Resistance-Guided Therapy for <i>Neisseria gonorrhoeae</i>

Allan‐Blitz, Lao‐Tzu; Adamson, Paul C; Klausner, Jeffrey D.

doi:10.1093/cid/ciac371

Cited by 14 publications

(17 citation statements)

References 39 publications

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“…Using genetic markers to guide antibiotic therapy, called resistance-guided therapy, is an emerging concept for N. gonorrhoeae ( 27 , 28 ). Understanding how many SNPs, and in which combinations, can predict resistance to ceftriaxone is important, as they can be used to develop molecular assays to predict ceftriaxone resistance.…”

Section: Discussionmentioning

confidence: 99%

Machine learning to predict ceftriaxone resistance using single nucleotide polymorphisms within a global database of Neisseria gonorrhoeae genomes

Ha,

Lin,

Klausner

et al. 2023

Microbiol Spectr

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Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent global health issue. Machine learning (ML) is a powerful tool that can aid in identifying mutations and predicting their impact on AMR. The study aimed to use ML models to predict ceftriaxone susceptibility and decreased susceptibility (S/DS). A public database of N. gonorrhoeae genomes with minimum inhibitory concentration (MIC) data was used to evaluate seven ML models using 97 single nucleotide polymorphisms (SNPs) known to be associated with ceftriaxone resistance. Ceftriaxone MICs ≤ 0.064 mg/L were classified as susceptible, and ceftriaxoneMICs > 0.064 mg/L were classified as DS. The contributions of individual SNPs to predict S/DS were calculated using SHapley Additive exPlanation (SHAP) values. An ML model was retrained using different combinations of SNPs with the highest SHAP values. The performance of ML models was assessed using different metrics including area under the curve (AUC) and balanced accuracy (bAcc). The ML analyses included 9,540 N . gonorrhoeae genomes; 368 (0.04%) were classified as DS. Of the models evaluated, the model trained with a random forest classifier had the highest performance (AUC 0.965; bAcc 0.926). A model retrained the top five SNPs, according to SHAP values, demonstrated a similar performance (AUC 0.916; bAcc 0.879) as the model with 97 SNPs. An ML approach using mutations in N. gonorrhoeae can be used to predict S/DS to ceftriaxone. The results highlight a practical application of ML to identify mutations most associated with S/DS to ceftriaxone, which can aid in the development of assays to predict AMR. IMPORTANCE Antimicrobial resistance in Neisseria gonorrhoeae is an urgent global health issue. The objectives of the study were to use a global collection of 12,936 N . gonorrhoeae genomes from the PathogenWatch database to evaluate different machine learning models to predict ceftriaxone susceptibility/decreased susceptibility using 97 mutations known to be associated with ceftriaxone resistance. We found the random forest classifier model had the highest performance. The analysis also reported the relative contributions of different mutations within the ML model predictions, allowing for the identification of the mutations with the highest importance for ceftriaxone resistance. A machine learning model retrained with the top five mutations performed similarly to the model using all 97 mutations. These results could aid in the development of molecular tests to detect resistance to ceftriaxone in N. gonorrhoeae . Moreover, this approach could be applied to building and evaluating machine learning models for predicting antimicrobial resistance in other pathogens.

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Section: Discussionmentioning

confidence: 99%

Machine learning to predict ceftriaxone resistance using single nucleotide polymorphisms within a global database of Neisseria gonorrhoeae genomes

Ha,

Lin,

Klausner

et al. 2023

Microbiol Spectr

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“…Resistance-guided therapy has demonstrated promise in treating gonorrhea. 25 Presently, N. gonorrhoeae currently demonstrates widespread ciprofloxacin resistance due to a single point mutation at the serine 91 codon of the GyrA gene. However, not all strains of N. gonorrhoeae exhibit this mutation.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of Cefixime for the Treatment of Neisseria gonorrhoeae Infection at 3 Anatomic Sites: A Systematic Review and Meta-Analysis

et al. 2022

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Background: To treat Neisseria gonorrhoeae infection, the Centers for Disease Control and Prevention recommends a single oral dose of cefixime as an alternative to injectable ceftriaxone. Methods:We conducted a systematic review and meta-analysis to describe the effectiveness of cefixime in treating N. gonorrhoeae infection at 3 different anatomic sites.We searched PubMed and Embase database to abstract treatment success rates and cefixime dosage/frequency for studies that reported the anatomical site of infection. We included reports published between January 1, 1980, and December 7, 2021. Twenty studies published between 1989 and 2015 were included in our meta-analysis. We calculated pooled treatment success percentages and 95% confidence intervals (CIs) using random-effects models.Results: Of patients who received a 400-mg single dose of cefixime, 824 of 846 (97%; 95% CI, 96%-98%) patients with urogenital infection, 107 of 112 (97%; 95% CI, 84%-100%) patients with rectal infection, and 202 of 242 (89%; 95% CI, 76%-96%) patients with pharyngeal infection were cured. Of patients who received an 800-mg single dose of cefixime, 295 of 301 (98%; 95% CI, 96%-99%) patients with urogenital infection and 21 of 26 (81%; 95% CI, 61%-92%) patients with pharyngeal infection were cured. Conclusions:Our meta-analysis found that cefixime is highly effective at treating urogenital infections and less effective at treating pharyngeal infections.We recommend more investigation into the effectiveness of cefixime in treating rectal infections and studying multidose therapy for the cefixime treatment of pharyngeal infection.N eisseria gonorrhoeae infection is a public health concern worldwide, due in large part to the fact that N. gonorrhoeae has demonstrated unprecedented capacity to develop antibiotic resistance. 1 There is evidence of N. gonorrhoeae antimicrobial resistance to all recommended antimicrobial agents. 2,3 The Centers for Disease Control and Prevention (CDC) identified antimicrobial-resistant N. gonorrhoeae as 1 of the top 3 ongoing public health threats. 4 For those reasons, identifying effective therapies is critical for clinicians, public health professionals, and patients.Current recommendations for the treatment of gonorrhea rely on ceftriaxone as first-line therapy. In their 2020 European guidelines on the treatment of gonorrhea, the International Union against Sexually Transmitted Infections put forward 2 recommendations. The first International Union against Sexually Transmitted Infections recommendation was dual therapy of ceftriaxone 1 g intramuscularly as a single dose with azithromycin 2 g as a single oral dose. Their second recommendation was monotherapy of ceftriaxone 1 g intramuscularly alone. 5 The British Association for Sexual Health and HIV, in their 2018 guidelines on the treatment of infection with N. gonorrhoeae, also recommended ceftriaxone 1 g intramuscularly. 6 The CDC's 2020 update on treatment guidelines for gonococcal infection recommended a single intramuscular dose of ceftriaxone 500 mg ...

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“…Point mutations in PBP proteins (PBP1 in the case of ponA and PBP2 in the case of penA), penA mosaic alleles, and single nucleotide polymorphisms (SNP) in ponA determine high-level penicillin resistance [56]. The mosaic region of penA is composed of DNA sequences inserted from commensal Neisseria transformation (the horizontal transfer of partial or whole genes) [55,57]. These acquired mosaic alleles are the main cause of cephalosporin resistance as well and are especially associated with higher cefixime minimum inhibitory concentrations (MICs).…”

Section: Mechanisms Of Resistance: Overviewmentioning

confidence: 99%

Addressing Sexually Transmitted Infections Due to Neisseria gonorrhoeae in the Present and Future

Colón Pérez,

Villarino Fernández,

Domínguez Lago

et al. 2024

Microorganisms

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It was in the 1800s when the first public publications about the infection and treatment of gonorrhoea were released. However, the first prevention programmes were only published a hundred years later. In the 1940s, the concept of vaccination was introduced into clinical prevention programmes to address early sulphonamide resistance. Since then, tons of publications on Neisseria gonorrhoeae are undisputed, around 30,000 publications today. Currently, the situation seems to be just as it was in the last century, nothing has changed or improved. So, what are we doing wrong? And more importantly, what might we do? The review presented here aims to review the current situation regarding the resistance mechanisms, prevention programmes, treatments, and vaccines, with the challenge of better understanding this special pathogen. The authors have reviewed the last five years of advancements, knowledge, and perspectives for addressing the Neisseria gonorrhoeae issue, focusing on new therapeutic alternatives.

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Resistance-Guided Therapy for Neisseria gonorrhoeae

Cited by 14 publications

References 39 publications

Machine learning to predict ceftriaxone resistance using single nucleotide polymorphisms within a global database of Neisseria gonorrhoeae genomes

Machine learning to predict ceftriaxone resistance using single nucleotide polymorphisms within a global database of Neisseria gonorrhoeae genomes

Effectiveness of Cefixime for the Treatment of Neisseria gonorrhoeae Infection at 3 Anatomic Sites: A Systematic Review and Meta-Analysis

Addressing Sexually Transmitted Infections Due to Neisseria gonorrhoeae in the Present and Future

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