Preventive Therapy for Contacts of Drug-Resistant Tuberculosis

Preventing the progression of a drug-resistant tuberculosis (DR-TB) infection to disease is an important pillar of the DR-TB elimination strategy. International guidelines have recently proposed fluoroquinolones for tuberculosis preventive therapy (TPT) in DR-TB contacts, although the available evidence is low quality. The pooled data from small observational studies suggest that a fluoroquinolone-based TPT is safe, effective and cost-effective as a preventive treatment in DR-TB contacts. Three clinical trials are currently ongoing to generate higher quality evidence on the efficacy of levofloxacin and delamanid as a DR-TB preventive therapy. Additional evidence is also needed, regarding TPT treatment in fluoroquinolone-resistant-TB contacts, patient and health care worker perceptions on DR-TB preventive therapy for contacts, and the service delivery models to increase DR-TPT access. This state-of-the-art review presents the current literature on TPT for contacts of DR-TB cases, focusing on the available evidence and international guidelines

Antimicrobial susceptibility of Mycobacterium abscessus and treatment of pulmonary and extra-pulmonary infections

International audienceBackground: Mycobacterium abscessus (MAB) is the mycobacterial species least susceptible to antimicrobials. Infections are difficult to treat, and cure rates are below 50% even after a combination of 4-5 drugs for many months.Objectives: To examine antimicrobial susceptibilities and treatment recommendations in light of what is known about mechanisms of resistance and pharmacodynamics/pharmacokinetics (PK/PD) interactions.Sources: Original papers on the topics of 'antimicrobials', 'susceptibility', 'treatment', and 'outcome' from 2019 onwards, in the context of the evidence brought by the guidelines published in 2020 for pulmonary infections.Content: MAB is susceptible in vitro to only a few antimicrobials. Breakpoints were set by the Clinical and Laboratory Standards Institute and are revised by the European Committee on Antimicrobial Susceptibility Testing for epidemiological cut-off values. Innate resistance is due to multiple resistance mechanisms involving efflux pumps, inactivating enzymes, and low drug-target affinity. In addition, MAB may display acquired resistance to macrolides and amikacin through mutations in drug binding sites. Treatment outcomes are better for macrolide-based combinations and MAB subspecies massiliense. New compounds in the family of cyclines, oxazolidinones, and penem-β-lactamase inhibitor combinations (described in another paper), as well as bedaquiline, a new antituberculous agent, are promising, but their efficacy remains to be proven. PK/PD studies, which are critical for establishing optimal dosing regimens, were mainly done for monotherapy and healthy individuals.Implications: Medical evidence is poor, and randomized clinical trials or standardized cohorts are needed to compare outcomes of patients with similar underlying disease, clinical characteristics, and identified MAB subspecies/sequevar. Microbiological diagnosis and susceptibility testing need to be harmonized to enable the comparison of agents and the testing of new compounds. Testing antimicrobial combinations requires new methods, especially for PK/PD parameters. Molecular testing may help in assessing MAB resistance prior to treatment. New antimicrobials need to be systematically tested against MAB to find an effective antimicrobial regimen

Molecular Detection of Isoniazid Monoresistance Improves Tuberculosis Treatment: A Retrospective Cohort in France.

International audienceOBJECTIVES: Isoniazid-monoresistant tuberculosis (HR-TB) requires early diagnosis and adapted treatment to achieve optimal outcomes. The primary aim of the study was to assess the impact of the implementation of rapid diagnostic tests on HR-TB treatment in France. METHODS: We designed a retrospective multicentre study including consecutive HR-TB patients diagnosed in 2016 and 2017. Implementation of a molecular assay detecting isoniazid resistance directly on a clinical sample was recorded. The association between early implementation of such assays and adequate treatment was assessed by a multivariable Cox proportional hazards model. RESULTS: Overall, 99 HR-TB patients were included from 20 University Hospitals. Among all smear-positive HR-TB patients, only 26% beneficiated from early molecular HR detection. This detection was independently associated with shorter time to adequate treatment (HR~=~2.0 [1.1-3.8], p~=~0.03). CONCLUSION: In our study, molecular detection of HR on an initial sample was independently associated with earlier treatment adaptation

Isoniazid-monoresistant tuberculosis in France: risk factors, treatment outcomes and adverse events

International audienceObjectives: Isoniazid-monoresistant tuberculosis (HR-TB) is the most prevalent form of drug-resistant TB worldwide and in France and is associated with poorer treatment outcomes compared to drug-susceptible TB (DS-TB). The objective of this study was to determine the characteristics of HR-TB patients in France and to compare outcomes and safety of treatment for HR-TB and DS-TB.Methods: A case-control multicentre study was performed to identify risk factors associated with HR-TB and to compare treatment outcomes and safety among HR-TB patients and DS-TB patients.Results: Characteristics of 99 HR-TB diagnosed and treated in university hospitals of Paris, Lille, Caen and Strasbourg were compared to 99 DS-TB's. Female sex (OR = 2.2; 1.0-4.7), birth in the West-Pacific WHO region (OR = 4.6; 1.1-18.7) and resistance to streptomycin (OR = 77.5; 10.1-594.4) were found to be independently associated with HR-TB. Rates of treatment success did not differ significantly between HR-TB and DS-TB.Conclusions: Factors associated with HR-TB are not relevant enough to efficiently screen TB patients at risk of HR-TB. The systematic implementation of rapid molecular testing on clinical samples remains the only effective way to make the early diagnosis of HR-TB and adapt the treatment

The park never born: Outcome of a quarter of a century of inaction on the sea-floor integrity of a proposed but not established Marine Protected Area

Marine Protected Areas (MPAs) are a major tool to conserve marine ecosystems but are also strongly attractive to tourists, the increased numbers of which can cause environmental issues if not properly managed. Proposing an MPA and then failing to establish it risks advertising the beauty of a marine area without managing the unavoidable increase in tourism. This is what happened at Gallinara Island (Ligurian Sea, north-western Mediterranean), where an MPA was proposed in 1990 but has not yet been established. Benthic data collected soon after the proposal (1990\u201392) have been compared with similar information obtained in subsequent periods (2009 and 2016): change has been assessed both visually and statistically, using multivariate and univariate techniques. The Gallinara sea floor supported five epibenthic communities in 1991, four of which corresponded to European Nature Information System (EUNIS) habitats; the fifth epibenthic community, characterized by the erect sponge Axinella polypoides, should be included in the next revision of EUNIS. In the 25 years since the original MPA proposal, all epibenthic communities have exhibited a reduction in their three-dimensional structure and biotic homogenization, and severe decreases in species diversity, and the sea floor has been littered with derelict fishing gear and other waste from boats. In absence of the MPA, proposals to develop a management plan for a marine Site of Community Importance (SCI) have been provided, to reduce sea-based human pressures. The dramatic alteration of Gallinara sea floor after 25 years of negligence and inaction is a sad warning for other unmanaged yet beautiful natural areas within urbanized regions of the world

Increased linezolid plasma concentrations are associated with the development of severe toxicity in MDR-TB treatment.

Auteurs : the LZDM groupInternational audienceAbstract Background Treatment of multidrug-resistant (MDR) tuberculosis with linezolid is characterized by high rates of adverse events. Evidence on therapeutic drug monitoring to predict drug toxicity is scarce. This study aimed to evaluate the association of linezolid trough concentrations with severe toxicity. Methods We retrospectively assessed consecutive patients started on linezolid for MDR tuberculosis between 2011 and 2017. The primary outcome was severe mitochondrial toxicity (SMT) due to linezolid, defined as neurotoxicity or myelotoxicity leading to drug discontinuation. The impact of plasma linezolid trough concentrations >2 mg/L was assessed in multivariate Cox proportional hazards models including time-varying covariates. Results SMT occurred in 57 of 146 included patients (39%) at an incidence rate of 0.38 per person-year (95% confidence interval, .30–.49). A maximum linezolid trough concentration >2 mg/L was detected in 52 patients (35.6%), while the mean trough concentration was >2 mg/L in 22 (15%). The adjusted hazard ratio for SMT was 2.35 (95% confidence interval, 1.26–4.38; P = .01) in patients with a mean trough concentration >2 mg/L and 2.63 (1.55–4.47; P < .01) for SMT after the first detection of a trough concentration >2 mg/L. In an exploratory analysis, higher maximum trough concentrations were dose-dependently associated with toxicity, while lowering elevated trough concentrations did not restore baseline risk. Conclusions Linezolid trough concentrations >2 mg/L are strongly associated with the development of severe treatment-emergent toxicity in patients treated for MDR tuberculosis. Pending further prospective evidence, an individual risk-benefit assessment on the continuation of linezolid treatment is warranted in any patient with trough concentrations >2 mg/L