Drug-Resistant Gonorrhea Forces Treatment Change

For sexually active Americans, gonorrhea has always cast a frightening shadow—almost 340,000 cases are reported each year, and at least that many may go unreported or undiagnosed. According to the Centers for Disease Control, the situation just got even scarier. The agency announced Thursday that it will no longer recommend a major class of antibiotics used to cure gonorrhea, a group of drugs called fluoroquinolones, also known as quinolones, because strains of the bacteria have become resistant to them and are circulating throughout the nation. Since doctors started treating gonorrhea in the 1940s, the disease has developed resistance against almost every antibiotic used, including penicillin and tetracycline; it is now unresponsive to all previously recommended drugs except one last group called cephalosporins. Someday, it may evolve resistance to those, too. NEWSWEEK's Mary Carmichael spoke with Dr. John Douglas, director of the CDC's Division of Sexually Transmitted Diseases Prevention. Excerpts:

NEWSWEEK: A primary treatment for gonorrhea no longer works in more than 13 percent of cases surveyed by the CDC. What about the other 87 percent? Should those patients keep taking quinolones, or do the CDC's new recommendations apply to them as well?
John Douglas: For all practical purposes, the new recommendation affects everybody. The reason is that most of the time patients don't know what strain they have. The old clinical tests for gonorrhea, where you grow bacteria in a culture and see what it takes to kill it, could tell you whether a strain was resistant or not. But most clinics have replaced those tests with more convenient methods that don't have the capacity to test for antibiotic susceptibility. So people don't usually know if they're in the 13 percent or the 87 percent.

You've traced the quinolone-resistant strains to western Asia, so you know where they started circulating. Why did they develop resistance in the first place?
We haven't yet fully worked that out. People often use quinolones to treat other diseases like urinary-tract infections. Some of those people might also have had gonorrhea and not realized it, and they wouldn't have necessarily taken enough to kill the gonorrhea, leading to survival of resistant strains.

What, exactly, was it that changed and made the bacteria resistant? 
The most important change was in an enzyme called DNA gyrase that helps the bacteria replicate their DNA. Quinolones work by inhibiting that enzyme. But there were several other mutations that occurred as well. Of all the bacterial STDs, gonorrhea is the most genetically versatile and complicated. It's got the biggest genome, and the bigger the genome, the more places there are for mutations to happen. It's also particularly susceptible to taking on new plasmids, or independent pieces of DNA that float around and get incorporated into the genome. When gonorrhea first became resistant to penicillin in the '80s, it was because it had picked up a new plasmid.

You started seeing quinolone-resistant strains in the United States as early as 2000. Why didn't you change the treatment recommendations then?
We saw them first in Hawaii, and in 2000 we stopped recommending quinolones to treat cases acquired there. We did the same thing for California in 2002. And in 2004 we stopped recommending quinolones for cases nationwide among men who have sex with men. But the thing is, with the nonresistant strains, the quinolones are really effective. They're also very cost-effective and easy to take. So when the resistant strains first got to Hawaii, the idea was that the rest of the U.S. was just fine. We were concerned the resistance would spread, but we didn't think continuing to use the quinolones would hasten that. But we also knew we should be ready to pull the plug when we needed to. And now we do.

After you changed the recommendations in Hawaii and California, did you see a drop in gonorrhea transmission there?
We did not. We would have expected to see that if we had been grossly mistreating a lot of infections. The good news is, it looks like our surveillance system picked up the drug-resistant strains early enough that we were able to maintain effective treatment for people who did get gonorrhea.

Gonorrhea is the second most common STD you track, but numbers are actually down overall, aren't they?
We reached historic heights in the '60s and '70s. And then starting in the early '80s, the numbers began to go way down. Since 1997 they've been relatively flat—although we did have a report last month that showed an almost 50 percent rise in reported cases in eight Western states. At least part of that increase seems to be because more people are getting tested. But not all of it. Some part of it can't be explained by increased testing, which has got us somewhat nervous. So far it doesn't look like this rise can be blamed on antibiotic resistance. There's been some concern that it's linked to the increased use of methamphetamines, which is in turn linked to risky sexual behavior. But that's very much a theory at this point.

So now gonorrhea is resistant to every recommended drug we have except the cephalosporins. Could it develop resistance to those drugs, too?
Absolutely. But we don't have any indication that that's happened with the cephalosporins yet. There have been suspicious reports from other countries of cephalosporin-resistant strains, but when those cultures have been sent to other labs, they haven't actually turned out to be resistant.

How long might it be before a true cephalosporin-resistant strain pops up?
There's no way to estimate it, and we don't truly know that it will happen at all. Cephalosporins have been used to treat gonorrhea for 25 years, and in that time, in terms of susceptibility, the disease hasn't budged. That's pretty good news. But it's not good enough news to allow us to say the cephalosporins will work forever.

How many types of effective cephalosporins are there?
There's a shot called Ceftriaxone, and then there's an oral drug called Cefixime that's only available in limited formulations in the U.S. It used to be manufactured as a pill and a liquid, but the company that manufactured the pill [Wyeth Pharmaceuticals], stopped making it, likely because it was not in their economic interest to continue making it. [The patent expired in 2002.] There's an Indian company called Lupin that's working now to bring the pill form back.

Are there new drugs in the pipeline that might help?
One of the reasons we're so concerned is the antibiotic pipeline is pretty skimpy. There are new varieties of cephalosporin antibiotics that might help, although they are pretty similar to existing drugs. But there's very little else in the pipeline that looks like it could be effective. We might end up trying some older drugs developed for other diseases. One is an alternative for people who are allergic to cephalosporins is called Spectinomycin, which is an injection. Unfortunately, it's currently not manufactured in the United States, so we are considering evaluating other drugs in this class that are still available. There's also a drug that's being used widely for chlamydia called Azithromycin. But the bottom line is, compared to the situation 20 years ago when we had to stop using penicillin for gonorrhea, we have a much less optimistic outlook.