title: Tentative susceptibility testing breakpoint for the neuroleptic drug thioridazine, a treatment option for multi- and extensively drug resistant tuberculosis.
abstract: BACKGROUND
  New drugs against multi-(MDR) and extensively drug (XDR) resistant tuberculosis are urgently needed. While new candidate drugs are being developed, reinvestigation of already approved drugs available for other indications could be of value. The objective of this study is to determine tentative drug susceptibility testing strategies and breakpoints for thioridazine, a well-known and well-tolerated neuroleptic drug, which has been shown to be effective against drug resistant tuberculosis both in vitro and in vivo.
  
  
  METHODS
  By testing the minimal inhibitory concentration (MIC) on Middlebrook 7H10 media, the wild-type distribution of thioridazine was established for Mycobacterium tuberculosis (n=51) and this distribution was compared to the MICs of M/XDR strains (n=67).
  
  
  RESULTS
  A tentative epidemiological cut off (ECOFF) of thioridazine at 16mg/L was suggested. Even though such concentrations are not clinically achievable in serum, thioridazine is concentrated intracellularly and concentrations of only 0.1mg/L has been shown to kill M. tuberculosis residing inside cells. MICs above the wild-type (MIC>16mg/L) were found in 4/67 (6%) of the M/XDR strains suggesting that resistance mechanisms against thioridazine may already be present in resistant clinical strains.
  
  
  CONCLUSIONS
  In view of the difficulties obtaining clinical outcome data for single drugs in the case of tuberculosis since combination therapy is mandatory, the tentative ECOFF may be considered a tentative clinical breakpoint, but the findings should be validated by others. The data from this study strengthens the use of thioridazine as a treatment option for M/XDR tuberculosis, although its proper place in the therapeutic arsenal should ideally be confirmed in clinical trials.
authors.affiliation: Department of Clinical Microbiology MTC, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden. Electronic address: kristian.angeby@karolinska.se.
authors.forename: Kristian
authors.initials: K
authors.lastname: Ängeby
authors.affiliation: Department of Preparedness, Swedish Institute for Communicable Disease Control, Solna, Sweden.
authors.forename: Pontus
authors.initials: P
authors.lastname: Juréen
authors.affiliation: Department of Clinical Microbiology MTC, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Erja
authors.initials: E
authors.lastname: Chryssanthou
authors.affiliation: Department of Infectious Diseases and Clinical Microbiology, Kalmar County Hospital, Kalmar, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schön
keywords: Antimycobacterial agents; Drug resistance; Drug susceptibility testing; Mycobacteria; Phenothiazines; Wild-type MIC distributions