title: Antibacterial Properties of Tebipenem Pivoxil Tablet, a New Oral Carbapenem Preparation against a Variety of Pathogenic Bacteria in Vitro and in Vivo.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacology, Yunnan Institute of Materia Medica, Kunming 650111, China. yaoqi313@126.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Department of GLP, Yunnan Institute of Materia Medica, Kunming 650111, China. jkun_wang@126.com.
authors.forename: Jingkun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Scientific Management, Yunnan Institute of Materia Medica, Kunming 650111, China. c_ttao@126.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Cui
authors.affiliation: Department of Chemical Pharmaceutics, Yunnan Institute of Materia Medica, Kunming 650111, China. zhi_yyang@126.com.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Yunnan Institute of Materia Medica, Kunming 650111, China. m_ssu@sina.com.
authors.forename: Mei
authors.initials: M
authors.lastname: Su
authors.affiliation: Department of Chemical Pharmaceutics, Yunnan Institute of Materia Medica, Kunming 650111, China. pyy_zhao@sohu.com.
authors.forename: Peiyue
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Yunnan Institute of Materia Medica, Kunming 650111, China. hong_yyan@163.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, Yunnan Institute of Materia Medica, Kunming 650111, China. yi_zhan91@tom.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Department of GLP, Yunnan Institute of Materia Medica, Kunming 650111, China. hb_yyang@sina.com.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D007710:Klebsiella Infections / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000254:growth & development; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D016019:Survival Analysis; D013607:Tablets
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D013607:Tablets; C500135:tebipenem
keywords: 100% MLD; MIC; bacterial sepsis; pathogenic bacteria; tebipenem pivoxil