Wild-Type Gyrase A Genotype of Neisseria gonorrhoeae Predicts In Vitro Susceptibility to Ciprofloxacin: A Systematic Review of the Literature and Meta-Analysis

Abstract

Multidrug-resistant Neisseria gonorrhoeae infections have been declared 1 of the top 3 urgent threats to public health. Approaches to combat resistance include targeted therapy with antibiotics previously thought to be ineffective, made possible by rapid molecular assays to predict susceptibility. Previous studies have associated the gyrase A (gyrA) gene of N. gonorrhoeae with in vitro resistance to ciprofloxacin. We conducted a systematic review of studies comparing N. gonorrhoeae gyrA genotype results with conventional antimicrobial susceptibility testing results. We identified 31 studies meeting inclusion criteria, among which 7 different loci for mutations in the gyrA gene were identified, from 16 countries between the years of 1996 and 2016. We then performed a meta-analysis among those studies stratifying by use of real-time polymerase chain reaction (PCR) or non-real-time PCR technique, and compared the summary receiver operating characteristic curves between the 2 PCR methods. Among studies using real-time PCR, the pooled estimate of sensitivity and specificity of gyrA genotype results for the prediction of N. gonorrhoeae susceptibility to ciprofloxacin were 98.2% (95% confidence interval [CI], 96.5-99.1%) and 98.6% (95% CI, 97.0-99.3%), respectively. The summary operating characteristic curves for studies using real-time PCR techniques were well separated from those using non-real-time PCR techniques, with only slight overlap in the CIs, suggesting that real-time PCR techniques were a more accurate approach. GyrA genotype testing is a novel approach to combating the emergence of multidrug-resistant N. gonorrhoeae and is a sensitive and specific method to predict in vitro ciprofloxacin susceptibility.

Figure 1

Sensitivity results for each study using non-real-time PCR-based techniques for determination of the gyrase A genotype compared to conventional methods of susceptibility testing. * Sensitivity values were calculated based on reported results Specificity results for each study using non-real-time PCR-based techniques for determination of the gyrase A genotype compared to conventional methods of susceptibility testing. *Specificity values were calculated based on reported results

Figure 1

Sensitivity results for each study using non-real-time PCR-based techniques for determination of the gyrase A genotype compared to conventional methods of susceptibility testing. * Sensitivity values were calculated based on reported results Specificity results for each study using non-real-time PCR-based techniques for determination of the gyrase A genotype compared to conventional methods of susceptibility testing. *Specificity values were calculated based on reported results

Figure 2

Sensitivity results for each study using real-time PCR-based techniques for determination of the gyrase A genotype compared to conventional methods of susceptibility testing. * Sensitivity values were calculated based on reported results Specificity results for each study using real-time PCR-based techniques for determination of the gyrase A genotype compared to conventional methods of susceptibility testing. *Specificity values were calculated based on reported results

Figure 2

Sensitivity results for each study using real-time PCR-based techniques for determination of the gyrase A genotype compared to conventional methods of susceptibility testing. * Sensitivity values were calculated based on reported results Specificity results for each study using real-time PCR-based techniques for determination of the gyrase A genotype compared to conventional methods of susceptibility testing. *Specificity values were calculated based on reported results

Figure 3

Summary operating characteristic curves for sensitivity and specificity comparing studies using non-real-time PCR and real-time PCR techniques for the determination of the gyrase A genotype. Solid and dashed circled areas represent the 95% confidence regions for studies using real-time PCR and non-real-time PCR techniques, respectively.