Establishing Novel Molecular Algorithms to Predict Decreased Susceptibility to Ceftriaxone in Neisseria gonorrhoeae Strains

Abstract

Background Globally, decreased susceptibility to ceftriaxone in Neisseria gonorrhoeae is rising. We aimed to compile a global collection of N. gonorrhoeae strains and assess the genetic characteristics associated with decreased susceptibility to ceftriaxone. Methods We performed a literature review of all published reports of N. gonorrhoeae strains with decreased susceptibility to ceftriaxone (>0.064 mg/L minimum inhibitory concentration) through October 2019. Genetic mutations in N. gonorrhoeae genes (penA, penB, mtrR, ponA), including determination of penA mosaicism, were compiled and evaluated for predicting decreased susceptibility to ceftriaxone. Results There were 3821 N. gonorrhoeae strains identified from 23 countries and 684 (18%) had decreased susceptibility to ceftriaxone. High sensitivities or specificities (>95%) were found for specific genetic mutations in penA, penB, mtrR, and ponA, both with and without determination of penA mosaicism. Four algorithms to predict ceftriaxone susceptibility were proposed based on penA mosaicism determination and penA or non-penA genetic mutations, with sensitivity and specificity combinations up to 95% and 62%, respectively. Conclusion Molecular algorithms based upon genetic mutations were proposed to predict decreased susceptibility to ceftriaxone in N. gonorrhoeae. Those algorithms can serve as a foundation for the development of future assays predicting decreased susceptibility to ceftriaxone within N. gonorrhoeae globally.

Reliability of Genetic Alterations in Predicting Ceftriaxone Resistance in Neisseria gonorrhoeae Globally

“…The analysis using the PathogenWatch database resulted in similar sensitivity and specificity values as the prior molecular markers, assays, and algorithms of interest. For example, having at least 1 alteration in either G120 or A121 of porB resulted in a 98.4% sensitivity and 44.6% specificity, which was in comparison to 96.6% and 42.1% sensitivity and specificity, respectively, found in our prior work ( 13 ) and 94.8% and 50.8% sensitivity and specificity, respectively, by Peterson et al ( 19 ). Having no penA mosaicism, adenine deletion in the promoter region of mtrR , and L421P in ponA as shown in the Fig.…”

“…Sensitivity and specificity values for molecular markers implicated in ceftriaxone resistance in N. gonorrhoeae are listed in Table 1 alongside comparisons to prior reports that analyzed these loci in predicting decreased ceftriaxone susceptibility ( 13 , 19 ). The four molecular algorithms we previously designed are shown in Fig.…”

“…The four molecular algorithms we previously designed are shown in Fig. 1 and Table S3 with new sensitivity and specificity values when applied to the PathogenWatch database in bold ( 13 ). The analysis using the PathogenWatch database resulted in similar sensitivity and specificity values as the prior molecular markers, assays, and algorithms of interest.…”

“…A molecular assay for ceftriaxone resistance is not yet available, largely due to the multiple mechanisms of resistance that N. gonorrhoeae employs, which primarily involve, but are not limited to, the four following genes: penA , ponA , penB , and mtrR ( 13 – 16 ). penA encodes the penicillin-binding protein (PBP) 2 for which mutations in at least six specific amino acid positions have been associated with decreased ceftriaxone susceptibility: A311V, A501V/P/T, N512Y, A516G, G542S, and G545S (described below) ( 2 ).…”

“…We previously designed four molecular algorithms for predicting decreased ceftriaxone susceptibility using at least one of penA , ponA , porB , and mtrR in a global collection of 3821 N. gonorrhoeae genomes, obtaining sensitivities and specificities up to 95% (with 62% specificity) and 72% (with 89% sensitivity), respectively ( 13 ). The algorithms differ in whether they utilized penA or non- penA genetic loci and whether mosaicism determination was performed.…”