Antibacterial activity of 65 2-acetylpyridine thiosemicarbazones and related compounds was determined by using clinical isolates of nine bacterial genera. Minimal inhibitory concentrations (MICs) of 0.002 to 0.062 ,ug/ml were obtained with 23% of the compounds for Neisseria gonorrhoeae and 0.016 to 0.062 ug/Iml with 17% of the compounds for N. meningitidis. Staphylococcus aureus was inhibited in the MIC range of 0.125 to 0.5 /Lg/ml by 18% of the thiosemicarbazones, whereas 26% inhibited group D enterococcus with an MIC of 0.25 to 2.0 Itg/ml.Poor antibacterial activity was shown toward the gram-negative bacilli, i.e., Pseudomonas, Klebsiella-Enterobacter, Shigella, Escherichia coli, and Proteus.
To study the treatment of infection with Pseudomonas aeruginosa, a leukopenic rat model was developed that closely mimics the pathogenesis of Pseudomonas infection in man. This model achieved approximately 90% mortality within 10 d of infection. Pseudomonas organisms were inconsistently shed from the feces despite gastrointestinal colonization (9 fecal v. 23 cecal cultures positive for challenge strain in 28 rats). Treatment of rats with oral ciprofloxacin at 40 mg/kg afforded complete protection. A suboptimal dose of ciprofloxacin (20 mg/kg), achieving peak levels of 0.31 micrograms/mL in serum and 26.3 micrograms/mL in stool, resulted in survival of 8 (40%) of 20 rats. Intraperitoneal administration of a monoclonal antibody directed at the lipopolysaccharide of the challenge strain of Pseudomonas resulted in survival of 5 rats (26%). The combination of the two increased the survival to 75% (15 of 20, P less than 0.05 compared to either treatment alone). Thus, the combination of suboptimal doses of ciprofloxacin and a monoclonal antibody appears to protect leukopenic rats from lethal infection better than either treatment alone.
We have investigated the in vitro antibacterial activity of 13 2-acetylpyridine-1-oxide thiosemicarbazones and 5 thiosemicarbazides against 80 clinically significant bacterial cultures, including 13 isolates with known antibiotic resistance. Of the thiosemicarbazones tested, 5 had minimal inhibitory concentrations (MICs) of 0.25 μg/ml for Neisseria gonorrhoeae isolates; 1 of these had an MIC range of 0.25–0.5 μg/ml for the Neisseria meningitidis cultures, and 2 had MICs of 2 and 2–4 μg/ml for Staphylococcus aureus and Streptococcus faecalis isolates, respectively. Two of the thiosemicarbazides had MICs of 0.25 μg/ml for N. gonorrhoeae, whereas 2 others had MICs of 2–4 and 4–8 μg/ml for S. aureus and S. faecalis isolates, respectively. The test compounds were ineffective against the gram-negative enteric cultures and the Pseudomonas isolates.
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