More Tailored Approaches to Tuberculosis Treatment and Prevention.

Recent advances in the treatment of tuberculosis (TB) have led to improvements unprecedented in our lifetime. Decades of research in developing new drugs, especially for multidrug-resistant TB, have created not only multiple new antituberculous agents but also a new approach to development and treatment, with a focus on maximizing the benefit to the individual patient. Prevention of TB disease has also been improved and recognized as a critical component of global TB control. While the momentum is positive, it will take continued investment at all levels, especially training of new dedicated TB researchers and advocates around the world, to maintain this progress.

What clinic closure reveals about care for drug-resistant TB: a qualitative study.

BACKGROUND: There have been calls for "person-centered" approaches to drug-resistant tuberculosis (DR-TB) care. In 2020, Charles James Hospital in South Africa, which incorporated person-centered care, was closed. Patients were referred mid-course to a centralized, tertiary hospital, providing an opportunity to examine person-centered DR-TB and HIV care from the perspective of patients who lost access to it. METHODS: The impact of transfer was explored through qualitative interviews performed using standard methods. Analysis involved grounded theory; interviews were assessed for theme and content. RESULTS: After switching to the centralized site, patients reported being unsatisfied with losing access to a single clinic and pharmacy where DR-TB, HIV and chronic disease care were integrated. Patients also reported a loss of care continuity; at the decentralized site there was a single, familiar clinician whereas the centralized site had multiple, changing clinicians and less satisfactory communication. Additionally, patients reported more disease-related stigma and less respectful treatment, noting the loss of a "special place" for DR-TB treatment. CONCLUSION: By focusing on a DR-TB clinic closure, we uncovered aspects of person-centered care that were critical to people living with DR-TB and HIV. These perspectives can inform how care for DR-TB is operationalized to optimize treatment retention and effectiveness.

Population Pharmacokinetics of AZD-5847 in Adults with Pulmonary Tuberculosis.

AZD-5847 is a new oxazolidinone derivative under development for the treatment of tuberculosis (TB). Here we describe the population pharmacokinetics (PK) of AZD-5847 in patients with tuberculosis based on a recently completed phase II study. The study included 60 patients with drug-susceptible TB. Patients were randomized to four dosages (500 mg once daily, 1,200 mg once daily, 500 mg twice daily, and 800 mg twice daily). Patients were intensively sampled on days 1 and 14. AZD-5847 pharmacokinetics were best described with a two-compartment model with lag time (Tlag) for absorption. AZD-5847 bioavailability was nonlinear and plateaued at 800 mg. We performed deterministic simulation to compare the PK/pharmacodynamics (PD) of AZD-5847, linezolid, and sutezolid. AZD-5847 PK/PD in terms of both area under the concentration-time curve for the free, unbound fraction (fAUC)/MIC and time the free concentration was above the MIC (fT>MIC) were less favorable than those for linezolid and sutezolid. This could help explain the poor bactericidal activity of AZD-5847 in the recent phase II study.

Early Bactericidal Activity of AZD5847 in Patients with Pulmonary Tuberculosis.

AZD5847 is an oxazolidinone antibiotic with in vitro activity against Mycobacterium tuberculosis The objective of this study was to evaluate the antimycobacterial activity, safety, and pharmacokinetics of AZD5847 in patients with pulmonary tuberculosis. Groups of 15 treatment-naive, sputum smear-positive adults with pulmonary tuberculosis were randomly assigned to receive AZD5847 at one of four doses (500 mg once daily, 500 mg twice daily, 1,200 mg once daily, and 800 mg twice daily) or daily standard chemotherapy. The primary efficacy endpoint was the mean daily rate of change in the log10 number of CFU of M. tuberculosis per milliliter of sputum, expressed as the change in log10 number of CFU per milliliter of sputum per day. The mean 14-day activity of the combination of isoniazid, rifampin, ethambutol, and pyrazinamide (-0.163 log10 CFU/ml sputum/day; 95% confidence interval [CI], -0.193, -0.133 log10 CFU/ml sputum/day) was consistent with that found in previous studies. AZD5847 at 500 mg twice daily significantly decreased the number of CFU on solid medium (-0.039; 95% CI, -0.069, -0.009; P = 0.0048). No bactericidal activity was detected at doses of AZD5847 of 500 mg once daily (mean early bactericidal activity [EBA], 0.02 [95% CI, -0.01, 0.05]), 1,200 mg once daily (mean EBA, 0.02 [95% CI, -0.01, 0.05]), and 800 mg twice daily (mean EBA, 0.02 [95% CI, -0.01, 0.05]). AZD5847 at doses of both 500 mg and 800 mg twice daily also showed an increase in the time to a positive culture in MGIT liquid culture medium. Two serious adverse events (grade 4 thrombocytopenia and grade 4 hyperbilirubinemia) occurred in patients receiving AZD5847 at higher doses. AZD5847 dosed twice daily kills tubercle bacilli in the sputum of patients with pulmonary tuberculosis and has modest early bactericidal activity. (This study has been registered at ClinicalTrials.gov under registration no. NCT01516203.).

The need to accelerate access to new drugs for multidrug-resistant tuberculosis.

Approximately half a million people are thought to develop multidrug-resistant tuberculosis annually. Barely 20% of these people currently receive recommended treatment and only about 10% are successfully treated. Poor access to treatment is probably driving the current epidemic, via ongoing transmission. Treatment scale-up is hampered by current treatment regimens, which are lengthy, expensive, poorly tolerated and difficult to administer in the settings where most patients reside. Although new drugs provide an opportunity to improve treatment regimens, current and planned clinical trials hold little promise for developing regimens that will facilitate prompt treatment scale-up. In this article we argue that clinical trials, while necessary, should be complemented by timely, large-scale, operational research that will provide programmatic data on the use of new drugs and regimens while simultaneously improving access to life-saving treatment. Perceived risks - such as the rapid development of resistance to new drugs - need to be balanced against the high levels of mortality and transmission that will otherwise persist. Doubling access to treatment and increasing treatment success could save approximately a million lives over the next decade.

On estime à un demi-million le nombre de personnes qui contractent chaque année la tuberculose multirésistante. De nos jours, à peine 20% d'entre elles reçoivent le traitement recommandé, et seulement 10% environ sont traitées avec succès. L'accès limité au traitement est probablement responsable de l'épidémie actuelle qui se propage par une transmission continue. L'amélioration de l'accès au traitement est freinée par les schémas thérapeutiques actuels, lesquels sont très longs, chers, mal tolérés et difficiles à gérer dans les régions où résident la plupart des patients. Bien que de nouveaux médicaments permettent d'améliorer les schémas thérapeutiques, les essais cliniques actuels et prévus ne laissent que peu d'espoir quant au développement de schémas qui favoriseraient l'amélioration rapide de l'accès au traitement. Dans cet article, nous soutenons que les essais cliniques sont certes nécessaires, mais qu'ils doivent être accompagnés d'une recherche opérationnelle de grande ampleur effectuée en temps voulu. Cette recherche permettrait d'obtenir des données programmatiques sur l'utilisation des nouveaux médicaments et schémas tout en améliorant l'accès à un traitement pouvant sauver des vies. Les risques perçus ­ tels que le développement rapide d'une résistance aux nouveaux médicaments ­ doivent être mis en balance avec les taux élevés de mortalité et de transmission qui se maintiendraient sans cela. Doubler l'accès au traitement et accroître son efficacité permettrait de sauver environ un million de vies au cours de la décennie à venir.

Se estima que alrededor de 500.000 personas al año desarrollan tuberculosis multirresistente. Apenas el 20% de estas personas recibe un tratamiento recomendado y solo el 10% se somete a un tratamiento eficaz. Probablemente la epidemia actual, a través de la transmisión continua, se deba al escaso acceso al tratamiento. La ampliación del tratamiento se ve obstaculizada por los regímenes terapéuticos actuales, que son prolongados, caros, producen intolerancia y son complicados de administrar en los lugares donde residen los pacientes. A pesar de que los nuevos fármacos son una oportunidad de mejorar los regímenes terapéuticos, los ensayos clínicos actuales y planificados no ofrecen demasiadas esperanzas para desarrollar regímenes que faciliten una ampliación del tratamiento a corto plazo. En este artículo sostenemos que los ensayos clínicos, mientras sea necesario, deberían ir acompañados de una investigación operativa oportuna a gran escala que proporcione información programática sobre el uso de los nuevos fármacos y regímenes, mientras mejora el acceso a un tratamiento que salvará vidas. Los riesgos, como el rápido desarrollo de la resistencia a nuevos fármacos, deberían equilibrarse frente a los altos niveles de mortalidad y transmisión que, de otro modo, continuarán existiendo. Duplicar el acceso al tratamiento y aumentar su éxito podría salvar alrededor de un millón de vidas en la próxima década.

Aggressive regimens for multidrug-resistant tuberculosis reduce recurrence.

BACKGROUND: Recurrent tuberculosis disease occurs within 2 years in as few as 1% and as many as 29% of individuals successfully treated for multidrug-resistant (MDR) tuberculosis. A better understanding of treatment-related factors associated with an elevated risk of recurrent tuberculosis after cure is urgently needed to optimize MDR tuberculosis therapy. METHODS: We conducted a retrospective cohort study among adults successfully treated for MDR tuberculosis in Peru. We used multivariable Cox proportional hazards regression analysis to examine whether receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion from positive to negative was associated with a reduced rate of recurrent tuberculosis. RESULTS: Among 402 patients, the median duration of follow-up was 40.5 months (interquartile range, 21.2-53.4). Receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion was associated with a lower risk of recurrent tuberculosis (hazard ratio, 0.40 [95% confidence interval, 0.17-0.96]; P = .04). A baseline diagnosis of diabetes mellitus also predicted recurrent tuberculosis (hazard ratio, 10.47 [95% confidence interval, 2.17-50.60]; P = .004). CONCLUSIONS: Individuals who received an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion experienced a lower rate of recurrence after cure. Efforts to ensure that an aggressive regimen is accessible to all patients with MDR tuberculosis, such as minimization of sequential ineffective regimens, expanded drug access, and development of new MDR tuberculosis compounds, are critical to reducing tuberculosis recurrence in this population. Patients with diabetes mellitus should be carefully managed during initial treatment and followed closely for recurrent disease.

Caring for children with drug-resistant tuberculosis: practice-based recommendations.

The management of children with drug-resistant tuberculosis (DR-TB) is challenging, and it is likely that in many places, the roll-out of molecular diagnostic testing will lead to more children being diagnosed. There is a limited evidence base to guide optimal treatment and follow-up in the pediatric population; in existing DR-TB guidelines, the care of children is often relegated to small "special populations" sections. This article seeks to address this gap by providing clinicians with practical advice and guidance. This is achieved through review of the available literature on pediatric DR-TB, including research studies and international guidelines, combined with consensus opinion from a team of experts who have extensive experience in the care of children with DR-TB in a wide variety of contexts and with varying resources. The review covers treatment initiation, regimen design and treatment duration, management of comorbid conditions, treatment monitoring, adverse events, adherence promotion, and infection control, all within a multidisciplinary environment.

Comprehensive treatment of extensively drug-resistant tuberculosis.

BACKGROUND: Extensively drug-resistant tuberculosis has been reported in 45 countries, including countries with limited resources and a high burden of tuberculosis. We describe the management of extensively drug-resistant tuberculosis and treatment outcomes among patients who were referred for individualized outpatient therapy in Peru. METHODS: A total of 810 patients were referred for free individualized therapy, including drug treatment, resective surgery, adverse-event management, and nutritional and psychosocial support. We tested isolates from 651 patients for extensively drug-resistant tuberculosis and developed regimens that included five or more drugs to which the infecting isolate was not resistant. RESULTS: Of the 651 patients tested, 48 (7.4%) had extensively drug-resistant tuberculosis; the remaining 603 patients had multidrug-resistant tuberculosis. The patients with extensively drug-resistant tuberculosis had undergone more treatment than the other patients (mean [+/-SD] number of regimens, 4.2+/-1.9 vs. 3.2+/-1.6; P<0.001) and had isolates that were resistant to more drugs (number of drugs, 8.4+/-1.1 vs. 5.3+/-1.5; P<0.001). None of the patients with extensively drug-resistant tuberculosis were coinfected with the human immunodeficiency virus (HIV). Patients with extensively drug-resistant tuberculosis received daily, supervised therapy with an average of 5.3+/-1.3 drugs, including cycloserine, an injectable drug, and a fluoroquinolone. Twenty-nine of these patients (60.4%) completed treatment or were cured, as compared with 400 patients (66.3%) with multidrug-resistant tuberculosis (P=0.36). CONCLUSIONS: Extensively drug-resistant tuberculosis can be cured in HIV-negative patients through outpatient treatment, even in those who have received multiple prior courses of therapy for tuberculosis.

Blood exposure at the 2010 International Federation of Football Association World Cup: time for universal adaptation of universal precautions.

OBJECTIVE: Injuries involving blood exposure are relatively common in football. The goal of this observational study was to assess the use of universal precautions at the 2010 International Federation of Football Association (FIFA) World Cup. DESIGN: Observational descriptive study of more than 4000 minutes of FIFA World Cup football. SETTING: Televised matches of football in the 2010 FIFA World Cup in the Republic of South Africa. ASSESSMENT OF RISK FACTORS: Injuries with visible blood that were attended to by health care providers were recorded. MAIN OUTCOME MEASURES: Number of injuries with visible blood in which gloves were used by responders. RESULTS: Twenty-two significant bloody injuries were noted in more than 4000 minutes of play observed. In none of these cases were universal precautions implemented. CONCLUSIONS: This brief report shows the need for better implementation of universal precautions in football and other team sports.

Drug-Resistant Tuberculosis: A Glance at Progress and Global Challenges.

Multidrug-resistant Mycobacterium tuberculosis remains a major public health threat; its management poses a significant economic burden. Treatment requires a programmatic approach with access to laboratory services, second-line medications, and adequate clinical resources. In recent years, we have seen rapid developments in diagnostic techniques with whole genome sequencing-based drug susceptibility prediction now in reach, an array of new drugs that transform treatment regimens to purely oral formulations, and a steady stream of multinational trials that inform us about most efficient combinations. Our hope is that the current momentum keeps the ambitious goal to end tuberculosis in 2030 in reach.

Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study.

BACKGROUND: Mycobacterium tuberculosis strains that cause untreatable drug-resistant disease are a threat worldwide. We describe the treatment, management, and outcomes of patients with extensively drug-resistant tuberculosis in Tomsk, Russia. METHODS: We undertook a retrospective cohort study of 608 patients with multidrug resistant tuberculosis who had treatment in civilian or prison services, between Sept 10, 2000, and Nov 1, 2004, according to the treatment strategy recommended by WHO. Clinical characteristics, management practices, and treatment outcomes of patients with extensively drug-resistant (XDR) tuberculosis and non-extensively drug-resistant (non-XDR) tuberculosis are described. The main outcome was the frequency of poor and favourable outcomes at the end of treatment. FINDINGS: Of 608 patients with multidrug resistant tuberculosis, 29 (4.8%) patients had baseline XDR tuberculosis. Treatment failure was more common in patients with XDR tuberculosis than in those with non-XDR tuberculosis (31%vs 8.5%, p=0.0008). 48.3% of patients with XDR tuberculosis and 66.7% of patients with non-XDR tuberculosis had treatment cure or completion (p=0.04). The frequency and management of adverse events did not differ between patients with XDR and non-XDR tuberculosis. INTERPRETATION: The chronic features of tuberculosis in these patients suggest that extensively drug-resistant tuberculosis may be acquired through previous treatments that include second-line drugs. Aggressive management of this infectious disease is feasible and can prevent high mortality rates and further transmission of drug-resistant strains of Mycobacterium tuberculosis.

Knowledge, attitudes, and practices of physicians in Tomsk Oblast tuberculosis services regarding alcohol use among tuberculosis patients in Tomsk, Russia.

In recent years, the Russian Federation has seen a dramatic rise in morbidity and mortality from tuberculosis (TB), attributed in part to an increase in alcohol use disorders (AUDs), which are associated with worse TB treatment outcomes. This study describes the knowledge, attitudes and practices of physicians who treat TB patients in Tomsk, Russia. We conducted semistructured interviews with 16 TB physicians and 1 addiction specialist. Interviews were audiorecorded, transcribed, translated and systematically analyzed. We identified four key domains: definitions of alcohol use and abuse and physicians' knowledge, attitudes and practices regarding these problems. Physicians described patients as largely precontemplative and reluctant to seek treatment. Physicians recognized their limited knowledge in diagnosing and treating AUDs but expressed interest in acquiring these skills. Few options are currently available for treatment of AUDs in TB patients in Tomsk. These findings suggest that Tomsk physicians are aware of the need to engage AUDs in TB patients but identify a knowledge gap that restricts their ability to do so. Training TB physicians to use simple screening instruments and deliver evidence-based alcohol interventions improves TB outcomes among patients with co-occurring AUDs.

Drug-Resistant Tuberculosis: Challenges and Progress.

Antimicrobial resistance is a natural evolutionary process, which in the case of Mycobacterium tuberculosis is based on spontaneous chromosomal mutations, meaning that well-designed combination drug regimens provided under supervised therapy will prevent the emergence of drug-resistant strains. Unfortunately, limited resources, poverty, and neglect have led to the emergence of drug-resistant tuberculosis throughout the world. The international community has responded with financial and scientific support, leading to new rapid diagnostics, new drugs and regimens in advanced clinical development, and an increasingly sophisticated understanding of resistance mechanisms and their application to all aspects of TB control and treatment.

Treatment Outcomes for Adolescents With Multidrug-Resistant Tuberculosis in Lima, Peru.

Treatment outcomes for adolescents with multidrug-resistant tuberculosis are rarely reported and, to date, have been poor. Among 90 adolescents from Lima, Peru, 68 (75.6%) achieved cure or completion of treatment. Unsuccessful treatment was less common in the Peru cohort than previously described in the literature.

Programmes and principles in treatment of multidrug-resistant tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) presents an increasing threat to global tuberculosis control. Many crucial management issues in MDR-TB treatment remain unanswered. We reviewed the existing scientific research on MDR-TB treatment, which consists entirely of retrospective cohort studies. Although direct comparisons of these studies are impossible, some insights can be gained: MDR-TB can and should be addressed therapeutically in resource-poor settings; starting of treatment early is crucial; aggressive treatment regimens and high-end dosing are recommended given the lower potency of second-line antituberculosis drugs; and strategies to improve treatment adherence, such as directly observed therapy, should be used. Opportunities to treat MDR-TB in developing countries are now possible through the Global Fund to Fight AIDS, TB, and Malaria, and the Green Light Committee for Access to Second-line Anti-tuberculosis Drugs. As treatment of MDR-TB becomes increasingly available in resource-poor areas, where it is needed most, further clinical and operational research is urgently needed to guide clinicians in the management of this disease.

HIV-related stigma in the dental setting: a qualitative study.

PURPOSE: To explore the experiences and expectations of HIV-related stigma in dental settings. METHODS: This was a cross-sectional study of 60 HIV+ adult volunteers. We conducted audio-recorded interviews; responses to four open-ended questions were analyzed qualitatively for theme and content. RESULTS: Twenty-seven participants (45%) reported ever having anticipated being judged, stigmatized or treated with disrespect in a dental setting due to HIV status. Thematic response categories included concerns about: (i) receiving humane and respectful treatment, (ii) being judged or stereotyped and (iii) giving HIV to the dentist. Regarding hesitancy to visit the dentist, subjects equally endorsed fear of the dentist (35%) and concerns about confidentiality and receiving humane treatment (35%). CONCLUSION: HIV+ individuals encounter many fears and concerns related to dental care; fear of the dentist and concerns about confidentiality and receiving humane treatment appear to be central issues. Dental providers should be aware of and better manage these issues.

Time to culture conversion and regimen composition in multidrug-resistant tuberculosis treatment.

Sputum cultures are an important tool in monitoring the response to tuberculosis treatment, especially in multidrug-resistant tuberculosis. There has, however, been little study of the effect of treatment regimen composition on culture conversion. Well-designed clinical trials of new anti-tuberculosis drugs require this information to establish optimized background regimens for comparison. We conducted a retrospective cohort study to assess whether the use of an aggressive multidrug-resistant tuberculosis regimen was associated with more rapid sputum culture conversion. We conducted Cox proportional-hazards analyses to examine the relationship between receipt of an aggressive regimen for the 14 prior consecutive days and sputum culture conversion. Sputum culture conversion was achieved in 519 (87.7%) of the 592 patients studied. Among patients who had sputum culture conversion, the median time to conversion was 59 days (IQR: 31-92). In 480 patients (92.5% of those with conversion), conversion occurred within the first six months of treatment. Exposure to an aggressive regimen was independently associated with sputum culture conversion during the first six months of treatment (HR: 1.36; 95% CI: 1.10, 1.69). Infection with human immunodeficiency virus (HR 3.36; 95% CI: 1.47, 7.72) and receiving less exposure to tuberculosis treatment prior to the individualized multidrug-resistant tuberculosis regimen (HR: 1.58; 95% CI: 1.28, 1.95) were also independently positively associated with conversion. Tachycardia (HR: 0.77; 95% CI: 0.61, 0.98) and respiratory difficulty (HR: 0.78; 95% CI: 0.62, 0.97) were independently associated with a lower rate of conversion. This study is the first demonstrating that the composition of the multidrug-resistant tuberculosis treatment regimen influences the time to culture conversion. These results support the use of an aggressive regimen as the optimized background regimen in trials of new anti-TB drugs.