Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

McEntee, Laura; Johnson, Adam; Farrington, Nicola; Unsworth, Jennifer; Dane, Aaron; Jain, Akash; Cotroneo, Nicole; Critchley, Ian A.; Melnick, David; Parr, Thomas; Ambrose, Paul G.; Das, Shampa; Hope, William

doi:10.1128/aac.00603-19

Cited by 37 publications

(34 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sulopenem failed to demonstrate non inferiority compared with ertapenem for compli cated intra abdominal infections in a recent phase III trial 71 . Sulopenem and tebipenem were developed for community acquired uncomplicated UTIs and for oral follow on after intravenous therapy for complicated UTIs 72,73 . If used widely, they will most likely exert a strong selection pressure for carbapenem resistance, like any other carbapenem 74 .…”

Section: New Stand-alone β-Lactam Antibioticsmentioning

confidence: 99%

Critical analysis of antibacterial agents in clinical development

Theuretzbacher¹,

et al. 2020

View full text Add to dashboard Cite

| 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. ✉

show abstract

Section: New Stand-alone β-Lactam Antibioticsmentioning

confidence: 99%

Critical analysis of antibacterial agents in clinical development

Theuretzbacher¹,

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Tebipenempivoxil HBr salt is currently under development for the treatment of complicated urinary tract infections in adults. Pharmacokinetics and pharmacodynamics activity showed that tebipenempivoxil HBr is a good alternative oral treatment for resistant Gram-negative pathogens and may serve as a new antibacterial agent [49].…”

Section: The Tebipenempivoxil Prodrugmentioning

confidence: 99%

Antibacterial Prodrugs to Overcome Bacterial Resistance

2020

View full text Add to dashboard Cite

Bacterial resistance to present antibiotics is emerging at a high pace that makes the development of new treatments a must. At the same time, the development of novel antibiotics for resistant bacteria is a slow-paced process. Amid the massive need for new drug treatments to combat resistance, time and effort preserving approaches, like the prodrug approach, are most needed. Prodrugs are pharmacologically inactive entities of active drugs that undergo biotransformation before eliciting their pharmacological effects. A prodrug strategy can be used to revive drugs discarded due to a lack of appropriate pharmacokinetic and drug-like properties, or high host toxicity. A special advantage of the use of the prodrug approach in the era of bacterial resistance is targeting resistant bacteria by developing prodrugs that require bacterium-specific enzymes to release the active drug. In this article, we review the up-to-date implementation of prodrugs to develop medications that are active against drug-resistant bacteria.

show abstract

“…[8][9][10][11][12] Time-dependent pharmacokinetic/pharmacodynamic (PK/PD) parameters (free drug area under the concentration curve/minimum inhibitory concentration [fAUC/MIC*1/tau] where tau represents the length of the dosing interval) is the best predictor of antimicrobial activity of TBP. 13,14 Previously, the PK of TBP were evaluated in a single-and multipleascending dose study in healthy subjects. 15 The PK profile of TBP generally was dose proportional and linear after single doses of 100 to 900 mg. After multiple daily doses of on May 2, 2021 by guest http://aac.asm.org/ Downloaded from 4 300 and mg q8h, TBP demonstrated dose-proportionality PK with no accumulation over 14 days.…”

Section: Introductionmentioning

confidence: 99%

Randomized, Double-Blind, Placebo- and Positive-Controlled Crossover Study of the Effects of Tebipenem Pivoxil Hydrobromide on QT/QTc Intervals in Healthy Subjects

Gupta

Maier²,

Eckburg

et al. 2021

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an orally available prodrug of TBP, a carbapenem with in vitro activity against multidrug-resistant gram-negative pathogens. This study evaluated the effects of single therapeutic and supratherapeutic doses of TBP-PI-HBr on the heart rate corrected QT interval (QTc) by assessing the concentration-QT (C-QT) relationship using exposure-response modeling. This was a randomized, double-blind, placebo- and active-controlled, single dose, 4-way, crossover study. Subjects received single oral doses of TBP-PI-HBr 600 and 1200 mg, placebo, and positive control, moxifloxacin 400 mg. Cardiodynamic electrocardiograms (ECGs) and blood samples were collected in each period. Twenty-four subjects were enrolled. TBP-PI-HBr had no clinically significant adverse effects on heart rate or ECG parameters. The model-predicted slope suggests that ddHR was not importantly affected by plasma tebipenem concentrations, supporting the use of QTcF as an appropriate correction method. The model predicted difference in corrected QT interval (ddQTcF) at mean peak concentration (Cmax) for TBP had negative predicted values for each dose, and no QTc prolongation was detected following TBP-PI-HBr 600 mg or 1200 mg. Assay sensitivity was established following moxifloxacin 400 mg. Exposure to TBP increased in a dose-dependent manner with 600 and 1200 mg doses. TBP area under the concentration curve from time 0 to infinity (AUC0-inf) and Cmax at the 1200 mg dose level were 1.8- and 1.3-fold higher than with the 600 mg dose. TBP-PI-HBr was generally safe and well tolerated with no effect on QT prolongation.

show abstract

Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

Cited by 37 publications

References 25 publications

Critical analysis of antibacterial agents in clinical development

Critical analysis of antibacterial agents in clinical development

Antibacterial Prodrugs to Overcome Bacterial Resistance

Randomized, Double-Blind, Placebo- and Positive-Controlled Crossover Study of the Effects of Tebipenem Pivoxil Hydrobromide on QT/QTc Intervals in Healthy Subjects

Contact Info

Product

Resources

About