The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

https://erj.ersjournals.com/content/erj/38/3/516.full.pdf

WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update

Part of the reason for failing to bring about a more rapid reduction in tuberculosis incidence worldwide is the lack of effective involvement of all practitioners-public and private-in the provision of high quality tuberculosis care. While health-care providers who are part of national tuberculosis programmes have been trained and are expected to have adopted proper diagnosis, treatment, and public-health practices, the same is not likely to be true for non-programme providers. Studies of the performance of the private sector conducted in several different parts of the world suggest that poor quality care is common. The basic principles of care for people with, or suspected of having, tuberculosis are the same worldwide: a diagnosis should be established promptly; standardised treatment regimens should be used with appropriate treatment support and supervision; response to treatment should be monitored; and essential public-health responsibilities must be carried out. Prompt and accurate diagnosis, and effective treatment are essential for good patient care and tuberculosis control. All providers who undertake evaluation and treatment of patients with tuberculosis must recognise that not only are they delivering care to an individual, but they are also assuming an important public-health function. The International Standards for Tuberculosis Care (ISTC) describe a widely endorsed level of care that all practitioners should seek to achieve in managing individuals who have, or are suspected of having, tuberculosis. The document is intended to engage all care providers in delivering high quality care for patients of all ages, including those with smear-positive, smear-negative, and extra-pulmonary tuberculosis, tuberculosis caused by drug-resistant Mycobacterium tuberculosis complex, and tuberculosis combined with HIV infection.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(06)70628-4.pdf

International standards for tuberculosis care.

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are generally thought to have high mortality rates. However, many cases can be treated with the right combination and rational use of available antituberculosis drugs. This Review describes the evidence available for each drug and discusses the basis for recommendations for the treatment of patients with MDR and XDR tuberculosis. The recommended regimen is the combination of at least four drugs to which the Mycobacterium tuberculosis isolate is likely to be susceptible. Drugs are chosen with a stepwise selection process through five groups on the basis of efficacy, safety, and cost. Among the first group (the oral first-line drugs) high-dose isoniazid, pyrazinamide, and ethambutol are thought of as an adjunct for the treatment of MDR and XDR tuberculosis. The second group is the fluoroquinolones, of which the first choice is high-dose levofloxacin. The third group are the injectable drugs, which should be used in the following order: capreomycin, kanamycin, then amikacin. The fourth group are called the second-line drugs and should be used in the following order: thioamides, cycloserine, then aminosalicylic acid. The fifth group includes drugs that are not very effective or for which there are sparse clinical data. Drugs in group five should be used in the following order: clofazimine, amoxicillin with clavulanate, linezolid, carbapenems, thioacetazone, then clarithromycin.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(10)70139-0.pdf

Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis

https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(17)30079-6.pdf

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking.

https://erj.ersjournals.com/content/erj/44/1/23.full.pdf

Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement

The demand for reliable drug-susceptibility testing (DST) increases with the expansion of antituberculosis drug-resistance surveillance, and with the need for an appropriate treatment of multidrug-resistant tuberculosis, whose incidence gradually increases in many parts of the world. However, the reliability of DST results obtained through widely used methods does not meet acceptable levels, except for DST to isoniazid and rifampicin. In general, susceptibility results are highly predictable, while resistance results show low predictive values when the resistance prevalence is <10%. Poor reliability stems from a weak correlation with clinical response and a low reproducibility due to the poor standardisation of the complex and fragile test procedures. Therefore, in vitro criteria of resistance for susceptibility testing should be carefully determined with representative clinical samples of Mycobacterium tuberculosis isolated from patients never treated with any antituberculosis drug, and from patients having failed treatment with a regimen containing the tested drug; DST should then be carefully standardised to obtain reproducible results. The critical concentration of some drugs is close to the minimal inhibitory concentration for wild susceptible strains and, thus, drug-susceptibility testing is prone to yield poorly reproducible results. These issues call for physicians' attention when using the results from drug-susceptibility testing for case management.

https://erj.ersjournals.com/content/erj/25/3/564.full.pdf

Drug-susceptibility testing in tuberculosis: methods and reliability of results

Ibrutinib plus br or r‐chop in previously treated patients with follicular or marginal zone lymphoma: the phase 3 selene study

Ibrutinib in Combination with Ifosfamide, Etoposide, and Rituximab Followed by Ibrutinib Maintenance Therapy in Patients with R/R‐PCNSL: A Multicenter Phase II Study

S. J. Kim

Papers

Drug-susceptibility testing in tuberculosis: methods and reliability of results

Ibrutinib plus br or r‐chop in previously treated patients with follicular or marginal zone lymphoma: the phase 3 selene study

Ibrutinib in Combination with Ifosfamide, Etoposide, and Rituximab Followed by Ibrutinib Maintenance Therapy in Patients with R/R‐PCNSL: A Multicenter Phase II Study