Goodbye, Magic Bullet: Hello, Highly Resistant Gonorrhea

One hundred years and some months ago — on March 16, 1911 — a publication called the Boston Medical and Surgical Journal printed a description of the treatment of 20 men at Walter Reed General Hospital in Washington, D.C. The men were members of the U.S. Army. Because medical privacy rules were a lot looser 100 years ago, we know most of their names, because the journal gave them: Cornwell, 22 years old; Smith, 24; Randall, 29; Simerly, 27; Brown, 23; Davis, 26; Waits, 22; Allen, 19; Kimmitt, 27; Megee, 29; Laird, 40; Brinson, 34; Franklin, 29; Clements, 34; Johnson, 24; Lorah, 23; and Crabbe, 27.

The men were in Walter Reed, which we now know as Walter Reed Medical Center, because they all had the sexually transmitted disease syphilis. A century later, it seems absurd to be hospitalized for an STD — but in the years before antibiotics, syphilis and gonorrhea were fantastically destructive of productivity. The men’s records, excerpted by the journal, capture that: They had arthritis, ulcerated skin, heart-valve failure, necrosis of the skull. Cornwell had been “on sick report” — unable to report to duty — for 4 months and 10 days; Simerly, for 5 months and 23 days; Kimmitt, for 11 months; Johnson, for 1 year.

The men were written up by the journal (which decades later evolved into the New England Journal of Medicine) because they were the first recipients of a new treatment compounded by a German chemist out of the ancient poison arsenic and the 19th-century discovery of aniline dyes. The compound’s technical name was arsphenamine, but its creator, Paul Ehrlich, called it Salvarsan. It was preferentially taken up by some tissues and not by others, and its effect on syphilis seemed miraculous. Ehrlich called it a “magic bullet.”

Capt. Harold Jones, who wrote the journal account, carefully noted how long the men had been under treatment with the crude formulas that were all that had been available: Megee, ointments containing the poisonous metal mercury for three months with no benefit; Simerly, mercury given by mouth, by injections and in ointments, five months; Crabbe, mercury and iodide for one year.

The men received injections of the new compound into muscle or veins over several weeks. Jones reported: “There were but two cases where visible lesions did not disappear, and both of these are at the present time 75 percent improved, and one has had his second dose so recently that the ultimate result cannot be predicted confidently.”

Salvarsan (whose 100-year history was recounted in NEJM last July by physician Kent Sepkowitz) was the first chemotherapeutic drug, literally “treatment with chemicals”; it set the stage for penicillin in 1928 and sulfa drugs in the 1930s. It made it possible to believe that patients could be flat-out cured of diseases that were disabling, deadly and incredibly common. When penicillin was released to the public in the 1940s, that drug performed the same miracle for gonorrhea.

Sexually transmitted diseases other than HIV — to this day, the most-reported infectious diseases in the United States — became a bad joke, a temporary embarrassment that could be cured in a single anonymous clinic visit with a quick prescription of pills or a single shot.

Well, goodbye to all that.

In this morning’s NEJM, physicians from the Centers for Disease Control and Prevention, University of North Carolina at Chapel Hill and University of Washington bluntly warn that gonorrhea at least threatens to become untreatable, thanks to the acquisition of antibiotic resistance:

It is time to sound the alarm. During the past 3 years, the wily gonococcus has become less susceptible to our last line of antimicrobial defense, threatening our ability to cure gonorrhea and prevent severe sequelae.

As I reported here last July, gonorrhea (which acquires resistance mutations much more easily than syphilis does) has been steadily becoming indifferent to entire classes of antibiotics used against it: first sulfa drugs, then penicillin, then tetracycline, then fluoroquinolones such as Cipro. The last class of drugs that worked against the disease easily, quickly and cheaply —  key attributes, if you’re running publicly funded clinics where people may not give you their real names — were the class called cephalosporins. But for the past several years, decreased susceptibility to cephalosporins has been moving across the globe, appearing first in Japan, and then spreading both west across Europe and east via Hawaii to the United States. One case of true resistance has been identified in Japan.

As it happens, I have been working on a story about resistant gonorrhea, and you’ll be able to read it soon in Scientific American (where my editor Christine Gorman wrote a blogpost last night). But here is the key point: Gonorrhea, which causes about 700,000 cases a year in the United States, is steadily ratcheting up the doses of drug necessary to cure it, while at the same time there are no new drugs in the pipeline to treat it.

For decades — since the magic bullets of antibiotics made it possible for STDs to become a public health priority — STD detection and treatment has followed a single well-worn pattern. Highly resistant STDs could change that, if they become widely distributed across the planet. Figuring out whether treatment works could require coaxing patients back for repeat visits, a sharp change from decades in which they could drop into a clinic once and be done. But effecting a cure of decreased susceptibility or frank resistance will require new drugs — and as with other diseases such as MRSA and CRKP, there are no new drugs on the horizon, because companies have not been encouraged to make them.

As the NEJM authors somberly report: “There is much to do, and the threat of untreatable gonorrhea is emerging rapidly.”

Cite: Bolan GM, Sparling PF and Wasserheit JN. The Emerging Threat of Untreatable Gonococcal Infection. N Engl J Med 2012; 366:485-487.

Library of Congress; South Carolina Health Department via Wikimedia.


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