Perspective

Experts warn again of drug-resistant gonorrhea

Health experts are again sounding the alarm over the specter of untreatable gonorrhea as the once easily curable STD continues to show decreased susceptibility to the last known effective treatment.

According to WHO data published on Thursday ahead of the STI and HIV World Congress in Rio de Janeiro, the number of countries that have reported drug-resistant gonorrhea infections increased between 2009 and 2014. Experts say the widespread resistance of gonorrhea underscores the urgent need for new antibiotics to fill a depleted pipeline that currently includes just three candidate drugs.

“Gonorrhea is a very smart bug. Every time you introduce a new class of antibiotics to treat gonorrhea, the bug becomes resistant to this antibiotic,” Teodora Wi, MD, medical officer in WHO’s Department of Reproductive Health and Research, said during a teleconference.

Each year, an estimated 78 million people are infected with gonorrhea worldwide, according to WHO, including nearly 400,000 reported cases in the United States in 2015. Left untreated, the infection can cause serious health problems, particularly among women.

Currently, both the CDC and WHO recommend a dual therapy of ceftriaxone and azithromycin to treat gonorrhea infection, but most countries reporting data to WHO have seen resistance to these drugs.

“In a few years, there is going to be resistance to the last-line treatment and we know that drug development takes years, so we need to prepare for this imminent resistance to treatment,” Wi said. “If we don’t have treatment for gonorrhea, we will have very serious consequences. Ultimately, we will also need to have a vaccine.”

A three-dimensional computer-generated image of drug-resistant Neisseria gonorrhoeae diplococcal bacteria.
A three-dimensional computer-generated image of drug-resistant Neisseria gonorrhoeae diplococcal bacteria.
Source: CDC

Study documents growing resistance

In a new study published in PLoS Medicine, Wi and colleagues reported on surveillance data from WHO’s Global Gonococcal Antimicrobial Surveillance Program (GASP). According to the study, in most countries, extended-spectrum cephalosporins (ESCs) — oral cefixime and injectable ceftriaxone — are the only remaining effective drugs for gonorrhea.

However, 66% of the 77 countries included in GASP reported seeing gonococcal isolates with decreased susceptibility or resistance to ESCs for at least 1 year between 2009 to 2014, whereas 81% reported isolates resistant to azithromycin. Most resistance is being documented in high-income countries, but Wi said it likely also exists in lower income countries, where it may go unnoticed or unreported because of surveillance systems that are not as strong.

Treatment failures also have been reported in several countries, according to the report. Wi said most of these patients had pharyngeal infections and were ultimately cured by increasing the dosage of the drugs.

“But we cannot always just be increasing the dosage,” she said. “The time will come that increasing dosage will not be possible. This is the time that we will have untreatable gonorrhea.”

Wi and colleagues noted that three extensively drug-resistant strains have been documented in past studies — one each in France, Japan and Spain. These so-called “superbug” gonorrhea infections showed high-level resistance to ceftriaxone. According to Wi, this means there are patients in the world capable of passing untreatable gonorrhea infections to others.

Along with resistance, the number of gonorrhea cases also is rising — a consequence of decreasing condom use, increased urbanization and travel, poor infection detection rates and inadequate or failed treatment, according to WHO.

Wi named Africa, Asia, the Eastern Mediterranean and parts of Latin America in the Caribbean as areas where there is a need for timely information of resistance to gonorrhea. In their paper, the researchers noted high rates of resistance to gonorrhea in Africa, where quinolones are still being used as the treatment of choice.

Wi said WHO recommended against the use quinolones for gonorrhea last year because of a high level of resistance.

“We need to be more vigilant now to support and collaborate actions to address the issue of antimicrobial resistance in gonorrhea,” she said. “We need countries to strengthen their gonococcal surveillance programs. We need countries to be equipped with sentinel clinics to detect antimicrobial resistance so we can help to refine treatment guidelines and have information for public health policy.”

Drug pipeline

According to a second paper published in PLoS Medicine, the current antibiotic pipeline for gonorrhea treatment includes just three candidate drugs: solithromycin (Cempra), zoliflodacin (Entasis) and gepotidacin (GlaxoSmithKline). Solithromycin is currently in a phase 3 trial, whereas phase 2 trials have finished on zoliflodacin and gepotidacin.

“[There are] obviously no guarantees these drugs may make it out of the pipeline, so the situation is actually fairly grim,” Manica Balasegaram, BMedSci, BMBS, MRCP, DTM&H, MSc, FRCP, director of the Global Antibiotic Research and Development Partnership (GARDP) and co-author of the study, said during the teleconference.

Pharmaceutical, biotechnology and diagnostic companies have called for more incentives to develop new antibiotics, which are unattractive commercially because they are taken over a short period of time — unlike drugs for chronic conditions — and their effectiveness wanes. Their use is also further restricted by physicians to avoid the development of drug resistance. Balasegaram announced that GARDP, which was launched by WHO last year, will partner with the pharmaceutical company Entasis to “accelerate the development and access” of zoliflodacin, which has shown activity against resistant strains of gonorrhea.

“We will work together to register and conduct public health trials and ensure sustainable access,” he said.

In their paper, Balasegaram and colleagues outlined four research and development routes to address resistance to gonorrhea: introduction of a new drug to treat gonorrhea, identification of an ideal combination of existing antibiotics, formulation of new fixed-drug combinations and establishment of a stewardship framework for the distribution and use of the new treatments.

“We have to be smart when we think about our approach to R&D. It’s not simply enough to develop and bring onto the market a new drug,” Balasegaram said. “We have to think about what the best way is to use that drug, including whether we have to combine it with other drugs, and what is the best way to introduce it to the general population, considering that this is largely a community-based infection and we often don’t have good diagnostic tools to understand which type of sexually transmitted infection we are dealing with.” – by Gerard Gallagher

References:

Alirol E, et al. PLoS Med. 2017;doi:10.1371/journal.pmed.1002344.

Cámara J, et al. J Antimicrob Chemother. 2012;doi:10.1093/jac/dks162.

Ohnishi M, et al. Antimicrob Agents Chemother. 2011;doi:10.1128/AAC.00325-11.

Unemo M, et al. Antimicrob Agents Chemother. 2012;doi:10.1128/AAC.05760-11.

WHO. WHO guidelines for the treatment of Neisseria gonorrhoeae. 2016. http://apps.who.int/iris/bitstream/10665/246114/1/9789241549691-eng.pdf?ua=1, Accessed July 6, 2017.

Wi T, et al. PLoS Med. 2017;doi:10.1371/journal.pmed.1002344.

Disclosure: The researchers report no relevant financial disclosures.

Health experts are again sounding the alarm over the specter of untreatable gonorrhea as the once easily curable STD continues to show decreased susceptibility to the last known effective treatment.

According to WHO data published on Thursday ahead of the STI and HIV World Congress in Rio de Janeiro, the number of countries that have reported drug-resistant gonorrhea infections increased between 2009 and 2014. Experts say the widespread resistance of gonorrhea underscores the urgent need for new antibiotics to fill a depleted pipeline that currently includes just three candidate drugs.

“Gonorrhea is a very smart bug. Every time you introduce a new class of antibiotics to treat gonorrhea, the bug becomes resistant to this antibiotic,” Teodora Wi, MD, medical officer in WHO’s Department of Reproductive Health and Research, said during a teleconference.

Each year, an estimated 78 million people are infected with gonorrhea worldwide, according to WHO, including nearly 400,000 reported cases in the United States in 2015. Left untreated, the infection can cause serious health problems, particularly among women.

Currently, both the CDC and WHO recommend a dual therapy of ceftriaxone and azithromycin to treat gonorrhea infection, but most countries reporting data to WHO have seen resistance to these drugs.

“In a few years, there is going to be resistance to the last-line treatment and we know that drug development takes years, so we need to prepare for this imminent resistance to treatment,” Wi said. “If we don’t have treatment for gonorrhea, we will have very serious consequences. Ultimately, we will also need to have a vaccine.”

A three-dimensional computer-generated image of drug-resistant Neisseria gonorrhoeae diplococcal bacteria.
A three-dimensional computer-generated image of drug-resistant Neisseria gonorrhoeae diplococcal bacteria.
Source: CDC

Study documents growing resistance

In a new study published in PLoS Medicine, Wi and colleagues reported on surveillance data from WHO’s Global Gonococcal Antimicrobial Surveillance Program (GASP). According to the study, in most countries, extended-spectrum cephalosporins (ESCs) — oral cefixime and injectable ceftriaxone — are the only remaining effective drugs for gonorrhea.

However, 66% of the 77 countries included in GASP reported seeing gonococcal isolates with decreased susceptibility or resistance to ESCs for at least 1 year between 2009 to 2014, whereas 81% reported isolates resistant to azithromycin. Most resistance is being documented in high-income countries, but Wi said it likely also exists in lower income countries, where it may go unnoticed or unreported because of surveillance systems that are not as strong.

Treatment failures also have been reported in several countries, according to the report. Wi said most of these patients had pharyngeal infections and were ultimately cured by increasing the dosage of the drugs.

PAGE BREAK

“But we cannot always just be increasing the dosage,” she said. “The time will come that increasing dosage will not be possible. This is the time that we will have untreatable gonorrhea.”

Wi and colleagues noted that three extensively drug-resistant strains have been documented in past studies — one each in France, Japan and Spain. These so-called “superbug” gonorrhea infections showed high-level resistance to ceftriaxone. According to Wi, this means there are patients in the world capable of passing untreatable gonorrhea infections to others.

Along with resistance, the number of gonorrhea cases also is rising — a consequence of decreasing condom use, increased urbanization and travel, poor infection detection rates and inadequate or failed treatment, according to WHO.

Wi named Africa, Asia, the Eastern Mediterranean and parts of Latin America in the Caribbean as areas where there is a need for timely information of resistance to gonorrhea. In their paper, the researchers noted high rates of resistance to gonorrhea in Africa, where quinolones are still being used as the treatment of choice.

Wi said WHO recommended against the use quinolones for gonorrhea last year because of a high level of resistance.

“We need to be more vigilant now to support and collaborate actions to address the issue of antimicrobial resistance in gonorrhea,” she said. “We need countries to strengthen their gonococcal surveillance programs. We need countries to be equipped with sentinel clinics to detect antimicrobial resistance so we can help to refine treatment guidelines and have information for public health policy.”

Drug pipeline

According to a second paper published in PLoS Medicine, the current antibiotic pipeline for gonorrhea treatment includes just three candidate drugs: solithromycin (Cempra), zoliflodacin (Entasis) and gepotidacin (GlaxoSmithKline). Solithromycin is currently in a phase 3 trial, whereas phase 2 trials have finished on zoliflodacin and gepotidacin.

“[There are] obviously no guarantees these drugs may make it out of the pipeline, so the situation is actually fairly grim,” Manica Balasegaram, BMedSci, BMBS, MRCP, DTM&H, MSc, FRCP, director of the Global Antibiotic Research and Development Partnership (GARDP) and co-author of the study, said during the teleconference.

Pharmaceutical, biotechnology and diagnostic companies have called for more incentives to develop new antibiotics, which are unattractive commercially because they are taken over a short period of time — unlike drugs for chronic conditions — and their effectiveness wanes. Their use is also further restricted by physicians to avoid the development of drug resistance. Balasegaram announced that GARDP, which was launched by WHO last year, will partner with the pharmaceutical company Entasis to “accelerate the development and access” of zoliflodacin, which has shown activity against resistant strains of gonorrhea.

PAGE BREAK

“We will work together to register and conduct public health trials and ensure sustainable access,” he said.

In their paper, Balasegaram and colleagues outlined four research and development routes to address resistance to gonorrhea: introduction of a new drug to treat gonorrhea, identification of an ideal combination of existing antibiotics, formulation of new fixed-drug combinations and establishment of a stewardship framework for the distribution and use of the new treatments.

“We have to be smart when we think about our approach to R&D. It’s not simply enough to develop and bring onto the market a new drug,” Balasegaram said. “We have to think about what the best way is to use that drug, including whether we have to combine it with other drugs, and what is the best way to introduce it to the general population, considering that this is largely a community-based infection and we often don’t have good diagnostic tools to understand which type of sexually transmitted infection we are dealing with.” – by Gerard Gallagher

References:

Alirol E, et al. PLoS Med. 2017;doi:10.1371/journal.pmed.1002344.

Cámara J, et al. J Antimicrob Chemother. 2012;doi:10.1093/jac/dks162.

Ohnishi M, et al. Antimicrob Agents Chemother. 2011;doi:10.1128/AAC.00325-11.

Unemo M, et al. Antimicrob Agents Chemother. 2012;doi:10.1128/AAC.05760-11.

WHO. WHO guidelines for the treatment of Neisseria gonorrhoeae. 2016. http://apps.who.int/iris/bitstream/10665/246114/1/9789241549691-eng.pdf?ua=1, Accessed July 6, 2017.

Wi T, et al. PLoS Med. 2017;doi:10.1371/journal.pmed.1002344.

Disclosure: The researchers report no relevant financial disclosures.

    Perspective
    David Gondek

    David Gondek

    The recent news from the WHO is the latest bellwether warning of the recent rise in STD infections and the emergence of antibiotic resistance. Because gonorrhea is capable of infecting the back of the throat, in addition to the genitourinary tract, the bacterium can interact with many other microbes that harbor antibiotic resistance genes. This co-mingling of bacterial genomes has led to the rapid rise of antibiotic resistance in gonorrhea. Physicians' combined efforts of a multipronged antibiotic approach as well as improved antibiotic stewardship are required to slow the spread of this disease.

    A New Zealand study published recently in The Lancet demonstrated some vaccine efficacy in protecting individuals from gonorrhea infection. The vaccine, originally designed to prevent Neisseria meningitidis, also has shown some cross-protective efficacy for combating Neisseria gonorrhoeaeIn the wake of rising antibiotic resistance to gonorrhea, an efficacious vaccine will become far more important and financially attractive to biotechnology companies.

    To prevent the spread of STDs, a robust screening of sexually active individuals must occur. The recent surge in STD infections also has led to the advent of several companies providing at-home STD testing kits. Although these kits cannot replace a more reliable exam and test at the doctor’s office, our society needs to acknowledge that these diseases are a rising problem and remove the stigma from discussing them with health care professionals. Through active monitoring, intervention and contacting partners, it is possible to control this growing epidemic.

    Reference:

    Petousis-Harris H, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)31449-6.

    • David Gondek, PhD
    • Assistant professor of biology, Ithaca College

    Disclosures: Gondek reports no relevant financial disclosures.