Nestled in the throat of a Japanese woman was a collection of clones that scientists abducted from their temporary habitat and christened H041 — a humdrum moniker for a strain of bacteria that would burn headlines in medical journals. Though the bacteria never caused symptoms in their host, they lingered in her throat from at least January until April of 2009, when a swab finally tested negative. Rather than succumbing to repeated bombardment by an antibiotic called ceftriaxone, the infection probably just went away on its own — as oral gonorrhea infections tend to do.
Resistance to ceftriaxone, our last good gonorrhea drug, has been reported in Japan, Australia, Sweden, France, and Spain.
The emergence of antibiotic-resistant gonorrhea is considered one of the most pressing problems in infectious disease — just two years ago, the Centers for Disease Control and Prevention named it an “urgent threat.” We have one remaining first-line gonorrhea treatment left: extended-spectrum cephalosporins, which include cefixime, which is taken orally, and ceftriaxone, which is administered as a shot. Resistance to cefixime was first documented in 1999, leaving ceftriaxone as our best remaining option, and the CDC’s first choice for treating gonorrhea. There are no good alternatives to ceftriaxone remaining, which is why reports of ceftriaxone-resistant gonorrhea are so deeply troubling.
What made H041 special was that it was the first extensively drug-resistant strain of Neisseria gonorrhoeae, the bacteria that cause gonorrhea. With an unusually high level of resistance to ceftriaxone — four to eight times higher than the previous record holder — the strain was also resistant to a slew of other antibiotics: penicillin and its relatives, fluoroquinolones, macrolides, tetracycline, trimethoprim-sulfamethoxazole, chloramphenicol, nitrofurantoin, cefpodoxime, cefixime, ciprofloxacin, and levofloxacin — and had reduced susceptibility to azithromycin to boot.
Another thing that made H041 special — as special as clones can be, anyway — is that it never reappeared. After its discovery, researchers in Kyoto and Osaka intensified their surveillance, trying to uncover it again and track its spread through the population. However, their search for H041 turned up empty handed. But other ceftriaxone-resistant strains have been documented around the world.
H041 may have fizzled out, but another alphanumerically named strain, F89, also with increased resistance to ceftriaxone, was documented in Europe in 2010. The first sighting was in France, and it was spotted again in two patients in the more southerly climes of Spain. Luckily, all three F89 sufferers were cured with other antibiotics.
Ceftriaxone resistance can also be documented even when doctors aren’t aware of treatment failures. For instance, researchers in Puerto Rico tested a sample taken from a man’s urethra in 2010 and found that it exhibited elevated resistance to ceftriaxone, despite the fact that they weren’t aware of any cases of gonorrhea on the island that weren’t cured with ceftriaxone. And the French patient mentioned above was actually never given ceftriaxone — his infection wasn’t cured with cefixime, a related oral drug, but it was only a later analysis in the lab that revealed that his gonorrhea strain also had increased resistance to ceftriaxone.
Since oral gonorrhea infections are more difficult to cure, recalcitrant throat infections could act as early warnings of emerging drug resistance. One team documented three patients in Sweden in 2013, all reporting unprotected oral sex, whose resulting gonorrhea infections were not cured with a massive 500 mg dose of ceftriaxone. It took a dose twice as high 22 days later to clear the infection once and for all. Another team, drawing on two unrelated cases in Australia from around 2007, described oral gonorrhea infections that were not cured with normal doses of ceftriaxone. The first patient was a tourist from England, and they lost track of him after administering a second, higher dose of ceftriaxone. The second patient, however, was cured after receiving 1 g of ceftriaxone — the same huge dosage that cured the Swedish patients. The authors proposed that a new type of antibiotic resistance had arisen in a novel strain from Down Under.
Last year, in a letter to the editor in the New England Journal of Medicine, Australian researchers described a gonorrhea strain found in the vaginal sample of a European tourist in 2013. While its resistance to ceftriaxone was only borderline, it did share alarming genetic similarities with H041. Meanwhile, in Japan, scientists have been experimenting with H041’s ceftriaxone-resistance gene, and have found that it can be easily swapped between one bacterium and another. N. gonorrhoeae have the ability to grab DNA from related bacteria and incorporate it into their own genomes, which means that, theoretically, a gene only has to arise by mutation once in order to infiltrate the gonorrhea-bacteria population as a whole. These gene-swapping abilities also give an N. gonorrhoeae bacterium the chance to “collect them all” — and incorporate multiple antibiotic-resistance genes in a single cell, ready to clone itself.
Mutations conferring extensive resistance to our last good treatment for gonorrhea have arisen spontaneously across the world, and according to H041’s discoverers, if history is any guide, we have one or two decades before ceftriaxone resistance has spread globally. Is it only a matter of time until one mutant outpaces them all, equipped with both extensive drug resistance and the survival skills necessary to run rampant in susceptible populations?
Time will tell, but in the meantime, it’s incumbent upon all of us to avoid gonorrhea infections. Preventive strategies sexually active people can employ include using condoms and dental dams, knowing the STD status of sexual partners, getting tested regularly, and being monogamous or limiting partners. You can be tested and treated for gonorrhea, or drop by to pick up condoms, at any Planned Parenthood health center.
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