J.S. Maritz

Early Bactericidal Activity of High-Dose Rifampin in Patients with Pulmonary Tuberculosis Evidenced by Positive Sputum Smears

ABSTRACT 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.

Isoniazid pharmacokinetics in children treated for respiratory tuberculosis.

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.

Early bactericidal activity of antituberculosis agents.

The early bactericidal activity (EBA) of an antituberculosis agent is arbitrarily defined as the fall in log10 colony forming units (cfu) of Mycobacterium tuberculosis per ml sputum per day during the first 2 days of treatment. Determining the EBA is an important preliminary step in the clinical evaluation of an antituberculosis agent. We review the results of eight published studies of the EBA of different antituberculosis agents, the impact of these results on our understanding of the actions of the respective agents, the clinical characteristics and sputum findings of patients included in these studies, and explore sources of variation in the EBA results. Patients in these studies had a mean age of 31–36 years, a mean weight of 50–57 kg, 67% were male and 56% had lung involvement covering an area of more than one lung, and 90% had multicavitary disease. None of these findings were related to EBA in any study. The mean log10 cfu per ml sputum in the first specimen was 6.474. This was related to radiological extent of disease and cavity size in one study (p < 0.001) and, in the case of isoniazid to EBA with a rise in EBA of 0.094 (95% CL 0.029–0.158) for each tenfold rise in cfu counts/ml sputum. The overall variation in EBA in these studies was 0.0303, that due to laboratory processing of specimens was 0.0011, and due to patient characteristics and sputum sampling 0.0212. The EBA is a reproducible investigation that has contributed significantly to our knowledge of the actions and characteristics of both established and new antituberculosis agents. The greatest source of variation in EBA results appears to be that due to interpatient variation in disease characteristics and sputum sampling.

Time to detection of the growth of Mycobacterium tuberculosis in MGIT 960 for determining the early bactericidal activity of antituberculosis agents

Evaluation of early bactericidal activity (EBA) by the determination of a fall in viable colony-forming units (CFU) of Mycobacterium tuberculosis in sputum is a first step in the clinical study of new antituberculosis agents. The time to detection (TTD) of growth in liquid media is more sensitive and could substitute for CFU counting on solid media. Overnight sputum samples collected during the evaluation of the novel agent TMC207 in comparison to isoniazid and rifampicin were studied. For the determination of CFU, we incubated 10-fold dilutions of homogenized sputum on selective 7H10 agar. The TTD was measured by incubating decontaminated sputum in the BACTEC MGIT 960 system. The fall in bacillary load over 7 days determined by CFU counting closely matched the prolongation of the TTD in the BACTEC MGIT 960 system. The CFU counts correlated significantly with the TTD. While the ranking of agents and different dosages of TMC207 was similar, the highest dose of TMC207 showed markedly better activity when measured by the TTD than CFU counting when compared to the activity of isoniazid. Automated TTD could augment, or, in future, replace, CFU counting to determine sputum bacillary load in EBA clinical trials pending a more formal evaluation of the correlation of the measurements.

Time to liquid culture positivity can substitute for colony counting on agar plates in early bactericidal activity studies of antituberculosis agents.

The measurement of early bactericidal activity (EBA) is the first step in the clinical investigation of antituberculosis agents. EBA is determined by quantifying the viable sputum mycobacterial load on consecutive days of treatment. To investigate whether time to positivity (TTP) in mycobacterial liquid culture can substitute for colony forming unit (CFU) counting on agar plates we compared the error variation of TTP and CFU in 2115 pooled sputum samples collected overnight from 250 individuals included in five EBA studies. We found that the technical variation between duplicate laboratory measurements and the within-subject or day-to-day variation were similar for TTP (8.5% and 27.4% of total variation, respectively) and CFU (6.7% and 29.3% of total variation). The ability of the measurements to separate the EBA of 22 treatment arms was determined with group rank correlation of means and one-way analysis of variance. Except for the EBA over 0-2 days, individual and group EBAs measured with TTP and CFU were highly correlated. Treatment group means rank correlation coefficients were r=0.472, r=0.910 and r=0.818, respectively, for EBA 0-2 days, EBA 0-7 days and EBA 0-14 days. Analysis of variance significantly favoured TTP over CFU for discrimination between groups with F values of 6.58 and 1.87, 7.77 and 4.58, and 8.71 and 3.56, respectively. We conclude that TTP is an acceptable alternative to CFU counting for the determination of the viable sputum mycobacterial load in EBA studies of up to 14 days duration.

The pharmacokinetics and pharmacodynamics of rifampicin in adults and children in relation to the dosage recommended for children

The dosages of antituberculosis agents recommended for treatment of childhood tuberculosis often reflect those for adult patients with similar mg/kg body weight dosages and ranges advised. Literature relating to the pharmacokinetics and pharmacodynamics of rifampicin (RMP) is reviewed and the serum concentrations reached by adults, both patients and healthy volunteers and children, established or not established on RMP, compared. Straight line regression of maximum RMP serum concentrations (C(max)) on dosage, weighted for the number of individuals, found slopes (SE) of 1.025 (0.067) and 0.881 (0.046) respectively for adult volunteers not established and established on RMP (P = 0.076), and similarly 0.748 (0.057) and 0.684 (0.038) respectively for adult patients (P < 0.001) and 0.622 (0.050) and 0.368 (0.041) respectively for children (P < 0.001). These results indicate that for equivalent RMP dosages adult patients reach a lower C(max) than adult volunteers and that adults, both volunteers and patients established on RMP reach higher C(max) values than children; children established on RMP require approximately twice the mg/kg body weight dosage of RMP to reach serum concentrations equivalent to those of adults. It is noteworthy that many adult patients receiving currently recommended RMP dosages also do not reach the often recommended RMP 2 h serum concentration of 8 μg/mL.

Pyrazinamide pharmacokinetics and efficacy in adults and children

Pyrazinamide (PZA) is an essential sterilizing drug and with rifampicin enables six-month short-course antituberculosis chemotherapy. Despite routine use for nearly forty years uncertainty remains regarding the most appropriate PZA dosage for children. In view of this uncertainty literature relating to the efficacy and pharmacokinetics of PZA in children treated for tuberculosis and in adult volunteers and patients was reviewed. Making use of the PZA maximum concentration (C(max)) following various PZA dosages in different groups straight line regression of concentration on dosage was fitted through the origin by least squares and weighted for the numbers of subjects. The fitted line offers an approximation of the likely PZA C(max) that would result from a particular dosage. The slopes of C(max)/dosage of the fitted lines are 1.32 (SE 0.099) for paediatric patients, 1.36 (SE 0.051) for adult volunteers and 1.35 (SE 0.037) for adult patients; there is little difference between the C(max) concentrations achieved in children and adults, whether patients or healthy volunteers, following various mg/kg body weight dosages, suggesting that children and adults receiving the same mg/kg body weight PZA dosage will reach a similar C(max). Children can receive the same mg/kg body weight PZA dosage as adults.

Predictors of survival in infants with congenital diaphragmatic hernia - systemic oxygenation status versus dynamic compliance of the respiratory system

Objective . To compare whether early measurement of blood gases and/or dynamic compliance of the respiratory system (CRS dyn ) predicts outcome in high-risk infants with unilateral congenital diaphragmatic hernia (CDH). Patients and methods. A retrospective study was performed at Tygerberg Children’s Hospital between January 1992 and August 2001. High-risk infants with unilateral CDH, who presented with respiratory distress within 6 hours of birth, were included. Patients with other lethal congenital abnormalities were excluded. The first arterial blood gas value after endotracheal intubation was documented and the arterial-alveolar oxygen tension (a:A) ratio was calculated. CRS dyn was measured within 24 hours of birth. The ability of these measurements to predict outcome (survival or death during the newborn period) was determined. Results . Seventeen of 40 infants with CDH were categorised as high risk and included in the study. Eight of them (47%) survived the neonatal period. The best single predictors of outcome were, in order, partial pressure of oxygen in arterial blood (PaO 2 ), a:A ratio and dynamic compliance of the respiratory system standardised for body weight (CRS dyn /kg). The specificity and sensitivity at a PaO 2 cut-off of 19.3 kPa were 7/8 (95% confidence interval (CI): 0.473 - 0.997) and 9/9 (95% CI: 0.634 - 1.000) respectively. Results for a:A ratio were cut-off 0.321, specificity 6/8 (95% CI: 0.349 - 0.968), and sensitivity 9/9 (95% CI: 0.634 - 1.000). Results for CRS dyn /kg were cut-off 0.259, specificity 6/8 (95% CI: 0.349 - 0.968), and sensitivity 9/9 (95% CI: 0.634 - 1.000). A linear discriminant function based on the 3 best single predictors was found to be no more effective than the first PaO 2 . Conclusions . Early oxygenation status predicts outcome better than the CRS dyn /kg in infants with unilateral CDH. However, both measurements predict outcome with high accuracy.