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A genomic perspective on the near-term impact of doxycycline post-exposure prophylaxis on Neisseria gonorrhoeae antimicrobial resistance.

ABSTRACT: Post-exposure prophylaxis with doxycycline (doxyPEP) is being introduced to prevent bacterial sexually transmitted infections (STIs). Pre-existing tetracycline resistance in Neisseria gonorrhoeae limits doxyPEP effectiveness against gonorrhea, and selection for tetracycline resistant lineages may influence prevalence of resistance to other antimicrobials via selection for multi-drug resistant strains. Using genomic and antimicrobial susceptibility data from 5,644 clinical isolates of N. gonorrhoeae , we assessed the near-term impact of doxyPEP on N. gonorrhoeae antimicrobial resistance. We found that the impact on antimicrobial resistance is likely to be influenced by the strength of selection for plasmid-encoded and chromosomally-encoded tetracycline resistance, as isolates with high-level, plasmid-encoded resistance had lower minimum inhibitory concentrations to other antimicrobials compared to isolates with low-level tetracycline resistance. The impact of doxyPEP may differ across demographic groups and geographic regions within the United States due to variation in pre-existing tetracycline resistance.

SUBMITTER: Mortimer TD

PROVIDER: S-EPMC10055447 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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A genomic perspective on the near-term impact of doxycycline post-exposure prophylaxis on Neisseria gonorrhoeae antimicrobial resistance.

Mortimer Tatum D TD Grad Yonatan H YH

medRxiv : the preprint server for health sciences 20230317

Post-exposure prophylaxis with doxycycline (doxyPEP) is being introduced to prevent bacterial sexually transmitted infections (STIs). Pre-existing tetracycline resistance in Neisseria gonorrhoeae limits doxyPEP effectiveness against gonorrhea, and selection for tetracycline resistant lineages may influence prevalence of resistance to other antimicrobials via selection for multi-drug resistant strains. Using genomic and antimicrobial susceptibility data from 5,644 clinical isolates of N ...[more]

PMID: 36993406

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Project description:Doxycycline post-exposure prophylaxis (doxy-PEP) reduces bacterial sexually transmitted infections among men who have sex with men and transgender women. Although poised for widespread clinical implementation, the impact of doxy-PEP on antimicrobial resistance remains a primary concern as its effects on the gut microbiome and resistome, or the antimicrobial resistance genes (ARGs) present in the gut microbiome, are unknown. To investigate these effects, we studied participants from the DoxyPEP trial, a randomized clinical trial comparing doxy-PEP use, a one-time doxycycline 200-mg dose taken after condomless sex (DP arm, n = 100), to standard of care (SOC arm, n = 50) among men who have sex with men and transgender women. From self-collected rectal swabs at enrollment (day-0) and after 6 months (month-6), we performed metagenomic DNA sequencing (DNA-seq) or metatranscriptomic RNA sequencing (RNA-seq). DNA-seq data were analyzable from 127 samples derived from 89 participants, and RNA-seq data were analyzable from 86 samples derived from 70 participants. We compared the bacterial microbiome and resistome between the two study arms and over time. The median number of doxycycline doses taken since enrollment by participants with DNA-seq data was zero (interquartile range (IQR): 0-7 doses) for the SOC arm and 42 (IQR: 27-64 doses) for the DP arm. Tetracycline ARGs were detected in all day-0 DNA-seq samples and in 85% of day-0 RNA-seq samples. The proportional mass of tetracycline ARGs in the resistome increased between day-0 and month-6 in DP participants from 46% to 51% in the metagenome (P = 2.3 × 10-2) and from 4% to 15% in the metatranscriptome (P = 4.5 × 10-6), but no statistically significant increases in other ARG classes were observed. Exposure to a higher number of doxycycline doses correlated with proportional enrichment of tetracycline ARGs in the metagenome (Spearman's ρ = 0.23, P = 9.0 × 10-3) and metatranscriptome (Spearman's ρ = 0.55, P = 3.7 × 10-8). Bacterial microbiome alpha diversity, beta diversity and total bacterial mass did not differ between day-0 and month-6 samples from DP participants when assessed by either DNA-seq or RNA-seq. In an abundance-based correlation analysis, we observed an increase over time in the strength of the correlation between tetracycline ARGs and specific bacterial taxa, including some common human pathogens. In sum, doxy-PEP use over a 6-month period was associated with an increase in the proportion of tetracycline ARGs comprising the gut resistome and an increase in the expression of tetracycline ARGs. At 6 months of doxy-PEP use, no residual differences were observed in alpha and beta diversity or taxonomic composition of the gut microbiome. As doxy-PEP is implemented as a public health strategy, further studies and population-level surveillance of doxycycline-resistant pathogens are needed to understand the implications of these findings. ClinicalTrials.gov registration number: NCT03980223 .

Project description:Doxycycline post-exposure prophylaxis (doxy-PEP) is a preventative strategy demonstrated to reduce bacterial sexually transmitted infections in high-risk populations. However, the impact of doxy-PEP on antibiotic resistance acquisition in key members of our microbiomes, is as of yet unclear. For example, commensal Neisseria are known reservoirs of resistance for gonococci through horizontal gene transfer (HGT), and are more likely to experience bystander selection due to doxy-PEP as they are universally carried. Thus, the consequences of doxycycline selection on commensal Neisseria will be critical to investigate to understand possible resistance mechanisms that may be transferred to an important human pathogen. Here, we use in vitro antibiotic gradients to evolve four Neisseria commensals (N. cinerea, N. canis, N. elongata, and N. subflava, n=4 per species) across a 20-day time course; and use whole genome sequencing to nominate derived mutations. After selection, 12 of 16 replicates evolved doxycycline resistance (> 1 μg/mL). Across resistant lineages: An A46T substitution in the repressor of the Mtr efflux pump (MtrR) and a V57M substitution in the 30 ribosomal protein S10 were clearly associated with elevated MICs. Additional mutations in ribosomal components also emerged in strains with high MICs (i.e., 16S rRNA G1057C, RplX A14T). We find the MtrR 46T, RpsJ 57M, and RplX 14T circulating in natural commensal populations. Furthermore, in vitro co-evolution of N. gonorrhoeae with Neisseria commensals demonstrated rapid transfer of the pConj plasmid to N. subflava and N. cinerea, and pbla to N. cinerea. Finally, collection of novel commensals from human hosts reveals 46% of isolates carrying doxycycline resistance; and doxycycline resistance was significantly greater in participants self-reporting doxycycline use in the past 6 months. High-level doxycycline resistance (> 8 μg/mL) was always associated with carriage of the ribosomal protection protein (tetM) and pConj. Ultimately, characterizing the contemporary prevalence of doxycycline resistance, and underlying resistance mechanisms, in commensal communities may help us to predict the long-term impact of doxy-PEP on Neisseria, and the likelihood of transferring particular genotypes across species' boundaries.

Project description:BackgroundAntimicrobial-resistant (AMR) Neisseria gonorrhoeae is an urgent threat to public health, as strains resistant to at least one of the two last-line antibiotics used in empiric therapy of gonorrhoea, ceftriaxone and azithromycin, have spread internationally. Whole genome sequencing (WGS) data can be used to identify new AMR clones and transmission networks and inform the development of point-of-care tests for antimicrobial susceptibility, novel antimicrobials and vaccines. Community-driven tools that provide an easy access to and analysis of genomic and epidemiological data is the way forward for public health surveillance.MethodsHere we present a public health-focussed scheme for genomic epidemiology of N. gonorrhoeae at Pathogenwatch ( https://pathogen.watch/ngonorrhoeae ). An international advisory group of experts in epidemiology, public health, genetics and genomics of N. gonorrhoeae was convened to inform on the utility of current and future analytics in the platform. We implement backwards compatibility with MLST, NG-MAST and NG-STAR typing schemes as well as an exhaustive library of genetic AMR determinants linked to a genotypic prediction of resistance to eight antibiotics. A collection of over 12,000 N. gonorrhoeae genome sequences from public archives has been quality-checked, assembled and made public together with available metadata for contextualization.ResultsAMR prediction from genome data revealed specificity values over 99% for azithromycin, ciprofloxacin and ceftriaxone and sensitivity values around 99% for benzylpenicillin and tetracycline. A case study using the Pathogenwatch collection of N. gonorrhoeae public genomes showed the global expansion of an azithromycin-resistant lineage carrying a mosaic mtr over at least the last 10 years, emphasising the power of Pathogenwatch to explore and evaluate genomic epidemiology questions of public health concern.ConclusionsThe N. gonorrhoeae scheme in Pathogenwatch provides customised bioinformatic pipelines guided by expert opinion that can be adapted to public health agencies and departments with little expertise in bioinformatics and lower-resourced settings with internet connection but limited computational infrastructure. The advisory group will assess and identify ongoing public health needs in the field of gonorrhoea, particularly regarding gonococcal AMR, in order to further enhance utility with modified or new analytic methods.

Dataset Information

A genomic perspective on the near-term impact of doxycycline post-exposure prophylaxis on Neisseria gonorrhoeae antimicrobial resistance.

Publications

A genomic perspective on the near-term impact of doxycycline post-exposure prophylaxis on <i>Neisseria gonorrhoeae</i> antimicrobial resistance.

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