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In vitro activity of AT-4140 against quinolone- and methicillin-resistant Staphylococcus aureus
T Kojima1, M Inoue, S Mitsuhashi
1Episome Institute, Gunma, Japan.
Abstract:
Eighty-nine clinical isolates of Staphylococcus aureus that were resistant to both ciprofloxacin (MIC, greater than or equal to 3.13 micrograms/ml) and methicillin (MIC, greater than or equal to 12.5 micrograms/ml) were divided into two groups with respect to their susceptibilities to AT-4140. Most isolates that were moderately resistant to ciprofloxacin (MICs, 3.13 to 12.5 micrograms/ml) or ofloxacin (MICs, 0.78 to 6.25 micrograms/ml) were susceptible to AT-4140 (MICs, 0.05 to 0.2 microgram/ml). Most isolates that were highly resistant to ciprofloxacin (MIC, greater than or equal to 25 micrograms/ml) or ofloxacin (MIC, greater than or equal to 12.5 micrograms/ml) were resistant to AT-4140 (MICs, 3.13 to 25 micrograms/ml). The appearance of spontaneous single-step, quinolone-resistant mutants of S. aureus P-20, a methicillin-resistant isolate, was more frequent than was that of S. aureus 209P JC-1, a susceptible laboratory strain. Spontaneous single-step, quinolone-resistant mutants of P-20 were not selected by AT-4140, and those selected by existing fluoroquinolones were susceptible to AT-4140. Spontaneous double-step, quinolone-resistant mutants of P-20 were selected by various fluoroquinolones. All second-step mutants selected by AT-4140 or ofloxacin from P-20-C, a spontaneous single-step mutant of P-20 selected by ciprofloxacin, were resistant to all the quinolones. All second-step mutants selected by nonfloxacin were resistant to all existing fluoroquinolones but were less resistant to AT-4140. There was a close resemblance between the resistance profiles of spontaneous quinolone-resistant mutants and those of clinically isolated quinolone- and methicillin-resistant S. aureus.
Insights
This study investigated AT-4140
Area of Science:
- Microbiology and Infectious Diseases
- Pharmacology and Drug Discovery
- Clinical Medicine
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant public health threat due to its resistance to multiple antibiotics.
- Fluoroquinolone resistance in Staphylococcus aureus is a growing concern, complicating treatment options.
- The emergence of multidrug-resistant bacteria necessitates the development of novel antimicrobial agents.
Purpose of the Study:
- To evaluate the in vitro activity of a novel antimicrobial agent, AT-4140, against clinical isolates of Staphylococcus aureus resistant to ciprofloxacin and methicillin.
- To investigate the potential of AT-4140 in selecting for or against the development of quinolone resistance in Staphylococcus aureus.
- To compare the resistance profiles of spontaneous quinolone-resistant mutants with those of clinically isolated resistant strains.
Main Methods:
- Susceptibility testing of 89 clinical Staphylococcus aureus isolates against ciprofloxacin, methicillin, and AT-4140 using minimum inhibitory concentration (MIC) determination.
- Induction of spontaneous single-step and double-step quinolone-resistant mutants from methicillin-resistant Staphylococcus aureus (MRSA) strain P-20 and susceptible strain S. aureus 209P JC-1.
- Evaluation of AT-4140 activity against these induced mutants and comparison with existing fluoroquinolones.
Main Results:
- Most Staphylococcus aureus isolates moderately resistant to ciprofloxacin or ofloxacin were susceptible to AT-4140 (MICs, 0.05 to 0.2 µg/ml).
- Highly resistant isolates showed resistance to AT-4140 (MICs, 3.13 to 25 µg/ml).
- AT-4140 did not select for spontaneous single-step quinolone-resistant mutants, and mutants selected by other fluoroquinolones remained susceptible to AT-4140. However, double-step mutants exhibited cross-resistance to various quinolones, with some retaining reduced susceptibility to AT-4140.
Conclusions:
- AT-4140 demonstrates promising in vitro activity against a significant proportion of ciprofloxacin- and methicillin-resistant Staphylococcus aureus clinical isolates.
- The distinct resistance profile of AT-4140 suggests a potentially lower propensity for rapid resistance development compared to existing fluoroquinolones.
- Further investigation into AT-4140's mechanism of action and clinical efficacy is warranted for treating infections caused by multidrug-resistant Staphylococcus aureus.