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SK&F 75073, new parenteral broad-spectrum cephalosporin with high and prolonged serum levels
Abstract:
SK&F 75073, a new parenteral cephalosporin, was found to have broad in vitro and in vivo antibacterial activity including isolates usually resistant to cephalothin and cefazolin. This activity included indole-positive Proteus and Enterobacter species and some Serratia isolates. Proteus mirabilis strains were particularly susceptible, as were Haemophilus influenzae and Neisseria species. The activity of SK&F 75073 against gram-positive bacteria was poorer than that of the control cephalosporins. This cephalosporin is highly bound to serum proteins, and a loss in in vitro activity was observed in the presence of serum. Parenteral administration of SK&F 75073 to experimental animals (mice, dogs, squirrel monkeys) resulted in high and prolonged serum levels when compared with cefazolin and other injectable cephalosporins. This favorable serum profile was reflected in the excellent protection observed in mice infected with pathogenic bacteria.
Insights
SK&F 75073, a novel parenteral cephalosporin, demonstrates broad-spectrum antibacterial activity against resistant Gram-negative bacteria. Despite reduced Gram-positive efficacy and serum protein binding, it achieves high, prolonged serum levels in animals, offering excellent protection against infections.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Cephalosporins are a vital class of antibiotics used to treat bacterial infections.
- Existing cephalosporins face challenges with resistance in certain bacterial strains, necessitating the development of new agents.
- Understanding the spectrum of activity and pharmacokinetic properties of novel cephalosporins is crucial for clinical application.
Purpose of the Study:
- To evaluate the in vitro and in vivo antibacterial activity of SK&F 75073, a new parenteral cephalosporin.
- To compare the efficacy of SK&F 75073 against resistant bacterial isolates with established cephalosporins like cephalothin and cefazolin.
- To assess the pharmacokinetic profile and therapeutic efficacy of SK&F 75073 in animal models.
Main Methods:
- In vitro susceptibility testing against a panel of bacterial isolates, including resistant strains.
- In vivo efficacy studies in mouse infection models.
- Pharmacokinetic studies involving parenteral administration in mice, dogs, and squirrel monkeys to determine serum levels.
Main Results:
- SK&F 75073 exhibited broad antibacterial activity against Gram-negative bacteria, including indole-positive Proteus, Enterobacter, and some Serratia species, as well as Haemophilus influenzae and Neisseria species.
- Activity against Gram-positive bacteria was less potent compared to control cephalosporins.
- The compound showed high serum protein binding, leading to reduced in vitro activity in the presence of serum.
- Parenteral administration resulted in high and prolonged serum concentrations in animal models, superior to cefazolin.
- Excellent protection was observed in infected mice, correlating with favorable serum profiles.
Conclusions:
- SK&F 75073 is a promising parenteral cephalosporin with significant activity against resistant Gram-negative pathogens.
- Its favorable pharmacokinetic profile, characterized by high and sustained serum levels, contributes to its in vivo efficacy.
- Further investigation is warranted to explore its therapeutic potential, considering its limitations against Gram-positive bacteria and serum protein binding.