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1.
Acta Derm Venereol ; 101(2): adv00393, 2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33554267

RESUMEN

The aims of this study were to assess the prevalence of, and risk factors for, Chlamydia trachomatis in attendees recruited prospectively from October 2018 to January 2019 at the only sexually transmitted infections clinic in Iceland (in Reykjavík), and to evaluate the cobas 4800 CT/NG Test and Aptima Combo 2 Assay for C. trachomatis detection in male urine and female vaginal swabs. Prevalence of C. trachomatis was 15.8% among 487 women and 13.6% among 491 men (no Neisseria gonorrhoeae positive patients were found). C. trachomatis detection was independently and positively associated with being tested for contact tracing, 18-24 years of age, and reporting ≥ 6 sexual partners within 12 months. Reporting sex with non-residents of Iceland was associated with a lower risk of C. trachomatis infection. Both assays had a high sensitivity in detection of C. trachomatis (Aptima Combo 2: 100%; cobas 4800 CT/NG: 95.1%) and high specificity (100% and 99.6%, respectively). The high local prevalence of C. trachomatis and increased acquisition risk following sex with residents are of public health concern.

3.
Artículo en Inglés | MEDLINE | ID: mdl-33564854

RESUMEN

OBJECTIVES: Novel antimicrobials for treatment of gonorrhoea are imperative. The first-in-class spiropyrimidinetrione zoliflodacin is promising and currently in an international Phase 3 randomized controlled clinical trial (RCT) for treatment of uncomplicated gonorrhoea. We evaluated the in vitro activity of and the genetic conservation of the target (GyrB) and other potential zoliflodacin resistance determinants among 1209 consecutive clinical Neisseria gonorrhoeae isolates obtained from 25 EU/European Economic Area (EEA) countries in 2018 and compared the activity of zoliflodacin with that of therapeutic antimicrobials currently used. METHODS: MICs of zoliflodacin, ceftriaxone, cefixime, azithromycin and ciprofloxacin were determined using an agar dilution technique for zoliflodacin or using MIC gradient strip tests or an agar dilution technique for the other antimicrobials. Genome sequences were available for 96.1% of isolates. RESULTS: Zoliflodacin modal MIC, MIC50, MIC90 and MIC range were 0.125, 0.125, 0.125 and ≤0.004-0.5 mg/L, respectively. The resistance was 49.9%, 6.7%, 1.6% and 0.2% to ciprofloxacin, azithromycin, cefixime and ceftriaxone, respectively. Zoliflodacin did not show any cross-resistance to other tested antimicrobials. GyrB was highly conserved and no zoliflodacin gyrB resistance mutations were found. No fluoroquinolone target GyrA or ParC resistance mutations or mutations causing overexpression of the MtrCDE efflux pump substantially affected the MICs of zoliflodacin. CONCLUSIONS: The in vitro susceptibility to zoliflodacin was high and the zoliflodacin target GyrB was conserved among EU/EEA gonococcal isolates in 2018. This study supports further clinical development of zoliflodacin. However, additional zoliflodacin data regarding particularly the treatment of pharyngeal gonorrhoea, pharmacokinetics/pharmacodynamics and resistance selection, including suppression, would be valuable.

4.
Artículo en Inglés | MEDLINE | ID: mdl-33411920

RESUMEN

OBJECTIVES: Surveillance of antimicrobial resistance (AMR) in Neisseria gonorrhoeae, supported by molecular typing, ideally through genome sequencing, is imperative. We defined N. gonorrhoeae Sequence Typing for Antimicrobial Resistance (NG-STAR) clonal complexes (CCs) and validated their usefulness in gonococcal AMR surveillance. METHODS: All NG-STAR alleles and STs available in the public database (https://ngstar.canada.ca/) were analysed using PHYLOViZ 2.0 to define CCs according to the closest founder ST with ≥5 identical alleles and founding ST with the highest number of links. The published 2013 European gonococcal dataset (n = 1054), the 2016 WHO reference strain panel (n = 14) and N. gonorrhoeae isolates with ceftriaxone resistance determinant penA-60.001 (n = 7) from several countries were used for validation. RESULTS: The majority of the isolates (n = 1063) were designated to 71 CCs. The most common CC was CC90 (n = 194), followed by CC63 (n = 166), CC139 (n = 73), CC158 (n = 73) and CC127 (n = 62). CC90 included isolates belonging to the internationally spread MDR clone N. gonorrhoeae Multi-Antigen Sequence Typing (NG-MAST) G1407 (predominantly MLST ST1901). The ceftriaxone-resistant isolates with penA-60.001 (n = 7) belonged to CC73 or STs linking between CC90 and CC73 (ST233 and ST1133). Phylogenomic analysis revealed that NG-STAR CCs more appropriately correlated to phylogenomic AMR clusters compared with MLST STs, NG-MAST STs, NG-MAST genogroups and NG-STAR STs. CONCLUSIONS: NG-STAR CCs: are consistent with the gonococcal genome phylogeny; allow rapid visualizations with limited computational requirements; provide a simple, reproducible and portable nomenclature (for WGS and conventional Sanger sequencing data); and predict AMR lineages. Phenotypic AMR surveillance, supplemented with WGS, is imperative and NG-STAR CCs can effectively support this.

5.
J Antimicrob Chemother ; 76(1): 84-90, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-32929456

RESUMEN

BACKGROUND: Accurate molecular assays for prediction of antimicrobial resistance (AMR)/susceptibility in Neisseria gonorrhoeae (Ng) can offer individualized treatment of gonorrhoea and enhanced AMR surveillance. OBJECTIVES: We evaluated the new ResistancePlus® GC assay and the GC 23S 2611 (beta) assay (SpeeDx), for prediction of resistance/susceptibility to ciprofloxacin and azithromycin, respectively. METHODS: Nine hundred and sixty-seven whole-genome-sequenced Ng isolates from 20 European countries, 143 Ng-positive (37 with paired Ng isolates) and 167 Ng-negative clinical Aptima Combo 2 (AC2) samples, and 143 non-gonococcal Neisseria isolates and closely related species were examined with both SpeeDx assays. RESULTS: The sensitivity and specificity of the ResistancePlus® GC assay to detect Ng in AC2 samples were 98.6% and 100%, respectively. ResistancePlus® GC showed 100% sensitivity and specificity for GyrA S91 WT/S91F detection and 99.8% sensitivity and specificity in predicting phenotypic ciprofloxacin resistance. The sensitivity and specificity of the GC 23S 2611 (beta) assay for Ng detection in AC2 samples were 95.8% and 100%, respectively. GC 23S 2611 (beta) showed 100% sensitivity and 99.9% specificity for 23S rRNA C2611 WT/C2611T detection and 64.3% sensitivity and 99.9% specificity for predicting phenotypic azithromycin resistance. Cross-reactions with non-gonococcal Neisseria species were observed with both assays, but the analysis software solved most cross-reactions. CONCLUSIONS: The new SpeeDx ResistancePlus® GC assay performed well in the detection of Ng and AMR determinants, especially in urogenital samples. The GC 23S 2611 (beta) assay performed relatively well, but its sensitivity, especially for predicting phenotypic azithromycin resistance, was suboptimal and further optimizations are required, including detection of additional macrolide resistance determinant(s).

6.
BMC Infect Dis ; 20(1): 958, 2020 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-33327946

RESUMEN

BACKGROUND: Group B Streptococcus (GBS) is the leading cause of invasive neonatal disease in the industrialized world. We aimed to genomically and phenotypically characterise invasive GBS isolates in Slovenia from 2001 to 2018 and contemporary colonising GBS isolates from screening cultures in 2018. METHODS: GBS isolates from 101 patients (invasive isolates) and 70 pregnant women (colonising isolates) were analysed. Basic clinical characteristics of the patients were collected from medical records. Antimicrobial susceptibility and phenotypic capsular serotype were determined. Whole-genome sequencing was performed to assign multilocus sequence types (STs), clonal complexes (CCs), pathogenicity/virulence factors, including capsular genotypes, and genome-based phylogeny. RESULTS: Among invasive neonatal disease patients, 42.6% (n = 43) were females, 41.5% (n = 39/94) were from preterm deliveries (< 37 weeks gestation), and 41.6% (n = 42) had early-onset disease (EOD). All isolates were susceptible to benzylpenicillin with low minimum inhibitory concentrations (MICs; ≤0.125 mg/L). Overall, 7 serotypes were identified (Ia, Ib, II-V and VIII); serotype III being the most prevalent (59.6%). Twenty-eight MLST STs were detected that clustered into 6 CCs. CC-17 was the most common CC overall (53.2%), as well as among invasive (67.3%) and non-invasive (32.9%) isolates (p < 0.001). CC-17 was more common among patients with late-onset disease (LOD) (81.4%) compared to EOD (47.6%) (p < 0.001). The prevalence of other CCs was 12.9% (CC-23), 11.1% (CC-12), 10.5% (CC-1), 8.2% (CC-19), and 1.8% (CC-498). Of all isolates, 2.3% were singletons. CONCLUSIONS: A high prevalence of hypervirulent CC-17 isolates, with low genomic diversity and characteristic profile of pathogenicity/virulence factors, was detected among invasive neonatal and colonising GBS isolates from pregnant women in Slovenia. This is the first genomic characterisation of GBS isolates in Slovenia and provides valuable microbiological and genomic baseline data regarding the invasive and colonising GBS population nationally. Continuous genomic surveillance of GBS infections is crucial to analyse the impact of IND prevention strategies on the population structure of GBS locally, nationally, and internationally.


Asunto(s)
Genotipo , Enfermedades del Recién Nacido/epidemiología , Complicaciones Infecciosas del Embarazo/epidemiología , Serogrupo , Infecciones Estreptocócicas/epidemiología , Streptococcus agalactiae/genética , Adulto , Antibacterianos/farmacología , Femenino , Humanos , Recién Nacido , Enfermedades del Recién Nacido/microbiología , Masculino , Pruebas de Sensibilidad Microbiana , Tipificación de Secuencias Multilocus , Penicilina G/farmacología , Filogenia , Polimorfismo de Nucleótido Simple , Embarazo , Complicaciones Infecciosas del Embarazo/microbiología , Prevalencia , Estudios Retrospectivos , Eslovenia/epidemiología , Infecciones Estreptocócicas/microbiología , Streptococcus agalactiae/efectos de los fármacos , Streptococcus agalactiae/aislamiento & purificación , Secuenciación Completa del Genoma
7.
J Glob Antimicrob Resist ; 23: 377-384, 2020 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-33207228

RESUMEN

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.

9.
Expert Rev Mol Diagn ; 20(11): 1063-1074, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33095669

RESUMEN

INTRODUCTION: Mycoplasma genitalium (MG) causes frequently asymptomatic STIs. MG prevalence figures are lacking and management is complicated by the lack of etiological diagnostics and high antimicrobial resistance in many countries. Appropriately validated, quality-assured, and FDA-approved MG diagnostic assays have been lacking. AREAS COVERED: The clinical and analytical performance characteristics of the Aptima® MG assay, the first FDA-approved MG nucleic acid amplification test (NAAT), are summarized. Key priorities in the management and control of MG infections are also discussed. EXPERT OPINION: Highly sensitive, specific, and quality-assured MG NAATs, e.g. the Aptima MG assay on the automated and flexible Panther® platform, are imperative to improve the management and control of MG infections internationally. This testing, combined with macrolide-resistance testing (not yet available on the Panther platform), offers a rapid, high-throughput, and appropriate diagnosis of MG. Macrolide resistance-guided sequential treatment needs to be implemented for MG infections. Dual antimicrobial therapy, novel antimicrobials and, ideally, a vaccine may become essential.

10.
Sex Transm Infect ; 2020 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-33082237

RESUMEN

OBJECTIVES: The emergence of multidrug-resistant Neisseria gonorrhoeae (NG) is a major global health threat necessitating response and control measures. NG antimicrobial resistance (AMR) surveillance data from sub-Saharan countries is exceedingly limited. This paper aims to describe the establishment, design and implementation of a standardised and quality-assured gonococcal surveillance programme and to describe the susceptibility patterns of the cultured gonococcal isolates in Kampala, Uganda. METHODS: From March 2018 to September 2019, using the WHO Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) protocol, consecutive males with urethral discharge syndrome were recruited from 10 surveillance sites in Kampala City, Uganda, in collaboration with the Ministry of Health. Males completed a questionnaire and provided a urethral swab specimen. Culture, identification and antimicrobial susceptibility testing (Etest) were performed. RESULTS: Of the 1013 males recruited, 73.1% (740/1013) had a positive Gram stain and 51.1% (n=518) were culture-positive for NG. Using Etest (458 isolates), the resistance to ciprofloxacin was 99.6%. Most isolates were susceptible to azithromycin, cefoxitin and gentamicin, that is, 99.8%, 98.5% and 92.4%, respectively, and all isolates were susceptible to ceftriaxone and cefixime. CONCLUSIONS: We established a standardised, quality-assured WHO EGASP. Using Etest, 458 isolates were characterised, with associated epidemiological surveillance data, in 1.5 years, which by far exceed the minimum 100 isolates per year and country requested in the WHO Global GASP, to detect AMR levels with confidence. These isolates with the epidemiological data can be used to develop population level interventions.

11.
Euro Surveill ; 25(41)2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33063655

RESUMEN

BackgroundEmerging antimicrobial resistance (AMR) challenges gonorrhoea treatment and requires surveillance.AimThis observational study describes the genetic diversity of Neisseria gonorrhoeae isolates in Germany from 2014 to 2017 and identifies N. gonorrhoeae multi-antigen sequence typing (NG-MAST) genogroups associated with AMR or some patient demographics.Methods1,220 gonococcal isolates underwent AMR testing and NG-MAST. Associations between genogroups and AMR or sex/age of patients were statistically assessed.ResultsPatients' median age was 32 years (interquartile range: 25-44); 1,078 isolates (88.4%) originated from men. In total, 432 NG-MAST sequence types including 156 novel ones were identified, resulting in 17 major genogroups covering 59.1% (721/1,220) of all isolates. Genogroups G1407 and G10557 (G7072) were significantly associated with decreased susceptibility to cefixime (Kruskal-Wallis chi-squared: 549.3442, df: 16, p < 0.001). Their prevalences appeared to decline during the study period from 14.2% (15/106) to 6.2% (30/481) and from 6.6% (7/106) to 3.1% (15/481) respectively. Meanwhile, several cefixime susceptible genogroups' prevalence seemed to increase. Proportions of isolates from men differed among genogroups (Fisher's exact test, p < 0.001), being e.g. lower for G25 (G51) and G387, and higher for G5441 and G2992. Some genogroups differed relative to each other in affected patients' median age (Kruskal-Wallis chi-squared: 47.5358, df: 16, p < 0.001), with e.g. G25 (G51) and G387 more frequent among ≤ 30 year olds and G359 and G17420 among ≥ 40 year olds.ConclusionAMR monitoring with molecular typing is important. Dual therapy (ceftriaxone plus azithromycin) recommended in 2014 in Germany, or only the ceftriaxone dose of this therapy, might have contributed to cefixime-resistant genogroups decreasing.

12.
PLoS One ; 15(9): e0237424, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32870912

RESUMEN

BACKGROUND: There is a need for a rapid diagnostic point of care test to detect Neisseria gonorrhoeae (NG) infection to prevent incorrect, lack or excess of treatment resulting from current syndromic management in low-resource settings. An assay to identify NG antimicrobial resistance (AMR) is also highly desirable to facilitate antibiotic stewardship. Here we describe the development of two target product profiles (TPPs): one for a test for etiological diagnosis of NG and Chlamydia trachomatis (CT) (TPP1) and one for the detection of NG AMR/susceptibility (TPP2). METHODS: Draft TPPs were initially developed based on a landscape analysis of existing diagnostics and expert input. TPPs were refined via an online Delphi survey with two rounds of input from 68 respondents. TPP characteristics on which <75% of non-industry respondents agreed were further discussed and revised by an expert working group. RESULTS: The need for a test to identify NG in patients with urethral or vaginal discharge was identified as a minimal requirement of TPP1, with a test that can diagnose NG in asymptomatic patients as the optimal requirement. A sensitivity of 80% was considered acceptable, either in context of syndromic management or screening high-risk populations. For TPP2, the agreed minimal requirement was for a test to be used at level 2 healthcare facilities and above, with an optimal requirement of level 1 or above. A lateral flow format was preferred for TPP1, while it was considered likely that TPP2 would require a molecular format. A total of 31 test characteristics were included in TPP1 and 27 in TPP2. CONCLUSIONS: Following the working group revisions, TPPs were posted online for public feedback for two months, and are now finalized. The final TPPs are currently guiding the development of new diagnostics that meet the defined characteristics to reach the market within two years.


Asunto(s)
Infecciones por Chlamydia/diagnóstico , Farmacorresistencia Bacteriana , Gonorrea/diagnóstico , Pruebas en el Punto de Atención , Chlamydia trachomatis/aislamiento & purificación , Pruebas Diagnósticas de Rutina , Humanos , Neisseria gonorrhoeae/aislamiento & purificación
13.
Nat Rev Urol ; 17(11): 609-610, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32929254
14.
J Antimicrob Chemother ; 75(11): 3163-3172, 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-32785692

RESUMEN

OBJECTIVES: Neisseria gonorrhoeae antimicrobial resistance (AMR) surveillance is imperative internationally, but only eight (22.9%) countries in the WHO Region of the Americas reported complete AMR data to the WHO Global Gonococcal Antimicrobial Surveillance Program (WHO GASP) in 2016. Genomic studies are ideal for enhanced understanding of gonococcal populations, including the spread of AMR strains. To elucidate the circulating gonococcal lineages/sublineages, including their AMR determinants, and the baseline genomic diversity among gonococcal strains in Brazil, we conducted WGS on 548 isolates obtained in 2015-16 across all five macroregions in Brazil. METHODS: A total of 548 gonococcal isolates cultured across Brazil in 2015-16 were genome sequenced. AMR was determined using agar dilution and/or Etest. Genome sequences of isolates from Argentina (n = 158) and the 2016 WHO reference strains (n = 14) were included in the analysis. RESULTS: We found 302, 68 and 214 different NG-MAST, MLST and NG-STAR STs, respectively. The phylogenomic analysis identified one main antimicrobial-susceptible lineage and one AMR lineage, which was divided into two sublineages with different AMR profiles. Determination of NG-STAR networks of clonal complexes was shown as a new and valuable molecular epidemiological analysis. Several novel mosaic mtrD (and mtrR and mtrE) variants associated with azithromycin resistance were identified. CONCLUSIONS: We describe the first genomic baseline data to support the Brazilian GASP. The high prevalence of resistance to ciprofloxacin, tetracycline and benzylpenicillin, and the high number of isolates with mosaic penA and azithromycin resistance mutations, should prompt continued and strengthened AMR surveillance, including WGS, of N. gonorrhoeae in Brazil.

15.
Clin Microbiol Infect ; 26(12): 1630-1635, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32798687

RESUMEN

BACKGROUND: Increasing multidrug resistance rates in Neisseria gonorrhoeae have raised concerns and an urgent call for new antibiotics for treatment of gonorrhoea. Several decades of subdued drug development in this field and the recent failures of two new antibiotics to show non-inferiority compared with the current first-line antibiotics ceftriaxone plus azithromycin highlight the need for improved preclinical tools to predict clinical outcome of new drugs in the development process. OBJECTIVES: To summarize current pharmacokinetic/pharmacodynamic (PK/PD) knowledge and dose-finding strategies for antibiotics against gonorrhoea. SOURCES: Literature review of published papers and discussions by global experts at a special workshop on this topic. CONTENT: We review current knowledge of gonococcal specific PK/PD principles and provide an update on new in vitro and in vivo models to correlate drug exposure with clinical outcome, and identify challenges and gaps in gonococcal therapeutic research. IMPLICATIONS: Identifying the ideal antimicrobial agent and dose for treating uncomplicated urogenital and pharyngeal gonococcal disease requires appropriate validated non-clinical PK/PD models. Recent advances in adapting in vitro and in vivo models for use in gonorrhoea are an important step for enabling the development of new drugs with reduced risk of failure in Phase 3 clinical development and diminish the risk of emergence of resistance.

16.
Nat Commun ; 11(1): 4126, 2020 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-32807804

RESUMEN

Neisseria gonorrhoeae is an urgent public health threat due to rapidly increasing incidence and antibiotic resistance. In contrast with the trend of increasing resistance, clinical isolates that have reverted to susceptibility regularly appear, prompting questions about which pressures compete with antibiotics to shape gonococcal evolution. Here, we used genome-wide association to identify loss-of-function (LOF) mutations in the efflux pump mtrCDE operon as a mechanism of increased antibiotic susceptibility and demonstrate that these mutations are overrepresented in cervical relative to urethral isolates. This enrichment holds true for LOF mutations in another efflux pump, farAB, and in urogenitally-adapted versus typical N. meningitidis, providing evidence for a model in which expression of these pumps in the female urogenital tract incurs a fitness cost for pathogenic Neisseria. Overall, our findings highlight the impact of integrating microbial population genomics with host metadata and demonstrate how host environmental pressures can lead to increased antibiotic susceptibility.


Asunto(s)
Proteínas Bacterianas/metabolismo , Cuello del Útero/microbiología , Neisseria gonorrhoeae/efectos de los fármacos , Neisseria gonorrhoeae/genética , Animales , Proteínas Bacterianas/genética , Farmacorresistencia Microbiana/genética , Femenino , Regulación Bacteriana de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Pruebas de Sensibilidad Microbiana , Mutación/genética , Neisseria gonorrhoeae/metabolismo , Operón/genética , Regiones Promotoras Genéticas/genética
17.
J Antimicrob Chemother ; 75(11): 3244-3247, 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-32712655

RESUMEN

BACKGROUND: The rising incidence of antimicrobial resistance in Neisseria gonorrhoeae may result in untreatable gonorrhoea in certain circumstances and development of novel antimicrobials is urgently needed. OBJECTIVES: To evaluate the in vitro activity of a novel small-molecule antimicrobial with a new mechanism of action, DIS-73285, against a large geographically, temporally and genetically diverse collection of clinical N. gonorrhoeae isolates and reference strains, including various types of high-level resistant, MDR and XDR gonococcal isolates (n = 262). METHODS: MICs (mg/L) of DIS-73285 were determined by agar dilution and by Etest for ceftriaxone, cefixime, azithromycin, ciprofloxacin, ampicillin, spectinomycin and tetracycline. RESULTS: DIS-73285 was substantially more potent than any of the currently or previously used therapeutic antimicrobials, with MICs ranging from ≤0.001 to 0.004 mg/L, and the MIC50, MIC90 and modal MIC all ≤0.001 mg/L (lowest MIC tested). No correlation with the MICs of DIS-73285 and the MICs of any of the currently or previously used antimicrobials was observed. CONCLUSIONS: The novel chemotype, small-molecule antimicrobial DIS-73285, demonstrated high in vitro potency against all tested N. gonorrhoeae isolates. Further in vitro and in vivo studies, evaluating efficacy, resistance emergence, pharmacokinetic/pharmacodynamic parameters, toxicity and safety, should be conducted to evaluate DIS-73285 as a therapy specifically for urogenital and extra-genital gonorrhoea.

18.
J Clin Microbiol ; 58(9)2020 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-32611793

RESUMEN

Mycoplasma genitalium is prevalent among attendees in sexually transmitted infection (STI) clinics, and therapy is hampered by rapidly rising levels of resistance to azithromycin and moxifloxacin. In this study, we evaluated, for the first time in Iceland, the prevalence of M. genitalium and azithromycin and moxifloxacin resistance-associated mutations and assessed the diagnostic performance of the CE/in vitro diagnosis (IVD)-marked S-DiaMGTV (Diagenode Diagnostics) versus the U.S. FDA/CE/IVD-approved Aptima MG (AMG; Hologic) for M. genitalium detection. From October 2018 to January 2019, urine and vaginal swabs were provided by male and female attendees at Iceland's only STI clinic. Specimens were tested with S-DiaMGTV and AMG, and resistance-associated mutations were determined by 23S rRNA gene and parC sequencing. Demographic and clinical data were collected from patient records. M. genitalium prevalence was 9.3% overall; 7.7% (38/491) among male and 10.9% (53/487) among female participants. Azithromycin and moxifloxacin resistance-associated mutations were found in 57.0% (45/79) and 0.0% (0/80) of evaluable specimens, respectively. Sensitivity was 72.5% and 100%, and specificity was 99.9% and 100% for S-DiaMGTV and AMG, respectively. No association was found between M. genitalium and symptoms of urethritis in men. Prevalence rates for M. genitalium and azithromycin resistance-associated genes in Iceland are among the highest reported in Europe. The significantly higher sensitivity of AMG over that of S-DiaMGTV can have important clinical implications. More information is urgently needed to clarify the significance of false-negative results obtained with S-DiaMGTV and other similarly performing widely used real-time PCR methods for diagnosis and management of this sexually transmitted infection.

19.
Lancet Infect Dis ; 20(11): 1302-1314, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32622378

RESUMEN

BACKGROUND: Mycoplasma genitalium is now recognised as an important bacterial sexually transmitted infection. We summarised data from studies of mutations associated with macrolide and fluoroquinolone resistance in M genitalium to establish the prevalence of resistance. We also investigated temporal trends in resistance and aimed to establish the association between resistance and geographical location. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, and MEDLINE for studies that included data for the prevalence of mutations associated with macrolide and fluoroquinolone resistance in M genitalium published in any language up to Jan 7, 2019. We defined prevalence as the proportion of M genitalium samples positive for key mutations associated with azithromycin resistance (23S rRNA gene, position 2058 or 2059) or moxifloxacin resistance (S83R, S83I, D87N, or D87Y in parC), or both, among all M genitalium samples that were successfully characterised. We used random-effects meta-analyses to calculate summary estimates of prevalence. Subgroup and meta-regression analyses by WHO region and time period were done. This study was registered with PROSPERO, number CRD42016050370. RESULTS: Overall, 59 studies from 21 countries met the inclusion criteria for our study: 57 studies of macrolide resistance (8966 samples), 25 of fluoroquinolone resistance (4003 samples), and 22 of dual resistance to macrolides and fluoroquinolones (3280 samples). The summary prevalence of mutations associated with macrolide resistance among M genitalium samples was 35·5% (95% CI 28·8-42·5); prevalence increased from 10·0% (95% CI 2·6-20·1%) before 2010, to 51·4% (40·3-62·4%) in 2016-17 (p<0·0001). Prevalence of mutations associated with macrolide resistance was significantly greater in samples in the WHO Western Pacific and Americas regions than in those from the WHO European region. The overall prevalence of mutations associated with fluoroquinolone resistance in M genitalium samples was 7·7% (95% CI 4·5-11·4%). Prevalence did not change significantly over time, but was significantly higher in the Western Pacific region than in the European region. Overall, the prevalence of both mutations associated with macrolide resistance and those associated with fluoroquinolone resistance among M genitalium samples was 2·8% (1·3-4·7%). The prevalence of dual resistance did not change significantly over time, and did not vary significantly by geographical region. INTERPRETATION: Global surveillance and measures to optimise the efficacy of treatments-including resistance-guided strategies, new antimicrobials, and antimicrobial combination approaches-are urgently needed to ensure cure in a high proportion of M genitalium infections and to prevent further spread of resistant strains. FUNDING: Australian National Health and Medical Research Council.

20.
Emerg Microbes Infect ; 9(1): 1388-1392, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32552547

RESUMEN

Mycoplasma genitalium has developed resistance to first-line azithromycin and second-line moxifloxacin. Third-line pristinamycin is only 75% effective. Gepotidacin, a novel triazaacenaphthylene topoisomerase II inhibitor, blocks bacterial DNA replication. We determined the in vitro activity of gepotidacin alone and in combination with doxycycline against a diverse collection of Mycoplasma genitalium isolates (n = 54). Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined by a Vero-cell culture method. Macrolide resistance was present in 31 (57%) isolates, fluoroquinolone resistance in 18 (33%) isolates, and 17 (31%) had dual resistance. Synergy testing was performed for gepotidacin and doxycycline by checkerboard analysis for two macrolide- and two dual-resistant isolates. Gepotidacin was active against all 54 M. genitalium isolates with median and modal MICs of 0.125 mg/L and MIC90 of 0.25 mg/L (range ≤0.016-0.5 mg/L). No difference in gepotidacin MIC between macrolide-resistant and -susceptible isolates (p = 0.24) or between fluoroquinolone-, dual-resistant and -susceptible isolates (p = 0.2) was demonstrated. Gepotidacin MBCs were available for 44 M. genitalium isolates with median MIC of 0.064 mg/L and median MBC of 0.125 mg/L. All isolates had ≤4-fold difference between MIC and MBC, suggesting bactericidal effect for gepotidacin. Checkerboard analysis indicated synergistic effect for gepotidacin in combination with doxycycline [fractional inhibitory concentration index (ΣFICI) of 0.5] for two isolates and additive/indifference (ΣFICI at 0.62 and 0.75) for two isolates. Gepotidacin warrants further evaluation in clinical treatment trials for M. genitalium. Combination therapy with doxycycline should be clinically studied to assess effect and potential protection against development and/or spread of gepotidacin resistance.

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