Orapenem (tebipenem pivoxil) / Spero Therap, Meiji Seika, GSK - LARVOL DELTA

A Study to Characterize Single and Repeat Dose Pharmacokinetics of Tebipenem-Pivoxil-Hydrobromide (TBP-PI-HBr) and Its Major Metabolite (SPR1349) in Healthy Participants (clinicaltrials.gov) - P1 | N=39 | Completed | Sponsor: Spero Therapeutics | Recruiting ➔ Completed

Trial completion

Comparative evaluation of five β-Lactamase inhibitors in combination with β-Lactams against multidrug-resistant Mycobacterium tuberculosis in vitro. (PubMed, BMC Infect Dis) - "the combination of tebipenem and relebactam shows the most potent activity against MDR-TB isolates. In addition, the Ser111Arg and Asn213Thr substitution of BlaC may be associated with increased susceptibility of MDR-TB isolates to meropenem in thepresence of clavulanate and sulbactam."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Antimicrobial activity of tebipenem to Escherichia coli isolates from outpatients with complicated urinary tract infections. (PubMed, J Infect Chemother) - "These results were comparable to those of intravenous carbapenems such as imipenem and meropenem. TBPM may be a promising treatment option for cUTIs caused by ESBL-producing E. coli, offering an alternative to intravenous therapies and potentially reducing the need for hospitalization. However, careful use of TBPM in antimicrobial stewardship programs is crucial to prevent resistance and ensure its continued efficacy in outpatient settings."

Journal • Infectious Disease • Nephrology

Activity of novel ceftibuten-avibactam, ceftazidime-avibactam, and comparators against a challenge set of Enterobacterales from outpatient centers and nursing homes across the United States (2022-2024). (PubMed, Antimicrob Agents Chemother) - "Susceptibility rates were as follows: cefpodoxime (2.6%), ceftriaxone (1%), ceftazidime-avibactam (99.6%), tebipenem (89%), ertapenem (94.4%), levofloxacin (26.6%), trimethoprim-sulfamethoxazole (40.2%), and fosfomycin (96.8%). Ceftibuten-avibactam demonstrates potent in vitro activity against cephalosporin non-susceptible isolates."

Journal

Toward a Bactericidal Oral Drug Combination for the Treatment of Mycobacterium abscessus Lung Disease. (PubMed, ACS Infect Dis) - "Here, we combined oral representatives of three well-tolerated bactericidal drug classes, the β-lactam tebipenem (together with the β-lactamase inhibitor avibactam), the fluoroquinolone moxifloxacin, and the rifamycin rifabutin, and profiled the combination in vitro and in vivo. The triple-drug combination also exerted a pronounced postantibiotic effect and reduced emergence of spontaneous resistant mutants. Collectively, this work provides a combination prototype for optimization and a profiling workflow that may be useful for the development of sterilizing regimens."

Journal • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases

Repurposing drugs to advance the treatment of Buruli ulcer. (PubMed, Antimicrob Agents Chemother) - "Using a virulent reporter strain of M. ulcerans with intrinsic bioluminescence (MuAL), we compared the minimum inhibitory concentration (MIC) of moxifloxacin, bedaquiline, telacebec, tebipenem, omadacycline, and epetraborole with standard-of-care drugs-rifampin and clarithromycin. The MuAL strain is useful in the rapid screening of drugs' efficacy and potency against M. ulcerans. We should leverage the progress made in the tuberculosis drug development pipeline to repurpose the drugs for the rapid development of new therapeutic modalities for Buruli ulcer."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Spero Therapeutics Announces Fourth Quarter and Full Year 2024 Operating Results and Provides a Business Update (GlobeNewswire) - "Together with GSK, we are conducting a pre-specified interim analysis of the Phase 3 PIVOT-PO clinical trial of tebipenem HBr. This pre-specified interim analysis is expected in Q2 2025....SPR206: The Company announced discontinuation of the SPR206 program following a reprioritization of the pipeline in Q1 2025."

Discontinued • P3 data • Infectious Disease

Impact of tebipenem pivoxil on the intestinal microbiota and on establishment of colonization with carbapenem-resistant Klebsiella pneumoniae in mice. (PubMed, Microbiol Spectr) - "The effect of antibiotic treatment (daily for 3 days with subcutaneous saline [control], subcutaneous clindamycin, oral tebipenem pivoxil alone and in combination with CS319-piv-Sac, or oral CS319-piv-Sac) on the intestinal microbiota was assessed by culture for enterococci and facultative Gram-negative bacilli and by 16S rRNA amplicon sequencing. We found that while treatment with tebipenem pivoxil plus the prodrug of CS319 caused alteration of the intestinal microbiota, it did not promote the overgrowth of carbapenem-resistant K. pneumoniae. Although additional studies are needed to examine the impact of tebipenem pivoxil treatment on other multidrug-resistant Gram-negative bacilli, Clostridioides difficile, and Candida spp., our study is a step forward in the understanding of the potential effect of this oral carbapenem on the indigenous microbiota of the colon and on the promotion of colonization by pathogens."

Journal • Preclinical • Infectious Disease • Pneumonia

Beta-lactam combination treatment overcomes rifampicin resistance in Mycobacterium tuberculosis. (PubMed, Eur J Clin Microbiol Infect Dis) - "The combination of tebipenem-clavulanate/rifampicin and cephradine-clavulanate/rifampicin were found to be synergistic and highly effective against clinical isolates of MDR-TB, overcoming rifampicin resistance in vitro. Beta-lactam synergy may provide viable combination therapies with rifampicin to address the issue of drug resistance in TB."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Tebipenem pivoxil as an alternative to ceftriaxone for clinically non-responding children with shigellosis: a randomised non-inferiority trial protocol. (PubMed, BMJ Open) - P2 | "Oral azithromycin and intravenous ceftriaxone are the recommended first-line and second-line therapies for shigellosis in Bangladesh, respectively, but growing antibiotic resistance will require new antibiotic options. In addition, the use of tebipenem pivoxil in shigellosis was approved by the Directorate General of Drug Administration of Bangladesh. NCT05121974."

Clinical • Clinical protocol • Head-to-Head • Journal • Gastroenterology • Pain • Pediatrics

FL058, a novel β-lactamase inhibitor, increases the anti-Mycobacterium abscessus activity of imipenem. (PubMed, Int J Antimicrob Agents) - "The elevated anti-MABC activity exhibited by imipenem combined with FL058 suggests a potential new approach to treating MABC infections."

Journal • Infectious Disease

Durlobactam in combination with β-lactams to combat Mycobacterium abscessus. (PubMed, Antimicrob Agents Chemother) - "Imipenem demonstrated high binding affinity to LDTs and PBPs, with extremely low inhibition constants (Ki,app; ≤0.002 mg/L for LDT1-2, ≤0.6 mg/L for PBPs), while cephalosporins, sulopenem, tebipenem, and amoxicillin exhibited moderate to low binding affinity...Durlobactam alone showed ~2 log10 reduction, and when combined with imipenem or two β-lactams, durlobactam achieved near-eradication of Mab, surpassing the current therapy (amikacin + clarithromycin + imipenem/cefoxitin). Inactivation of PBP-lipo by sulopenem, imipenem, durlobactam, and amoxicillin (with avibactam) led to morphological changes, showing filaments. This study demonstrates the mechanistic basis of combinations therapy, particularly imipenem + durlobactam, in overcoming β-lactam resistance in Mab."

Journal

A Study to Characterize Single and Repeat Dose Pharmacokinetics of Tebipenem-Pivoxil-Hydrobromide (TBP-PI-HBr) and Its Major Metabolite (SPR1349) in Healthy Participants (clinicaltrials.gov) - P1 | N=46 | Recruiting | Sponsor: Spero Therapeutics

New P1 trial

SQ31f is a potent non-tuberculous mycobacteria antibiotic by specifically targeting the mycobacterial F-ATP synthase. (PubMed, J Antimicrob Chemother) - "SQ31f represents an attractive inhibitor to tackle the issues associated with NTM drug tolerance and toxicity. Its combinatory potency with anti-M. abscessus drugs holds potential for overcoming resistance, while also reducing intensive compound synthesis and associated costs."

Journal • Nontuberculous mycobacteria • Infectious Disease • Nontuberculous Mycobacterial Disease • Respiratory Diseases

Antioxidant and Pro-Oxidant Properties of Selected Clinically Applied Antibiotics: Therapeutic Insights. (PubMed, Pharmaceuticals (Basel)) - "These findings could be significant for both therapy, where the antibacterial effect is enhanced by radical scavenging activity, and biotechnology, where substantial pro-oxidant activity might limit microbial viability in cultures and consequently affect yield."

Journal

Synergistic oral beta-lactam combinations for treating tuberculosis. (PubMed, J Appl Microbiol) - "Beta-lactam synergy may provide viable combination therapies for the treatment of TB."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Novel agents in development for the treatment of resistant Gram-negative infections. (PubMed, Expert Rev Anti Infect Ther) - "While many of these novel agents demonstrate in vitro activity against carbapenem-resistant GNB, their efficacy has mainly been evaluated in phase-3 randomized controlled trials (RCT) for infections caused by carbapenem-susceptible GNB. Although evidence from real-world observational studies is generally less robust than that from RCT, it could be crucial for updating clinical guidelines on treating carbapenem-resistant GNB with these new agents in the absence of dedicated RCT."

Gram negative • Journal • Review • Infectious Disease

PK/PD Analysis and Dose Optimization of Tebipenem and Faropenem against ESBL-Producing Enterobacterales in Patients with UTI Considering Renal Function (IDWeek 2024) - No abstract available

Clinical • PK/PD data • Infectious Disease

Evaluation of Factors Predictive of Efficacy Among Patients With Complicated Urinary Tract Infection and/or Acute Pyelonephritis. (PubMed, Open Forum Infect Dis) - "Using data from 366 tebipenem pivoxil hydrobromide- and 378 ertapenem-treated patients from the Study to Assess the Efficacy, Safety and Pharmacokinetics of Orally Administered Tebipenem Pivoxil Hydrobromide (SPR994) Compared to Intravenous Ertapenem in Participants With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) infected with Enterobacterales uropathogens, multivariable analyses for dichotomous efficacy endpoints were performed using logistic regression and pharmacokinetic-pharmacodynamic relationships were evaluated. Reductions of overall and microbiologic response in patients with cUTI/AP were associated with anatomical or functional urinary tract disorders, but not with the magnitude or duration of plasma antibiotic exposure. Results of these analyses serve to advance our understanding of factors predictive of outcome in patients with cUTI/AP."

Clinical • Journal • Infectious Disease • Metabolic Disorders • Nephrology

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. (PubMed, Antimicrob Agents Chemother) - "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. 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."

Journal • VIM

In vitro effects of the new oral β-lactamase inhibitor xeruborbactam in combination with oral β-lactams against clinical Mycobacterium abscessus isolates. (PubMed, Microbiol Spectr) - "We aimed to evaluate the in vitro effects of xeruborbactam, a cyclic boronic acid β-lactamase inhibitor, against M. abscessus when combined with five β-lactams (amoxicillin, tebipenem, cefdinir, cefuroxime, and cefoxitin). Xeruborbactam lowered the MIC90 values of tebipenem by five dilutions, and the number of susceptible isolates increased from 1/43 (2%) to 43/43 (100%). We showed that the tebipenem-xeruborbactam combination might be of interest to explore further as a potentially effective oral regimen for outpatient treatment of M. abscessus pulmonary disease."

Combination therapy • Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

In Vitro Activity of Ceftibuten-Ledaborbactam and Comparators against Baseline Enterobacterales Pathogens from a Phase 3 Study of Adults with Complicated Urinary Tract Infection (CUTI) (ASM Microbe 2024) - P3 | "Each isolate was tested against ceftibuten ± ledaborbactam, amoxicillin-clavulanate, cefazolin, ertapenem, and tebipenem and additional comparator agents. https://doi.org/10.1128/aac.02385-20This study serves as a reference for ceftibuten-ledaborbactam in vitro activity against orally bioavailable comparators in a panel of contemporary cUTI isolates containing substantial proportions of MDR, ESBL, and AMC-R strains. Further development of ceftibuten-ledaborbactam for the treatment of infections due to resistant isolates of Enterobacterales is warranted."

P3 data • Preclinical • Infectious Disease • Nephrology

Exploring Structure-Activity Relationships (SAR) of Beta-Lactam Antibiotics with DacB1, a D,D-Darboxypeptidase from Mycobacterium Tuberculosis (MTB) (ASM Microbe 2024) - "Based upon studies with meropenem (MEM), the active site of DacB1 was shown to possess three penicillin-binding protein motifs: SXXK, SXN, and KTG (PDB 4PPR)...Timed electrospray ionization mass spectrometry (ESI-MS) was employed to capture acyl-enzyme adducts of purified DacB1 with BLs [amoxicillin (AMX), ceftriaxone (CRO), tebipenem (TBP), imipenem (IPM), and MEM) or BLIs (clavulanate (CLA), sulbactam (SUL)]... IPM preferentially binds to DacB1 compared to other carbapenems (MEM and TBP) and BLs, shedding light on crucial SAR for drug development. This study advances our understanding of the molecular mechanisms governing DacB1 interactions with BLs, offering insights on how carbapenems may inhibit important enzymatic targets in Mtb peptidoglycan synthesis."

Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A pairwise approach to revitalize β-lactams for the treatment of TB. (PubMed, Antimicrob Agents Chemother) - "Through a comprehensive screen of oral β-lactam pairs, we have discovered that cefuroxime strongly potentiates the bactericidal activity of tebipenem and sulopenem-advanced clinical candidates-and amoxicillin, at concentrations achieved clinically. β-lactam pairs thus have the potential to reduce TB treatment duration."

Journal • Infectious Disease • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Dual β-lactam therapy to improve treatment outcome in Mycobacterium abscessus disease. (PubMed, Clin Microbiol Infect) - "Future clinical strategies should entail either dual β-lactam or β-lactam/β-lactamase inhibitor combinations. Imipenem-ceftaroline and an all oral tebipenem-avibactam combination are promising leads but still require a complete preclinical portfolio, target product profiles as well as clinical trial confirmation."

Journal • Review • Infectious Disease