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Antimicrobial Agents and Chemotherapy, February 1999, p. 335-340, Vol. 43, No. 2
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Effects of NorA Inhibitors on In Vitro Antibacterial Activities and Postantibiotic Effects of Levofloxacin, Ciprofloxacin, and Norfloxacin in Genetically Related Strains of Staphylococcus aureus

Jeffrey R. Aeschlimann,1,2 Linda D. Dresser,1,2 Glenn W. Kaatz,2,3,4 and Michael J. Rybak1,2,4,*

Anti-Infective Research Laboratory, Department of Pharmacy Services, Detroit Receiving Hospital and University Health Center,1 Veteran's Administration Medical Center,3 and College of Pharmacy and Allied Health Professions2 and Department of Internal Medicine, Division of Infectious Diseases, School of Medicine, Wayne State University,4 Detroit, Michigan 48201

Received 18 February 1998/Returned for modification 25 July 1998/Accepted 28 November 1998

NorA is a membrane-associated multidrug efflux protein that can decrease susceptibility to fluoroquinolones in Staphylococcus aureus. To determine the effect of NorA inhibition on the pharmacodynamics of fluoroquinolones, we evaluated the activities of levofloxacin, ciprofloxacin, and norfloxacin with and without various NorA inhibitors against three genetically related strains of S. aureus (SA 1199, the wild-type; SA 1199B, a NorA hyperproducer with a grlA mutation; and SA 1199-3, a strain that inducibly hyperproduces NorA) using susceptibility testing, time-kill curves, and postantibiotic effect (PAE) methods. Levofloxacin had the most potent activity against all three strains and was minimally affected by addition of NorA inhibitors. In contrast, reserpine, omeprazole, and lansoprazole produced 4-fold decreases in ciprofloxacin and norfloxacin MICs and MBCs for SA 1199 and 4- to 16-fold decreases for both SA 1199B and SA 1199-3. In time-kill experiments reserpine, omeprazole, or lansoprazole increased levofloxacin activity against SA 1199-3 alone by 2 log10 CFU/ml and increased norfloxacin and ciprofloxacin activities against all three strains by 0.5 to 4 log10 CFU/ml. Reserpine and omeprazole increased norfloxacin PAEs on SA 1199, SA 1199B, and SA 1199-3 from 0.9, 0.6, and 0.2 h to 2.5 to 4.5, 1.1 to 1.3, and 0.4 to 1.1 h, respectively; similar effects were observed with ciprofloxacin. Reserpine and omeprazole increased the levofloxacin PAE only on SA 1199B (from 1.6 to 5.0 and 3.1 h, respectively). In conclusion, the NorA inhibitors dramatically improved the activities of the more hydrophilic fluoroquinolones (norfloxacin and ciprofloxacin). These compounds may restore the activities of these fluoroquinolones against resistant strains of S. aureus or may potentially enhance their activities against sensitive strains.

* Corresponding author. Mailing address: The Anti-Infective Research Laboratory, Department of Pharmacy Services (1B), Detroit Receiving Hospital and University Health Center, 4201 St. Antoine Blvd., Detroit, MI 48201. Phone: (313) 745-4554. Fax: (313) 993-2522. E-mail: mrybak{at}dmc.org.

Antimicrobial Agents and Chemotherapy, February 1999, p. 335-340, Vol. 43, No. 2
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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