Delamanid (OPC-67683) is a novel mycolic acid biosynthesis inhibitor active against Mycobacterium tuberculosis at a low minimum inhibitory concentration.
Forty-eight patients with smear-positive ...tuberculosis (63% male; 54.7 ± 9.9 kg; 30.7 ± 10.8 years) were randomly assigned to receive delamanid 100, 200, 300 or 400 mg daily for 14 days. Colony forming units (cfu) of M. tuberculosis were counted on agar plates from overnight sputum collections to calculate early bactericidal activity (EBA), defined as fall in log(10) cfu/ml sputum/day.
The EBA of delamanid was monophasic and not significantly different between dosages; however, more patients receiving 200 mg (70%) and 300 mg (80%) experienced a response of ≥0.9 log(10) cfu/ml sputum decline over 14 days than those receiving 100 mg (45%) and 400 mg (27%). The average EBA of all dosages combined (0.040 ± 0.056 log(10) cfu/ml sputum/day) was significant from day 2 onward. Delamanid exposure was less than dosage-proportional, reaching a plateau at 300 mg, likely due to dose-limited absorption. Moderate but significant correlation was found between C(max) and EBA, indicating exposure dependence. Delamanid was well tolerated without significant toxicity.
Delamanid at all dosages was safe, well tolerated and demonstrated significant exposure-dependent EBA over 14 days, supporting further investigation of its pharmacokinetics and anti-tuberculosis activity.
Introduction
This study explores the uses of microcalorimetry to detect Mycobacterium tuberculosis (TB) in sputum. Microcalorimetry measures metabolic heat evolution during cellular proliferation of ...tuberculosis (TB) and is considered as a possible alternative to conventional diagnostic tools.
Objectives
To compare the time to detection (TTD) from the BACTEC™ MGIT™ 960 and the calScreener™ calorimetric system.
Methods
Sixty‐four sputa samples were selected from patients with confirmed pulmonary tuberculosis. Those sample were then decontaminated and analysed using calorimetry and BACTEC MGIT 960 system.
Results
The incubation period until detection of M. tuberculosis in the sample was 8·5 ± 3·7 days for the MGIT system and 10·1 ± 4·1 days (mean ± SD) for calorimetry.
Conclusions
The microincubations in the 48‐well format calScreener offers potential for rapid and accurate diagnostic of TB in different samples. Although TTD from calorimetry is still longer than with the MGIT, our findings suggest that several improvements are possible. Still, the instrument is ideal for continuous, real‐time analysis of net metabolic heat release of limited sample numbers.
Significance and Impact of the Study
Our result emphasizes that with further optimization, calorimetry can become an alternative detection method for tuberculosis.
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.
Summary Quantification of mycobacteria in sputum from pulmonary tuberculosis patients has been used to evaluate patient's response to treatment since the earliest days of anti-tuberculosis ...chemotherapy. More recently the early bactericidal activity (EBA) of anti-tuberculosis agents, measured as the fall in viable colony forming units of Myco-bacterium tuberculosis in sputum early in therapy, has been shown to be an objective, repeatable measure of the ability of an agent to kill the metabolically active bacilli found in the sputum of patients with sputum microscopy smear-positive pulmonary tuberculosis. EBA offers an opportunity to rapidly demonstrate that a new agent has a detectable anti-tuberculosis effect in a relatively small number of patients, what the most appropriate dose is to take forward to more extensive clinical trials and allows the study of the relationship between pharmacokinetics and bactericidal activity and toxicity of the relevant agent.
Thoracoscopy is the most accurate yet most expensive tool for establishing the diagnosis of tuberculous (TB) pleurisy. However, most high TB-incidence regions have limited financial resources, lack ...the infrastructure needed for routine thoracoscopy and require an alternative, cost-effective diagnostic approach for pleural effusions. Altogether, 51 patients with undiagnosed exudative pleural effusions were recruited for a prospective, direct comparison between bronchial wash, pleural fluid microbiology and biochemistry (adenosine deaminase (ADA) and cell count), closed needle biopsy, and medical thoracoscopy. The final diagnosis was TB in 42 patients (82%), malignancy in five (10%) and idiopathic in four patients (8%). Sensitivity of histology, culture and combined histology/culture was 66, 48 and 79%, respectively for closed needle biopsy and 100, 76 and 100%, respectively for thoracoscopy. Both were 100% specific. Pleural fluid ADA of > or = 50 U x L(-1) was 95% sensitive and 89% specific. Combined ADA, lymphocyte/neutrophil ratio > or = 0.75 plus closed needle biopsy reached 93% sensitivity and 100% specificity. A combination of pleural fluid adenosine deaminase, differential cell count and closed needle biopsy has a high diagnostic accuracy in undiagnosed exudative pleural effusions in areas with high incidences of tuberculosis and might substitute medical thoracoscopy at considerably lower expense in resource-poor countries.
According to the World Health Organization (WHO), tuberculosis is the leading cause of death attributed to a single microbial pathogen worldwide. In addition to the large number of patients affected ...by tuberculosis, the emergence of Mycobacterium tuberculosis drug‐resistance is complicating tuberculosis control in many high‐burden countries. During the past 5 years, the global number of patients identified with multidrug‐resistant tuberculosis (MDR‐TB), defined as bacillary resistance at least against rifampicin and isoniazid, the two most active drugs in a treatment regimen, has increased by more than 20% annually. Today we experience a historical peak in the number of patients affected by MDR‐TB. The management of MDR‐TB is characterized by delayed diagnosis, uncertainty of the extent of bacillary drug‐resistance, imprecise standardized drug regimens and dosages, very long duration of therapy and high frequency of adverse events which all translate into a poor prognosis for many of the affected patients. Major scientific and technological advances in recent years provide new perspectives through treatment regimens tailor‐made to individual needs. Where available, such personalized treatment has major implications on the treatment outcomes of patients with MDR‐TB. The challenge now is to bring these adances to those patients that need them most.
Content List ‐ Read more articles from the symposium: “The 10th International Conference on the Pathogenesis of Mycobacterial Infections”.
Summary 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 ( Cmax ) 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 Cmax than adult volunteers and that adults, both volunteers and patients established on RMP reach higher Cmax 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.
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