Global Transmission of the penA Allele 60.001–Containing High-Level Ceftriaxone-Resistant Gonococcal FC428 Clone and Antimicrobial Therapy of Associated Cases: A Review

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Abstract
Neisseria gonorrhoeae is a multidrug-resistant bacterial pathogen for which ceftriaxone is the only remaining recommended first-line therapy. However, ceftriaxone susceptibility has been waning in a number of countries over the last decade and ceftriaxone treatment failures have been reported, commonly as a result of sporadic high-level ceftriaxone-resistant strains. In recent years, N. gonorrhoeae strains associated with the high-level ceftriaxone-resistant FC428 clone or strains that acquired its main ceftriaxone resistance determinant, penA allele 60.001, have shown global transmission, resulting in ceftriaxone treatment failure in a number of cases. The FC428 clone was first encountered in Japan in 2015 and subsequently in China, Europe, Australia, North America and Southeast Asia afterward. Strains associated with the FC428 clone commonly display a ceftriaxone minimum inhibitory concentration of 0.5–1 mg/L. However, where penA alleles encountered in sporadic high-level ceftriaxone-resistant isolates induce an in vitro growth defect, penA allele 60.001 does not seem to affect in vitro growth. The limited impact of penA allele 60.001 on biological fitness might be associated with its successful global transmission. Although the FC428 clone displays high-level ceftriaxone resistance, most gonorrhea cases associated with this clone were still successfully cured with ceftriaxone when intramuscular or intravenous doses of 500 mg to 2 g were used. A successful alternative therapy seems to be ertapenem given at 1-g doses, although further clinical studies are required to validate ertapenem efficacy. This review summarizes the global transmission of strains associated with the FC428 clone and antimicrobial treatment of associated cases.

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