May 8, 2014

The Growing Threat of Clever, Drug-Resistant Pathogens: Continued

On Tuesday, I reviewed the World Health Organization’s April report about antimicrobial resistance (AMR), the alarming proliferation of dangerous, adapting pathogens that are impervious to our latest drugs. The WHO analysis actually used the word “apocalyptic” to sound the alarm.

The AMR theme reappeared yesterday, when I read an article in the April 2, 2014 issue of the Princeton Alumni Weekly titled “Invasion of the Superbugs: The stubborn problem of drug-resistant bacterial diseases is escalating.”

That article makes many interesting points:
  • In the USA, two million people become infected each year by drug-resistant pathogens. About 23,000 of them die.
  • Big Pharma isn’t scrambling to develop new antibiotics, since research costs are too high for the small profit those drugs might generate. In the 1980s, the FDA approved 30 new antibiotics. Since 1999, it has approved only 15.
  • Even Congress – action-averse these days on most issues – passed legislation two years ago that gave priority to applications for new antibiotics. The law also extended the period BEFORE new antibiotics would become available as cheaper generics – more financial incentive for Big Pharma.
  • For the most drug-resistant, disease-causing bacteria, the last line of defense is now highly toxic antibiotics that can damage the liver and other organs. These extreme cases now affect about 240,000 Americans each year, and the number is growing.
  • Drug-resistant varieties of MRSA (methicillin-resistant Staphylococcus aureus) bacteria – the one found often in hospitals – is now appearing more frequently outside healthcare settings. That bacteria now kills more than 11,000 Americans each year.
  • According to the CDC, half of all antibiotic prescriptions are either unnecessary or not issued for the correct dose.
  • The CDC estimates that a whopping 70 percent of all antibiotics in America are used on farm animals – to prevent disease and make animals bigger. The use of antibiotics on the farm gives bacteria that much more opportunity to develop drug resistance. In December 2013, the FDA suggested a voluntary removal of certain antibiotics from livestock feed, but it’s unlike to meaningfully reduce drugs in farm feeds when such great profits are at stake.
Ramanan Laxminarayan, a Princeton economist who works with the government on drug-resistant antibiotics, said, “People start paying attention when people start dying, and many more people are now dying from bacterial infections around the world.”

As part of that interesting article, in a section titled "Tackling antibiotic resistance one bug at a time," several Princeton professors weighed in on issues they've been working on:
Zemer Gitai, associate professor of molecular biology
Pseudomonas aeruginosa is the bane of many hospitals. The rod-shaped bacterium has several skinny tails that help it to slink through catheters, water pipes, and our respiratory and urinary tracts, against the flow of moving liquids. “It can act like a bacterial salmon, moving upstream of flow,” Zemer Gitai says. This mobility allows it to colonize environments that are inaccessible to other surface-attaching bacteria, including the tissues and organs of those who have compromised immune systems, causing inflammation and sepsis.In collaboration with Howard Stone, a Princeton professor of mechanical and aerospace engineering, Gitai’s lab has shown that these tails — called pili — act like hooks to pull the bacteria forward, resulting in a twitching, zigzag movement against liquid flow. The lab is trying to identify chemicals that can inhibit this unique motion. Rather than killing bacterial cells by targeting their ability to multiply, these drugs could block Pseudomonasfrom colonizing people’s bodies and hospital pipes, preventing infection. “If the bacteria does not have the capability to move through the hospital equipment or our tissues, we may be able to prevent people from getting sick,” Gitai says.
Robert Austin, professor of physics How do bacteria develop resistance in the real world? In the laboratory, bacteria are grown in test tubes and Petri dishes. But these environments do not necessarily mimic bacteria’s real-world habitats, which are complex and constantly changing. Robert Austin has developed a device that exposes bacteria to antibiotics in gradually increasing amounts rather than in a constant concentration, which more closely imitates true conditions. In an experiment with Princeton microbiologist Julia Bos, Austin found that E. coli that are gradually exposed to the antibiotic Cipro evolve resistance to the drug within 10 hours, or about 20 bacteria generations — much faster than under normal lab conditions. Bos and Austin are working to understand exactly how resistance develops and spreads within the bacterial population. Low concentrations of antibiotics appear to speed up the emergence of antibiotic resistance, the scientists say. “There are a lot of tricks the bacteria have. They are more sophisticated than we thought,” Austin says.
Mark Brynildsen, professor of chemical and biological engineering
Mark Brynildsen is working to develop antibiotics that target bacteria more precisely. Existing antibiotics attack bacteria indiscriminately, which results in more rapid development of resistance. Brynildsen is working on an approach that would cripple only the bacteria in the host that are causing illness. His lab also focuses on combating bacterial persistence, a type of hibernation state that allows bacteria to become tolerant or immune to antibiotics. “In the presence of antibiotics, persisters lie dormant for long periods of time, and when the antibiotic is removed, they wake up and re-populate the environment,” Brynildsen says. He is working to devise methods to identify these cells and find drugs to prevent their formation.
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Earlier this week, I saw that WHO had issued another warning, this time about the resurgence of polio. Ten countries now have people infected by the virus, which seemed in check just a year ago. According to the WHO report, “A coordinated international response is deemed essential to stop the international spread of wild poliovirus….” Many media outlets covered the story, including the BBC's update, "World facing polio health emergency." In the polio case, inadequate immunization programs seem to be the issue, not clever adaptations by the viral pathogen. Here's the new polio map issued by WHO:

Then on Tuesday, many PBS stations around the country aired a Frontline special (#3114), "Hunting The Nightmare Bacteria." The PBS webpage for this show begins, "The world is heading towards a post-antibiotic era, in which common infections can kill because there are no drugs left to fight them." For the time being, you can watch the program here.

The story of proliferating drug-resistant pathogens -- and the increasing ineffectiveness of our therapies to combat them -- is getting lots of attention these days. 

It's a story that won't be going away anytime soon.

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