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.”

Source: https://www.statnews.com/2018/07/17/gonorrhea-grows-resistant-to-antibiotics-researchers-look-to-bespoke-treatments/

Chlamydia Infection May Pave Way For Cancer via DNA Damage

The bacterium Chlamydia trachomatis is a leading cause of sexually transmitted disease that infects over 90 million people worldwide every year. Chlamydia infection often goes unnoticed, can persist for years with little or no symptoms, and can damage women's reproductive organs.

As well as this, the bacterium is proving increasingly stubborn to shift: antibacterial drugs are often no longer strong enough to eradicate it completely, so it goes into persistent mode, leading to chronic infection with no symptoms.

Chlamydia Uses Various Tactics to Ensure Survival

Chlamydia uses "Trojan horse" tactics to enter host cells unnoticed. A protein called Pgp3 enhances Chlamydia's ability to enter host cells unnoticed and then evade host defences.

To ensure survival, Chlamydia needs to make the most of the resources inside the host cell, which is where the bacterium spends most of its life. Once inside the host cell, the pathogen goes about changing the cell to make itself at home. It re-arranges host cell processes to favour its own growth and proliferation. But it's not clear how this affects the cell's normal functions and whether it leads to disease.

However, there is evidence that it might: there is a growing mountain of epidemiological data linking Chlamydia infections to the development of cervical and ovarian cancer development. But exactly how this might come about has been somewhat of a mystery - until now.

Chlamydia Causes Lasting Genetic Damage to Host Cells

In this new study, the researchers show that Chlamydia makes a long-lasting impression on the genome and epi-genome of host cells. Such changes are increasingly implicated in the development of a range of cancers.

They found host cells acutely and persistently infected with Chlamydia had increased levels of different kinds of DNA breaks.

In normal cells, when these types of breaks occur, they either go into cell suicide mode (apoptosis, where the cell is removed, broken down and its material parts recycled) or DNA repair mode.

In DNA repair mode, special proteins trigger a process called DNA Damage Response which attempts to reseal the broken strands of DNA to make sure the correct sequence of genetic code is restored (so when the cell replicates it produces healthy daughter cells).

But not only did the researchers find that Chlamydia-infected cells had altered DNA, but also that their DNA Damage Response didn't work properly: so the broken DNA didn't get repaired in those cells that didn't go down the cell suicide route.

Chlamydia disrupted the host cell DNA Damage Response by stopping key proteins from reaching the sites of DNA damage.

Chlamydia Damage to Cells Is Similar to that Which Leads to Cancer

Thus Chlamydia-infected, damaged cells that did not go down the cell suicide route continued to proliferate, passing on the DNA damage, and also spurred by some extra pro-survival signals activated in the host cell by the pathogen.

The result is an increasing population of rogue host cells that have escaped the normal mechanisms that ensure faulty DNA is not replicated: a hallmark of cancer.

The discovery is important because if it is established that an infection leads to cancer, then vaccination to prevent the infection, or antibiotics to eliminate it, may also prevent the cancer.

Such preventive methods are already working with other cancer-causing agents such as Human Papilloma Virus (HPV) and Helicobacter pylori, which can cause cervical and gastric cancer, respectively.

However, the path from infection to cancer needs to be firmly established before such a strategy can be considered in the case of Chlamydia.

Source: https://www.medicalnewstoday.com/articles/262350.php

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