Before antibiotics, many “treatments” for gonorrhea were more cringe-inducing than the disease: mercury injections in the urethra, for example, or hot water flushed into a woman’s genital tract. For men suffering from “chordee” — a complication where the penis becomes curved — one 19th-century doctor recommended placing the organ on a table and striking “a violent blow with a book.”
Mercifully, such remedies are only found in the history books and for more than 80 years, gonorrhea infections have been cured — painlessly — with antibiotics.
But with the rise of drug-resistant superbugs, and sexually transmitted disease rates rebounding around the world, doctors are once again worrying about a threat that they haven’t had to face since pre-war times: untreatable gonorrhea.
“Gonorrhea has mostly (become) a nuisance infection,” said Dr. Vanessa Allen, chief medical microbiologist with Public Health Ontario. “But now the concern is that we could go back to a time when we’ll have to be hospitalized or use very antiquated and mechanical treatments.
“It begs the question: What will gonorrhea look like in the new world?”
Antimicrobial resistance is now widely recognized as a major global health problem that threatens to reverse medical advances and cripple economies, particularly in the developing world.
Last month, the United Nations held a historic meeting to discuss the superbug crisis, which the World Health Organization calls a “slow-motion tsunami.
“Ultimately, the future of humanity may depend on our ability to respond to the great challenges of antimicrobial resistance,” said Peter Thomson, president of the 71st UN General Assembly.
But among the many villains populating the superbug universe, Neisseria gonorrhoeae is a particularly worrisome character.
For starters, gonorrhea is the second-most common sexually-transmitted bacterial disease, after chlamydia. The World Health Organization says as many as 110 million people are infected each year and when left untreated, infections can lead to painful complications, infertility, or even death, in rare cases.
And as a superbug, gonorrhea is particularly super. Resistant strains have now emerged against every class of antibiotic and doctors are down to their last available treatment: a dual therapy that combines azithromycin, an antibiotic in pill form, and ceftriaxone, an injectable.
If this end-of-the-line therapy stops working, there will be no antibiotics left in the medicine cabinet. While new drugs are under development, they are still years or decades away from reaching market.
And the current treatment is already losing ground. In June, British doctors reported the first-known gonorrhea case that was highly resistant to both antibiotics.
Last month, U.S. health officials also reported seven gonorrhea cases in Hawaii with reduced susceptibility to the dual therapy, a first in the U.S.
A similar case has already been seen in Canada, too. In January 2009, a Quebec woman was infected with a strain that had a weaker response to ceftriaxone — and failed to respond to azithromycin at all.
While all of these cases were ultimately treatable, they are red flags to the global health community. “If resistance continues to increase and spread our current treatment regimen will eventually fail,” the U.S. Centers for Disease Control and Prevention warned last month.
Meanwhile, sexually-transmitted diseases are once again on the rise. In 2014, the Public Health Agency of Canada recorded 16,285 cases of gonorrhea — up 15 per cent from the previous year, and the highest number since 1990.
Researchers are still trying to understand these troubling trends. Some experts suspect hookup apps are playing a role. Others are studying whether PrEP — a daily pill that at-risk people can take to prevent HIV infection — is encouraging people to ditch condoms, though STD rates were already trending upwards before the prophylaxis became widely available.
No matter the reason, one thing is clear: whenever the super-gonorrhea comes along, the environment is ripe for it to take off.
“We’re starting to see pan-drug resistant strains that are really untreatable (and) with gonorrhea we’re getting very, very close to that point,” said Dr. Michael Mulvey, chief of antimicrobial resistance with the Public Health Agency of Canada.
“The alarm bells are ringing right now.”
Gonorrhea has been a part of the human condition for thousands of years. Its treatment, on the other hand, has only been around for less than 90.
Ancient descriptions of gonorrhea can be found in Chinese and Middle Eastern texts from as early as 3500 B.C. A reference can also be found in the Bible, where the Book of Leviticus warns of an unclean “man that hath a running issue out of his flesh.”
Even the slang for gonorrhea — the “clap” — dates back to the 14th century, according to a paper in , likely inspired by a Parisian red-light district known as Les Clapiers.
“And because it’s a strict human pathogen — and it’s been infecting human beings for thousands of years — it has developed ways to resist the host defences that we naturally have.”
Neisseria gonorrhoeae is a feeble organism outside of the human body, where it can’t live for long. So to ensure itself a home, the bacteria has evolved ways to manipulate human defences and dampen our immune response when it invades.
Gonorrhea has also evolved to sometimes cause silent infections, allowing the bacteria to thrive undetected and spread more widely. Gonorrhea can also thrive in the rectum or throat, where infections are more common than people realize and tend to cause no symptoms at all.
Of course, the Neisseria gonorrhoeae’s greatest coup is exploiting the one transmission route that will forever be reliable: sex.
“What (gonorrhea) has done is it’s adapted itself to the host so that it can be transmitted by something that’s always going to happen in the human population,” Shafer said. “It’s a chameleon.”
For the vast majority of human history, nothing has worked for treating gonorrhea. Countless miserable patients have had their genitals injected, irrigated or soaked in everything from mercury to potassium permanganate. French doctors in the 18th century recommended injecting cow’s milk or “frog spawn water.”
As better remedies were developed for everything from pneumonia to syphilis, doctors despaired that gonorrhea would forever remain an unsolvable mystery.
“A gonorrhea begins and God alone knows when it will end,” lamented the 19th century French venereologist Phillipe Ricord.
The arrival of sulfa drugs in 1935, compounds derived from industrial dyes, gave the world its first antimicrobial — and its first effective gonorrhea treatment.
Sulfa drugs initially cured up to 90 per cent of cases. When resistance began to emerge in the 40s, few were concerned because penicillin, an antibiotic naturally produced by a mould, had arrived on scene. This new “wonder drug” worked so well that doctors mused about the end of gonorrhea altogether.
But, as has happened time and time again, we underestimated the lowly bacterium. Neisseria gonorrhoeae soon developed resistance against penicillin — and would do so for every subsequent class of antibiotics developed for treating gonorrhea: tetracycline, spectinomycin, fluoroquinolnes, macrolides and finally, now, cephalosporins, our last line of defence.
“Of all the bugs, gonorrhea is among those that are the most prone to an increasing development of drug resistance,” Allen said. “The bug is fickle.”
Just as gonorrhea has learned to navigate the human immune system, it has developed multiple strategies for deking antibiotic attacks.
Neisseria gonorrhoeae use “efflux” pumps to spit out antibiotics when they get inside the cell. The bug can also borrow DNA from neighbouring bacteria — for example, from other types of harmless Neisseria bacteria that naturally live inside the human throat. It can also change its own genome, mutating to develop new strategies for beating antibiotics.
A few years ago, when surveillance efforts started noticing treatment failures against cefixime — the previously recommended treatment for gonorrhea, taken as a single pill — public health bodies started changing their guidelines to recommend a two-punch therapy of azithromycin and ceftriaxone — the rationale being that if one fails, the other will hopefully still work.
But high-level resistance against azithromycin was already emerging in the late 2000s. In 2009, a Japanese sex worker had a strain of gonorrhea in her throat that was highly resistant to ceftriaxone; similar strains have since popped up in Spain and France.
Public health officials are now dreading the explosion of a strain that is resistant to both antibiotics. For many, the recent Hawaii cluster — which was highly resistant to one, and starting to resist the other — is a step in that direction.
“It’s a warning sign,” said Dr. Melanie Taylor, a medical officer with the World Health Organization’s department of reproductive health and research. “The next step is full-on resistance.”
What would it mean to live in a world with untreatable gonorrhea? For one, people would have to live longer with infections and suffer more complications.
In men, that tends to be a narrowing of the urethra, which makes it difficult to urinate, or epididymitis, a painful swelling of the scrotum. In men and women, gonorrhea can cause infertility — but women are particularly affected, because infections can lead to pelvic inflammatory disease or life-threatening ectopic pregnancies, when the fetus develops outside of the uterus.
Babies who get infected by their mothers are at risk of going blind and gonorrhea makes people more susceptible to other STDs, including HIV.
Neisseria gonorrhoeae can also spread throughout the body — unlike Chlamydia infections, which stay localized in the genital region — causing systemic damage or even death, in rare cases.
In the absence of effective treatments, there will be plenty of misery. Consider these lurid descriptions of 19th century gonorrhea patients, published in a British medical journal:
“T.J., August 1st, 1850. Has a very bad gonorrhea; the chordee has been most distressing; he has some painful erections, which compel him to rise two or three times in the night.”
“N.S. contracted clap, July, 1850; it was very bad and accompanied by much scalding pain etc.”
“J.B., Feb. 22nd, 1851. Has had gonorrhea for some time. It is very severe, the running being thick and green.”
Furious efforts are now underway to prepare for the day when the current treatment regimen fails — an “inevitable” outcome, according to WHO’s Taylor.
But even if our last-line therapy fails overnight, doctors won’t be left completely empty-handed, Taylor noted. They will likely reach for older antibiotics or try different drug combinations, though many of these could carry toxic side effects or prove to be prohibitively expensive.
“They’re now talking about using (an antibiotic called) gentamicin,” said Dr. Alan Katz, associate director with the Office of Public Health Studies at the University of Hawaii.
“That’s something we used to use in medical school for septic shock and here we’re talking about using it for gonorrhea. That’s pretty unbelievable.”
There are also new drugs finally in the pipeline, some of which show promise. Last month, the CDC announced early-stage results from a clinical trial of a new antibiotic called ETX0914, which represents a new class of antibiotics and was safe and effective in a small trial of 179 volunteers.
Even if this antibiotic proves successful, it’s still many years or decades from reaching market. And when it does, chances are good that it, too, will eventually fail.
“Are we ever going to have an antibiotic that the bug doesn’t develop resistance to? My quick answer is no,” Shafer said. “Resistance will happen. It is predictable, it is inevitable.”
Shafer believes it’s time to start thinking beyond antibiotics and look for new ways to fight back against gonorrhea.
He believes the key is to develop a gonorrhea vaccine — a strategy that “failed miserably” 30 years ago and is now being resurrected. Scientists are also investigating cutting-edge strategies for tripping the immune system to react more effectively when Neisseria gonorrhoeae invades.
But no matter how much research is funded, or how many drugs are developed, this ancient war against gonorrhea is one that everyone can fight. How? By consuming antibiotics more responsibly and practicing safe sex.
Both, however, require restraint and responsible decision-making — neither of which have been hallmarks of the human species, as bugs like Neisseria gonorrhoeae can well attest.
“If people used condoms every time they had sex, we wouldn’t need to have any STD clinics,” Katz said. “It’s not like getting an airborne infection from someone that coughs near you.
“This is something that’s pretty much 100 per cent preventable.”
How doctors used to fight it
Copaiba — In 1859, Great Britain imported 68,000 kilograms of Copaiba, a South American tree extract used in varnishes and lacquers, to treat venereal infections. Occasionally applied as an ointment, copaiba was mostly ingested in capsules or as a liquid, perhaps mixed in to coffee, mint water or wine to mask the bitter taste.
Mercury — Doctors used mercury to treat both syphilis and gonorrhea, sometimes injecting preparations into the urethra or vagina with a syringe. In massive doses, mercury caused terrible side effects like “loss of teeth, tongue fissures, and hemorrhaging of the bowel,” according to the book No Magic Bullet by science historian Allan Brandt.
Mouthwash — Before it became a famous mouthwash, Listerine was marketed as a 19th century floor cleaner, surgery antiseptic — and gonorrhea treatment. “Listerine was kind of looking for a raison d’être,” said Maxime Chouinard, curator at Kingston’s Museum of Health Care. Australian researchers gave Listerine a second look as a gonorrhea treatment in July, publishing a study on whether it can prevent throat infections.
Heat — In the 20s and 30s, one method to treat gonorrhea involved something called the “fever cabinet.” A patient’s entire body — with the exception of the head — would be enclosed in a hot box; the patient would bake for four to six hours at over 41 C.
This “apparatus” — This 1932 graphic, by a Dr. H.M. Kanner of Sacramento, Calif., describes a “simple and inexpensive” apparatus (left) for applying heat to treat a woman’s gonorrhea infection. As Kanner explains, the “irrigator’ should be inserted into the vagina and pumped with water, gradually increased in temperature “until it is as hot as the patient can stand.” The device on the right is for home use.
Penicillin — Discovered in 1928 by Alexander Fleming, penicillin kicked off the golden age of antibiotics and in 1943, it was shown to be an excellent cure for gonorrhea. By 1946, however, doctors were already seeing drug-resistant strains and today, penicillin-resistant gonorrhea is common around the world.