In vitro growth of multidrug-resistant Neisseria gonorrhoeae isolates is inhibited by ETX0914, a novel spiropyrimidinetrione

Papp, John R.; Lawrence, Kenneth; Sharpe, Samera; Mueller, John P.; Kirkcaldy, Robert D.

doi:10.1016/j.ijantimicag.2016.05.018

Cited by 19 publications

(15 citation statements)

References 10 publications

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“…[22][23][24][25][26][27] Novel antimicrobials for effective treatment of urogenital and extragenital gonorrhoea are essential. The first-in-class spiropyrimidinetrione zoliflodacin, with a novel mode of action, appears promising for the future treatment of gonorrhoea based on in vitro activity against wild type, MDR and XDR N. gonorrhoeae strains, phase I and II RCTs, [29][30][31][32][33][34] and a multi-continental phase III RCT is planned in 2019. In the phase II RCT, the cure rate for the low number of pharyngeal gonococcal infections was lower than the one for anogenital infections, which is the case for most antimicrobials.…”

Section: Discussionmentioning

confidence: 99%

“…30 Follow-up investigations of contemporary, consecutive and/or selected clinical isolates in Europe, USA, and China further verified the potent activity and lack of resistance to zoliflodacin. [31][32][33] A phase II randomised controlled clinical trial (RCT) evaluating single oral doses of zoliflodacin (2 g or 3 g) for the treatment of uncomplicated gonorrhoea was recently completed. The cure rates for urogenital gonorrhoea were 98% (48/49) and 100% (47/47), respectively.…”

Section: Introductionmentioning

confidence: 99%

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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

Drusano

Golparian

Neely

et al. 2019

Journal of Antimicrobial Chemotherapy

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Drusano

Golparian

Neely

et al. 2019

Journal of Antimicrobial Chemotherapy

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“…Zoliflodacin antibacterial activity has been extensively evaluated in preclinical studies (5,7,9,10). In vitro studies have shown that resistant Gram-positive and Gramnegative pathogens, including fluoroquinolone-and vancomycin-resistant staphylococci and ciprofloxacin-, ceftriaxone-, and penicillin-resistant N. gonorrhoeae, remain sensitive to zoliflodacin (6,8,11,12).…”

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confidence: 99%

Single-Dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers

O’Donnell

Lawrence

Vishwanathan

et al. 2019

Antimicrob Agents Chemother

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Zoliflodacin is a novel spiropyrimidinetrione with activity against bacterial type II topoisomerases that inhibits DNA biosynthesis and results in accumulation of double-strand cleavages in bacteria. We report results from two phase 1 studies that investigated the safety, tolerability, and pharmacokinetics (PK) of zoliflodacin and absorption, distribution, metabolism, and excretion (ADME) after single doses in healthy volunteers. In the single ascending dose study, zoliflodacin was rapidly absorbed, with a time to maximum concentration of drug in serum (Tmax) between 1.5 and 2.3 h. Exposure increased dose proportionally up to 800 mg and less than dose proportionally between 800 and 4,000 mg. Urinary excretion of unchanged zoliflodacin was <5.0% of the total dose. In the fed state, absorption was delayed (Tmax, 4 h), accompanied by an increase in the area under the concentration-time curve (AUC) at 1,500- and 3,000-mg doses. In the ADME study (3,000 mg orally), the PK profile of zoliflodacin had exposure (AUC and maximum concentration of drug in serum [Cmax]) similar to that of the ascending dose study and a median Tmax of 2.5 h. A total of 97.8% of the administered radioactivity was recovered in excreta, with urine and fecal elimination accounting for approximately 18.2% and 79.6% of the dose, respectively. The major clearance pathway was via metabolism and elimination in feces with low urinary recovery of unchanged drug (approximately 2.5%) and metabolites accounting for 56% of the dose excreted in the feces. Zoliflodacin represented 72.3% and metabolite M3 accounted for 16.4% of total circulating radioactivity in human plasma. Along with the results from these studies and based upon safety, PK, and PK/pharmacodynamics targets, a dosage regimen was selected for evaluation in a phase 2 study in urogenital gonorrhea. (The studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01929629 and NCT02298920.)

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“…susceptibility to zoliflodacin was proven to be high in the United States (23) and the Netherlands (24). However, the susceptibility to zoliflodacin among N. gonorrhoeae strains circulating in Thailand and South Africa remains unknown.…”

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confidence: 99%

“…The levels of susceptibility to the internationally recommended therapeutic antimicrobials ceftriaxone, cefixime, azithromycin, and spectinomycin were also high. Zoliflodacin previously demonstrated potent in vitro activity against temporally and genetically diverse clinical N. gonorrhoeae isolates and international reference strains from 21 European Union/European Economic Area countries (MIC 50 , 0.064 g/ml; MIC 90 , 0.125 g/ml; MIC range, 0.002 to 0.25 g/ml), the United States (MIC 50 , 0.06 g/ ml; MIC 90 , 0.125 g/ml; MIC range, 0.008 to 0.25 g/ml), and China (MIC 50 , 0.03 g/ml; MIC 90 , 0.06 g/ml; MIC range, Յ0.002 to 0.125 g/ml) (23,24,30,34). Zoliflodacin has additionally shown in vitro activity against other STI pathogens, i.e., Chlamydia trachomatis and Mycoplasma genitalium (35,36).…”

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confidence: 99%

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

Jacobsson

Kularatne

Kittiyaowamarn

et al. 2019

Antimicrob Agents Chemother

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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.

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In vitro growth of multidrug-resistant Neisseria gonorrhoeae isolates is inhibited by ETX0914, a novel spiropyrimidinetrione

Cited by 19 publications

References 10 publications

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

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

Single-Dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers

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

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