Wednesday, 18 July 2018

No more ‘sledgehammer’: As gonorrhea grows resistant to antibiotics, researchers look to bespoke treatments

With antibiotic resistance on the rise, the days when doctors and clinics could rely on one treatment to cure all gonorrhea cases may be waning.
In fact, clinicians may find that some of their patients respond best to drugs of the past. But how will they know which patients?
To answer that question, a handful of researchers and companies are trying to develop rapid, point-of-care diagnostics that would signal which drugs work for a given patient and permit clinicians to tailor treatment to the bacterial strain. A future, in other words, of bespoke treatment, in which a greater variety of drugs are used to treat a very common sexually transmitted disease — potentially prolonging the utility of several antibiotics.
“It would allow for smarter medicine,” Dr. Jeffrey D. Klausner, a professor of infectious diseases medicine at the University of California, Los Angeles, told STAT. “Right now, we’re treating gonorrhea with a sledgehammer, we’re treating everything with the same exact regime. And it’s not a surprise that the organism will become resistant to what we’re currently using.”
Klausner has collaborated with several companies working in this area but has not received payment from the companies. The companies have made contributions to UCLA, he said.
Gonorrhea is spread by sexual contact, and infection can occur in the genitals, the rectum, and the throat. The World Health Organization estimates that about 78 million people a year are infected with gonorrhea; roughly 820,000 of those infections occur in the United States.

Left untreated, gonorrhea can cause pelvic inflammatory disease and infertility in women and sterility in men. Infection increases a person’s risk of contracting HIV. Babies born to an infected woman can develop blindness.
From a treatment point of view, the ideal regimen for curing gonorrhea is an oral antibiotic — and was long the standard of care. But gonorrhea is a wily bacterium, adept at learning tricks that allow it to evade the power of antibiotics. One after another, the available drugs have started to fail.
For several years, the recommended regimen for gonorrhea has been a dual-therapy approach, the thinking being that it is harder for resistance to develop to a drug combination than to a single drug. The current recommended therapy is one injection of the antibiotic ceftriaxone followed by a multiday course of azithromycin. But even that approach is starting to show signs of weakness.
At the same time, there has been a belief that, even as medicine has moved on, there is life left in the drugs that have been abandoned — if you could figure out in whom they would work.
“We’ve been treating empirically and a lot of times ignoring the fact that the majority of organisms, the majority of infections we’re seeing, are actually fully susceptible to the old drugs,” said Fred Tenover, vice president for scientific affairs at Cepheid Inc., a California-based maker of molecular diagnostics.
“So now we have to have a change in philosophy and say: You know what? Now it’s time to go and do what we do for every other infection, which is actually define what the best therapeutic is up front.”
Cepheid is exploring the idea of developing such a test, Tenover said. “We’re trying to figure out what it would look like and what it would cost,” he said. “This is not in our pipeline officially. It’s something we’re looking at, something we haven’t committed to, but we have figured out how to make the assay.”
Other smaller companies are in the hunt. SpeeDx, an Australian-American firm, has a test in development that it hopes will receive licensing approval in Europe this autumn. The company is currently conducting a clinical trial in the United States in hopes of with the goal of filing for approval with the Food and Drug Administration.
The test both diagnoses gonorrhea and indicates whether the infecting strain can be treated with Cipro, said CEO Colin Denver. It currently would need to be processed by a central lab, but the plan is to develop the assay as a point-of-care test that could be used in a clinic or doctor’s office.
Shield Diagnostics, of Santa Clara, Calif., has a similar idea in mind. The company has a proprietary testing platform; CEO Fred Turner said it will roll out its first test this fall. The test can diagnose gonorrhea and ascertain if the strain is susceptible to Cipro.
For now, it is not a point-of-care test; that may be three or four years down the road, Turner said. In the meantime, Shield will process the tests in its own laboratories. Turner said the testing will likely take two to three days. Ideally, over time, both companies hope their assays will be expanded to give a broader resistance profile, one that indicates whether other drugs would be effective.
“Our ultimate goal is to have clinicians utilize a test-and-treat algorithm so that you don’t have to use these empiric therapies,” Denver said.
A patient would come into a clinic and specimens to test would be taken. While he or she is seeing the doctor, the test would be run. Within an hour or so, the doctor would know whether a single dose of Cipro or cefixime (also an oral drug) would do, or whether the ceftriaxone-azithromycin combination would be the better option.
“It’s like personalized medicine — your individual infection treated with the antibiotic you know is going to work,” Denver said.
But in order for these types of tests to be truly useful, they’ll need to be affordable and produce a rapid answer, said Dr. Lindley Barbee, an assistant professor of infectious diseases at the University of Washington and medical director of the Public Health – Seattle & King County STD Clinic. Not a day or two later, but while the person was in the clinic.
Many clinics that treat sexually transmitted infections are government funded, Barbee noted: “You have to get the cost low enough to make it worthwhile.”
That’s clearly a factor that has slowed development of these tests. “If you say to somebody who’s paying $10 for this test now, ‘Well, I can better define your therapy but it’s going to cost $17 a test, not $10 a test,’ that may be beyond the reach of a lot of public health clinics or STI clinics. And that’s probably what it would take,” said Cepheid’s Tenover.
“To date the return on investment has not been positive enough to make these commercially available,” he said. “That may be changing. And I think as we talk more and more about the spread of superbug gonorrhea, people may be more and more interested in doing this. But in the past there hasn’t been a market for these types of tests.”


Tuesday, 17 July 2018

New antibody attacks 99% of HIV strains

Scientists have engineered an antibody that attacks 99% of HIV strains and can prevent infection in primates.
 It is built to attack three critical parts of the virus - making it harder for HIV to resist its effects.
The work is a collaboration between the US National Institutes of Health and the pharmaceutical company Sanofi.
The International Aids Society said it was an "exciting breakthrough". Human trials will start in 2018 to see if it can prevent or treat infection.
Our bodies struggle to fight HIV because of the virus' incredible ability to mutate and change its appearance.
These varieties of HIV - or strains - in a single patient are comparable to those of influenza during a worldwide flu season.
So, the immune system finds itself in a fight against an insurmountable number of strains of HIV.
But after years of infection, a small number of patients develop powerful weapons called "broadly neutralising antibodies" that attack something fundamental to HIV and can kill large swathes of HIV strains.
Researchers have been trying to use broadly neutralising antibodies as a way to treat HIV or prevent infection in the first place.

The study, published in the journal Science, combines three such antibodies into an even more powerful "tri-specific antibody".
Dr Gary Nabel, the chief scientific officer at Sanofi and one of the report authors, told the BBC News website: "They are more potent and have greater breadth than any single naturally occurring antibody that's been discovered."
The best naturally occurring antibodies will target 90% of HIV strains.
"We're getting 99% coverage, and getting coverage at very low concentrations of the antibody," said Dr Nabel.
Experiments on 24 monkeys showed none of those given the tri-specific antibody developed an infection when they were later injected with the virus.
Dr Nabel said: "It was quite an impressive degree of protection."
The work included scientists at Harvard Medical School, The Scripps Research Institute, and the Massachusetts Institute of Technology.
Clinical trials to test the antibody in people will start next year.
Prof Linda-Gail Bekker, the president of the International Aids Society, told the BBC: "This paper reports an exciting breakthrough.
"These super-engineered antibodies seem to go beyond the natural and could have more applications than we have imagined to date.
"It's early days yet, and as a scientist I look forward to seeing the first trials get off the ground in 2018.
"As a doctor in Africa, I feel the urgency to confirm these findings in humans as soon as possible."
Dr Anthony Fauci, the director of the US National Institute of Allergy and Infectious Diseases, said it was an intriguing approach.
He added: "Combinations of antibodies that each bind to a distinct site on HIV may best overcome the defences of the virus in the effort to achieve effective antibody-based treatment and prevention."

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