by Michael Smith, North American Correspondent, MedPage TodayJuly 06, 2017
Action Points
Rising antibiotic resistance around the world is making gonorrhea harder -- and in a handful of cases so far, impossible -- to treat, the World Health Organization is warning.
Of 77 countries with available data for the period 2009 through 2014, 66% reported finding gonorrhea cases that had decreased sensitivity to extended spectrum cephalosporins, the backbone antibiotics recommended to treat the disease, according to Teodora Wi, MD, of the WHO's Department of Reproductive Health and Research in Geneva, and colleagues.
Also, of the 72 countries monitoring ciprofloxacin resistance and the 58 monitoring azithromycin resistance, 97% and 81% respectively reported finding resistant isolates, they wrote online in PLoS Medicine.
But the picture is likely worse than that, Wi told reporters in a telephone briefing, since those data come from high-income countries with good surveillance and reporting systems. Many low-income countries have a toxic mix of high gonorrheal burden, inappropriate antibiotic use, and poor surveillance.
"There are more cases of untreatable gonorrhea in those countries and they are not really being documented at this point," Wi told reporters.
Wi said most "untreatable" cases eventually respond to medication -- but at much higher than recommended doses. But she added that the WHO knows of three cases -- one each in Japan, France, and Spain -- where even those higher doses were ineffective and the gonorrhea was not cured. One of the patients has been lost to follow-up, she added.
Several cases of difficult-to-treat gonorrhea have been reported in the U.S., including a cluster of seven cases seen last year in Hawaii.
In those cases, all patients were eventually treated successfully with the recommended drug combination but testing isolates showed high levels of resistance to azithromycin and reduced susceptibility -- but not outright resistance -- to ceftriaxone.
Currently, the WHO recommends treating gonorrhea with one gram of azithromycin as a single dose, with either a single intramuscular dose of ceftriaxone (250 mg), or 400 mg of cefixime orally as a single dose.
But resistance to cefixime has been rising and in the U.S. the CDC no longer recommends it. Instead, for uncomplicated genital, rectal, or pharyngeal gonorrhea, the agency now suggests combination therapy with intramuscular ceftriaxone, with either azithromycin or doxycycline, at 100 mg orally twice daily for seven days.
The problem is that the extended spectrum cephalosporins are the last antibiotics known to work against the disease and very few new drugs are in the pipeline, according to Manica Balasegaram, MD, director of the Global Antibiotic Research and Development Partnership, also in Geneva.
"Ever since antibiotics appeared on the scene," he told reporters, "Neisseria gonorrhoeaehas been quick to develop resistance."
Indeed, Wi and colleagues noted, "since the introduction of antimicrobial treatment, resistance has rapidly emerged to sulphonamides, penicillins, tetracyclines, macrolides, fluoroquinolones, and early-generation cephalosporins."
And resistance can emerge quickly, she said: It took just two years from the appearance of gonorrheal resistance to fluoroquinolones to the point where the drugs could no longer be used empirically as therapy.
Indeed, Wi told reporters, "we are still banking on ceftriaxone and azithromycin" to control gonorrhea, but resistance to azithromycin in some countries has been reported at about 30% of isolates.
The WHO argues that when resistance rates rise above 5%, it's time to change medication guidelines. "Once we see the tip of the iceberg," Wi said, "it's only a matter of time."
The WHO is calling for a range of measures to slow the spread of drug-resistant gonorrhea, including:
- More vigilance. The agency argues that better surveillance will help officials get a grip on the issue.
- Timely release of information of resistance, when it's noticed.
- Education campaigns about safer sex.
- Screening to find asymptomatic patients. Some 40% of men and 80% of women do not display clinical signs and symptoms immediately.
- Tracing and treating sexual partners.
- The development of inexpensive point-of-care tests that would help stop the practice of syndromic treatment of sexually transmitted diseases, including empiric treatment for gonorrhea.
- The discovery and development of new antibiotics.
But "gonorrhea is a very smart bug," she said, and new antibiotics will likely quickly go the way of older drugs. Instead, the key step would be the development of a vaccine.
That has been difficult, Wi said, because there is no natural immunity to gonorrhea and researchers have been unable to find antigens that could be used to develop artificial immunity.
That might be changing, she noted, with evidence that a vaccine against a related pathogen --Neisseria meningitides -- might hold clues to a vaccine for gonorrhea. When the meningitis B vaccine was deployed in New Zealand in 2004 and 2005, observers noted that cases of gonorrhea appear to fall at the same time.
Subsequent analysis confirmed the effect, and suggested the meningitis vaccine was about 31% effective against gonorrhea, Helen Petousis-Harris, PhD, of the University of Auckland reported at the 2016 STI prevention conference in Atlanta.
That's probably not enough to suggest simply using the same vaccine, but it might give investigators somewhere to start to develop a drug specific for gonorrhea, she said then.
The authors said they received no specific funding for the work and declared that no competing interests exist.
- Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
