What change looks like

The practice of medicine changes slowly, at least more slowly than science changes our understanding of disease.  There are some good reasons for this, and some bad.  The good reasons are that science does not always proceed smoothly from lesser to greater understanding.  Partial understanding of complex processes - and few are more complex than health and disease - can lead to actions and recommendations that are more harmful than helpful.  One does not have to look far for examples: the classification of homosexuality as a disease, the use of general anesthesia during childbirth (my mother had to physically fight this off), and any number of misguided dietary recommendations.  In many cases, doctors and their patients are well-served by a conservative and skeptical attitude toward modernization of medical practices.  If a change is not clearly going to lead to better outcomes, then perhaps it is best to wait before adopting it.  Scientists are free to proclaim the beauty and elegance of their new findings without having to deal with any messy unexpected consequences.  Doctors have no such luxury.

Bad reasons to resist change can be described in many ways, but mostly comes down to ego and money.  No one like to be told that they way they have been doing things is wrong.  No one likes it, and some like it so little that they refuse to see the obvious.  This has been the state of play in antibiotic prescribing practices for the last decade or so.  Doctors, for the most part, have not treated patients; they have not treated specific pathogens; instead they have treated signs and symptoms.  Urinary tract infection? Prescribe ciprofloxacin - even though 30% of E coli UTIs are resistant to fluoroquinolines.  Child with a fever? Time for Augmentin.  Respiratory tract infection?  A Z-pack should take care of that.  The names of the antibiotics have changed over the decades, but the approach has not: a certain set of symptoms triggers a corresponding prescription.  No microbiological data are involved.

This system was unavoidable when it took 2-3 days to get a microbiology result.  No one, doctor or patient, should wait that long for a treatment that is well-tolerated and highly likely to be effective.  But rapid tests for microbiology have been available for close to a decade now.  These tests certainly have their limitations, and they are more pricey than streaking bugs on a Petri dish and waiting.  However, most doctors are very comfortable with the practice of evidence-free (empiric) prescription, and are not demanding data from rapid tests.  If the doctors are not demanding rapid test results, the clinical microbiology lab is very unlikely to expend the time and money needed to provide them.  The weak sales of existing rapid tests starves their developers of the capital needed to create better tests, creating a death spiral for their companies.

There are signs that this invidious dynamic may be beginning to change.  Cohen et al recently published “A multifaceted ‘omics’ approach for addressing the challenge of antimicrobial resistance”, describing some of the changes that new technology is poised to make in the treatment of infectious disease.  They include a wonderful infographic that succinctly summarizes the causes, challenges and costs of resistance:

Some of their predictions and recommendations for the use of “omics” technology are overkill: phenotypic testing of susceptibility and resistance will always be more reliable than molecular methods such as proteomic profiling.  But that’s fine.  These issues will work them selves out in due time.

The important point of the paper is not any specific recommendation or prediction.  The important part is its emphasis on data-driven treatment of infectious diseases, as part of the “TAILORED-treatment” research program.  Ultimately it doesn’t matter whether individualized treatment data comes from PCR, or mass-spec, or accelerated culture methods.   All of these data can be used to improve public health by enabling the prudent use of antibiotics, and to improve patient health by providing the most effective treatment.

These data are sometimes available now, and will become more and more available as the technology gets better.  The question is, how hard will it be to get doctors to use the data?  Let’s hope that this generation of doctors is more open to positive change than their antecedents.

From Quora: Discovery of Teixobactin (January 2015): What is the potential of Teixobactin?

Teixobactin is still in preclinical development.  At least 90% of new entities at this stage fail to gain clearance and make it to the clinic.  That is the most probable outcome, based on historical trends.  However, the results reported in the Nature paper are pretty strong, and I expect the odds are much better for teixobactin than for the average new entity.  But it is still 50:50 at best that it will ever be cleared.

Assuming it does get cleared, here is what we know about its properties that would affect its ultimate utility:

1 - It is effective against a wide spectrum of Gram-positive bacteria (eg, Staphylococcus)

2 - It not effective against Gram-negative bacteria (eg, E. coli or Acinetobacter)

3 - It is unlikely to be orally available

Here's what we don't know:

1 - Its biodistribution and efficacy in various tissues and organs.

2 - Its pharmacokinetics in humans

3 - Its side-effect and toxicity profile

The upside that I see for teixobactin is that it is used much as daptomycin is today: an alternative to vancomycin for treating systemic Gram-positive infections.  As it will probably have to be administered by IV, its use will largely be confined to hospitalized patients, unless its side-effect profile and pharmacokinetics are sufficiently favorable to allow use in outpatient clinics.

Teixobactin has definite potential to be a valuable tool.  But it does nothing to solve the most pressing issue in antibiotic development, the need for new agents that are effective against multi-drug resistant Gram-negative organisms.

From Quora: How do doctors determine if a patient has a viral or bacterial infection when the symptoms look like a common cold?

Unfortunately, they don’t.  The vast majority of these infections are viral, yet some 60% of patients walk away with a prescription for antibiotics that will do them no good whatsoever.

The chart below gives you some idea of the number of visits to primary care physicians for respiratory infections (a lot), the frequency of these that are bacterial infections (few) and the rate of antibiotic prescriptions for these infections (way too many).

Gonzales et al (2001)

There are no good rapid diagnostics that will distinguish bacterial from viral infections.  There are rapid Strep tests for pharyngitis, but their sensitivities are only about 80%, meaning that a negative result does not rule out the possibility of Strep throat.  There are the Centor criteria and other signs algorithms, but their accuracy is also around 80% at best.  White blood cell counts are of no value in differentiating viral from bacterial pneumonia, and it is unlikely that they are any more accurate in differentiating other respiratory infections.

Doctors know that they are overprescribing antibiotics, but they do it anyway.  The principal reasons they cite are patient expectations, time pressures and diagnostic uncertainty.  There is a perception that there is some prophylactic value in prescribing antibiotics to patients who have viral infections; that this will reduce the risk of a complicating bacterial infection.  However there is no evidence for this view.

Instead, there is a significant risk of adverse events from needless prescription of antibiotics.  There are some 140,000 visits to Emergency Departments each year due to antibiotic use, mostly for allergic reactions and diarrhea.  C. difficile infections kill some 14,000 Americans each year, and are almost always associated with prior use of antibiotics.  Our increasing understanding of the gut microbiome suggests that antibiotics may increase the risk of asthma, obesity and diabetes, especially when given early in life.  And of course, antibiotic overuse is undoubtedly a contributing factor to antibiotic resistant infections, which kill some 23,000 Americans each year.

So, back to your question: Doctors use a variety of methods to distinguish bacterial from viral infections; none of these is very good; consequently, they overprescribe antibiotics; public health is damaged.

From Quora: Will antibiotics ever become useless?

This article: Imagining the Post-Antibiotics Future points out that over the years, it has taken fewer and fewer years for antibiotic resistant strains of bacteria to emerge after every new antibiotic is discovered. Is it likely that in the near future bacteria will evolve quickly enough, and the corresponding diseases spread fast enough that there will be lots of infectious diseases that are not treatable by antibiotics?

No.  Although the usefulness of antibiotics has become attenuated by the spread of resistant strains, they will never become useless.  There is generally a fitness cost associated with antibiotic resistance: either in maintaining additional genes and proteins that confer resistance, or in the decreased performance of genes mutated to confer resistance.  Thus in the absence of selective pressure - that is, in the absence of antibiotic use - the frequency of antibiotic resistant strains decreases.  Not right away, and certainly not to zero, but it does decrease.  We are seeing this effect in the case of methicillin-resistant S. aureus (MRSA), where the frequency of MRSA among all S. aureus in US hospitals has dropped from 50-60% to 40-50% in the last decade.  Although the cause of this decrease is not known with certainty, it is likely that increased efforts to promote prudent use of antibiotics has played a role.

Nearly all strains of pathogenic bacteria are susceptible to at least one antibiotic.  The trick is to determine which one within a clinically meaningful time frame.  This determination results in more effective treatment for the patient and less selective advantage for resistant strains.  Unfortunately, there are few rapid tests available for susceptibility determinations, and hospitals have been slow to adopt the ones that are available.  Apparently 23,000 deaths per year and a 40-50% misprescription rate are not a sufficient incentive to make the investment in labs and testing that are required.

From Quora: Do antibiotics weaken one's immune system? If yes, how?

This is a question that has a superficially simple answer - "No" - that has already been given by other respondents.  As best we know, antibiotics do not interact with the cells and molecules of the immune system, so there is no simple mechanism through which they could weaken the immune system.

However, consider this: many bacteria secrete molecules which modulate the activities of the immune system.  An example is Staphylococcus epidermidis, a skin commensal.  It secretes compounds that activate  toll-like receptors in keratinocytes (skin cells) which in turn stimulates the release of antimicrobial peptides.  These peptides suppress the growth of potentially pathogenic bacteria.  Another example: bacteria in the gut release polysaccharides which modulate the activity of CD4+ and CD8+ immune cells.  In both of these examples commensal bacteria are manipulating the immune response to suppress competitors.  If these competitors are also human pathogens, then the interaction is mutually beneficial.  Killing these bacteria with antibiotics might well weaken the immune system.

This sort of research is still in its infancy, and it is too early to say with any certainty what the effects of antibiotics on immune responses are.  But if we start thinking about the bacteria in and on our body as part of a tightly connected ecosystem, rather than as alien invaders, then the answer to your question becomes fairly obvious.  Although we really don't understand how, the likelihood that disrupting our bacterial ecosystems (which antibiotics most surely do) will also alter our immune systems is very, very high.

From Quora: If bacteriophages are cheap, effective and don't lead to resistance, why isn't the healthcare industry replacing antibiotics with them?

Why isn't there an aggressive push being made by the healthcare industry to replace antibiotics with bacteriophages when they are cheap, effective and don't cause antibiotic resistance?

As you might suspect, there are a number of issues.

First and foremost, antibiotics have been a terrible investment for pharmaceutical development for the last few decades.  Brad Spellberg has estimated that the Net Present Value of a new antibiotic is negative $50M USD.  That is, discovering a new antibiotic and bringing it to market is likely to be a money loser.  We have come to expect antibiotics to be cheap, so margins are low.  Antibiotics are typically taken for a few days, so there is no long-running revenue stream.  Low margin + short-term use = no profits to be made.

Brad's calculation was made for tradtional antibiotic entities - small molecules whose development and manufacture the pharma industry has perfected to a high degree.  Bacteriophage are much messier - fragile and finicky biological entities whose purity and integrity are much harder to assess, particularly at large scale.  Thus R&D costs are likely to be higher and riskier, making the NPV numbers even worse for bacteriophage.

Bacteriophage are also much harder to protect as intellectual property.  The concept of using phage as antibiotics is a century old, and cannot be patented.  Individual phage certainly can - but because phage are so diverse and abundant, there is a good chance that a competitor could find an unrelated phage that is functionally equivalent to a patented phage.  Thus it is much harder to keep competitors at bay once you have shown the feasibility and profitability of a given phage formulation.

And not least - phage science has been a backwater for decades, and a lot of the people who work in this field produce weak science.  There are any number of examples of publications showing some small effect in a contrived clinical model which claim a breakthrough.  This has been going on for a couple of decades now.  The only sign of actual progress has been from AmpliPhi Bio (formerly BioControl), who have gotten as far as Phase II clinical trials with a phage treatment for Pseudomonas ear infections.

The bottom line is that there is not enough money in antibiotic development in general, and bacteriophage development in particular, to fund a serious and sustained effort to bring the technology to maturity.  It absolutely is technically feasible, and there absolutely is a clinical need.  But until society assigns the same sort of value to antibiotics as it does to (for instance) cancer therapeutics, progress will be very slow.

From Quora: Why is it important to determine the difference between bacteria?

Ideally, doctors would have two bits of information available to guide antibiotic therapy: bacterial identification and antibiotic susceptibility.  Not all antibiotics work on all types of bacteria.  In particular, Gram-negative bacteria (those with an outer membrane covering their cell wall) are treatable with fewer and different antibiotics than Gram-positive bacteria (those with a naked cell wall).  Within those two categories, optimal antibiotics vary by species.

In the era before widespread antibiotic resistance, bacterial identification was sufficient to insure appropriate antibiotic treatment in the vast majority of cases.  This is no longer the case, although doctors and hospitals have been slow to recognize the new reality.  Resistance rates for first-line antibiotics are now commonly 30-60%.  Doctors have responded to these high levels of resistance by treating ALL infections with broad-spectrum antibiotics.  One of these, vancomycin, is now the most commonly prescribed drug in US hospitals.  The inevitable consequence of this behavior is to hasten the day when these antibiotics are no longer effective.

In the best-case scenario, doctors would have (and use) timely antibiotic susceptibility results in addition to identification results, so that they would prescribe broad-spectrum antibiotics only to patients whose infections are resistant to narrow-spectrum antibiotics.  This would not only preserve the usefulness of broad-spectrum antibiotics, but result in better patient outcomes.