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Tuesday, 24 May 2016 15:50

Resisting Resistance in Microbial Infections: ASM Has a Big Role to Play (Part 1)

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More than 30-Year Void in Discovery of New Types of Antibiotics. Adapted from Lynn L. Silver, “Challenges of Antibacterial Discovery,” Clinical Microbiology Review (2011) More than 30-Year Void in Discovery of New Types of Antibiotics. Adapted from Lynn L. Silver, “Challenges of Antibacterial Discovery,” Clinical Microbiology Review (2011)

The age of antibiotics is not even a century old, yet it is in serious jeopardy. Imagine returning to the time when the simplest wound or minimal surgery could quickly become a matter of life or death. This how humans lived—and died—until the mid-20th century, when biologists and physicians opened the path of discovery to effective antimicrobial drugs. A possible return to the dark ages before antibiotics is the specter behind the cover story in the May 21 issue of The Economist magazine. 

Infectious diseases continue to take a heavy toll on human health. It's estimated that every year 700,000 people are killed by drug-resistant infections. Yet things are likely to get much worse. Infectious disease experts are now predicting that by 2050, that number could reach 10 million. To understand the magnitude of the threat, compare that to the estimated 8.2 million deaths currently caused by all forms of cancer. The problem is particularly serious in developing countries where, for example, multidrug-resistant strains of tuberculosis alone cause 200,000 deaths every year. It's time to pay attention to the problem of antibiotic resistance before we find ourselves back in the dark.

The Problem of Microbial Resistance

Soon after Alexander Fleming made his groundbreaking discovery in 1928, he realized that bacteria could quickly achieve resistance to penicillin. We now know that evolutionary selection is the powerful force driving microbial resistance. Bacteria can quickly acquire resistance through a process called lateral gene transfer, in which plasmids carrying genes conferring resistance to antibiotics are passed not only to their descendants but also to other bacteria—of the same species and other species as well. This microbial wildfire can spread very quickly and resist all efforts at control. Now microbial firefighters are sounding the alarm. Last week, the Pew Charitable Trust and the Wellcome Trust issued separate reports calling the world's attention to the increasing danger of antimicrobial resistance.

A Classic Public Good Problem

Microbial drug resistance problem is a difficult to tackle because it is in part related to the classic economic dilemma known as the "tragedy of the commons." From an economic perspective, antimicrobial effectiveness (called susceptibility), which is the opposite of resistance, can be seen as a natural resource where current use lowers effectiveness in the future. It is like the problem of overfishing. Acting for individual profit, each fisherman has the incentive to catch more fish. Yet all fishermen are affected by overfishing, which makes it more and more difficult for any one fisherman to make a profitable catch. Without allowing time for species to reproduce, overfishing depletes fisheries, creating ever more problems for all fishermen.

The Importance of Incentives

The typical solution to protecting a common resource, be it fish or bacterial susceptibility, is to establish incentives that foster good stewardship, create practical regulations, and enforce restrictions. All of these elements are present in the two reports issued last week.

If we think about the economic challenge of antimicrobial treatment, we need to balance costs and benefits. The main benefit from the use of antimicrobials clearly falls to the individual who is sick; an additional benefit of use is to others who will be spared from infection. But the cost of each individual use of antibiotics also includes the risk of developing common resistance. Further, resistant infections are more expensive to treat clinically, while the costs of developing new, more powerful antimicrobials, that can penetrate the cell walls of gram-negative bacteria and avoid being pumped out, is that much greater.

Therefore, when considering effective incentives, policy makers must balance costs and benefits. Such approaches will need good stewardship to manage the many agents involved. These include:

  • Patients, who need to be better educated on the use and misuse of antibiotics. Many are tempted by the idea of taking an antibiotic "just in case."
  • Physicians, who may presently be incentivized by fee-for-service practices, or simply a desire to protect themselves from patient complaints, into prescribing antibiotics "just in case."
  • Hospitals, where a large fraction of resistant infections occur, need incentives to keep patients infection-free.
  • Hospitals and insurers, who need incentives in formulary management to discourage antimicrobial overuse and misuse.
  • The drug industry, which needs incentives to enter the antimicrobial market, where profits can be relatively low and the working life of new antibiotics relatively short.

As the Pew Trust reports makes clear, it is shocking to realize that every antibiotic in use today is based on discoveries made more than 30 years ago and that there has been no new class of antibiotics introduced since 1984, as shown in the figure. If antibiotics were telephones, we would still be calling each other using clunky rotary dials and copper lines. Forget about texting, emailing, and social media—your physician could be writing you prescriptions developed in the age of postage stamps.

The Wellcome Trust report also highlights the role of industry in developing better diagnostics to combat antimicrobial resistance. Last week ASM hosted the Clinical Virology Symposium, where over 1,000 participants gathered to discuss advances in diagnostics. The field is hot, and the buzz in the lecture halls and on the exhibit floor reflected the excitement. For example, if we had a rapid test that could distinguish a bacterial from a viral infection in less than 30 minutes, we could dramatically reduce "just in case"prescribing. A rapid and accurate test would give physicians confidence and patients reassurance in a viral diagnosis that doesn't warrant antibiotic treatment. No one wants the risk of a runaway bacterial infection, but nearly everyone realizes that the more widely we use antibiotics, the more narrowly they work. Along these lines, I was encouraged by a paper I read earlier this year in Science Translational Medicine that showed significant progress in distinguishing bacterial versus viral acute respiratory infections by analyzing biomarkers of the host response to distinguish the nature of the infection. Tests with this high level of positive predictive value, specificity, and sensitivity are not ready yet for clinical use, but the approach sounds encouraging.

Next week, I'll lay out more of the good news—and some of the bad—facing microbiologists in the struggle to resist microbial resistance.

Last modified on Friday, 27 May 2016 09:32

1 comment

  • Comment Link Hua Wang Wednesday, 25 May 2016 23:50 posted by Hua Wang

    We now know that actually a major risk factor for the rapid rise of antibiotic resistance is the mainstream oral administration of antibiotics, due to its direct impact on gut microbiota, which is the key breeding ground for AR. AR-rich feces further is the most impactful factor for the environmental AR gene pool. Simply by changing antibiotic administration from oral to injective (of course certain category of drugs, based on metabolic pathways) we are already able to achieve effective mitigation of fecal AR gene pool up to 5 logs to almost undetectable. Therefore prompt disease prevention and treatment with minimized risk of antibiotic resistance becomes possible. ASM did a Press Release in 2013 but certainly the message still needs to be broadly disseminated, and globally (i.e., there are serious health consequences we are dealing with in China due to the lack of access to the cutting-edge knowledge and misinterpretation of the mainstream information). Can we get connected by email for more discussion? Love to follow-up with you. Thanks,-Hua

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