Infectious Disease

Hope on the horizon of more and more drug-resistant gonorrhea

December 23, 2020

5 min read

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Cooper and Shihadeh do not report any relevant financial information.

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Neisseria gonorrhoeae is the pathogen that causes gonorrhea, the second most common sexually transmitted infection in the United States.

There are more than 1.1 million new gonorrhea infections every year, according to the CDC, and the annual incidence continues to rise. N. gonorrhoeae can infect men or women and is transmitted to the genitals, rectum, or throat through sexual contact. The most common symptoms are dysuria and genital discharge, but many infected people are asymptomatic, making it possible to infect others without knowing it. Untreated infection can lead to serious complications in both men and women. Regular screening of those at high risk is therefore essential.

Maggie Cooper
Maggie Cooper

Kati Shihadeh
Kati Shihadeh

Although gonorrhea is generally curable with antibiotics, increasing rates of antibiotic resistance have drastically reduced the number of treatment options available. In the mid-1930s, sulfa compounds emerged as the first effective treatment option for gonococci, but resistance developed quickly and sulfa drugs were quickly replaced by penicillin. Within 10 to 15 years, the minimum inhibitory concentration (MIC) of penicillin began to increase due to the acquisition of two beta-lactamase-encoding plasmids. Higher doses of penicillin were given to overcome this resistance. However, by the 1980s, penicillin was no longer recommended for treating gonococcal infections. Fortunately, there were several other antibiotics – such as fluoroquinolones, macrolides, and tetracyclines – that proved effective, and these alternative antibiotics became the mainstay of treatment. Tetracyclines eventually lost their activity when N. gonorrhoeae acquired the tetM gene, and fluoroquinolones became ineffective when gyrA and parC mutations developed. Currently, third generation cephalosporins are the only class of antibiotics with reliable activity against N. gonorrhoeae. Unfortunately, cefixime malfunctions have become more common in recent years and there are fears that ceftriaxone will catch up and treatment options will not be available.

Current treatment

For uncomplicated gonococcal infections, the 2015 CDC guidelines recommend an intramuscular dose of ceftriaxone 250 mg plus an orally administered dose of azithromycin 1 g. Although ceftriaxone has reliable effectiveness, it is recommended in combination with azithromycin to slow down the rate of cephalosporin resistance. Increasing the dose of ceftriaxone is another possible option for optimizing pharmacodynamic properties. Countries with higher resistance rates recommend up to 1 g ceftriaxone. In China, a recent surveillance study found that 9.8% of N. gonorrhoeae isolates were less sensitive to ceftriaxone. Despite the increased resistance rates, all patients included in the study experienced clinical healing. The majority of patients received 1 g or more of intramuscular ceftriaxone, and these high doses may have contributed to the high cure rate. Higher doses of ceftriaxone can increase the length of time that ceftriaxone is above the MIC, increasing the likelihood of microbiological clearance, even in infections with a high MIC. However, increasing the dose of ceftriaxone is likely to provide only a short-term solution to increasing resistance and more reliable treatment options will be needed.

Future directions

In the 2013 and 2019 Antibiotic Resistance Threats Report, the CDC identified drug-resistant N. gonorrhoeae as an urgent threat that requires urgent and aggressive action. In 2013 a call to action for the development of new antibiotics was published. Within a few years, the FDA developed incentives to develop new drugs called Fast Track and QIDP (Qualified Infectious Disease Product). These guidelines expand market exclusivity to encourage research and development of antimicrobial agents for severe or life-threatening infections.

Using the Fast Track and QIDP names, two new antibiotics, zoliflodacin and gepotidacin, are currently being tested in phase 3 studies to determine their effectiveness in treating gonococcal infections. Zoliflodacin has a novel mechanism of action and is the first antibiotic in the spiropyrimidinetrione class. It inhibits type II isomerase to prevent bacterial DNA synthesis. In a multicentre, open-label phase 2 study, a single oral dose of zoliflodacin was not inferior to a single intramuscular dose of 500 mg ceftriaxone for the treatment of genitourinary and rectal infections. Both the 2 g and 3 g doses of zoliflodacin were found to be effective, but the 3 g dose was associated with adverse events, the majority of which were gastrointestinal complaints. Gepotidacin is another novel antibiotic in the new class of triazaacenaphthyls. It binds to unique sites on DNA gyrase and topoisomerase to inhibit bacterial DNA replication. A phase 2 randomized open-label study demonstrated the effectiveness of a single 1.5g or 3g dose in treating uncomplicated urogenital gonorrhea. The most common adverse events were diarrhea, gas, and abdominal pain, but no adverse event was serious enough to cause study discontinuation. Unfortunately, neither zoliflodacin nor gepotidacin improved healing rates in pharyngeal infections, which have historically been more difficult to eradicate. However, with their unique mechanisms of action, they have shown activity against fluoroquinolone and ceftriaxone resistant strains of N. gonorrhoeae, which gives hope for the availability of future treatment options.

Another possible option to reduce the threat of drug-resistant N. gonorrhoeae is to use a vaccine to prevent infection. Neisseria meningitidis and N. gonorrhoeae share about 80% to 90% of their genetic sequence, and there is evidence that the meningitis vaccine offers protection against gonococcal infections. After massive meningitis vaccination campaigns in New Zealand, public health experts noted a later decrease in gonorrhea infections, without the same decrease in other sexually transmitted diseases. In a retrospective case-control study, the researchers found that the Group B (MenB) meningococcal vaccine had approximately 31% effectiveness against N. gonorrhoeae. This is a breakthrough for gonococcal vaccines as many other vaccine trials have shown no benefit. Larger clinical studies are needed to confirm these results. Although the COVID-19 pandemic has made it difficult to find suitable test materials for screening study participants, a phase 2 clinical trial to investigate the effectiveness of the MenB vaccine Bexsero (GlaxoSmithKline) against gonorrhea will begin in multiple locations in the United States . The study’s lead researcher recently reported on Infectious Disease News.

Conclusion

While new and exciting treatment strategies are on the horizon, safe sexual practices and early screening and treatment are the main strategies for preventing the spread of sexually transmitted diseases in the community until they are available.

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