2.1. Tebipenem Pivoxil Displays Excellent Antibacterial Activity against a Variety of Pathogenic Bacteria in Vitro
The MIC
90 values of tebipenem pivoxil against MSSA, MRSA, MSSE, MRSE were ≤0.125, 16, 0.5, 8 μg/mL, lower than meropenem (0.25, 32, 1, 16 μg/mL), imipenem and cilastatin (2, 128, 1, 64 μg/mL), and ceftriaxone (4, >128, 16, >128 μg/mL). The antibacterial activity of tebipenem pivoxil against
Pyogenic streptococcus was similar to that of meropenem (both MIC
90 ≤ 0.125 μg/mL) and stronger than those of imipenem and cilastatin (MIC
90 = 0.25 μg/mL) and ceftriaxone (MIC
90 = 8 μg/mL). The MIC
90 values of tebipenem pivoxil against
Enterococcus faecalis and
Enterococcus faecium were 32 and 128 μg/mL, respectively, lower than meropenem (>128 and >128 μg/mL), imipenem and cilastatin (>128 and >128 μg/mL), and ceftriaxone (>128 and >128 μg/mL) (
Table 1 and
Figure 1).
Figure 1.
Cumulative inhibition curves of tebipenem pivoxil and other antibiotics against gram-positive bacteria tested. ◆, Tebipenem Pivoxil; ■, Meropenem; ▲, Imipenem and cilastatin; ×, Ceftriaxone.
Figure 1.
Cumulative inhibition curves of tebipenem pivoxil and other antibiotics against gram-positive bacteria tested. ◆, Tebipenem Pivoxil; ■, Meropenem; ▲, Imipenem and cilastatin; ×, Ceftriaxone.
Table 1.
MICs of tebipenem pivoxil and other antibiotics against tested Gram-positive bacteria.
Table 1.
MICs of tebipenem pivoxil and other antibiotics against tested Gram-positive bacteria.
Strain | MIC50/MIC90 (μg/mL) |
---|
Tebipenem Pivoxil | Meropenem | Imipenem and Cilastatin | Ceftriaxone |
---|
MSSA | ≤0.125/0.125 | ≤0.125/0.25 | ≤0.125/2 | 2/4 |
MRSA | 8/16 | 16/32 | 32/128 | >128/>128 |
MSSE | ≤0.125/0.5 | ≤0.125/1 | ≤0.125/1 | 1/16 |
MRSE | 8/8 | 16/16 | 16/64 | 64/>128 |
Enterococcus faecalis | 0.25/32 | 2/>128 | 4/>128 | 32/>128 |
Enterococcus faecium | 64/128 | >128/>128 | >128/>128 | >128/>128 |
Pyogenic streptococcus | ≤0.125/≤0.125 | ≤0.125/≤0.125 | ≤0.125/0.25 | 4/8 |
Among all the Gram-negative bacteria tested, tebipenem pivoxil had a significant antibacterial activity against
Escherichia coli, with a MIC
90 value of 1 μg/mL, which was as same as meropenem, imipenem and cilastatin (MIC
90 = 1 μg/mL), and significantly higher than ceftriaxone (MIC
90 > 128 μg/mL). The antibacterial activity of tebipenem pivoxil against
Klebsiella pneumoniae,
Enterobacter aerogenes,
Haemophilus influenzae (MIC
90 = 0.5, ≤0.125, 0.25 μg/mL) was better than that of meropenem (MIC
90 = 1, 0.25, 0.5 μg/mL), imipenem and cilastatin (MIC
90 = 4, 2, 1 μg/mL), and ceftriaxone (MIC
90 = >128, 32, 16 μg/mL). For
Enterobacter cloacae,
Proteus mirabilis,
Citrobacter freundii and
Serratia marcescens, the MIC
90 values of tebipenem pivoxil were 1, ≤0.125, 0.25, 16 μg/mL, respectively, lower than meropenem (2, 0.5, 0.5, 32 μg/mL), imipenem and cilastatin (2, 0.5, 0.5, 64 μg/mL), and ceftriaxone (>128, 64, >128, >128 μg/mL). The MIC
90 values of tebipenem pivoxil against
Stenotrophomonas maltophilia and
Acinetobacter baumannii were 64 μg/mL, higher than meropenem (32, 32 μg/mL), and lower than imipenem and cilastatin (128, 128 μg/mL), and ceftriaxone (>128, >128 μg/mL), respectively. The MIC
90 of tebipenem pivoxil against
Pseudomonas aeruginosa was 64 μg/mL, higher than meropenem (32 μg/mL), lower than imipenem and cilastatin (128 μg/mL), and ceftriaxone (>128 μg/mL). The antibacterial activity of tebipenem pivoxil against
Haemophilus influenzae and
Proteus mirabilis (MIC
90 = 0.25, ≤0.125 μg/mL) was stronger than that of meropenem (MIC
90 = 0.5, 0.5 μg/mL), imipenem and cilastatin (MIC
90 = 1, 0.5 μg/mL), and ceftriaxone (MIC
90 = 16, 64 μg/mL) (
Table 2 and
Figure 2).
Figure 2.
Cumulative inhibition curves of tebipenem pivoxil and other antibiotics against gram-negative bacteria tested. ◆, Tebipenem Pivoxil; ■, Meropenem; ▲, Imipenem and cilastatin; ×, Ceftriaxone.
Figure 2.
Cumulative inhibition curves of tebipenem pivoxil and other antibiotics against gram-negative bacteria tested. ◆, Tebipenem Pivoxil; ■, Meropenem; ▲, Imipenem and cilastatin; ×, Ceftriaxone.
Table 2.
MICs of tebipenem pivoxil and other antibiotics against the tested Gram-negative bacteria.
Table 2.
MICs of tebipenem pivoxil and other antibiotics against the tested Gram-negative bacteria.
Strain | MIC50/MIC90 (μg/mL) |
---|
Tebipenem Pivoxil | Meropenem | Imipenem and Cilastatin | Ceftriaxone |
---|
Escherichia coli | ≤0.125/1 | ≤0.125/1 | 0. 25/1 | 64/>128 |
Klebsiella pneumoniae | ≤0.125/0.5 | ≤0.125/1 | 0.5/4 | 2/>128 |
Enterobacter cloacae | ≤0.125/1 | ≤0.125/2 | 0.25/2 | 128/>128 |
Enterobacter aerogenes | ≤0.125/≤0.125 | ≤0.125/0.25 | 0.5/2 | 0.5/32 |
Citrobacter freundii | ≤0.125/0.25 | ≤0.125/0.25 | ≤0.125/0.5 | 64/>128 |
Acinetobacter baumannii | 16/64 | 32/64 | 64/128 | 128/>128 |
Stenotrophomonas maltophilia | 32/64 | 32/128 | >128/>128 | >128/>128 |
Pseudomonas aeruginosa | 8/64 | 2/32 | 16/128 | 128/>128 |
Serratia marcescens | ≤0.125/16 | ≤0.125/32 | 2/64 | 8/>128 |
Haemophilus influenzae | ≤0.125/0.25 | ≤0.125/0.5 | ≤0.125/1 | 2/16 |
Proteus mirabilis | ≤0.125/≤0.125 | ≤0.125/0.5 | ≤0.125/0.5 | 16/64 |
The MBC values of tebipenem pivoxil were determined in 10
Escherichia coli, 10
Staphylococcus epidermidis, and 10
Klebsiella pneumoniae. The results showed that 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 MBC values were 1–8 times, 2–8 times, 2–8 times the MIC value against
Escherichia coli,
Staphylococcus aureus,
Klebsiella pneumoniae, respectively, suggesting a strong bactericidal activity of tebipenem pivoxil against
Escherichia coli,
Staphylococcus aureus,
Klebsiella pneumoniae (
Table 3).
Table 3.
MBC/MIC values of tebipenem pivoxil in Escherichia coli, Staphylococcus aureus, and Klebsiella pneumonia.
Table 3.
MBC/MIC values of tebipenem pivoxil in Escherichia coli, Staphylococcus aureus, and Klebsiella pneumonia.
Strain | MBC/MIC (μg/mL) |
---|
Escherichia coli |
ATCC25922 | 0.031/0.016 |
Clinical strain 03 | 0.125/0.016 |
Clinical strain 10 | 1/0.25 |
Clinical strain 14 | 2/1 |
Clinical strain 17 | 0.25/0.031 |
Clinical strain 49 | 0.125/0.125 |
Clinical strain 63 | 1/0.5 |
Clinical strain 75 | 0.25/0.063 |
Clinical strain 79 | 0.016/0.016 |
Clinical strain 80 | 0.031/0.031 |
Staphylococcus aureus |
ATCC25923 | 0.125/0.031 |
Clinical strain 02 | 0.063/0.016 |
Clinical strain 14 | 2/0.25 |
Clinical strain 19 | 0.125/0.063 |
Clinical strain 21 | 32/4 |
Clinical strain 24 | 4/2 |
Clinical strain 27 | 2/1 |
Clinical strain 31 | 8/4 |
Clinical strain 33 | 4/1 |
Clinical strain 34 | 4/2 |
Klebsiella pneumoniae |
ATCC10031 | 1/0.5 |
Clinical strain 07 | 0.063/0.031 |
Clinical strain 18 | 1/0.25 |
Clinical strain 20 | 32/8 |
Clinical strain 28 | 0.125/0.016 |
Clinical strain 39 | 0.031/0.016 |
Clinical strain47 | 0.5/0.063 |
Clinical strain 64 | 1/0.125 |
Clinical strain 70 | 2/0.5 |
Clinical strain 73 | 0.063/0.016 |
2.3. Tebipenem Pivoxil Tablet Protects Sepsis Mice from Lethal Challenges with Pathogenic Bacteria
In all the sepsis models, the animals in the vehicle group were dead within 72 h, suggesting successful establishment of the sepsis models. In all the sepsis models, compared with the vehicle, tebipenem pivoxil tablet (50, 100 mg/kg) significantly increased the survival number of the sepsis mice within a 168-h observation period (
Figure 3). Further, the survival number in the tebipenem pivoxil tablet group (100 mg/kg) was markedly higher than that in the meropenem group in all the sepsis models tested. In the sepsis models challenged with
Staphylococcus aureus ATCC29213,
Escherichia coli ATCC25922,
Pseudomonas aeruginosa ATCC27853,
Pseudomonas aeruginosa clinical strain, respectively, tebipenem pivoxil tablet (100 mg/kg) displayed a better protective effect than tebipenem pivoxil granules (100 mg/kg) (
Figure 3).
Figure 3.
The survival cures for sepsis mice challenged with pathogenic bacteria. After the bacteria injections, the mice received different treatments once. The death of the animals was recorded every day. On the 7th day, the survival curves were made to assess the anti-infection effects of the drugs: Symbols: ×, Vehicle; △, Meropenem 50 mg/kg; ○, Tebipenem pivoxil granules 100 mg/kg; ▲, Tebipenem pivoxil tablet 100 mg/kg; +, Tebipenem pivoxil tablet 50 mg/kg. * p < 0.01 vs. Vehicle, # p < 0.05, ## p < 0.01 vs. Meropenem, † p < 0.05 vs. Tebipenem pivoxil granules (Kaplan-Meier).
Figure 3.
The survival cures for sepsis mice challenged with pathogenic bacteria. After the bacteria injections, the mice received different treatments once. The death of the animals was recorded every day. On the 7th day, the survival curves were made to assess the anti-infection effects of the drugs: Symbols: ×, Vehicle; △, Meropenem 50 mg/kg; ○, Tebipenem pivoxil granules 100 mg/kg; ▲, Tebipenem pivoxil tablet 100 mg/kg; +, Tebipenem pivoxil tablet 50 mg/kg. * p < 0.01 vs. Vehicle, # p < 0.05, ## p < 0.01 vs. Meropenem, † p < 0.05 vs. Tebipenem pivoxil granules (Kaplan-Meier).