The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid.

OBJECTIVE: This study evaluated the pharmacokinetics of isoniazid (INH) associated with optimal early bactericidal activity (EBA), defined as 90% of the maximum EBA (EBA(90)) and the influence of N-acetyltransferase-2 (NAT2) subtype on the ability of pulmonary tuberculosis (PTB) patients to reach the identified pharmacokinetic values after INH doses ranging from 0.2 to 10-12 mg/kg body weight. METHODS: INH serum concentrations and NAT2 subtype were determined during four studies of PTB patients in three of whom the EBA of INH was determined. The relationship of EBA to area under the curve (AUC) (AUC(0-infinity)) and 2-h serum concentrations was examined by exponential regression and fitted curves estimated the AUC(0-infinity) and 2-h serum concentrations at which EBA(90) was reached. RESULTS: EBA(90) was reached at an AUC(0-infinity) of 10.52 microg/ml per hour and 2-h serum concentrations of 2.19 microg/ml. An AUC(0-infinity) of 10.52 microg/ml per hour was reached by all 66 patients receiving a 10-12 mg/kg INH dose and all 21 receiving 6 mg/kg, except 1 of 10 (10%) homozygous fast (FF) acetylators; however, at 5 mg/kg, 4 of 12 (33%) FF and 26 of 27 (96%) heterozygous fast (FS), but all 21 homozygous slow (SS) acetylators did so; and 1 of 3 (33%) FF, 2 of 6 (33%) FS, but all 4 SS acetylators at dose 3 mg/kg. An INH 2-h serum concentration of 2.19 microg/ml was reached by all 66 patients receiving 10-12 mg/kg and all 21 receiving 6 mg/kg, except for 2 (20%) FF acetylators at a dose of 5 mg/kg; however, only 3 (25%) of 12 FF acetylators, but 26 (96%) of 27 FS acetylators, and all 21 SS acetylators reached this concentration; and at a dose of 3 mg/kg, 1 (33%) of 3 FF acetylators, 2 (33%) of 6 FF, but all 4 SS acetylators. CONCLUSIONS: At a 6 mg/kg dose, all except a minority of FF NAT2 acetylators, achieve an INH AUC(0-infinity) and 2-h INH serum concentrations associated with EBA(90), as did all 4 SS acetylators receiving 3 mg/kg. Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH.

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.

The influence of human N-acetyltransferase genotype on the early bactericidal activity of isoniazid.

The elimination of isoniazid is subject to the influence of the N-acetyltransferase 2 (NAT2) genotype, and individuals may be homozygotic slow, heterozygotic fast, or homozygotic fast acetylators of isoniazid. The early bactericidal activity (EBA) of an antituberculosis agent can be determined by quantitative culture of Mycobacterium tuberculosis in sputum samples obtained from patients with pulmonary tuberculosis during the first days of treatment. In these studies, the EBA of isoniazid during the first 2 days of treatment was determined for 97 patients with sputum smear-positive pulmonary tuberculosis following isoniazid doses of < or =37.5 mg, 75 mg, 150 mg, 300 mg, and 600 mg. The NAT2 genotype was determined in 70 patients, and the association between EBA and genotype was examined in this subgroup. Similarly, the relationship between EBA and isoniazid serum concentration was evaluated in 87 patients. The mean EBA of isoniazid increased with dose, but it levelled off between doses of 150 mg (mean EBA, 0.572) and 300 mg (mean EBA, 0.553). Significant differences were found in the mean EBA of isoniazid between the homozygous slow acetylator group and the heterozygous fast acetylator group and between the homozygous slow acetylator group and the homozygous fast acetylator group, but not between the heterozygous fast acetylator group and the homozygous fast acetylator group. The EBA appeared to reach a maximum at a 2-h isoniazid concentration of 2-3 microg/mL. These data confirm a significant effect of NAT2 genotype on the EBA of isoniazid over a range of doses.

Early bactericidal activity of antituberculosis agents.

The early bactericidal activity (EBA) of an antituberculosis agent is arbitrarily defined as the fall in log(10) 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 log(10) 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.

The early bactericidal activity of streptomycin.

SETTING: Patients with sputum smear-positive, newly diagnosed pulmonary tuberculosis studied at Tygerburg Hospital, Cape Town, for their early response to streptomycin (SM). OBJECTIVE: To determine the standard early bactericidal activity (EBA), namely the fall in viable counts of tubercle bacilli in 16-hour sputum collections during the first 2 days of treatment with SM. DESIGN: Patients were randomised to logarithmically spaced daily doses of 7.5, 15 or 30 mg/kg SM. A comparison by standard biological assay methods was then made with previous estimations of the EBA of paromomycin in doses of 7.5 and 15 mg/kg. RESULTS: An EBA of 0.133 obtained with 30 mg/kg SM differed significantly from zero (P = 0.0009), while the EBAs of 0.043 with 15 mg/kg and -0.025 with 7.5 mg/kg did not so differ. A linear regression equation of EBA = -0.2587 + 0.2627 log10 dose was obtained with significant slope (P = 0.007). Paromomycin was estimated to be 1.745 more potent than SM with wide 95% confidence limits (0.6-28.6), indicating that it cannot be considered more potent than SM. CONCLUSIONS: The low EBAs show that SM has low, dose-related, bactericidal activity in cavities, consistent with results from clinical trials. If streptomycin-resistant bacilli are present, paromomycin is probably the aminoglycoside of choice.

The early bactericidal activity of a low-clearance liposomal amikacin in pulmonary tuberculosis.

The early bactericidal activity (EBA) of a liposomal preparation of amikacin (MiKasome) with a long plasma half-life of 120-200 h was examined in seven patients with newly diagnosed, smear-positive pulmonary tuberculosis. Liposomal amikacin was given in slow iv infusions of 30 mg total amikacin/kg body weight on three successive days. Cfu counts were set up on 16 h sputum collections preceding the first dose and following each dose and were used for calculating the EBA. Despite the high concentrations of total amikacin, >1000 mg/L, obtainable in plasma, no evidence of EBA was obtained. In view of the considerable activity of liposomal amikacin in experimental murine tuberculosis, this finding indicates that liberation of amikacin from the long-life liposomes occurs only in macrophages that are not usually present in the vicinity of the large extracellular clumps of bacilli in the cavity caseum.

Population screening for isoniazid acetylator phenotype.

PURPOSE: To establish a useful method for acetylator phenotypification and therapeutic drug monitoring of patients receiving isoniazid. METHODS: Sixty patients with uncomplicated pulmonary tuberculosis were given a 5-mg/kg oral dose of isoniazid each. Plasma concentrations of isoniazid and its metabolite, acetyl-isoniazid, were determined by HPLC analyses at various post-dose times. From the isoniazid concentration and the concentration ratio of acetyl-isoniazid and isoniazid (metabolic ratio), phenotypification methods were assessed. RESULTS: The metabolic ratios at 3 h post-dose revealed a trimodal distribution; a fast, intermediate and slow acetylator phenotype group. The 2-h and 6-h data showed different bimodal combinations of these phenotype groups. The metabolic ratio phenotypification method could be simplified by using the HPLC data directly without converting it to absolute concentrations. CONCLUSIONS: A single-sample test based upon the plasma isoniazid concentration, combined with the metabolic ratio of acetyl-isoniazid and isoniazid, appears to be a reliable parameter for phenotype discrimination and for bioavailability testing.

Cortical lens opacities in the young patient--an indication for a lipogram?

AIM: To determine the characteristics and prevalence of lenticular opacification in patients with underlying dyslipidaemia. METHODS: Eighty patients of both genders and all ages (18-90 years) were enrolled in the trial if they met the inclusion criteria for dyslipidaemia. Patients were included if their fasting serum cholesterol and triglyceride concentrations were > 5.2 mmol/l and > 2.3 mmol/l, respectively, when measured on three separate occasions over a 1-month period. Patients were excluded if they suffered from any condition known to cause or predispose them to elevated lipid levels or lenticular opacification. Lenticular changes were assessed by means of a slit-lamp through the fully dilated pupil and other physical signs were documented subsequent to thorough physical evaluation. RESULTS: In addition to the classic clinic signs of dyslipidaemia, 31% of patients had cortical lens opacities. Cortical opacities were twice as prevalent as Achilles tendon thickening (16.3%) in our study, the second most prevalent sign of elevated lipid levels. In the subgroup of patients aged under 50 years, 55% had lenticular opacities, predominantly cortical (80%). CONCLUSIONS: Cortical lens opacification was the most prevalent sign of dyslipidaemia and it occurred at a relatively young age in our trial population in those patients who were affected. Cortical lenticular opacification should be regarded as an indication for blood lipid profile evaluation.

Early bactericidal activity of amoxicillin in combination with clavulanic acid in patients with sputum smear-positive pulmonary tuberculosis.

The early bactericidal activity (EBA) of an antituberculosis agent is the rate of decrease in viable colony-forming units (CFU) per milliliter of sputum during the first 2 d of treatment of patients with previously untreated smear-positive pulmonary tuberculosis. The objective of this open randomized study was to evaluate the EBA of the combination of amoxicillin 3 g and clavulanic acid 750 mg. Ten patients with a mean age of 34 y and a mean weight of 56 kg received amoxicillin/clavulanic acid and 5 patients with a mean age of 34 y and a mean weight of 57 kg received no drug. In the patients receiving 1 dose of amoxicillin/clavulanic acid daily for 2 d the mean log10CFU/ml of sputum before treatment was 6.7402 (SD 0.539) and after 2 d of treatment 6.7046 (SD 0.609); the corresponding values in patients receiving no drug were 6.7823 (SD 0.563) and 6.7502 (SD 0.673), respectively. The EBA of 0.018 (SD 0.130) in patients receiving amoxicillin/clavulanic acid did not differ significantly from that of 0.016 (SD 0.069) in patients receiving no drug. It is unlikely that the combination of amoxicillin/clavulanic acid has an important place in the treatment of tuberculosis with the exception of those patients with multidrug-resistant tuberculosis who are otherwise therapeutically destitute.

The early bactericidal activity of amikacin in pulmonary tuberculosis.

SETTING: Stellenbosch University, a tertiary care hospital in Cape Town, South Africa. OBJECTIVE: To determine the early bactericidal activity (EBA) of amikacin in dosages of 5 mg/kg, 10 mg/kg and 15 mg/kg body weight in comparison to that of isoniazid 6 mg/kg body weight or no drug. DESIGN: An open, randomised trial. PATIENTS: Patients with previously untreated, sputum smear-positive pulmonary tuberculosis. INTERVENTION: Patients received amikacin 5 mg/kg (12 patients), 10 mg/kg (13 patients) or 15 mg/kg (15 patients), isoniazid 6 mg/kg (9 patients) or no drug (10 patients). RESULTS: The rate of decrease in log viable colony forming units of Mycobacterium tuberculosis per ml of sputum per day during the first 2 days of treatment with amikacin 5 mg/kg, 10 mg/kg and 15 mg/kg was 0.041 (SD 0.100), 0.045 (SD 0.144) and 0.052 (SD 0.096), respectively, 0.515 (SD 0.173) in the patients receiving isoniazid 6 mg/kg, and 0.041 (SD 0.113) in those receiving no drug. The EBA found in patients receiving amikacin did not differ significantly from that of the no drug group. However, as the EBA in the no drug group was the highest ever encountered at Stellenbosch University, the mean in patients receiving drug was tested against 0 and found to differ significantly (P = 0.03), suggesting minimal activity. Mean amikacin serum concentrations 1 hour after intramuscular drug administration were 13.5 microg/ml, 26.7 microg/ml and 39.2 microg/ml in the patients receiving 5 mg, 10 mg and 15 mg per kg body weight, respectively. CONCLUSION: Despite serum concentrations well in excess of the minimal inhibitory concentration of 2-4 microg/ml, the EBA of amikacin in patients with smear-positive pulmonary tuberculosis was only just detectable.

Early bactericidal activity of paromomycin (aminosidine) in patients with smear-positive pulmonary tuberculosis.

The early bactericidal activity of the aminoglycoside paromomycin (aminosidine) in doses of 7.5 and 15 mg/kg of body weight was measured in 22 patients with previously untreated smear-positive pulmonary tuberculosis. The fall in log(10) CFU per milliliter of sputum per day during the first 2 days of treatment for 7 patients receiving a paromomycin dosage of 7.5 mg/kg/day was 0.066, with a standard deviation (SD) of 0.216 and confidence limits from -0.134 to 0.266, and that for 15 patients receiving 15 mg/kg/day was 0.0924, with an SD of 0.140 and confidence limits from 0.015 to 0.170. The difference between the mean and zero was not significant for the 7. 5-mg/kg dose group but was significant for the 15-mg/kg dose group (t = 2.55, P = 0.023). Since paromomycin has no cross-resistance with streptomycin and has no greater toxicity than other aminoglycosides, these results suggest that it has the potential to substitute for streptomycin in antituberculosis regimens and may be a particularly valuable addition to the drug armamentarium for the management of multidrug-resistant tuberculosis.

Flap repair: an effective strategy for minimising sexual morbidity associated with the surgical management of vulval intra epithelial neoplasia.

OBJECTIVE: To assess the sexual function after local excision and flap repair for symptomatic vulval intraepithelial neoplasia (VIN). STUDY DESIGN: A retrospective analysis of five sexually active women who had persistent, symptomatic VIN diagnosed in a dedicated tertiary referral vulval clinic and treated with local excision and flap repair. Sexual function was assessed using a modified version of the Sabbatsberg Sexual Self-Rating Scoring (SRS) system. RESULTS: The mean age of the cohort was 32 years (range 30 to 51). Four patients had previously been unsuccessfully treated with local excision. Follow up ranged from 5 to 33 months. The SRS scores were 90, 90, 81, 72 and 25. Endogenous depression may explain this last score. There has been no recurrence of VIN. CONCLUSION: In sexually active women with symptomatic VIN III, a flap reconstruction should be considered in addition to local excision as the treatment of choice.

Flap repair: an effective strategy for minimising sexual morbidity associated with the surgical management of vulval intra epithelial neoplasia

Objective: To assess the sexual function after local excision and flap repair for symptomatic vulval intraepithelial neoplasia (Vin). Study Design: A retrospective analysis of five sexually active women who had persistent, symptomatic VIN diagnosed in a dedicated tertiary referral vulval clinic and treated with local excision and flap repair. Sexual function was assessed using a modified version of the Sabbatsberg Sexual Self-Rating Scoring (SRS) system. Results: The mean age of the cohort was 32 years (range 30 to 51). Four patients had previously been unsuccessfully treated with local excision. Follow up ranged from 5 to 33 months. The SRS scores were 90, 90, 81, 72 and 25. Endogenous depression may explain this last score. There has been no recurrence of VIN. Conclusion: In sexually active women with symptomatic VIN III, a flap reconstruction should be considered in addition to local excision as the treatment of choice (AU)

Practical management of therapeutic diphenylhydantoin concentrations in children.

OBJECTIVE: Development of easy, practical methods for the management and optimisation of therapeutic diphenylhydantoin (DPH) concentrations in children. DESIGN: Investigation of DPH concentration profiles and pharmacokinetic parameters in children with poorly controlled epilepsy. Subsequent determination of individual-specific DPH maintenance dosage and volume of distribution data suitable for use in routine therapeutic concentration management procedures. SETTING: Department of Paediatrics and Child Health and Department of Pharmacology, University of Stellenbosch, Tygerberg Hospital. SUBJECTS: Children of both sexes between the ages of 4 and 12 years with poorly controlled epilepsy receiving DPH as sole medication. RESULTS: In all subjects evaluated epilepsy was unsatisfactorily controlled because of inadequate DPH dosage regimens. Individual-specific maintenance dosage and volume of distribution data could be calculated for all individuals participating in the trial. The calculated data were suitable for use in routine management procedures and in no instance was it necessary to recalculate parameters in a 12-month follow-up period subsequent to evaluation. CONCLUSIONS: Therapeutic DPH concentration profiles can be managed satisfactorily in children in individual-specific DPH pharmacokinetic parameters are derived and skillfully applied.

Massive posterior fossa tuberculous abscess developing in a young child treated for miliary tuberculosis. Possible role of very rapid acetylation of isoniazid.

A 21-month-old infant presented with acute obstructive hydrocephalus due to a large tuberculous abscess in the posterior fossa 3 months after starting treatment for miliary tuberculosis. Insertion of a ventriculo-peritoneal shunt resulted in some clinical improvement but subsequent neurological deterioration occurred due to massive enlargement of the tuberculous abscess despite apparently adequate antituberculosis therapy. Repeated drainage procedures of the abscess eventually resulted in resolution and clinical improvement. As part of the workup for poor weight gain and the unusual clinical course, the patient's acetylation status for isoniazid was determined and found to be very rapid. Doubling the daily dose of isoniazid was followed by a dramatic weight increase and further clinical improvement. Decreasing the load of tuberculous antigen by draining the abscesses and increasing the pulse exposure of isoniazid is the best possible explanation for the clinical improvement finally seen in this patient.

The early bactericidal activity of isoniazid related to its dose size in pulmonary tuberculosis.

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.

The early bactericidal activity of ciprofloxacin in patients with pulmonary tuberculosis.

The early bactericidal activity (EBA) of ciprofloxacin (CIP) was measured in 80 patients with previously untreated, smear-positive pulmonary tuberculosis by counting viable bacilli in sputum collections during the first 2 d of treatment. Groups of about 10 patients were treated daily with graded doses of CIP or with 300 mg isoniazid or with no drug. The mean EBA, defined as the fall in log CFU/ ml sputum/d, increased from -0.011 in the no drug group to 0.046, 0.092, 0.121, and 0.205 in the groups receiving 250, 500, 1,000, or 1,500 mg CIP, respectively, a highly significant trend. These results demonstrate the antimycobacterial activity of CIP in high dosage, though the mean EBAs of 0.55 and 0.66 in two groups receiving isoniazid were much higher.

Trimodality of isoniazid elimination: phenotype and genotype in patients with tuberculosis.

The study was undertaken to show that polymorphic isoniazid elimination in humans is trimodal; that the acetylator genotype and eliminator phenotype of the individual patient are concordant; and that the differences in the pharmacokinetic parameters of fast, intermediate, and slow eliminator subgroups are statistically significant. Sixty adult patients of both sexes and of mixed race with tuberculosis participated in the trial. The apparent elimination rate constant (k, h(-1)) and the area under the isoniazid concentration-time curve (AUC, mg/L/h), over the interval 2 to 6 h after oral isoniazid were determined in all patients; NAT2 allele composition was determined in 47 patients. Serum INH concentrations were determined by HPLC and genotypes by PCR/restriction enzyme analysis. Three eliminator phenotypes could be distinguished, and concordance between the phenotype and the genotype of the individual could be demonstrated. The isoniazid concentration-time profiles of the three eliminator subgroups were significantly different (p < 0.05). The NAT2*12A allele, which codes for fast acetylation, has a high frequency in the population studied, the intermediate acetylator genotype is constituted of codominant fast and slow alleles, and the distribution of phenotypes/genotypes in the population is consistent with Hardy-Weinberg predictions. The therapeutic implications of polymorphic isoniazid metabolism are discussed.

Fluctuation of the volume of distribution of amikacin and its effect on once-daily dosage and clearance in a seriously ill patient.

OBJECTIVE: The main aim of the trial was to determine the extent to which the volume of distribution of amikacin fluctuates in a seriously ill patient receiving copious quantities of i.v. fluid over an extended term of treatment. The impact of the volume fluctuation on amikacin therapeutic peak concentrations was also assessed. DESIGN AND SETTING: The case report describes a young, previously healthy male adult admitted to the surgical ICU of a teaching hospital following trauma to the head and central nervous system. INTERVENTION: The patient received 1 g of amikacin once-daily i.v. for 35 consecutive days as part of an antimicrobial regimen. Blood samples were drawn for routine amikacin concentration determinations on 14 occasions, extending over the entire term of treatment, from which the required pharmacokinetic parameters were determined. RESULTS: The volume of distribution of amikacin varied extensively from 0.27 to 0.61 l/kg (normal range 0.27 +/- 0.06 1/kg) notwithstanding the fact that amikacin clearance remained satisfactorily high throughout the term of treatment. CONCLUSIONS: Once-daily therapeutic amikacin concentrations fluctuate extensively and rapidly in the seriously ill patient receiving copious quantities of i.v. fluids, despite competent renal function. The volume expansion seen in our patient is difficult to account for in terms of the extracellular fluid compartment only. RECOMMENDATIONS: (a) Once-daily regimen amikacin peak concentrations should be frequently monitored in the seriously ill patient; (b) once-daily amikacin regimens are best monitored using blood specimens drawn at 1 and 6-8 h post administration.

Early bactericidal activity of ethambutol, pyrazinamide and the fixed combination of isoniazid, rifampicin and pyrazinamide (Rifater) in patients with pulmonary tuberculosis.

The early bactericidal activity (EBA) of ethambutol, pyrazinamide and the fixed combination of isoniazid, rifampicin and pyrazinamide (Rifater: Mer National) was evaluated in patients with pulmonary tuberculosis who were sputum-positive on microscopy for acid-fast bacilli. Twenty-eight patients (mean age 33 years and weight 51 kg on average; range 40-59 kg) were studied. The fall in viable counts of Mycobacterium tuberculosis in sputum collections during the 2 days following the start of treatment was estimated from counts of colony-forming units (CFUs) of M. tuberculosis per ml of sputum cultured on selective 7H10 agar medium. The EBA for ethambutol determined in 9 patients was 0.245 +/- 0.046, log10 CFU/ml sputum/day, that for pyrazinamide was 0.003 +/- 0.014 log10 CFU/ml sputum/day and that for Rifater 0.558 +/- 0.054 log10 CFU/ml sputum/day. The results obtained are similar to those reported in a previous study of the first 2 days of treatment, but in smaller numbers of patients, and confirm the moderate EBA of ethambutol while pyrazinamide is again shown to have very little EBA. Rifater has a marked EBA which may be due mainly to the action of isoniazid. This methodology may be valuable in the rapid evaluation of the bactericidal activity of new antituberculosis agents and the comparison of different dose sizes of agents of the same class.