Molecular test targets ciprofloxacin-susceptible gonorrhea

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Experts in antibiotic resistance and sexually transmitted diseases (STDs) have long been worried about the growing resistance to the antibiotics used to treat gonorrhea. And with the emergence of multidrug-resistant strains of gonorrhea in recent years, those concerns have taken on a new urgency.

Those strains threaten the efficacy of the currently recommended, and last remaining, treatment regimen for gonorrhea—a shot of ceftriaxone, with or without an oral dose of azithromycin. New antibiotics for gonorrhea are in clinical trials, but because gonorrhea has quickly developed resistance to all the antibiotics that have been used to treat it, there are questions about how long any new antibiotic would remain effective.

That dilemma led Jeffrey Klausner, MD, MPH, a professor of epidemiology and medicine at the University of California–Los Angeles (UCLA), and researchers from around the country to examine a different approach to treating the third most common STD in the United States. The approach involves targeting patients whose infections are still susceptible to antibiotics that were previously recommended.

The results of a new study that tested this strategy, published late last week in Clinical Infectious Diseases, suggests the approach could be highly effective.

Genotypic test detects resistance mutation

In the study, Klausner and colleagues from other US universities and public health departments used a genotypic polymerase chain reaction (PCR) test to screen patients with gonorrhea infections for the presence of genetic mutation in the gyrase subunit A (gyrA) enzyme. The mutation renders the antibiotic ciprofloxacin, which was the recommended treatment for gonorrhea until 2007, ineffective. If the Neisseria gonorrhoeae samples from the patients didn't contain the single point mutation in the gyrA gene, that would be an indication that their infection could be treated with ciprofloxacin.

"We know that 70 to 80 percent of gonococcal infections in the United States are actually susceptible to cipro, but we never had a test that could tell in that individual patient if their infection is amenable to ciprofloxacin treatment," said Klausner, an STD expert who helped develop the genotypic test.

Klausner had noticed that N gonorrhoeae isolates with the altered gene were resistant to ciprofloxacin when he worked at the San Francisco Department of Public Health.

"Based on that discovery of the association with this molecular marker, or altered gene, I thought we could develop a test that would then be able to predict resistance in Neisseria gonorrhoeae based on alteration of this gene," he said.

While the test has been available for several years, its use has not been studied in clinical settings. But previous studies have found that a single dose of ciprofloxacin is highly effective in gonorrhea infections that are susceptible to the drug, specifically when the infection is caused by the wild-type gyrA serine 91 N gonorrhoeae genotype, which doesn't contain the genetic mutation.

After screening patients with untreated gonorrhea at sexual health clinics in seven US cities for wild-type gyrA N gonorrhoeae, Klausner and his colleagues enrolled patients who tested positive and tested them again for confirmation. They then treated the patients with a single 500 milligram tablet of ciprofloxacin, and conducted susceptibility on patient samples to confirm they were susceptible to ciprofloxacin. Subjects returned for a test-of-cure visit at 5 to 10 days.

100% cure rate

The results showed that in the 106 patients with 117 gonorrhea infections caused by the wild-type gyrA serine 91 N gonorrhoeae genotype, all samples were susceptible to ciprofloxacin, and all patients were cured with the single dose of the drug. Two patients with non–wild-type gyrA infections, who were accidentally included, failed the therapy.

"Our results provide very strong evidence that the gyrA serine 91 N gonorrhoeae genotype reliably predicts clinical outcome in patients treated with ciprofloxacin," the authors of the study wrote.

"We thought this was the case, but we never had the clinical outcome study to really prove it, and that's why this study is so important," Klausner said. "This is one of the few studies that actually takes a new test and demonstrates, in a clinical study, that on the basis of the test, people can have a 100-percent cure."

Klausner says one of the values of ciprofloxacin is that, unlike ceftriaxone, which is administered by injection, it can be taken orally and doesn't require an additional clinic visit.

"Patients are certainly going to prefer that," he said. "This also makes it easier to treat partners…which will potentially help our ability to control gonorrhea in the general population."

It's also possible that targeting those patients whose infections are susceptible to ciprofloxacin could reduce selection pressure for resistance to ceftriaxone and azithromycin, the regimen that has been recommended by the Centers for Disease Control and Prevention (CDC) since 2010. That would be significant, since resistance to azithromycin among gonorrhea samples has been rising in recent years. But Klausner said that at this point that theory is speculative.

Alan Katz, MD, MPH, an STD and public health expert at the University of Hawaii who was not involved in the study, called the findings an important contribution to the field.

"Klausner et al's molecular approach to identifying resistance could be an invaluable strategy in identification of ciprofloxacin resistance, allowing for targeted treatment for persons infected with a susceptible strain," Katz said in an email. "As Klausner and colleagues recognize, the development of rapid point-of-care tests to identify markers of resistance in N gonorrhoeae will address a critical need in our efforts to stay one step ahead of an untreatable gonococcus."

Next steps

Klausner said he anticipates that, based on these results, the CDC might include screening for ciprofloxacin resistance in its next STD treatment guidelines, which are expected in the coming months. If the CDC does recommend that patients be screened for the mutation, the ideal scenario would be to integrate the genotypic test, which can return a result within 30 minutes, with the nucleic acid amplification tests that determine whether a person has a gonorrhea infection.

The test is already being used in Europe and Australia. Australian diagnostics company SpeeDx has a point-of-care device that tests for gonorrhea and for the wild-type and mutant forms of the gyrA 91 gene.

Klausner said he hopes inclusion in the CDC's STD guidelines will encourage US diagnostics manufacturers to develop a point-of-care test that detects the genetic markers, and clinicians to adopt it.

"I'm hoping that clinicians are going to recognize the value of treating someone with a pill versus a shot," he said.

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