VIENNA – Two combination regimens using antibiotics already approved for U.S. use eradicated urogenital gonorrhea infections with virtually 100% efficacy in a multicenter U.S. study with about 400 patients, providing solid evidence for the potential of both combinations as backup treatments for Neisseria gonorrhoeae at a time when resistance in the pathogen has whittled standard treatment options down to one primary drug, ceftriaxone.
"The emergence of cephalosporin resistance complicates empiric treatment" of gonorrhea infections, Dr. Robert D. Kirkcaldy said at the joint meeting of the International Society for Sexually Transmitted Diseases Research and the International Union Against Sexually Transmitted Infections.
The two new combinations he and his associates tested – gentamicin plus azithromycin (Zithromax) and gemifloxicin (Factive) plus azithromycin – "may be useful for patients unsuccessfully treated with ceftriaxone or patients with a cephalosporin allergy, but neither [of the two new combinations] is a magic bullet," said Dr. Kirkcaldy, a medical epidemiologist in the division of STD prevention at the Centers for Disease Control and Prevention. "The gastrointestinal side effects [seen with both new regimens] may limit their routine use."
Gastrointestinal adverse effects occurred in 47% of the patients who received gentamicin plus azithromycin and in 55% of those who got gemifloxacin plus azithromycin. But Dr. Kirkcaldy highlighted that all of these effects were mild to moderate, none was serious, and the vast majority of patients were able to hold the oral drugs they received for more than an hour; 3% of the gentamicin recipients and 8% of the gemifloxacin recipients vomited within an hour of receiving treatment and were excluded from the primary efficacy analysis as a result.
"These trial results are an exciting step in the right direction in the fight against drug-resistant gonorrhea, but patients need more oral options with fewer side effects," Dr. Gail Bolan, director of the CDC’s division of STD prevention, commented in a written statement.
Less than a year ago, in August 2012, a panel of CDC staffers and outside experts released updated recommendations for treating all types of uncomplicated gonococcal infections, including anorectal, pharyngeal, and urogenital infections. The CDC recommended a single intramuscular injection of ceftriaxone (Rocephin) along with a single oral dose of azithromycin or a 7-day course of doxycycline given b.i.d. (MMWR 2012;61:590-4).
This recommendation came about because of an increasing U.S. incidence of gonococcal infections by strains resistant to cefixime (Suprax), the prior mainstay of treatment. The need to move from cefixime to ceftriaxone also concerned the CDC. The agency projects that patients may soon also face ceftriaxone-resistant gonorrhea.
"Ceftriaxone became the one remaining first-line option. The antimicrobial pipeline is running dry, and N. gonorrhoeae continues to acquire resistance. We wanted to repurpose approved drugs that could be used for salvage treatment on cetriaxone failures and for patients allergic to cephalosporins," Dr. Kirkcaldy said.
The study enrolled patients aged 15-60 years who presented at any one of five participating U.S. medical centers with uncomplicated, untreated urogenital gonorrhea. The 401 patients who completed the study averaged about 28 years of age. About a third were men who have sex with men, slightly more than half were men who have sex with women, and about 10% were women. Just under 10% were HIV positive. Patients received either 240 mg gentamicin as an intramuscular injection at two separate sites (with the dosage adjusted downward for patients weighing 45 kg or less) or a single, 320-mg oral dose of gemifloxacin. All patients also received a 2-g oral dose of azithromycin.
Gentamicin, a drug primarily used for hospitalized patients with endocarditis, was chosen because of its known, modest (about 91.5%) efficacy for gonorrhea, low risk of toxicity with a single dose in otherwise healthy men and women, and its U.S. availability, Dr. Kirkcaldy said. Gemifloxacin was selected because it’s an oral drug approved for sale in the United States that’s been shown to be active in vitro against ciprofloxacin-resistant strains of N. gonorrhoeae. Azithromycin was added because of its known activity against gonorrhea, although with recent eradication rates of 97%-99%, it is now deemed too unreliable for monotherapy.
The study's primary efficacy endpoint was the percentage of patients who successfully received treatment and returned for a follow-up microbiologic test of eradication. This happened in all 202 patients treated with gentamicin plus azithromycin, and in 198 of the 199 (99.5%) treated with gemifloxacin plus azithromycin. A small percentage of the patients enrolled also had rectal or pharyngeal gonococcal infections in addition to their urogenital infection. Both treatments were 100% effective at eradicating infections at those sites, but the numbers were too small to conclusively prove efficacy for these sites, he said.