scholarly journals Genetic Resistance Determinants, In Vitro Time-Kill Curve Analysis and Pharmacodynamic Functions for the Novel Topoisomerase II Inhibitor ETX0914 (AZD0914) in Neisseria gonorrhoeae

2015 ◽  
Vol 6 ◽  
Author(s):  
Sunniva Foerster ◽  
Daniel Golparian ◽  
Susanne Jacobsson ◽  
Lucy J. Hathaway ◽  
Nicola Low ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Topoisomerase Ii ◽  
Genetic Resistance ◽  
Curve Analysis ◽  
The Novel ◽  
Topoisomerase Ii Inhibitor ◽  
Resistance Determinants ◽  
Kill Curve ◽  
Time Kill

scholarly journals In vitro antimicrobial combination testing of and evolution of resistance to the first-in-class spiropyrimidinetrione zoliflodacin combined with six therapeutically relevant antimicrobials for Neisseria gonorrhoeae

2019 ◽  
Vol 74 (12) ◽  
pp. 3521-3529 ◽  
Author(s):  
Sunniva Foerster ◽  
George Drusano ◽  
Daniel Golparian ◽  
Michael Neely ◽  
Laura J V Piddock ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Single Agent ◽  
Curve Analysis ◽  
Phase Iii ◽  
Transmitted Infection ◽  
Kill Curve ◽  
Time Kill ◽  
Selection Of ◽  
Selection Of Resistance

Abstract Objectives Resistance in Neisseria gonorrhoeae to all gonorrhoea therapeutic antimicrobials has emerged. Novel therapeutic antimicrobials are imperative and the first-in-class spiropyrimidinetrione zoliflodacin appears promising. Zoliflodacin could be introduced in dual antimicrobial therapies to prevent the emergence and/or spread of resistance. We investigated the in vitro activity of and selection of resistance to zoliflodacin alone and in combination with six gonorrhoea therapeutic antimicrobials against N. gonorrhoeae. Methods The international gonococcal reference strains WHO F (WT) and WHO O, WHO V and WHO X (strains with different AMR profiles) were examined. Zoliflodacin was evaluated alone or combined with ceftriaxone, cefixime, spectinomycin, gentamicin, tetracycline, cethromycin or sitafloxacin in chequerboard assays, time–kill curve analysis and selection-of-resistance studies. Results Zoliflodacin alone or in combination with all six antimicrobials showed rapid growth inhibition against all examined strains. The time–kill curve analysis indicated that tetracycline or cethromycin combined with zoliflodacin can significantly decrease the zoliflodacin kill rate in vitro. The frequency of selected zoliflodacin-resistance mutations was low when evaluated as a single agent and further reduced for all antimicrobial combinations. All resistant mutants contained the GyrB mutations D429N, K450T or K450N, resulting in zoliflodacin MICs of 0.5–4 mg/L. Conclusions Zoliflodacin, alone or in combination with sexually transmitted infection therapeutic antimicrobials, rapidly kills gonococci with infrequent resistance emergence. Zoliflodacin remains promising for gonorrhoea oral monotherapy and as part of dual antimicrobial therapy with low resistance emergence potential. A Phase III trial evaluating efficacy and safety of zoliflodacin for uncomplicated gonorrhoea treatment is planned in 2019.

In vitro activity and time-kill curve analysis of sitafloxacin against a global panel of antimicrobial-resistant and multidrug-resistant Neisseria gonorrhoeae isolates

Apmis ◽  
2017 ◽  
Vol 126 (1) ◽  
pp. 29-37 ◽  
Author(s):  
Agnez Jönsson ◽  
Sunniva Foerster ◽  
Daniel Golparian ◽  
Ryoichi Hamasuna ◽  
Susanne Jacobsson ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Multidrug Resistant ◽  
Curve Analysis ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Kill Curve ◽  
Time Kill

AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 2034-2040 ◽  
Author(s):  
Jing Yang ◽  
Takayuki Ikezoe ◽  
Chie Nishioka ◽  
Taizo Tasaka ◽  
Ayuko Taniguchi ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
Growth Arrest ◽  
Leukemia Cells ◽  
Aurora B ◽  
Thymidine Uptake ◽  
Aurora B Kinase ◽  
Aurora Kinases ◽  
Topoisomerase Ii Inhibitor

Abstract Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. We have recently shown that hematopoietic malignant cells including those from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) aberrantly expressed Aurora A and B kinases, and ZM447439, a potent inhibitor of Aurora kinases, effectively induced growth arrest and apoptosis of a variety of leukemia cells. The present study explored the effect of AZD1152, a highly selective inhibitor of Aurora B kinase, on various types of human leukemia cells. AZD1152 inhibited the proliferation of AML lines (HL-60, NB4, MOLM13), ALL line (PALL-2), biphenotypic leukemia (MV4-11), acute eosinophilic leukemia (EOL-1), and the blast crisis of chronic myeloid leukemia K562 cells with an IC50 ranging from 3 nM to 40 nM, as measured by thymidine uptake on day 2 of culture. These cells had 4N/8N DNA content followed by apoptosis, as measured by cell-cycle analysis and annexin V staining, respectively. Of note, AZD1152 synergistically enhanced the antiproliferative activity of vincristine, a tubulin depolymerizing agent, and daunorubicin, a topoisomerase II inhibitor, against the MOLM13 and PALL-2 cells in vitro. Furthermore, AZD1152 potentiated the action of vincristine and daunorubicin in a MOLM13 murine xenograft model. Taken together, AZD1152 is a promising new agent for treatment of individuals with leukemia. The combined administration of AZD1152 and conventional chemotherapeutic agent to patients with leukemia warrants further investigation.

scholarly journals In VitroandIn VivoActivities of the Novel Ketolide RBx 14255 against Clostridium difficile

2012 ◽  
Vol 56 (11) ◽  
pp. 5986-5989 ◽  
Author(s):  
Manoj Kumar ◽  
Tarun Mathur ◽  
Tarani K. Barman ◽  
G. Ramkumar ◽  
Ashish Bhati ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Time Dependent ◽  
Kinetics Study ◽  
The Novel ◽  
Promising Candidate ◽  
Hamster Model ◽  
Bacterial Killing ◽  
Content Type ◽  
Time Kill

ABSTRACTThe MIC90of RBx 14255, a novel ketolide, againstClostridium difficilewas 4 μg/ml (MIC range, 0.125 to 8 μg/ml), and this drug was found to be more potent than comparator drugs. Anin vitrotime-kill kinetics study of RBx 14255 showed time-dependent bacterial killing forC. difficile. Furthermore, in the hamster model ofC. difficileinfection, RBx 14255 demonstrated greater efficacy than metronidazole and vancomycin, making it a promising candidate forC. difficiletreatment.

scholarly journals Pharmacodynamic Analysis of the Activity of Quinupristin-Dalfopristin against Vancomycin-ResistantEnterococcus faecium with Differing MBCs via Time-Kill-Curve and Postantibiotic Effect Methods

1998 ◽  
Vol 42 (9) ◽  
pp. 2188-2192 ◽  
Author(s):  
Jeffrey R. Aeschlimann ◽  
Michael J. Rybak
Keyword(s):  
Antibacterial Activities ◽  
Water Soluble ◽  
Postantibiotic Effect ◽  
Curve Method ◽  
Highly Correlated ◽  
Kill Curve ◽  
The Individual ◽  
Time Kill

ABSTRACT Quinupristin-dalfopristin (Q-D) is a new water-soluble, semisynthetic antibiotic that is derived from natural streptogramins and that is combined in a 30:70 ratio. A number of studies have described the pharmacodynamic properties of this drug, but most have investigated only staphylococci or streptococci. We evaluated the relationship between Q-D, quinupristin (Q), and/or dalfopristin (D) susceptibility parameters and antibacterial activities against 22 clinical isolates of vancomycin-resistant Enterococcus faecium (VREF) by using the concentration-time-kill-curve method and by measuring postantibiotic effects. Q-D, Q, and D MICs and minimum bactericidal concentrations (MBCs) ranged from 0.125 to 1 and 0.25 to 64, 8 to 512 and >512, and 2 to 8 and 8 to 512 μg/ml, respectively. There were no significant relationships between susceptibilities to the individual components and the susceptibilities to the Q-D combination product. In the time-kill-curves studies, Q-D at a concentration of 6 μg/ml was at least bacteriostatic against all VREF tested. There was increased activity against more susceptible isolates when the isolates were grouped either by Q-D MBCs or by Q MICs. By multivariate regression analyses, the percent change in the inoculum from that at the baseline was significantly correlated with the Q MIC (R = 0.74; P = 0.008) and the Q-D concentration-to-MBC ratio (R = 0.58;P = 0.02) and was inversely correlated with the Q-D MBC-to-MIC ratio (R = 0.68; P = 0.003). A strong correlation existed between the killing rate and the Q-D concentration-to-MBC ratio (R = 0.99;P < 0.0001). Time to 99.9% killing was best correlated with the Q-D MBC (R = 0.96;P < 0.0001). The postantibiotic effect ranged from 0.2 to 3.2 h and was highly correlated with the Q-D concentration-to-MBC ratio (R = 0.96;P < 0.0001) and was less highly correlated with the Q MIC (R = 0.42; P = 0.04). Further study of these relationships with in vitro or in vivo infection models that simulate Q-D pharmacokinetics should further define the utility of these pharmacodynamic parameters in the prediction of Q-D activity for the treatment of VREF infections in humans.

In vitro activity of the novel antibacterial agent ibezapolstat (ACX-362E) against Clostridioides difficile

2020 ◽  
Author(s):  
Beverly Murray ◽  
Cindy Wolfe ◽  
Andrea Marra ◽  
Chris Pillar ◽  
Dean Shinabarger
Keyword(s):  
Therapeutic Potential ◽  
Oral Treatment ◽  
Clinical Development ◽  
Vitro Activity ◽  
The Novel ◽  
In Vitro Activity ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Time Kill

Abstract Background Ibezapolstat (ACX-362E) is the first DNA polymerase IIIC inhibitor undergoing clinical development for the oral treatment of Clostridioides difficile infection (CDI). Methods In this study, the in vitro activity of ibezapolstat was evaluated against a panel of 104 isolates of C. difficile, including those with characterized ribotypes (e.g. 027 and 078) and those producing toxin A or B and was shown to have similar activity to those of comparators against these strains. Results The overall MIC50/90 (mg/L) for ibezapolstat against evaluated C. difficile was 2/4, compared with 0.5/4 for metronidazole, 1/4 for vancomycin and 0.5/2 for fidaxomicin. In addition, the bactericidal activity of ibezapolstat was evaluated against actively growing C. difficile by determining the MBC against three C. difficile isolates. Time–kill kinetic assays were additionally performed against the three C. difficile isolates, with metronidazole and vancomycin as comparators. Conclusions The killing of C. difficile by ibezapolstat was observed to occur at concentrations similar to its MIC, as demonstrated by MBC:MIC ratios and reflected in time–kill kinetic assays. This activity highlights the therapeutic potential of ibezapolstat for the treatment of CDI.

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.

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