Florian von Groote-Bidlingmaier

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 One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol.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).

Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis

BACKGROUND New antituberculosis regimens are urgently needed to shorten tuberculosis treatment. Following on from favourable assessment in a 2 week study, we investigated a novel regimen for efficacy and safety in drug-susceptible and multidrug-resistant (MDR) tuberculosis during the first 8 weeks of treatment. METHODS We did this phase 2b study of bactericidal activity--defined as the decrease in colony forming units (CFUs) of Mycobacterium tuberculosis in the sputum of patients with microscopy smear-positive pulmonary tuberculosis-at eight sites in South Africa and Tanzania. We enrolled treatment-naive patients with drug-susceptible, pulmonary tuberculosis, who were randomly assigned by computer-generated sequences to receive either 8 weeks of moxifloxacin, 100 mg pretomanid (formerly known as PA-824), and pyrazinamide (MPa100Z regimen); moxifloxacin, 200 mg pretomanid, and pyrazinamide (MPa200Z regimen); or the current standard care for drug-susceptible pulmonary tuberculosis, isoniazid, rifampicin, PZA, and ethambutol (HRZE regimen). A group of patients with MDR tuberculosis received MPa200Z (DRMPa200Z group). The primary outcome was bactericidal activity measured by the mean daily rate of reduction in M tuberculosis CFUs per mL overnight sputum collected once a week, with joint Bayesian non-linear mixed-effects regression modelling. We also assessed safety and tolerability by monitoring adverse events. This study is registered with ClinicalTrials.gov, number NCT01498419. FINDINGS Between March 24, 2012, and July 26, 2013 we enrolled 207 patients and randomly assigned them to treatment groups; we assigned 60 patients to the MPa100Z regimen, 62 to the MPa200Z regimen, and 59 to the HRZE regimen. We non-randomly assigned 26 patients with drug-resistant tuberculosis to the DRMPa200Z regimen. In patients with drug-susceptible tuberculosis, the bactericidal activity of MPa200Z (n=54) on days 0-56 (0·155, 95% Bayesian credibility interval 0·133-0·178) was significantly greater than for HRZE (n=54, 0·112, 0·093-0·131). DRMPa200Z (n=9) had bactericidal activity of 0·117 (0·070-0·174). The bactericidal activity on days 7-14 was strongly associated with bactericidal activity on days 7-56. Frequencies of adverse events were similar to standard treatment in all groups. The most common adverse event was hyperuricaemia in 59 (29%) patients (17 [28%] patients in MPa100Z group, 17 [27%] patients in MPa200Z group, 17 [29%] patients. in HRZE group, and 8 [31%] patients in DRMPa200Z group). Other common adverse events were nausea in (14 [23%] patients in MPa100Z group, 8 [13%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 8 [31%] patients in DRMPa200Z group) and vomiting (7 [12%] patients in MPa100Z group, 7 [11%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 4 [15%] patients in DRMPa200Z group). No on-treatment electrocardiogram occurrences of corrected QT interval more than 500 ms (an indicator of potential of ventricular tachyarrhythmia) were reported. No phenotypic resistance developed to any of the drugs in the regimen. INTERPRETATION The combination of moxifloxacin, pretomanid, and pyrazinamide, was safe, well tolerated, and showed superior bactericidal activity in drug-susceptible tuberculosis during 8 weeks of treatment. Results were consistent between drug-susceptible and MDR tuberculosis. This new regimen is ready to enter phase 3 trials in patients with drug-susceptible tuberculosis and MDR-tuberculosis, with the goal of shortening and simplifying treatment. FUNDING Global Alliance for TB Drug Development.

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.

Transthoracic ultrasonography for the respiratory physician.

Transthoracic ultrasonography is still not utilized to its full potential by respiratory physicians, despite being a well-established and validated imaging modality. It allows for an immediate and mobile assessment that can potentially augment the physical examination of the chest. Ultrasound (US)-assisted procedures can be performed by a single clinician with no sedation and with minimal monitoring, even outside of theatre. The main indications for the use of transthoracic US are: the qualitative and quantitative description of pleu-ral effusions, pleural thickening, diaphragmatic dysfunction and chest-wall and pleural tumours. It may also be used to visualise lung tumours and other parenchymal pulmonary processes provided they abut the pleura. It is at least as sensitive as chest radiographs as far as the detection of a pneumothorax is concerned. It is the ideal tool to assist with thoracocentesis and drainage of effusions. The US-assisted fine-needle aspiration and/or cutting-needle biopsy of extrathoracic lymph nodes, lesions arising from the chest wall, pleura, peripheral lung and mediastinum, are safe and have a high yield in the hands of chest physicians. US may also guide the aspiration and biopsy of diffuse pulmonary infiltrates, consolidations and lung abscesses, provided the chest wall is abutted. Advanced applications of transthoracic US include the diagnosis of pulmonary embolism.

Novel drugs against tuberculosis: a clinician's perspective

The United Nations Millennium Development Goal of reversing the global spread of tuberculosis by 2015 has been offset by the rampant re-emergence of drug-resistant tuberculosis, in particular fluoroquinolone-resistant multidrug-resistant and extensively drug-resistant tuberculosis. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis. This review largely discusses six novel drugs that have been evaluated in phase II and III clinical trials, with focus on the clinical evidence for efficacy and safety, potential drug interactions, and prospect for using multiple novel drugs in new regimens. A review of the efficacy, safety, and potential of new drugs to improve TB therapy from the perspective of clinicians http://ow.ly/Das5l

The diagnostic yield and safety of ultrasound-assisted transthoracic biopsy of mediastinal masses.

Background: Ultrasound (US)-assisted transthoracic biopsy offers a less invasive alternative to surgical biopsy in the setting of mediastinal masses. Objectives: The aim of this 1-year prospective study was to assess the diagnostic yield and safety of a novel single-session sequential approach of US-assisted transthoracic fine-needle aspirations (TTFNA) with rapid on-site evaluation (ROSE) followed by cutting needle biopsies (CNB) performed by physicians on patients with anterosuperior mediastinal masses. Methods: US-assisted TTFNA with ROSE was performed on 45 consecutive patients (49.5 ± 27.7 years, 24 males), immediately followed by CNB where a provisional diagnosis of epithelial carcinoma or tuberculosis could not be established, provided a safety range could be assured. Results: TTFNA alone was deemed adequate by means of ROSE in 27 (60%) patients. CNB could be performed in 17 of the remaining 18. The on-site diagnosis corresponded to the final diagnosis in 26/45 (57.8%). An accurate cytological diagnosis was made in 33 (73.3%), and was more likely to be diagnostic in epithelial carcinoma and tuberculosis (28/30) than all other pathologies (5/15, p < 0.001). CNB yielded a diagnosis in 15/17 (88.2%). Overall, 42/45 patients were diagnosed by the single-session approach (93.3%). The final diagnoses included 41 neoplasms, with small cell lung cancer (n = 13) the commonest diagnosis. We observed no pneumothorax or major haemorrhage. Conclusions: A single-session sequential approach of US-assisted TTFNA with ROSE followed by CNB, where indicated, has a high diagnostic yield for anterosuperior mediastinal masses, is safe and offers an alternative to surgical biopsy.

The utility of ultrasound-guided thoracentesis and pleural biopsy in undiagnosed pleural exudates

We assessed the utility of ultrasound to guide the selection of closed pleural biopsy technique and site and to assess the respective contributions of repeat thoracentesis and closed pleural biopsy in 100 consecutive patients with undiagnosed pleural exudates. Thoracentesis was more likely to be diagnostic in TB than malignancy (77.8% vs 31.0%, p<0.001). The addition of ultrasound-guided biopsy increased the combined yield for all diagnoses from 48.0% to 90.0% (p<0.001), for malignancy from 31.0% to 89.7% (p<0.001) and for TB from 77.8% to 88.9% (p=0.688). Our findings suggest that this minimally invasive approach has a high diagnostic yield.

Blood loss during flexible bronchoscopy: a prospective observational study.

Background: Haemorrhage remains a complication of flexible bronchoscopy. Objectives: We aimed to measure the actual blood loss in patients at low risk of bleeding and to assess its association with the underlying pulmonary pathology, superior vena cava (SVC) syndrome, procedure(s) performed and laboratory values. Methods: We screened all patients scheduled for flexible bronchoscopy and enrolled 234 subjects over 18 months. Subjects with a history of haemorrhagic tendency, platelets <20 × 103/µl, a history of anti-coagulation or anti-platelet therapy and a history or clinical evidence of liver failure were excluded. Blood loss during the procedure was measured from aspirated secretions with a haemoglobin detector and categorised into minimal (<5 ml), mild (5–20 ml), moderate (20–100 ml) and severe bleeding (>100 ml). Results: Overall, 210 subjects had minimal, 19 had mild and 5 had moderate bleeding. No subject experienced severe blood loss. Patients with SVC syndrome had the highest mean blood loss (6.0 ml) when compared to bronchogenic carcinoma without SVC syndrome (p = 0.033) and other diagnosis (p = 0.026). The blood loss with trans-bronchial needle aspiration (TBNA, mean 3.4 ml) was significantly less than with TBNA combined with endobronchial or transbronchial biopsy (mean 5.0 ml, p < 0.001). Anaemia, a platelet count of 25–155 × 103/µl and an international normalized ratio of >1.3 were not associated with an increased risk of bleeding. Conclusions: We found no severe bleeding in this cohort preselected to have a low clinical risk of bleeding. Moreover, our data suggest that clinical screening and a platelet count ≥20 × 103/µl alone may be sufficient to identify low-risk patients.

Time to positivity in liquid culture predicts colony forming unit counts of Mycobacterium tuberculosis in sputum specimens

Time to liquid culture positivity (TTP) is a technically accessible and widely available measure of viable mycobacterial load in sputum samples. We describe the ability of TTP to predict colony forming unit counts of Mycobacterium tuberculosis from sputum samples collected before or during the first 14 days of antituberculosis therapy.

Speed of ascent during stair climbing identifies operable lung resection candidates.

Background: Preoperative evaluation of lung resection candidates with impaired pulmonary reserves includes measurement of aerobic capacity. Stair climbing is an attractive low-cost alternative to treadmill exercise testing but it lacks standardisation. Objectives: To directly compare stair climbing and treadmill exercise testing with respect to an established cut-off value for lung resection. Methods: We subjected 56 lung resection candidates to both symptom-limited treadmill exercise testing and stair climbing to a maximum of 20 m. Both exercise tests were monitored with the same portable spiroergometer. Subjects were on average 46.6 years old, 61% were male and 54% had FEV1/FVC < 70%. Mean FEV1 and DLCOc were 51.6 and 57.1%, respectively. Results: Mean altitude reached, exercise time, speed of ascent and peak VO2 were 16.9 m, 74 s, 14.7 m/min and 22.4 ml/min/kg, respectively, in 54 subjects completing stair climbing. Thirty-one subjects (58%) reached 20 m without stopping. Treadmill tests were completed by 51 subjects and lasted longer (432 s; p < 0.001), but VO2max was not different compared to stair climbing (22.7 ml/min/kg; p = 0.673). Speed of ascent was significantly correlated to both stair climbing peak VO2 (r = 0.63) and treadmill VO2max (r = 0.67). All 19 subjects (34%) who reached 20 m in 80 s or less (≥15 m/min) had a VO2max of ≥20 ml/min/kg. Conclusions: We found a clinically useful correlation between speed of ascent during stair climbing and VO2max during treadmill exercise testing. Climbing to 20 m with an average speed of ascent of ≥15 m/min accurately identified subjects qualifying for pneumonectomy according to established criteria.