scholarly journals In VitroActivity of the New Fluoroketolide Solithromycin (CEM-101) against a Large Collection of Clinical Neisseria gonorrhoeae Isolates and International Reference Strains, Including Those with High-Level Antimicrobial Resistance: Potential Treatment Option for Gonorrhea?

2012 ◽  
Vol 56 (5) ◽  
pp. 2739-2742 ◽  
Author(s):  
Daniel Golparian ◽  
Prabhavathi Fernandes ◽  
Makoto Ohnishi ◽  
Jörgen S. Jensen ◽  
Magnus Unemo
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Treatment Option ◽  
Treatment Options ◽  
Effective Treatment Option ◽  
Content Type ◽  
New Treatment ◽  
High Level ◽  
Drug Resistant Strains ◽  
Reference Strains

ABSTRACTGonorrhea may become untreatable, and new treatment options are essential. We investigated thein vitroactivity of the first fluoroketolide, solithromycin. ClinicalNeisseria gonorrhoeaeisolates and reference strains (n= 246), including the two extensively drug-resistant strains H041 and F89 and additional isolates with clinical cephalosporin resistance and multidrug resistance, were examined. The activity of solithromycin was mainly superior to that of other antimicrobials (n= 10) currently or previously recommended for gonorrhea treatment. Solithromycin might be an effective treatment option for gonorrhea.

scholarly journals In VitroActivity of Ertapenem versus Ceftriaxone against Neisseria gonorrhoeae Isolates with Highly Diverse Ceftriaxone MIC Values and Effects of Ceftriaxone Resistance Determinants: Ertapenem for Treatment of Gonorrhea?

2012 ◽  
Vol 56 (7) ◽  
pp. 3603-3609 ◽  
Author(s):  
Magnus Unemo ◽  
Daniel Golparian ◽  
Athena Limnios ◽  
David Whiley ◽  
Makoto Ohnishi ◽  
...  
Keyword(s):  
Treatment Options ◽  
Genetic Resistance ◽  
Effective Treatment Option ◽  
Content Type ◽  
Therapy Regimen ◽  
Resistance Determinants ◽  
Clinical Resistance ◽  
New Treatment ◽  
High Level

ABSTRACTClinical resistance to the currently recommended extended-spectrum cephalosporins (ESCs), the last remaining treatment options for gonorrhea, is being reported. Gonorrhea may become untreatable, and new treatment options are crucial. We investigated thein vitroactivity of ertapenem, relative to ceftriaxone, againstN. gonorrhoeaeisolates and the effects of ESC resistance determinants on ertapenem. MICs were determined using agar dilution technique or Etest for international reference strains (n= 17) and clinicalN. gonorrhoeaeisolates (n= 257), which included the two extensively drug-resistant (XDR) strains H041 and F89 and additional isolates with high ESC MICs, clinical ESC resistance, and other types of clinical high-level and multidrug resistance (MDR). Genetic resistance determinants for ESCs (penA,mtrR, andpenB) were sequenced. In general, the MICs of ertapenem (MIC50= 0.032 μg/ml; MIC90= 0.064 μg/ml) paralleled those of ceftriaxone (MIC50= 0.032 μg/ml; MIC90= 0.125 μg/ml). The ESC resistance determinants mainly increased the ertapenem MIC and ceftriaxone MIC at similar levels. However, the MIC ranges for ertapenem (0.002 to 0.125 μg/ml) and ceftriaxone (<0.002 to 4 μg/ml) differed, and the four (1.5%) ceftriaxone-resistant isolates (MIC = 0.5 to 4 μg/ml) had ertapenem MICs of 0.016 to 0.064 μg/ml. Accordingly, ertapenem hadin vitroadvantages over ceftriaxone for isolates with ceftriaxone resistance. Thesein vitroresults suggest that ertapenem might be an effective treatment option for gonorrhea, particularly for the currently identified ESC-resistant cases and possibly in a dual antimicrobial therapy regimen. However, further knowledge regarding the genetic determinants (and their evolution) conferring resistance to both antimicrobials, and clear correlates between genetic and phenotypic laboratory parameters and clinical treatment outcomes, is essential.

scholarly journals In Vitro Efficacy of Gentamicin Alone and in Combination with Ceftriaxone, Ertapenem, and Azithromycin against Multidrug-Resistant Neisseria gonorrhoeae

2021 ◽  
Author(s):  
Xuechun Li ◽  
Wenjing Le ◽  
Xiangdi Lou ◽  
Biwei Wang ◽  
Caroline A. Genco ◽  
...  
Keyword(s):  
Public Health ◽  
Neisseria Gonorrhoeae ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Health Concern ◽  
Global Public Health ◽  
Public Health Concern ◽  
Content Type ◽  
New Treatment

Antimicrobial-resistant Neisseria gonorrhoeae is a major global public health concern. New treatment options are urgently needed to successfully treat multidrug-resistant (MDR) Neisseria gonorrhoeae infections.

scholarly journals In Vitro Activity of Gepotidacin (GSK2140944) against Neisseria gonorrhoeae

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
D. J. Farrell ◽  
H. S. Sader ◽  
P. R. Rhomberg ◽  
N. E. Scangarella-Oman ◽  
R. K. Flamm
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Single Step ◽  
Topoisomerase Iv ◽  
Bacterial Dna ◽  
Content Type ◽  
Resistance Selection ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Time Kill

ABSTRACT Gepotidacin (formerly GSK2140944) is a novel, first-in-class, triazaacenaphthylene antibacterial that inhibits bacterial DNA gyrase and topoisomerase IV via a unique mechanism and has demonstrated in vitro activity against Neisseria gonorrhoeae, including drug-resistant strains, and also targets pathogens associated with other conventional and biothreat infections. Broth microdilution was used to evaluate the MIC and minimum bactericidal concentration (MBC) activity of gepotidacin and comparators against 25 N. gonorrhoeae strains (including five ciprofloxacin-nonsusceptible strains). Gepotidacin activity was also evaluated against three N. gonorrhoeae strains (including a ciprofloxacin-nonsusceptible strain) for resistance development, against three N. gonorrhoeae strains (including two tetracycline- and azithromycin-nonsusceptible strains) using time-kill kinetics and checkerboard methods, and against two N. gonorrhoeae strains for the investigation of postantibiotic (PAE) and subinhibitory (PAE-SME) effects. The MIC50 and MIC90 for gepotidacin against the 25 N. gonorrhoeae isolates tested were 0.12 and 0.25 μg/ml, respectively. The MBC50 and MBC90 for gepotidacin were 0.25 and 0.5 μg/ml, respectively. Gepotidacin was bactericidal, and single-step resistance selection studies did not recover any mutants, indicating a low rate of spontaneous single-step resistance. For combinations of gepotidacin and comparators tested using checkerboard methods, there were no instances where antagonism occurred and only one instance of synergy (with moxifloxacin; fractional inhibitory concentration, 0.375). This was not confirmed by in vitro time-kill studies. The PAE for gepotidacin against the wild-type strain ranged from 0.5 to >2.5 h, and the PAE-SME was >2.5 h. These in vitro data indicate that further study of gepotidacin is warranted for potential use in treating infections caused by N. gonorrhoeae.

scholarly journals Endocarditis Caused by Highly Penicillin-Resistant Viridans Group Streptococci: Still Room for Vancomycin-Based Regimens

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Juan M. Pericàs ◽  
Ruvandhi Nathavitharana ◽  
Cristina Garcia-de-la-Mària ◽  
Carles Falces ◽  
Juan Ambrosioni ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Treatment Options ◽  
Content Type ◽  
High Level ◽  
Viridans Group Streptococci ◽  
Time Kill

ABSTRACT Optimal treatment options remain unknown for infective endocarditis (IE) caused by penicillin-resistant (PEN-R) viridans group streptococcal (VGS) strains. The aims of this study were to report two cases of highly PEN-R VGS IE, perform a literature review, and evaluate various antibiotic combinations in vitro and in vivo. The following combinations were tested by time-kill studies and in the rabbit experimental endocarditis (EE) model: PEN-gentamicin, ceftriaxone-gentamicin, vancomycin-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin. Case 1 was caused by Streptococcus parasanguinis (PEN MIC, 4 μg/ml) and was treated with vancomycin plus cardiac surgery. Case 2 was caused by Streptococcus mitis (PEN MIC, 8 μg/ml) and was treated with 4 weeks of vancomycin plus gentamicin, followed by 2 weeks of vancomycin alone. Both patients were alive and relapse-free after ≥6 months follow-up. For the in vitro studies, except for daptomycin-ampicillin, all combinations demonstrated both synergy and bactericidal activity against the S. parasanguinis isolate. Only PEN-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin demonstrated both synergy and bactericidal activity against the S. mitis strain. Both strains developed high-level daptomycin resistance (HLDR) during daptomycin in vitro passage. In the EE studies, PEN alone failed to clear S. mitis from vegetations, while ceftriaxone and vancomycin were significantly more effective (P < 0.001). The combination of gentamicin with PEN or vancomycin increased bacterial eradication compared to that with the respective monotherapies. In summary, two patients with highly PEN-R VGS IE were cured using vancomycin-based therapy. In vivo, regimens of gentamicin plus either β-lactams or vancomycin were more active than their respective monotherapies. Further clinical studies are needed to confirm the role of vancomycin-based regimens for highly PEN-R VGS IE. The emergence of HLDR among these strains warrants caution in the use of daptomycin therapy for VGS IE.

scholarly journals In Vitro Activity of New Tetracycline Analogs Omadacycline and Eravacycline against Drug-Resistant Clinical Isolates of Mycobacterium abscessus

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Amit Kaushik ◽  
Nicole C. Ammerman ◽  
Olumide Martins ◽  
Nicole M. Parrish ◽  
Eric L. Nuermberger
Keyword(s):  
Salvage Therapy ◽  
Treatment Options ◽  
Oral Formulation ◽  
Mycobacterium Abscessus ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
In Vitro Activity ◽  
Content Type ◽  
New Treatment

ABSTRACT Tigecycline is used in multidrug regimens for salvage therapy of Mycobacterium abscessus infections but is often poorly tolerated and has no oral formulation. Here, we report similar in vitro activity of two newly approved tetracycline analogs, omadacycline and eravacycline, against 28 drug-resistant clinical isolates of M. abscessus complex. Since omadacycline and eravacycline appear to be better tolerated than tigecycline and since omadacycline is also formulated for oral dosing, these tetracycline analogs may represent new treatment options for M. abscessus infections.

scholarly journals Multidrug-Resistant Neisseria gonorrhoeae Isolates from Nanjing, China, Are Sensitive to Killing by a Novel DNA Gyrase Inhibitor, ETX0914 (AZD0914)

2015 ◽  
Vol 60 (1) ◽  
pp. 621-623 ◽  
Author(s):  
Xiao-Hong Su ◽  
Bao-Xi Wang ◽  
Wen-Jing Le ◽  
Yu-Rong Liu ◽  
Chuan Wan ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Effective Treatment ◽  
Treatment Option ◽  
Dna Gyrase ◽  
Multidrug Resistant ◽  
Effective Treatment Option ◽  
Content Type

ABSTRACTWe tested the activity of ETX0914 against 187Neisseria gonorrhoeaeisolates from men with urethritis in Nanjing, China, in 2013. The MIC50, MIC90, and MIC range for ETX0914 were 0.03 μg/ml, 0.06 μg/ml, and ≤0.002 to 0.125 μg/ml, respectively. All isolates were resistant to ciprofloxacin, and 36.9% (69/187) were resistant to azithromycin. Of the isolates, 46.5% were penicillinase-producingN. gonorrhoeae(PPNG), 36% were tetracycline-resistantN. gonorrhoeae(TRNG), and 13% (24 isolates) had an MIC of 0.125 μg/ml for ceftriaxone. ETX0914 may be an effective treatment option for gonorrhea.

scholarly journals In VitroActivity of Delafloxacin against Clinical Neisseria gonorrhoeae Isolates and Selection of Gonococcal Delafloxacin Resistance

2016 ◽  
Vol 60 (5) ◽  
pp. 3106-3111 ◽  
Author(s):  
Olusegun O. Soge ◽  
Stephen J. Salipante ◽  
David No ◽  
Erin Duffy ◽  
Marilyn C. Roberts
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Spontaneous Mutation ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Content Type ◽  
Resistant Mutants ◽  
Reference Strains ◽  
Selection Of

ABSTRACTWe evaluated thein vitroactivity of delafloxacin against a panel of 117Neisseria gonorrhoeaestrains, including 110 clinical isolates collected from 2012 to 2015 and seven reference strains, compared with the activities of seven antimicrobials currently or previously recommended for treatment of gonorrhea. We examined the potential for delafloxacin to select for resistant mutants in ciprofloxacin-susceptible and ciprofloxacin-resistantN. gonorrhoeae. We characterized mutations in thegyrA,gyrB,parC, andparEgenes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) by PCR and sequencing and by whole-genome sequencing. The MIC50, MIC90, and MIC ranges of delafloxacin were 0.06 μg/ml, 0.125 μg/ml, and ≤0.001 to 0.25 μg/ml, respectively. The frequency of spontaneous mutation ranged from 10−7to <10−9. The multistep delafloxacin resistance selection of 30 daily passages resulted in stable resistant mutants. There was no obvious cross-resistance to nonfluoroquinolone comparator antimicrobials. A mutant with reduced susceptibility to ciprofloxacin (MIC, 0.25 μg/ml) obtained from the ciprofloxacin-susceptible parental strain had a novel Ser91Tyr alteration in thegyrAgene. We also identified new mutations in thegyrAand/orparCandparEgenes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) of two mutant strains with elevated delafloxacin MICs of 1 μg/ml. Although delafloxacin exhibited potentin vitroactivity againstN. gonorrhoeaeisolates and reference strains with diverse antimicrobial resistance profiles and demonstrated a low tendency to select for spontaneous mutants, it is important to establish the correlation between these excellentin vitrodata and treatment outcomes through appropriate randomized controlled clinical trials.

scholarly journals Mycobacterium abscessus l,d-Transpeptidases Are Susceptible to Inactivation by Carbapenems and Cephalosporins but Not Penicillins

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Pankaj Kumar ◽  
Varsha Chauhan ◽  
José Rogério A. Silva ◽  
Jerônimo Lameira ◽  
Felipe B. d'Andrea ◽  
...  
Keyword(s):  
Treatment Options ◽  
Mycobacterium Abscessus ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Computational Simulations ◽  
Content Type ◽  
Resistant Strains ◽  
New Treatment ◽  
Drug Resistant Strains ◽  
Insight Into

ABSTRACT As a growing number of clinical isolates of Mycobacterium abscessus are resistant to most antibiotics, new treatment options that are effective against these drug-resistant strains are desperately needed. The majority of the linkages in the cell wall peptidoglycan of M. abscessus are synthesized by nonclassical transpeptidases, namely, the l,d-transpeptidases. Emerging evidence suggests that these enzymes represent a new molecular vulnerability in this pathogen. Recent studies have demonstrated that inhibition of these enzymes by the carbapenem class of β-lactams determines their activity against Mycobacterium tuberculosis. Here, we studied the interactions of β-lactams with two l,d-transpeptidases in M. abscessus, namely, LdtMab1 and LdtMab2, and found that both the carbapenem and cephalosporin, but not penicillin, subclasses of β-lactams inhibit these enzymes. Contrary to the commonly held belief that combination therapy with β-lactams is redundant, doripenem and cefdinir exhibit synergy against both pansusceptible M. abscessus and clinical isolates that are resistant to most antibiotics, which suggests that dual-β-lactam therapy has potential for the treatment of M. abscessus. Finally, we solved the first crystal structure of an M. abscessus l,d-transpeptidase, LdtMab2, and using substitutions of critical amino acids in the catalytic site and computational simulations, we describe the key molecular interactions between this enzyme and β-lactams, which provide an insight into the molecular basis for the relative efficacy of different β-lactams against M. abscessus.

scholarly journals High-Level Cefixime- and Ceftriaxone-Resistant Neisseria gonorrhoeae in France: NovelpenAMosaic Allele in a Successful International Clone Causes Treatment Failure

2011 ◽  
Vol 56 (3) ◽  
pp. 1273-1280 ◽  
Author(s):  
Magnus Unemo ◽  
Daniel Golparian ◽  
Robert Nicholas ◽  
Makoto Ohnishi ◽  
Anne Gallay ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Treatment Failure ◽  
Treatment Strategies ◽  
Public Health Response ◽  
Content Type ◽  
Health Response ◽  
Primary Determinant ◽  
Confirmatory Tests ◽  
New Treatment ◽  
High Level

ABSTRACTRecently, the firstNeisseria gonorrhoeaestrain (H041) highly resistant to the expanded-spectrum cephalosporins (ESCs) ceftriaxone and cefixime, which are the last remaining options for first-line gonorrhea treatment, was isolated in Japan. Here, we confirm and characterize a second strain (F89) with high-level cefixime and ceftriaxone resistance which was isolated in France and most likely caused a treatment failure with cefixime. F89 was examined using six species-confirmatory tests, antibiograms (33 antimicrobials),porBsequencing,N. gonorrhoeaemultiantigen sequence typing (NG-MAST), multilocus sequence typing (MLST), and sequencing of known gonococcal resistance determinants (penA,mtrR,penB,ponA, andpilQ). F89 was assigned to MLST sequence type 1901 (ST1901) and NG-MAST ST1407, which is a successful gonococcal clone that has spread globally. F89 has high-level resistance to cefixime (MIC = 4 μg/ml) and ceftriaxone (MIC = 1 to 2 μg/ml) and resistance to most other antimicrobials examined. A novelpenAmosaic allele (penA-CI), which waspenA-XXXIVwith an additional A501P alteration in penicillin-binding protein 2, was the primary determinant for high-level ESC resistance, as determined by transformation into a set of recipient strains.N. gonorrhoeaeappears to be emerging as a superbug, and in certain circumstances and settings, gonorrhea may become untreatable. Investigations of the biological fitness and enhanced understanding and monitoring of the ESC-resistant clones and their international transmission are required. Enhanced disease control activities, antimicrobial resistance control and surveillance worldwide, and public health response plans for global (and national) perspectives are also crucial. Nevertheless, new treatment strategies and/or drugs and, ideally, a vaccine are essential to develop for efficacious gonorrhea management.

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.

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