Journal article
Mechanisms and Frequency of Resistance to Gatifloxacin in Comparison to AM-1121 and Ciprofloxacin in Staphylococcus aureus
Antimicrobial agents and chemotherapy, Vol.45(10), pp.2755-2764
10/2001
DOI: 10.1128/AAC.45.10.2755-2764.2001
PMCID: PMC90727
PMID: 11557465
Abstract
Gatifloxacin, an 8-methoxyfluoroquinolone, was found to be two- to fourfold more active against wild-type
Staphylococcus aureus
ISP794 than its desmethoxy derivative, AM-1121, and ciprofloxacin, another desmethoxy fluoroquinolone. Single
grlBA
mutations caused two- to fourfold increases in the MIC of gatifloxacin, and a single gyrase mutation was silent. Double mutations in
gyrA
and
grlA
or
grlB
caused a 32-fold increase in the MIC of gatifloxacin, in contrast to a 128-fold increase for ciprofloxacin and AM-1121. Overexpression of the NorA efflux pump had minimal effect on the MIC of gatifloxacin. The bactericidal activity of the three quinolones at four times the MIC differed only for a double mutant, with gatifloxacin exhibiting a killing pattern similar to that for ISP794, whereas ciprofloxacin and AM-1121 failed to show any killing. With gatifloxacin, selection of resistant mutants at twice the MIC was 100- to 1,000-fold less frequent than with the comparison quinolones, and mutants could rarely be selected at four times the MIC. The limit resistance in ISP74 was 512 times the MIC of gatifloxacin and 1,024 times the MICs of ciprofloxacin and AM-1121. Novel mutations in topoisomerase IV were selected in five of the six single-step mutants, three of which were shown to cause quinolone resistance by genetic studies. In conclusion, topoisomerase IV is the primary target of gatifloxacin. In contrast to comparison quinolones, mutations in both topoisomerase IV and gyrase are required for resistance to gatifloxacin by clinical breakpoints and do not abolish bactericidal effect, further supporting the benefit of the 8-methoxy substituent in gatifloxacin.
Details
- Title: Subtitle
- Mechanisms and Frequency of Resistance to Gatifloxacin in Comparison to AM-1121 and Ciprofloxacin in Staphylococcus aureus
- Creators
- Dilek Ince - Infectious Disease Division and Medical Services, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114-2696David C Hooper - Infectious Disease Division and Medical Services, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114-2696
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.45(10), pp.2755-2764
- DOI
- 10.1128/AAC.45.10.2755-2764.2001
- PMID
- 11557465
- PMCID
- PMC90727
- NLM abbreviation
- Antimicrob Agents Chemother
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Publisher
- American Society for Microbiology
- Language
- English
- Date published
- 10/2001
- Academic Unit
- Infectious Diseases; Internal Medicine
- Record Identifier
- 9984094746702771
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