The Growing Challenge of Gonorrhea: A Detailed Analysis of Global Trends, Resistance and Surveillance


Gonorrhea continues to be a major global public health challenge. This sexually transmitted infection, caused by the bacterium Neisseria gonorrhoeae, affects millions of people worldwide. The World Health Organization (WHO) reported approximately 82.4 million new cases of gonorrhea among individuals aged 15–49 years in 2020. In China, a total of 96,313 cases were reported in 2022, positioning gonorrhea as the fourth most prevalent of the class A and class B notifiable infectious diseases in the country, following viral hepatitis, pulmonary tuberculosis, and syphilis. In the United States, the Centers for Disease Control and Prevention (CDC) noted a staggering 648,056 cases in the same year.

The emergence of gonococcal resistance to multiple antibiotics has compounded the challenge of controlling this disease. The preferred first-line treatment for gonorrhea in both China and the United States involves the antibiotic ceftriaxone. In China, a single 1 g dose is administered intramuscularly, while in the United States, the dosage is 500 mg for persons weighing less than 150 kg. Despite this, resistance to ceftriaxone, particularly the ceftriaxone-resistant clone FC428, first identified in Beijing in 2016, has been observed increasing globally, signaling a distressing trend in the fight against gonorrhea.

The China Gonococcal Resistance Surveillance Program (China-GRSP), established in 1987, plays a critical role in monitoring this resistance. The 2022 surveillance data showed participation from 13 of the 19 province-level jurisdictions in China, encompassing six of the seven regions of the country. N. gonorrhoeae isolates were collected from urethral and endocervical swab specimens of 2,804 patients included in the program. These specimens underwent rigorous testing processes, including culture on selective media, microscopic examination, and susceptibility testing using the agar dilution method.

The results from these tests were alarming. Out of the 2,804 isolates, resistance was observed at high rates across several antibiotics. Notably, 97.6% of the isolates were resistant to ciprofloxacin, 77.8% to penicillin, and 77.1% to tetracycline. Resistance to the first-line treatment ceftriaxone was recorded at 8.1%. Azithromycin and cefixime also saw significant resistance rates of 16.9% and 16.0%, respectively.

The distribution of resistance varied significantly across different provinces. Some regions like Sichuan, Tianjin, and Xinjiang reported more than 20% resistance to ceftriaxone, markedly higher than other areas. The situation calls for urgent and tailored public health responses, especially in provinces with resistance rates exceeding 10%.

Internationally, the picture remains grim but varied. For example, the United Kingdom reported a much lower percentage of strains with reduced susceptibility to ceftriaxone (0.21%) in 2022, while the U.S. CDC’s Gonococcal Isolate Surveillance Project indicated that elevated ceftriaxone minimum inhibitory concentrations fluctuated around 0.2% during 2016−2020. Canada saw a relatively stable prevalence of decreased susceptibility to ceftriaxone at approximately 0.6% during 2017–2021.

The high rates of resistance in China and the global spread of resistant strains like FC428 highlight the critical need for a comprehensive strategy to tackle antibiotic-resistant N. gonorrhoeae. This includes identifying and addressing factors contributing to resistance, enhancing screening and treatment protocols, and ensuring appropriate antibiotic use. Moreover, the ongoing genomic studies of isolates and the collaboration across borders for surveillance and response are crucial.

Discussion: Navigating the Evolving Landscape of Gonococcal Resistance

Gonorrhea persists as a significant global health threat, with regional and temporal variations in antibiotic resistance underscoring the complexity of its management. The phenotypic characterization of Neisseria gonorrhoeae resistance is intricately linked to minimum inhibitory concentration (MIC) values aligned with susceptibility breakpoints. These breakpoints are crucial, integrating in vitro microbiological data, pharmacokinetic/pharmacodynamic (PK/PD) parameters, and clinical outcomes to guide therapeutic decisions.

Recent data from Nanjing, China, underscores the severe antimicrobial resistance of N. gonorrhoeae. Between 2013 and 2020, resistance rates to penicillin, tetracycline, and ciprofloxacin were alarmingly high, often nearing or reaching complete resistance. This situation likely stems from the extensive misuse of antibiotics, a challenge that is not confined to China but observed globally. When MIC values reach critical levels, the probability of target attainment (PTA) of standard dosages of these antibiotics falls below 90%, indicating a high likelihood of treatment failure. This reinforces the global shift away from older antibiotics like penicillin, tetracycline, and ciprofloxacin towards more effective treatments.

The dual therapy of ceftriaxone and azithromycin, once the cornerstone of gonorrhea treatment, has been reassessed due to rising azithromycin resistance rates. For instance, in Nanjing, despite the availability of higher dosages, the PTA for azithromycin remains suboptimal, supporting the U.S. CDC’s decision in December 2020 to revise treatment guidelines by excluding azithromycin due to escalating resistance.

The third-generation cephalosporins, primarily ceftriaxone, remain the WHO-recommended first-line treatment for gonorrhea. Yet, in places like Nanjing and broader regions of China, the emergence of ceftriaxone resistance is troubling. Despite a zero resistance rate in earlier years, resistance emerged and grew from 2017 to 2020. This trend was paralleled in other areas of China and indicates a worrying rise in the MIC values of ceftriaxone, prompting considerations for increased dosages.

Monte Carlo simulations coupled with PK/PD analyses suggest that augmenting ceftriaxone doses could counteract rising MIC levels. When faced with resistant strains exhibiting MICs greater than 1 µg/ml, the efficacy of standard doses plummeted, while increasing the dose substantially improved treatment success rates. This data supports international moves towards higher dosages of ceftriaxone for the treatment of gonorrhea, acknowledging however that such increases could potentially lead to more frequent adverse reactions.

Amidst this scenario, zoliflodacin emerges as a promising candidate. This novel antibiotic targets the GyrB subunit of DNA gyrase, crucial for bacterial DNA replication. Clinical trials have shown high efficacy rates for zoliflodacin against gonorrhea, including challenging infections like pharyngeal gonorrhea. The MIC data supports the use of higher doses to maintain high PTAs, which are essential for achieving clinical cure and setting new susceptibility breakpoints for future guidance.

Despite these advancements, the study acknowledges several limitations, including the variability of PK/PD data across populations and the regional specificity of the MIC data to Nanjing. Furthermore, the impact of underlying health conditions on drug metabolism could skew the predictions of antibiotic efficacy. The absence of data on newer antibiotics like gepotidacin and solithromycin also limits the scope of current recommendations.

To navigate the evolving landscape of gonococcal resistance effectively, continuous monitoring through robust surveillance systems, adaptation of treatment guidelines based on emerging data, and the development of new antibiotics are imperative. Additionally, increasing global cooperation in research and public health response will be crucial in managing and ultimately reducing the burden of gonorrhea worldwide.

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