title: Mutant prevention concentration of tigecycline for clinical isolates of Streptococcus pneumoniae and Staphylococcus aureus.
abstract: BACKGROUND
  The mutant prevention concentration (MPC) reflects the antimicrobial susceptibility of the resistant mutant subpopulations present in large bacterial populations. In principle, combining the MPC with pharmacokinetic measurements can guide treatment to restrict the enrichment of resistant subpopulations, just as the MIC is used with pharmacokinetics to restrict the growth of bulk, susceptible populations. Little is known about the MPC of tigecycline, one of the more recently approved antimicrobials. Tigecycline is particularly interesting because it shows good activity against Gram-positive pathogens.
  
  
  METHODS
  MPCs were determined using tigecycline-containing agar plates for clinical isolates of Streptococcus pneumoniae (n=47), MRSA (n=50) and MSSA (n=50).
  
  
  RESULTS
  Trypticase soy agar containing sheep red blood cells, commonly used for the growth of S. pneumoniae, gave tigecycline MPC90 values that were two orders of magnitude higher than expected. The addition of agar to Todd-Hewitt broth (solidified Todd-Hewitt broth) allowed the high-density growth of S. pneumoniae in the absence of red blood cells and lowered the MPC90 of tigecycline by 100-fold to 0.5 mg/L. The addition of red blood cells to solidified Todd-Hewitt broth raised the MPC90 by 100-fold. Thus, red blood cells reduce the efficacy of tigecycline against S. pneumoniae. The growth of Staphylococcus aureus was not sensitive to red blood cells; values of MPC90 were 2 and 4 mg/L for MSSA and MRSA, respectively.
  
  
  CONCLUSIONS
  Values of MPC constitute a concentration threshold for restricting the emergence of tigecycline resistance that can now be used in animal studies to determine pharmacodynamic thresholds. The off-label treatment of S. pneumoniae blood infections with tigecycline may require caution due to blood-cell-mediated interference with the antimicrobial.
authors.affiliation: Department of Pathology, Microbiology and Immunology and Ophthalmology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: C K
authors.initials: CK
authors.lastname: Hesje
authors.affiliation: Department of Public Health Research Institute and Department of Microbiology & Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren Street, Newark, NJ, USA.
authors.forename: K
authors.initials: K
authors.lastname: Drlica
authors.affiliation: Department of Pathology, Microbiology and Immunology and Ophthalmology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada Division of Clinical Microbiology, Royal University Hospital and the Saskatoon Health Region, Saskatoon, Saskatchewan, Canada joseph.blondeau@saskatoonhealthregion.ca.
authors.forename: J M
authors.initials: JM
authors.lastname: Blondeau
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D009154:Mutation / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline
keywords: blood agar; mutant selection window; resistance