Antistaphylococcal Activity of Dihydrophthalazine Antifolates, a Family of Novel Antibacterial Drugs
- 1 April 2009
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 53 (4), 1353-1361
- https://doi.org/10.1128/aac.01619-08
Abstract
For a panel of 153 Staphylococcus aureus clinical isolates (including 13 vancomycin-intermediate or heterogeneous vancomycin-intermediate and 4 vancomycin-resistant strains), MIC 50 s and MIC 90 s of three novel dihydrophthalazine antifolates, BAL0030543, BAL0030544, and BAL0030545, were 0.03 and 0.25 μg/ml, respectively, for methicillin-susceptible strains and 0.03 and ≤0.25 μg/ml, respectively, for methicillin-resistant strains. For a panel of 160 coagulase-negative staphylococci (including 5 vancomycin-intermediate and heterogeneous vancomycin-intermediate strains and 7 linezolid-nonsusceptible strains), MIC 50 s and MIC 90 s were ≤0.03 and ≤0.06 μg/ml, respectively, for methicillin-susceptible strains and 0.06 and 0.5 μg/ml, respectively, for methicillin-resistant strains. Vancomycin was active against 93.0% of 313 staphylococci examined; linezolid was active against all S. aureus strains and 95.6% of coagulase-negative staphylococcus strains, whereas elevated MICs of clindamycin, minocycline, trimethoprim, and rifampin for some strains were observed. At 4× MIC, the dihydrophthalazines were bactericidal against 11 of 12 staphylococcal strains surveyed. The prolonged serial passage of some staphylococcal strains in the presence of subinhibitory concentrations of BAL0030543, BAL0030544, and BAL0030545 produced clones for which dihydrophthalazines showed high MICs (>128 μg/ml), although rates of endogenous resistance development were much lower for the dihydrophthalazines than for trimethoprim. Single-step platings of naïve staphylococci onto media containing dihydrophthalazine antifolates indicated considerable variability among strains with respect to preexistent subpopulations nonsusceptible to dihydrophthalazine antifolates.Keywords
This publication has 34 references indexed in Scilit:
- United States resistance surveillance results for linezolid (LEADER Program for 2007)Diagnostic Microbiology and Infectious Disease, 2008
- Toxicity of extended courses of linezolid: results of an Infectious Diseases Society of America Emerging Infections Network surveyDiagnostic Microbiology and Infectious Disease, 2008
- NorB, an Efflux Pump in Staphylococcus aureus Strain MW2, Contributes to Bacterial Fitness in AbscessesJournal of Bacteriology, 2008
- First Report of cfr -Mediated Resistance to Linezolid in Human Staphylococcal Clinical Isolates Recovered in the United StatesAntimicrobial Agents and Chemotherapy, 2008
- Treatment and Outcomes of Infections by Methicillin-Resistant Staphylococcus aureus at an Ambulatory ClinicAntimicrobial Agents and Chemotherapy, 2007
- Epidemiological Profile of Linezolid‐Resistant Coagulase‐Negative StaphylococciClinical Infectious Diseases, 2006
- Cloning and Characterization of a Novel Trimethoprim-Resistant Dihydrofolate Reductase from a Nosocomial Isolate of Staphylococcus aureus CM.S2 (IMCJ1454)Antimicrobial Agents and Chemotherapy, 2005
- Necrotizing Fasciitis Caused by Community-Associated Methicillin-ResistantStaphylococcus aureusin Los AngelesThe New England Journal of Medicine, 2005
- Methicillin-resistant staphylococciClinical Microbiology & Infection, 1999
- Identical genes for trimethoprim‐resistant dihydrofolate reductase from Staphylococcus aureus in Australia and Central EuropeFEBS Letters, 1990