Effect of mass treatment on the long-term prevalence of gonorrhoea, chlamydia and syphilis-a systematic review.

BACKGROUND: Selective mass treatment of STIs may lead to a durable reduction in the prevalence of STIs or a temporary reduction associated with an increased probability of antimicrobial resistance emerging. METHODS: We searched PubMed and Google Scholar for studies evaluating the impact of mass STI treatment on the long-term prevalence of chlamydia, gonorrhoea, syphilis and chancroid. The primary outcomes were the long term (≥3 months post the intervention) impact of the intervention on prevalence/incidence of the STI and on antimicrobial resistance. RESULTS: Our search yielded 269 studies, of which 4 met the inclusion criteria. With the exception of the Carletonville study, where this was not assessed, three of the four studies found that intensive STI treatment was associated with a reduced prevalence of the targeted STI during or immediately after the intervention. In all four studies, there was no evidence that the intense treatment had a long-term effect on prevalence. In the only study where this was assessed, the intensive use of penicillin to reduce gonococcal prevalence was associated with the emergence of reduced susceptibility to penicillin in N. gonorrhoeae. CONCLUSION: The available evidence suggests that mass treatment of chlamydia, gonorrhoea and syphilis in high prevalence populations is only associated with a temporary reduction in the prevalence of these infections and may select for antimicrobial resistance.

The Discovery of Oropharyngeal Microbiota with Inhibitory Activity against Pathogenic Neisseria gonorrhoeae and Neisseria meningitidis: An In Vitro Study of Clinical Isolates.

With increasing incidence of pathogenic Neisseria infections coupled with emerging resistance to antimicrobials, alternative approaches to limit the spread are sought. We investigated the inhibitory effect of oropharyngeal microbiota on the growth of N. gonorrhoeae and N. meningitidis and the impact of the essential oil-based mouthwash Listerine Cool Mint® (Listerine). Oropharyngeal swabs from 64 men who have sex with men (n = 118) from a previous study (PReGo study) were analysed (ClinicalTrials.gov, NCT03881007). These included 64 baseline and 54 samples following three months of daily use of Listerine. Inhibition was confirmed by agar overlay assay, and inhibitory bacteria isolated using replica plating and identified using MALDI-TOF. The number of inhibitory isolates were compared before and after Listerine use. Thirty-one pharyngeal samples (26%) showed inhibitory activity against N. gonorrhoeae and/or N. meningitidis, and 62 inhibitory isolates were characterised. Fourteen species belonging to the genera Streptococci and Rothia were identified. More inhibitory isolates were observed following Listerine use compared to baseline, although this effect was not statistically significant (p = 0.073). This study isolated and identified inhibitory bacteria against pathogenic Neisseria spp. and established that daily Listerine use did not decrease their prevalence. These findings could provide a new approach for the prevention and treatment of pharyngeal Neisseria infections.

Successful Intra- but Not Inter-species Recombination of msr(D) in Neisseria subflava.

Resistance acquisition via natural transformation is a common process in the Neisseria genus. Transformation has played an important role in the emergence of resistance to many antimicrobials in Neisseria gonorrhoeae and Neisseria meningitidis. In a previous study, we found that currently circulating isolates of Neisseria subflava had acquired an msr(D) gene that has been found to result in macrolide resistance in other bacteria but never found in Neisseria species before. To determine if this resistance mechanism is transferable among Neisseria species, we assessed if we could transform the msr(D) gene into other commensal and pathogenic Neisseria under low dose azithromycin pressure. Intraspecies recombination in commensal N. subflava was confirmed with PCR and resulted in high-level macrolide resistance. Whole-genome sequencing of these transformed strains identified the complete uptake of the msr(D) integration fragment. Sequence analysis showed that a large fragment of DNA (5 and 12 kb) was transferred through a single horizontal gene transfer event. Furthermore, uptake of the msr(D) gene had no apparent fitness cost. Interspecies transformation of msr(D) from N. subflava to N. gonorrhoeae was, however, not successful.

Global epidemiology of antimicrobial resistance in commensal Neisseria species: A systematic review.

BACKGROUND: Commensal Neisseria species (spp). represent an important reservoir of antimicrobial resistance genes for pathogenic Neisseria spp. In this systematic review, we aimed to assess the antimicrobial susceptibility of commensal Neisseria spp. and how this has evolved over time. We also aimed to assess if commensal Neisseria spp. showed intrinsic resistance to four antimicrobials - penicillin, azithromycin, ceftriaxone and ciprofloxacin. METHODS: Pubmed and Google Scholar were searched following the PRISMA guidelines. Articles reporting MICs of commensal Neisseria spp. were included according to inclusion/exclusion criteria, and the quality of the articles was assessed using a pre-designed tool. Individual and summary measures of penicillin, azithromycin, ceftriaxone and ciprofloxacin MICs were collected. Additional data was sought to perform a comparison between the MICs of pathogenic and commensal Neisseria spp. RESULTS: A total of 15 studies met our criteria.We found no evidence of intrinsic AMR in commensal Neisseria spp. We did find evidence of an increasing trend in MICs of commensal Neisseria spp. over time for all antimicrobials assessed. These findings were similar in various countries. Eight additional studies were included to compare pathogenic and commensal Neisseria spp. CONCLUSION: The MICs of commensal Neisseria spp. appear to be increasing in multiple countries. Surveillance of MICs in commensals could be used as an early warning system for antimicrobial resistance emergence in pathogens. Our findings underline the need for antibiotic stewardship interventions, particularly in populations with high antimicrobial consumption.

Country-level association between antimicrobial consumption and resistance in Neisseria meningitidis: An ecological study.

BACKGROUND: It is unclear what is responsible for the large variations in the prevalence of meningococcal resistance to cephalosporins and quinolones. METHODS: We used mixed-effects linear regression to assess if country-level prevalence of reduced susceptibility to cefotaxime and ciprofloxacin was associated with the population-level consumption of cephalosporins and quinolones in 13 European countries. RESULTS: Positive correlations were found between the prevalence of reduced susceptibility to ciprofloxacin and the consumption of quinolones (coef. 0.16, 95% CI 0.05-0.27; P = 0.003). The same positive association was found for cefotaxime/cephalosporins (coef. 0.1, 95% CI 0.04-0.15; P = 0.001). CONCLUSIONS: Meningococcal reduced susceptibility to cefotaxime and ciprofloxacin is linked to homologous class antimicrobial consumption. This finding provides additional motivation for strengthening antimicrobial stewardship programs.

Sub-Inhibitory Concentrations of Chlorhexidine Induce Resistance to Chlorhexidine and Decrease Antibiotic Susceptibility in Neisseria gonorrhoeae.

Objectives: Chlorhexidine digluconate (chlorhexidine) and Listerine® mouthwashes are being promoted as alternative treatment options to prevent the emergence of antimicrobial resistance in Neisseria gonorrhoeae. We performed in vitro challenge experiments to assess induction and evolution of resistance to these two mouthwashes and potential cross-resistance to other antimicrobials. Methods: A customized morbidostat was used to subject N. gonorrhoeae reference strain WHO-F to dynamically sustained Listerine® or chlorhexidine pressure for 18 days and 40 days, respectively. Cultures were sampled twice a week and minimal inhibitory concentrations (MICs) of Listerine®, chlorhexidine, ceftriaxone, ciprofloxacin, cefixime and azithromycin were determined using the agar dilution method. Isolates with an increased MIC for Listerine® or chlorhexidine were subjected to whole genome sequencing to track the evolution of resistance. Results: We were unable to increase MICs for Listerine®. Three out of five cultures developed a 10-fold increase in chlorhexidine MIC within 40 days compared to baseline (from 2 to 20 mg/L). Increases in chlorhexidine MIC were positively associated with increases in the MICs of azithromycin and ciprofloxacin. Low-to-higher-level chlorhexidine resistance (2-20 mg/L) was associated with mutations in NorM. Higher-level resistance (20 mg/L) was temporally associated with mutations upstream of the MtrCDE efflux pump repressor (mtrR) and the mlaA gene, part of the maintenance of lipid asymmetry (Mla) system. Conclusion: Exposure to sub-lethal chlorhexidine concentrations may not only enhance resistance to chlorhexidine itself but also cross-resistance to other antibiotics in N. gonorrhoeae. This raises concern regarding the widespread use of chlorhexidine as an oral antiseptic, for example in the field of dentistry.

Is There a Resistance Threshold for Macrolide Consumption? Positive Evidence from an Ecological Analysis of Resistance Data from Streptococcus pneumoniae, Treponema pallidum, and Mycoplasma genitalium.

If we were to keep macrolide consumption below a certain threshold, would this reduce the probability of macrolide resistance emerging? No study that we are aware of has addressed this question. We, therefore, assessed at a country level if there was a macrolide consumption threshold for the selection of a prevalence of macrolide resistance of over 5% in Streptococcus pneumoniae, Treponema pallidum, and Mycoplasma genitalium. In this ecological-level analysis, we found evidence for a macrolide consumption threshold of 1.3 defined daily doses per 1,000 inhabitants per day (DID) for M. genitalium, 1.8 DID for T. pallidum, and 2.3 DID for S. pneumoniae. Our results provide further motivation for macrolide stewardship campaigns that strive to reduce macrolide consumption to levels below at least 2 DID.

Gonorrhoea treatment combined with population-level general cephalosporin and quinolone consumption may select for Neisseria gonorrhoeae antimicrobial resistance at the levels of NG-MAST genogroup: An ecological study in Europe.

OBJECTIVES: The prevalence of Neisseria gonorrhoeae NG-MAST genogroup G1407, associated with decreased susceptibility to extended-spectrum cephalosporins and fluoroquinolone resistance, has declined in Europe and it switched from circulating predominantly in men who have sex with men (MSM) in 2009-2010 to heterosexuals in 2013. We hypothesise that changes to gonorrhoea treatment guidelines combined with differences in country-level consumption of cephalosporins and quinolones contributed to this shift. METHODS: Linear regression was used to evaluate the association between changes in prevalence of G1407 between 2009-2010 and 2013 and country-level consumption of quinolones and cephalosporins in 2011/12 in 20 European countries. RESULTS: Whilst the prevalence of G1407 declined between 2009-2010 and 2013 in the EU/EEA, its absolute prevalence increased by 10% or more in three countries. The national prevalence of G1407 in 2013 was positively associated with population-level general cephalosporin and quinolone consumption in the preceding 2 years. The association between the prevalence of G1407 and proportion of the national sample derived from MSM was non-significant in 2009-2010 and was negative in 2013. CONCLUSIONS: Our results are broadly compatible with the hypothesis that changes in gonorrhoea therapy to the more efficacious ceftriaxone (plus azithromycin) from 2010 to 2011 onwards resulted in a reduced prevalence of the resistance-associated G1407 overall but in MSM in particular. High population-level consumption of quinolones and cephalosporins in certain countries then contributed to the selection of G1407 predominantly in heterosexuals in these countries.

Gonococcal resistance can be viewed productively as part of a syndemic of antimicrobial resistance: an ecological analysis of 30 European countries.

BACKGROUND: It is unclear how important bystander selection is in the genesis of antimicrobial resistance (AMR) in Neisseria gonorrhoeae. METHODS: We assessed bystander selection in a novel way. Mixed-effects linear regression was used to assess if country-level prevalence of gonococcal AMR in 30 European countries predicts homologous AMR in other bacteria. The data used was from the European Antimicrobial Resistance Surveillance Network. RESULTS: The prevalence of gonococcal ciprofloxacin resistance was found to be positively associated with AMR prevalence in E. coli (coef. 0.52; P = 0.007), Acinetobacter spp. (coef. 0.13; P = 0.044) and Pseudomonas aeruginosa (coef. 0.36; P = 0.020) but not Klebsiella pneumoniae. Azithromycin resistance in N. gonorrhoeae was positively associated with macrolide resistance in Streptococcus pneumoniae (coef. 0.01; P = 0.018). No association was found for cephalosporins. CONCLUSIONS: Gonococcal AMR is linked to that in other bacteria. This finding is likely explained by high antimicrobial consumption in affected populations and provides additional motivation for strengthening antimicrobial stewardship programs.

Strong association between adolescent obesity and consumption of macrolides in Europe and the USA: An ecological study.

BACKGROUND: The reasons underpinning the large variations in the prevalence of childhood obesity are inadequately understood. Individual level studies have found that macrolide consumption at a young age increases the risk of subsequent obesity. We hypothesized that differences in population level consumption of macrolides may explain part of the variation in the prevalence of childhood obesity. METHODS: Mixed effects beta regression was used to assess the association between the prevalence of childhood obesity in countries in Europe/ states in the United States and population level consumption of macrolides and total antibiotics. Different time lags between consumption and obesity measurement were used. RESULTS: We found that in both the USA and Europe, population level consumption of macrolides was positively associated with subsequent childhood obesity prevalence. According to our model, the observed differences in population-level macrolide consumption in Europe/USA would translate into a 13%/72% higher odds of childhood obesity 5 years later. The association held regardless of the lag period used between exposure and outcome. The association with total antibiotic consumption was more equivocal. CONCLUSIONS: Reducing macrolide consumption to that of low consumption countries may result in considerable reductions in childhood obesity.

Cultural Drivers of Antibiotic Consumption in High-Income Countries: A Global Ecological Analysis.

Background: Previous studies evaluating the cultural and structural factors underpinning the large variations in the consumption of antibiotics in high-income countries have reached different conclusions. Some studies have found that corruption plays a dominant role, whereas other studies have concluded that cultural factors such as the degree of uncertainty avoidance (UA) and performance-orientation versus cooperation-orientation (POCO) are more important. These studies have been limited to Europe, and we, therefore, aimed to expand this analysis to all high-income countries with available data. Methods: Using antibiotic consumption data from the IQVIA MIDAS database, linear regression models were constructed with country-level cephalosporin, fluoroquinolone, and macrolide consumption (defined daily doses/1,000 population/year) as the outcome variables and country-specific scores of UA and POCO (obtained from the Hofstede Index), gross domestic product/capita, world region and markers of effective governance (Control of Corruption and Regulatory Quality extracted from the World Bank data) as the explanatory variables. All data, excluding the Hofstede Indices, used country-level averages for the years 2013 to 2015. Results: Complete data were available for 37 countries from 4 world regions. Consumption of cephalosporins, macrolides, and fluoroquinolones was associated with POCO and UA, but not the markers of effective governance. In the case of macrolide consumption, the association with UA narrowly missed statistical significance. Repeat analyses limited to first European countries and second to non-European countries revealed similar findings. Conclusions: More thought should be given to construct antibiotic stewardship campaigns that are tailored to the local extent of UA and POCO.

Commensal Neisseria Are Shared between Sexual Partners: Implications for Gonococcal and Meningococcal Antimicrobial Resistance.

Antimicrobial resistance in pathogenic Neisseria parallels reduced antimicrobial susceptibility in commensal Neisseria in certain populations, like men who have sex with men (MSM). Although this reduced susceptibility can be a consequence of frequent antimicrobial exposure at the individual level, we hypothesized that commensal Neisseria are transmitted between sexual partners. We used data from a 2014 microbiome study in which saliva and tongue swabs were taken from 21 couples (42 individuals). Samples were analyzed using 16S rRNA gene sequencing. We compared intimate partners with unrelated individuals and found that the oral Neisseria communities of intimate partners were more similar than those of unrelated individuals (average Morisita-Horn dissimilarity index for saliva samples: 0.54 versus 0.71, respectively (p = 0.005); and for tongue swabs: 0.42 versus 0.63, respectively (p = 0.006)). This similarity presumably results from transmission of oral Neisseria through intimate kissing. This finding suggests that intensive gonorrhea screening in MSM may, via increased antimicrobial exposure, promote, rather than prevent, the emergence and spread of antimicrobial resistance in Neisseria. Non-antibiotic strategies such as vaccines and oral antiseptics could prove more sustainable options to reduce gonococcal prevalence.

Surprisal analysis of genome-wide transcript profiling identifies differentially expressed genes and pathways associated with four growth conditions in the microalga Chlamydomonas.

The usual cultivation mode of the green microalga Chlamydomonas is liquid medium and light. However, the microalga can also be grown on agar plates and in darkness. Our aim is to analyze and compare gene expression of cells cultivated in these different conditions. For that purpose, RNA-seq data are obtained from Chlamydomonas samples of two different labs grown in four environmental conditions (agar@light, agar@dark, liquid@light, liquid@dark). The RNA seq data are analyzed by surprisal analysis, which allows the simultaneous meta-analysis of all the samples. First we identify a balance state, which defines a state where the expression levels are similar in all the samples irrespectively of their growth conditions, or lab origin. In addition our analysis identifies additional constraints needed to quantify the deviation with respect to the balance state. The first constraint differentiates the agar samples versus the liquid ones; the second constraint the dark samples versus the light ones. The two constraints are almost of equal importance. Pathways involved in stress responses are found in the agar phenotype while the liquid phenotype comprises ATP and NADH production pathways. Remodeling of membrane is suggested in the dark phenotype while photosynthetic pathways characterize the light phenotype. The same trends are also present when performing purely statistical analysis such as K-means clustering and differentially expressed genes.