Threat of Untreatable Gonorrhea Real, Growing

Megan Brooks

July 07, 2017

Antibiotic resistance is making gonorrhea much harder, and sometimes impossible, to treat, the World Health Organization (WHO) warned yesterday.

"We are soon going to have a threat of untreatable gonorrhea in the future," Teodora Wi, PhD, medical officer with the WHO's Department of Reproductive Health and Research, said during a press briefing hosted by the WHO and the Global Antibiotic Research and Development Partnership (GARDP). GARDP is a nonprofit research and development organization launched in 2016 by the WHO and the Drugs for Neglected Diseases Initiative (DNDi).

"Serious Situation"

"Gonorrhea is a very smart bug. Every time you introduce a new class of antibiotics to treat gonorrhea, the bug becomes resistant. We are already seeing resistance to the last-line treatment, which is a cephalosporin and azithromycin, so we need to be more vigilant now and support and collaborate actions to address issues of antimicrobial resistance in gonorrhea," said Dr Wi.

Some countries, particularly high-income countries, where surveillance is best, are finding cases of gonorrhea that are untreatable by all known antibiotics, she noted.

And these cases may "just be the tip of the iceberg, since systems to diagnose and report untreatable infections are lacking in lower-income countries, where gonorrhea is actually more common," Dr Wi added in a news release issued jointly by the WHO and DNDi.

"This is a serious situation," GARDP Director Manica Balasegaram, MD, told the briefing. There are currently only three antibiotic candidates in the pipeline, "and there is no guarantee they will make it out of the pipeline," said Dr Balasegaram.

In a report published in a special supplement of PLOS Medicine, Dr Wi and colleagues note that an estimated 78 million people are infected with gonorrhea each year, including 35.2 million in the WHO Western Pacific region, 11.4 million in the Southeast Asian region, 11.4 million in the African region, 11 million in the region of the Americas, 4.7 million in the European region, and 4.5 million in the Eastern Mediterranean region.

According to the WHO Global Gonococcal Antimicrobial Surveillance Programme, which monitors trends in drug-resistant gonorrhea, data from 2009 to 2014 show widespread resistance to ciprofloxacin, with 97% of countries reporting drug-resistant strains, the authors state.

In addition, 81% of countries report increasing resistance to azithromycin, and 66% report the emergence of resistance to the extended-spectrum cephalosporins (ESCs) – oral cefixime or injectable ceftriaxone – which are currently the last-resort treatment options.

Currently, in most countries, ESCs are the only single antibiotic that remain effective for treating gonorrhea. But resistance to cefixime – and, more rarely, to ceftriaxone – has been reported in more than 50 countries, report Dr Wi and colleagues. This fact prompted the WHO in 2016 to issue updated global treatment recommendations advising clinicians to use two antibiotics: ceftriaxone and azithromycin.

Pressing Need

In a separate article in the PLOS Medicine supplement, Dr Balasegaram and colleagues outline a research and development roadmap to discover new antibiotics for multidrug-resistant gonorrhea and to provide more detail on the three drug candidates currently in the pipeline. Those drugs are as follows:

  • Solithromycin (Cempra Inc), an oral fluoroketolide with activity against gram-positive and fastidious gram-negative bacteria, including Neisseria gonorrhoeae, Mycoplasma genitalium, and Chlamydia trachomatis. Solithromycin targets three prokaryotic ribosomal sites. It showed good efficacy in a phase 2 study, with 100% efficacy for genital, oral, and rectal sites of infection in men and women. A phase 3 trial is ongoing, the authors say.

  • Zoliflodacin (Entasis Therapeutics), a first-in-class spiropyrimidinetrione topoisomerase II inhibitor with activity against several pathogens, including N gonorrhoeae and C trachomatis. Zoliflodacin proved highly effective in vitro against geographically and genetically diverse N gonorrhoeae isolates. Results from a phase 2 trial showed high efficacy in urogenital infections (98% to 100% microbiological cure rate, depending on dose). More than 90% of participants were male.

  • Gepotidacin (GlaxoSmithKline) is another bacterial topoisomerase II inhibitor with good in vitro activity against a wide range of drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus, extended-spectrum beta-lactamase-producing Enterobacteriaceae, and N gonorrhoeae. A phase 2 trial was recently completed; cure rates of 96.7% and 94.8% were achieved with 1500 mg and 3000 mg, respectively. More than 90% of the participants were male.

    "To address the pressing need for new treatments for gonorrhea, we urgently need to seize the opportunities we have with existing drugs and candidates in the pipeline. In the short term, we aim to accelerate the development and introduction of at least one of these pipeline drugs and will evaluate the possible development of combination treatments for public health use," Dr Balasegaram said in the release. "Any new treatment developed should be accessible to everyone who needs it, while ensuring it's used appropriately, so that drug resistance is slowed as much as possible."

    "To control gonorrhea, we need new tools and systems for better prevention, treatment, earlier diagnosis, and more complete tracking and reporting of new infections, antibiotic use, resistance, and treatment failures," added Marc Sprenger, MD, PhD, director of antimicrobial resistance at the WHO. "Specifically, we need new antibiotics, as well as rapid, accurate, point-of-care diagnostic tests – ideally, ones that can predict which antibiotics will work on that particular infection – and, longer term, a vaccine to prevent gonorrhea."

    The two articles in the PLOS Medicine supplement were published before the STI & HIV World Congress, which will take place July 9 to 12 in Rio de Janeiro, Brazil.

    PLoS Med. 14(7):e1002344.

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