sq-109 and Tuberculosis--Pulmonary

Although treatment of drug-susceptible tuberculosis (TB) under ideal conditions may be successful in >or=95% of cases, cure rates in the field are often significantly lower due to the logistical challenges of administering and properly supervising the intake of combination chemotherapy for 6-9 months. Success rates are far worse for multidrug-resistant and extensively drug-resistant TB cases. There is general agreement that new anti-TB drugs are needed to shorten or otherwise simplify treatment for drug-susceptible and multidrug-resistant/extensively drug-resistant-TB, including TB associated with HIV infection. For the first time in over 40 years, a nascent pipeline of new anti-TB drug candidates has been assembled. Eleven candidates from seven classes are currently being evaluated in clinical trials. They include novel chemical entities belonging to entirely new classes of antibacterials, agents approved for use against infections other than TB, and an agent already approved for limited use against TB. In this article, we review the current state of TB treatment and its limitations and provide updates on the status of new drugs in clinical trials. In the conclusion, we briefly highlight ongoing efforts to discover new compounds and recent advances in alternative drug delivery systems.

Topics: Adamantane; Animals; Antitubercular Agents; Carbapenems; Clinical Trials as Topic; Diarylquinolines; Drug Delivery Systems; Ethylenediamines; Fluoroquinolones; Humans; Isonicotinic Acids; Mice; Mycobacterium tuberculosis; Nitroimidazoles; Oxazolidinones; Patient Compliance; Pyrroles; Quinolines; Rifamycins; Tuberculosis, Pulmonary

It is estimated that a third of the world's population is currently infected with tuberculosis, leading to 1.6 million deaths annually. The current drug regimen is 40 years old and takes 6-9 months to administer. In addition, the emergence of drug resistant strains and HIV co-infection mean that there is an urgent need for new anti-tuberculosis drugs. The twenty-first century has seen a revival in research and development activity in this area, with several new drug candidates entering clinical trials. This review considers new potential first-line anti-tuberculosis drug candidates, in particular those with novel mechanisms of action, as these are most likely to prove effective against resistant strains. A brief overview of current first-line and recent drugs (such as fluoroquinolones, rifampicin and isoniazid analogues) is initially presented. This is followed by a description of structure-activity relationships, in vitro and in vivo activity, pharmacokinetics, mechanism of action, combination regimens and clinical trials of the new drug candidates SQ109, PA-824, OPC-67683, TMC207 and others.

Topics: Adamantane; Animals; Antitubercular Agents; Diarylquinolines; Drug Design; Drug Resistance, Multiple, Bacterial; Ethylenediamines; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Quinolines; Structure-Activity Relationship; Tuberculosis, Pulmonary

The current 6-month tuberculosis (TB) therapy is suboptimal with significant side effects and a poor patient compliance problem that frequently selects drug-resistant organisms. The increasing drug-resistant TB problem highlights the need to develop new and more effective drugs. Significant progress has been made recently with several new drug candidates currently in clinical trials. Improved understanding of persister biology and development of persister drugs are likely to be important for developing a more effective therapy.

Topics: Adamantane; AIDS-Related Opportunistic Infections; Animals; Anti-Bacterial Agents; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Drugs, Investigational; Ethylenediamines; Extensively Drug-Resistant Tuberculosis; Fluoroquinolones; Humans; Isoniazid; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Rifampin; Treatment Refusal; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Tuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis.. We did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15-20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15-20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186).. Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22-2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3-5 adverse events, with similar proportions in each arm.. A dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost.. The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC).

Topics: Adamantane; Adult; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Ethylenediamines; Female; Fluoroquinolones; Humans; Isoniazid; Male; Moxifloxacin; Pyrazinamide; Rifampin; South Africa; Tanzania; Tuberculosis, Pulmonary

SQ109, an asymmetrical diamine, is a novel anti-TB drug candidate. This first study in patients was done to determine safety, tolerability, pharmacokinetics and bacteriological effect of different doses of SQ109 alone and in combination with rifampicin when administered over 14 days.. Smear-positive pulmonary TB patients were randomized into six groups of 15 to receive once-daily oral treatment with 75, 150 or 300 mg of SQ109, rifampicin (10 mg/kg body weight), rifampicin plus 150 mg of SQ109, or rifampicin plus 300 mg of SQ109 for 14 days. Patients were hospitalized for supervised treatment, regular clinical, biochemical and electrocardiographic safety assessments, pharmacokinetic profiling and daily overnight sputum collection.. SQ109 was safe and generally well tolerated. Mild to moderate dose-dependent gastrointestinal complaints were the most frequent adverse events. No relevant QT prolongation was noted. Maximum SQ109 plasma concentrations were lower than MICs. Exposure to SQ109 (AUC0-24) increased by drug accumulation upon repeated administration in the SQ109 monotherapy groups. Co-administration of SQ109 150 mg with rifampicin resulted in decreasing SQ109 exposures from day 1 to day 14. A higher (300 mg) dose of SQ109 largely outweighed the evolving inductive effect of rifampicin. The daily fall in log cfu/mL of sputum (95% CI) was 0.093 (0.126-0.059) with rifampicin, 0.133 (0.166-0.100) with rifampicin plus 150 mg of SQ109 and 0.089 (0.121-0.057) with rifampicin plus 300 mg of SQ109. Treatments with SQ109 alone showed no significant activity.. SQ109 alone or with rifampicin was safe over 14 days. Upon co-administration with rifampicin, 300 mg of SQ109 yielded a higher exposure than the 150 mg dose. SQ109 did not appear to be active alone or to enhance the activity of rifampicin during the 14 days of treatment.

Topics: Adamantane; Adult; Antitubercular Agents; Drug Therapy, Combination; Ethylenediamines; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

Dormant, slow-growing, antibiotic-tolerant Mycobacterium tuberculosis undermine the shortening of tuberculosis treatment to less than 6 months and are thought to be characterised by intracellular lipid bodies. Antibiotic effects on such persisting bacilli escape evaluation as they cannot be readily cultured. We identified cells containing lipid bodies in sputum smears from 86 newly diagnosed pulmonary tuberculosis patients and monitored these cells daily in 42 patients over the first 14 days of treatment with rifampicin, the experimental compound SQ-109, or both agents combined. Counts of Nile-Red-positive lipid-body containing cells were correlated with those of Auramine-O-positive cells and colony forming units of viable Mycobacterium tuberculosis on agar plates. Rifampicin but not SQ-109 significantly reduced colony forming units but all treatments distinctively and significantly changed the proportions of lipid body-containing bacilli and viable Mycobacterium tuberculosis. Monitoring lipid-body containing bacilli in sputum during treatment with experimental antituberculosis regimens may identify putative treatment-shortening regimens.

Topics: Adamantane; Antitubercular Agents; Bacterial Load; Benzophenoneidum; Colony Count, Microbial; Drug Monitoring; Drug Therapy, Combination; Ethylenediamines; Fluorescent Dyes; Humans; Lipid Droplets; Microscopy, Fluorescence; Mycobacterium tuberculosis; Oxazines; Predictive Value of Tests; Rifampin; South Africa; Sputum; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary