JAC Advance Access originally published online on September 28, 2007
Journal of Antimicrobial Chemotherapy 2007 60(6):1380-1383; doi:10.1093/jac/dkm375
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Daptomycin inoculum effects and mutant prevention concentration with Staphylococcus aureus
Public Health Research Institute and Department of Microbiology and Molecular Genetics, UMDNJ—New Jersey Medical School, 225 Warren Street, Newark, NJ 07103, USA
Received 31 May 2007; returned 3 July 2007; revised 4 September 2007; accepted 5 September 2007
* Corresponding author. Tel: +1-973-854-3364; Fax: +1-973-854-3101; E-mail: zhaox5{at}umdnj.edu
Background: Antimutant activity of antimicrobials can be estimated by comparing drug pharmacokinetics with mutant prevention concentration (MPC). Large bacterial inocula known to reduce susceptibility have not been studied for effects on MPC determination.
Methods: Staphylococcus aureus inoculum size was varied with solid and liquid media containing daptomycin and Ca2+, a cation expected to lower inoculum effects, to assess effects on MIC and MPC.
Results: With drug-containing agar, individual colonies were obtained over a narrow range of inoculum size that shifted to higher inoculum size as daptomycin concentration increased. Increasing Ca2+ supplementation from 1 to 50 mM lowered MIC by 2-fold and MPC from 20 to 3 mg/L, the latter determined by extrapolation of population analysis profiles to an inoculum size of 1010 cfu. Cells of colonies recovered from daptomycin-containing agar had wild-type MIC. With liquid medium, supplemented with 1 mM Ca2+and containing 1010 cfu, MPC was between 2.5 and 5 mg/L at an inoculum density of 107 cfu/mL. Bacteria recovered from liquid assays exhibited a 4- to 8-fold increase in MIC and contained point mutations in mprF.
Conclusions: Inoculum effects on MPC can be reduced by measurement with low-density (large volume) liquid bacterial cultures. Retesting putative mutants for susceptibility can be important: stable mutants having genetic variations in the mprF gene were recovered from liquid medium, but not from agar. Daptomycin MPC with S. aureus was below minimal plasma drug concentration with approved doses, which is consistent with resistance to daptomycin arising rarely.
Keywords: mutant selection window , liquid medium , daptomycin-resistant mutants , resistant allele
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