How did a common and easily treatable venereal disease become an incurable disease?

What could be cured with a pill 20 years ago now requires an injection. In another 10 years, we may need antibiotics with more severe side effects, or even fail to cure it. After that, gonorrhea may even become an incurable disease.

By Ed Cara

Compilation | Kestrel

Gonorrhea is a sexually transmitted disease (STI) that we often hear about. However, in February this year, British public health officials reported three special cases of gonorrhea - they were infected with highly drug-resistant strains. This "super gonorrhea" may become the first health threat with the risk of widespread spread in the so-called "post-antibiotic era" today.

The pathogen of gonorrhea is Neisseria gonorrhoeae, commonly known as gonococcus, which is a pathogen that parasitizes humans and was first isolated by German doctor Albert Neisser in 1879. Like many infectious diseases, gonorrhea has long been well treated with antibiotics, but the emergence of drug-resistant strains has made some diseases a problem again, and gonorrhea is one of them.

Figure 1. Gonorrhea | Source: phil.cdc.gov/details.aspx?pid=16874

Drug-resistant bacteria are also called "superbugs." In 2019, the number of deaths directly caused by superbugs worldwide totaled 1.27 million, even higher than the total number of deaths caused by tuberculosis, AIDS, and malaria that year. According to a recent report published in The Lancet, the total number of deaths involving superbugs may have reached 5 million. A study published in 2018 estimated that in 2010, as many as 160,000 Americans died from superbugs.

These superbugs usually come to us when we are most vulnerable - when we are sick. Hospitals are often the breeding ground for these superbugs. First, the population here often has various health conditions; second, antibiotics are widely used in hospitals, making it easier to screen out drug-resistant bacteria. So now the fight against superbugs focuses on hospitals and other medical places. But this does not mean that antibiotics are only used in these places. Farms are also places where antibiotics are widely used (see "Crisis on the Table: Can We Still Eat Meat Safely?" for details).

But gonorrhea is much more widespread. And over the years, we have used various drugs to treat it, and it has developed resistance. For many patients who are infected, gonococci are the first superbug they face. In fact, when we start using antibiotics, we face the risk of bacteria evolving escape mechanisms. If you look closely at the history of gonorrhea treatment, you will find that the problem of gonococcal resistance has emerged in 1930. Sulfonamide antibiotics were first used, and then doctors began to encounter treatment failures - they were there at the beginning, but the non-resistant bacteria that infected humans were slowly replaced by resistant bacteria, and the number of treatment failures increased over time. David Hyun, director of the Antibiotic Resistance Project at The Pew Charitable Trusts, pointed out that this incident reflects the historical context of the formation of antibiotic resistance.

In recent years, our arms race against gonorrhea has reached a point where only two antibiotics are recommended for standard treatment—azithromycin, an oral drug, and ceftriaxone, an injectable drug—and it’s getting worse. Azithromycin is a macrolide antibiotic that inhibits bacterial protein synthesis by binding to the 23S rRNA of the bacterial 50S ribosomal subunit and inhibits the synthesis of the 50S ribosomal subunit. Ceftriaxone has the same antibacterial mechanism as penicillin, which is to inhibit the final transpeptidation step of peptidoglycan synthesis by binding to one or more penicillin binding proteins (PBPs), thereby inhibiting bacterial cell wall synthesis and, in turn, bacterial growth. However, ceftriaxone is highly stable to β-lactamases (including penicillinases and cephalosporinases).

Around 2015, a large number of azithromycin-resistant strains appeared in some areas, so doctors in the United States and many other countries adopted a strategy of using two drugs in combination.

In 2018, experts’ worst fears came to pass: a British patient was infected with a strain that was also highly resistant to the drug combination. Soon, two similar cases were reported in Australia.

The cases can be traced back to Southeast Asia, so some people suspect that the super gonorrhea is related to the sex tourism industry there. But the skeptics have no solid evidence, only speculation based on an investigation by an EU official (only one of the three patients admitted that he was infected from sex workers there). Hyun pointed out that many developing countries have limited ability to track resistant strains, which means that we cannot understand the dynamics of so-called "pan-resistant infections" before they spread like wildfire.

The existing hard data on gonorrhea resistance does not look optimistic. A report published in The Lancet by scientists from the World Health Organization (WHO) in 2021 showed that resistance to azithromycin and ceftriaxone increased in 73 countries around the world from 2017 to 2018 [2]. The Centers for Disease Control and Prevention (CDC) in the United States estimated that in 2020, about half of gonorrhea infections were resistant to at least one of the two antibiotics mentioned above, usually resistant to azithromycin, so the CDC and other organizations have stopped recommending the use of azithromycin for patients with uncomplicated gonorrhea [3].

The only option left is ceftriaxone—a higher dose than usual. At least in the United States, gonorrhea resistance to ceftriaxone is still relatively low. But there is no guarantee that it will remain so low, after all, this is the only option left for first-line treatment.

In December 2020, around the same time the CDC stopped recommending azithromycin, doctors reported the first case in the United States of a mutated gonococcal strain that was resistant to ceftriaxone.

Figure 2. The history of the development of resistance in gonococci. Since the discovery of cefixime resistance in 2010, multidrug-resistant gonococci have been called superbugs [6].

Gonorrhea is often difficult to notice. Statistics show that about half of cases have no symptoms. But sometimes patients feel very sick, may have vomit-like stool, urination is accompanied by pain or burning, and women may have increased bleeding during menstruation. But in fact, the most dangerous situation of gonorrhea is that it is not treated. Especially in women, the inflammation caused by gonorrhea can cause permanent damage to the reproductive system, leading to infertility. It is rare for gonococci to enter the bloodstream, but if it happens, it can cause life-threatening complications such as arthritis, endocarditis or meningitis. If a mother has gonorrhea and the mother transmits it to the baby during delivery, the bacteria may cause blindness or even death to the baby. Gonorrhea also increases the risk of contracting other sexually transmitted diseases, especially HIV.

If gonorrhea becomes difficult to treat, then the above situations will be more serious, and life may become more difficult for those infected. What could be solved with a pill 20 years ago now requires injections. In another 10 years, we may need antibiotics with more serious side effects, or even fail to cure it. Gonorrhea may even become an incurable disease in the future.

Every case of treatment failure means that gonorrhea will continue to exist, and the possibility of transmission to others will continue. In a 2018 interview, Teodora Wi, a sexually transmitted disease expert at the World Health Organization, said that if drug-resistant gonorrhea spreads widely, it could cause up to 300,000 deaths each year. [4] Even if the death toll is not so high, other consequences are severe: more people will lose the opportunity to have their own children, and more newborns will lose their eyesight.

Fortunately, such a bad situation can still be avoided. According to the latest report of Pew Foundation in February this year, there are four potential new antibiotics that can be used to treat gonorrhea that are about to be approved. But it should be pointed out that only two of them are considered new drugs. The distinction between drug types is important here, because bacteria are more likely to develop resistance to analogues of drugs that are already in use.

To provide longer-term protection, we need a gonorrhea vaccine—one that won't give the bacteria as much of a chance to develop resistance. Creating a gonorrhea vaccine is challenging because humans don't naturally develop lasting immunity to gonorrhea. Fortunately, at least one drug has made it to Phase II clinical trials and has the potential to overcome this hurdle.

Last year, the Oxford team also announced that it was developing its own candidate. We may even get some help from existing vaccines. A study published in April 2022 showed that adolescents who received the meningococcal serogroup B bacteria (a close relative of gonococci) vaccine gained some protection against gonorrhea infection,[5] but it was not clear how long the protection lasted. Currently, the vaccine is only recommended in the United States for adolescents at high risk of severe meningitis, and it is not clear whether it will be recommended for everyone in the future.

New drugs and vaccines are one thing, but our long-term strategy for super gonorrhea is to cut off the transmission route, which is the same as dealing with most infectious diseases. Unfortunately, things are moving in the opposite direction. In April of this year, the US Centers for Disease Control and Prevention announced that in 2020, the number of gonorrhea and syphilis cases in the United States increased for seven consecutive years and hit a record high of 670,000 cases. Worldwide, the annual infection rate of sexually transmitted diseases has been declining since the 1990s, but a study published in April 2022 showed that the absolute number of cases in 2019 was climbing.

Gonorrhea is a shameful disease, and any STD is no exception. But the bug has been with us for thousands of years, and like other infectious diseases, it has learned to defeat us time and again. Evolution and antibiotic resistance are inevitable—but our current predicament is avoidable. More than a decade ago, gonorrhea rates in the United States were at their lowest ever, but we lost ground because our government failed to provide accessible condoms and education, persuade the public to practice safe sex, and help people get tested regularly. The health care system we rely on has been eroding. Like so many things, the coronavirus pandemic has only made it worse. The pandemic has stretched the bandwidth and capacity of the health care system, increasing the number of health care-associated infections, including those that are antibiotic-resistant.

We’ve known almost since the beginning that antibiotics aren’t the invincible wonders they first seemed. For decades, scientists have been warning us about the problem of drug resistance and calling for changes in the way we use and develop these precious resources. Yet people continue to abuse antibiotics, both in medical and agricultural settings. In stark contrast, the development of new antibiotics is moving at a snail’s pace.

Fortunately, there are still many people and organizations in the world who are committed to changing the situation in the battle between humans and superbugs. We hope to adopt new incentive models and invest new funds to try to persuade pharmaceutical companies to reinvest in antibiotic research and development. Others call for more radical measures, such as letting governments take the lead in collective research and development of antibiotics. But no matter which one it is, we have to hurry up.

“If we don’t take multiple steps to turn the tide, we may see some diseases that were once easily treatable become less treatable in the near future,” Hyun warned.

Drug-resistant gonorrhea may be the first superbug to infect someone close to you, but unless things change, it will certainly not be the last.

References

[1] https://gizmodo.com/the-rise-of-super-gonorrhea-1848808707

[2] Unemo, M., Lahra, MM, Escher, M., Eremin, S., Cole, MJ, Galarza, P., Ndowa, F., Martin, I., Dillon, JR, Galas, M., Ramon-Pardo, P., Weinstock, H., & Wi, T. (2021). WHO global antimicrobial resistance surveillance for Neisseria gonorrhoeae 2017-18: a retrospective observational study. Lancet Microbe, 2(11), e627-e636. https://doi.org/10.1016/S2666-5247(21)00171-3

[3] https://www.naccho.org/blog/articles/2020-update-to-cdcs-treatment-for-gonococcal-infections

[4] https://www.who.int/campaigns/world-antimicrobial-awareness-week/2018/features-from-around-the-world/super-gonorrhoea-qa-with-dr.-teodora-wi

[5] Abara, WE, Bernstein, KT, Lewis, FMT, Schillinger, JA, Feemster, K., Pathela, P., Hariri, S., Islam, A., Eberhart, M., Cheng, I., Ternier, A., Slutsker, JS, Mbaeyi, S., Madera, R., & Kirkcaldy, RD (2022). Effectiveness of a serogroup B outer membrane Vesicle meningococcal vaccine against gonorrhoea: a retrospective observational study. Lancet Infect Dis, 22(7), 1021-1029. https://doi.org/10.1016/S1473-3099(21)00812-4

[6] Unemo, M., & Shafer, WM (2011). Antibiotic resistance in Neisseria gonorrhoeae: origin, evolution, and lessons learned for the future. Ann NY Acad Sci, 1230, E19-28. https://doi.org/10.1111/j.1749-6632.2011.06215.x

This article is compiled from
https://gizmodo.com/the-rise-of-super-gonorrhea-1848808707

Produced by: Science Popularization China

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