Lia D’Ambrosio

ERS/WHO Tuberculosis Consilium assistance with extensively drug-resistant tuberculosis management in a child: case study of compassionate delamanid use

To the Editor: The European Respiratory Society (ERS) and the World Health Organization (WHO) Regional Office for Europe implemented a consultation body, the ERS/WHO Tuberculosis (TB) Consilium, in late April 2013 [1–4]. This is a novel, high-priority initiative, as part of the 2012–2013 Presidential plan, to face the growing problem of drug-resistant TB in Europe and globally to support clinicians in managing difficult-to-treat TB cases. Clinicians are increasingly challenged by difficult-to-treat cases of multidrug-resistant (MDR)-TB ( i.e. TB caused by Mycobacterium tuberculosis strains resistant to isoniazid and rifampicin) and extensively drug-resistant (XDR)-TB ( i.e. TB caused by MDR-TB strains that are also resistant to at least one fluoroquinolone and one injectable second-line anti-TB drug) [5–8]. MDR/XDR-TB is seriously hampering TB control and elimination in Europe [9–11], as patients require long and expensive regimens with significant adverse effects, while cure rates remain low [7, 8, 12–14]. Clinicians can upload a case description and queries via the ERS/WHO TB Consilium website (www.tbconsilium.org), the process of which takes up to 20 minutes. The case is then assigned to global experts who provide feedback to the clinician’s questions in a limited timeframe, free of charge. At the time of writing, the TB Consilium has provided expert opinion on 51 cases (and two outbreaks from 11 countries), with an average response time of 36 h. The most frequently posed questions are related to the design and duration of the most appropriate regimens for difficult-to-treat patients [4]. In the absence of a sufficient number of medicines to which a strain is sensitive in vivo , life-saving treatment may rely on the use of new medicines (bedaquiline or delamanid) either under conditional or through compassionate use [15– …

Carbapenems to Treat Multidrug and Extensively Drug-Resistant Tuberculosis: A Systematic Review

Background: Carbapenems (ertapenem, imipenem, meropenem) are used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB), even if the published evidence is limited, particularly when it is otherwise difficult to identify the recommended four active drugs to be included in the regimen. No systematic review to date has ever evaluated the efficacy, safety, and tolerability of carbapenems. Methods: A search of peer-reviewed, scientific evidence was carried out, aimed at evaluating the efficacy/effectiveness, safety, and tolerability of carbapenem-containing regimens in individuals with pulmonary/extra-pulmonary disease which was bacteriologically confirmed as M/XDR-TB. We used PubMed to identify relevant full-text, English manuscripts up to the 20 December 2015, excluding editorials and reviews. Results: Seven out of 160 studies satisfied the inclusion criteria: two on ertapenem, one on imipenem, and four on meropenem, all published between 2005 and 2016. Of seven studies, six were retrospective, four were performed in a single center, two enrolled children, two had a control group, and six reported a proportion of XDR-TB cases higher than 20%. Treatment success was higher than 57% in five studies with culture conversion rates between 60% and 94.8%. Conclusions: The safety and tolerability is very good, with the proportion of adverse events attributable to carbapenems below 15%.

Classifying new anti-tuberculosis drugs: rationale and future perspectives

The classification of anti-tuberculosis (TB) drugs is important as it helps the clinician to build an appropriate anti-TB regimen for multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB cases that do not fulfil the criteria for the shorter MDR-TB regimen. The World Health Organization (WHO) has recently approved a revision of the classification of new anti-TB drugs based on current evidence on each drug. In the previous WHO guidelines, the choice of drugs was based on efficacy and toxicity in a step-down manner, from group 1 first-line drugs and groups 2-5 second-line drugs, to group 5 drugs with potentially limited efficacy or limited clinical evidence. In the revised WHO classification, exclusively aimed at managing drug-resistant cases, medicines are again listed in hierarchical order from group A to group D. In parallel, a possible future classification is independently proposed. The aim of this viewpoint article is to describe the evolution in WHO TB classification (taking into account an independently proposed new classification) and recent changes in WHO guidance, while commenting on the differences between them. The latest evidence on the ex-group 5 drugs is also discussed.

Combined Use of Delamanid and Bedaquiline to Treat Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: A Systematic Review

The new drugs delamanid and bedaquiline are increasingly being used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB). The World Health Organization, based on lack of evidence, recommends their use under specific conditions and not in combination. No systematic review has yet evaluated the efficacy, safety, and tolerability of delamanid and bedaquiline used in combination. A search of peer-reviewed, scientific evidence was carried out, aimed at evaluating the efficacy/effectiveness, safety, and tolerability of delamanid and bedaquiline-containing regimens in individuals with pulmonary/extrapulmonary disease, which were bacteriologically confirmed as M/XDR-TB. We used PubMed to identify any relevant manuscripts in English up to the 23 December 2016, excluding editorials and reviews. Three out of 75 manuscripts retrieved satisfied the inclusion criteria, whilst 72 were excluded for dealing with only one drug (three studies), being recommendations (one study) or identifying need for their use (one study), focusing on drug resistance aspects (six studies) or being generic reviews/other studies (61 papers). The studies retrieved reported two XDR-TB cases observed for six months and achieving consistent sputum smear and culture conversion. Case 2 experienced a short break of bedaquiline, which was re-started after introducing verapamil. After a transient and symptom-free increase of the QT interval from week 5 to 17, it then decreased below the 500 ms threshold.

WHO strategies for the programmatic management of drug-resistant tuberculosis

ABSTRACT Introduction: Adequate management of drug-resistant tuberculosis (TB), including multidrug- (MDR) and extensively drug-resistant (XDR-) TB are within the priorities of the newly launched World Health Organizations End TB and Elimination Strategies. Areas covered: This manuscript presents the evidence on the MDR- /XDR-TB epidemiology and discusses how the five recommended priority actions can be applied at the programmatic level to tackle the epidemic: 1) prevent development of MDR-TB thorough high quality treatment of drug- susceptible TB; 2) expand rapid testing and detection of drug-resistant TB; 3) provide immediate access to effective treatment and proper care; 4) prevent transmission through infection control; 5) increase political commitment and financing. A non-systematic review using Pubmed was carried out in addition to additional relevant information taken from the abstracts of international scientific conferences. Expert commentary: Current and future control of MDR-TB significantly relies on the correct use of new diagnostics and new drugs from one side, and on the consistent application of the five core interventions at the programmatic level. In addition, it is mandatory to tackle the social determinants and socio-economic barriers favouring the MDR-TB, otherwise it will not be possible to reach the planned goals as well as TB Elimination.

Multidrug-resistant tuberculosis.

ABSTRACT: BACKGROUND: With almost 9 million new cases each year, tuberculosis remains one of the most feared diseases on the planet. Led by the STOP-TB Partnership and WHO, recent efforts to combat the disease have made considerable progress in a number of countries. However, the emergence of mutated strains of Mycobacterium tuberculosis that are resistant to the major anti-tuberculosis drugs poses a deadly threat to control efforts. Multidrug-resistant tuberculosis (MDR-TB) has been reported in all regions of the world. More recently, extensively drug resistant-tuberculosis (XDR-TB) that is also resistant to second line drugs has emerged in a number of countries. To ensure that adequate resources are allocated to prevent the emergence and spread of drug resistance it is important to understand the scale of the problem. In this article we propose that current methods of describing the epidemiology of drug resistant tuberculosis are not adequate for this purpose and argue for the inclusion of population based statistics in global surveillance data. DISCUSSION: Whereas the prevalence of tuberculosis is presented as the proportion of individuals within a defined population having disease, the prevalence of drug resistant tuberculosis is usually presented as the proportion of tuberculosis cases exhibiting resistance to anti-tuberculosis drugs. Global surveillance activities have identified countries in Eastern Europe, the former Soviet Union and regions of China as having a high proportion of MDR-TB cases and international commentary has focused primarily on the urgent need to improve control in these settings. Other regions, such as sub-Saharan Africa have been observed as having a low proportion of drug resistant cases. However, if one considers the incidence of new tuberculosis cases with drug resistant disease in terms of the population then countries of sub-Saharan Africa have amongst the highest rates of transmitted MDR-TB in the world. We propose that inclusion of population based statistics in global surveillance data is necessary to better inform debate on the control of drug resistant tuberculosis. SUMMARY: Re-appraisal of global MDR-TB data to include population based statistics suggests that the problem of drug resistant tuberculosis in sub-Saharan Africa is more critical than previously perceived.To the Editor: The study by Gler et al. (June 7 issue)1 provides a needed reminder regarding the development pipeline for drugs for tuberculosis and multidrug-resistant (MDR) tuberculosis.2 Delamanid with bedaquiline is increasing the potential for improving current regimens for tuberculosis. In their editorial in the same issue, Chaisson and Nuermberger3 go one step further, posing the question of how these drugs should be used and highlighting the need for combination trials to maximize effectiveness and minimize negative drug interactions among new drugs for tuberculosis. These issues are of key importance. Knowing the complexity of tuberculosis control and the difficulty of limiting dangerous misuse of drugs in the community, it is imperative that those of us who are involved in public health, health policy, and the treatment of patients with tuberculosis face the issue of the rational use of drugs for tuberculosis. The mistakes we committed with rifampin and the fluoroquinolones4,5 are readily evident. The reality is that single new drugs will inevitably be used in the community regardless of who develops them and the regulatory indications for them. The only solution is to anticipate the challenges of the misuse of new drugs well before any combination regimen is conceived and developed. Lia D’Ambrosio, M.A. Rosella Centis, M.Sc. Giovanni B. Migliori, M.D.

European policies in the management of tuberculosis among migrants

Globally 10.4 million new tuberculosis (TB) incident cases were estimated to have occurred in 2015, of which 3% were reported in the World Health Organization European Region. Importantly, about 25% of the global multidrug-resistant TB (MDR-TB) cases are reported in the European Region, representing one of the greatest challenges to TB control; these are reported particularly in the countries of the Former Soviet Union. Over a quarter of TB cases in the European Union and European Economic Area (EU/EEA) are reported among foreign-born individuals. In line with the recent increase of migration flows towards Europe, TB among migrant populations is also on the rise, emphasizing the need for a better understanding of the TB trends at the regional and sub-regional levels, and of the existing policies on migrants and refugees. The present article is aimed at describing the policies and practices of European countries with a low and intermediate TB incidence with regard to the detection and management of TB and latent TB infection (LTBI) among refugees in Europe.

Delamanid and bedaquiline to treat multidrug-resistant and extensively drug-resistant tuberculosis in children: a systematic review

The new drugs delamanid and bedaquiline are increasingly used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB). As evidence is lacking, the World Health Organization recommends their use under specific conditions in adults, delamanid only being recommended in children ≥6 years of age. No systematic review has yet evaluated the efficacy, safety and tolerability of the new drugs in children. A search of peer-reviewed, scientific evidence was performed, to evaluate the efficacy/effectiveness, safety, and tolerability of delamanid or bedaquiline-containing regimens in children with confirmed M/XDR-TB. We used PubMed and Embase to identify any relevant manuscripts in English until 31 December 2016, excluding editorials and reviews. Three out of 96 manuscripts retrieved satisfied the inclusion criteria, while 93 were excluded because dealing exclusively with adults (12: 4 on delamanid and 8 on bedaquiline), being recommendations or guidelines (8 manuscripts), reviews (17 papers) or other studies (56 papers). One of the studies retrieved reported evidence on 19 M/XDR-TB children, 16 of them treated under compassionate use with delamanid (13 achieving consistent bacteriological conversion) and 3 candidates for the drug. Two studies reported details on the first paediatric case treated (and cured) with a delamanid-containing regimen. Eight trials including children were also retrieved (clinicaltrials.gov). Although the methodology used in the study was rigorous, the results are limited by the paucity of the studies available in the literature on the use of new anti-TB drugs in children. In conclusion, more evidence is needed on the use of delamanid and bedaquiline in paediatric patients.

Shifting from tuberculosis control to elimination: Where are we? What are the variables and limitations? Is it achievable?

Tuberculosis (TB) is a priority in terms of incidence and mortality, with about 10.4 million new incident cases and 1.8 million deaths in 2015. The End-TB strategy recently launched by the World Health Organization in the context of the post-2015 agenda, aimed to achieve TB elimination, represents an evolution of the previous historical strategies originally aimed to achieve TB control. Globally, the current decline in TB incidence is rather slow at approximately 1,5% per year to reach the TB pre-elimination phase by 2035 (A more aggressive approach based on diagnosis and treatment of latently infected individuals has been proposed in the context of TB elimination to ensure future generations free of TB. We describes 4 scenarios which, combined, describe the TB epidemiology in a given setting: 1) in absence of interventions, 2) with early TB diagnosis and effective treatment, 3) with irregular TB treatment, 4) with TB co-infected by HIV not undergoing anti-retroviral treatment. To achieve TB Elimination, a more concerted action by funders and governments will be required for further investments into TB prevention, detection and treatment.

La diabetes se asocia con reacciones adversas graves en la tuberculosis multirresistente

INTRODUCTION Diabetes mellitus (DM), a very common disease in Mexico, is a well-known risk factor for tuberculosis (TB). However, it is not known by which extent DM predisposes to adverse events (AE) to anti-TB drugs and/or to worse outcomes in patients with multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB). The main objective of this study was to describe the outcomes of TB treatment, the impact of DM and the prevalence of AE in a cohort of patients with MDR-/XDR pulmonary TB treated at the national TB referral centre in Mexico City. RESULTS Ninety patients were enrolled between 2010 and 2015: 73 with MDR-TB (81.1%), 11 with pre-XDR-TB (12.2%) and 6 (6.7%) with XDR-TB, including 49 (54.4%) with DM, and 3 with Human Immunodeficiency Virus (HIV) co-infection (3.3%). In 98% of patients, diagnosis was made by culture and drug susceptibility testing, while in a single case the diagnosis was made by a molecular test. The presence of DM was associated with an increased risk of serious drug-related AEs, such as nephrotoxicity (Odds Ratio [OR]=6.5; 95% Confidence Interval [95% CI]: 1.9-21.8) and hypothyroidism (OR=8.8; 95% CI: 1.8-54.2), but not for a worse outcome. CONCLUSIONS Our data suggest that DM does not impact second-line TB treatment outcomes, but patients with DM have a higher risk of developing serious AEs to drug-resistant TB treatment, such as nephrotoxicity and hypothyroidism.