Antibiotic overuse in the ER - rapid test needed

A lot of antibiotics get prescribed from the ER. And unfortunately, a lot of antibiotics get prescribed inappropriately there. That's the take home from a report by Donnelly et al in AAC this month.

Over 12M Americans visit the ER for acute respiratory infections every year, and about 60% leave with a prescription for antibiotics. This number has decreased only slightly in the last decade, from 62% to 58%, despite increased stewardship efforts.

The key parameter is how many of these patients got antibiotics who should not have, and here the numbers are discouraging: about 48% of patients not diagnosed with a bacterial infection still got antibiotics.

It's not too hard to understand why this happens, especially given the transient nature of the doctor-patient relationship in the ER setting. But that's a lot of antibiotics to be challenging our collective microbiomes with, and almost certainly a major driver of the spread of antibiotic resistance.

More education seems unlikely to help, and requiring pharmacist or ID doc sign off for prescribing seems unrealistic for ER care. The ideal solution would be a rapid test that distinguishes bacterial from viral infections.

Given that there are hundreds of potential pathogens for respiratory infections, the strategy for developing a viral vs bacterial test can't be based on pathogen detection. Instead, this test would take advantage of the differential response of our immune systems to bacterial vs viral infections.

One such test already exists, the procalcitonin test. PCT is a mediator of cytokine responses, the molecules which different cell types in the immune system use to communicate and coordinate their responses to infection. PCT levels rise in response to bacterial but not viral infections. The availability of PCT assays in the ER has been shown to reduce excessive antibiotic use by 30-80%. Unfortunately PCT has some limitations as a biomarker - its levels rise in response to a number of shock states, not just bacterial infections.

It is unlikely that PCT or any other single biomarker will serve to adequately distinguish bacterial from viral infections. However, a couple of studies (here and here)have shown that arrays of biomarkers - some 15 to 30 in all - collectively perform quite well at this task.

So the concept of a bacterial-viral test is sound, but the path to execution is not yet obvious. The vast majority of diagnostic assays measure a single analyte. There are a few multiplexed assays for bacterial identification and resistance gene detection, such as the Cepheid Xpert or the Nanosphere Verigene systems. But the genes of immune cells don't vary in response to infection - it is the pattern of mRNA and protein expression that changes. Neither the Cepheid or Nanosphere systems currently measures mRNA levels, and therefore some serious product development would be required for either of these platforms.

For detection of protein expression, the only multiplex platforms are mass spectrometry and the SomaLogic SomaScan system. Sample prep is always the Achilles heel of mass spec - the amount of sample cleanup required to get a good signal makes it a poor platform for a rapid test. The SomaScan system is currently configured only as a lab-developed test that takes a couple of days to return results. It could potentially be developed into an IVD platform, but that hasn't happened yet.

So there is a significant opportunity here - urgent unmet clinical need, much wasteful spending, very large markets. Is anyone up to the challenge?

 

Posted with Blogsy

Doing what the FDA won't

I haven't written about the FDAs new voluntary relabeling of antibiotics for livestock use because I don't expect it to have much effect. It is a positive step in the sense that it acknowledges the problem of antibiotic overuse in livestock production, but that's about it.

The Netherlands tried a similar approach in the 2000s, banning the use of antibiotics as growth promoters. The "therapeutic" use of antibiotics promptly expanded to the point where overall consumption of antibiotics remained unchanged. The result for public health? Being a pig farmer classifies you as a presumptive carrier of MRSA in Dutch hospitals, which are otherwise nearly free of MRSA.

So that didn't work out so well there, and I expect the results of the FDAs action to be about the same here. The tell is that the antibiotic manufacturers are going along with it, not squealing too loudly, you might say. Thus they expect little disruption to their business model.

Ideally we might follow the lead of Denmark, which has instituted an effective ban, and had no trouble maintaining or increasing their production of pork and chicken. But that sort of edict is not likely to happen here - the political power of of rural constituencies and drug suppliers is much greater than that of public interest regulators.

Raising the cost of antibiotics would be the most effective way to ensure that they are put to the highest-value uses. A tax on antibiotics would discourage indiscriminate use. If the proceeds were rebated to producers on a per-pig basis, farmers would be incentivized to minimize use of antibiotics. In effect, the antibiotic-free producers would get a subsidy. They would be the winners, helping to split political opposition to the tax. The heavy users of antibiotics and the pharmas who manufacture and sell them would be the losers. However, given the power of the status quo in American governance, they would likely be able to block change.

Like it or not, some mechanism to preserve pharma profits will have to be found. This could come in the form of a "floor" on antibiotic prices, much like price supports for milk and other commodities. A floor would allow margins to go up as volume goes down, preserving profitability.

This sort of solution is ugly - it basically amounts to bribing farmers and pharmas to not endanger public health. But it would actually result in reduced usage of antibiotics in livestock. That's something that the FDA is unlikely to ever do on its own.

 

Posted with Blogsy

"Stumpage" fees for animal antibiotics

Aidan Hollis and Ziana Ahmed have published a short and terrific letter in NEJM outlining the benefits of a user fee for agricultural uses of antibiotics (h/t HuffPost). Key points:.

1. More than 13M kg of antibiotics are sold for ag use in the US each year, at a cost of less than $25/kg.
2. A ban on the use of antibiotics as growth promoters would raise prices some $2B per year.
3. The medical value of antibiotics is more than $60T in the US; thus even a 1% loss of susceptibility due to ag use is a big economic loss, much larger than the economic benefits of ag use.
4. They liken antibiotic susceptibility to a commons, and propose a user fee that would be akin to stumpage fees paid by loggers.

There's more - but go read it for yourself.

 

Posted with Blogsy

High prices for antibiotics - a good thing

The problem of antibiotic resistance is getting another profile boost with its inclusion in the NYT's "Room for Debate" series. There is actually little debate in the section, save the attempt by the Pork Council to downplay the threat of overuse of antibiotics in the livestock industry. Instead, there are good, but somewhat unconnected pleas for test-driven use of antibiotics (David Gilbert), better financial incentives for antibiotic R&D (Brad Spellberg), a more rigorous, top-down approach to infection control (John Bartlett), and advocacy of phage therapy (Matti Jalasvuori).

I'd like to connect the dots by suggesting that most of our problems with antibiotics have an underlying root cause: that antibiotics are too cheap.

Cheap antibiotics do not produce a return on investment for R&D. Cheap antibiotics are too readily prescribed for minor respiratory infections that are predominantly viral. Cheap antibiotics can be used as a growth promoter for livestock, and as a substitute for clean living conditions.

If a life-saving course of antibiotics cost thousands of dollars, rather than hundreds, pharma companies would race to develop them. If Z-packs cost hundreds of dollars, doctors would not be so quick to prescribe them for sore throats. If it cost tens of dollars, rather than pennies, to dose hogs with tetracyclines, then routine use of them would cease.

Antibiotic susceptibility in bacteria is not precisely a finite resource - it's not as though there are only a certain number of prescriptions that can be written before a given drug becomes useless. But it is certainly a common resource, one that can be depleted rapidly or husbanded for the use of future generations. We have been choosing to deplete their effectiveness rapidly, but we don't have to.

We could preserve effectiveness by a top-down approach, placing limits on who could prescribe antibiotics, or requiring test results for prescription. But these regulations would quickly become outdated as new technologies and diseases emerge. Regulation also would provide no financial incentive for R&D investment.

In contrast, high prices would make development of narrowly-targeted antibiotics more attractive, and would rein in overuse in both humans and livestock. Although individuals might pay more, society and the health care system would pay less, as there would be fewer patient deaths and fewer long stays in the ICU due to untreatable infections.

How would we obtain high-enough prices for antibiotics? Cancer drugs often cost many tens of thousands of dollars for a course of therapy. It's not clear how they obtained this pricing power, other than the fear of cancer that our society has cultivated. We've lost our fear of bacteria, but starting a scare campaign to restore it hardly seems ethical or feasible.

A conservation tax would raise prices to end-users, but would not provide a ROI for developers, unless the tax proceeds were channelled back to them. This system would be susceptible to abuse. Another approach might be to set a floor on prices, much as we do for milk and other commodities. A guaranteed price would reduce market risk for developers, as well as suppress overuse of currently available antibiotics. A price that is determined by trends in the development of resistance would make this system more effective, and somewhat less arbitrary and prone to abuse.

Higher antibiotic prices would reflect their true value to society. They would let us get to a future where new antibiotics are being developed, while old ones maintain their usefulness. It's a step we need to take.

 

Posted with Blogsy

Empiric therapy - not a substitute for rapid testing

In the last post I wrote about the case for the value proposition of narrowly-targeted antibiotics as developed by Spellberg and Rex. Their model has an implicit assumption - that the hypothetical high-priced antibiotic will be prescribed in a timely manner to patients who will benefit from it, and only to those patients. My point in that post was that a companion rapid diagnostic would be needed in order to realize this scenario, that such a test is likely to have a significant cost as well, and that this cost needs to be factored into the analysis.
David Shlaes has taken issue with this view, explaining that

"Luckily, physicians don't wait for the diagnosis before treating. They treat empirically - and if they are in a hospital where MDR Acinetobacter is a risk - they will use a new expensive drug to cover for that possibility until they have confirmation or not. "

He is of course correct. No physician faced with a failing patient would withhold a drug that might have a significant therapeutic benefit. But this practice has all sorts of implications for the value of narrowly-targeted antibiotics, and none of them are good. I'm not sure that "luckily" is the adverb I would have chosen to describe the situation.
Let's be clear - empiric prescribing is a necessary response to imperfect information. But there should be no illusions that physicians have some magic powers that make empiric prescriptions much better than guessing. Indeed, a careful study of prescribing practices is entitled "Empirical antimicrobial therapy for bloodstream infections ...: No better than a coin toss". As the title suggests, when faced with a binary choice between choosing an antibiotic that is optimal for MRSA and one that is optimal for MSSA, doctors did no better than predicted by chance. There is no reason to think they would do any better in choosing optimal antibiotics for Gram-negative infections.
Combine this element of chance with the fact that the organism of interest in this scenario is not all that common, and the case for the value of an antibiotic narrowly targeted toward it can deteriorate pretty quickly. Acinetobacter infections are not currently likely to constitute more than 10% of Gram-negative infections in any hospital in North America. Although not dominant, this level is high enough to be a threat in any patient with a serious infection, and physicians will have to treat accordingly.
If they prescribe the antibiotic to cover possible Acinetobacter infections in half of these patients when only 10% are actually infected, then there are several unintended consequences, all of them bad (except for the 10% who actually have Acinetobacter infections).
First, the value proposition for the antibiotic becomes far weaker. In Spellberg and Rex's median case the antibiotic costs $10K per dose, and the net cost for an additional year of life saved is only $3K (anything less than $50K is considered to have a favorable cost-benefit ratio). But if the antibiotic has no benefit for the patients who turn out not to have an Acinetobacter infection (and this is stipulated in their scenario), then use of the drug is a dead loss economically. If 50% of patients receive the antibiotic when only 10% are infected with Acinetobacter, then the cost per year of life saved goes from $3K to $15K, a much less attractive proposition.
Second, the non-Acinetobacter patients are exposed to the risk of adverse events, with no corresponding clinical benefit to compensate. Since this is a hypothetical drug, there is no point in trying to quantify this risk, but it is surely not zero.
Third, this level of overuse will accelerate the development of resistance to the drug. Although narrowly targeted by definition, it is biologically implausible that it would have no negative effect on the fitness of any of the thousands of species of bacteria that comprise the human microbiome. And once resistance develops in one species, it is only a matter of time until it spreads to many species, including the targeted pathogen.
Now imagine that there are several narrowly targeted antibiotics available: one for Pseudomonas, another for carbapenem-resistant Enterobacteriaceae, etc. In the absence of a rapid test, how will a physician decide which to prescribe? Should she prescribe all of them? If she does, all of the negative effects of inappropriate therapy listed above would be compounded.
All of these problems go away if there is a rapid test. If I were a pharma exec, I would not begin considering a program to develop a narrowly-targeted antibiotic unless I felt pretty confident that a companion rapid test could also be developed. The path to clinical and economic value is just too full of land mines otherwise.

Posted with Blogsy

Can't have the drug without the test

As I've written before, antibiotics are too cheap. Drug companies simply can't get sufficient ROI on a product that is used once and costs a few hundred dollars. They would much rather develop drugs that patients take every day for the rest of their lives, or develop cancer medications that bring in $50-100K for a course of therapy.

Via David Shlaes, I see that Brad Spellberg and John Rex have looked into the question of how much a course of antibiotics could cost, and still return a net benefit to all parties. Their hypothetical drug is narrowly targeted toward carbapenem-resistant Acinetobacter baumanii (CRAB), a bug for which all current therapies are ineffective or highly toxic.

They find that at $10K for a course of therapy, an Acinetobacter-specific drug which reduced mortality from 20% to 10% would end up costing some $3000 per year of life saved. The comparable value for Avastin, a best-selling cancer drug, is $168,000. In other words, even a $10K antibiotic is actually pretty cheap.

What Spellberg and Rex don't address is how that cheap/expensive antibiotic gets prescribed in the first place. Since the hypothetical drug is narrowly targeted, there first needs to be an identification that the infectious agent is indeed Acinetobacter, and that it is in fact carbapenem resistant. Standard hospital micro lab procedures can do this, but it typically takes 3 days to get a result. In that time the patient is being treated with ineffective antibiotics, and may well be past the point of recovery by the time the correct diagnosis is made.

The obvious answer - and I know Brad is an advocate of this - is to develop rapid diagnostics that would identify Acinetobacter and determine carbapenem resistance in a few hours from a patient sample or positive blood culture. The first part of this is very doable using nucleic acid technologies. Verigene has a research-use test that ID's Acinetobacter spp, and other platforms surely have the same capacity. However, carbapenemase genes come in lots of varieties and developing a gene sequence test for them that has high sensitivity is no trivial task. And it's necessary, because 25-50% of Acinetobacter infections are still susceptible to carbapenemase, and you don't want to use the new, expensive antibiotic unless it is known that other agents won't work.

But let's say it's doable - what then? To have an impact, the hospital micro lab will have to test every Gram-negative blood culture with this test. Acinetobacter infections are on the rise, but they are still only a few percent of bloodstream infections in the US. Let's say they are 4%. That means that the micro lab will have to run - and pay for - 25 tests to catch a single positive case. Current PCR tests for MRSA, which are much simpler than a prospective carbapenemase test, cost $50-100. A dedicated CRAB test would have to cost at least $200, when fully capitalized and staffed. So the micro lab will have to spend $5000 to make a single diagnosis that drives use of the new $10,000 antibiotic.

That's a lot, but it still makes good economic sense, from a societal standpoint, to spend that money and treat the infection effectively. But society (at least in the US) doesn't make the spending decision - individual actors, such as doctors and microbiology lab managers do, and their incentives do not always align with society's.

We found this out the hard way at MicroPhage. Our test allowed patients with methicillin-susceptible S aureus infections (about half of all S aureus infections) to be taken off empiric vancomycin, and be treated with more-effective and less-toxic beta-lactams. It cost $50, and a typical hospital would have to spend about $2000 in testing to get an actionable result. The savings in health care costs would be $10,000+, making the test very cost-effective.

It was an utter flop in the marketplace, with sales of about $50K in its first and only year on the market. The problem? The micro lab manager, who had to buy the test, paid all of the costs and saw none of the savings. That was pretty much a deal-breaker.

Absent significant structural reform, the hypothetical CRAB test would likely meet the same fate. And without the test, the antibiotic would have much less impact, and likely fail to generate a decent ROI.

None of this is meant as a criticism of Spellberg and Rex. But it points out another layer of structural barriers that we have unwittingly erected to the development of new antibiotics. Unfortunately, until all of these problems are solved, it's as if none of them are solved.

 

Posted with Blogsy

The sore throat menace

The IDSA's report on infectious disease IVDs is out now, and it is squarely focused on the need for tests that will enhance antibiotic stewardship efforts. In particular, a test that would distinguish viral from bacterial infections is needed. Tens of millions of patients seek medical aid for upper respiratory infections each year in the US. About 10% of them have bacterial infections, but 60% or more go home with a prescription for antibiotics. Worse, the fraction of these prescriptions that are for broad-spectrum antibiotics is steadily increasing.

This is pure folly in so many different ways. Antibiotic susceptibility is a finite resource. Of the few sore throats that are bacterial infections, nearly all are due to Strep pyogenes, and nearly all strains are susceptible to penicillin. How many patients who went home with Cipro later ended up with C. difficile diarrhea or became infected by some cephalosporin-resistant bug?

A place where the report's authors did not go is to advocate restrictions on the ability of physicians to prescribe antibiotics as promiscuously as they have become accustomed to doing. Guidelines and education are all that is advocated. But this approach has been in place for decades and has stalled out: antibiotic prescriptions for upper respiratory infections went from 80% of patients in the 90's to 60% in the 00's, and has stayed there ever since.

 

From Barnett and Lindner 2013

Two developments are needed to have an impact. The technological fix would be a point of care test that distinguishes viral from bacterial infections, and this is certainly near the top of the IDSA's wish list. But availability of a test that will improve prescribing practices is not enough to ensure its adoption. We developed such a test at MicroPhage, and it sank like a rock in the clinical marketplace. There also needs to be some form of coercion, or if you like, encouragement, to do the right thing rather than the expedient thing. The growth of electronic medical record keeping means that it should be possible to track MDs who prescribe excessive amounts of antibiotics. A letter from the state medical board, or the FDA, might be a good way of gaining the attention of these miscreants. Or just knowing that someone is watching is often sufficient to improve behavior.

If this seems heavy-handed, consider that these physicians are creating a public health hazard, while providing minimal clinical benefit to their patients and exposing them to an increased risk of adverse events. I think that is sufficient rationale for impinging on physician autonomy.

 

Posted with Blogsy