Abstract
The recent emergence of strains of Neisseria gonorrhoeae associated with treatment failures to ceftriaxone, the foundation of current treatment options, has raised concerns over a future of untreatable gonorrhea. Current global data on gonococcal strains suggest that several lineages, predominately characterized by mosaic penA alleles, are associated with elevated minimum inhibitory concentrations (MICs) to extended spectrum cephalosporins (ESCs). Here we report on whole genome sequences of 813 N. gonorrhoeae isolates collected through the Gonococcal Isolate Surveillance Project in the United States. Phylogenomic analysis revealed that one persisting lineage (Clade A, multi-locus sequence type [MLST] ST1901) with mosaic penA-34 alleles, contained the majority of isolates with elevated MICs to ESCs. We provide evidence that an ancestor to the globally circulating MLST ST1901 clones potentially emerged around the early to mid-20th century (1944, credibility intervals [CI]: 1935–1953), predating the introduction of cephalosporins, but coinciding with the use of penicillin. Such results indicate that drugs with novel mechanisms of action are needed as these strains continue to persist and disseminate globally.
Highlights
The recent emergence of strains of Neisseria gonorrhoeae associated with treatment failures to ceftriaxone, the foundation of current treatment options, has raised concerns over a future of untreatable gonorrhea
Isolates belonging to the ST1901 (71%, 235/332; P < 0.0001) and ST1580 (10%, 30/332; P < 0.0001) groups were significantly associated with cefixime MICs (CFMem); only those from the ST1901 were significantly associated with ceftriaxone MICs (CROem) (75%, 75/104; P < 0.0001)
Isolates were assigned to 198 unique N. gonorrhoeaemulti-antigen sequencing typing (NG-MAST) sequence types (STs), which differentiated many of the broader multilocus sequencing typing (MLST) ST groups (MLST STs differing by 1 allele)
Summary
The recent emergence of strains of Neisseria gonorrhoeae associated with treatment failures to ceftriaxone, the foundation of current treatment options, has raised concerns over a future of untreatable gonorrhea. Beginning with sulfonamides in the late 1930s, the gonococcus has successively developed resistance to all previously recommended antimicrobial drugs used for treatment of gonorrhea (e.g., penicillins, tetracyclines, macrolides, fluoroquinolones, and extended-spectrum cephalosporins [ESCs])[4]. This led to several countries including the United States in 2010 to recommend combination therapy for gonorrhea treatment as it was theorized that other co-administered agents (e.g., doxycycline or azithromycin) would delay the emergence and dissemination of cephalosporin-resistant gonococcal strains[5]. By the 1980s, studies had noted penicillin-resistant strains with altered forms of PBP2 characterized by an Asp-345 insertion and other mutations, which was later attributed to interspecies recombination with Neisseria commensals[17,18]
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