A century ago, the top three causes of death were all infectious diseases: pneumonia or influenza, tuberculosis, or gastrointestinal infections.  More than half of all people dying in the United States died then because of germs.  Today, those germs account for about a few percent of deaths at most.  

We owe much of that, of course, to antibiotics.  The discovery of Prontosil, the first synthetic modern antibiotic, earned (?~0:25) the Nobel Prize in 1939.  Mass produced Penicillin earned Alexander Fleming, (?~0:30), and Howard (?~0:32) one in 1945.  It's hard to overstate how much less of a threat infectious diseases pose to us today, but we take antibiotics for granted.  We use them inappropriately and indiscriminately.  This has led many to worry that our days of receiving benefits from them are numbered.  That's the topic of this week's Healthcare Triage.

(Intro)

When I was a medical student, doctors around me were panicking about (?~1:01) resistant staphylococcus aureus, or MRSA.  Before then, infection with that bacteria had been almost exclusively contained to healthcare facilities.  In the 1990s, it was then starting to appear in the wider community.  Today, community-acquired MRSA is so common that we pretty much assume that any staph infection is MRSA.  

Concern about the rise of resistance often focuses on overuse of antibiotics.  There's plenty of evidence that we, the users, are the problem.  In a recent multi-country study conducted by the World Health Organization, almost 2/3 of people believed that antibiotics could be used to treat colds and the flu, which are, of course, caused by viruses.  Anitibiotics kill bacteria, not viruses.

The same number of people also knew that antibiotic resistance was a real problem that could affect them, but this knowledge did not seem to prevent them from mis-using the drugs.  Every time we use antibiotics, we increase the chance for resistant strains to develop.  Bacteria are very good at the evolution game, and killing off more susceptible strains leaves them more resistant ones to fill the gap.

Bacteria have also become good at transmitting resistance abilities through plasmids, which are small, circular, DNA molecules that can be transferred like a hand-off from bacteria to bacteria without any reproduction.  The wide-spread use of antibiotics in the raising of animals has clearly contributed to the development of resistance as well.  The Food and Drug Administration estimates that more kilograms of antibiotics are sold in the United States for food producing animals than for people. 

Animals are also where the most recent worry is focused.  Until very recently, even as some E. coli have become resistant to nearly every antibiotic we have, they've remained susceptible to colistin, an old but rarely used (at least in humans) drug.  Being old though, the drug is cheap and for that reason, it's become popular to add colistin to animal feed in some countries like China in order to produce cheaper pork and other meats.

In a recent report published in Lancet Infectious Diseases, scientists discovered colistin-resistant E. coli in 21% of slaughtered pigs in China.  They found isolates in 15% of meat sold from those animals in retail sites.  They even detected resistant E. coli in more than 1% of hospitalized patients.  

Most horrifying, it appears that the resistance is transmitted by plasmids.  This means the bacteria don't just pass on resistance to their "children", they can pass it among one another and to completely different strains of bacteria.  Scientists were also able to detect colistin-resistance from the same gene in (?~3:36) pneumonia in hospitalized patients.  The accompanying editorial to the colistin report called this, and I'm quoting, "A major breach in our last line of defense."  

While the concern is reaching a fever pitch, it's important to remember that resistance isn't new.  We can't blame all of our problems on antibiotic overuse and mis-use.  Even the proper use of antibiotics will eventually lead to resistance.  Our response to these setbacks has been to create new types of drugs.  Penicillin-resistant staphylococcus were already being seen in labs in 1940, a few years before mass produced Penicillin was introduced.  

Tetracycline was introduced in 1950 and resistant shigella were identified in 1959.  Erythromicin's introduction in 1953 was followed by resistant streptococcus in 1968.  Gentomycin developed in 1967 saw resistance in 1979.  Vancomycin, developed in 1972, saw resistance in 1988, and Imipenem, released in 1985, saw resistance in 1998.

We're also failing in this game of catch up.  15 of the 18 largest pharmaceutical companies have abandoned the antibiotic market entirely.  Research funding in all areas of academia have been cut back significantly as well.  While 19 new antibiotics were approved by the FDA from 1980 to 1984, only 13 were approved from 2000-2014.  We aren't keeping pace with resistance.

We can quibble about the exact cost of bringing a new drug to market as I've done in previous episodes, but we can all agree, it's a lot of money.  Drugs in the United States are profitable, when they're sold in great volume or when they're very expensive.  Antibiotics, as a class of drug, provide a poor return on investment for pharmaceutical companies.  They face low-priced and generic competition.  Any breakthrough drug will almost certainly be held in reserve for only the most resistant cases, meaning there's not a huge immediate market for it when a company still has exclusivity.  

Many people have proposed new ways to incentivize and reward innovation.  The G7 group is poised to coordinate action, as is the G20 group and the WHO.  In Davos in January, nearly the entire drug industry agreed.  It released a statement calling for big changes in how we pay for antibiotic research and development, including the idea of de-linkage, or paying for value as opposed to volume of antibiotics sold.  

There are other glimmers of good news.  The federal budget agreement passed late last year increased spending in this area by more than $375 million.  Almost half of that went to the Centers for Disease Control to help prevent and monitor outbreaks.  The National Institutes for Health received $100 million for antibiotic resistance research.  The Biomedical Advanced Research and Development Authority also received an additional $96 million to help explore new drugs.  Later this year, the agency will start an antibiotic research and development accelerator, with $30 million available each year over the next few years.

It's this new drug investment that might bring the most hope.  For many years, spending on antibiotic resistance research was flat.  Only in the last year or two, as both the President and Congress seemed especially interested in pushing for more funding.   New antibiotics are a public good, not necessarily an area for private rewards.  Huge public support for researching new classes of antibiotics will be necessary to combat this growing threat.  As a sage observer once noted, though, bringing new antibiotics to market without changing how we use them is akin to providing alcoholics with a finer grade of brandy.

For this reason, most new funding goes toward prevention, infection control, and managing antibiotic use.  The best outcome is preventing infections through vaccination or public health measures so that we improve human health without increasing resistance to antibiotics.

Healthcare Triage is supported in part by viewers like you through patreon.com, a service that allows you to support the show through a monthly donation.  Your support makes this show bigger and better.  We'd especially like to thank our research associate Joe Sevits, and thank our surgeon admiral, Sam.  More information can be found at patreon.com/healthcaretriage.