Tebipenem Research Articles

The interaction of the azetidine thiazole side chain with the active site loop (ASL) 3 drives the evolution of IMP metallo-β-lactamase against tebipenem.

Imipenemase (IMP) metallo-β-lactamases (MBLs) hydrolyze almost all available β-lactams including carbapenems and are not inhibited by any commercially available β-lactamase inhibitor. Tebipenem (TP) pivoxil is the first orally available carbapenem and possesses a unique bicyclic azetidine thiazole moiety located at the R2 position. TP has potent in vitro activity against Enterobacterales producing extended-spectrum and/or AmpC β-lactamases. Thus far, the activity of TP against IMP-producing strains is understudied. To address this knowledge gap, we explored the structure activity relationships of IMP MBLs by investigating whether IMP-6, IMP-10, IMP-25, and IMP-78 [MBLs with expanded hydrolytic activity against meropenem (MEM)] would demonstrate enhanced activity against TP. Most of the Escherichia coli DH10B strains expressing IMP-1 variants displayed a ≥twofold MIC difference between TP and MEM, while those expressing VIM or NDM variants demonstrated comparable MICs. Catalytic efficiency (kcat/KM) values for the TP hydrolysis by IMP-1, IMP-6, IMP-10, IMP-25, and IMP-78 were significantly lower than those obtained for MEM. Molecular dynamic simulations reveal that V67F and S262G substitutions (found in IMP-78) reposition active site loop 3, ASL-3, to better accommodate the bicyclic azetidine thiazole side chain, allowing microbiological/catalytic activity to approach that of comparison MBLs used in this study. These findings suggest that modifying the R2 side chain of carbapenems can significantly impact hydrolytic stability. Furthermore, changes in conformational dynamics due to single amino acid substitutions should be used to inform drug design of novel carbapenems.

Bioequivalence Study of Tebipenem Pivoxil in Healthy Chinese Adults.

Tebipenem pivoxil (TP) is a carbapenem and is applied against pneumonia, otitis media, and sinusitis. This study compared the pharmacokinetics (PK) and safety of a test (T) preparation and reference (R) preparation of TP in healthy Chinese adults. This study was a single-center, randomized, open, single-dose (fasting/postprandial) oral administration, two-agent, two-sequence, two-cycle, crossover bioequivalence trial. A total of 60 participants were enrolled (24 fasting and 36 postprandial). All participants were randomly assigned to the TR sequence and RT sequence. Subsequently, they switched T sequences or R sequences 7 days later. PK blood samples were collected according to the protocol, plasma TP concentration was determined by liquid chromatography-mass spectrometry, main PK parameters were calculated based on a non-compartment model, and adverse events were recorded during the test. In the feeding arm, the geometric mean ratio of maximum concentration (Cmax) was 89.84% (90% confidence interval 84.33-95.70), the geometric mean ratio of area under the plasma concentration-time curve from time 0 to last time of quantifiable concentration (AUC0-t) was 86.80% (83.62-90.10), and the geometric mean ratio of area under the plasma concentration-time curve from time 0 to infinity time of quantifiable concentration (AUC0-∞) was 86.90% (83.73-90.20), which were within the acceptable range of bioequivalence (80-125%). In the fasting arm, the geometric mean ratio of Cmax was 96.07% (89.62-102.99), the geometric mean ratio of AUC0-t was 93.09% (90.47-95.78), and the geometric mean ratio of AUC0-∞ was 93.09% (90.48-95.77), which was within the acceptable range of bioequivalence (80-125%). Hence, the T preparation and R preparation of TP had bioequivalence in the fasting arm and feeding arm of the clinical trial. In addition, all adverse events were mild, and no severe adverse events were noted. Preparations T and R of TP were bioequivalent in the fasting and postprandial groups in clinical trials, and TP was safe.

Effect of tebipenem pivoxil hydrobromide on the normal gut microbiota of a healthy adult population in Sweden: a randomised controlled trial

Antimicrobials cause perturbations in the composition and diversity of the host microbiome. We aimed to compare gut microbiome perturbations caused by oral tebipenem pivoxil hydrobromide (a novel carbapenem) and by amoxicillin-clavulanic acid (an orally administered β-lactam-β-lactam inhibitor combination widely used in clinical practice). We did a phase 1, single-centre, randomised, parallel-group, active-control trial to evaluate the effect of tebipenem pivoxil hydrobromide on the human gut microbiota. Healthy participants aged 18 years or older with no documented illnesses during recruitment were enrolled at Karolinska University Hospital (Stockholm, Sweden). Study participants were stratified by sex and block-randomised in a 1:1 ratio to treatment with either tebipenem pivoxil hydrobromide (600 mg orally every 8 h) or amoxicillin-clavulanic acid (500 mg amoxicillin and 125 mg clavulanic acid orally every 8 h). The study included 10 days of treatment (days 1-10) and four follow-up visits (days 14, 21, 90, and 180). The trial was open-label for clinical investigators and patients, but masked for microbiology investigators. Faecal samples were collected at all visits. Sequencing of 16S rDNA was used to measure the diversity metrics, and quantitative culture to quantify selected taxa. The primary outcomes were changes in the α and β diversity and log count of colony-forming units for selected taxa between samples compared with baseline (day 1), and whether any changes reverted during the follow-up period. The analyses were done in the intention-to-treat population. This study was registered with ClinicalTrials.gov (NCT04376554). The study was conducted between Jan 23, 2020, and April 6, 2021. 49 volunteers were screened for eligibility, among whom 30 evaluable participants (14 men and 16 women) were assigned: 15 (50%) to the tebipenem pivoxil hydrobromide group and 15 (50%) to the amoxicillin-clavulanic acid group. Baseline characteristics were similar between groups. Complete follow-up was available for all participants, and all participants except one completed treatment as assigned. The diversity metrics showed significant changes from baseline during the treatment period. Significant decreases in richness were observed on days 4-10 (p≤0·0011) in the amoxicillin-clavulanic acid group and on days 4-14 (p≤0·0019) in the tebipenem pivoxil hydrobromide group. Similarly, evenness was significantly decreased during treatment in the amoxicillin-clavulanic acid group (day 4, p=0·030) and the tebipenem pivoxil hydrobromide group (days 4-10, p<0·0001) compared with baseline. Quantitative cultures showed significant decreases in Enterobacterales (days 4-7, p≤0·0030), Enterococcus spp (days 4-14, p=0·025 to p<0·0001), Bifidobacterium spp (days 2-4, p≤0·026), and Bacteroides spp (days 4-10, p≤0·030) in the tebipenem pivoxil hydrobromide group. Similarly, in amoxicillin-clavulanic acid recipients, significant changes were observed in Enterobacterales (days4-10, p≤0·048), Bifidobacterium spp (days 2-4, p≤0·013), and Lactobacillus spp (days 2-4, p≤0·020). Samples from the follow-up period were not significantly different from those at baseline in βdiversity analysis (PERMANOVA, p>0·99). By the end of the study, no significant change was observed compared with baseline in either group. There were no deaths or severe adverse events. The impact of tebipenem pivoxil hydrobromide on the gut microbiome was similar to that of amoxicillin-clavulanic acid. The safety of antibiotic use with regard to the microbiome should be given attention, as dysbiosis is associated with health and disease. Spero Therapeutics.

Do dietary interventions exert clinically important effects on the bioavailability of β-lactam antibiotics? A systematic review with meta-analyses.

Managing drug-food interactions may help to achieve the optimal action and safety profile of β-lactam antibiotics. We conducted a systematic review with meta-analyses in adherence to PRISMA guidelines for 32 β-lactams. We included 166 studies assessing the impact of food, beverages, antacids or mineral supplements on the pharmacokinetic (PK) parameters or PK/pharmacodynamic (PK/PD) indices. Eighteen of 25 β-lactams for which data on food impact were available had clinically important interactions. We observed the highest negative influence of food (AUC or Cmax decreased by >40%) for ampicillin, cefaclor (immediate-release formulations), cefroxadine, cefradine, cloxacillin, oxacillin, penicillin V (liquid formulations and tablets) and sultamicillin, whereas the highest positive influence (AUC or Cmax increased by >45%) for cefditoren pivoxil, cefuroxime and tebipenem pivoxil (extended-release tablets). Significantly lower bioavailability in the presence of antacids or mineral supplements occurred for 4 of 13 analysed β-lactams, with the highest negative impact for cefdinir (with iron salts) and moderate for cefpodoxime proxetil (with antacids). Data on beverage impact were limited to 11 antibiotics. With milk, the extent of absorption was decreased by >40% for cefalexin, cefradine, penicillin G and penicillin V, whereas it was moderately increased for cefuroxime. No significant interaction occurred with cranberry juice for two tested drugs (amoxicillin and cefaclor). Factors such as physicochemical features of antibiotics, drug formulation, type of intervention, and patient's health state may influence interactions. Due to the poor actuality and diverse methodology of included studies and unproportionate data availability for individual drugs, we judged the quality of evidence as low.

Impact of antibiotic pharmacokinetics in urine on recurrent bacteriuria following treatment of complicated urinary tract infections.

The clinical relevance of bacteriuria following antibiotic treatment of complicated urinary tract infections in clinical trials remains controversial. We evaluated the impact of urine pharmacokinetics on the timing of recurrent bacteriuria in a recently completed trial that compared oral tebipenem pivoxil hydrobromide to intravenous ertapenem. The urinary clearance and urine dwell time of ertapenem were prolonged relative to tebipenem and were associated with a temporal difference in the repopulation of bladder urine with bacteria following treatment, potentially confounding the assessment of efficacy.

Population Pharmacokinetic Analyses for Tebipenem after Oral Administration of Pro-Drug Tebipenem Pivoxil Hydrobromide.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral (PO) carbapenem pro-drug that is converted to the active moiety tebipenem in the enterocytes. Tebipenem has activity against multidrug-resistant Gram-negative pathogens, including extended-spectrum beta lactamase-producing Enterobacterales, and is being developed for the treatment of patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). The objectives of these analyses were to develop a population pharmacokinetic (PK) model for tebipenem using data from three phase 1 studies and one phase 3 study and to identify covariates that described the variability in tebipenem PK. Following construction of the base model, a covariate analysis was conducted. The model was then qualified by performing a prediction-corrected visual predictive check and evaluated by using a sampling-importance-resampling procedure. The final population PK data set was composed of data from 746 subjects who provided 3,448 plasma concentrations, including 650 patients (1,985 concentrations) with cUTI/AP. The final population PK model that best described tebipenem PK was found to be a two-compartment model with linear, first-order elimination and two transit compartments to describe the rate of drug absorption after PO administration of TBP-PI-HBr. The relationship between renal clearance (CLR) and creatinine clearance (CLcr), the most clinically significant covariate, was described using a sigmoidal Hill-type function. No dose adjustments are warranted on the basis of age, body size, or sex as none of these covariates were associated with substantial differences in tebipenem exposure in patients with cUTI/AP. The resultant population PK model is expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships for tebipenem.

Absorption, Metabolism, and Excretion of [14C]-Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) in Healthy Male Subjects.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug of pharmacologically active moiety tebipenem (TBP), which is a carbapenem with activity against multidrug-resistant Gram-negative pathogens. Conversion from the prodrug to the active moiety, namely, TBP, occurs in the enterocytes of the gastrointestinal tract via intestinal esterases. The absorption, metabolism, and excretion in humans were evaluated, following the administration of a single oral dose of [14C]-TBP-PI-HBr. Healthy male subjects (n = 8) received a single 600 mg oral dose of TBP-PI-HBr containing approximately 150 μCi of [14C]-TBP-PI-HBr. Blood, urine, and fecal samples were collected to determine the total radioactivity, concentrations of TBP (plasma only), and metabolite profiling and identification. The overall mean recovery of the total radioactivity in urine (38.7%) and feces (44.6%) combined was approximately 83.3% of the administered dose, with individual recoveries ranging from 80.1% to 85.0%. Plasma TBP LC-MS/MS and metabolite profiling data suggest that TBP was the main circulating component in plasma and that it accounts for approximately 54% of the total plasma radioactivity, based on the plasma AUC ratio of TBP/total radioactivity. The ring-open metabolite LJC 11562 was another major component in plasma (>10%). TBP (M12), LJC 11562, and four trace to minor metabolites were identified/characterized in the urine. TBP-PI, TBP (M12), and 11 trace to minor metabolites were identified/characterized in the feces. The renal and fecal routes are major clearance pathways in the elimination of [14C]-TBP-PI-HBr, with a mean combined recovery of 83.3%. TBP and its inactive ring-open metabolite LJC 11562 were the major circulating metabolites in the plasma.

Effect of an Antacid (Aluminum Hydroxide/Magnesium Hydroxide/Simethicone) or a Proton Pump Inhibitor (Omeprazole) on the Pharmacokinetics of Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) in Healthy Adult Subjects.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is a novel oral carbapenem prodrug being developed for the treatment of serious bacterial infections. This open-label, 3-period, fixed sequence study evaluated the effect of gastric acid-reducing agents, aluminum hydroxide/magnesium hydroxide/simethicone, and omeprazole on the pharmacokinetics (PK) of tebipenem (TBP), the active moiety, following coadministration with immediate release TBP-PI-HBr during fasting. In Period 1, subjects received a single oral dose of TBP-PI-HBr 600 mg (2 × 300 mg tablets). In Period 2, subjects received a single oral dose of aluminum hydroxide 800 mg/magnesium hydroxide 800 mg/simethicone 80 mg suspension co-administered with a single dose of TBP-PI-HBr 600 mg. In Period 3, subjects received a single oral dose of omeprazole 40 mg once daily over 5 days, followed by single dose administration of TBP-PI-HBr 600 mg on day 5. In each period, whole blood samples were obtained prior to, and up to 24 h, following TBP-PI-HBr dose administration in order to characterize TBP PK. A 7-day washout was required between periods. Twenty subjects were enrolled and completed the study. Following co-administration of TBP-PI-HBr with either aluminum hydroxide/magnesium hydroxide/simethicone or omeprazole, total TBP exposure (area under the curve [AUC]) was approximately 11% (geometric mean ratio 89.2, 90% confidence interval: 83,2, 95.7) lower, and Cmax was 22% (geometric mean ratio 78.4, 90% confidence interval: 67.9, 90.6) and 43% (geometric mean ratio 56.9, 90% confidence interval: 49.2, 65.8) lower, respectively, compared to administration of TBP-PI-HBr alone. Mean TBP elimination half-life (t1/2) was generally comparable across treatments (range: 1.0 to 1.5 h). Concomitant administration of TBP-PI-HBr with omeprazole or aluminum hydroxide/magnesium hydroxide/simethicone is not expected to impact the efficacy of TBP-PI-HBr, as there is minimal impact on TBP plasma AUC, which is the pharmacodynamic driver of efficacy. Co-administration was generally safe and well tolerated.

Antibiotska terapija kod kritično obolelih pacijenata sa sepsom - od koncepta FK/FD do novih lekova

Early detection of sepsis and its severity is critical for initiating proper therapy, including antibiotics, as soon as possible to maximize survival chances. Understanding the pathophysiological changes in septic shock that impact antimicrobial pharmacokinetics and pharmacodynamics (PK/PD), understanding the basics of PK/PD, and knowing PK-PD strategies in septic shock patients are all critical for appropriate therapy. By definition multi-drug resistant (MDR) microorganisms are those with acquired non-susceptibility to at least one agent in three or more antimicrobial categories. In the race between bacteria and novel antibiotics development, unfortunately, the number of new antibiotics/indications is not keeping pace with resistance and needs, especially for MDR Gram-negative microorganisms. When we fast forward to the approved antibiotics in the last five years, the list is rather short. Lefamulin is a novel pleuromutilin antibiotic which manifests activity against most Gram-positive pathogens. Cefiderocol is an injectable siderophore cephalosporin. Like other b-lactam antibiotics, it inhibits Gram-negative bacterial cell wall formation by binding to penicillin-binding proteins. Imipenem/cilastatin/relebactam is a new b-lactam/b-lactamase inhibitor combination with activity against MDR Gram-negative bacteria, including many CRE but excluding Metallo-b-lactamase (MBL)-producing Enterobacterales and CRAB. Those three antibiotics were FDA approved in 2019 and European Medicines Agency (EMA) approved in 2020. Plazomicin is a new semisynthetic aminoglycoside with activity against several MDR Gram-negative organisms, including CRE (FDA-approved in 2018). Meropenem-vaborbactam is a fixed-dose combination product of a carbapenem and a cyclic boronic acid b-lactamase inhibitor with potent activity against resistant Gram-negative bacteria like Klebsiella pneumoniae carbapenemase (KPC)-producing CRE; it is inactive against CRAB (FDA-approved in 2017; EMA-approved in 2018). Eravacycline is a new completely synthesized fluorocycline. It has a high level of effectiveness against Grampositive and Gram-negative bacterial strains that have developed tetracycline-specific resistance mechanisms; it is inactive against Pseudomonas aeruginosa (FDAand EMA-approved in 2018). Concluding this list of recently approved antibiotics is omadacycline, novel aminomethylcycline and a derivative of minocycline, with a chemical structure similar to tigecycline. Like other tetracyclines, omadacycline inhibits bacterial protein synthesis and possesses broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic, anaerobic, and atypical bacteria including CRAB. It is inactive against Pseudomonas aeruginosa (FDA-approved in 2018). There are three novel carbapenems sulopenem, tebipenem pivoxil hydrobromide and benapenem. There is a group of antibiotics in phase III clinical trials: the combination aztreonam/ avibactam, sulbactam/durlobactam, cefepime/enmetazobactam, cefepime/zidebactam, cefepime/taniborbactam. An interesting approach to antimicrobial treatment is antimicrobial drug repurposing. Drug combinations could be a strategy to extend the life of antibiotics in the XXI century due to the multi-targeting mechanisms of agents. New active substances are urgently required to stop the spread of antibiotic-resistant bacteria. However, it could be a rather cumbersome and expensive procedure. Antimicrobial misuse and/or overuse contribute greatly to this very important global healthcare problem.

1692. Ceftibuten-Xeruborbactam: In vitro Potency against Enterobacterales in Comparison with Other Oral Beta-lactams (BL) and Beta-lactamase Inhibitor (BLI) Combinations

Abstract Background The broad spectrum BLI xeruborbactam (XER, formerly, QPX7728) can be delivered IV or orally as the isobutyryloxymethyl prodrug. The prodrug form is in clinical development in combination with ceftibuten (BUT) for oral treatment of resistant gram-negative infections. The objective of this study was to compare the in vitro potency of BUT-XER to that of other investigational oral BL/BLI combinations and tebipenem (TBP) in blinded head-to-head testing against extended beta-lactamase (ESBL) producing and carbapenem-resistant Enterobacterales (CRE). Methods A total of 980 Enterobacterales including 515 ESBL and 460 CRE, including 195 KPC-, 97 OXA-48-like- and 168 metallo beta-lactamase (MBL) producers, were susceptibility tested by reference broth microdilution against BUT-XER (at fixed 4 mg/L) and comparator BLs or BL/BLI combinations (tested at their recommended BLI concentrations). MIC testing was conducted blinded to drug identity using CLSI reference microdilution methods and controlled using approved quality control bacterial strains and ranges. Results BLI inhibitor combinations and TBP had excellent potency against ESBL isolates with MIC90 in the ≤ 0.03-0.06 mg/L range for BUT-avibactam (AVI) and BUT-XER and in 0.125-0.25 mg/L range for TBP, BUT-VNTX-6236 (VNRX) and cefpodoxime (CPD)-ETX1317 (ETX) (Table). Against KPC and OXA-48-producers, BUT-XER and BUT-AVI (MIC90 0.25-0.5 mg/L) were 4-fold more potent than BUT-VNRX and CPD-ETX (MIC90 of 1-2 mg/L); TBP was not active against these strains. BUT-XER and CPD-ETX were the most potent agents against MBL-producing strains; however, anti-MBL activity of CPD-ETX was due to intrinsic antibacterial activity of ETX. TPB, BUT-AVI and BUT-VNTX did not have any relevant activity against MBL-producing strains. Conclusion BUT-XER had the broadest antimicrobial profile, with activity against ESBL and all carbapenemase producing isolates. Its potency against ESBL-producing isolates was comparable to the carbapenem TBP. Its in vitro potency and spectrum combined with the potential of once-daily administration based on PK studies warrants further clinical development. Disclosures Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Jill Lindley, BS, AbbVie: Grant/Research Support.

1714. In Vitro Activity of Tebipenem Against Clinically Significant Gram-Positive Bacteria Isolated from Patients with Cancer

Abstract Background Carbapenems represent the most potent and broad-spectrum β-lactams and are minimally affected by most β-lactamase enzymes. however, all carbapenems currently in use including meropenem and ertapenem, are parenterally administered. Tebipenem pivoxil (TBPM-PI-HBr) is a new broad-spectrum orally-administered antibiotic, from the carbapenem subgroup of β-lactam antibiotics. It is the only oral carbapenem and could be an alternative to intravenous injection carbapenem antibiotic therapy. This study aimed to evaluate the in vitro activity of tebipenem, a novel oral carbapenem, against recent gram-positive clinical isolates from cancer patients. Methods We tested 300 gram-positive isolates are recently isolated (2019-2021) from our cancer patients, collected from blood cultures against tebipenem and comparators. Clinical and laboratory Standards Instituted (CLSI) approved broth microdilution method was used with appropriate ATCC controls. MIC50, MIC90, MIC ranges and percent of susceptibility calculations were made using FDA breakpoints when available. There is no tebipenem susceptibility breakpoint for gram-positive isolates currently. MIC90 and MICs range of tebipenem and comparators against 300 gram-positive isolates from cancer patients Results MIC90 and range of tebipenem and comparators are shown in table(1). Tebipenem gave the lowest MIC90 and MIC ranges against most gram-positive isolates including Bacillus species, Corynebacterium species, Enterococcus faecalis, Micrococcus species, MSSA S.aureus, Staphylococcus lugdunensis. β-hemolytic Streptococcus, Streptococcus pneumonie, Viridans group streptococci, and Rothia species. The comparative potency of tebipenem vs meropenem as a carbapenem in this study showed that, tebipenem MIC values were generally lower at least 2-4 fold. Conclusion Our data demonstrate that oral tebipenem has promising activity against clinically significant bacterial pathogens isolated from cancer patients and it has compatible activity to that of meropenem as a carbapenem in this study. Further clinical evolution for oral carbapenem treatment of bacterial infections is warranted. Disclosures All Authors: No reported disclosures.

222. Clinical and microbiological outcomes for Enterobacterales uropathogens in the Phase 3 ADAPT-PO Study of oral tebipenem pivoxil hydrobromide

Abstract Background Enterobacterales (ENT) are frequently implicated in complicated urinary tract infection, including acute pyelonephritis (cUTI/AP), with Escherichia coli (EC) being the most prevalent. Extended-spectrum β-lactamase (ESBL)-producing organisms are increasing and often coresistant to existing oral antibiotics such as the fluoroquinolones (FQ) and trimethoprim-sulfamethoxazole (TMP-SMX). Tebipenem pivoxil hyrdrobromide (TBP-PI-HBr) — a novel oral carbapenem under development — was shown to be non-inferior to IV ertapenem (ETP) in the treatment of cUTI/AP in the ADAPT-PO trial. The goal of this analysis was to assess clinical response (CR) and by-pathogen microbiological responses (MR) for ENT pathogens, including those with resistant phenotypes. Methods ADAPT-PO was a Phase 3 multinational, double-blind trial evaluating oral TBP-PI-HBr vs. IV ertapenem in 1372 hospitalized adult patients with cUTI/AP. Patients were randomized 1:1 to oral TBP-PI-HBr or IV ertapenem for 7-10 days. CR and MR at the test-of-cure (TOC) for patients with ENT including resistant phenotypes were assessed in the microbiological intent-to-treat population (micro-ITT). Results 90.2% of patients in the micro-ITT population were infected with ENT; EC was the most prevalent (64.2%), followed by Klebsiella pneumoniae (14.3%), Proteus mirabilis (6.7%) and Enterobacter cloacae (2.2%). ESBL-positive, FQ non-susceptible (NS) and TMP-SMX-R phenotypes were 23.5%, 38.4% and 41.8% of ENT, respectively. MIC90 vales for both TBP and ETP against ENT were 0.12 µg/mL. At TOC, the CR for TBP-PI-HBr and ETP and all ENT were 92.7% and 94.0%, respectively, and MR was 59.7% and 65.9%, respectively. CR at TOC for ESBL positive ENT was 87.6% and 95.3%, respectively and MR was 54.7% and 61.6%, respectively. Similar MR rates were observed among EC and resistant EC phenotypes. Conclusion At TOC CR rates for ENT pathogens were high and similar between treatment groups, including resistant subsets. MR rates for all pathogens were lower in both treatment groups, translating to to a phenomenon consistent with other cUTI trials representing asymptomatic bacteriuria. TBP-PI-HBr and ETP showed similar MR rates for EC, the most prevalent uropathogens, including resistant phenotypes. Disclosures Ian A. Critchley, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Ian A. Critchley, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Paul B. Eckburg, MD, AN2 Therapeutics: Stocks/Bonds|Spero Therapeutics: Advisor/Consultant Lori A. Muir, B.Sc., Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Lori A. Muir, B.Sc., Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Aaron Dane, MSc, Amplyx: Advisor/Consultant|AN2 therapeutics: Advisor/Consultant|Artizan: Advisor/Consultant|Cidara: Advisor/Consultant|ContraFect: Advisor/Consultant|Correvio: Advisor/Consultant|Davolterra: Advisor/Consultant|Destiny Pharma: Advisor/Consultant|Entasis: Advisor/Consultant|F2G Limited: Advisor/Consultant|GSK: Advisor/Consultant|Humanigen: Advisor/Consultant|Kymab: Advisor/Consultant|Modis: Advisor/Consultant|Orca: Advisor/Consultant|Pfizer: Advisor/Consultant|Phico: Advisor/Consultant|Pled Pharma: Advisor/Consultant|Rare Thyroid: Advisor/Consultant|Roche: Advisor/Consultant|Scynexis: Advisor/Consultant|Sinovent: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant|Transcrip: Advisor/Consultant|Venatorx: Advisor/Consultant Gary E. Moore, PhD, Spero Therapeutics: Advisor/Consultant David Melnick, MD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Angela K. Talley, MD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds.

Pharmacokinetics and soft-tissue distribution of tebipenem pivoxil hydrobromide using microdialysis: a study in healthy subjects and patients with diabetic foot infections.

Tebipenem pivoxil hydrobromide is a novel oral carbapenem prodrug of tebipenem, the active moiety. We assessed tebipenem steady-state pharmacokinetics in the skin and soft tissue in healthy subjects and infected patients with diabetes using in vivo microdialysis. Six healthy subjects and six patients with an ongoing diabetic foot infection (DFI) received tebipenem pivoxil hydrobromide 600 mg orally every 8 h for three doses. A microdialysis probe was inserted in the thigh of healthy subjects or by the wound margin in patients. Plasma and dialysate samples were obtained immediately prior to the third dose and sampled over 8 h. Tebipenem plasma protein binding (mean ± SD) was 50.2% ± 2.4% in healthy subjects and 53.5% ± 5.6% in infected patients. Mean ± SD tebipenem pharmacokinetic parameters in plasma for healthy subjects and infected patients were: maximum free concentration (fCmax), 3.74 ± 2.35 and 3.40 ± 2.86 mg/L, respectively; half-life, 0.88 ± 0.11 and 2.02 ± 1.32 h; fAUC0-8, 5.61 ± 1.64 and 10.01 ± 4.81 mg·h/L. Tebipenem tissue AUC0-8 was 5.99 ± 3.07 and 8.60 ± 2.88 mg·h/L for healthy subjects and patients, respectively. The interstitial concentration-time profile largely mirrored the free plasma profile within both populations, resulting in a penetration ratio of 107% in healthy subjects and 90% in infected patients. Tebipenem demonstrated excellent distribution into skin and soft tissue of healthy subjects and patients with DFI following oral administration of 600 mg of tebipenem pivoxil hydrobromide.

GSK licenses Spero antibiotic

GSK will pay $66 million up front to license a late-stage antibiotic from Spero Therapeutics. The drug, tebipenem pivoxil, is the “first oral carbapenem antibiotic to potentially treat complicated urinary tract infections,” the companies say. In June, the US Food and Drug Administration sent Spero a letter outlining deficiencies in its new drug application for tebipenem. The FDA later informed the firm that it could resubmit the application after completing an additional Phase 3 clinical trial. Spero said it would pursue the trial with a partner firm.

Enhancing antimicrobial activity of β-lactam antibiotic via functionalized mesoporous carbon-based delivery platforms

Bacterial immunity to antibiotics is currently increasing as a result of inadequate drug use and the generation of antimicrobial resistance. Developing new antibiotics is challenging, hence suitable carriers are sought to enhance activity of already known drugs. The ordered mesoporous carbons modified with urea, thiourea, and cetyltrimethylammonium bromide (CTAB), presented in this study, show great potential as carrier platforms for tebipenem pivoxil - a broad-spectrum orally-administered β-lactam antibiotic. The functional groups generated on the surface of carbon materials contributed to the reduction of their negative surface charge, which turned into positive under low pH conditions. At the same time, they led to a decrease in the hexagonal structure ordering of the carbon samples and a deterioration of the textural parameters. The effect of the amount of modifier used on the ability of carbon materials to release the selected antibiotic was investigated. The drug release process was carried out in two different environments (neutral and strongly acidic). It has been shown that the presence of functional groups on the surface of carbon carriers determines the amount of antibiotic liberated, especially at pH 7.0. The antimicrobial activity of the tebipenem pivoxil-loaded into the carbon carriers was assessed on a group of gram-positive and gram-negative bacteria. The highest decrease in the minimal inhibitory concentration value for the CTAB-modified systems was demonstrated, indicating a better antimicrobial efficiency against pathogenic strains coupled with an improvement in tebipenem pivoxil solubility. Small and negatively charged worm-like particles of the surfactant-functionalized carbon carrier are characterized by better dispersion in the receptor fluid resulting in faster and more effective diffusion of the antibiotic molecules from their outer surface. Ordered mesoporous carbons in addition to increased antibiotic dissolution rate, have no impact on drug permeability in the gastrointestinal tract in the in vitro model.

Evaluation of Tebipenem Hydrolysis by β-Lactamases Prevalent in Complicated Urinary Tract Infections.

Tebipenem pivoxil is the first orally available carbapenem antibiotic and has been approved in Japan for treating ear, nose, and throat and respiratory infections in pediatric patients. Its active moiety, tebipenem, has shown potent antimicrobial activity in vitro against clinical isolates of Enterobacterales species from patients with urinary tract infections (UTIs), including those producing extended-spectrum β-lactamases (ESBLs) and/or AmpC β-lactamase. In the present study, tebipenem was tested for stability to hydrolysis by a set of clinically relevant β-lactamases, including TEM-1, AmpC, CTX-M, OXA-48, KPC, and NDM-1 enzymes. In addition, hydrolysis rates of other carbapenems, including imipenem, meropenem, and ertapenem, were determined for comparison. It was found that, similar to other carbapenems, tebipenem was resistant to hydrolysis by TEM-1, CTX-M, and AmpC β-lactamases but was susceptible to hydrolysis by KPC, OXA-48, and NDM-1 enzymes with catalytic efficiency values (kcat/Km) ranging from 0.1 to 2 × 106 M-1s-1. This supports the reported results of antimicrobial activity of tebipenem against ESBL- and AmpC-producing but not carbapenemase-producing Enterobacterales isolates. Considering that CTX-M and AmpC β-lactamases represent the primary determinants of multidrug-resistant complicated UTIs (cUTIs), the stability of tebipenem to hydrolysis by these enzymes supports the utility of its prodrug tebipenem, tebipenem pivoxil hydrobromide (TBP-PI-HBr), as an oral therapy for adult cUTIs.

Tebipenem pivoxil hydrobromide. Penicillin-binding protein (PBP) (bacterial) inhibitor, Carbapenem antibiotic, Treatment of urinary tract infections

Tebipenem pivoxil hydrobromide. Penicillin-binding protein (PBP) (bacterial) inhibitor, Carbapenem antibiotic, Treatment of urinary tract infections

Bioequivalence of two oral formulations of tebipenem pivoxil hydrobromide in healthy subjects.

Tebipenem pivoxil hydrobromide (TBP‐PI‐HBr) is a novel oral carbapenem prodrug of tebipenem (TBP), the active moiety, currently in development for treating serious bacterial infections. This study assessed the bioequivalence (BE) of the clinical trial and registration tablet formulations of TBP‐PI‐HBr and evaluated the effect of food on the pharmacokinetics (PKs) of tebipenem. This was a single center, open‐label, randomized, single‐dose, three‐sequence, four‐period crossover, BE, and food‐effect study. Subjects received single 600 mg oral doses of TBP‐PI‐HBr as the reference clinical trial tablet (treatment A) and test registration tablet (treatment B) formulations in alternating sequence while fasting, and then the test formulation under fed conditions. Whole blood samples were collected predose and at specified intervals up to 24 h postdose to evaluate TBP PK parameters. Safety and tolerability were monitored. Thirty‐six healthy, adult subjects were enrolled and completed the study. The criteria for BE were met for the TBP‐PI‐HBr test (registration tablet) and reference (clinical trial tablet) formulations as the 90% confidence intervals for the geometric mean ratios for TBP area under the curve (AUC)0‐t , AUC0‐inf, and maximum plasma concentration (C max) fell within the established 80% to 125% BE limits. Dosing with food had no meaningful effect on TBP PK parameters. Five (14%) subjects reported adverse events (AEs) of mild severity. No deaths, serious AEs, or discontinuations due to AEs were reported, and no clinically relevant electrocardiograms, vital signs, or safety laboratory findings were observed. The study results demonstrate the BE of oral TBP‐PI‐HBr registration and clinical trial tablet formulations and indicate that TBP‐PI‐HBr can be administered without regard to meals.

Pharmacokinetics of Oral Tebipenem Pivoxil Hydrobromide in Subjects with Various Degrees of Renal Impairment.

ABSTRACTTebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug antimicrobial agent with broad-spectrum activity that includes multidrug-resistant (MDR) Enterobacterales. This study evaluated the safety, tolerability, and pharmacokinetics of TBP-PI-HBr in healthy subjects with normal renal function (cohort 1) and subjects with various degrees of renal impairment (RI [cohorts 2 to 4]) or end-stage renal disease (ESRD) receiving hemodialysis (HD) (cohort 5). Subjects in cohorts 1 to 4 received a single oral dose of TBP-PI-HBr (600 mg). Subjects in cohort 5 received single-dose administration (600 mg) in 2 separate periods: pre-HD (period 2) and post-HD (period 1). Pharmacokinetic (PK) parameters for TBP, the active moiety, were determined using noncompartmental analysis. Compared with cohort 1, the TBP plasma area under the curve (AUC) increased 1.4- to 4.5-fold among cohorts 2 to 4, the maximum concentration of drug in plasma (Cmax) increased up to 1.3-fold and renal clearance (CLR) decreased from 13.4 L/h to 2.4 L/h as the severity of RI increased. Plasma TBP concentrations decreased over 8 to 12 h in cohorts 1 to 4, and apparent total body clearance (CL/F) correlated (R2 = 0.585) with creatinine clearance (CLCR). TBP urinary excretion ranged from 38% to 64% of the administered dose for cohorts 1 to 4. Subjects in cohort 5 had an approximately 7-fold increase in TBP AUC and elimination half-life (t1/2) versus cohort 1. After 4 h of HD, mean TBP plasma exposure decreased by approximately 40%. Overall, TBP plasma exposure increased with increasing RI, highlighting the renal route importance in TBP elimination. A dose reduction of TBP-PI-HBr may be needed in patients with RI (CLCR of ≤50 mL/min) and those with ESRD on HD. TBP-PI-HBr was well tolerated across all cohorts. (This study has been registered at ClinicalTrials.gov under registration no. NCT04178577.).

Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection

BackgroundThere is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase–producing and fluoroquinolone-resistant strains.MethodsIn this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%.ResultsA total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, −3.3 percentage points; 95% confidence interval [CI], −9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, −0.6 percentage point; 95% CI, −4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache.ConclusionsOral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.)