Infectious Disease

Understanding and Combating Antibiotic Resistance

We must begin embracing a terrifying idea: antibiotic-resistant superbugs don't just live in hospitals anymore. They live in the sand, on the cliffs and coves we share with birds, and in seawater. And there's nothing to suggest they won't continue spreading into our lives.

Resistant, resistant, resistant. The E. coli that grew in my nursing home patient's prior urine culture resisted every antibiotic short of meropenem. Meropenem! Carbapenems, as we learned in medical school, are mostly considered a last resort. And yet, my febrile and delirious patient was receiving meropenem as her first-line antibiotic.

The rise of antibiotic resistance has been a problem in hospitals for quite some time. However, secondary to the widespread use of antibiotics in agriculture and its leakage into water streams, antibiotic resistances are now even encountered in animals. Recent news from Murdoch University announced that seagulls all over Australia carry bacteria that are resistant to most known antibiotics including meropenem.1 We must begin embracing a terrifying idea: antibiotic-resistant superbugs don't just live in hospitals anymore. They live in the sand, on the cliffs and coves we share with birds, and in seawater. And there's nothing to suggest they won't continue spreading into our lives. 

Today, there are more than 100,000 known antibiotic-resistance genes spanning almost every known antibiotic class.2,3 And there are more than 1,000 unique enzymes that can metabolize penicillin alone.4

If bacteria can resist existing antibiotics, then we logically need to use new antibiotics — drugs the bacteria haven't seen yet. However, the vast majority of antibiotics in use today were discovered before the 1970s.5 According to CDC data, 10 antibiotic classes made up the majority of prescriptions in the U.S. from 2011-2015.6 That's a very small arsenal, especially against multidrug-resistant bacteria.

Why has the rate of antibiotic discovery slowed to a crawl?5,7

The general explanation is natural selection. Bacteria find solutions to antibiotics faster than we create them. A growing body of research demonstrated that bacterial evolution only partly explains why the antibiotic pipeline is frozen.2,8,9

"Antibiotic discovery is not a scientific problem," says microbiologist Dr. Ronald Breaker, an investigator at the Howard Hughes Medical Institute and the first person to isolate DNA enzymes. "There are other forces at play that are preventing us from seeing our path forward."

If it's not all about evolution, why can't humans come up with new antibiotics? "Scientists can figure out all sorts of ways of killing microbes that you want dead. We're in a state largely driven by economics where we're on a trajectory to die like it's the 1930s again," explains Dr. Breaker.

Economics does indeed lie at the heart of the frozen antibiotic pipeline, and antibiotic resistance altogether. To understand why, it helps to imagine PharmaX, a fictional small pharmaceutical company trying to bring a new drug to market. They start by finding a promising molecule, one that's exciting enough to encourage investors to give the company money. This can be expensive. For example, in 2008, GlaxoSmithKline famously spent $720 million buying Sirtris, a small company investigating resveratrol and other molecules purported to fight aging.10

After identifying a molecule, PharmaX must pass trial after trial demonstrating the molecule is not only safe and effective but at least as effective as drugs that already exist. A 2018 study found the median cost for FDA trials is about $19 million, but larger clinical trials — like the trials needed for new antibiotics — would cost about $300 million.11 Overall, developing a new drug is estimated to cost $2-$3 billion.12

This is unfortunate but understandable. Investing a large sum of money into an idea that is presently untestable without a guaranteed is difficult. If we can't rely on the antibiotics pipeline because it's cost-prohibitive, then what are we left with?

"It's also a diagnostics issue, right?" explains Dr. Kazmierczak. "You need to identify the pathogens to target them, and I think that's where things fall apart."

In other words, if we could know at the point-of-care which commonly available antibiotics will treat an infection, then we could avoid using unnecessary antibiotics. With fewer exposures, bacteria would have fewer opportunities to develop resistance. A 2017 study supports this -  if you force physicians to make educated guesses about antibiotic regimens, resistance rises dramatically.15 But if we have access to point-of-care testing, resistance develops less frequently. 

In sum, new antibiotics are incredibly expensive to develop.  

Dr. Breaker has some ideas: "Somebody in a position of responsibility should decide that a particular microbe is enemy No. 1, and through government funding or private funding or both, put out a $1 billion prize. If you get a novel antibiotic class that hits this organism or this class of organisms, and it must have certain properties, certain efficacy, certain safety, and then you get this billion-dollar prize."

And if the solution isn't exactly what Dr. Breaker is describing, his central point is clear: The economics of antibiotic discovery and diagnostic development need to make sense. 


References

  1. Mukerji S, Stegger M, Truswell AV, et al. Resistance to critically important antimicrobials in Australian silver gulls (Chroicocephalus novaehollandiae) and evidence of anthropogenic origins. Journal of Antimicrobial Chemotherapy. 2019;74:2566-2574.
  2. Munita JM, Arias CA. Mechanisms of Antibiotic Resistance. Microbiology spectrum. 2016;4:10.1128/microbiolspec.VMBF-0016-2015.
  3. Jia B, Raphenya AR, Alcock B, et al. CARD 2017: expansion and model-centric curation of the comprehensive antibiotic resistance database. Nucleic acids research. 2017;45:D566-D573.
  4. Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiology and molecular biology reviews : MMBR. 2010;74:417-433.
  5. Lewis K. Platforms for antibiotic discovery. Nature Reviews Drug Discovery. 2013;12:371.
  6. CDC. Outpatient Antibiotic Use2017.
  7. Wohlleben W, Mast Y, Stegmann E, Ziemert N. Antibiotic drug discovery. Microbial Biotechnology. 2016;9:541-548.
  8. Sundqvist M. Reversibility of antibiotic resistance. Upsala journal of medical sciences. 2014;119:142-148.
  9. Holmes AH, Moore LSP, Sundsfjord A, et al. Understanding the mechanisms and drivers of antimicrobial resistance. The Lancet. 2016;387:176-187.
  10. Herper M. Why Glaxo Bought Sirtris: Forbes; 2008.
  11. Moore TJ, Zhang H, Anderson G, Alexander G. Estimated costs of pivotal trials for novel therapeutic agents approved by the us food and drug administration, 2015-2016. JAMA Internal Medicine. 2018.
  12. DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics. 2016;47:20-33.
  13. Wade N. Doubt on Anti-Aging Molecule as Drug Trial Stops. New York Times2010.
  14. Ledford H. GSK absorbs controversial ‘longevity’ company: Nature; 2013.
  15. Tuite AR, Gift TL, Chesson HW, Hsu K, Salomon JA, Grad YH. Impact of Rapid Susceptibility Testing and Antibiotic Selection Strategy on the Emergence and Spread of Antibiotic Resistance in Gonorrhea. The Journal of infectious diseases. 2017;216:1141-1149.
  16. Kuehn BM. Idsa: Better, faster diagnostics for infectious diseases needed to curb overtreatment, antibiotic resistance. JAMA. 2013;310:2385-2386.
  17. McAdams D. Resistance diagnosis and the changing economics of antibiotic discovery. Annals of the New York Academy of Sciences. 2017;1388:18-25.
  18. McAdams D. Resistance diagnosis and the changing epidemiology of antibiotic resistance. Annals of the New York Academy of Sciences. 2017;1388:5-17.

19. CDC. Nearly half a million Americans suffered from Clostridium difficile infections in a single year. 2015.

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