Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis

Abstract

In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose ( < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).

Synergy between induction heating, antibiotics, and N-acetylcysteine eradicates Staphylococcus aureus from biofilm

“…To study the possible synergistic effect of antibiotics, NAC and induction heating, the titanium alloy coupons with biofilm were also exposed (after induction heating) to vancomycin (10 mg/l or 1 mg/l) and rifampicin (1 mg/l) with and without NAC (0.5 mg/l, all from Sigma-Aldrich, Chicago, IL) for 24 h at 37 C. These concentrations were chosen to represent clinically relevant concentrations [22][23][24]. To represent clinical practice, we added rifampicin to the antibiotic treatment because the studied S. aureus strain (ATCC 29213) is sensitive to rifampicin [25,26].…”

Updates in the Treatment of Active and Latent Tuberculosis

“…This led to a phase II open-label randomized controlled trial evaluating the efficacy of daily RIF at 600, 900, and 1,200 mg for 2 months with the primary endpoints of assessing safety and tolerability. 29 Bacteriologic clearance was not different among the study arms; however, a follow-up study evaluating a combination of RIF doses with or without moxifloxacin or SQ109 found faster time to culture conversion in participants receiving 35 mg/kg doses of RIF. 30 In vitro studies, animal models, and human studies suggest rifapentine (RPT) may have increased bactericidal activity compared with RIF.…”

Pharmacotherapy Approaches in Nontuberculous Mycobacteria Infections

“…Rifampin and rifabutin are commonly used for the treatment of MAC, M kansasii, and other select NTM. 7,53,54 Rifampin is a strong inducer for the hepatic cytochrome (CYP) enzyme system, (eg, strong inducer for CYP3A4 and CYP2C19; moderate inducer for CYP2B6, CYP2C8, and CYP2C9; weak inducer for CYP1A2) and an inducer for the P-glycoprotein pathway. Rifabutin induces CYP3A4 to a lesser extent compared with rifampin.…”