Hope on the horizon for increasingly drug-resistant gonorrhea
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Neisseria gonorrhoeae is the pathogen that causes gonorrhea, the second most common sexually transmitted infection in the United States.
According to the CDC, there are more than 1.1 million new gonorrhea infections each year, and the annual incidence continues to rise. N. gonorrhoeae can infect men or women and is spread to the genitals, rectum or throat through sexual contact. The most common symptoms are dysuria and genital discharge, but many infected individuals are asymptomatic, making it possible to infect others without knowing. Untreated infection can lead to serious complications in both males and females, so regular screening of high-risk individuals is imperative.
Although gonorrhea is generally curable with antibiotics, increasing rates of antimicrobial resistance have drastically reduced the number of available treatment options. In the mid-1930s, sulfa compounds were found to be 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 started rising because of the acquisition of two beta-lactamase-encoding plasmids. Higher doses of penicillin were given to overcome this resistance, but by the 1980s, penicillin was no longer recommended for the treatment of gonococcal infections. Luckily, there were several other antibiotics — such as fluoroquinolones, macrolides and tetracyclines — that were found to be 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, within the past several years, cefixime treatment failures have become more frequent, and there is fear that ceftriaxone will follow suit, leaving no available treatment options.
Current treatment
For uncomplicated gonococcal infections, the 2015 CDC guidelines recommend one dose of ceftriaxone 250 mg given intramuscularly plus one dose of azithromycin 1 g given orally. Although ceftriaxone has reliable efficacy, it is recommended in combination with azithromycin to slow the rate of cephalosporin resistance. Increasing the dose of ceftriaxone is another potential option to optimize its pharmacodynamic properties. Countries with higher rates of resistance recommend up to 1 g of ceftriaxone. In China, a recent surveillance study demonstrated decreased ceftriaxone susceptibility in 9.8% of N. gonorrhoeae isolates. Despite the increased rates of resistance, all patients included in the study experienced a clinical cure. The majority of patients received 1 g or more of intramuscular ceftriaxone, and these high doses could have contributed to the high cure rate. Higher doses of ceftriaxone can increase the duration of time that ceftriaxone concentration is above the MIC, thereby increasing likelihood of microbiological clearance, even in infections with a high MIC. However, increasing the dose of ceftriaxone will likely offer only a short-term solution to increasing resistance, and more reliable treatment options are needed.
Future directions
In the 2013 and 2019 Antibiotic Resistance Threats Report, the CDC classified drug-resistant N. gonorrhoeae as an urgent threat that requires urgent and aggressive action. In 2013, it issued a call to action for the development of new antibiotics. Within a few years, the FDA developed incentives for new drug development with the fast track designation and the qualified infectious disease product (QIDP) designation. These policies extend market exclusivity to promote the research and development of antimicrobials for serious or life-threatening infections.
With the help of the fast track and QIDP designations, two new antibiotics, zoliflodacin and gepotidacin, are currently undergoing phase 3 trials to determine their efficacy in 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 phase 2, multicenter, open-label trial, a one-time oral dose of zoliflodacin was noninferior to a one-time 500 mg intramuscular dose of ceftriaxone for treatment of urogenital 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 more adverse events, which were mostly gastrointestinal complaints. Gepotidacin is another novel antibiotic in the new triazaacenaphthylene class. It binds to unique sites on DNA gyrase and topoisomerase to inhibit bacterial DNA replication. A phase 2, randomized open-label trial demonstrated efficacy of a single 1.5 g or 3 g dose in the treatment of uncomplicated urogenital gonorrhea. The most common adverse events were diarrhea, flatulence and abdominal pain, but no adverse event was severe enough to cause withdrawal from the study. Unfortunately, neither zoliflodacin nor gepotidacin improved cure rates in pharyngeal infections, which historically have been more difficult to eradicate. However, with their unique mechanisms of action, they have demonstrated activity against fluoroquinolone- and ceftriaxone-resistant strains of N. gonorrhoeae, providing some hope for the availability of future treatment options.
Another potential option for reducing the threat of drug-resistant N. gonorrhoeae is using a vaccine to prevent infections. Neisseria meningitidis and N. gonorrhoeae share about 80% to 90% of their genetic sequence, and there is some evidence that the meningitis vaccine has provided protection against gonococcal infections. After massive meningitis vaccine campaigns in New Zealand, public health experts noticed a subsequent decline in gonorrhea infections, without the same decline in other STIs. In a retrospective case-control study, the researchers found that the meningococcal group B (MenB) vaccine had about 31% effectiveness against N. gonorrhoeae. This is a breakthrough for gonococcal vaccines because many other vaccine trials had failed to show any benefit. Larger clinical trials are needed to confirm these findings. Even as the COVID-19 pandemic has made it difficult to find adequate testing supplies to screen trial participants, a phase 2 clinical trial studying the efficacy of the MenB vaccine Bexsero (GlaxoSmithKline) against gonorrhea is poised to begin at several sites in the U.S., the study’s principal investigator told Infectious Disease News recently.
Conclusion
Although new and exciting treatment strategies are on the horizon, until these are readily available, safe sexual practice as well as early screening and treatment are the main strategies for preventing the spread of STIs in the community.
- References:
- Azze RFO. Clin Exp Vaccine Res. 2019;doi:10.7774/cevr.2019.8.2.110.
- CDC. Antibiotic resistance threats in the United States, 2019. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. Accessed December 2, 2020.
- CDC. Sexually transmitted disease surveillance 2018. https://www.cdc.gov/std/stats18/STDSurveillance2018-full-report.pdf. Accessed December 2, 2020.
- Chisholm SA, et al. J Antimicrob Chemother. 2010;doi:10.1093/jac/dkq289.
- Han Y, et al. Clin Infect Dis. doi:10.1093/cid/ciz170.
- Petousis-Harris H, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)31449-6.
- Taylor SN, et al. Clin Infect Dis. 2018;doi:10.1093/cid/ciy145.
- Taylor SN, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1706988.
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- Workowski KA, Bolan GA. MMWR Morb Mortal Wkly Rep. 2015:64;1-137.
- For more information:
- Maggie Cooper, PharmD, is a PGY2 infectious diseases pharmacy resident at Denver Health Medical Center. Cooper can be reached at margaret.cooper@dhha.org.
- Kati Shihadeh, PharmD, BCIDP, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.
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