aureus, and MRSA in particular, seem to have such a predilection for causing secondary bacterial pneumonia after a severe bout of the flu.

Citing recent research, Auwaerter thinks that severe influenza may disrupt the Staph/MRSA biofilm in the nasal passages: “About one third of people harbor S aureus in the nostrils, and dispersal from the biofilm in this setting may lead to aspiration of S aureus into the lungs, which might be more susceptible to infection.”

The remedy, he says, is prevention, i.e. the flu vaccine – but not just any old flu vaccine:

With this ferocious influenza season, it has become obvious that we need to do better with prevention. Specifically, influenza vaccines need to be reformulated every year, and this year, it was estimated that the flu vaccine effectiveness was only in the mid-30% range, although it was perhaps better among pediatric populations.

Many people, including both adults and children, don’t get immunized. There seems to be a genuine need, that I view as quite urgent, that more effort be given to developing a universal influenza vaccine – one that might be more durable and would cover most strains. This not only would lead to less influenza, hospitalizations, and deaths, but also would have a huge economic impact from less absenteeism from work or school, as well as the benefits to individual health.

On International Women’s Day Meet Canadian Scientist Julia Levy

 

VANCOUVER, CANADA  #IWD2018  #WomenInMicrobiology

Dr. Julia Levy’s research at the University of British Columbia in the 1980s led to the development of photodynamic therapy (PDT), initially for the treatment of cancer.

Julia Levy was born in Singapore. Her father was captured by the Japanese during WWll and put into a POW camp. Just before this, her mother had escaped to Vancouver with Julia and another daughter.

Inspired by her grade 11 biology teacher, a woman, Julia went on to obtain her BA in biology from the University of British Columbia, her PhD in experimental pathology from University College London, and after grauation became a professor of microbiology at UBC.

Together with her colleagues at UBC they developed photosensitive drugs which, upon being exposed to light, change in a way that makes them toxic to cells. The initial targets were cancer cells: cancers of the skin, lung, esophagus, stomach, bladder and cervix.

Dr. Levy also formed her own company, embarking on research that broadened the reach of PDT to treat other diseases such as skin infections, arthritis, psoriasis, multiple sclerosis, and – perhaps the most promising target – age-related macular degeneration. “It’s way beyond cancer,” Levy tells science.ca, excited about the potential to cure other diseases with this technology.

But here’s what’s most impressive about Dr. Levy – the impulse that led to her corporate success:

In 1986 she was giving a talk to some doctors in Waterloo, Ontario about her work on new light-activated drugs. The doctors were trying these drugs on cancer patients and they were very upset because Johnson & Johnson was closing down their drug development program which appeared to be effective against cancer. Many people were being helped by this technology, but soon they would not be able to get the drug. “It was a very upsetting experience for me,” says Levy, who until that point had worked on these drugs only in a laboratory. “For the first time, I became aware that we were talking about real patients being treated for real cancer.” And so right then and there Levy decided that “We’ve got to do something.” So she made a deal with J & J, raised $15 million, and took over the Canadian subsidiary. It was a major turning point for Levy and her company – and for cancer patients in Canada.

These days she lives a varied life. Some days are spent in meetings with other companies, others reading scientific literature, still others meeting her colleagues to work out business strategies. Levy likes everything about her work – except the travelling and talking to investors.

Looking back on it all, Dr. Levy is quick to credit the value of teamwork: “Well, when I look at it I think … me? And a lot of other people – you can’t do it alone.” And despite the wealth she has generated says, convincingly, “I’ve never found money to be a compelling reason to do anything.”

 

 

 

 

 

 

 

Antibiotic Therapy: Shorter = Better, Especially For Sicker Patients

A core issue in antibiotic therapy these past few years is duration; namely, should patients complete every dose of antibiotics prescribed, even after they feel better? The emerging consensus is no, and one of the leading proponents of this school of thought is the impeccably qualified Brad Spellberg, MD, Chief Medical Officer of the Los Angeles County-University of Southern California Medical Center, who says:

Every randomized clinical trial that has ever compared short-course therapy with longer-course therapy … has found that shorter-course therapies are just as effective.… Patients should be told that if they feel substantially better, with resolution of symptoms of infection, they should call the clinician to determine whether antibiotics can be stopped early. Clinicians should be receptive to this concept, and not fear customizing the duration of therapy.

That was in 2016 – and now we have an update. Just last week Dr. Spellberg added to the shorter is better mantra by saying that with sicker patients, those on 5-day courses of antibiotics have better treatment outcomes than those on 10-day courses. And that’s because the shorter duration group experience less antibiotic-driven superinfections, less drug resistance, and less antibiotic side effects.

The following are Dr. Spellberg’s remarks given at a webinar last week hosted by the Health Services Advisory Group in the United States. He addresses the antibiotic duration question beginning at the 41-minute mark. If you haven’t heard Spellberg in action, you want to. The written word cannot capture his passionate, sometimes sardonic, quick-witted way of speaking:

Since then, studies have come out on the sicker type of patients…. And the trials with the sicker patients found the same thing – not only are the antibiotics just as safe & effective [but] [t]here was one subpopulation in which there was a statistically significant difference found. That was the Port 4 & 5 population [people who should be hospitalized].

The sicker patient was the only population that found a difference in outcome between the short course therapy and the long course therapy group. And here’s the fascinating thing: The patients who were sicker did better with short course therapy. They actually had better clinical outcomes when they got 5 days than 10.

And so somebody commented to me at one point, Well that doesn’t make any sense. That would only be true if antibiotics were harmful. YEAH! That’s what it’s telling you. Antibiotics are harmful. They’re not this thing that magically cures disease and has no unfortunate side effects – that’s not real. Antibiotics have lots of problems associated with them: They breed out resistance. They breed out superinfections like C. diff [an antibiotic-driven bacterial infection] and Candida [a fungal infection]. They cause side effects.

Right? Who gets the resistance, the superinfections and the side effects? The sickest patients in the ICU. This makes perfect sense. Not only was there no improved outcome with longer therapy, patients who were sicker did better … with short course therapy.

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