High susceptibility to zoliflodacin and conserved target (GyrB) for zoliflodacin among 1209 consecutive clinical Neisseria gonorrhoeae isolates from 25 European countries, 2018

2021 ◽  
Author(s):  
Magnus Unemo ◽  
Josefine Ahlstrand ◽  
Leonor Sánchez-Busó ◽  
Michaela Day ◽  
David Aanensen ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Efflux Pump ◽  
Cross Resistance ◽  
Controlled Clinical Trial ◽  
European Economic Area ◽  
Resistance Mutations ◽  
Dilution Technique ◽  
In Vitro Susceptibility ◽  
Agar Dilution

Abstract 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.

scholarly journals High In Vitro Susceptibility to the First-in-Class Spiropyrimidinetrione Zoliflodacin among Consecutive Clinical Neisseria gonorrhoeae Isolates from Thailand and South Africa

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Susanne Jacobsson ◽  
Ranmini Kularatne ◽  
Rossaphorn Kittiyaowamarn ◽  
Venessa Maseko ◽  
Porntip Paopang ◽  
...  
Keyword(s):  
South Africa ◽  
Neisseria Gonorrhoeae ◽  
Cross Resistance ◽  
Controlled Clinical Trial ◽  
Phase 3 ◽  
In Vitro Susceptibility ◽  
Content Type ◽  
Randomized Controlled ◽  
Highly Active

ABSTRACT We evaluated the in vitro susceptibility to the first-in-class spiropyrimidinetrione zoliflodacin among recent consecutive clinical Neisseria gonorrhoeae isolates cultured in Thailand (n = 99) (in 2018) and South Africa (n = 100) (in 2015 to 2017). Zoliflodacin was highly active in vitro against all tested isolates (MIC range, 0.004 to 0.25 μg/ml; MIC50, 0.064 μg/ml; MIC90, 0.125 μg/ml), with no cross-resistance to any of the seven comparator antimicrobials. Our data support the initiation of the global phase 3 randomized controlled clinical trial of zoliflodacin for uncomplicated gonorrhea.

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Jolein G. E. Laumen ◽  
Christophe Van Dijck ◽  
Sheeba S. Manoharan-Basil ◽  
Saïd Abdellati ◽  
Irith De Baetselier ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Efflux Pump ◽  
Treatment Options ◽  
Fold Increase ◽  
Cross Resistance ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Minimal Inhibitory Concentrations ◽  
Evolution Of Resistance

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.

scholarly journals HighIn VitroSusceptibility to the Novel Spiropyrimidinetrione ETX0914 (AZD0914) among 873 Contemporary Clinical Neisseria gonorrhoeae Isolates from 21 European Countries from 2012 to 2014

2015 ◽  
Vol 59 (9) ◽  
pp. 5220-5225 ◽  
Author(s):  
Magnus Unemo ◽  
Johan Ringlander ◽  
Catherine Wiggins ◽  
Hans Fredlund ◽  
Susanne Jacobsson ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
European Countries ◽  
Cross Resistance ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
The Novel ◽  
Content Type ◽  
Agar Dilution

ABSTRACTResistance inNeisseria gonorrhoeaeagainst all antimicrobials available for the treatment of gonorrhea has emerged. The first gonococcal strains with high-level resistance to ceftriaxone, the last option for first-line empirical antimicrobial monotherapy, were recently described. Consequently, new treatment options are essential. In this study, thein vitroactivity of the novel spiropyrimidinetrione ETX0914 (AZD0914), a DNA topoisomerase II inhibitor, was investigated among contemporary consecutive clinicalN. gonorrhoeaeisolates obtained in 21 European countries and compared to the activities of antimicrobials currently or previously recommended for treatment. Consecutive clinicalN. gonorrhoeaeisolates (n= 873) cultured in 21 European countries from 2012 to 2014 were examined for their susceptibility to ETX0914. The MICs of ETX0914 were determined using the agar dilution method. For comparison, the MICs of ceftriaxone, cefixime, azithromycin, and ciprofloxacin were determined using Etest or the agar dilution method. For ETX0914, the MIC range, modal MIC, MIC50, and MIC90were ≤0.002 to 0.25 mg/liter, 0.125 mg/liter, 0.064 mg/liter, and 0.125 mg/liter, respectively. The MIC values were substantially lower than those of the fluoroquinolone ciprofloxacin and most other antimicrobials examined. No cross-resistance with any other examined antimicrobial was observed. In conclusion, thein vitrosusceptibility to the novel spiropyrimidinetrione ETX0914 (AZD0914) among 873 contemporary clinical isolates from 21 European countries was high, and no cross-resistance to antimicrobials currently or previously used for gonorrhea treatment was indicated. Additional studies investigating thein vitroandin vivoinduction and mechanisms of ETX0914 resistance in gonococci, pharmacokinetics/pharmacodynamics in modeling/simulations and in humans, and performance in randomized controlled gonorrhea treatment trials are essential.

scholarly journals In Vitro Susceptibility to Closthioamide among Clinical and Reference Strains of Neisseria gonorrhoeae

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Victoria F. Miari ◽  
Priya Solanki ◽  
Yonek Hleba ◽  
Richard A. Stabler ◽  
John T. Heap
Keyword(s):  
Antimicrobial Resistance ◽  
Neisseria Gonorrhoeae ◽  
Related Species ◽  
Cross Resistance ◽  
Drug Resistant ◽  
In Vitro Susceptibility ◽  
Content Type ◽  
Reference Strains ◽  
Species Cross

ABSTRACT Neisseria gonorrhoeae is one of the leading antimicrobial resistance threats worldwide. This study determined the MICs of closthioamide to be 0.008 to 0.5 mg/liter for clinical N. gonorrhoeae strains and related species. Cross-resistance with existing antimicrobial resistance was not detected, indicating that closthioamide could be used to treat drug-resistant N. gonorrhoeae.

scholarly journals Testing of In Vitro Susceptibility of Neisseria gonorrhoeae to Azithromycin: Comparison of Disk Diffusion and Reference Agar Dilution Methods

2020 ◽  
Vol 58 (11) ◽  
Author(s):  
Ricardo Gianecini ◽  
Lucia Irazu ◽  
Marcelo Rodríguez ◽  
Paula Cristaldo ◽  
Claudia Oviedo ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Inhibition Zone ◽  
Disk Diffusion ◽  
Good Separation ◽  
First Line ◽  
In Vitro Susceptibility ◽  
High Agreement ◽  
Content Type ◽  
Agar Dilution

ABSTRACT Azithromycin in combination with ceftriaxone is recommended as the first-line treatment for uncomplicated gonorrhea in many countries. Therefore, monitoring of azithromycin susceptibility of Neisseria gonorrhoeae isolates is essential. In 2019, the Clinical and Laboratory Standards Institute (CLSI) listed the MIC breakpoint for a susceptible-only category to azithromycin, but breakpoints for disk diffusion are not yet available. In this study, we evaluated the usefulness of disk diffusion for testing the susceptibility of N. gonorrhoeae isolates to azithromycin. A total of 189 clinical isolates susceptible and nonsusceptible to azithromycin were used. Agar dilution MICs were correlated with inhibition zone diameters of azithromycin disks (15-μg) manufactured by BBL and Oxoid. In addition, an interlaboratory study involving two clinical microbiology laboratories was conducted. There was a strong correlation between disk diffusion and agar dilution for BBL disks (r = −0.74; P < 0.001) and Oxoid disks (r = −0.75; P < 0.001). Using a zone diameter breakpoint of ≥27 mm (susceptible) and ≤26 mm (nonsusceptible) yielded good separation between susceptible and nonsusceptible isolates and the least number of discrepancies. Compared to agar dilution, disk diffusion showed high agreement and kappa values of 95.2% and 0.899 (P < 0.001) for BBL disks and 96.8% and 0.933 (P < 0.001) for Oxoid disks, respectively. Major and very major discrepancies were observed in isolates with azithromycin MICs (1 and 2 μg/ml, respectively) near to the breakpoint. These data illustrate that disk diffusion could be a reliable method in clinical laboratories to test susceptibility to azithromycin in N. gonorrhoeae isolates.

scholarly journals In vitro activity of the novel triazaacenaphthylene gepotidacin (GSK2140944) against MDR Neisseria gonorrhoeae

2018 ◽  
Vol 73 (8) ◽  
pp. 2072-2077 ◽  
Author(s):  
Susanne Jacobsson ◽  
Daniel Golparian ◽  
Nicole Scangarella-Oman ◽  
Magnus Unemo
Keyword(s):  
Antimicrobial Resistance ◽  
Neisseria Gonorrhoeae ◽  
Efflux Pump ◽  
Resistance Mutation ◽  
Vitro Activity ◽  
Fluoroquinolone Resistance ◽  
Cross Resistance ◽  
In Vitro Activity ◽  
The Impact

Abstract Objectives Increased antimicrobial resistance surveillance and new effective antimicrobials are crucial to maintain treatable gonorrhoea. We examined the in vitro activity of gepotidacin, a novel triazaacenaphthylene, and the effect of efflux pump inactivation on clinical Neisseria gonorrhoeae isolates and international reference strains (n = 252) and compared gepotidacin with antimicrobials currently or previously recommended for gonorrhoea treatment. Methods MICs (mg/L) were determined by agar dilution (gepotidacin) or by Etest (seven other antimicrobials). The gyrA and parC genes were sequenced and the impact of inactivation of the MtrCDE, MacAB and NorM efflux pumps on gepotidacin MICs was examined. Results Gepotidacin showed potent in vitro activity against all gonococcal isolates (n = 252; MIC ≤4 mg/L). The modal MIC, MIC50, MIC90 and MIC range of gepotidacin were 0.5, 0.5, 1 and 0.032–4 mg/L, respectively. Inactivation of the MtrCDE efflux pump, but not MacAB or NorM, decreased the gepotidacin MICs for most strains. No significant cross-resistance between gepotidacin and any other antimicrobials, including the fluoroquinolone ciprofloxacin, was identified. However, the ParC D86N mutation (possibly together with additional antimicrobial resistance mutation), which is associated with fluoroquinolone resistance, was associated with increased gepotidacin MICs. Conclusions Gepotidacin demonstrated high in vitro activity against gonococcal strains, indicating that gepotidacin could potentially be an effective option for gonorrhoea treatment, particularly in a dual antimicrobial therapy regimen and for patients with resistance or allergy to extended-spectrum cephalosporins. Nevertheless, elucidating in vitro and in vivo resistance emergence and mechanisms in detail, together with further gonorrhoea clinical studies, ideally also including chlamydia and Mycoplasma genitalium are essential.

scholarly journals In Vitro Susceptibility of Neisseria gonorrhoeae Strains to Mupirocin, an Antibiotic Reformulated for Parenteral Administration in Nanoliposomes

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Ahuva Cern ◽  
Kristie L. Connolly ◽  
Ann E. Jerse ◽  
Yechezkel Barenholz
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Topical Administration ◽  
Parenteral Administration ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Potential Treatment ◽  
In Vitro Susceptibility ◽  
Antibiotic Resistant ◽  
Content Type

ABSTRACT Neisseria gonorrhoeae is an urgent antibiotic-resistant threat. This study determined the MICs of mupirocin to be 0.0039 to 0.0625 μg/ml for 94 N. gonorrhoeae strains. Cross-resistance with other antibiotics was not detected. Mupirocin, which is currently limited to topical administration, demonstrated activity by injection when delivered in nanoliposomes. The nanoliposomal formulation of mupirocin is a potential treatment for drug-resistant N. gonorrhoeae .

scholarly journals Molecular Epidemiology and Antifungal Susceptibility of Trichophyton Isolates in Greece: Emergence of Terbinafine-Resistant Trichophytonmentagrophytes Type VIII Locally and Globally

2021 ◽  
Vol 7 (6) ◽  
pp. 419
Author(s):  
Maria Siopi ◽  
Ioanna Efstathiou ◽  
Konstantinos Theodoropoulos ◽  
Spyros Pournaras ◽  
Joseph Meletiadis
Keyword(s):  
Molecular Epidemiology ◽  
Antifungal Susceptibility ◽  
Reference Method ◽  
Cross Resistance ◽  
Squalene Epoxidase ◽  
In Vitro Susceptibility ◽  
Type Viii ◽  
In Vitro Antifungal Susceptibility ◽  
Resistance Rates

Trichophyton isolates with reduced susceptibility to antifungals are now increasingly reported worldwide. We therefore studied the molecular epidemiology and the in vitro antifungal susceptibility patterns of Greek Trichophyton isolates over the last 10 years with the newly released EUCAST reference method for dermatophytes. Literature was reviewed to assess the global burden of antifungal resistance in Trichophyton spp. The in vitro susceptibility of 112 Trichophyton spp. molecularly identified clinical isolates (70 T. rubrum, 24 T. mentagrophytes, 12 T. interdigitale and 6 T. tonsurans) was tested against terbinafine, itraconazole, voriconazole and amorolfine (EUCAST E.DEF 11.0). Isolates were genotyped based on the internal transcribed spacer (ITS) sequences and the target gene squalene epoxidase (SQLE) was sequenced for isolates with reduced susceptibility to terbinafine. All T. rubrum, T. interdigitale and T. tonsurans isolates were classified as wild-type (WT) to all antifungals, whereas 9/24 (37.5%) T. mentagrophytes strains displayed elevated terbinafine MICs (0.25–8 mg/L) but not to azoles and amorolfine. All T. interdigitale isolates belonged to ITS Type II, while T. mentagrophytes isolates belonged to ITS Type III* (n = 11), VIII (n = 9) and VII (n = 4). All non-WT T. mentagrophytes isolates belonged to Indian Genotype VIII and harbored Leu393Ser (n = 5) and Phe397Leu (n = 4) SQLE mutations. Terbinafine resistance rates ranged globally from 0–44% for T. rubrum and 0–76% for T. interdigitale/T. mentagrophytes with strong endemicity. High incidence (37.5%) of terbinafine non-WT T. mentagrophytes isolates (all belonging to ITS Type VIII) without cross-resistance to other antifungals was found for the first time in Greece. This finding must alarm for susceptibility testing of dermatophytes at a local scale particularly in non-responding dermatophytoses.

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