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[In vitro antibacterial activity of a new parenteral penem, sulopenem]
T Yoshida1, E Tateda, K Hiramatsu
1Department of Bacteriology, School of Medicine, Juntendo University, Tokyo, Japan.
Abstract:
Eighty percent minimum inhibitory concentrations (MIC80) of sulopenem against clinically isolated 12 to 80 strains of each of different bacteria were as follows: methicillin-susceptible Staphylococcus aureus (MSSA): 0.20 micrograms/ml, methicillin-resistant S. aureus (MRSA): 50 micrograms/ml, coagulase-negative staphylococci: 3.13 micrograms/ml, Streptococcus pyogenes: < or = 0.013 microgram/ml, Streptococcus pneumoniae: < or = 0.013 microgram/ml, beta-streptococci: 0.05 microgram/ml, Enterococcus faecalis: 12.5 micrograms/ml, Enterococcus faecium: > 100 micrograms/ml, Escherichia coli CS2(R+): 0.10 microgram/ml, Klebsiella pneumoniae: 0.05 microgram/ml, Proteus mirabilis: 0.10 microgram/ml, Proteus vulgaris: 0.20 microgram/ml, Morganella morganii: 0.39 micrograms/ml, Providencia rettgeri: 3.13 micrograms/ml, Citrobacter freundii: 0.20 microgram/ml, Enterobacter cloacae: 0.39 microgram/ml, Serratia marcescens: 1.56 micrograms/ml, Pseudomonas aeruginosa: 50 micrograms/ml, Pseudomonas cepacia: 3.13 micrograms/ml, Xanthomonas maltophilia: > 100 micrograms/ml, Acinetobacter calcoaceticus: 1.56 micrograms/ml, ampicillin-resistant Haemophilus influenzae: 0.39 microgram/ml and Bacteroides fragil is: 0.20 microgram/ml, respectively. Sulopenem possesses a stronger activity than flomoxef or cefuzonam against Gram-positive bacteria, the strongest activity among the antibiotics tested against Gram-negative bacteria except P. aeruginosa. Sulopenem has stronger affinities than imipenem to all fractions of PBPs of S. aureus, E. coli, P. vulgaris, S. marcescens, even of P. aeruginosa. Affinities of sulopenem to PBPs-1 and -3 of S. aureus, PBP-2 of E. coli were much stronger than those of imipenem (IPM). Sulopenem generally has small Ki values to all types of beta-lactamases and also has stronger permanent inactivation effect to Ia and IIb types of beta-lactamases than IPM. No synergistic bactericidal activity of sulopenem was apparent with serum complement. However, synergism of sulopenem with macrophages was prominent in bactericidal activity. The cells of E. coli were well phagocytosed and rapidly digested by cultured macrophages in the presence of a higher than 1/8 MIC of sulopenem. Moreover, sulopenem was more stable than imipenem against swine and human dehydropeptidase-Is. Sulopenem is one of the antibiotics that do not induce the appearance of subclones resistant to the drug.
Insights
Sulopenem demonstrates potent broad-spectrum antibacterial activity, outperforming other antibiotics against many Gram-positive and Gram-negative bacteria. It exhibits enhanced efficacy through synergistic activity with macrophages and stability against dehydropeptidase-I, without inducing resistance.
Area of Science:
- Microbiology
- Pharmacology
- Medicinal Chemistry
Context:
- Sulopenem is a novel antibiotic agent.
- Understanding its spectrum of activity and mechanism of action is crucial for clinical application.
- Comparison with existing antibiotics like imipenem is essential.
Purpose:
- To evaluate the in vitro antibacterial activity of sulopenem against a wide range of clinically isolated bacteria.
- To investigate sulopenem's mechanism of action, including its binding to penicillin-binding proteins (PBPs) and its effect on beta-lactamases.
- To assess sulopenem's synergistic activity with host immune components and its stability against enzymatic degradation.
Summary:
- Sulopenem exhibits potent minimum inhibitory concentrations (MIC80) against various Gram-positive and Gram-negative bacteria, including methicillin-susceptible Staphylococcus aureus (MSSA), Streptococcus pneumoniae, and Escherichia coli.
- It demonstrates stronger activity than flomoxef and cefuzonam against Gram-positive bacteria and is highly effective against most Gram-negative bacteria, except Pseudomonas aeruginosa.
- Sulopenem shows higher affinity to PBPs of S. aureus and E. coli compared to imipenem and possesses a strong inactivating effect on beta-lactamases.
- Synergistic bactericidal activity with macrophages was observed, enhancing phagocytosis and digestion of E. coli.
- Sulopenem is more stable than imipenem against dehydropeptidase-Is and does not induce resistant subclones.
Impact:
- Sulopenem represents a promising new antibiotic with broad-spectrum activity and a favorable resistance profile.
- Its unique mechanism of action and synergistic effects with macrophages suggest potential for treating challenging bacterial infections.
- Further clinical studies are warranted to establish its therapeutic efficacy in human patients.