- Antibiotic resistance is one of the biggest threats to global health, food security and development
- The Global Antibiotic Research and Development Partnership has chosen to focus on gonorrhea
Mark King has had the clap so many times he's renamed it "the applause. "
The first time King had gonorrhea, he was a teenager in the late 1970s, growing up in Louisiana.
King visited a clinic and gave a fake name and phone number. He was treated quickly with antibiotics and sent on his way.
A few years later, the symptoms reappeared. By this time, the 22-year-old was living in West Hollywood, hoping to launch his acting career.
Los Angeles had a thriving a gay scene where King, for the first time, could embrace his sexuality freely. He frequented bathhouses and also met men in dance clubs and along the bustling sidewalks. There was lots of sex to be had.
Like a few years earlier, the doctor gave him a handful of antibiotics to take for a few days that would clear up the infection. It wasn't a big deal. In fact, as King describes it, it was "simply an errand to run."
But it was the calm before the storm, in more ways than one.
When King picked up gonorrhea again in the 1990s, he was greatly relieved that treatment was now just one dose.
Penicillin was no longer effective, but ciprofloxacin was now the recommended treatment and it required only one dose. In King's eyes, getting gonorrhea was even less of a hassle.
But this was actually a symptom of treatment regimens starting to fail.
The bacteria Neisseria gonorrheae was on the way to developing resistance to nearly every drug ever used to treat it.
A global threat
When Alexander Fleming received the 1945 Nobel Prize in Physiology or Medicine for discovering penicillin, he finished his lecture with a warning: "There is the danger," he told the audience, "that the ignorant man may easily underdose himself and, by exposing his microbes to non-lethal quantities of the drug, make them resistant."
In other words, we have known about bacteria's ability to evolve resistance to drugs since the dawn of the antibiotic era.
"All antibiotics will have a shelf life; that's just evolution," says Dr. Manica Balasegaram. "It's just a question of how quickly it will happen."
Balasegaram is director of the Global Antibiotic Research and Development Partnership, based in Geneva. It's a joint initiative between the Drugs for Neglected Diseases Initiative and the World Health Organization and aims to develop new or improved treatments for bacterial infections.
Antibiotic resistance is one of the biggest threats to global health, food security and development. Common infections, such as pneumonia and tuberculosis, are becoming increasingly difficult to treat.
But the Global Antibiotic Research and Development Partnership has chosen to focus its attention on gonorrhea as one of its four main priorities.
The sexually transmitted infection, or STI, caught Balasegaram's eyes for a host of reasons.
Acquiring resistance quickly
For one, a lot of the antibiotics that are currently used against gonorrhea are used widely for other infections, and N. gonorrheae has the ability to acquire resistance from other bacteria frighteningly quickly, meaning it can rapidly build up resistance.
Secondly, untreated gonorrhea infections bring with them a range of potentially serious health implications that can have devastating consequences.
Every year an estimated 78 million people are infected with gonorrhea, making it the second most frequently reported bacterial STI after chlamydia, according to the WHO.
Gonorrhea can infect the genitals, rectum and throat. Symptoms include discharge from the urethra or vagina and burning during urination called urethritis, caused by inflammation of the urethra. However, many who are infected don't experience any symptoms, meaning they go undiagnosed and untreated.
Complications of untreated gonorrhea can be severe and disproportionately affect women, who are more likely to experience no symptoms.
Untreated gonorrhea not only increases the risk of contracting HIV but is also linked with an increased risk of pelvic inflammatory disease, which can cause ectopic pregnancy and infertility. A pregnant woman can also pass on the infection to her baby, which can cause blindness.
A major concern is that because N. gonorrheae can live in the throat without someone even knowing, the bug can acquire resistance from other bacteria that also live there and which have been exposed to antibiotics in the past. And with evidence that oral sex is becoming increasingly common in some parts of the world, this is particularly challenging.
"People are dying from drug-resistant infections. This is undoubtedly because this area has not been prioritized in the past because other areas of R&D are far more lucrative," Balasegaram says.
"Antibiotics are a global public good. I don't think it's easy to put a financial value to it."
Seeing half the picture
Recent data collected by WHO examined trends in drug-resistant gonorrhea in 77 countries -- countries that are part of the health agency's Gonococcal Antimicrobial Surveillance Programme, a global network of regional and subregional laboratories that track the emergence and spread of resistance.
And the results are grim.
More than 80 per cent of the countries that reported on azithromycin, a commonly prescribed antibiotic used to treat numerous common infections, including STIs, found resistance.
Of greatest concern is that 66 per cent of countries surveyed have reported cases that resist last-resort antibiotics called extended-spectrum cephalosporins.
Dr Teodora Wi, a medical officer in WHO's Department of Reproductive Health and Research in Geneva, says that the real-world picture is undoubtedly far bleaker, because global surveillance for drug-resistant gonorrhea is patchy and more frequently done in higher-income countries, which have greater resources.
For example, of the 77 countries that were surveyed, few were in sub-Saharan Africa, a region where rates of gonorrhea are high.
"We're only seeing half of the real picture. We need to prepare for the future when there's no cure," Wi says.
But in a sign that time is running out, in March this year health experts' worst fears were confirmed: a case of super-gonorrhea, dubbed the world's "worst ever" case, was found in a man who had attended a local sexual health clinic.
He had reportedly had sexual contact with a woman in Southeast Asia.
Health officials said it was the first time this strain could not be cured with any of the antibiotics normally used to treat the disease. Although the patient has since responded to another antibiotic, doctors described him as "very lucky". It's an indication of a wider crisis -- and one that knows no boundaries.
The Thai front line
Thailand is one country on the front line of the fight against antibiotic-resistant gonorrhea. It's a key destination for the sex tourism industry, where STIs like gonorrhea can spread easily and quickly across borders and beyond.
And like many other countries in the region, it has an over-the-counter culture of antibiotic access, which means patients put themselves at risk of being prescribed the wrong drugs -- or even worse.
But while experts acknowledge that restricting the sale of antibiotics -- particularly in rural and remote areas where there are few, if any, proper doctors -- isn't the answer, this still presents a major challenge in the fight against drug-resistant infections.
"The problem is that when you go to a pharmacist and take antibiotics, maybe... your symptoms have disappeared, but in fact you still have the infection. That means you can transmit the infection and cause more resistance," Wi says.
The casual handing out of antibiotics without a prescription is a huge concern across the rest of the region and in other parts of the world, with no clear vision of how to tackle this growing problem.
Handing out antibiotics that likely no longer work for people with gonorrhea has also been happening in high-income countries.
A study published in the BMJ in 2015 found that many GPs in England were prescribing ciprofloxacin, even though it hasn't been recommended for treating gonorrhea since 2005. In 2007, ciprofloxacin still made up almost half of prescriptions for gonorrhea. As recently as 2011, GPs still prescribed it in 20 percent of cases.
On a balmy afternoon in bustling Bangkok, I visit Silom Community Clinic @ TropMed, an STI clinic northeast of the city center dedicated to men who have sex with men (called MSM) and transgender women who have sex with men.
Dr Eileen Dunne is an American epidemiologist and the head of the behavioral and clinical research section of the HIV/STI program here, which is run as part of a collaboration between Thailand's Ministry of Public Health and the US Centers for Disease Control and Prevention. She, along with her Thai staff, are Thailand's best line of defense in slowing gonorrhea resistance.
In 2015, recognizing the worldwide danger of increasingly difficult to treat gonorrhea infections -- and the specific threat they posed to Thailand -- the CDC, the WHO and the Thai Ministry of Public Health joined forces to launch a program to track and ultimately limit the spread of antibiotic-resistant gonorrhea.
The program is an enhanced local version of the WHO's Gonococcal Antimicrobial Surveillance Programme and is the first of its kind in the world. It's called EGASP.
It works like this. If a male patient comes into one of its two clinics with the telltale symptoms of gonorrhea, he will have a sample collected for analysis and will fill out a questionnaire, which contains questions such as: "Did you take antibiotics in the last two weeks?" To create an open environment, the clinics are anonymous and the questionnaire is done privately on a computer.
Men are the target group in the program, Dunne explains, because the yield for isolating N. gonorrheae is very high among men who have urethritis compared with women and those who are asymptomatic. MSM are an important population, she adds, because research shows they are likelier to develop resistance earlier than the general population, for reasons that aren't precisely known.
Samples are cultured from the swabs taken from the patients' penises. The next step is antibiotic susceptibility testing at a lab downstairs. The bacteria that have grown will be measured for resistance to five antibiotics, including ciprofloxacin and the last-resort drugs cefixime and ceftriaxone. It's resistance to these latter two which is of greatest concern.
From the beginning of EGASP until October 20, of the 845 confirmed diagnoses of gonorrhea that underwent antibiotic susceptibility testing, almost all isolates had widespread resistance to ciprofloxacin, as in many other countries.
But encouragingly, none have shown resistance to the last-line drugs.
"People are surprised and have asked, 'Oh, why are you doing this if you don't show resistance?' " Dunne says.
But having strong surveillance activity in a region in which this is likely to emerge is important, she says, so it can be detected early.
Thailand's neighbors, specifically Myanmar, India, Indonesia and China, have recorded a significantly higher percentage of gonorrhea isolates that are resistant to last-line treatments compared to Thailand.
With the increasing movement of people around the world and Thailand's popularity for sex tourism, I can see just how rapidly this threat could have far-reaching consequences.
The number of people infected with gonorrhea has risen rapidly in recent years. In England, gonorrhea cases rose by 53 per cent between 2012 and 2015, led by young people, gay men and other MSM. Meanwhile, in the USA cases rose by nearly 50 per cent between 2009 and 2016.
Looking ahead, at what point will it be more common to have a gonorrhea infection that can't be treated with antibiotics than one that can? The answer is difficult to predict, but it's also a potential reality that isn't farfetched.
"We are in a situation now where we are worryingly using the last line of antibiotics for many infections or seeing even resistance to these last-line antibiotics," Balasegaram says.
The Global Antibiotic Research and Development Partnership has partnered with Entasis Therapeutics, a US biotech company, to accelerate the development of a new antibiotic that will be produced specifically to target drug-resistant gonorrhea.
Zoliflodacin is a novel first-in-class oral antibiotic -- in other words, a new and unique mechanism of potentially treating gonorrhea -- and is one of only three potential new antibiotic candidates currently undergoing trials. It had previously been put through clinical trials in 2015, but a lack of investment stopped the drug from progressing further.
This year the Global Antibiotic Research and Development Partnership and Entasis will launch the last phase of trials of zoliflodacin, involving 650 people in Thailand, South Africa, the USA and parts of Europe.
If the drug is approved by regulators, Entasis will permit the Global Antibiotic Research and Development Partnership to introduce it in 168 low- and middle-income countries. It's hoping it will be registered by 2021 and available on the market by 2023.
"We still don't know whether this project will succeed or not," says Balasegaram. "But it's a project that we feel is extremely important and that we're very committed to."
The development of new antibiotics raises myriad questions: How can we ensure they are used appropriately so we can preserve their effectiveness? And how can we ensure those who really need the drugs get them?
One way would be a point-of-care rapid diagnostic test -- ideally one that could predict which antibiotics will work on a particular infection and that could be used in settings around the world.
Balasegaram says they've been looking for a simple diagnostic tool like this but haven't yet found one. Diagnostic tools aside, the responsible use of new antibiotics also relies on robust national and international treatment guidelines and strong regulatory authorities to guide and monitor antibiotic use.
A major strength of the partnership between the Global Antibiotic Research and Development Partnership and Entasis is that it will be able to limit what infections zoliflodacin is used for. "If you have developed an antibiotic for narrow use, you have to think about how to market the drug. We do not want to drop large quantities of it around the world. But we also want to make sure those who need it get it," he says.
This is where strong surveillance programs, like Thailand's, are critical.
But it's inevitable that bugs will develop resistance to the next antibiotic and then the next. So Balasegaram wants more investment in R&D that focuses not only on new antibiotics but also on alternative ways to treat bacterial infections.
"This may include novel and non-conventional approaches," he says. "I think that is a job that is going to last decades."