Lia D'Ambrosio

Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Towards tuberculosis elimination: an action framework for low-incidence countries

This paper describes an action framework for countries with low tuberculosis (TB) incidence (<100 TB cases per million population) that are striving for TB elimination. The framework sets out priority interventions required for these countries to progress first towards “pre-elimination” (<10 cases per million) and eventually the elimination of TB as a public health problem (less than one case per million). TB epidemiology in most low-incidence countries is characterised by a low rate of transmission in the general population, occasional outbreaks, a majority of TB cases generated from progression of latent TB infection (LTBI) rather than local transmission, concentration to certain vulnerable and hard-to-reach risk groups, and challenges posed by cross-border migration. Common health system challenges are that political commitment, funding, clinical expertise and general awareness of TB diminishes as TB incidence falls. The framework presents a tailored response to these challenges, grouped into eight priority action areas: 1) ensure political commitment, funding and stewardship for planning and essential services; 2) address the most vulnerable and hard-to-reach groups; 3) address special needs of migrants and cross-border issues; 4) undertake screening for active TB and LTBI in TB contacts and selected high-risk groups, and provide appropriate treatment; 5) optimise the prevention and care of drug-resistant TB; 6) ensure continued surveillance, programme monitoring and evaluation and case-based data management; 7) invest in research and new tools; and 8) support global TB prevention, care and control. The overall approach needs to be multisectorial, focusing on equitable access to high-quality diagnosis and care, and on addressing the social determinants of TB. Because of increasing globalisation and population mobility, the response needs to have both national and global dimensions. Action framework for countries with low tuberculosis incidence: a coherent approach for eliminating tuberculosis http://ow.ly/H03ZZ

Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB : systematic review and meta-analysis

Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis. 12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases were identified based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using the individual data of 121 patients with a definite treatment outcome (cure, completion, death or failure). Most MDR-TB cases achieved sputum smear (86 (92.5%) out of 93) and culture (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (inter-quartile range) times for smear and culture conversions were 43.5 (21–90) and 61 (29–119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage ≤600 mg versus >600 mg). Adverse events were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major adverse events that included anaemia (38.1%), peripheral neuropathy (47.1%), gastro-intestinal disorders (16.7%), optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg. The study results suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid.

Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes

A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB) (resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable drugs on treatment outcome. Compared with treatment failure, relapse and death, treatment success was higher in MDR-TB patients infected with strains without additional resistance (n=4763; 64%, 95% CI 57–72%) or with resistance to second-line injectable drugs only (n=1130; 56%, 95% CI 45–66%), than in those having resistance to fluoroquinolones alone (n=426; 48%, 95% CI 36–60%) or to fluoroquinolones plus second-line injectable drugs (extensively drug resistant (XDR)-TB) (n=405; 40%, 95% CI 27–53%). In XDR-TB patients, treatment success was highest if at least six drugs were used in the intensive phase (adjusted OR 4.9, 95% CI 1.4–16.6; reference fewer than three drugs) and four in the continuation phase (OR 6.1, 95% CI 1.4–26.3). The odds of success in XDR-TB patients was maximised when the intensive phase reached 6.6–9.0 months duration and the total duration of treatment 20.1–25.0 months. In XDR-TB patients, regimens containing more drugs than those recommended in MDR-TB but given for a similar duration were associated with the highest odds of success. All data were from observational studies and methodologies varied between centres, therefore, the bias may be substantial. Better quality evidence is needed to optimise regimens.

European union standards for tuberculosis care.

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis

The broadest pattern of tuberculosis drug resistance for which a consensus definition exists is extensively drug-resistant tuberculosis (XDR-TB). It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR-alone and three non-mutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) capreomycin and kanamycin/amikacin (XDR+2sli); XDR plus resistance to second-line injectables and to ≥1 Group 4 drug, i.e. : ethionamide/prothionamide, cycloserine/terizidone or PAS (XDR+sliG4); and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR-alone; 68 XDR+2sli; 48 XDR+sliG4; and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted Odds Ratio (aOR): 0.4; 95% Confidence Interval: 0.2–0.8) compared to XDR-alone, while odds of failure+death were higher in all XDR patients with additional resistance (aOR range: 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current DST methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2–0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Rapid molecular TB diagnosis: evidence, policy making and global implementation of Xpert MTB/RIF

If tuberculosis (TB) is to be eliminated as a global health problem in the foreseeable future, improved detection of patients, earlier diagnosis and timely identification of rifampicin resistance will be critical. New diagnostics released in recent years have improved this perspective but they require investments in laboratory infrastructure, biosafety and staff specialisation beyond the means of many resource-constrained settings where most patients live. Xpert MTB/RIF, a new assay employing automated nucleic acid amplification to detect Mycobacterium tuberculosis, as well as mutations that confer rifampicin resistance, holds the promise to largely overcome these operational challenges. In this article we position Xpert MTB/RIF in today’s TB diagnostic landscape and describe its additional potential as an adjunct to surveillance and surveys, taking into account considerations of pricing and ethics. In what could serve as a model for the future formulation of new policy on diagnostics, we trace the unique process by which the World Health Organization consulted international expertise and systematically assessed published evidence and freshly emerging experience from the field ahead of its endorsement of the Xpert MTB/RIF technology in 2010, summarise subsequent research findings and guidance on who to test and how, and provide perspectives on scaling up the new technology.

Old ideas to innovate tuberculosis control: preventive treatment to achieve elimination

The introduction of new rapid diagnostic tools for tuberculosis (TB) and the promising TB drugs pipeline together with the development of a new World Health Organization Strategy post 2015 allows new discussions on how to direct TB control. The European Respiratory Society’s European Forum for TB Innovation was created to stimulate discussion on how to best take advantage of old and new opportunities, and advances, to improve TB control and eventually progress towards the elimination of TB. While TB control is aimed at reducing the incidence of TB by early diagnosis and treatment of infectious cases of TB, TB elimination requires focus on sterilising the pool of latently infected individuals, from which future TB cases would be generated. This manuscript describes the three core components that are necessary to implement the elimination strategy fully. 1) Improve diagnosis of latent TB infected individuals. 2) Improve regimens to treat latent TB infection. 3) ensure public health commitment to make both 1) and 2) possible. Old and new evidence is critically described, focusing on the European commitment to reach elimination and on the innovative experiences and best practices available. Diagnosis and treatment of latent TB infection is the core intervention to reach elimination http://ow.ly/mjW0R

Tuberculosis elimination: theory and practice in Europe

Although Europe identified the pathway to tuberculosis (TB) elimination in 1990, no information on programmes for country preparedness is available. A questionnaire investigating TB elimination activities was submitted to 38 national TB programme representatives of low TB incidence (<20 cases per 100 000 population) European countries/territories of the World Health Organization European region. Out of 31 providing a complete answer, 17 (54.8%) reported to have a dedicated national TB programme, 20 (64.5%) a national plan including TB elimination (13 (41.9%) including targets), 22 (71%) guidelines, 14 (45.2%) a specific budget for TB activities, and 23 (74.2%) TB reference centres. All countries reported having case-based electronic TB surveillance, 19 (61.3%) perform regular supervision, 12 (38.7%) have a monitoring and evaluation plan and five (16.1%) perform modelling. In three countries (9.7%), TB health services are free for insured individuals only. In 22 countries/territories (71%) not all TB drugs were available, while in 12 (38.7%) drug stock-outs have been described. Although high-risk group screening for latent TB infection is performed by the majority of countries, only 6 (19.4%) provided figures on preventive treatment completion rates. Not all elements identified as essential for country preparedness to achieve TB elimination are available in the countries surveyed. As TB elimination interventions are sub-optimally applied, more training, awareness and political commitment are necessary http://ow.ly/ru6PV

Efficacy and safety of meropenem–clavulanate added to linezolid-containing regimens in the treatment of MDR-/XDR-TB

Clinical experience on meropenem–clavulanate to treat tuberculosis (TB) is anecdotal (according to case reports on 10 patients). The aim of our case–control study was to evaluate the contribution of meropenem–clavulanate when added to linezolid-containing regimens in terms of efficacy and safety/tolerability in treating multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB cases after 3 months of second-line treatment. 37 cases with MDR-/XDR-TB were prescribed meropenem–clavulanate (3 g daily dose) in addition to a linezolid-containing regimen (dosage range 300–1200 mg·day−1), designed according to international guidelines, which was prescribed to 61 controls. The clinical severity of cases was worse than that of controls (drug susceptibility profile, proportion of sputum-smear positive and of re-treatment cases). The group of cases yielded a higher proportion of sputum-smear converters (28 (87.5%) out of 32 versus nine (56.3%) out of 16; p=0.02) and culture converters (31 (83.8%) out of 37 versus 15 (62.5%) out of 24; p=0.06). Excluding XDR-TB patients (11 (11.2%) out of 98), cases scored a significantly higher proportion of culture converters than controls (p=0.03). One case had to withdraw from meropenem–clavulanate due to increased transaminase levels. The results of our study provide: 1) preliminary evidence on effectiveness and safety/tolerability of meropenem–clavulanate; 2) reference to design further trials; and 3) a guide to clinicians for its rationale use within salvage/compassionate regimens.