Six penA Codons Accurately and Reliably Predict Cefixime-Decreased Susceptibility in Neisseria gonorrhoeae

To the Editor—We read with great interest the article by Thomas et al [1], describing the whole-genome-sequencing data of 649 US-based Neisseria gonorrhoeae strains with decreased susceptibility to cephalosporins and azithromycin collected through the Centers for Disease Control’s Gonococcal Isolate Surveillance Project. The World Health Organization recommends cefixime, an oral third-generation cephalosporin, for the treatment of gonorrhea either in combination with 1 gram of oral azithromycin or alone as a single drug if recent local resistance data confirm susceptibility [2]. Previous investigators have shown that infections with gonococcal strains with a cefixime minimum inhibitory concentration (MIC) ≥0.12 µg/mL were significantly more likely to fail cefixime treatment than strains with MIC <0.12 µg/mL. Among the 649 strains, 121 had cefixime-decreased susceptibility (defined as MIC ≥0.12 µg/mL) [3].

We previously described that the penA gene for N gonorrhoeae penicillin-binding protein-2 reliably predicts cefixime-decreased susceptibility [4]. We found 6 codons in penA (amino acid position 375–377, 501, 542, and 551) that, when any 1 codon was mutated, predicted cefixime-decreased susceptibility in 413 (99.5%) of those 415 strains collected globally between 1996 and 2017 [4].

Using sequence data from the additional 121 strains with decreased susceptibility to cefixime reported by Thomas et al [1], our 6-codon algorithm correctly predicted cefixime-decreased susceptibility in 115 (95.9%). Combining our prior work with that of Thomas et al [1], the accuracy was 528 (98.5%) of 536. The genetic and epidemiologic characteristics of the 8 strains that were not identified by our algorithm are varied and do not contain the typical mosaic penA mutations associated with extended-spectrum cephalosporin- decreased susceptibility (Table 1).

Table 1.

Characteristics of the 8 Cefixime-Decreased Susceptible Gonococcal Strains That Had No Alterations at Amino Acid Position 375–377, 501, 542, or 551 of penA

Reference	Accession Number	Year of Collection	Country of Collection	penA type by NG-STARa	Cefixime MIC (µg/mL)
[7]	No report	2013	Spain	Resembling 36b	≥0.125c
	No report	2013	Spain	Resembling 36b	≥0.125c
[1]	SRR8071198	2014	USA	2	0.125
	SRR8071266	2015	USA	14	0.125
	SRR8071414	2016	USA	14	0.125
	SRR8071120	2014	USA	19	0.125
	SRR8071395	2016	USA	19	0.125
	SRR5990438	2016	USA	68	0.25

Abbreviations: MIC, minimum inhibitory concentration; NG-STAR, Neisseria gonorrhoeae sequence typing for antimicrobial resistance.

^a Neisseria gonorrhoeae sequence typing for antimicrobial resistance (https://ngstar.canada.ca).

^bComplete nucleotide or amino acid sequence data were not reported by the authors.

^cSpecific MIC value was not reported by the authors.

We have verified that the parsimonious 6-codon molecular assay that we recently proposed would successfully predict cefixime-decreased susceptibility in a very high proportion of N gonorrhoeae strains with cefixime-decreased susceptibility currently circulating. We propose that surveillance efforts monitor mutations in those 6 codons in penA using real-time polymerase chain reaction methods [5] to supplement conventional phenotypic monitoring of antimicrobial resistance in N gonorrhoeae.

In addition, the development and implementation of such an assay for clinical use could make cefixime an effective alternative to dual therapy or injectable high-dose ceftriaxone therapy in settings where cefixime-decreased susceptibility is a concern [6]. In settings where cefixime-decreased susceptibility is rare, resistance-guided therapy could help slow down the continued emergence of antimicrobial resistance in N gonorrhoeae.

Notes

Financial support. Funding was provided by the National Institute of Allergy and Infectious Diseases, Grant R21 AI117256 (to J. D. K.).

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.