Variation in supplemental carbon dioxide requirements defines lineage-specific antibiotic resistance acquisition in <i>Neisseria gonorrhoeae</i>

2022

Preprint

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The etiologic agent of gonorrhea, Neisseria gonorrhoeae, has become resistant to each of the first line antibiotics used to treat it. However, most isolates in the US remain susceptible to ciprofloxacin, leading to the hypothesis that a diagnostic that accurately reports susceptibility to ciprofloxacin may allow its reintroduction into clinical use. One diagnostic approach is to identify codon 91 in gyrA, where coding for the wildtype serine is associated with ciprofloxacin susceptibility and phenylalanine with resistance. Here, we found that escape from this diagnostic method can occur through gyrA F91S reversion and expansion of pre-existing ciprofloxacin non-susceptible N. gonorrhoeae lineages with gyrA 91S. Furthermore, we found that mutations conferring ciprofloxacin resistance in gyrA 91S isolates led to cross-resistance with zoliflodacin, an antibiotic in phase 3 trial for treatment of gonorrhea. These findings define N. gonorrhoeae mutations that should be monitored via surveillance systems, particularly in populations and regions deploying gyrA 91-based diagnostics, and demonstrate how diagnostics that guide antibiotic therapy can have unintended consequences.

Section: Methodsmentioning

confidence: 99%

Neisseria gonorrhoeae diagnostic escape from a gyrA-based test for ciprofloxacin susceptibility can lead to increased zoliflodacin resistance

Rubin

Mortimer

2022

Preprint

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“…

25

) of gonorrhoea cases without causing an increase in cefixime resistance levels, which would reduce the risk of emergence of resistance to the currently used antibiotics. Moreover, the extent of the fitness cost of resistance can vary by genomic background [ 11 ], such that the effect of interventions that seek to capitalize on the fitness costs of resistance may be lineage dependent. Therefore, it is necessary to estimate fitness costs at the per lineage level.…”

Section: Introductionmentioning

confidence: 99%

Estimating the fitness cost and benefit of antimicrobial resistance from pathogen genomic data

Helekal

Keeling

et al. 2023

J. R. Soc. Interface.

Self Cite

Increasing levels of antibiotic resistance in many bacterial pathogen populations are a major threat to public health. Resistance to an antibiotic provides a fitness benefit when the bacteria are exposed to this antibiotic, but resistance also often comes at a cost to the resistant pathogen relative to susceptible counterparts. We lack a good understanding of these benefits and costs of resistance for many bacterial pathogens and antibiotics, but estimating them could lead to better use of antibiotics in a way that reduces or prevents the spread of resistance. Here, we propose a new model for the joint epidemiology of susceptible and resistant variants, which includes explicit parameters for the cost and benefit of resistance. We show how Bayesian inference can be performed under this model using phylogenetic data from susceptible and resistant lineages and that by combining data from both we are able to disentangle and estimate the resistance cost and benefit parameters separately. We applied our inferential methodology to several simulated datasets to demonstrate good scalability and accuracy. We analysed a dataset of Neisseria gonorrhoeae genomes collected between 2000 and 2013 in the USA. We found that two unrelated lineages resistant to fluoroquinolones shared similar epidemic dynamics and resistance parameters. Fluoroquinolones were abandoned for the treatment of gonorrhoea due to increasing levels of resistance, but our results suggest that they could be used to treat a minority of around 10% of cases without causing resistance to grow again.

“…These estimates were used to predict that cefixime could be reintroduced to treat a minority (∼ 25%) of gonorrhoea cases without causing an increase in cefixime resistance levels, which would reduce the risk of emergence of resistance to the currently used antibiotics. Moreover, the extent of the fitness cost of resistance can vary by genomic background [11], such that the effect of interventions that seek to capitalize on the fitness costs of resistance may be lineage dependent. Therefore, it is necessary to estimate fitness costs at the per lineage level.…”

Section: Introductionmentioning

confidence: 99%

Estimating the fitness cost and benefit of antimicrobial resistance from pathogen genomic data

Helekal

Keeling

et al. 2022

Preprint

Increasing levels of antibiotic resistance in many bacterial pathogen populations is a major threat to public health. Resistance to an antibiotic provides a fitness benefit when the bacteria is exposed to this antibiotic, but resistance also often comes at a cost to the resistant pathogen relative to susceptible counterparts. We lack a good understanding of these benefits and costs of resistance for many bacterial pathogens and antibiotics, but estimating them could lead to better use of antibiotics in a way that reduces or prevents the spread of resistance. Here, we propose a new model for the joint epidemiology of susceptible and resistant variants, which includes explicit parameters for the cost and benefit of resistance. We show how Bayesian inference can be performed under this model using phylogenetic data from susceptible and resistant lineages and that by combining data from both we are able to disentangle and estimate the resistance cost and benefit parameters separately. We applied our inferential methodology to several simulated datasets to demonstrate good scalability and accuracy. We analysed a dataset of Neisseria gonorrhoeae genomes collected between 2000 and 2013 in the USA. We found that two unrelated lineages resistant to fluoroquinolones shared similar epidemic dynamics and resistance parameters. Fluoroquinolones were abandoned for the treatment of gonorrhoea due to increasing levels of resistance, but our results suggest that they could be used to treat a minority of around 10% of cases without causing resistance to grow again.