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?

 

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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.

 

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"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.

 

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