A Phase 1 Study in Healthy Subjects to Investigate Safety, Pharmacokinetics, and Effect on Intestinal Flora of Multiple Ascending Doses of DS-2969b, A Novel Oral DNA Gyrase B Inhibitor for The Treatment of Clostridium difficile Infection

Inoue, Satoshi; Dennie, Justin; Nagasawa, Yasuo; Gajee, Roohi; Masuda, Nobuhisa; Zamora, Cynthia; Senaldi, Giorgio

doi:10.1093/ofid/ofx163.1371

Cited by 3 publications

(4 citation statements)

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“…5), fT MIC correlated the best with the in vivo efficacies of DS-2969b (R 2 ϭ 0.65) and DS11960558 (R 2 ϭ 0.80), and the static percent fT MIC values for DS-2969b and DS11960558 were 48.9 and 43.0%, respectively. After a single oral administration of DS-2969b at 400 mg to humans (36), the percent fT MIC against strains with an MIC of 0.25 g/ml was more than the static percent fT MIC values in murine PK-PD studies. After multiple oral administrations (36), the percent fT MIC in humans increased with repeated administration and reached almost 100% at steady state.…”

Section: Discussionmentioning

confidence: 87%

“…After a single oral administration of DS-2969b at 400 mg to humans (36), the percent fT MIC against strains with an MIC of 0.25 g/ml was more than the static percent fT MIC values in murine PK-PD studies. After multiple oral administrations (36), the percent fT MIC in humans increased with repeated administration and reached almost 100% at steady state. These data suggest that 400 mg QD could be sufficient for the treatment of MRSA infections; however, further studies are required for predicting the pharmacologically active dose for MRSA infections.…”

Section: Discussionmentioning

confidence: 87%

“…These data suggest that 400 mg QD could be sufficient for the treatment of MRSA infections; however, further studies are required for predicting the pharmacologically active dose for MRSA infections. DS-2969b was safe and well tolerated when it was given at a dose of up to 400 mg QD in the multiple-ascending-dose study (36). DS-2969b displayed potent in vitro and in vivo activities against MRSA.…”

Section: Discussionmentioning

confidence: 98%

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In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, and Its Water-Soluble Prodrug, DS11960558, against Methicillin-Resistant Staphylococcus aureus

Barman

Kumar

Mathur

et al. 2018

Antimicrob Agents Chemother

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DS-2969b is a novel GyrB inhibitor under clinical development. In this study, the activity of DS-2969b and the activities of DS-2969b and its water-soluble prodrug, DS11960558, against methicillin-resistant (MRSA) were evaluated. DS-2969b inhibited the supercoiling activity of DNA gyrase and the decatenation activity of its topoisomerase IV. DS-2969b showed antibacterial activity against Gram-positive aerobes but not against Gram-negative aerobes, except for and DS-2969b was active against MRSA with an MIC of 0.25 μg/ml, which was 8-fold lower than that of linezolid. The presence of a pulmonary surfactant did not affect the MIC of DS-2969b. DS-2969b showed time-dependent slow killing against MRSA. The frequency of spontaneous resistance development was less than 6.2 × 10 in all four isolates at 4× MIC of DS-2969b. In a neutropenic MRSA-induced murine muscle infection model, DS-2969b was more efficacious than linezolid by both the subcutaneous and oral routes. DS-2969b and DS11960558 showed efficacy in a neutropenic murine MRSA lung infection model. The pharmacokinetics and pharmacodynamics of DS-2969b and DS11960558 against MRSA were characterized in a neutropenic murine thigh infection model; the percentage of time during the dosing period in which the free drug concentration exceeded the MIC () correlated best with efficacy, and the static percent was 43 to 49%. A sufficient was observed in a phase 1 multiple-ascending-dose study of DS-2969b given orally at 400 mg once a day. These results suggest that DS11960558 and DS-2969b have potential for use as intravenous-to-oral step-down therapy for treating MRSA infections with a higher efficacy than linezolid.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 98%

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In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, and Its Water-Soluble Prodrug, DS11960558, against Methicillin-Resistant Staphylococcus aureus

Barman

Kumar

Mathur

et al. 2018

Antimicrob Agents Chemother

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“…Plasma half-life of DS-2969b was determined to be approximately 15 h, with mainly renal excretion, but also via faecal routes [195]. Drug-related adverse reactions occurred in three subjects given the 400 mg dose [196], with the commonest treatment-emergent adverse events being constipation (1/18, 5.6%), abdominal bloating (1/18, 5.6%), left lower quadrant abdominal pain with hematochezia (1/18, 5.6%), and diarrhoea (1/18, 5.6%), with no dose-effect relationship identified [195,196].…”

Section: Ds-2969mentioning

confidence: 99%

Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

Koulenti

Song

et al. 2020

Microorganisms

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Antimicrobial agents are currently the mainstay of treatment for bacterial infections worldwide. However, due to the increased use of antimicrobials in both human and animal medicine, pathogens have now evolved to possess high levels of multi-drug resistance, leading to the persistence and spread of difficult-to-treat infections. Several current antibacterial agents active against Gram-positive bacteria will be rendered useless in the face of increasing resistance rates. There are several emerging antibiotics under development, some of which have been shown to be more effective with an improved safety profile than current treatment regimens against Gram-positive bacteria. We will extensively discuss these antibiotics under clinical development (phase I-III clinical trials) to combat Gram-positive bacteria, such as Staphylococcus aureus, Enterococcus faecium and Streptococcus pneumoniae. We will delve into the mechanism of actions, microbiological spectrum, and, where available, the pharmacokinetics, safety profile, and efficacy of these drugs, aiming to provide a comprehensive review to the involved stakeholders.

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In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, against Clostridium difficile

Mathur

Barman

Kumar

et al. 2018

Antimicrob Agents Chemother

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DS-2969b is a novel GyrB inhibitor that is currently under clinical development for the treatment of infection (CDI). In this study, the and activities of DS-2969b were evaluated. DS-2969b inhibited the supercoiling activity of DNA gyrase. DS-2969b showed potent activity against clinical isolates with a MIC of 0.06 μg/ml, which was 2-, 32-, and 16-fold lower than the MICs of fidaxomicin, vancomycin, and metronidazole, respectively. DS-2969b did not select spontaneously resistant mutants of various strains at 4× MIC, and the frequency of resistance development was less than 4.8 × 10 In a hamster CDI model, 5-day oral administration of DS-2969b conferred complete protection from recurrence and mortality at 0.3 mg/kg of body weight once a day, in contrast to a 50% survival rate with fidaxomicin at 3 mg/kg once a day and 0% with vancomycin at a 50-mg/kg/dose twice a day. Even a single oral administration of 1 mg/kg of DS-2969b in the CDI model exhibited 100% animal survival without recurrence. DS-2969b was also efficacious by 5-day subcutaneous administration in the CDI model. DS-2969b showed similar levels of fecal excretion after intravenous and oral administrations in rats. These data support further development of DS-2969b as a drug for oral and intravenous treatment of CDI.

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A Phase 1 Study in Healthy Subjects to Investigate Safety, Pharmacokinetics, and Effect on Intestinal Flora of Multiple Ascending Doses of DS-2969b, A Novel Oral DNA Gyrase B Inhibitor for The Treatment of Clostridium difficile Infection

Cited by 3 publications

References 0 publications

In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, and Its Water-Soluble Prodrug, DS11960558, against Methicillin-Resistant Staphylococcus aureus

In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, and Its Water-Soluble Prodrug, DS11960558, against Methicillin-Resistant Staphylococcus aureus

Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, against Clostridium difficile

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