Drug-resistant tuberculosis treatments, the case for a phase III platform trial.

Most phase III trials in drug-resistant tuberculosis have either been underpowered to quantify differences in microbiological endpoints or have taken up to a decade to complete. Composite primary endpoints, dominated by differences in treatment discontinuation and regimen changes, may mask important differences in treatment failure and relapse. Although new regimens for drug-resistant tuberculosis appear very effective, resistance to new drugs is emerging rapidly. There is a need for shorter, safer and more tolerable regimens, including those active against bedaquiline-resistant tuberculosis. Transitioning from multiple regimen A versus regimen B trials to a single large phase III platform trial would accelerate the acquisition of robust estimates of relative efficacy and safety. Further efficiencies could be achieved by adopting modern adaptive platform designs. Collaboration among trialists, affected community representatives, funders and regulators is essential for developing such a phase III platform trial for drug-resistant tuberculosis treatment regimens.

La majorité des essais de phase III relatifs à la tuberculose pharmacorésistante soit n'étaient pas assez puissants pour quantifier les fluctuations au niveau des critères microbiologiques, soit étaient trop longs, se poursuivant parfois pendant dix ans. Les critères primaires composites, dominés par des différences dans l'interruption du traitement et les changements de schéma, pourraient dissimuler d'importantes variations en termes d'échec thérapeutique et de rechute. Bien que les nouveaux traitements contre la tuberculose pharmacorésistante semblent très efficaces, la résistance aux nouveaux médicaments évolue rapidement. Il est donc nécessaire d'opter pour des traitements plus courts, plus sûrs et mieux tolérés, y compris ceux actifs contre la tuberculose résistant à la bédaquiline. Délaisser la multitude d'essais opposant un schéma de traitement A à un schéma de traitement B pour se diriger vers un unique essai plateforme de phase III de grande envergure permettrait d'obtenir plus vite des estimations solides concernant l'innocuité et l'efficacité relative. En outre, adopter des modèles de plateforme modernes et adaptatifs contribuerait à de meilleures performances. Enfin, la collaboration entre investigateurs, représentants des communautés concernées, bailleurs de fonds et organismes de réglementation est essentielle à l'élaboration de ce type d'essai plateforme de phase III sur les traitements contre la tuberculose pharmacorésistante.

La mayoría de los ensayos en fase III sobre tuberculosis resistente a los fármacos no ha tenido la potencia suficiente para cuantificar diferencias en los criterios de valoración microbiológicos o ha tardado hasta una década en completarse. Los criterios de valoración principales compuestos, dominados por las diferencias en la interrupción del tratamiento y los cambios de régimen, pueden ocultar diferencias importantes en el fracaso del tratamiento y la recaída. Aunque los nuevos regímenes de tratamiento para la tuberculosis resistente a los fármacos parecen muy eficaces, la resistencia a los nuevos fármacos está apareciendo rápidamente. Se necesitan regímenes de tratamiento más cortos, seguros y tolerables, incluidos los activos contra la tuberculosis resistente a la bedaquilina. La transición de múltiples ensayos de régimen A frente a régimen B a un único gran ensayo de plataforma en fase III aceleraría la obtención de estimaciones sólidas de la eficacia y seguridad relativas. Podrían lograrse mayores eficiencias si se adoptaran diseños de plataforma adaptativos modernos. La colaboración entre los autores de los ensayos, los representantes de las comunidades afectadas, los financiadores y los reguladores es esencial para desarrollar un ensayo de plataforma en fase III de este tipo para los regímenes de tratamiento de la tuberculosis resistente a los fármacos.

Impact of a pharmacist-led collaborative approach to care for treatment of COVID-19 in the outpatient setting.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: The SARS-CoV-2 virus, causing COVID-19, remains a threat to patients and healthcare systems across the country. Oral antiviral therapy is available to reduce risk of patient hospitalization and death; however, limited access to medications, complex drug interactions, and the importance of timeliness in initiating therapy have proven to be challenging. This report aims to describe a pharmacist-driven telehealth service that provided safe and efficient access to antivirals for the treatment of COVID-19 and assess the population impacted. SUMMARY: This observational study was conducted from January 2022 to September 2023, during which time a COVID-19 pharmacist referral hub was utilized at Legacy Health. Patients documented to be positive for COVID-19 infection and who had a primary care provider within Legacy Health were included in the study. Demographics and descriptive data regarding antiviral prescribing for patients who were managed by an ambulatory care pharmacist were assessed. Patient demographics were statistically compared between groups to investigate antiviral access for marginalized populations. A total of 22,983 unique COVID-19 infections occurred during the study period, and ambulatory care pharmacists within Legacy Health managed 19.8% of all documented COVID-19 infections in our study population. The pharmacy team generated 3,820 antiviral prescriptions for treatment of COVID-19. The median time from symptom onset to antiviral prescription was 1 day. CONCLUSION: This pharmacist-led telehealth service had a significant impact in expanding access to COVID-19 antiviral treatment, which is pivotal in broadening access to timely COVID-19 antiviral treatment for all vulnerable patient groups when resources are limited.

Bedaquiline: what might the future hold?

Tuberculosis drug development has stagnated for decades, so the recent availability of bedaquiline is welcome. Bedaquiline-containing regimens, now the first-line therapy recommended by WHO, have transformed the treatment of drug-resistant tuberculosis, offering safer and more effective oral treatment options. However, key obstacles need to be overcome to ensure global access and prevent the rapid development of resistance against this promising class of drugs. In this Personal View, building on an international workshop held in 2023, we evaluate the current evidence and suggest possible ways forward, recognising the tension between increasing use and slowing the rise of resistance. We also discuss problems in accessing bedaquiline-containing regimens, the potential widening of their use beyond drug-resistant tuberculosis, and lessons for utilising new drugs as they are developed.

Distanciation as a technology of control in the UK hostile environment.

This article considers how distanciation, understood as the active production of different forms of distance as a method of control, is used to manage people racialised and criminalised as migrants within the UK's hostile environment. Analysing different policies introduced under the hostile environment agenda, as well as the more recent New Plan for Immigration, we argue distanciation is a key tactic that shapes these policies and their implementation as well as offers us insight into changing forms of governing migration. Drawing on the analysis of a wide range of policy documents, the paper attends to different forms of distanciation used as a method of control within the UK's wider hostile environment and then presents the results of a case-study of how distanciation is mobilised within the English National Health Service, under the Migrant and Visitor Cost Recovery Programme in particular, which was introduced in 2014 to ensure the NHS receives 'a fair contribution' from people racialised as migrants. Addressing different forms of distanciation such as - spatial, legal and emotional - we argue that the lens of distance can offer insights into how detachment - increasing distance between different agents in immigration law and border enforcement is an intentional design to control empathy, solidarity and resistance. Tracing ways these forms of distanciation are designed into legislative and administrative measures helps us better understand how hostile environment policies work as well as locating agencies and possibilities of resistance within different spaces, agents and subjects of bordering.

BTS clinical statement for the diagnosis and management of ocular tuberculosis.

The BTS clinical statement for the diagnosis and management of ocular tuberculosis (TB) draws on the expertise of both TB and and ophthalmic specialists to outline the current understanding of disease pathogenesis, diagnosis and management in adults. Published literature lacks high-quality evidence to inform clinical practice and there is also a paucity of data from animal models to elucidate mechanisms of disease. However, in order to improve and standardise patient care, this statement provides consensus points with the currently available data and agreed best practice.

Charging of overseas visitors in England and universal health coverage: a cross-sectional analysis of NHS trusts.

BACKGROUND: In 2017, new regulations in England introduced upfront charging for non-urgent care within the National Health Service (NHS). Individuals from outside the European Economic Area who have not paid the immigration surcharge are chargeable for NHS care at 150% of cost. METHODS: A freedom of information (FOI) request was sent to 135 acute non-specialist NHS trusts in England to create a database of overseas visitors charges. This was analysed using multiple linear regression to explore the relationship between sex, age, nationality, ethnicity, urgency and the cost of healthcare. RESULTS: Of 135 acute non-specialist trusts in England 64 replied, providing a data set of 13 484 patients. Women were found to be invoiced higher amounts than men (P = 0.002). Patients were more likely to be women (63 versus 37% men), and within this group, almost half of patients were of reproductive age, with 47.9% (3165) aged 16-40 years old. Only seven trusts supplied data on urgency, and within these trusts the urgency of treatment was significantly related to cost, with the most urgent (immediately necessary) treatment costing the most (P < 0.001). CONCLUSION: This research reflects that that migrant women, and particularly undocumented women, are disproportionately impacted by the NHS charging policies in England.

Utility of EBUS-TBNA in diagnosing mediastinal tuberculous lymphadenitis in East London.

OBJECTIVES: To characterise and describe the diagnostic utility of Endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) in intrathoracic tuberculosis in a cohort of patients with mediastinal lymphadenopathy of unknown aetiology. METHODS: Consecutive patients with intrathoracic lymphadenopathy undergoing EBUS-TBNA between 2012 and 2016 were identified. Demographic data, biopsy cytopathology and mycobacteriology results, HIV and vitamin D status, susceptibility results and final diagnoses were recorded. Pre- and post-procedure probability scores were assigned to each case to reflect the probability of tuberculosis. RESULTS: 315 cases were identified; 54 (17.1%) had tuberculosis and 261 (82.9%) had a non-tuberculosis diagnosis. amongst TB cases, the sensitivity of EBUS-TBNA was 59.3% (95% CI 45.06-72.14), specificity 100% (95% CI 98.19-100) and the negative predictive value (NPV) was 92.23% (95% CI 88.31-94.95). 19/54 (35%) TB cases were confirmed by EBUS mycobacterial culture and 13/54 (24.1%) by cytopathology.  33 (61.1%) of the TB cases, had a low to medium pre-test probability score assigned prior to EBUS-TBNA. Amongst EBUS culture-confirmed cases, we found a resistance rate of 10.5% to one or more first line TB drugs, with one case of multi-drug resistant TB. CONCLUSIONS: We confirmed the utility of EBUS-TBNA in the diagnosis of intrathoracic tuberculosis in an undifferentiated cohort of patients with mediastinal lymphadenopathy of unknown aetiology and advocate sending samples for mycobacterial culture in all cases in high tuberculosis incidence areas.

Patients or passports? The 'hostile environment' in the NHS.

Throughout the pandemic, the NHS has continued to charge certain patients for their care based on their immigration status and to report patients with outstanding debt to the Home Office. Research has consistently shown that these policies act as a significant barrier to healthcare access for already minoritised communities, and that during the pandemic patients have remained fearful and reluctant to seek care due to charging, including care for 'exempt' conditions such as COVID-19. Charging policies, and associated data sharing, represent only one of the myriad ways in which structural and 'every day' racism operate to impact health; however, they undoubtedly form a part of the picture as to why COVID-19 has disproportionately affected many minoritised communities.

Accuracy of a Modified qSOFA Score for Predicting Critical Care Admission in Febrile Children.

BACKGROUND AND OBJECTIVES: The identification of life-threatening infection in febrile children presenting to the emergency department (ED) remains difficult. The quick Sequential Organ Failure Assessment (qSOFA) was only derived for adult populations, implying an urgent need for pediatric scores. We developed and validated a novel, adapted qSOFA score (Liverpool quick Sequential Organ Failure Assessment [LqSOFA]) and compared its performance with qSOFA, Pediatric Early Warning Score (PEWS), and National Institute for Health and Care Excellence (NICE) high-risk criteria in predicting critical care (CC) admission in febrile children presenting to the ED. METHODS: The LqSOFA (range, 0-4) incorporates age-adjusted heart rate, respiratory rate, capillary refill, and consciousness level on the Alert, Voice, Pain, Unresponsive scale. The primary outcome was CC admission within 48 hours of ED presentation, and the secondary outcome was sepsis-related mortality. LqSOFA, qSOFA, PEWS, and NICE high-risk criteria scores were calculated, and performance characteristics, including area under the receiver operating characteristic curve, were calculated for each score. RESULTS: In the initial (n = 1121) cohort, 47 CC admissions (4.2%) occurred, and in the validation (n = 12 241) cohort, 135 CC admissions (1.1%) occurred, and there were 5 sepsis-related deaths. In the validation cohort, LqSOFA predicted CC admission with an area under the receiver operating characteristic curve of 0.81 (95% confidence interval [CI], 0.76 to 0.86), versus qSOFA (0.66; 95% CI, 0.60 to 0.71), PEWS (0.93; 95% CI, 0.90 to 0.95), and NICE high-risk criteria (0.81; 95% CI, 0.78 to 0.85). For predicting CC admission, the LqSOFA outperformed the qSOFA, with a net reclassification index of 10.4% (95% CI, 1.0% to 19.9%). CONCLUSIONS: In this large study, we demonstrate improved performance of the LqSOFA over qSOFA in identifying febrile children at risk for CC admission and sepsis-related mortality. Further validation is required in other settings.

Improving cardiovascular disease risk communication in NHS Health Checks: a qualitative study.

OBJECTIVE: The NHS Health Check programme is a public screening and prevention initiative in England to detect early signs of cardiovascular ill health among healthy adults. We aimed to explore patient perspectives and experiences of a personalised Risk Report designed to improve cardiovascular risk communication in the NHS Health Check. DESIGN AND SETTING: This is a qualitative study with NHS Health Check attendees in three general practices in the London Borough of Newham. INTERVENTION AND PARTICIPANTS: A personalised Risk Report for the NHS Health Check was developed to improve communication of results and advice. The Risk Report was embedded in the electronic health record, printed with auto-filled results and used as a discussion aid during the NHS Health Check, and was a take-home record of information and advice on risk reduction for the attendees. 18 purposively sampled socially diverse participants took part in semistructured interviews, which were analysed thematically. RESULTS: For most participants, the NHS Health Check was an opportunity for reassurance and assessment, and the Risk Report was an enduring record that supported risk understanding, with impact beyond the individual. For a minority, ambivalence towards the Risk Report occurred in the context of attending for other reasons, and risk and lifestyle advice were not internalised or acted on. CONCLUSION: Our findings demonstrate the potential of a personalised Risk Report as a useful intervention in NHS Health Checks for enhancing patient understanding of cardiovascular risk and strategies for risk reduction. Also highlighted are the challenges that must be overcome to ensure transferability of these benefits to diverse patient groups. TRIAL REGISTRATION NUMBER: NCT02486913.

Perioperative interdisciplinary approach for reduction of opioid use in pediatric tonsillectomy: Protocol using dexmedetomidine and bupivicaine as adjunct agents.

IMPORTANCE: Pediatric tonsillectomy is a common procedure now being performed most often for patients with obstructive sleep apnea, which has been associated with increased sensitivity to the respiratory side effects of opioid medications. This study investigates a strategy to decrease the use of opiate medications in a particularly vulnerable population. OBJECTIVE: Describe an interdisciplinary approach between Otolaryngologists and Anesthesiologists to decrease opiate use in tonsillectomy patients. Demonstrate safety of this protocol. Evaluate the effect of the protocol on intraoperative need for opiate medications and inhaled anesthetic use. Perform cost analysis of the protocol. DESIGN: Retrospective case-control study with cost analysis. SETTING: Tertiary Care Hospital. PARTICIPANTS: Pediatric patients undergoing tonsillectomy at a tertiary care hospital. INTERVENTIONS: Preoperative and intraoperative dexmedetomidine with local bupivacaine injection into the tonsillar fossa. MEASURES: Intraoperative need for sevoflurane, opiate, and propofol. Post-operative pain scores, and utilization of post-operative opiate, acetaminophen, and ibuprofen pain medications. Post-operative adverse events. Cost analysis of protocol. RESULTS: This protocol led to a decrease in intraoperative opiate use by 49.6%, a decrease in intraoperative sevofluorane use by 18%, and a lower reported maximum post-operative pain score without any increase in adverse events. The protocol added a small increase in medication cost of $4.07 to each procedure. CONCLUSION: The use of dexmedetomidine and local anesthetic in pediatric tonsillectomy is a safe and effective protocol that allows for the reduction of opiate use and improved post-operative pain control. KEY POINTS: Question: Can the combination of dexmedetomidine and infiltration of local anesthetic reduce overall opioid use for peediatric patients undergoing tonsillectomy? FINDINGS: In this case-control study, use of dexmedetomidine and local anesthetic injected into the tonsillar fossa led to a decrease in intraoperative opiate use by 49.6%, a decrease in intraoperative sevofluorane use by 18%, and a lower reported maximum pain score without an increase in adverse events. Meaning: Use of dexmedetomidine and local anesthetic as anesthetic adjuncts may help reduce need for intraoperative opiates and decrease the use of volatile anesthetic agents in pediatric tonsillectomy patients, which are undesirable medications in the pediatric population for their respective respiratory depression and potentially neurotoxic side effects.

The challenge of the new tuberculosis drugs.

Tuberculosis (TB) continues to cause more deaths worldwide than any other single infectious disease. Even though tuberculosis appears to be decreasing in incidence globally for some time, the proportion of drug resistance is increasing, contributing to greater complexity, morbidity and mortality as well as cost. Since the advent of rifampicin in the 1960s, and the implementation of standard quadruple anti-tuberculosis regimen in the late 1970s, no new drugs have been changed the first line regimen. This regimen is effective however it is pill burden, and duration has not received investment and innovation. Drug-resistant regimens are long and frequently poorly tolerated due to significant toxicity. This review is an update on what is new in the treatment of drug-susceptible and drug-resistant tuberculosis, new TB drugs currently being used and studied in clinical trials are also mentioned. Fortunately, there have been many significant advances in this field in recent years. The horizon is changing with the new WHO shorter multidrug-resistant tuberculosis regimens and with the increasing availability of new or repurposed drugs like bedaquiline, delamanid, clofazimine and linezolid. These drugs pose new challenges relating to their rational use to prevent selection of resistant strains of Mycobacterium tuberculosis even before a new regimen has been studied. The availability of these new drugs is offering hope and new possibilities for saving patients who had few or no treatment options. Their use and combination into effective regimens need to be studied; trials are in progress. It is hoped that soon we will be able to treat sensitive and drug-resistant cases with a universal regimen, this would revolutionise treatment and take us another step closer towards elimination.

Moxifloxacin: An Alternative to Ethambutol for the Treatment of Presumed Ocular Tuberculosis.

OBJECTIVE: To present moxifloxacin as an alternative treatment option to ethambutol in an anti-tubercular therapy (ATT) regime in patients with presumed ocular tuberculosis (TB). METHODS: We identified all cases in our hospital referred for treatment of presumed ocular TB between 2009 and 2013. Age, gender, ophthalmic examination, blood tests, treatment regimens, adverse drug reactions, and outcomes were collected and analyzed for the patients who had moxifloxacin as part of their ATT. RESULTS: Forty-three cases of presumed ocular TB were treated with moxifloxacin as a part of ATT. Mean age was 44.18 ± 12.47 years; 62.8% were male. A response to treatment, with no evidence of disease recurrence, was seen in 72.1% of cases. Shortened ATT duration was associated with increased risk of treatment failure (p = 0.02, 95% CI: -0.77 to -0.00). CONCLUSIONS: Moxifloxacin can be considered as a safe and effective alternative to ethambutol for the treatment of presumed ocular TB.