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OCTOBER 2014
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Abel-Santos

Post-op stomach infections kill thousands, but UNLV chemist Ernesto Abel-Santos and his team just might tame the beast in the belly. 

A nurse wakes you up in the hospital; the doctor wants a word. Although still groggy from the sleeplessness of compulsive clinical care, you feel better. You’re breathing easier, the elephant on your chest is gone — just a touch of stomach cramps and diarrhea, undoubtedly from the cafeteria food. What could the doctor want?

It turns out not to be about your pneumonia, the reason you were admitted to begin with. He says you’ve contracted a secondary illness, called Clostridium Difficile (C. diff) Infection, “CDI” in medical parlance. It seems the antibiotics that you were given killed more than the infection in your lungs; they also eradicated intestinal bacteria that help keep you healthy. Without these superhero gut flora to ward off unwanted intruders, an army of tiny, dormant spores have awakened, spilled into your intestines and begun spreading harmful toxins through your digestive system. Without treatment, they could cause severe diarrhea and damage the lining of your intestines. But perhaps the worst news is this: Because you’ve contracted a hospital-borne infection, your insurance may deem it a “never event,” and deny coverage for any of the services you’ve received.

Sound like a nightmare? It’s real. CDI sickens a quarter-million Americans each year, contributing to the deaths of 14,000 of them, according to the Centers for Disease Control and Prevention. A 2011 study by the European Society of Clinical Microbiology and Infectious Diseases estimated that the annual U.S. economic burden of CDI is $496 million for hospitals, $547 million for third-party payers and $796 million for society at large.

“This is such a serious issue,” says Skip Galla, an RN in the infection-prevention program at UMC. “It’s adding insult to injury: You’re hospitalized to be treated for something, and you end up staying in the hospital to be treated for something else that you caught while you were there. It’s very challenging for hospitals.”

The scope of the crisis is why Ernesto Abel-Santos set aside his previous work on anthrax to focus on C. diff in 2007, when he moved here from New York’s Albert Einstein University to teach chemistry at UNLV. The associate professor of chemistry and his team have developed a compound that could prevent CDI, and, thanks to a deal he struck with a pharmaceutical company in Boston, it could be helping the public wake up from its hospital-infection nightmare within a few years.

 

Bacteria versus bacteria

A graduate student gave Abel-Santos’ compound the name CamSA. Ask him what it stands for, and you’ll get a shrug, accompanied by his frequently deployed and thoroughly disarming giggle. “Colic acid meta sulfonic something something,” he says, in the heavy Spanish accent he’s kept since leaving his native Dominican Republic to do a Ph.D. in chemistry at the University of Miami in the late ’90s. (After Hurricane Andrew shut down his department there, he finished his degree at the Washington University School of Medicine in St. Louis.)

Never mind its name. Abel-Santos prefers to talk about how CamSA works. It all starts with spores, he says. Most bacteria replicate like other normal life: They consume sugars, use oxygen, produce protein, divide every 20 minutes, and so on. Spores are different. When a particular kind of bacteria is starving, rather than die off, it forms a hard, resistant structure that can lie dormant for long periods.

“Think about a seed,” Abel-Santos says. “You can have it in a package in your garage for years, and it just remains a seed. Then, you put it under the right conditions — soil, water, light — and it germinates and makes a plant, right? Same thing with a spore.”

C. diff tends to harmlessly colonize infants, although only 5-10 percent of them carry it into adulthood. Most spores get into the grownup stomach when a person touches a contaminated surface and then his mouth. The risk of this is high in hospitals — even those with staunch anti-infection protocols, such as UMC.

“The spores need nothing to live,” Galla says. “They live so long on a bedside surface that we’re unable to eradicate them. Soap and water don’t really even kill them; it just rinses them away. Bacteria are like glitter: If they’re in one place, they’re all over everything.”

If someone picks up the spores while his gut flora are thriving, nothing will happen. Like seeds in a garden, C. diff spores need certain conditions to germinate. These conditions include the absence of the good bacteria that are natural infection-preventers. So, if the person is taking antibiotics — especially the broad-spectrum kind — his healthy bacteria may die along with the harmful ones, creating fertile ground for C. diff spores.

How do you kill a C. diff infection? There are only a couple ways available to patients right now, and the most common one can create a brutal Catch-22.

“The ironic part is that, in order to kill CDI, you have to take a different antibiotic than the one you took for the original infection,” Abel-Santos says. “But that new antibiotic is still going to be killing the rest of your gut flora, and remember: C. diff doesn’t die; it just forms spores. So, now you’re cured, and they take you off the antibiotics before your gut flora can come back. What happens? You get a new round of CDI. It’s a recurring infection.”

This cycle can continue over months or years, spreading toxins that eat away at the intestinal lining. Worst-case scenarios include colitis, colostomy (removal of part of the intestine), even death.

Besides antibiotics, another possible cure that’s still in the early stages of adoption is fecal transplantation. This, Abel-Santos says, is essentially “eating poop. The idea is that, by ingesting bacteria from a healthy donor, you replenish your gut flora before C. diff can germinate.”

Fecal transplantation shows promise, he says. Still, for many patients, it’s an unpleasant choice.

 

The anti-germination approach

The absence of infection-preventing gut flora alone doesn’t cause C. diff spores to germinate; a trigger is also required. To find this trigger, Abel-Santos and his team homed in on signals found only in the intestines. They narrowed it down to bile salts, cholesterol-type molecules that the liver releases into the intestines. If they could block those signals, they theorized, they could prevent C. diff germination.

Over the following years, Abel-Santos and chemistry Ph.D. student Amber Howerton developed artificial versions of a bile salt that acts as an anti-germinant. Theoretically, patients on antibiotics would concurrently take an anti-germinant so, even if they ingested C. diff spores, the spores would just pass through the system without causing infection.

Working with about a half-dozen other students, Howerton has done most of the lab work — from test-tube experiments to animal testing — homing in on CamSA, a compound that inhibits spore germination. They had to convert a teaching lab to a research lab, because there was previously no space for the type of work they’re doing. Standing in front of a tall, glass-and-metal totem pole (a gel chromatography structure, used to isolate compounds) in the cramped basement of UNLV’s biology building, Howerton recalls the hours she spent watching YouTube videos and consulting with veterinarians in order to learn how to safely and effectively conduct animal tests. The work, which took on a starker meaning when an aunt in Oklahoma contracted CDI a few years ago, culminated in her Ph.D. dissertation.

“CamSA worked much better than we expected,” she says. “We prevented infection in mice with a single dose.”

It is also an ideal candidate for a drug in a clinical setting, because scientists know exactly when patients are at risk of getting CDI (when they’re in the hospital and taking broad-spectrum antibiotics). If physicians could give the anti-germinant together with the antibiotics, they could cure the original infection while preventing the secondary one. When the patient is cured, all treatment is stopped, his gut flora return and life goes back to normal.

Widespread application of the discovery is obvious, so when Abel-Santos took his idea to UNLV’s Lee Business School, it was easy for a group of grad students to come up with a scheme for commercializing CamSA. Their business plan, which won second place in the 2013 Southern Nevada Business Competition (a precursor to the Governor’s Cup), called for setting up a company here in Las Vegas, but Abel-Santos said he couldn’t get it to work.

“The problem was lack of research infrastructure,” he says, referring to a scarcity in the type of lab space required for the trials that the drug will have to go through before hitting the market.

Undeterred, the UNLV team partnered with Spordiff Therapeutics, a Boston-based startup cofounded by a pharmaceutical investor and a couple of scientists doing work similar to Abel-Santos and Howerton’s. Spordiff will carry out laboratory testing and clinical trials while the UNLV team keeps tinkering with the compound. The university holds the patent, and Spordiff will lease an option for it; Abel-Santos maintains claim to the original compound, but any new compounds will be the property of the pharma company. The university will get royalties on any eventual sales, with the inventors taking a cut.

Abel-Santos and Howerton are already moving on. She has accepted a position as associate professor of chemistry at Nevada State College. He and his students are working with several new bacteria in the lab, incorporating collaborations with other scientists across the country. One of their papers has appeared in two scientific publications, and Abel-Santos been invited to present his work in London, Lisbon and Chicago.

Despite having hit the big-time, neither plans to leave Las Vegas. Family ties, a love of the outdoors and the city’s unique combination of big-city attractions and small-town accessibility keep them happy here.

“I like the people here,” Abel-Santos says. “I like the fact that it’s a new university. There’s a lot of things that we can do to move it forward. So, it’s a more exciting environment than a set, older university.”

Even if it could use a bigger, better lab.


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