Lorenzo Guglielmetti

Compassionate Use of Bedaquiline for the Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: Interim Analysis of a French Cohort

BACKGROUND Bedaquiline is a new antibiotic that was approved for the treatment of multidrug-resistant (MDR) tuberculosis. We aimed to evaluate the short-term microbiological efficacy and the tolerability profile of bedaquiline. METHODS We performed a retrospective cohort study among patients with MDR tuberculosis receiving bedaquiline for compassionate use between January 2010 and July 2013 and evaluated at 6 months of bedaquiline treatment. RESULTS A total of 35 patients with MDR tuberculosis were included in the study. Nineteen (54%) had extensively drug-resistant (XDR) tuberculosis, and 14 (40%) had isolates resistant to fluoroquinolones (Fqs) or second-line injectables. Bedaquiline was associated with a median of 4 (range, 2-5) other drugs, including linezolid in 33 (94%) cases. At 6 months of bedaquiline treatment, culture conversion was achieved in 28 of 29 (97%) cases with culture-positive pulmonary tuberculosis at bedaquiline initiation. Median time to culture conversion was 85 days (range, 8-235 days). Variables independently associated with culture conversion were treatment with a Fq (P = .01), absence of lung cavities (P < .001), and absence of hepatitis C virus infection (P = .001). A total of 7 patients (20%) experienced a ≥60-ms increase in QT interval, leading to bedaquiline discontinuation in 2 (6%) cases. Severe liver enzyme elevation occurred in 2 patients (6%). During the study period, 1 death (3%) occurred and was reported as unrelated to tuberculosis or antituberculosis treatment. CONCLUSIONS The use of bedaquiline combined with other active drugs has the potential to achieve high culture conversion rates in complicated MDR and XDR tuberculosis cases, with a reassuring safety profile at 6 months of treatment.

Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis

Bedaquiline, a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB), is recommended for a duration of 24 weeks. There are scarce data on patients treated with this drug outside clinical trials. All MDR-TB patients who started treatment from January 1, 2011 to December 31, 2013 and received ≥30 days of bedaquiline were included in a multicentre observational cohort. Among 45 MDR-TB patients, 53% harboured isolates resistant to both fluoroquinolones and second-line injectables, and 38% harboured isolates resistant to one of these drug classes. Median bedaquiline treatment duration was 361 days and 33 patients (73%) received prolonged (>190 days) bedaquiline treatment. Overall, 36 patients (80%) had favourable outcome, five were lost to follow-up, three died, and one failed and acquired bedaquiline resistance. No cases of recurrence were reported. Severe and serious adverse events were recorded in 60% and 18% of patients, respectively. Values of Fridericia-corrected QT interval (QTcF) >500 ms were recorded in 11% of patients, but neither arrhythmias nor symptomatic cardiac side-effects occurred. Bedaquiline was discontinued in three patients following QTcF prolongation. No significant differences in outcomes or adverse events rates were observed between patients receiving standard and prolonged bedaquiline treatment. Bedaquiline-containing regimens achieved favourable outcomes in a large proportion of patients. Prolonged bedaquiline treatment was overall well tolerated in this cohort. Treatment regimens including prolonged bedaquiline use are effective and overall well tolerated in MDR-TB patients http://ow.ly/vhtl305CYJj

Rapid emergence of Mycobacterium tuberculosis bedaquiline resistance: lessons to avoid repeating past errors

Bedaquiline (BDQ) has demonstrated potent clinical activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis complex strains [1–3]. It has now been used in >50 countries, and it is estimated that ∼2500 patients had been treated with BDQ by the end of 2015. In spite of its recent clinical use, there are few reports of BDQ-resistant strains [4, 5]. Mutations in the rv0678 gene encoding the MmpL5 efflux pump repressor generate low-level BDQ resistance and clofazimine (CFZ) cross-resistance [6]. To our knowledge, this is the sole mechanism of BDQ resistance described in clinical strains [4, 5]. Despite its introduction in France in 2011 for XDR- and MDR-tuberculosis (TB) treatment, we report herein four BDQ-resistant cases, and discuss strategies to avoid a surge of BDQ resistance. Bedaquiline resistance appears rapidly both after treatment and in patients that have never been treated http://ow.ly/mxEM30604OF

Human infections due to nontuberculous mycobacteria: the infectious diseases and clinical microbiology specialists' point of view

Nontuberculous mycobacteria (>150 species such as Mycobacterium avium, Mycobacterium kansasii, Mycobacterium chelonae and Mycobacterium abscessus) are opportunistic pathogens causing lung and extrarespiratory infections, beside M. ulcerans and M. marinum that are pathogens causing specific skin and soft tissue infections. Disseminated infections occur only in severe immunosuppressed conditions such as AIDS. The diagnosis is based on repeated isolations of the same mycobacterium associated with clinical and radiological signs, and the absence of tuberculosis. Precise species identification is obtained by molecular biology. Therapeutic antibiotic regimens differ with regard to the mycobacterial species that are involved. Prevention of iatrogenic infections relies on using sterile water in all injections, healthcare and cosmetic occupations. Future perspectives are to set effective antibiotic regimens tested in randomized therapeutic trials.

Infections caused by Mycobacterium abscessus: epidemiology, diagnostic tools and treatment

ABSTRACT Introduction: Mycobacterium abscessus is an emerging mycobacteria that is responsible for lung diseases and healthcare-associated extrapulmonary infections. Recent findings support its taxonomic status as a single species comprising 3 subspecies designated abscessus, bolletii and massiliense. We performed a review of English-language publications investigating all three of these subspecies. Areas covered: Worldwide, human infections are often attributable to environmental contamination, although the isolation of M. abscessus in this reservoir is very rare. Basic research has demonstrated an association between virulence and cell wall components and cording, and genome analysis has identified gene transfer from other bacteria. The bacteriological diagnosis of M. abscessus is based on innovative tools combining molecular biology and mass spectrometry. Genotypic and phenotypic susceptibility testing are required to predict the success of macrolide (clarithromycin or azithromycin)-based therapeutic regimens. Genotyping methods are helpful to assess relapse and cross-transmission and to search for a common source. Treatment is not standardised, and outcomes are often unsatisfactory. Expert commentary: M. abscessus is still an open field in terms of clinical and bacteriological research. Further knowledge of its ecology and transmission routes, as well as host-pathogen interactions, is required. Because the number of human cases is increasing, it is also necessary to identify more active treatments and perform clinical trials to assess standard effective regimens.

Is bedaquiline as effective as fluoroquinolones in the treatment of multidrug-resistant tuberculosis?

Bedaquiline (Bdq) is approved for the treatment of multidrug-resistant (MDR) tuberculosis (TB). In a phase IIb trial, Bdq allowed a significant reduction in time to culture conversion and improved outcome in MDR-TB patients [1, 2]. Preliminary reports of Bdq compassionate use have shown promising results [3–5]. However, in an early bactericidal activity (EBA) study, the association of moxifloxacin (Mfx) with PA-824 and pyrazinamide showed better activity than Bdq-based associations [6]. In addition, resistance to fluoroquinolones (Fq) has been associated with poorer outcome in MDR-TB before Bdq use [7]. These data reinforce the pivotal role of Fq. Comparing Bdq to Fq in interventional studies is challenging. Indeed, the paucity of drugs available for MDR-TB treatment, and the need for combination therapy, often impose the need to use all available drugs. Bedaquiline and fluoroquinolone treatments give similar culture conversion rates at 6 months in MDR-TB patients http://ow.ly/oqVY300mJCy

Lymphocyte subpopulations in active tuberculosis: association with disease severity and the QFT-GIT assay.

Cell-mediated immune response plays an essential role in the pathogenesis of tuberculosis (TB). We retrospectively evaluated lymphocyte subpopulations in 177 active TB patients compared to 93 healthy controls, finding a relevant decrease in total lymphocytes and CD8+ cells. Conversely, activated human leukocyte antigen (HLA-DR+) and CD4+CD57+ cells were higher in the TB group. B-1a (CD5+CD19+) lymphocytes were reduced in TB subjects, particularly those with extended and cavitary pulmonary forms, suggesting increased compartmentalisation at the infection site. QuantiFERON-TB Gold In-Tube positive results were associated with higher HLA-DR+CD4+ and CD4+CD57+ cells, while interferon-gamma response and total lymphocyte levels were lower in advanced pulmonary TB cases.Cell-mediated immune response plays an essential role in the pathogenesis of tuberculosis (TB). We retrospectively evaluated lymphocyte subpopulations in 177 active TB patients compared to 93 healthy controls, finding a relevant decrease in total lymphocytes and CD8+ cells. Conversely, activated human leukocyte antigen (HLA-DR+) and CD4+CD57+ cells were higher in the TB group. B-1a (CD5+CD19+) lymphocytes were reduced in TB subjects, particularly those with extended and cavitary pulmonary forms, suggesting increased compartmentalisation at the infection site. QuantiFERON®-TB Gold In-Tube positive results were associated with higher HLA-DR+CD4+ and CD4+CD57+ cells, while interferon-gamma response and total lymphocyte levels were lower in advanced pulmonary TB cases.

False-negative interferon-γ release assay results in active tuberculosis: a TBNET study

Tuberculosis is one of the leading causes of morbidity and mortality worldwide [1]. Rapid identification of contagious tuberculosis patients and effective treatment are necessary to prevent the spread of Mycobacterium tuberculosis, the causative bacterium of the disease. Although interferon-γ release assays (IGRAs) have been developed for the diagnosis of latent infection with M. tuberculosis, these assays are sometimes used as adjunctive tests in the diagnostic workup for active tuberculosis, despite poor specificity [2]. Advanced age was the only risk factor for false-negative IGRAs in this study of active tuberculosis http://ow.ly/Cvp5G

Treatment outcome definitions in nontuberculous mycobacterial pulmonary disease: an NTM-NET consensus statement

Nontuberculous mycobacterial pulmonary diseases (NTM-PD) are increasingly recognised as opportunistic infections of humans. These chronic pulmonary infections have two main presentations. The first is a fibro-cavitary disease, that occurs in patients with pre-existing pulmonary diseases, such as chronic obstructive pulmonary disease, bronchiectasis, previous tuberculosis or other structural lung disease. The second presentation is a nodular-bronchiectatic disease of primarily the lingula and middle lobe that tends to affect a middle-aged and elderly female population [1]. Improving treatment outcome reporting in NTM disease: NTM-NET (@ntmnet) consensus statement on treatment outcome definitions http://ow.ly/c6IC30iwLM4

Safety and efficacy of exposure to bedaquiline-delamanid in MDR-TB: a case series from France and Latvia

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) represent a therapeutic challenge [1]. Two anti-TB agents, bedaquiline and delamanid, have been recently approved for the treatment of MDR/XDR-TB. Bedaquiline has a terminal half-life of 5.5 months, in contrast with the short half-life of delamanid (38 h). Both drugs increase the QTcF (Fridericia-corrected QT) interval, although no clinically significant cardiac events have been reported in patients treated with one of these drugs [2, 3]. The clinical trials that led to approval of bedaquiline and delamanid tested these drugs by adding one of them, for a duration of 24 weeks and 6–8 months, respectively, to optimised background [2, 3]. To date, only six cases treated with the bedaquiline−delamanid combination have been reported, mostly presenting interim results [4–6]. The World Health Organization (WHO) recommends to use these drugs for a standardised duration of 24 weeks, the concomitant use of bedaquiline and delamanid being restricted to patients with “no other therapeutic options”. Otherwise, it is recommended to start the two drugs sequentially after a washout period of 6 months, when switching from bedaquiline to delamanid, and 5 days, when switching from delamanid to bedaquiline [7]. We report the results of exposure to concomitant and sequential treatment with bedaquiline and delamanid, including treatment courses beyond 24 weeks, as part of multidrug MDR/XDR-TB regimens. Good tolerability of exposure to bedaquiline−delamanid association in MDR/XDR-TB patients http://ow.ly/4uvr30i7az4