Antimicrobial Activity Evaluation of Tebipenem (SPR859), an Orally Available Carbapenem, against a Global Set of Enterobacteriaceae Isolates, Including a Challenge Set of Organisms

Arends, S J Ryan; Rhomberg, Paul R.; Cotroneo, Nicole; Rubio, Aileen; Flamm, Robert K.; Mendes, Rodrigo E.

doi:10.1128/aac.02618-18

Cited by 36 publications

(32 citation statements)

References 14 publications

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“…formulations, highlighting the unmet need for an oral formulation of carbapenems to treat serious infections due to MDR pathogens. Results from in vitro studies demonstrated that tebipenem has potent antibacterial activity against MDR strains, including ESBL-producing Enterobacteriaceae (6–8). Combined with the promising PK and tolerability of its orally available TBPM-PI-HBr formulation, tebipenem is well positioned to address this unmet need.…”

Section: Discussionmentioning

confidence: 99%

Safety, Pharmacokinetics, and Food Effect of Tebipenem Pivoxil Hydrobromide after Single and Multiple Ascending Oral Doses in Healthy Adult Subjects

Eckburg

Jain

Walpole

et al. 2019

Antimicrob Agents Chemother

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Tebipenem pivoxil hydrobromide (TBPM-PI-HBr, formerly SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacteriaceae. The safety and pharmacokinetics (PK) of tebipenem were studied after administration of single and multiple ascending oral doses of TBPM-PI-HBr in fed and fasted states. Healthy adults received single oral doses of TBPM-PI-HBr at 100 mg to 900 mg or placebo (n = 108) or multiple doses of 300 mg or 600 mg every 8 h or placebo (n = 16) for 14 days. In the single-ascending-dose (SAD) phase, mean tebipenem plasma concentrations increased in a linear and dose proportional manner for doses of 100 to 900 mg and were comparable in the fasted and fed states for the 300- and 600-mg doses. In the MAD phase, tebipenem maximum concentration (Cmax) was reached within 1.5 h and was dose proportional on day 1 and higher than dose proportional (2.7-fold) on day 14. AUC was more than 2-fold greater on day 1 (2.7-fold) and day 14 (2.5-fold) for 600 mg q8h than for 300 mg q8h. Approximately 55% to 60% of tebipenem was recovered in the urine. TBPM-PI-HBr was well tolerated; mild, transient diarrhea was the most commonly reported adverse event. TBPM-PI-HBr provides an orally bioavailable carbapenem option to treat serious infections caused by MDR Enterobacteriaceae and has the potential to decrease the need for intravenous antibiotic therapy in the hospital or outpatient setting. (This study has been registered at ClinicalTrials.gov under identifier NCT03395249.)

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Section: Discussionmentioning

confidence: 99%

Safety, Pharmacokinetics, and Food Effect of Tebipenem Pivoxil Hydrobromide after Single and Multiple Ascending Oral Doses in Healthy Adult Subjects

Eckburg

Jain

Walpole

et al. 2019

Antimicrob Agents Chemother

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“…1 ) with potent in vitro and in vivo activity against A. baumannii , P. aeruginosa , and multiple clinically important species of Enterobacterales , including drug-resistant ESBL-producing and Ambler class A, B, C, and D beta-lactamase-producing strains. In vitro studies have shown SPR206 exhibits lower MICs (MIC 90 range, 0.12 to 0.5 μg/ml) than colistin and meropenem against A. baumannii , Klebsiella pneumoniae , and P. aeruginosa ( 22 – 27 ), and in vivo studies in thigh, lung, and urinary tract infection models in mice indicate that SPR206 achieves efficacy endpoints (reduction in bacterial burden in CFU/g) at similar or lower required doses (mg/kg) than polymyxin B (PMB) with a change from baseline in Log 10 of −4.6 for SPR206 and −2.8 for polymyxin B at 20 mg/kg ( 28 – 30 ). Nonclinical toxicology studies in mice, rats, and nonhuman primates have demonstrated that SPR206 exhibits a lower risk for kidney toxicity (nephrotoxicity) than colistin and polymyxin B, including a mouse model where no histopathological changes in the kidney were noted with SPR206 compared with all animals with polymyxin B ( 22 , 31 , 32 ).…”

Section: Introductionmentioning

confidence: 99%

Single- and Multiple-Ascending-Dose Study of the Safety, Tolerability, and Pharmacokinetics of the Polymyxin Derivative SPR206

Bruss

Lister

Gupta

et al. 2021

Antimicrob Agents Chemother

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Carbapenem-resistant Acinetobacter baumannii and Enterobacterales are identified as urgent threats, and multidrug-resistant (MDR) Pseudomonas aeruginosa and extended-spectrum beta-lactamases (ESBL)-producing pathogens are identified as a serious threat by the Centers for Disease Control and Prevention (CDC). SPR206 is a novel polymyxin derivative with potent in vitro and in vivo activity against A. baumannii , P. aeruginosa , and multiple clinically important species of Enterobacterales, including multidrug- and extensively drug-resistant strains. This was a first-in-human (FIH) double-blind, placebo-controlled, single- and multiple ascending dose study of the safety, tolerability, and pharmacokinetics (PK) of SPR206 in 94 healthy subjects. Following IV administration (1 h infusion) at single doses of 10 mg to 400 mg and multiple doses of 25 mg to 150 mg q8h for 7 days and 100 mg q8h for 14 days, SPR206 was generally safe and generally well tolerated. While the incidence of adverse events increased with dose, most were of mild severity. Systemic exposure (C max and AUC) to SPR206 was approximately dose proportional, time to peak concentrations ranged from 1.1 to 1.3 hours, and half-life ranged from 2.4 to 4.1 hours. No appreciable accumulation occurred with repeated dosing of SPR206 and trough concentrations suggest that steady state was achieved by Day 2. Urinary excretion of unchanged SPR206 was dose dependent across single- (SAD) and multiple ascending dose (MAD) cohorts, and the percentage of dose excreted as SPR206 was up to >50%. Importantly, no evidence of nephrotoxicity was observed over 14 days of 100 mg q8h dosing of SPR206; a dosing regimen anticipated to exceed requirements for clinical efficacy.

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“…(90) 1 0.06–4 ESBL-positive Proteus spp. (93) 1 ≤ 0.015–32 Ceftibuten/VNRX-7145 (oral) Ceftibuten (65%) VNRX5236 (NA) Ceftibuten (75–90%) VNRX5236 (NA) Ceftibuten (57–59%) VNRX5236 (NA) Enterobacterales (205) 1 ≤ 0.015 to > 32 [ 40 ] ESBL-producing Enterobacterales (50) 0.12 ≤ 0.015 to > 32 KPC-producing Enterobacterales (50) 0.5 ≤ 0.015–8 OXA-48-like-producing Enterobacterales (50) 1 ≤ 0.015 to > 32 Enterobacterales (1066) 2 ≤ 0.25 to > 32 [ 41 ] ESBL-positive Enterobacterales (634) 0.5 ≤ 0.25 to > 32 KPC-positive Enterobacterales (61) 2 ≤ 0.25–32 Ceftibuten/ARX-1796 (oral) ARX-1796 (NA) ARX-1796 (NA) ARX-1796 (NA) ESBL-producing Enterobacterales (50) 0.06 ≤ 0.03–0.12 [ 42 ] Ceftibuten/QPX7728 (oral and IV) Ceftibuten (65%) QPX7728 (NA) Ceftibuten (75–90%) QPX7728 (NA) Ceftibuten (57–59%) QPX7728 (NA) E. coli (92) ≤ 0.015 NA [ 43 ] NA Not available …”

Section: Carbapenemsmentioning

confidence: 99%

Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections

2021

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The treatment of urinary tract infections (UTIs) has been complicated by the emergence of multidrug-resistant, b-lactamase-expressing pathogens. As a result of the limited treatment options, patients often require hospitalization and intravenous therapy. In essence, a strong unmet need for oral antibiotics, active against extended-spectrum b-lactamase (ESBL) uropathogens has emerged. Oral carbapenems (tebipenem and sulopenem) and oral cephalosporin/b-lactamase inhibitor combinations are in various stages of clinical development for the treatment of uncomplicated and complicated UTI. Tebipenem, if approved, will be the first oral treatment for complicated UTI while sulopenem will be for uncomplicated UTI. The b-lactamase inhibitors ETX0282, VNRX7145, ARX1796, and QPX7728 are combined with cefpodoxime proxetil or ceftibuten that achieve favorable exposures in urine compared to other uropathogen-active oral cephalosporins.The combination ceftibuten-QPX7728 has potential broad-spectrum coverage against carbapenemase producers including metallo b-lactamase producers. Other novel combinations, namely cefpodoxime/ETX0282, ceftibuten/VNRX-7145, and ceftibuten/ ARX1796, have also demonstrated excellent activity against Klebsiella pneumoniae carbapanemase (KPC) and OXA-48-like producers. All these agents, upon their arrival for commercial use, would strengthen the outpatient therapy.

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Antimicrobial Activity Evaluation of Tebipenem (SPR859), an Orally Available Carbapenem, against a Global Set of Enterobacteriaceae Isolates, Including a Challenge Set of Organisms

Cited by 36 publications

References 14 publications

Safety, Pharmacokinetics, and Food Effect of Tebipenem Pivoxil Hydrobromide after Single and Multiple Ascending Oral Doses in Healthy Adult Subjects

Safety, Pharmacokinetics, and Food Effect of Tebipenem Pivoxil Hydrobromide after Single and Multiple Ascending Oral Doses in Healthy Adult Subjects

Single- and Multiple-Ascending-Dose Study of the Safety, Tolerability, and Pharmacokinetics of the Polymyxin Derivative SPR206

Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections

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