Research Article: Systematic review and survey of Neisseria gonorrhoeae ceftriaxone and azithromycin susceptibility data in the Asia Pacific, 2011 to 2016

Date Published: April 3, 2019

Publisher: Public Library of Science

Author(s): C. R. Robert George, Rodney P. Enriquez, Barrie J. Gatus, David M. Whiley, Ying-Ru Lo, Naoko Ishikawa, Teodora Wi, Monica M. Lahra, William M. Shafer.


Antimicrobial resistance in Neisseria gonorrhoeae is a global concern, with the ongoing emergence of ceftriaxone and azithromycin resistance threatening current treatment paradigms. To monitor the emergence of antimicrobial resistance in N. gonorrhoeae, the World Health Organization (WHO) Gonococcal Antimicrobial Surveillance Programme (GASP) has operated in the Western Pacific and South East Asian regions since 1992. The true burden of antimicrobial resistance remains unknown. In response, the objective of this study was to survey ceftriaxone and azithromycin susceptibility in N. gonorrhoeae across the western Pacific and south-east Asia, and interlink this data with systematically reviewed reports of ceftriaxone and azithromycin resistance.

The WHO Collaborating Centre for Sexually Transmitted Infections and Antimicrobial Resistance, Sydney, coordinated annual surveys of gonococcal susceptibilities with participating laboratories, and additionally undertook a systematic review of reports detailing gonococcal ceftriaxone and azithromycin susceptibility data for locations geographically in the Asia Pacific from 2011 to 2016. It was found that surveillance of gonococcal antimicrobial resistance remains limited in the Asia Pacific, with weaker surveillance of azithromycin versus ceftriaxone. Ninety-three published reports were identified (including national reports) which documented susceptibility data for ceftriaxone and azithromycin. GASP survey data was available for 21 countries, territories or areas, and suggested MICs are increasing for ceftriaxone and azithromycin. Between 2011 and 2016, the percentage of locations reporting >5% of gonococcal isolates with MICs to ceftriaxone meeting WHO’s definition of decreased susceptibility (MIC ≥ 0.125 mg/L) increased from 14.3% to 35.3% and the percentage of locations reporting >5% of gonococcal isolates with azithromycin resistance (MIC ≥ 1 mg/L) increased from 14.3% to 38.9%. Published reports were available for several countries that did not provide GASP surveillance responses for ceftriaxone (n = 5) and azithromycin (n = 3) respectively. Over the study period, there was a 183% increase in the number of countries providing surveillance data for GASP for both ceftriaxone and azithromycin, and a 30.6% increase in ceftriaxone MIC testing across the Asia Pacific facilitated by this project.

This study provides the first comprehensive illustration of increasing MICs to ceftriaxone in the Asia Pacific. The survey and literature review additionally detail increasing resistance to azithromycin. Further surveillance system strengthening is required to monitor these trends in order to address and curb gonococcal AMR in the region.

Partial Text

The development of antimicrobial resistance in Neisseria gonorrhoeae is of global concern [1], with increased ceftriaxone non-susceptibility, and reports of ceftriaxone resistant strains in Japan, France, Spain, and Australia [2]. Over the past 100 years, N. gonorrhoeae has established resistance to every class of clinically tested antimicrobial agent [3]. Currently many countries recommend dual therapy treatment using the extended spectrum cephalosporin ceftriaxone and the macrolide azithromycin. However, as recognized in the WHO report Antimicrobial resistance: global report on surveillance 2014, there are significant gaps in N. gonorrhoeae antimicrobial resistance surveillance, particularly where disease rates are highest [4]. Of concern, azithromycin resistance has been increasing since first being documented in the 1990s, and the past decade has seen the emergence of ceftriaxone resistant strains including H041 (Japan, 2009), F89 (France, 2010; Spain, 2011), A8806 (Australia, 2013), GU140106 (Japan, 2014), and FC428 and FC460 (Japan, 2015); however, the true extent of this emergence remaining largely unknown [1, 4–6]. The quality of antimicrobial surveillance in the Asia Pacific is of particular interest given apparently higher overall rates of resistance compared with North America and Europe; of concern, however, is rate at which global transportation of such strains permits their spread globally. Numerous factors influence antimicrobial surveillance efforts, including resources, and political and technical constraints (e.g., sample viability during transport, availability of skilled technicians able to perform susceptibility testing). Interplay between such factors at local, national, regional and international levels contributes to the gaps and deficits in AMR testing, surveillance and reporting.

The emergence of ceftriaxone and azithromycin resistance in N. gonorrhoeae represents a major global concern that carries far-reaching public health implications given no ideal alternative treatment has been identified. With increasing ceftriaxone MICs and reports of ceftriaxone resistant strains in the Asia Pacific, and subsequently in Europe and North America, azithromycin was added to ceftriaxone in dual therapy as a method of limiting the selection of ceftriaxone resistant mutants [1, 2]. Historically, the WHO has utilised a 5% threshold of antimicrobial resistance in N. gonorrhoeae to identify when alternative agents should be utilised [12]. This study confirms that the WHO 5% resistance threshold for change has been breached in many sites in the WPR and SEAR, with an increasing proportion of alert level MICs for ceftriaxone and resistance for azithromycin being observed. This observation likely reflects a global phenomenon.




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