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

Hongbo Yang,Hong Yan,Qi Yao,Peiyue Zhao,Yi Zhan,Zhi Yang,Tao Cui,Mei Su,Jingkun Wang

doi:10.3390/molecules21010062

Abstract

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 ≤0.125, 16, 0.5, 8, ≤0.125, and 32 μg/mL, respectively. Correspondingly, the MIC90 values of tebipenem pivoxil against Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Haemophilus influenzae, Pseudomonas aeruginosa, and Acinetobacter baumannii were 1, 0.5, ≤0.125, 0.25, 64, 64 μg/mL, respectively. The MBC values of tebipenem pivoxil against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae were 0.016–2, 0.063–32, 0.031–32 μg/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.

Highlights

Tebipenem pivoxil, belonging to the carbapenem class, was firstly developed by Pfizer Inc.(New York, NY, USA) and its granule preparation, a product of Meiji Inc., (Tokyo, Japan), was approved and listed in April 2009
The results showed that the minimal inhibitory concentration (MBC) values of tebipenem pivoxil against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae were 0.016–2, 0.063–32, 0.031–32 μg/mL respectively
These findings suggested that tebipenem pivoxil tablet had an excellent antibacterial activity against various common pathogenic bacteria, and that tebipenem pivoxil tablet had a stronger anti-infective effect against Escherichia coli than other pathogenic bacteria

Summary

Introduction

Tebipenem pivoxil, belonging to the carbapenem class, was firstly developed by Pfizer Inc.(New York, NY, USA) and its granule preparation, a product of Meiji Inc., (Tokyo, Japan), was approved and listed in April 2009. A nitrogen heterocyclic group at the C3 side chain in the chemical structure forms a prodrug by interacting with C2 carboxylic acids, significantly elevating oral absorption, which plays a key role in a better antibacterial activity of tebipenem pivoxil compared with most other β-lactam antibiotics. Tebipenem pivoxil has a broad antibacterial spectrum [1,2]. It has a stronger antibacterial activity than penicillin or cephalosporin series compounds against majority of Gram-positive and -negative bacteria such as methicillin-resistant Saphylococcus aureus (MRSA), methicillin-resistant. Compared with other carbapenem antibiotics, tebipenem pivoxil shows more efficient antibacterial activity, especially for infections in children mainly due to penicillin-resistant Streptococcus pneumoniae (PRSP), Erythromycin-resistant Streptococcus pneumoniae (MRSP) and Haemophilus influenzae (Hib)

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