Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

Clinical standards for drug-susceptible pulmonary TB.

BACKGROUND: The aim of these clinical standards is to provide guidance on 'best practice´ for diagnosis, treatment and management of drug-susceptible pulmonary TB (PTB).METHODS: A panel of 54 global experts in the field of TB care, public health, microbiology, and pharmacology were identified; 46 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all 46 participants.RESULTS: Seven clinical standards were defined: Standard 1, all patients (adult or child) who have symptoms and signs compatible with PTB should undergo investigations to reach a diagnosis; Standard 2, adequate bacteriological tests should be conducted to exclude drug-resistant TB; Standard 3, an appropriate regimen recommended by WHO and national guidelines for the treatment of PTB should be identified; Standard 4, health education and counselling should be provided for each patient starting treatment; Standard 5, treatment monitoring should be conducted to assess adherence, follow patient progress, identify and manage adverse events, and detect development of resistance; Standard 6, a recommended series of patient examinations should be performed at the end of treatment; Standard 7, necessary public health actions should be conducted for each patient. We also identified priorities for future research into PTB.CONCLUSION: These consensus-based clinical standards will help to improve patient care by guiding clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment for PTB.

Outcome of treatment of MDR-TB or drug-resistant patients treated with bedaquiline and delamanid: Results from a large global cohort.

The World Health Organization (WHO) recommends countries introduce new anti-TB drugs in the treatment of multidrug-resistant tuberculosis. The aim of the study is to prospectively evaluate the effectiveness of bedaquiline (and/or delamanid)- containing regimens in a large cohort of consecutive TB patients treated globally. This observational, prospective study is based on data collected and provided by Global Tuberculosis Network (GTN) centres and analysed twice a year. All consecutive patients (including children/adolescents) treated with bedaquiline and/or delamanid were enrolled, and managed according to WHO and national guidelines. Overall, 52 centres from 29 countries/regions in all continents reported 883 patients as of January 31st 2021, 24/29 countries/regions providing data on 100% of their consecutive patients (10-80% in the remaining 5 countries). The drug-resistance pattern of the patients was severe (>30% with extensively drug-resistant -TB; median number of resistant drugs 5 (3-7) in the overall cohort and 6 (4-8) among patients with a final outcome). For the patients with a final outcome (477/883, 54.0%) the median (IQR) number of months of anti-TB treatment was 18 (13-23) (in days 553 (385-678)). The proportion of patients achieving sputum smear and culture conversion ranged from 93.4% and 92.8% respectively (whole cohort) to 89.3% and 88.8% respectively (patients with a final outcome), a median (IQR) time to sputum smear and culture conversion of 58 (30-90) days for the whole cohort and 60 (30-100) for patients with a final outcome and, respectively, of 55 (30-90) and 60 (30-90) days for culture conversion. Of 383 patients treated with bedaquiline but not delamanid, 284 (74.2%) achieved treatment success, while 25 (6.5%) died, 11 (2.9%) failed and 63 (16.5%) were lost to follow-up.

Clinical perspectives on treatment of rifampicin-resistant/multidrug-resistant TB.

Rapid diagnostics, newer drugs, repurposed medications, and shorter regimens have radically altered the landscape for treating rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB). There are multiple ongoing clinical trials aiming to build a robust evidence base to guide RR/MDR-TB treatment, and both observational studies and programmatic data have contributed to advancing the treatment field. In December 2019, the WHO issued their second 'Rapid Communication´ related to RR-TB management. This reiterated their prior recommendation that a majority of people with RR/MDR-TB receive all-oral treatment regimens, and now allow for specific shorter duration regimens to be used programmatically as well. Many TB programs need clinical advice as they seek to roll out such regimens in their specific setting. In this Perspective, we highlight our early experiences and lessons learned from working with National TB Programs, adult and pediatric clinicians and civil society, in optimizing treatment of RR/MDR-TB, using shorter, highly-effective, oral regimens for the majority of people with RR/MDR-TB.

Clinical features associated with linezolid resistance among multidrug resistant tuberculosis patients at a tertiary care hospital in Mumbai, India.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is an increasing problem worldwide, and 24% occurs in India. Linezolid is associated with improved MDR-TB treatment outcomes but causes significant side-effects and drug susceptibility testing (DST) is rarely available. This study assessed whether clinical factors could predict linezolid resistance. METHODS: An observational cohort of adults and adolescents with MDR-TB at a tertiary care hospital in Mumbai, India was analyzed for clinical, laboratory, and radiographic findings associated with linezolid resistance. RESULTS: In total, 343 MDR-TB patients had linezolid DST performed, and 23 (6.7%) had linezolid-resistant MDR-TB. Univariable analysis associated linezolid resistance with underweight (odds ratio (OR)-1.07, 95% confidence interval (CI):1.01-1.12); number of previous providers (OR:1.03, 95% CI:1.00-1.05); previous treatment with linezolid (OR:1.12, 95% CI:1.06-1.05), bedaquiline (OR:1.55, 95% CI:1.22-1.98), or clofazimine (OR:1.08 95% CI:1.03-1.16); cavitary disease (OR:1.10, 95% CI:1.04-1.16) and percent lung involvement (OR:1.02, 95% CI:1.01-1.03) on radiograph. DST associated linezolid resistance with resistance to fluoroquinolones (OR:1.08, 95% CI:1.01-1.14), injectables (OR:1.09, 95% CI:1.03-1.15), ethionamide (OR:1.09, 95% CI:1.03-1.15), and PAS (OR:1.13, 95% CI:1.06-1.21). In multivariate analysis, only prior linezolid and percent lung involvement were associated with linezolid resistance. CONCLUSION: To maximize treatment benefits while minimizing toxicity, DST remains an important tool to identify linezolid resistance.

From pulmonary susceptible tuberculosis to extensively drug resistant tuberculosis: An interesting case report of a young Indian girl.

Tuberculosis is one of the top ten causes of death and the leading cause from a single infectious agent. Drug-resistant Tuberculosis continues to be a public health crisis. Urgent action is required to improve the coverage and quality of diagnosis, treatment and care for people with drug-resistant Tuberculosis. Patients with pulmonary Tuberculosis can spread the disease by coughing, sneezing, or simply talking. For that reason, it is important to diagnosis Tuberculosis in order to start treatment as soon as possible. In the present manuscript we present the case of a 25-year-old Indian HIV-negative female, no comorbidity, with a history of drug susceptible tuberculosis diagnosed in 2015 which advanced in extensively drug-resistant tuberculosis after two years of treatment. This case report highlights the risk of mismanagement of patient affected by Tuberculosis and the consequences related which could harm the patient's health.

Imatinib-induced pleural effusion: A case report.

Imatinib is a tyrosine kinase inhibitor and has rarely been reported to cause pleural effusion. We report the case of an 88-year-old male, known case of gastrointestinal stromal tumor on treatment with imatinib, who presented with a 2-week history of cough and dyspnea. He was diagnosed to have a right-sided pleural effusion and thoracentesis of the fluid revealed an exudate with low adenosine deaminase and negative cytology. Withdrawal of the drug lead to resolution of symptoms. We report this case to highlight the side effect profile of imatinib and warn physicians regarding this potential adverse effect which may be mistaken for metastasis or infection.

Mobility patterns of persons at risk for drug-resistant tuberculosis in Mumbai, India.

SETTING: Tuberculosis (TB) hospital in Mumbai, India. OBJECTIVE: To describe the mobility patterns of persons with suspected drug-resistant tuberculosis (DR-TB) and to assess whether there were significant differences in demographic or risk characteristics based on mobility. DESIGN: Observational cohort study of TB clinic patients at risk for DR-TB. RESULTS: Among 602 participants, 37% had ever moved from their place of birth; 14% were local movers (within state), and 23% were distant movers, between states or countries. Univariate multinomial logistic regression models showed that distant movers were more likely than non-movers to have lower income, less education, a greater number of previous TB episodes, and to have ever smoked. Compared to non-movers, local movers were more likely to have lower income and were more likely to have seen a doctor in the past 2 years. Clinical outcomes, including DR-TB, diabetes, and human immunodeficiency virus (HIV), did not differ between the three mobility groups. CONCLUSION: Mobility was common among patients at risk for DR-TB in Mumbai. TB programs should consider the implications of mobility on the protracted treatment for DR-TB in India.

Determination of MICs of levofloxacin for Mycobacterium tuberculosis with gyrA mutations.

The purpose of the present study was to correlate gyrA mutations found in Mycobacterium tuberculosis isolates using the GenoType(®) MTBDRsl assay with minimum inhibitory concentrations of the fluoroquinolone levofloxacin (LVX). Of 123 archived clinical M. tuberculosis isolates evaluated, 93 isolates had an Ala90Val, Ser91Pro, Asp94Ala, Asn/Tyr, Gly or His mutation and 30 were wild-type. Phenotypically, gyrA mutations Ala90Val, Ser91Pro or Asp94Ala showed a low level of resistance to LVX, while Asp94Asn/Tyr, Asp94Gly or Asp94His mutations had high-level resistance.

Initial experience of bedaquiline use in a series of drug-resistant tuberculosis patients from India.

Drug-resistant tuberculosis (DR-TB) is a major problem both in India and worldwide. Newer drugs such as TMC-207 (bedaquiline) may have an important role to play in making up an effective drug regimen in such cases. There have been a few reports of bedaquiline use in a non-trial setting from Europe. Our series of five patients is the first series of DR-TB patients from India to receive bedaquiline. All five patients showed striking improvement, with microbiological conversion and an absence of notable adverse effects (e.g., prolonged QTcF), indicating the potential impact of this drug in such a population.

Thoracoscopic and endovascular management of retained haemothoarx associated with an intercostal artery pseudoaneurysm.

Intercostal artery pseudoaneurysm (IAP) is a rare entity and may complicate a percutaneous intervention through an intercostal space or follow thoracic trauma. Its rupture into the pleural space can give rise to haemothorax, which if untreated may lead to a retained haemothorax (RH). Traditionally both the IAP and the RH are managed by a thoracotomy. We report a patient who developed an IAP with haemothorax following a trauma. The diagnosis was established by computed tomography. The patient was treated by endovascular embolisation of the IAP followed by thoracoscopic decortications of the RH.

Evaluation of light emitting diode-based fluorescence microscopy for the detection of mycobacteria in a tuberculosis-endemic region.

OBJECTIVES: To evaluate fluorescence microscopy (FM) using light emitting diode (LED) technology for the detection of acid-fast bacilli at a tertiary referral centre in Mumbai, India, a tuberculosis-endemic country. DESIGN: LED FM was introduced into a laboratory experienced with Ziehl-Neelsen (ZN) microscopy but unfamiliar with FM. It was evaluated in parallel with routine ZN microscopy services and compared with mycobacterial culture as a reference standard. RESULTS: A total of 1357 pulmonary and 917 extra-pulmonary specimens were examined during the study. LED FM had 78.3% sensitivity and 92.0% specificity against mycobacterial culture when using pulmonary specimens, and 34.0% sensitivity and 88.8% specificity for extra-pulmonary specimens. The mean time per smear examination was 2.48 min for ZN vs. 1.41 min for LED FM. Several biases in study design and operation identified during analysis, which are likely to lead to underestimates of LED FM accuracy, are discussed in the context of future LED FM evaluations. CONCLUSIONS: Although LED FM has significant benefits over both ZN microscopy and conventional FM, its implementation and validation may be prone to difficulties which could hamper evaluation of its performance. Adequate training and detailed standard operating procedures are important to maximise accuracy.

Pulmonary alveolar proteinosis with respiratory failure-anaesthetic management of whole lung lavage.

SUMMARY: Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by accumulation of amorphous acellular phospholipid material in the lungs. Whole lung lavage is the standard therapy which gives dramatic clinical improvement and offers a long term survival to these patients. A 43-year-old man suffering from PAP presented to casualty with NYHA grade IV dyspnoea with oxygen saturation (SaO(2)) on pulseoximetry 67% on room air and 78% with O(2) 6 L/min. He underwent whole lung lavage under general anaesthesia using one lung ventilation with 37 F left end bronchial double lumen tube. The lung lavage was initially performed for the left lung and for the right lung 4 days later. The patient was discharged home with oxygen saturation of 96 % on room air.

Increasing incidence of fluoroquinolone-resistant Mycobacterium tuberculosis in Mumbai, India.

SETTING: Tertiary referral centre, private hospital, Mumbai, India. OBJECTIVE: To analyse the incidence of fluoroquinolone (FQ) resistant Mycobacterium tuberculosis (TB) in our laboratory from 1995 to 2004. DESIGN: Retrospective review and analysis of the drug susceptibility test records of all M. tuberculosis culture-positive samples from our Microbiology Department from 1995 to 2004. RESULTS: FQ resistance has increased exponentially in our laboratory, from 3% in 1996 to 35% in 2004. The incidence of multidrug-resistant tuberculosis has also increased during the same period, from 33% in 1995 to 56% in 2004. CONCLUSION: The incidence of FQ-resistant M. tuberculosis is gradually increasing to alarming levels. This may be due to widespread use of this vital group of drugs in the treatment of community-acquired infections. We urge that these broad spectrum antibiotics be used judiciously, and ideally be reserved for treatment of resistant TB in TB-endemic areas.

Cryptogenic organizing pneumonia: clinical profile in a series of 34 admitted patients in a hospital in India.

OBJECTIVES: Cryptogenic Organizing Pneumonia (COP) is a relatively rare disorder which is gratifying to treat due to its prompt steroid responsiveness. There have been only 2 case reports on COP from India but no large series entity reported from this country. METHODS: The medical records of all patients with biopsy (histopathology) proven COP admitted in a tertiary care hospital in Mumbai (2000-2005) were retrospectively analyzed. We looked at clinical and radiographic profiles, initial diagnosis and treatment, lag period to starting definitive therapy and steroid responsiveness. RESULTS: When compared to other series of patients with COP, our series showed several similarities and some differences. Distinctive features were the striking female preponderance and the utility of transbronchial biopsies in establishing the diagnosis. Long delays in diagnosis with patients mislabeled as tuberculosis or pneumonia, lead to delays in starting steroids resulting in 21% of our patients continuing to deteriorate. CONCLUSIONS: This comprehensive review of COP, the first of its kind from India, reveals its varied clinical and radiographic spectrum. A high index of suspicion will lead to prompt steroid therapy which will result in better patient outcome.