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Multidrug-resistant tuberculosis (MDR-TB) is a major global health problem. The loss of susceptibility to an increasing number of drugs behoves us to consider the evaluation of non-traditional anti-tuberculosis drugs.Clarithromycin, a macrolide antibiotic, is defined as a group 5 anti-tuberculosis drug by the World Health Organization; however, its role or efficacy in the treatment of MDR-TB is unclear. A systematic review of the literature was conducted to summarise the evidence for the activity of macrolides against MDR-TB, by evaluating in vitro, in vivo and clinical studies. PubMed and Embase were searched for English language articles up to May 2014.Even though high minimum inhibitory concentration values are usually found, suggesting low activity against Mycobacterium tuberculosis, the potential benefits of macrolides are their accumulation in the relevant compartments and cells in the lungs, their immunomodulatory effects and their synergistic activity with other anti-TB drugs.A future perspective may be use of more potent macrolide analogues to enhance the activity of the treatment regimen.

The prevalence of pulmonary nontuberculous mycobacterial (pNTM) disease is increasing [1]. The most commonly isolated disease-causing NTMs belong to the Mycobacterium avium complex [1]. Susceptibility to and clinical manifestation of NTM disease are largely governed by the immune status of a person. Disseminated or extrapulmonary NTM infections are strongly associated with severe immunosuppression, such as those with frank defects in the interferon (IFN)-γ–interleukin (IL)-12 axis [2]. Isolated pNTM is strongly associated with certain underlying conditions, such as cystic fibrosis, chronic obstructive pulmonary disease and primary ciliary dyskinesia [3, 4]. However, substantial numbers of pNTM patients have no apparent risk factors, and a significant proportion of them exhibit a body morphotype characterised by lifelong slender body habitus, pectus excavatum, scoliosis and mitral valve prolapse [5, 6], also called the Lady Windermere syndrome. A modest reduction in IFN-γ production and an increase in transforming growth factor (TGF)-β levels have been described [7–10]. Fowler et al. [11] quantified ciliary beat frequency of 58 pNTM patients and 40 controls and found reduced ciliary beat frequency in the pNTM patients. Szymanski et al. [12] performed whole-exome sequencing on patients with pNTM, their unaffected family members and a control group and concluded that pNTM is a multigenic disease, encompassing potential defects in proteins encoded by cilia genes, the cystic fibrosis transmembrane conductance regulator gene, connective tissue genes and certain immune-related genes.

Mycobacterium tuberculosis (Mtb) causes the disease tuberculosis (TB). The virulent Mtb H37Rv strain encodes 20 cytochrome P450 (CYP) enzymes, many of which are implicated in Mtb survival and pathogenicity in the human host. Bioinformatics analysis revealed that CYP144A1 is retained exclusively within the Mycobacterium genus, particularly in species causing human and animal disease. Transcriptomic annotation revealed two possible CYP144A1 start codons, leading to expression of (i) a "full-length" 434 amino acid version (CYP144A1-FLV) and (ii) a "truncated" 404 amino acid version (CYP144A1-TRV). Computational analysis predicted that the extended N-terminal region of CYP144A1-FLV is largely unstructured. CYP144A1 FLV and TRV forms were purified in heme-bound states. Mass spectrometry confirmed production of intact, His6-tagged forms of CYP144A1-FLV and -TRV, with EPR demonstrating cysteine thiolate coordination of heme iron in both cases. Hydrodynamic analysis indicated that both CYP144A1 forms are monomeric. CYP144A1-TRV was crystallized and the first structure of a CYP144 family P450 protein determined. CYP144A1-TRV has an open structure primed for substrate binding, with a large active site cavity. Our data provide the first evidence that Mtb produces two different forms of CYP144A1 from alternative transcripts, with CYP144A1-TRV generated from a leaderless transcript lacking a 5'-untranslated region and Shine-Dalgarno ribosome binding site.

Lung disease caused by nontuberculous mycobacteria (NTM) is an emerging infectious disease of global significance. Epidemiologic studies have shown the Hawaiian Islands have the highest prevalence of NTM lung infections in the United States. However, potential environmental reservoirs and species diversity have not been characterized. In this cross-sectional study, we describe molecular and phylogenetic comparisons of NTM isolated from 172 household plumbing biofilms and soil samples from 62 non-patient households and 15 respiratory specimens. Although non-uniform geographic sampling and availability of patient information were limitations, Mycobacterium chimaera was found to be the dominant species in both environmental and respiratory specimens. In contrast to previous studies from the continental U.S., no Mycobacterium avium was identified. Mycobacterium intracellulare was found only in respiratory specimens and a soil sample. We conclude that Hawai’i’s household water sources contain a unique composition of Mycobacterium avium complex (MAC), increasing our appreciation of NTM organisms of pulmonary importance in tropical environments., Author Summary In the U.S., the Hawaiian Islands have the highest number of nontuberculous mycobacterial (NTM) lung disease cases per capita. The tropical climate, geographical isolation of the islands, and aquifer water sources may have influence such prevalence. Previous studies suggest that NTM thrive in water biofilms and soil. To broaden our understanding of potential environmental reservoirs and species composition of NTM in the Hawaiian Islands, we sampled environmental sites and examined patient isolates. Our recovery and identification of Mycobacterium chimaera and several other clinically relevant NTM species and the absence of Mycobacterium avium in both the indigenous environment and clinical specimens underscore the need for further studies to define the environmental factors that drive NTM lung disease and species composition in high prevalence locations such as the Hawaiian Islands.

Multidrug-resistant tuberculosis (MDR-TB) is a major global health problem. The loss of susceptibility to an increasing number of drugs behoves us to consider the evaluation of non-traditional anti-tuberculosis drugs.Clarithromycin, a macrolide antibiotic, is defined as a group 5 anti-tuberculosis drug by the World Health Organization; however, its role or efficacy in the treatment of MDR-TB is unclear. A systematic review of the literature was conducted to summarise the evidence for the activity of macrolides against MDR-TB, by evaluating in vitro, in vivo and clinical studies. PubMed and Embase were searched for English language articles up to May 2014.Even though high minimum inhibitory concentration values are usually found, suggesting low activity against Mycobacterium tuberculosis, the potential benefits of macrolides are their accumulation in the relevant compartments and cells in the lungs, their immunomodulatory effects and their synergistic activity with other anti-TB drugs.A future perspective may be use of more potent macrolide analogues to enhance the activity of the treatment regimen.

Mycobacterium species adhere to the respiratory mucosa via mucus and fibronectin of extracellular matrix exposed by damaged epithelium. We have investigated whether inhibiting adherence to fibronectin influences subsequent infection of human respiratory tissue by Mycobacterium avium complex and Mycobacterium tuberculosis. Human respiratory tissue was pretreated with mycobacterial fibronectin attachment proteins prior to infection with M. avium complex and M. tuberculosis and the number of recoverable bacteria over time was compared to untreated controls. Inhibition significantly reduced recovery of M. avium complex at 15min ( P =0.02), 7days ( P =0.04), and 14days ( P =0.03); whereas recovery of M. tuberculosis was only reduced at 15min ( P =0.01) and not at later timepoints. We conclude that M. avium complex and M. tuberculosis infection of the mucosa proceeds by different mechanisms, since M. tuberculosis infection is independent of fibronectin adherence.

To the Editors: Nontuberculous mycobacteria (NTM) are opportunistic pathogens that are widely present in our environment, i.e. in the soil and in natural and processed water. This group of organisms, with varying biological properties and clinical relevance, has gained notoriety over the past two decades due to their capability to cause severe disease in patients with immunodeficiency and/or chronic lung disease [1]. Despite their rising isolation frequency and growing clinical importance, NTM infections receive little scientific or public health attention. This partly results from the dogma that these NTM infections are not transmitted from male-to-male [1]. During our previous research of Mycobacterium malmoense infection in the Netherlands [2], we studied two patients with M. malmoense pulmonary infection with a strong epidemiological link. Human transmission was suspected because an acid-fast bacilli (AFB) smear-positive patient was in close contact with an immunocompromised patient. Herein, we present details of the cases and the results of the molecular diagnostics that were performed. The patients gave informed consent; ethical approval was not required for this retrospective study. A 38-yr-old male with a medical history of chronic obstructive pulmonary disease and spontaneous pneumothorax reported to the respiratory physician with progressive dyspnoea, productive cough, fever, night sweats, malaise and weight loss. A chest radiograph revealed infiltrates with cavities in the upper lobes. Laboratory diagnostics showed a raised erythrocyte sedimentation rate (90 mm·h−1) and leukocytosis (white blood cell count …

The majority of investigations of the epidemiology of nontuberculous mycobacteria (NTM) have focused on highly developed nations with a low prevalence of tuberculosis. In contrast, the Para state of north Brazil represents an area of high tuberculosis prevalence and increasing NTM incidence. Toward the goal of understanding the dynamics of infection by all Mycobacterium species, we report patient characteristics and the identification of NTM strains isolated from sputum samples from patients that were residents of Para, a state in the Amazon region, Northern of Brazil, over the period January 2010 through December 2011 (2 years). The 29 NTM patients comprised 13.5% of positive mycobacterial cultures over the 2-year period. A major risk factor for NTM pulmonary disease was previous tuberculosis (76%). Further, the average age of NTM patients (52 years) was significantly higher than that of tuberculosis patients (39 years) and more were female (72.4% vs. 37.4%). Unlike other Brazilian states, NTM pulmonary patients in Para were infected with a different spectrum of mycobacteria; primarily the rapidly growing Mycobacterium massiliense and Mycobacterium simiae complex. Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico; Evandro Chagas Institute, Ananindeua, Para, Brazil This work was supported by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico and the Evandro Chagas Institute, Ananindeua, Para, Brazil. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Concentrations of antimycobacterial drugs are an intermediary link between doses administered and eventual response to the drugs. Few pharmacokinetic (PK) studies have focused on drug treatment for nontuberculous mycobacterial (NTM) disease, although a favourable treatment response occurs in just over 50% of patients despite drug treatment for >= 1 year. A prospective, descriptive PK study was performed to assess the plasma pharmacokinetics of rifampicin, ethambutol, clarithromycin, 14-OH-clarithromycin, azithromycin, isoniazid and moxifloxacin. Intensive PK sampling was performed in 14 patients with clinically relevant NTM lung disease. PK parameters were assessed and were compared with available data from the literature. Exposure to clarithromycin when combined with rifampicin was very low [area under the concentration-time curve over 12 h (AUC(0-12) h), geometric mean 2.6 h.mg/L, range 1.6-3.2 h.mg/L; peak concentration in plasma (C-max), geometric mean 0.3 mg/L, range 0.1-0.7 mg/L]. The mean parent-to-metabolite ratios for clarithromycin to 14-OH-clarithromycin were 0.4 and 0.3 for AUC(0-12) hand C-max, instead of the typical ratio of ca. 3, probably reflecting increased metabolism of clarithromycin to its (virtually inactive) 14-OH metabolite. Exposure to rifampicin was relatively high, with all patients having a rifampicin C-max within the reference range. The majority of ethambutol C-max values were within the reference range. The current study re-emphasises the relevant PK interaction between clarithromycin and rifampicin. This calls for a re-evaluation of dosing strategies in NTM lung disease, as suboptimal drug exposure may contribute to inadequate response to treatment of NTM disease. (C) 2013 Elsevier B. V. and the International Society of Chemotherapy. All rights reserved.

Symptoms of chronic rhinosinusitis (CRS) often persist despite treatment. Because nontuberculous nnycobacteria (NTM) are resistant to commonly used antimicrobial drugs and are found in drinking water that patients may use for sinus irrigation, we investigated whether some CRS patients were infected with NTM in New York, New York, USA, during 2001-2011. Two approaches were chosen: 1) records of NTM-infected CRS patients were reviewed to identify common features of infection and Mycobacterium species; 2) samples from plumbing in households of 8 NTM-infected patients were cultured for NTM presence. In 3 households sampled, M. avium sharing rep-PCR and pulsed field gel electrophoresis fingerprints identified M. avium isolates clonally related to the patients' isolates. We conclude that patients with treatment-resistant CRS may be infected with NTM and should have cultures performed for NTM so appropriate therapy can be instituted. In addition, the results suggest that CRS patients can be infected by NTM in their household plumbing. Amon Carter Foundation Work in the Mycobacteria/Nocardia Laboratory at the University of Texas Health Science Center was supported by the Amon Carter Foundation.

To determine whether plumbing could be a source of nontuberculous mycobacteria (NTM) infection, during 2007-2009 I isolated NTM from samples from household water systems of NTM patients. Samples from 22/37 (59%) households and 109/394 (28%) total samples yielded NTM. Seventeen (46%) of the 37 households yielded >= 1 Mycobacterium spp. isolate of the same species as that found in the patient; in 7 of those households, the patient isolate and 1 plumbing isolate exhibited the same repetitive sequence-based PCR DNA fingerprint. Households with water heater temperatures = 130 degrees F (>= 55 degrees C) (p = 0.0107). Although households with water from public or private water systems serving multiple households were more likely to have NTM (19/27, 70%) compared with households with a well providing water to only 1 household (5/12, 42%), that difference was not significant (p = 0.1532). Nontuberculous Mycobacteria Research and Information Foundation, Inc. The study was supported by a grant from the Nontuberculous Mycobacteria Research and Information Foundation, Inc.

Environmental opportunistic mycobacteria, including Mycobacterium avium, M. terrae, and the new species M. immunogenum, have been implicated in outbreaks of hypersensitivity pneumonitis or respiratory problems in a wide variety of settings. One common feature of the outbreaks has been exposure to aerosols. Aerosols have been generated from metalworking fluid during machining and grinding operations as well as from indoor swimming pools, hot tubs, and water-damaged buildings. Environmental opportunistic mycobacteria are present in drinking water, resistant to disinfection, able to provoke inflammatory reactions, and readily aerosolized. In all outbreaks, the water sources of the aerosols were disinfected. Disinfection may select for the predominance and growth of mycobacteria. Therefore, mycobacteria may be responsible, in part, for many outbreaks of hypersensitivity pneumonitis and other respiratory problems in the workplace and home.

Summary Background Infections with non-tuberculous mycobacteria (NTM) represent an increasing problem. Their clinical relevance is still largely unknown as well as predictors for mortality in affected patients. The objective was to describe prevalence and clinical relevance of different NTM and to identify risk factors for mortality. Methods Retrospective cohort study of 124 patients with NTM detection between January 2001 and December 2011. Clinical characteristics like symptoms and radiological appearance were assessed at presentation. The primary outcome was all cause mortality during the follow-up period. Univariate and multivariate survival analyses using Cox proportional hazard models were employed for statistical analysis. Results Over the study period, the frequency of NTM isolation varied from 4 to 12 patients per year. Twenty-nine out of 124 patients (23%) had a clinically relevant infection, according to the criteria of the American Thoracic Society (ATS). Mycobacterium avium was isolated most frequently, but Mycobacterium kansasii, Mycobacterium malmoense and Mycobacterium xenopi had the highest clinical relevance. Symptoms were mostly diverse and non-specific. On radiology, cavities were observed more frequently than a nodular-bronchiectatic variant or consolidation. In 75% of all patients, follow up time was more than two years. Median survival was 6.5 years (95%CI = 2.7–10.3). Factors significantly influencing survival time were haemoptysis (HR = 0.2, 95%CI = 0.1–0.6) and a consolidation on imaging (HR = 5.1, 95%CI 1.4–18.2). Conclusions The presentation of an infection with NTM can be diverse and depends mainly on the causative NTM pathogen. The most important predictor for increased mortality is the radiological appearance of a consolidation.