Double-barreled news today from the US Centers for Disease Control and Prevention. In an analysis of several sets of hospital data, gathered by the agency and also purchased from independent databases, the CDC said it found that more than 37 percent of prescriptions written in hospitals involved some sort of error or poor practice, increasing the risk of serious infections or antibiotic resistance. And in a surprise announcement timed to the release of the federal draft budget, the agency said it is in line to receive $30 million to enhance its work combating antibiotic resistance in the US.
Happy new year, constant readers. Here’s the most urgent thing I have to say today: Stop reading and go set your DVRs for 8pm ET tonight. The fantastic The Poisoner’s Handbook, written by Wired colleague and dear friend Deborah Blum, has been adapted by PBS and airs tonight on The American Experience. It’s going to be superb.
Back? OK, on to business. Just before the holidays, the Food and Drug Administration finalized its long-aborning plan to ask the meat-production industry to reduce its use of routinely administered antibiotics. (My posts on the move here and here.) The FDA’s guidance to industry, as it is called, is not a regulation but rather a request for voluntary action on the part of veterinary-drug companies. It has met with skepticism and concerns that manufacturers will redefine the uses of their drugs in such a way that nothing will change.
The FDA action is aimed at the routine use of antibiotics for what is called growth promotion — causing animals to gain muscle faster than they would without the drugs being used — and is modeled on a ban on growth promoters enacted by the European Union in 2005. The goal, as in the EU, is to reduce the drugs’ use, and therefore the antibiotic-resistant bacteria that use stimulates.
In a recent New England Journal of Medicine, University of Calgary economist Aidan Hollis suggests though that a ban may not be the most useful or practical approach to the problem of drug overuse. In its place, he suggests the pocketbook persuasion of having to pay a fee.
The World Health Organization released a statement this afternoon, prompted by news of the NDM-1 multi-resistance gene. It’s worth taking a look: The agency recommends that countries around the world pay serious attention to the emergence of this resistance factor.
WHO calls for broad action within countries, from
hospital infection-control and antibiotic-stewardship programs, to
increased surveillance for the emergence of resistance, to
legislative control of over-the-counter sales. Those sound like (and are) minimal and rational suggestions — but they have the potential to be quite controversial in some countries, from India where OTC antibiotic purchases are a major economic sector, to the US where best practices for hospital control of resistant organisms continue to be, umm, vociferously debated.
The WHO says:
Those called upon to be alert to the problem of antimicrobial resistance and take appropriate action include consumers, prescribers and dispensers, veterinarians, managers of hospitals and diagnostic laboratories, patients and visitors to healthcare facilities, as well as national governments, the pharmaceutical industry, professional societies, and international agencies.
WHO strongly recommends that governments focus control and prevention efforts in four main areas:
- surveillance for antimicrobial resistance;
- rational antibiotic use, including education of healthcare workers and the public in the appropriate use of antibiotics;
- introducing or enforcing legislation related to stopping the selling of antibiotics without prescription; and
- strict adherence to infection prevention and control measures, including the use of hand-washing measures, particularly in healthcare facilities.
The WHO has been working on antibiotic resistance for a while now, though the effort seems to be continually obscured by urgent news of outbreaks such as SARS, H5N1, H1N1 and so on. Here’s their short fact sheet, detailed program page, and Global Strategy for Containment of Antibiotic Resistance (sadly 9 years old, so it predates the emergence of community MRSA, not to mention NDM-1).
Let’s play a thought experiment. Imagine that you’re a major pharmaceutical company, a public company, with shareholders that you answer to, and market analysts looking over your shoulder to see whether this quarter’s earnings are up to projections. Imagine that you want to make a new drug. Let’s make it an antibiotic, because — as we talk about here all the time (and SUPERBUG explores in detail) — new antibiotics that can leapfrog over existing drug resistance are very needed. Thus, you imagine, a new antibiotic ought to sell well, even though any individual course of that antibiotic will only be a few weeks by mouth, or maybe a few months by IV if the patient is very sick. You know there’s a big market out there.
But: Imagine — as is generally accepted to be true — that it will take about 10 years, and about $1 billion dollars, to get that novel antibiotic through the development pipeline and into the marketplace. And then imagine that — as has been shown for a number of drugs, most recently the new antibiotic daptomycin — bacteria begin developing resistance to your drug within a year of its deployment in patients. And after that, imagine — as has been cited in a number of papers — that once local resistance to your antibiotic appears in approximately 20% of isolates, physicians will cease prescribing your antibiotic, for fear their patient will be one of that 20%.
So, to recap: 10 years, $1 billion; short course; short market life; rapid obsolescence.
Would you make that investment? Or would you, if you were a pharma company, opt instead to make insulin, which Type 1 diabetics will take every day for the rest of their lives? Or statins, which at this point we’re practically ready to put in the water supply? Or a cancer drug that costs $10,000 per dose? Or Viagra, or Cialis?
If you’re a company that is responsible to its shareholders, or listening to its analysts — or even capable of doing basic math — the answer’s obvious: Antibiotics lose. Which goes a long way to explaining why so many companies have backed off from making antibiotics, and why many of the few antibiotics in the pipeline are “me too” formulations, rather than new compounds with truly new mechanisms of action.
How to respond to this impasse has been an active debate for a while, largely focused on proposals to give market incentives, changes in tax credits, or patent extensions to pharma companies to persuade them to stay in or re-enter the marketplace. The Infectious Diseases Society of America, the specialty society for infectious-disease physicians (many of whom are also academic researchers), has been addressing this through its campaign “10x 20”, which has a goal of getting 10 new compounds into if not through the pipeline by the year 2020.
But, as a new article in the British Medical Journal points out, good incentivizing demands complexity — not just in developing both “push” and “pull” mechanisms (say, tax incentives to fund research v. prizes and wildcard patent extensions), but also in making sure that the incentives can be taken advantage of by companies of all sizes, not just the international mega-pharmas:
The characteristics of an ideal incentive mechanism and the desire for an equitable approach that engages developers of all sizes would suggest that neither push, pull, nor lego-regulatory mechanisms would be optimal to spur the desired investment in antibiotics …. Rather, elements of each should be combined. The exact shape of the ideal package is, however, as yet unclear. (Morel et al.)
And an accompanying editorial emphasizes that new antibiotics are not the only things needed; new diagnostic tests, for instance, need funding as well:
Catchy as 10×20 sounds, the public sector strategy for funding such research and development must prioritise among different health technologies, such as diagnostics and vaccines, to combat antibiotic resistance. For example, three million children die each year from acute respiratory bacterial infections in developing countries, but penicillin sensitive pneumococcal strains have declined to a half, even a quarter, in some countries. A diagnostic test for bacterial pneumonia would save an estimated 405 000 lives a year, by targeting treatment and avoiding overprescription of antibiotics. New vaccines may also reduce reliance on drugs as the use of pneumococcal vaccine has suggested. (So et al.)
This is a hard discussion. I confess, as a longtime reporter, I flinch reflexively at the thought of handing more money to the pharmacos. At the same time, the state of the market demonstrates that the current model is not working. And though I would much prefer we focus on the ecological model of preserving antibiotics as a resource — dialing back on overuse and encouraging rigorous stewardship — it’s clear that we’ll always need new drugs for the most serious, most resistant infections.
So some sort of incentivizing seems necessary. And the multi-layered approach recommended in the BMJ, with appropriate attention paid to incentivizing the development of tests and vaccines as well, seems worth heeding.
As promised, lots to catch up on — so here’s a quick round-up of some great reading that I have been stashing and that you may have missed in the past few weeks.
BBC News: Disinfectants may train bacteria to resist antibiotics
The BBC Health page (bookmark it!) translates a paper from the journal Microbiology on Pseudomonas aeruginosa’s newly recognized ability to pump the active ingredient in disinfectants out of its cells — and then to apply that same ability to the antibiotic Ciprofloxacin, even when it has never been exposed to Cipro before. Money quote: “... Residue from incorrectly diluted disinfectants left on hospital surfaces could promote the growth of antibiotic-resistant bacteria.”
Associated Press: Solution to killer superbug found in Norway
In the latest installment in a 6-month series, AP writers Martha Mendoza and Margie Mason examine Norway’s success in forcing down rates of hospital MRSA. chiefly by extremely strict control of antibiotics dispensed in hospitals. I have some disagreements with this story; I don’t think they account for how much easier it is to do antibiotic stewardship, as it’s called, in a single-payer health system such as Norway or their second example, England, compared to the extremely complex US system. But I’m very glad to see the AP (and the Nieman Foundation at Harvard, where Mason was a fellow) support public exploration of antibiotic resistance, which I obviously feel gets insufficient attention. (Stay tuned for SUPERBUG’s discussion of one US stewardship program that has worked and may be replicable.)
Time: Should weight factor into antibiotic dosage?
Time.com looks at a provocative new paper in the Lancet that questions whether standard prescribed dosing of antibiotics isn’t really a form of inappropriate use. Money quote: “Dosage according to body mass is standard in anesthetics, pediatrics, oncology and other fields, [but] when it comes to antibiotics and antimicrobials the dosing guidelines are too broad… and may undermine a medications efficacy. …In the face of both widespread obesity and the increasing prevalence of antibiotic-resistance, tailoring dosage for optimal results is increasingly important.”
And finally, new today:
Science Daily: Bacteria Are More Capable of Complex Decision-Making Than Thought
University of Tennessee researchers explore the ability of a bacterium (the soil bacterium Azospirillum brasilense) to sense changes in its environment, process that information and make surprisingly complex decisions in response.
UK and EU readers can hug themselves with self-congratulation this morning (OK, admittedly, for you it’s afternoon already): It’s Antibiotic Awareness Day across the European Union, featuring a slate of public-awareness activities, public-service announcements, educational efforts, and random appearances by the charming little hedgehog above (kicking antibiotics, don’t you see). It’s all meant to convince people that antibiotics are a precious resource and that misusing them encourages antibiotic resistance.
The campaign is organized by the European Centre for Disease Prevention and Control (the EU equivalent of the US CDC) and is being carried out by an enviably long list of national agencies within the EU. It’s accompanied by the publication in the journal Eurosurveillance of an article setting out the challenges of controlling antibiotic resistance across such diverse nationalities and geographies.
There are materials on the site that would be useful for anyone attempting to get the message of antibiotic stewardship across to physicians, family members or friends: There’s a fact sheet for the general public, one for physicians and other experts, and one that specifically addresses the temptation to take antibiotics in cases of H1N1 flu.
There’s also a short film explaining the genesis of Antibiotic Awareness Day and the basics of antibiotic resistance, and a marvelous set of pull-no-punches short video spots. This one — comparing antibiotics to a lightbulb slowly burning out — is my favorite.
Folks, I mentioned that I’m way behind in working down a stack of great articles. Here’s a very good one that I missed when it came out two weeks ago and is well worth your time.
A team from John H. Stroger Hospital (the new location of the iconic Cook County Hospital, public hospital for downtown Chicago) and from the Alliance for the Prudent Use of Antibiotics at Tufts University (headed by Dr. Stuart Levy, dean of antibiotic resistance scholarship in the US) has analyzed the direct and distributed costs of resistant infections, and their results are stunning. They took a random sample of patients seen at the hospital, sorted out a subgroup that suffered from resistant infections, and computed the costs that those infections imposed: in medical costs, increased length of stay, and excess deaths. Those sort of calculations have been done before at other institutions (cf. for instance the excellent work of Susan Cosgrove of Johns Hopkins), but what makes this Chicago study striking is an additional layer of analysis that computes the “social cost” to the families of those infected.
In the study’s words:
In a sample of 1391 patients, 188 (13.5%) had [antibiotic-resistant infections]. The medical costs attributable to ARI ranged from $18,588 to $29,069 per patient in the sensitivity analysis. Excess duration of hospital stay was 6.4–12.7 days, and attributable mortality was 6.5%. The societal costs were $10.7–$15.0 million.
(Just to underline: These are almost certainly underestimates of the current problem and its current costs — because to get very solid data, the Stroger team went back in their database to patients who were treated in 2000. That’s before the emergence and dominance of CA-MRSA USA300 nationwide, and its subsequent movement into hospitals. Since 2000, the MRSA epidemic has gotten worse.)
An accompanying editorial takes the next step in logic, stressing that if we’re not going to work to reduce ARIs because it is good medicine to do so, we should do it because it is critically cost-saving:
…[T]he findings of Roberts et al  are significant, making a strong case for both the medical and financial benefits of reducing antimicrobial resistance. This is an important and timely question, considering the national focus on the prevention of health care–acquired infections, a significant proportion of which are caused by antimicrobial-resistant organisms, and the call for institutions to develop antimicrobial stewardship programs. These data should help inform decisions regarding the structure and implementation of health care initiatives designed to improve patient care while controlling unnecessary costs.
The cite for the study is: Rebecca R. Roberts, Bala Hota, Ibrar Ahmad et al. Hospital and Societal Costs of Antimicrobial‐Resistant Infections in a Chicago Teaching Hospital: Implications for Antibiotic Stewardship. Clinical Infectious Diseases 2009 49:8, 1175-1184.