Tebipenem

Tebipenem is an orally available carbapenem antibiotic, shows broad-spectrum activity against Gram-positive and -negative bacteria, except for Pseudomonas aeruginosa.

In Vitro:Tebipenem exhibits slow tight-binding inhibition at low micromolar concentrations versus the chromogenic substrate nitrocefin, and apparent Km and kcat values of 0.8 μM and 0.03 min-1, respectively[1]. Tebipenem shows potent activity against B. pseudomallei, with MIC50 and MIC90 values of both 2 mg/L[2]. Tebipenem shows good activity against S. pneumoniae, with the MIC range of ≤0.25 μg/mL in all of the S. pneumoniae isolates[3].

References:
[1]. Hazra S, et al. Tebipenem, a new carbapenem antibiotic, is a slow substrate that inhibits the β-lactamase from Mycobacterium tuberculosis. Biochemistry. 2014 Jun 10;53(22):3671-8. [2]. Seenama C, et al. In vitro activity of tebipenem against Burkholderia pseudomallei. Int J Antimicrob Agents. 2013 Oct;42(4):375. [3]. Li H, et al. In vitro antibacterial activities of two novel oral antibiotics, tebipenem and cefditoren, and other comparators against community-acquired respiratory tract infection-associated bacterial pathogens: A multicentre study in China. Int J Antimicrob Agents. 2014 Jan;43(1):92-3.

Antibacterial Properties of Tebipenem Pivoxil Tablet, a New Oral Carbapenem Preparation against a Variety of Pathogenic Bacteria in Vitro and in Vivo.[Pubmed:26751436]

Molecules. 2016 Jan 6;21(1):62.

AIMS: To systemically investigate the in vitro and in vivo antibacterial properties of Tebipenem pivoxil tablet. In addition, acute toxicity of this preparation was also studied. METHODS: In vitro, minimum inhibitory concentration (MIC) or minimal inhibitory concentration (MBC) were determined by using the serial 2-fold broth or agar dilution methods. Further, cumulative MIC inhibition curves were then made to assess the antibacterial effects of the drug at various concentrations. In vivo, minimum lethal dose (MLD) in combination with maximum tolerance dose (MTD) was used to measure the acute toxicity of the Tebipenem pivoxil tablet in mice. After that, sepsis mouse models challenged with Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, respectively, were established to evaluate the anti-infective effect of this preparation. RESULTS: The MIC90 values of Tebipenem pivoxil against Gram-positive bacteria such as methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive Staphylococcus epidermidis (MSSE), methicillin-resistant Staphylococcus epidermidis (MRSE), Pyogenic streptococcus, and Enterococcus faecalis were Tebipenem pivoxil against Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Haemophilus influenzae, Pseudomonas aeruginosa, and Acinetobacter baumannii were 1, 0.5, Tebipenem pivoxil against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae were 0.016-2, 0.063-32, 0.031-32 mug/mL, respectively. The acute toxicity study showed that the MLD of the Tebipenem pivoxil tablet was 4.00 g/kg and the MTD was 3.40 g/kg in mice. In all the sepsis mouse models, the simultaneous administration of the Tebipenem pivoxil tablets significantly reduced mortality of the sepsis-model mice as compared with the control. Furthermore, the survival rate in the Tebipenem pivoxil tablet group was remarkably higher than that in the meropenem group in all the sepsis mouse models tested. In the sepsis model challenged with Staphylococcus aureus ATCC29213, Escherichia coli ATCC25922, Pseudomonas aeruginosa ATCC27853, and Pseudomonas aeruginosa clinical strain, respectively, Tebipenem pivoxil tablet (100 mg/kg) displayed a better protective effect than Tebipenem pivoxil granules (100 mg/kg). CONCLUSIONS: In summary, Tebipenem pivoxil displays an excellent antibacterial activity against a variety of pathogenic bacteria in vitro. Importantly, Tebipenem pivoxil tablet significantly protects the sepsis mice challenged with various pathogenic bacteria, which may provide a potential approach to treating bacterial sepsis in clinic.

Pediatric community-acquired pneumonia treated with a three-day course of tebipenem pivoxil.[Pubmed:28238680]

J Infect Chemother. 2017 May;23(5):307-311.

We evaluated the efficacy and safety of a 3-day treatment regimen of Tebipenem pivoxil for pediatric community-acquired pneumonia. Tebipenem pivoxil was administered to 49 patients, and its effectiveness was evaluated in 36 patients 2-4 days after initiation of treatment. Thirty-two patients were cured 7-15 days after initiation of treatment. Body temperature was significantly lower on the day following initial administration (median 38.8 to 37.0 degrees C, n = 33). Leukocyte counts and C-reactive protein levels were significantly reduced by Day 2-4 of treatment (median 16,100 to 7800 white blood cells/muL, and 5.6 to 1.5 mg/dL, respectively; n = 28). Six of the 49 patients had mild diarrhea. Thus, we concluded that 3-day treatment with Tebipenem pivoxil was safe and efficacious for treating pediatric community-acquired pneumonia.

Solid-state stability studies of crystal form of tebipenem.[Pubmed:26043654]

Drug Dev Ind Pharm. 2016;42(2):238-44.

The aim of this study was to determine the kinetic and thermodynamic parameters of Tebipenem degradation in the solid state. The process was analyzed based on the results obtained by a high performance liquid chromatography (HPLC) method using ultraviolet diode-array detector (DAD)/electrospray ionization tandem mass spectrometry (Q-TOF-MS/MS), Fourier transform infrared spectroscopy (FT-IR) and Raman spectroscopic (RS) studies. In dry air, the degradation of Tebipenem was a first-order reaction depending on the substrate concentration while at an increased relative air humidity Tebipenem was degraded according to the kinetic model of autocatalysis. The thermodynamic parameters: energy of activation (Ea), enthalpy (DeltaH( not equala)) and entropy (DeltaS( not equala)) of Tebipenem degradation were calculated. Following a spectroscopic analysis of degraded samples of Tebipenem, a cleavage of the beta-lactam bond was proposed as the main degradation pathway, next confirmation using HPLC-Q-TOF-MS/MS method.

[Evaluation of safety and efficacy of tebipenem pivoxil granules for pediatric in pneumonia, otitis media and sinusitis].[Pubmed:27290830]

Jpn J Antibiot. 2016 Feb;69(1):53-76.

We conducted a postmarketing surveillance of Tebipenem pivoxil granules (Orapenem(R) fine granules 10% for pediatric), an oral carbapenem antibacterial agent, between April 2010 and March 2013 to evaluate the safety and efficacy in patients with pneumonia or otitis media, or sinusitis Of 3,547 patients enrolled, 3,540 from whom survey forms were collected were analyzed. Of these 3,540 patients, there were a total of 3,331 patients included in the safety analysis, 2,844 in the efficacy analysis, 2,769 in the clinical efficacy analysis, and 461 in the bacteriological efficacy analysis. The incidence of adverse drug reactions (ADRs) was 9.97% (332/3,331 patients), and the major ADRs were gastrointestinal disorders including diarrhoea in 317 patients (9.52%). Diarrhoea was reported in 313 patients (316 events), which were not clinically significant and 94.9% (297/313 patients) were recovery and/or remission. The overall clinical efficacy rate was 94.0% (2,604/2,769 patients). The clinical efficacy rate by the type of infection was 95.6% (415/434 patients) for pneumonia, 93.7% (1,389/1,482 patients) for otitis media and 93.6% (659/704 patients) for sinusitis. The eradication rate of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella (Branhamella) catarrhalis which are major causative organisms in pediatric infection of pneumonia, otitis media and sinusitis were 94.4% (134/142 strains), 92.2% (130/141 strains) and 97.8% (45/46 strains), respectively. The compliance was good in 83.1% of the patients (2,767/3,331 patients). Overall, Orapenem(R) fine granules 10% for pediatric showed good safety, efficacy, and compliance. These results indicate that Orapenem(R) fine granules 10% for pediatric is a useful agent in pediatrics with pneumonia or otitis media, or sinusitis.

Tebipenem is an orally available carbapenem antibiotic, shows broad-spectrum activity against Gram-positive and -negative bacteria, except for Pseudomonas aeruginosa.

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