Tuberculosis is a global pandemic, with 9 million new cases of the disease and approximately 2 million deaths each year. More than 98% of patients treated for
tuberculosis in the United States between 1993 and 2007 had
drug-susceptible strains. The standard treatment regimen for
drug-susceptible
tuberculosis has not changed in decades and was developed on the basis of empiric observations of different treatment regimens. Only recently has the veracity of the scientific basis for standard
therapy been examined. The backbone of
therapy is still
isoniazid,
rifampin, and
pyrazinamide, although
fluoroquinolones are being investigated as a replacement for
isoniazid. Recent population pharmacokinetic studies have demonstrated the importance of individualized dosing of
isoniazid,
pyrazinamide, and
rifampin.
Isoniazid serum clearance differs depending on the patient's number of N-
acetyltransferase 2 gene *4 (NAT2*4) alleles.
Pyrazinamide serum clearance has been shown to increase with increases in
body weight.
Rifampin's volume of distribution, clearance, and absorption have wide between-patient and within-patient variability. Microbial pharmacokinetic-pharmacodynamic (PK-PD) indexes and targets to optimize microbial killing and minimize resistance have been identified for
rifampin,
isoniazid,
pyrazinamide, and the
fluoroquinolones. These PK-PD indexes suggest that different doses and dosing schedules than those currently recommended could optimize
therapy and perhaps shorten
duration of therapy. Efflux pump inhibition is also being investigated to enhance first-line antituberculosis
drug therapy. Comorbid conditions such as
diabetes mellitus and genetically determined
iron overload syndromes have been associated with significantly worse patient outcomes.
Therapy for these and other patient groups needs further improvement. These patient factors, the covariates for pharmacokinetic variability, and PK-PD factors suggest the need to individualize
therapy for patients with
tuberculosis in order to optimize outcomes and reduce the
duration of therapy.