title: Cure of tuberculosis despite serum concentrations of antituberculosis drugs below published reference ranges.
abstract: BACKGROUND
  Therapeutic target serum concentrations of first-line antituberculosis drugs have not been well defined in clinical studies in tuberculosis (TB) patients.
  
  
  METHODS
  We retrospectively investigated the estimated maximum serum concentrations (eC max) of antituberculosis drugs and clinical outcome of TB patients with therapeutic drug monitoring performed between 2010-2012 at our institution, and follow-up until March 2014. The eC max was defined as the highest serum concentration during a sampling period (2, 4 and 6 hours after drug ingestion). We compared the results with published eC max values, and categorised them as either "within reference range", "low eC max", or "very low eC max".Low/very low eC max-levels were defined as follows: isoniazid 2-3/<2 mg/l, rifampicin 4-8/<4 mg/l, rifabutin 0.2-0.3/<0.2 mg/l, ethambutol 1-2/<0.1 mg/l and pyrazinamide <20 mg/l.
  
  
  RESULTS
  Concentrations of antituberculosis drugs in 175 serum samples of 17 patients with TB were analysed. In 12 (71%) patients, multiple therapeutic drug monitoring samples were collected over time, in 5 (29%) patients only one sample was available for therapeutic drug monitoring. Overall, 94% of all patients had at least one low antituberculosis drug concentration. Overall, 64% of all eC max levels were classified as "low" or "very low". The eC max was below the relevant reference range in 80% of isoniazid, 95% of rifampicin, 30% of pyrazinamide, and 30% of ethambutol measurements. All but one patient were cured of tuberculosis.
  
  
  CONCLUSIONS
  Although many antituberculosis drug serum concentrations were below the widely used reference ranges, 16 of 17 patients were cured of tuberculosis. These results challenge the use of the published reference ranges for therapeutic drug monitoring.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Monica
authors.initials: M
authors.lastname: Meloni
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Natascia
authors.initials: N
authors.lastname: Corti
authors.affiliation: Institute of Clinical Chemistry, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Müller
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Lars
authors.initials: L
authors.lastname: Henning
authors.affiliation: Institute of Clinical Chemistry, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Gutteck
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Amrei
authors.initials: A
authors.lastname: von Braun
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Weber
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Fehr
mesh_terms: D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D015658:HIV Infections / Q000150:complications; D006801:Humans; D007538:Isoniazid / Q000097:blood* / Q000627:therapeutic use; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011718:Pyrazinamide / Q000097:blood* / Q000627:therapeutic use; D012016:Reference Values; D012189:Retrospective Studies; D012293:Rifampin / Q000097:blood* / Q000627:therapeutic use; D013557:Switzerland; D014376:Tuberculosis / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin