We studied the early bactericidal activity of twice the standard dose of rifampin in subjects with pulmonary tuberculosis evidenced by positive smears. The observed mean 2-day activity was almost double that reported at the standard dose. Further studies are warranted to establish whether higher rifampin doses might assist in shortening tuberculosis treatment.Rifampin (RMP) is a key drug in standard antituberculosis regimens. The sterilizing properties of RMP in conjunction with pyrazinamide lay the foundation for the current "shortcourse" 6-month regimens (11). The standard RMP dose of 8 to 12 mg/kg of body weight (21) is probably at the lower limit of optimal efficacy (11,13,18,20), but it is not clear whether higher doses of RMP could increase its activity (12). We studied the pharmacokinetics and the 2-day and 5-day early bactericidal activities (EBA) of RMP at a dose of 20 mg/kg of body weight.We included treatment-naïve patients with pulmonary tuberculosis, evidenced by positive smears, who had no past history of liver disease and normal serum transaminase and bilirubin levels. RMP was given daily over five days in a single dose before breakfast. Patients were monitored for unexpected signs and symptoms for 7 days in the hospital and again 2 weeks after the last dose of study medication. Sixteen-hour sputum specimens were collected overnight before and over 5 days after initiation of treatment. Patients commenced standard antituberculosis treatment on discharge. The Committee for Pharmaceutical Trials of the University of Stellenbosch and the South African Medicines Control Council approved the study. All patients gave written informed consent.After sputum digestion (Sputasol; Oxoid Ltd., Poole, England) and homogenization, two series of 10-fold dilutions were incubated on selective 7H10 agar plates for the enumeration of CFU as described previously (17). Serum samples were taken at 1, 1.5, 2, 2.5, 3,4,8,12, and 24 h after the first dose. RMP concentrations were measured by high-pressure liquid chromatography with UV detection as previously described (17). The EBA was defined as (Z 0 Ϫ Z D )/D, where Z 0 and Z D are logarithms of the CFU counts per ml sputum prior to the start of treatment and after D days of treatment, respectively (17). All data are displayed as mean Ϯ standard deviations unless stated otherwise.One of 14 enrolled patients was excluded following an episode of hemoptysis. Thirteen patients whose sputum was at least 2ϩ smear positive for acid-fast bacilli completed the study (age, 27 Ϯ 9 years; 61% male; body weight, 55 Ϯ 16 kg). On chest radiography, all patients had at least one cavity, and 7 (54%) had bilateral disease. Three patients (23%) were human immunodeficiency virus positive. Clinically observed adverse events were mild and transient. One patient suffered a secondary pneumothorax 2 weeks after discharge and received pleural drainage. No other serious adverse events occurred during the study or were evident at the 2-week follow-up.All strains isolated were susceptible to RMP (Bac...

Aims: To define the pharmacokinetics of isoniazid (INH) in children with tuberculosis in relation to the N-acetyltransferase 2 (NAT2) genotype. Methods: The first order elimination rate constant (k) and area under the concentration curve (AUC) were calculated in 64 children ,13 years of age (median 3.8) with respiratory tuberculosis from INH concentrations determined 2-5 hours after a 10 mg/kg INH dose. The NAT2 genotype was determined; 25 children were classified as homozygous slow (SS), 24 as heterozygous fast (FS), and 15 as homozygous fast (FF) acetylators. Results: The mean (SD) k values of the genotypes differed significantly from one another: SS 0.254 (0.046), FS 0.513 (0.074), FF 0.653 (0.117). Within each genotype a median regression of k on age showed a significant decrease in k with age. The mean (SD) INH concentrations (mg/l) two hours after INH administration were SS 8.599 (1.974), FS 5.131 (1.864), and FF 3.938 (1.754). A within genotype regression of 2-hour INH concentrations on age showed a significant increase with age. A within genotype regression of 3-hour, 4-hour, and 5-hour concentrations on age also showed a significant increase with age in each instance. In ethnically similar adults, mean (SD) 2-hour INH concentrations (mg/l) for each genotype were significantly higher than the children's: SS 10.942 (1.740), FS 8.702 (1.841), and FF 6.031 (1.431). Conclusions: Younger children eliminate INH faster than older children and, as a group, faster than adults, and require a higher mg/kg body weight INH dose to achieve serum concentrations comparable to adults.

Collections of sputum from 105 patients with newly diagnosed pulmonary tuberculosis were made before and at 1 and 2 d after the start of chemotherapy with isoniazid (INH) alone given to groups of patients in doses of 600 mg, 300 mg, 150 mg, 75 mg, 37.5 mg, 18.75 mg, and 9 mg daily, as well as from an untreated group. Counts of colony forming units (cfu) of Mycobacterium tuberculosis in the collections were set up on plates of selective 7H10 medium. The early bactericidal activity (EBA) of INH was defined as the decrease in log10 cfu/ml sputum/day during the first 2 d of treatment. A smooth curve relating EBA to log dose was obtained, with 600 mg INH yielding the highest mean EBA of 0.539, and 18.75 mg INH yielding the lowest EBA (0.111) that could be distinguished from the bactericidal activity of the untreated group. The ratio of the usual dose of 300 mg INH to the lowest dose, of 18.75 mg, that produced a detectable EBA, termed the therapeutic margin, was therefore 16, in contrast to the lower therapeutic margin of 4 for rifampin. The EBA was related to the INH acetylator genotype of patients treated with 600 mg or 9 mg INH.