Almost-Untreatable Gonorrhea: Proof That It's Here

If you’ve been following this blog for a while, you might have noticed a thread on health authorities’ growing concern over gonorrhea not responding to the drugs used against it. (And if you didn’t notice you can find those posts here.) A paper published Wednesday evening shows that worry has not been misplaced.

The concern is this: Treatment of STDs in infected people, and programs that aim to keep STDs from spreading from those people to others, rely on drugs that are inexpensive to buy, simple to administer, and work after a single dose and clinic visit. Since the late 1990s, there have been only two drugs that fulfill those criteria: an oral drug called cefixime and an injectable called ceftriaxone (both belonging to the same broader drug family called third-generation cephalosporins). Since the early 2000s, there have simultaneously been signs that resistance to cefixime has been spreading from the Pacific Rim — Japan and Hawaii — to North America, Europe and the rest of the world.

The earliest signs of this were spotted in California in 2008, and in the rest of the US in 2011. Last June, the World Health Organization called the situation an emergency; in August, the European CDC alerted its member countries to cases in Europe; and also in August, the US CDC advised doctors here that they should stop using that oral drug and stick only to the injectable.

In that several-year progression, though, there have been relatively few reports of clinics actually confronting cases of gonorrhea which simply did not respond to drug treatment. That is mostly because many of the public-health warnings were based, not on observations of individual patients, but on after-the-fact assessments of collections of bacterial isolates. Plus, since the expectation was “single dose equals cure,” someone who returned to a clinic with symptoms was assumed to have gotten reinfected, rather than being continuously infected because their treatment had not worked.

Now, though, comes a report from researchers in Canada — including personnel at the superbly named Hassle Free Clinic of Toronto — of standard cefixime treatment just not working in some patients there. As they describe in this week’s Journal of the American Medical Association, some of the patients were eventually treated with double the standard dose of cefixime (800mg instead of 400mg); others were treated with ceftriaxone (250mg as an intramuscular injection).

The numbers of patients are small, but the percentages of diminished susceptibility and resistance still exceed what the WHO previously set at the point where we should start being worried, and there are interesting details that hint at further trouble to come.

The researchers decided to assess every lab-confirmed case of gonorrhea that came through the clinic in a 12-month period, May 2010 through April 2011. At that clinic at the time (and still, throughout Canada), standard treatment for gonorrhea was the 400-mg oral dose of cefixime.

As part of its standard STD care, this clinic did two things that are not common, though the US CDC at least would like to see then happen. First, they did culture confirmation of gonorrhea infections, not just the DNA-based rapid tests that are now routine. This is important because culture tests, but not the DNA-based tests, preserves intact bacteria, allowing lab personnel to perform a test for antibiotic susceptibility — which this clinic did. Second, the clinic also  asked every patient to return for a “test of cure” to make sure the infection had been cleared, so that they could be sure that people who returned with symptoms had been reinfected, as opposed to having a persistent, resistant strain.

In that 12-month, 291 patients were confirmed to have gonorrhea:

  • 59 of them — 20 percent — were infected with strains that showed some diminished response to cefixime.
  • Of the 291, 158 (54 percent) did not return for their “test of cure” visit, including 31 whose isolates showed that diminished susceptibility.
  • 133 (45 percent), including 28 whose isolates originally showed diminished susceptibility, did return.
  • Of those 133, 13 had a second positive culture, failing the “test of cure.”
  • Of those 13, four were ruled out as possibly having been re-infected, even though their original infections did show diminished susceptibility.
  • That left nine patients (eight men and one woman) whose infections were non-susceptible enough to be classified as “treatment failure” — 6.77 percent of those who returned for test of cure. The WHO’s threshold for reconsidering the efficacy of cefixime is 5 percent.
  • Of those nine patients, the infections in three responded to the double-sized dose of cefixime. Six required injectable ceftriaxone instead.

There is a lot in that breakdown that is worrisome. The first is the rate of treatment failure. The second is the proportion of patients, including some with strains that were not responding to the standard drug dose, who did not return to be checked even though they were explicitly asked to do so. And the third is that we only know any of these percentages because this clinic happens to follow practices that are not routine in many of the STD clinics in the US —  which is to say, our rates could be this bad, or worse, and we would not know.

Balancing that discouraging assessment, it is worth noting that the treatment used in the Toronto clinic is not now recommended in the US; and, in addition, the CDC also recommends that patients be brought back for a test of cure. The problem with those recommendations, as the National Coalition of STD Directors has been warning for a while, is that they make STD care more expensive in a time of austerity. STD programs are run by states, with CDC assistance; the coalition said last August: “the vast majority of health department STD programs have seen significant budget reductions in recent years, some to the point where state and local contributions are zero.”

The reality remains: As these Canadian cases show, control of gonorrhea now hinges on a single remaining drug; there are no others lined up. (I once asked a friend who runs an STD clinic what comes after ceftriaxone, thinking she would say, “Well, an IV drug,” or “Well, checking into a hospital.” Instead, she made a face and said: “What comes afterward is clinical trials.”) And because that remaining drug is an injectable, control of gonorrhea is not only precarious, it is also already more expensive than it was.

There are not many options left, to keep gonorrhea from getting to untreatable. But in their statement from last fall, the STD directors’ coalition underlined why it is so important that we do:

 …the following could occur as a result of resistance over the next seven years: gonorrhea incidence could increase four-fold to nearly 6 million additional cases; nearly 800 additional HIV infections; a quarter million cases of pelvic inflammatory disease in women; and ultimately, over that seven year window, cost over three-quarter of a billion dollars in lifetime medical costs.

Cite: Allen VG, Mitterni L, Seah C et al. Neisseria gonorrhoeae Treatment Failure and Susceptibility to Cefixime in Toronto, Canada. Jan. 9, 2013. JAMA. 2013;309(2):163-170. doi:10.1001/jama.2012.176575.

N. gonorrhoeae image, PHIL, CDC


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