title: The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment.
abstract: BACKGROUND
  Currently recommended multidrug treatment regimens for Mycobacterium avium complex (MAC) lung disease yield limited cure rates. This results, in part, from incomplete understanding of the pharmacokinetics and pharmacodynamics of the drugs.
  
  
  OBJECTIVE
  To study pharmacokinetics, pharmacodynamics, and drug interactions of multidrug treatment regimens in a large cohort of patients with MAC lung disease.
  
  
  METHODS
  We retrospectively collected pharmacokinetic data of all patients treated for MAC lung disease in the Adult Care Unit at National Jewish Health, Denver, Colorado, in the January 2006 to January 2010 period; we retrospectively calculated areas under the time-concentration curve (AUC). Minimum inhibitory concentrations (MIC) of their MAC isolates were retrieved for pharmacodynamic calculations.
  
  
  RESULTS
  We included 531 pharmacokinetic analyses, performed for 481 patients (84% females; mean age, 63 yr; mean body mass index, 21.6). Peak serum concentrations (C(max)) below target range were frequent for ethambutol (48% of patients); clarithromycin (56%); and azithromycin (35%). Concurrent administration of rifampicin led to 68%, 23%, and 10% decreases in C(max) of clarithromycin, azithromycin, and moxifloxacin. C(max)/MIC or AUC/MIC ratios associated with bactericidal activity were seldom met; 57% of patients achieved target ratios for ethambutol, versus 42% for clarithromycin, 19% for amikacin, 18% for rifampicin, and 11% for moxifloxacin.
  
  
  CONCLUSIONS
  Currently recommended regimens for MAC lung disease yield important pharmacologic interactions and low concentrations of key drugs including macrolides. Pharmacodynamic indices for rifampicin, clarithromycin, amikacin, and moxifloxacin are seldom met. This may partly explain the poor outcomes of currently recommended treatment regimens. Trials of new drugs and new dosing strategies are needed.
authors: Division of Mycobacterial and Respiratory Infections, National Jewish Health, Denver, CO, USA. j.vaningen@mmb.umcn.nl
authors: Jakko
authors: J
authors: van Ingen
authors: Eric F
authors: EF
authors: Egelund
authors: Adrah
authors: A
authors: Levin
authors: Sarah E
authors: SE
authors: Totten
authors: Martin J
authors: MJ
authors: Boeree
authors: Johan W
authors: JW
authors: Mouton
authors: Rob E
authors: RE
authors: Aarnoutse
authors: Leonid B
authors: LB
authors: Heifets
authors: Charles A
authors: CA
authors: Peloquin
authors: Charles L
authors: CL
authors: Daley
mesh_terms: D000328:Adult; D000368:Aged; D000583:Amikacin / Q000493:pharmacokinetics; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D017291:Clarithromycin / Q000493:pharmacokinetics; D015331:Cohort Studies; D003120:Colorado; D004347:Drug Interactions; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D015269:Mycobacterium avium Complex / Q000187:drug effects* / Q000302:isolation & purification; D015270:Mycobacterium avium-intracellulare Infection / Q000175:diagnosis / Q000188:drug therapy*; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D012189:Retrospective Studies; D017828:Rifabutin / Q000493:pharmacokinetics; D012293:Rifampin / Q000493:pharmacokinetics
chemical_list: D000904:Antibiotics, Antitubercular; D017828:Rifabutin; D000583:Amikacin; D004977:Ethambutol; D017291:Clarithromycin; D012293:Rifampin