• Saving the world, one antibiotic at a time

    Jim O’Neill leads the Antimicrobial Resistance Review for the UK Government. They just issued their third report, now focused on how to bring effective antibiotics to the market.

    He calls for two new global institutions: an Antibiotic Innovation Fund, partially funded by the companies, to jump-start basic research. The target is US$2 billion over five years, which would be a very significant increase over existing funding levels (US NIH funding for non-TB antibiotic resistance has averaged only $90 million per year in 2013 & 2014; most NIAID funds go to viruses, retroviruses, parasites and mycobacteria). Given the flat funding environment for basic research, this is a very welcome step.

    But ideas will never move from the lab to the patient unless commercialization occurs. How do we incentivize companies to bring excellent antibiotics to market? For most products, the new features sell themselves, but for antibiotics, for very good reasons, a novel drug is mostly put on the shelf and reserved only for extreme cases. And this is the right thing to do, since we need to exhaust the older antibiotics first and conserve the new ones for emerging infections. Makes perfect sense for medicine and public health, but it undermines commercial incentives for the companies. Imagine if Apple had to prove that all previous generations of iPhones were defunct before customers were allowed to buy or use the latest phone? Phone innovation would grind to a halt.

    The emerging solution to this unique problem with antibiotics is called delinkage, which severs the link between antibiotic sales volumes and company profits. The O’Neill report embraces two versions of delinkage, paying companies for value of the antibiotics delivered to the market as opposed to mere volume of sales. Both would require a global coordinating institution. Antibiotic delinkage has been my major research focus for a decade, so this is a happy moment.

    Many details remain to be worked out – and a major Chatham House report on this topic is due next month – but this AMR Review report marks a watershed event as an authoritative endorsement of the principle. I also welcome the decision to focus public funds on the areas of greatest need (currently, Gram-negative bacteria, per the CDC).

    Background: a call for similar global institutions in the WHO Bulletin; and the US domestic issues in Health Affairs 2015; and my comments on the US National Strategy.

    Also, for model geeks, the AMR Review hired IMS Health to update the parameters in the Eastern Research Group model of antibiotic R&D expenses and revenues. The full model in Excel and data will be open access (!) is here.


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  • “Resistance” to vaccines

    While antibiotics degrade with use through resistance, most casual observers assume that vaccines are immune to these effects. They would be wrong. Resistance is simply evolutionary change under environmental pressure. For influenza vaccines, evolutionary changes render prior flu vaccines relatively ineffective each year, which is why influenza samples are collected in Southeast Asia each year and shared with 5 national labs to help develop the new vaccine each year. (In the US, the final decision is made by the VRBPAC – the Vaccine and Related Biological Products Advisory Committee at the FDA).

    Beyond influenza, we have mounting evidence that some vaccines affect the ecological balance of the susceptible and non-susceptible serotypes of the relevant pathogens. For example, the HPV-4 vaccine targets the 4 most serious serotypes of the HPV virus, but many dozens of other HPV serotypes are not covered by the vaccine. Likewise, the original pneumococcal conjugate vaccine (PCV-7) targeted 7 serotypes of pneumococcus; the newer one targets 13, but coverage remains incomplete.

    Over time, we are seeing evidence of “serotype replacement,” in pneumococcus and HPV meaning that as the vaccines work to remove the targeted types from the human environment, the non-targeted serotypes expand to fill the ecological niche. In addition, and even more troubling, is when vaccine-targeted pneumococcus acquire elements by recombinations, including capsule switches that render them protected from the vaccine (Science). Some data on the effect of PCV-13:


    Annual Report of the Chief Medical Officer, Vol. 2, 2011; see also LID 2011;11(10):760-68.

    Which brings me to the paper Marc Lipsitch & colleagues just published in Philosophical Transactions B.   Using stochastic math models, they explored how antibiotic use interacted with serotype replacement in pneumococcus. The presence of antibiotics confers an advantage on resistant strains, which affects the emergence of resistance:

    Under neutral conditions no emergence was observed. With a 1% advantage, emergence was observed in a minority of realizations for the high-burden setting. At 3% and above, emergence was nearly universal, indicating that antibiotic use is a key determinant of the emergence of resistant lineages following PCV introduction. (emphasis added)

    And from the discussion:

    We have integrated these factors into a single model with the conclusion that antibiotic pressure is likely the most important driver of the emergence of resistant, NVT [non-vaccine-type] lineages…(emphasis added)

    This combination of observed data and other modelling work lend credence to our finding that the expansion of a previously rare antibiotic-resistant lineage is probable following the introduction of a PCV targeting common resistant types. So long as vaccination targets only a subset of pneumococcal serotypes, antibiotic pressure will likely lead to the emergence of resistant lineages. This may be facilitated in settings that combine high or intermediate drug pressure with high carriage prevalence. (emphasis added)

    The solution is not to abandon vaccines, but to develop better vaccines that cover all serotypes and in the meantime to understand the impact on resistance.

    And if you have read this far, perhaps you are interested in joining the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria. Deadline for nominations closes on May 13, 2015, so hurry!



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  • A $4 item at Walmart could save the lives many children each year

    Antimicrobial resistance is undoubtedly a major public health concern, but it can be easy to overlook the much larger crisis (at present) of unnecessary deaths worldwide due to inadequate access to these drugs (WHO Bulletin). 700,000 children under 5 die each year from pneumonia, sepsis and meningitis. While data are not complete, most of these infections appear to be susceptible to many existing antibiotics. Hundreds of thousands of children are dying for lack of inexpensive generic antibiotics, the same ones that are $4 at Walmart. Key barriers include the cost of bringing your child to a hospital in low-income settings, the difficulties in training community health workers to give injectable drugs, as well as the cost of the drugs themselves. Could there be better ways to get antibiotics to these children?

    The Gates Foundation has funded a remarkable series of very practical studies (the African Neonatal Sepsis Trial, also sponsored by WHO), two of which were published in The Lancet this week. The studies identify sick infants in the community (in 5 locations in Africa) and refer to the local hospital when appropriate. But many parents refuse that referral on financial grounds. From this population, the studies randomize treatment with two sets of antibiotics, given in the community setting. One is typically the injectable antibiotic that would have likely been given in hospital; the other is the oral antibiotic amoxicillin. The study question is whether the treatments are equivalent. This matters because oral antibiotics can be given more easily in the community, with less well trained workers.

    The first study compared oral amoxicillin (twice a day for seven days) with injectable procaine benzylpenicillin plus gentamicin (once a day for seven days) in children suspected of pneumonia (with very simple protocols). The second study looked at other serious bacterial infections, comparing the same injectable antibiotics with three other options that included oral amoxicillin replacing some of the injections.

    Both studies concluded that all of the tested regimes were equivalent. Switching to oral amoxicillin can therefore be expected to save many children in low-income settings where referral to hospital is not possible and use of injectable antibiotics in the community is not feasible.

    My bottom line: we should do everything possible to preserve oral amoxicillin for these populations. But resistance to beta-lactams is growing, and the drugs are not being preserved for the best human uses: amoxicillin is routinely prescribed in the US for otitis media (ear ache), which is largely self-resolving. And on US farms, more than 800,000 kgs of drugs in this class were given to animals in 2013 (the last year data is available).

    Yet another reason for a comprehensive reform of how we create and use antibiotics (see the Administration’s plan here).


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  • The SGR fixed more than we thought: gainsharing

    In addition to the well-publicized aspects of the SGR fix, the legislation also addressed a long standing problem in the fraud and abuse laws that limited hospital “gainsharing” programs.

    Gainsharing is similar to the ACO “shared savings” bonuses paid by Medicare if the health system achieves cost and quality targets, but classic gainsharing agreements are entirely private (i.e., between health systems and physicians who practice there).  For example, a hospital and a group of surgeons might sign a gainsharing agreement that shared savings in the OR from more economical ordering and use of medical supplies and devices.

    The catch was Section 1128A(b)(1) of the Social Security Act, which prohibited any payments by a hospital to a physician as an inducement to reduce or limit services provided to Medicare or Medicaid beneficiaries who are under the direct care of the physician. Hospital counsel worried — with good reason — that a gainsharing program would be considered a payment to induce a reduction in services, resulting in very substantial civil monetary penalties.

    Even if the services were wasteful, unnecessary or dangerous, federal law prohibited these gainsharing payments. I co-authored a paper for the American Health Lawyers Association describing the problem in detail – in 1999.

    Fast forward 16 years and Congress has finally acted, by adding the words “medically necessary” to the statute.  Gainsharing is now permitted, so long as medically necessary services are not reduced or limited.  Alternative payment models now need not fear the CMP as much (see my 2014 TIE post on alternative payment model language in the SGR fix bill).

    For more on this gainsharing development, see a briefing by my former firm, MWE.


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  • Do we get MRSA from pigs?

    Eli Perencevich and colleagues at the University of Iowa continue to publish interesting work on the epidemiology of MRSA, using data their patients in the VA and their farm-state location near many animals.

    In a previous study, they found that living within 1 mile of a high-density pig farm nearly doubled the risk of colonization with MRSA upon admission (ICHE, 2014 Feb;35(2):190-3). Building on that work, they now report (in Antimicrobial Resistance & Infection Control) the links between nasal colonization and MRSA clinical infections (many are colonized, but fewer are clinically sick at the moment), by genetic testing of both samples from the same patients. Paired samples like this are rarely tested.

    They found that paired samples were genetically and phenotypically indistinguishable, suggesting that colonization was the source for clinical infection. The more surprising result was that classic “livestock-associated MRSA” or LA-MRSA spa types were not identified in these patients:

    Livestock-associated MRSA does not appear to contribute significantly to the prevalence of MRSA colonization or the burden of MRSA infections in ICVAHCS, despite the high density of livestock in the region.

    Before you (rashly) conclude that high-density pig farms are not a threat to human health, consider the alternative:

    Taken together, these results suggest that swine may be a source of non-LA-MRSA colonization and infections in humans.

    An excellent research question, indeed.


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  • The National Action Plan on Combating Antibiotic Resistance

    Antibiotic resistance is a complex social problem, with alarming global implications. That’s why it is exceedingly good news that the White House released the full National Action Plan today.  We’ve known that antibiotic resistance is a problem for more than 70 years, but today is the first time any Administration has taken the threat this seriously.  It’s the boldest move by any President on this issue. Ever.

    Do I wish it had gone further? Sure, but I’m an academic researcher. I always have new questions to explore. The report needs more heft on what happens to reimbursement after FDA approval, for instance.

    But look at the solid targets across many areas, the goals set in agriculture, the emphasis on global and regional coordination, and the significant attention to diagnostics.  Not just a good first step, but a dozen good steps.

    Congress should fund this as an insurance policy against a post-antibiotic era.


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  • UK Report: Steps we can take now on antimicrobial resistance

    In London this morning, the second Report on antimicrobial resistance has now been issued by Jim O’Neill. While many complex issues require further study on resistance (prior TIE posts here), the Report finds sufficient evidence on five issues to warrant action now:

    1. Increase basic research funding, primarily in the university setting;
    2. Extend the lives of existing drugs;
    3. Create and deploy diagnostics to reduce unnecessary use;
    4. Invest in human capital – the grad students, post-docs, research teams, and ID physicians who will be on the front lines of this effort for decades; and
    5. Build a modern surveillance system for infectious diseases, with digital capabilities in real time.

    O’Neill is right that there is broad consensus in the policy community for all five, and has been for some time, with the possible exception of number 4. The human capital issues have only been recently raised with sufficient vigor, most notably by our colleagues over at Controversies in Hospital Infection Prevention (especially the famous dumpster fire post and its sequel – instant classics). So let’s focus on the human capital section of the O’Neill Report.

    First, follow the money, and ID docs are among the worst paid specialists in the US. Train for several additional years, take difficult call schedules, but make less money than your peers:

    doc pay

    Second, building on the analysis by the CHIP crew, when medical residents match in the US, one of the few unfilled specialties is ID, with a large number of programs having unfilled slots. Every unfilled slot is a loss to future efforts to control hospital infections. Applications for the better paid specialties are robust by comparison:


    Third, the Report found evidence that citation rates are lower for journals specializing in resistance and microbiology, which makes academic careers and grant funding more difficult when compared to “hot” fields like cancer.

    I also worry about the effect of flat to declining research expenditures in bacterial research. R01 grants are always difficult to start a career as a researcher, but in bacterial fields they are harder still. Given the robust funding over the past decade for some biodefense threats like anthrax or plague, a young researcher might reasonably choose these organisms instead of those responsible for large impacts on current human health, such as gonorrhea, acinetobacter, e.coli or staph.

    For the White House plan on these issues, see Maryn’s summary here. Hopefully, Congress will work with this budget proposal and move some significant funding forward.


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  • The puzzle of antibiotic innovation

    Cross-posted from Health Affairs Blog

    Dame Sally Davies, the Chief Medical Officer of England, warns that we are approaching an antibiotic apocalypse. A former chief economist at Goldman Sachs estimates that unless dramatic action is taken now, antimicrobial resistance could kill 50 million people a year and cause $100 trillion in cumulative economic damages. In the US, dire warnings have issued from the CDC, the President’s Council of Advisors on Science and Technology, and the President himself through an Executive Order on Combating Antibiotic-Resistant Bacteria in September 2014 (summary here). The President’s new budget asks for $1.2 billion to be spent on antibiotic resistance.

    But last week, the science press breathlessly celebrated the discovery of a new antibiotic, teixobactin, cultured from soil samples collected in a grassy field in Maine (the study was published in Nature). Crisis over?

    Not so fast. Teixobactin has only been studied in mouse models, not humans. The point estimate failure rate for antibiotics from early discovery stage to actual drug approval for humans is 97% (only 3% survive) (see the ERG Study for the US Government, page 3-9). After approval, most antibiotics fail in the marketplace for commercial and safety reasons; antibiotics suffer market withdrawals at triple the rate of all other drugs (JLME).

    The Price-Volume Model

    But let’s assume that teixobactin makes it through 5-10 years of clinical trials and is approved by the FDA with great fanfare. Hundreds of millions will have been invested in these clinical trials. How will the company see a profit on their investment? A recent study conducted by the Eastern Research Group for the US Government suggests the company will lose money, even on a “successful” antibiotic.

    Under the existing “price-volume” model, drug companies make money by selling drugs, either with high prices, high volumes, or both. The October 2014 Health Affairs issue on specialty drugs highlighted many examples, including the new drugs for Hepatitis C.

    For antibiotics, the price-volume model is broken. For excellent clinical reasons, new antibiotics are adopted very slowly. Hospital stewardship programs rightly control the use of new drugs to delay resistance. This is good news for patients, but terrible news for the companies trying to sell an innovative new antibiotic. Imagine if the new iPhone 6 could not be sold until all of the existing iPhone models were completely exhausted first.

    Due to the threat of resistance, antibiotic innovation cannot be based on high volume of sales. As Scott Podolsky notes in his new book The Antibiotic Era, the US overmarketed antibiotics in the 1950s and 1960s, leading to the crisis today.

    Looking Beyond High Prices

    High prices are also not a likely solution, as antibiotics are more substitutable than many drug classes and many generic antibiotics remain effective competitors. Higher prices would also give companies an incentive to overmarket, while worsening access to these drugs for millions of patients around the world who need effective antibiotics. For all the concern about future deaths from resistance, it is clear that more people die today from susceptible bacterial infections than resistant ones, meaning that improving access will save more lives.

    In an article published in this month’s Innovation issue of Health Affairs, my colleagues and I lay out alternatives to the price-volume model for antibiotic innovation. Fixing the business model is urgent if we want antibiotics to make it out of the lab and into the patients who need them.


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  • Agricultural antibiotics in the President’s budget request

    More than 80% of US antibiotic use occurs in agriculture, especially in the production of meat from poultry, pigs and concentrated feed lot operations for beef cattle. A useful recent survey of the research on this issue for poultry and pigs was just published by Aude Teillant and Ramanan Laxminarayan, Economics of Antibiotic Use in U.S. Swine and Poultry Production.

    Three main take-aways here:

    1. Most of the studies showing a significant benefit from antibiotics as growth promoters (AGPs) were conducted decades ago, before many farms improved animal husbandry practices and before resistance grew. Studies on more modern operations show little or no benefit from AGPs.

    2. New antibiotic classes have been rare, and it seems likely that new classes will be restricted to human use. If so, the agricultural sector needs to protect and extend the usefulness of the antibiotics currently available. Agricultural antibiotics are a limited resource; they should not be used when other substitutes (better practices, vaccination) are available.

    3. The President’s antibiotic proposal in the budget calls for $77 million for the Department of Agriculture, a four-fold increase (Maryn McKenna). These funds could help us dramatically reduce total US antibiotic consumption, improving human health while not burdening our farmers.


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  • Don’t cut the CARBs

    Building on the ambitious Combatting Antibiotic-Resistant Bacteria (CARB) process, the President’s budget request this week called for dramatically increased funding, $1.2 billion. This funding request is at the correct magnitude and demonstrates appropriate balance between various priorities. While Congress will surely have views on the specifics, I hope for broad consensus that very bold action must be taken along the general lines described by the President. Paying $1.2 billion dollars a year as an “insurance premium” to avoid the end of antibiotics is a critical policy priority. I suspect that every scientist and policy wonk working on these issues would agree with this statement.

    We know resistance warrants at least a billion-dollar annual investment in the US, based on the economic and policy work undertaken over the last few years in the US (the ERG report for HHS and the CDC Threat Assessment), England (the Chatham House working group and the O’Neill Review on AMR), the EU (DRIVE-AB), and the WHO draft Global Action Plan on AMR. The policy consensus is strong to act boldly.

    This week the House Energy & Commerce Committee released a discussion draft of legislation under the 21st Century Cures Initiative (full text here). The proposals fall short of what we need.  Solving this problem will require spending real money.

    Section 1061 permits early release of antibiotics with less data on safety and efficacy, together with a more restrictive label. This provision is no surprise and has been in the works for a while (prior versions here and here). While it will undoubtably get antibiotics to the market more quickly, that will not be a panacea for antibiotic innovation unless we fix reimbursement. We will get some drugs several months earlier with thinner data packages on safety and efficacy; as a result, these drugs will not sell well until better data is available. Innovation will not be rewarded.

    Section 1062 updates how we test for antibiotic susceptibility and how that is communicated on the drug label. My concern is whether this provision would further encourage off-label use of antibiotics. Antibiotic should be used with better evidence of safety and effectiveness.

    Section 1063 creates “wildcard exclusivity,” a radical and controversial departure from our 226-year history with US patent law. The Constitution (Art. I, sec. 8, cl.8) gives Congress the authority to create IP:

    To promote the Progress of Science and useful Arts, by securing for limited Times to Authors and Inventors the exclusive Right to their respective Writings and Discoveries.

    The “exclusive right” is tied to the invention itself (“their respective writings and discoveries”). If you discover a new drug, you get a patent on that drug.

    Section 1063 breaks from the Constitutional standard and historical practice by offering a 12 month period of exclusivity on a completely unrelated drug. Create a new antibiotic, and the reward is a fully transferrable 12 months of exclusivity that could be given to a drug for cancer, heart disease or Hepatitis C. This reward is very indirect and inefficient, and can be quite costly as it will protect billions of dollars of drug sales from generic entry. The provision also calls for “donations” to the NIH and patient access programs, but understand that all of these funds come from our health insurance system through higher drug prices when generic drugs are delayed. It will also be very difficult to control this idea. If antibiotics are worthy of wildcard exclusivity, why not cancer, Alzheimer’s and every orphan drug?

    Data supports the need for billion-dollar incentives for antibiotics; wildcard exclusivity is just a poor way to achieve that goal.

    Finally, Section 1064 boosts the hospital DRG for the cost of new antibiotic drugs. But this fix only helps inpatient antibiotics (typically IV drugs) and we also need new oral antibiotics. While it increases payments to hospitals, there is no guarantee of any increase to companies unless they market to hospitals and convince them to pay more. Finally, this does nothing for reimbursement for infection control, diagnostics, vaccines, and antibiotic stewardship. Medicare should pay for those things too: we know that infection control has been essential in bending the curve on MRSA.

    The US Congress and the Administration have an opportunity to work together to truly reform the broken business model for antibiotics. Let’s make policy based on the best available evidence.

    Prior TIE coverage on antibiotics.


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