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Low frequency of bacterial resistance to enoxacin in vitro and in experimental pneumonia
Abstract:
The tendency for bacteria to develop resistance to enoxacin (Cl-919, AT-2266), a new oxyquinolone derivative, was investigated in vitro and in vivo. The mutation frequencies of Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Salmonella sp., and Haemophilus influenzae to enoxacin, norfloxacin, nalidixic acid, tobramycin, cephalexin, cefotaxime, ampicillin, azlocillin, oxacillin, and ticarcillin were determined by plating large numbers of organisms onto antibiotic-containing agar. Enoxacin resistance developed infrequently. For example, the mutation frequency of Ps. aeruginosa in the presence of enoxacin was 1 in 2.8 X 10(9) cells as compared to 1 in 1.1 X 10(6) for nalidixic acid. The increase in MIC after serial transfer through increasing concentrations of enoxacin ranged from 8-fold for Ps. aeruginosa and Staph. aureus to 256-fold for H. influenzae. Rats with chronic Ps. aeruginosa pneumonia were given subtherapeutic doses of enoxacin daily for ten weeks. Two rats were sacrificed weekly and the homogenized lungs were cultured on agar containing 5 mg/l of enoxacin and on antibiotic-free agar. No organisms resistant to 5 mg/l of enoxacin were recovered. No increase in the minimum inhibitory concentration of enoxacin for the infecting organism was seen.
Insights
Enoxacin, a new oxyquinolone, showed infrequent resistance development in bacteria like Pseudomonas aeruginosa. In vivo studies in rats also confirmed low resistance emergence during prolonged enoxacin exposure.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Antibiotic resistance is a growing global health concern.
- Oxyquinolone derivatives represent a class of antibiotics with potential therapeutic applications.
- Understanding the resistance potential of new antibiotics is crucial for their clinical utility.
Purpose of the Study:
- To investigate the in vitro and in vivo development of bacterial resistance to enoxacin, a novel oxyquinolone.
- To compare the mutation frequencies of various bacterial species against enoxacin and other reference antibiotics.
- To evaluate the emergence of enoxacin resistance in a chronic bacterial pneumonia model in rats.
Main Methods:
- Determined mutation frequencies of Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Salmonella sp., and Haemophilus influenzae to enoxacin and other antibiotics using agar plating.
- Assessed the increase in Minimum Inhibitory Concentration (MIC) after serial passage of bacteria through increasing enoxacin concentrations.
- Administered subtherapeutic doses of enoxacin to rats with chronic Pseudomonas aeruginosa pneumonia for ten weeks and monitored for resistant isolates.
Main Results:
- Enoxacin resistance developed infrequently across tested bacterial species, with significantly lower mutation frequencies compared to nalidixic acid.
- The increase in MIC after serial passage was variable, ranging from 8-fold for Pseudomonas aeruginosa and Staphylococcus aureus to 256-fold for Haemophilus influenzae.
- No enoxacin-resistant organisms were recovered from the lungs of rats treated with subtherapeutic enoxacin doses for ten weeks, and no increase in MIC was observed.
Conclusions:
- Enoxacin demonstrates a low propensity for inducing bacterial resistance in vitro.
- In vivo studies support the low resistance development potential of enoxacin under prolonged subtherapeutic exposure.
- These findings suggest that enoxacin may possess a favorable resistance profile for clinical development.