Gepotidacin (GSK2140944)
            <i>In Vitro</i>
            Activity against Gram-Positive and Gram-Negative Bacteria

Flamm, Robert K.; Farrell, David J.; Rhomberg, Paul R.; Scangarella-Oman, Nicole; Sader, Hélio S.

doi:10.1128/aac.00468-17

Cited by 63 publications

(66 citation statements)

References 9 publications

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“…[331] Nafithromycin (WCK-4873) is aketolide in which the original carbamate is replaced by alactone moiety. [330,332] It is currently under investigation in phase II studies for community-acquired bacterial pneumonia (CABP) by Wockhardt. Its in vitro activities are comparable to telithromycin, with advantages against some ketolideresistant Pneumococci.…”

Section: Tetracyclinesmentioning

confidence: 99%

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

et al. 2018

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The public view on antibiotics as reliable medicines changed when reports about "resistant superbugs" appeared in the news. While reasons for this resistance development are easily spotted, solutions for re-establishing effective antibiotics are still in their infancy. This Review encompasses several aspects of the antibiotic development pipeline from very early strategies to mature drugs. An interdisciplinary overview is given of methods suitable for mining novel antibiotics and strategies discussed to unravel their modes of action. Select examples of antibiotics recently identified by using these platforms not only illustrate the efficiency of these measures, but also highlight promising clinical candidates with therapeutic potential. Furthermore, the concept of molecules that disarm pathogens by addressing gatekeepers of virulence will be covered. The Review concludes with an evaluation of antibacterials currently in clinical development. Overall, this Review aims to connect select innovative antimicrobial approaches to stimulate interdisciplinary partnerships between chemists from academia and industry.

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Section: Tetracyclinesmentioning

confidence: 99%

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

et al. 2018

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“…Gepotidacin (GSK2140944) is a triazaacenaphthylene bacterial type II topoisomerase inhibitor with a novel mode of action with in vitro activity against most target pathogens resistant to established antibacterials (12)(13)(14)(15). Phase 2 studies have demonstrated the efficacy of gepotidacin in acute bacterial skin and skin structure infections and uncomplicated urogenital gonorrhea (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Phase 2a Pharmacokinetic, Safety, and Exploratory Efficacy Evaluation of Oral Gepotidacin (GSK2140944) in Female Participants with Uncomplicated Urinary Tract Infection (Acute Uncomplicated Cystitis)

Overcash¹,

Tiffany

Scangarella-Oman

et al. 2020

Antimicrob Agents Chemother

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Gepotidacin, a triazaacenaphthylene bacterial type II topoisomerase inhibitor, is in development for treatment of uncomplicated urinary tract infection (uUTI). This phase 2a study in female participants with uUTI evaluated the pharmacokinetics (primary objective), safety, and exploratory efficacy of gepotidacin. Eligible participants (n = 22) were confined to the clinic at baseline, received oral gepotidacin at 1,500 mg twice daily for 5 days (on-therapy period; days 1 to 5), and returned to the clinic for test-of-cure (days 10 to 13) and follow-up (day 28 ± 3) visits. Pharmacokinetic, safety, clinical, and microbiological assessments were performed. Maximum plasma concentrations were observed approximately 1.5 to 2 h postdose. Steady state was attained by day 3. Urinary exposure over the dosing interval increased from 3,742 μg·h/ml (day 1) to 5,973 μg·h/ml (day 4), with trough concentrations of 322 to 352 μg/ml from day 3 onward. Gepotidacin had an acceptable safety-risk profile with no treatment-limiting adverse events and no clinically relevant safety trends. Clinical success was achieved in 19 (86%) and 18 (82%) of 22 participants at test-of-cure and follow-up visits, respectively. Eight participants had a qualifying baseline uropathogen (growth; ≥105 CFU/ml). A therapeutic (combined clinical and microbiological [no growth; <103 CFU/ml]) successful response was achieved in 6 (75%) and 5 (63%) of 8 participants at test-of-cure and follow-up visits, respectively. Plasma area under the free-drug concentration-time curve over 24 h at steady state divided by the MIC (fAUC0–24/MIC) and urine AUC0–24/MIC ranged from 6.99 to 90.5 and 1,292 to 121,698, respectively. Further evaluation of gepotidacin in uUTI is warranted. (This study has been registered in ClinicalTrials.gov under identifier NCT03568942.)

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“…Gepotidacin is currently also being developed for uncomplicated UTIs. Its MICs against fluoroquinolone susceptible E. coli are much higher than for levofloxacin, but cross resistance to fluoroquinolones has not been described yet in E. coli 111,112 .…”

Section: Beyond Old Classes New Chemical Scaffolds New Targets or Bimentioning

confidence: 99%

Critical analysis of antibacterial agents in clinical development

Theuretzbacher¹,

et al. 2020

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| The antibacterial agents currently in clinical development are predominantly derivatives of well-established antibiotic classes and were selected to address the class-specific resistance mechanisms and determinants that were known at the time of their discovery. Many of these agents aim to target the antibiotic-resistant priority pathogens listed by the WHO, including Gram-negative bacteria in the critical priority category, such as carbapenem-resistant Acinetobacter, Pseudomonas and Enterobacterales. Although some current compounds in the pipeline have exhibited increased susceptibility rates in surveillance studies that depend on geography, pre-existing cross-resistance both within and across antibacterial classes limits the activity of many of the new agents against the most extensively drug-resistant (XDR) and pan-drug-resistant (PDR) Gram-negative pathogens. In particular, cross-resistance to unrelated classes may occur by co-selection of resistant strains, thus leading to the rapid emergence and subsequent spread of resistance. There is a continued need for innovation and new-class antibacterial agents in order to provide effective therapeutic options against infections specifically caused by XDR and PDR Gram-negative bacteria. ✉

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Gepotidacin (GSK2140944) In Vitro Activity against Gram-Positive and Gram-Negative Bacteria

Cited by 63 publications

References 9 publications

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

Phase 2a Pharmacokinetic, Safety, and Exploratory Efficacy Evaluation of Oral Gepotidacin (GSK2140944) in Female Participants with Uncomplicated Urinary Tract Infection (Acute Uncomplicated Cystitis)

Critical analysis of antibacterial agents in clinical development

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