Piet J. Becker

14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial

BACKGROUND New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development. METHODS In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851. FINDINGS The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0·233 [SD 0·128]) was significantly higher than that of bedaquiline (14; 0·061 [0·068]), bedaquiline-pyrazinamide (15; 0·131 [0·102]), bedaquiline-PA-824 (14; 0·114 [0·050]), but not PA-824-pyrazinamide (14; 0·154 [0·040]), and comparable with that of standard treatment (ten; 0·140 [0·094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol. INTERPRETATION PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens. FUNDING The Global Alliance for TB Drug Development (TB Alliance).

The effect of blood sample aging and food consumption on plasma total homocysteine levels

The stability of homocysteine in whole blood and plasma was investigated. Total homocysteine concentrations in whole blood increased rapidly to values in excess of 180% of the basal concentration if whole blood was left at ambient temperature. Sodium fluoride partially inhibited homocysteine accumulation, while refrigeration inhibited homocysteine accumulation for at least 4 h. Since intracellular concentrations of homocysteine were low, the results indicate continued metabolism of L-methionine to homocysteine after the blood sample had been obtained. In contrast to whole blood, homocysteine was stable in plasma, even at room temperature. Food consumption (normal breakfast) resulted in significantly lower plasma homocysteine concentrations, which returned to pre-prandial concentrations 8 h later. The results indicate that both blood sampling and food intake should be rigorously standardized in epidemiological studies to elucidate the possible role of elevated circulating homocysteine concentrations in premature vascular disease.

Facial soft-tissue thicknesses in the adult male Zulu

The morphometric method of forensic facial reconstruction rests heavily on the use of facial soft tissue depth measurements. In reconstructing the Negroid face, much use has been made of the tables of soft tissue thickness of American Negroid cadavers. However, the genetic complexities of American blacks are well known. In addition it is felt that measurements made on the living are of more value than those made on the dead. In view of this it was decided to set up a table of norms for facial soft tissue depths of the living Zulu, an African Negroid who has remained relatively free from genetic admixture with other populations. The tightly controlled sample consisted of 55 healthy male Zulus, aged 20 to 35. Tissue depths at established landmarks were measured from lateral and oblique cephalometric radiographs. These were then combined with ultrasonic readings at other landmarks on the subjects face to yield a comprehensive set of tissue depth data. This paper presents a set of average facial soft tissue depth measurements from the Zulu face that results in the development of a new profile. It also provides a method for linking two systems of measurement.

Superimposition and reconstruction in forensic facial identification: a survey

Forensic facial reconstruction, is the reproduction of the lost or unknown facial features of an individual, for the purposes of recognition and identification. It is generally accepted that facial reconstruction can be divided into four categories: (1) replacing and repositioning damaged or distorted soft tissues onto a skull; (2) the use of photographic transparencies and drawings in an identikit-type system; (3) the technique of graphic, photographic or video superimposition; (4) plastic or three-dimensional reconstruction of a face over a skull, using modelling clay. This paper sets out to review work done on both superimposition and plastic reconstruction, however, the authors believe that only the latter category can correctly be termed facial reconstruction. The survey is divided according to work done through anthropological evaluation of the skull, clinical examination and dissection of the soft tissues, as well as methods of measuring soft tissue thicknesses using tissue puncture, ultrasound, cephalometric radiography and magnetic resonance imaging. In addition, a method of the combined use of ultrasound and radiography to collect a wider range of facial soft tissue depths and a method of producing skull and face profiles are outlined.

Phase II Dose-Ranging Trial of the Early Bactericidal Activity of PA-824

ABSTRACT PA-824 is a novel nitroimidazo-oxazine under evaluation as an antituberculosis agent. A dose-ranging randomized study was conducted to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive adult pulmonary-tuberculosis patients to find the lowest dose giving optimal bactericidal activity (EBA). Fifteen patients per cohort received oral PA-824 in doses of 50 mg, 100 mg, 150 mg, or 200 mg per kg body weight per day for 14 days. Eight subjects received once-daily standard antituberculosis treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) as a positive control. The primary efficacy endpoint was the mean rate of decline in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log10 CFU/day/ml sputum (± standard deviation). The mean 14-day EBA of HRZE was consistent with previous studies (0.177 ± 0.042), and that of PA-824 at 50 mg, 100 mg, 150 mg, and 200 mg was 0.063 ± 0.058, 0.091 ± 0.073, 0.078 ± 0.074, and 0.112 ± 0.070, respectively. Although the study was not powered for testing the difference between arms, there was a trend toward significance, indicating a lower EBA at the 50-mg dose. Serum PA-824 levels were approximately dose proportional with respect to the area under the time-concentration curve. All doses were safe and well tolerated with no dose-limiting adverse events or clinically significant QTc changes. A dose of 100 mg to 200 mg PA-824 daily appears to be safe and efficacious and will be further evaluated as a component of novel antituberculosis regimens for drug-sensitive and drug-resistant tuberculosis.

CD4+ lymphocyte count in African patients co-infected with HIV and tuberculosis.

The objectives of this study were (a) to compare the CD4+ lymphocyte profiles over time of two groups of patients hospitalized for tuberculosis (TB) treatment [a group of patients with TB only (TB group) and a group dually infected by HIV and TB (HIV/TB group)] and (b) to assess the usefulness of the total lymphocyte count (TLC) as a surrogate of the CD4+ lymphocyte count in the HIV/TB group. A total of 345 patients were enrolled in the study of whom 104 (29.8%) were HIV seropositive (HIV/TB). On admission, the CD4+ lymphocyte counts of the HIV/TB cohort were significantly lower than the TB group with medians of 230 (interquartile range, 90-475) and 630 (500-865), respectively (p < 0.0001). The CD4+ lymphocyte count increased significantly in both cohorts on routine TB treatment. A TLC of 1,300-1,500 cells/mm3 was found to be predictive of a CD4+ lymphocyte count of < or = 200 cells/mm3 both on admission and after 1 month of TB therapy. We conclude from this study that the positive influence of TB therapy on the CD4+ lymphocyte count strongly suggests an additional avenue of influence on the course of HIV infection, whereas the usefulness of the TLC as a surrogate estimation of CD4+ lymphocyte count in HIV/TB patients has important implications for the developing world.

The BEST study--a prospective study to compare business class versus economy class air travel as a cause of thrombosis.

BACKGROUND As many as 10% of airline passengers travelling without prophylaxis for long distances may develop a venous thrombosis. There is, however, no evidence that economy class travellers are at increased risk of thrombosis. OBJECTIVES A suitably powered prospective study, based on the incidence of deep-vein thrombosis (DVT) reported in previous studies on long-haul flights, was designed to determine the incidence of positive venous duplex scans and D-dimer elevations in low and intermediate-risk passengers, comparing passengers travelling in business and economy class. PATIENTS/METHODS Eight hundred and ninety-nine passengers were recruited (180 travelling business class and 719 travelling economy). D-dimers were measured before and after the flight. A value greater than 500 ng/ml was accepted as abnormal. A thrombophilia screen was conducted which included the factor V Leiden mutation, the prothombin 20210A mutation, protein C and S levels, antithrombin levels, and anticardiolipin antibodies immunoglobulin G (IgG) and immunoglobulin M (IgM). On arrival, lower limb compression ultrasonography of the deep veins was performed. Logistical regression analysis was used to determine the risk factors related to abnormally high D-dimer levels. RESULTS Only 434 subjects had a full venous duplex scan performed. None had ultrasonic evidence of venous thrombosis. Nine passengers tested at departure had elevated D-dimer levels and these volunteers were excluded from further study. Seventy-four of the 899 passengers had raised D-dimers on arrival. Twenty-two of 180 business class passengers (12%) developed elevated D-dimers compared with 52 of 719 economy class passengers (7%). There was no significant association between elevation of D-dimers and the class flown (odds ratio (OR) 0.61, p = 0.109). The factor V Leiden mutation, factor VIII levels and the use of aspirin were, however, associated with raised D-dimers (OR 3.36, p = 0.024; OR 1.01, p = 0.014; and OR 2.04, p = 0.038, respectively). Five hundred and five passengers were contacted within 6 months and none reported any symptoms of a clinical thrombosis or pulmonary embolus. CONCLUSION The incidence of ultrasonically proven DVT is much lower than previously reported. However, more than 10% of all passengers developed raised D-dimers, which were unrelated to the class flown. A rise in D-dimers is associated with an inherent risk of thrombosis and/or thrombophilia, demonstrates activation of both the coagulation and fibrinolytic systems during long-haul flights, and may indicate the development of small thrombi.

Oestrogen and progesterone receptor concentrations in leiomyoma and normal myometrium.

The content of cytoplasmic 17β oestradiol and progesterone receptors in human uterine leiomyoma and normal myometrium in the Negroid population was determined. Eighteen women of reproductive age, at various stages of the menstrual cycle, were included in the study. The serum oestrogen and progesterone concentrations were also measured. This is the first report in the literature in which oestrogen and progesterone receptors in leiomyoma are significantly higher than in normal myometrium (P=0·0002). The steroid dependence of the growth of leiomyomas may be related to the steroid receptor level. The presence of persistently high concentrations of oestrogen and progesterone receptors in leiomyoma should be helpful in the treatment of this benign tumour.

Attention and working memory in resident anaesthetists after night duty: group and individual effects

Aims: To investigate the effects of a single period of night duty on measures of attention and working memory in a group of residents (registrars) in anaesthesiology. Emphasis was placed on individual deficits using a reference point of the equivalent effect of a blood alcohol concentration (BAC) >0.05% determined by other researchers. Methods: There were 33 subjects aged 26–42 years. Night duty was performed on a weekly basis. Baseline assessments were conducted at either 08 15 or 08 55 preceding night duty and repeated 24–25 hours later, just after the completion of duty. Questionnaires included items regarding duration of sleep and the Stanford Sleepiness Scale. A battery of four reaction time (RT) tasks of increasing difficulty, lasting approximately 35 minutes, was administered on a personal computer. These ranged from simple RT to progressively more complex RT tasks incorporating working memory. A significant change was regarded as >15% deterioration in respect of speed or accuracy. Results: The mean duration of sleep preceding night duty was 7.04 hours and 1.66 hours during the period of night duty. Intergroup comparisons revealed significant prolongation in mean response speed in the first three tests. Mean accuracy was significantly reduced only in respect of the two more complex tests. A >15% deterioration in response speed occurred in up to 30% of subjects on a single task, rising to 52% (17/33) overall. Deterioration occurred in a patchy distribution in most subjects, involving no more than one or two of the four tasks. As regards accuracy, the prevalence of deterioration increased with task complexity. Conclusions: Results are in general agreement with previous group analyses. A new dimension was added by the analysis of a broad spectrum of individual response to sleep deprivation. The effects of sleep loss in residents cannot be overlooked, even in a relatively benign work schedule.

Randomized Dose-Ranging Study of the 14-Day Early Bactericidal Activity of Bedaquiline (TMC207) in Patients with Sputum Microscopy Smear-Positive Pulmonary Tuberculosis

ABSTRACT Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant (P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group (P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies.