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 Radiometric studies of mycobacterium tuberculosis

1987 ◽  
Vol 29 (1) ◽  
pp. 18-25
Author(s):  
Edwaldo E. Camargo ◽  
Judith A. Kertcher ◽  
Marianne F. Chen ◽  
Patricia Charache ◽  
Henry N. Wagner Jr
Keyword(s):  
Palmitic Acid ◽  
Lauric Acid ◽  
Bacterial Suspension ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Experimental Conditions ◽  
Vitro Assay ◽  
Minimal Inhibitory Concentrations ◽  
Different Strains

An in vitro assay system that included automated radiometric quantification of 14CO2 released as a result of oxidation of 14C- substrates was applied for studying the metabolic activity of M. tuberculosis under various experimental conditions. These experiments included the study of a) mtabolic pathways, b) detection times for various inoculum sizes, c) effect of filtration on reproducibility of results, d) influence of stress environment e) minimal inhibitory concentrations for isoniazid, streptomycin, ethambutol and rifampin, and f) generation times of M. tuberculosis and M. bovis. These organisms were found to metabolize 14C-for-mate, (U-14C) acetate, (U-14C) glycerol, (1-14C) palmitic acid, 1-14C) lauric acid, (U-14C) L-malic acid, (U-14C) D-glucose, and (U-14C) D-glucose, but not (1-14C) L-glucose, (U-14C) glycine, or (U-14C) pyruvate to 14CO2. By using either 14C-for-mate, (1-14C) palmitic acid, or (1-14C) lauric acid, 10(7) organisms/vial could be detected within 24 48 hours and as few as 10 organisms/vial within 16-20 days. Reproducible results could be obtained without filtering the bacterial suspension, provided that the organisms were grown in liquid 7H9 medium with 0.05% polysorbate 80 and homogenized prior to the study. Drugs that block protein synthesis were found to have lower minimal inhibitory concentrations with the radiometric method when compared to the conventional agar dilution method. The mean generation time obtained for M. bovis and different strains of M. tuberculosis with various substrates was 9 ± 1 hours.

scholarly journals In vitro resistance and evolution of resistance to tavaborole in Trichophyton rubrum

2021 ◽  
Author(s):  
Diletta Mazzantini ◽  
Francesco Celandroni ◽  
Marco Calvigioni ◽  
Antonella Lupetti ◽  
Emilia Ghelardi
Keyword(s):  
Minimal Inhibitory Concentration ◽  
Topical Treatment ◽  
Inhibitory Concentration ◽  
Trichophyton Rubrum ◽  
Fungal Growth ◽  
Fold Increase ◽  
Cross Resistance ◽  
Evolution Of Resistance ◽  
Resistant Mutants

Tavaborole is currently used in the topical treatment of onychomycosis. In this study, we analyzed the in vitro emergence/evolution of resistance against tavaborole in Trichophyton rubrum. When T. rubrum strains were propagated on media containing the MIC of tavaborole, spontaneous resistant mutants were isolated at a frequency of 10−8. The frequency was almost 100-fold higher following fungal growth in the presence of a sub-inhibitory tavaborole concentration (0.5-fold the MIC) for ten transfers. All collected mutants showed similar 4- to 8-fold increase in the drug minimal inhibitory concentration. No cross-resistance to other antifungals was evidenced.

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 In vitro activities of eight macrolide antibiotics and RP-59500 (quinupristin-dalfopristin) against viridans group streptococci isolated from blood of neutropenic cancer patients.

1996 ◽  
Vol 40 (9) ◽  
pp. 2117-2120 ◽  
Author(s):  
F Alcaide ◽  
J Carratala ◽  
J Liñares ◽  
F Gudiol ◽  
R Martin
Keyword(s):  
Cancer Patients ◽  
High Rate ◽  
Cross Resistance ◽  
Macrolide Antibiotics ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Agar Dilution ◽  
Resistant Strains ◽  
Viridans Group Streptococci

From January 1988 to December 1994, 66 consecutive blood culture isolates of viridans group streptococci collected from febrile neutropenic cancer patients were tested for antimicrobial susceptibilities by the agar dilution method. The antibiotics studied were erythromycin, clarithromycin, roxithromycin, dirithromycin, azithromycin, josamycin, diacetyl-midecamycin, spiramycin, and quinupristin-dalfopristin. A total of 26 (39.4%) strains were resistant to erythromycin with an MIC range of 0.5 to > 128 micrograms/ml. The strains were classified into three groups according to their penicillin susceptibility: 42 (63.6%) were susceptible, 8 (12.1%) were intermediately resistant, and 16 (24.3%) were highly resistant. The percentages of erythromycin-resistant strains in each group were 23.8, 62.5, and 68.8%, respectively. Streptococcus mitis was the species most frequently isolated (83.3%) and showed the highest rates of penicillin (40%) and erythromycin (43.6%) resistance. MICs of all macrolide antibiotics tested and of quinupristin-dalfopristin were higher for penicillin-resistant strains than for penicillin-susceptible strains. All macrolide antibiotics tested had cross-resistance to erythromycin, which was not observed with quinupristin-dalfopristin. Our study shows a high rate of macrolide resistance among viridans group streptococci isolated from blood samples of neutropenic cancer patients, especially those infected with penicillin-resistant strains. These findings make macrolides unsuitable prophylactic agents against viridans group streptococcal bacteremia in this patient population.

scholarly journals Overexpression of target enzyme gene fabI and efflux pump decrease triclosan susceptibility in Escherichia coli

2020 ◽  
Author(s):  
Weiliang Zeng ◽  
Wenya Xu ◽  
Ye Xu ◽  
Wenli Liao ◽  
Yajie Zhao ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Close Association ◽  
Opportunistic Pathogen ◽  
Cross Resistance ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
E Coli ◽  
Resistant Strains ◽  
Triclosan Resistance

Abstract Background: Escherichia coli isolates, the most opportunistic pathogen in the gut, are responsible for the most acquired infections. Triclosan is an effective disinfectant for inhibits microorganisms, but its widespread use causes its residue in urine, resulting in long-term exposure of E. coli in the intestine to triclosan environment and increasing triclosan resistance. We aim to provide the mechanism of action of E. coli isolates against triclosan and the molecular epidemiological analysis of triclosan-resistant strains.Results: Five triclosan-resistant isolates were screened out from 200 E. coli isolates by agar dilution method by to further study, interestingly, multidrug-resistant and cross-resistance phenotypes were observed in triclosan-resistant strains, but not in susceptible strains, and all except one exhibited an inhibition of efflux pump activity by efflux pump inhibition testing. Furthermore, compared with susceptible E. coli strain ATCC 25922, except fabI, increased expression were also found in efflux pump encoding genes ydcV, ydcU, ydcS, ydcT, cysP, yihV, acrB, acrD and mdfA in studied strains which had different PFGE patterns and STs types.Conclusions: These findings indicated that triclosan resistance in E. coli were mainly involved by overexpression of fabI gene, and there was a close association between overexpression of efflux pump with reducing susceptibility to triclosan. Besides, we described cross-resistance between triclosan and antibiotics may be related to the exposure time of triclosan.

scholarly journals Characterization of the Novel DNA Gyrase Inhibitor AZD0914: Low Resistance Potential and Lack of Cross-Resistance in Neisseria gonorrhoeae

2014 ◽  
Vol 59 (3) ◽  
pp. 1478-1486 ◽  
Author(s):  
Richard A. Alm ◽  
Sushmita D. Lahiri ◽  
Amy Kutschke ◽  
Linda G. Otterson ◽  
Robert E. McLaughlin ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Oral Treatment ◽  
Bacterial Species ◽  
Treatment Options ◽  
Dna Gyrase ◽  
Cross Resistance ◽  
Topoisomerase Iv ◽  
Content Type

ABSTRACTThe unmet medical need for novel intervention strategies to treatNeisseria gonorrhoeaeinfections is significant and increasing, as rapidly emerging resistance in this pathogen is threatening to eliminate the currently available treatment options. AZD0914 is a novel bacterial gyrase inhibitor that possesses potentin vitroactivities against isolates with high-level resistance to ciprofloxacin and extended-spectrum cephalosporins, and it is currently in clinical development for the treatment ofN. gonorrhoeaeinfections. The propensity to develop resistance against AZD0914 was examined inN. gonorrhoeaeand found to be extremely low, a finding supported by similar studies withStaphylococcus aureus. The genetic characterization of both first-step and second-step mutants that exhibited decreased susceptibilities to AZD0914 identified substitutions in the conserved GyrB TOPRIM domain, confirming DNA gyrase as the primary target of AZD0914 and providing differentiation from fluoroquinolones. The analysis of available bacterial gyrase and topoisomerase IV structures, including those bound to fluoroquinolone and nonfluoroquinolone inhibitors, has allowed the rationalization of the lack of cross-resistance that AZD0914 shares with fluoroquinolones. Microbiological susceptibility data also indicate that the topoisomerase inhibition mechanisms are subtly different betweenN. gonorrhoeaeand other bacterial species. Taken together, these data support the progression of AZD0914 as a novel treatment option for the oral treatment ofN. gonorrhoeaeinfections.

scholarly journals Comparison of in vitro activity of various macrolides against Helicobacter pylori

2018 ◽  
Vol 20 (3) ◽  
pp. 192-197
Author(s):  
Natalya N. Dekhnich ◽  
Nataly V. Ivanchik ◽  
Roman S. Kozlov
Keyword(s):  
Vitro Activity ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
In Vitro Activity ◽  
Minimal Inhibitory Concentrations ◽  
Biopsy Specimens ◽  
Agar Dilution ◽  
H Pylori ◽  
Comparison Of The Results

Objective. Compare the in vitro activity of clarithromycin, erythromycin, azithromycin and josamycin against the collection of H. pylori strains isolated in 2010–2017 in Smolensk. Materials and Methods. H. pylori strains were collected prospectively from biopsy specimens of the gastric mucosa. Antimicrobial susceptibility testing of H. pylori was performed by the agar dilution method. Interpretation of the results of the susceptibility determination for clarithromycin was carried out in accordance with the recommendations of EUCAST (v 8.0) 2018. The resistance breakpoints for erythromycin, azithromycin, and josamycin were all set at ≥1.0 mg/L. For comparison of the results, the value of the minimal inhibitory concentrations of the tested antibiotic inhibiting the growth of 50% (MIC50) and 90% (MIC90) of H. pylori strains was used. Results. A total of 276 H. pylori strains were tested. 90% of the MIC values of clarithromycin were in the range from 0.015 to 0.125 mg/l. The percentages of resistance were as follows: clarithromycin 5.1%, azithromycin 7.5%, erythromycin 8%, josamycin 23.2%. Clarithromycin demonstrated significantly higher activity in suppressing the growth of H. pylori strains than azithromycin, erythromycin, and josamycin. Conclusions. Among the tested macrolide antibiotics maximal anti-H. pylori activity in vitro was observed in clarithromycin.

scholarly journals Doripenem versus Pseudomonas aeruginosa In Vitro: Activity against Characterized Isolates, Mutants, and Transconjugants and Resistance Selection Potential

2004 ◽  
Vol 48 (8) ◽  
pp. 3086-3092 ◽  
Author(s):  
Shazad Mushtaq ◽  
Yigong Ge ◽  
David M. Livermore
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Laboratory ◽  
Acquired Resistance ◽  
Single Step ◽  
Cross Resistance ◽  
National Committee ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Resistant Mutants

ABSTRACT Doripenem is a broad-spectrum parenteral carbapenem under clinical development in Japan and North America. Its activities against (i) Pseudomonas aeruginosa isolates with graded levels of intrinsic efflux-type resistance, (ii) mutants with various combinations of AmpC and OprD expression, (iii) PU21 transconjugants with class A and D β-lactamases, and (iv) P. aeruginosa isolates with metallo-β-lactamases were tested by the agar dilution method of the National Committee for Clinical Laboratory Standards. Selection of resistant P. aeruginosa mutants was investigated in single- and multistep procedures. Doripenem MICs for isolates without acquired resistance mostly were 0.12 to 0.5 μg/ml, whereas meropenem MICs were 0.25 to 0.5 μg/ml and imipenem MICs were 1 to 2 μg/ml. The MICs of doripenem, meropenem, ertapenem, and noncarbapenems for isolates with increased efflux-type resistance were elevated, whereas the MICs of imipenem were less affected. The MICs of doripenem were increased by the loss of OprD but not by derepression of AmpC; nevertheless, and as with other carbapenems, the impermeability-determined resistance caused by the loss of OprD corequired AmpC activity and was lost in OprD− mutants also lacking AmpC. The TEM, PSE, PER, and OXA enzymes did not significantly protect P. aeruginosa PU21 against the activity of doripenem, whereas MICs of ≥16 μg/ml were seen for clinical isolates with VIM and IMP metallo-β-lactamases. Resistant mutants seemed to be harder to select with doripenem than with other carbapenems (or noncarbapenems), and the fold increases in the MICs were smaller for the resistant mutants. Single-step doripenem mutants were mostly resistant only to carbapenems and had lost OprD; multistep mutants had broader resistance, implying the presence of additional mechanisms, putatively including up-regulated efflux. Most mutants selected with aminoglycosides and quinolones had little or no cross-resistance to carbapenems, including doripenem.

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.

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