Wouter Hoefsloot

The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study

A significant knowledge gap exists concerning the geographical distribution of nontuberculous mycobacteria (NTM) isolation worldwide. To provide a snapshot of NTM species distribution, global partners in the NTM-Network European Trials Group (NET) framework (www.ntm-net.org), a branch of the Tuberculosis Network European Trials Group (TB-NET), provided identification results of the total number of patients in 2008 in whom NTM were isolated from pulmonary samples. From these data, we visualised the relative distribution of the different NTM found per continent and per country. We received species identification data for 20 182 patients, from 62 laboratories in 30 countries across six continents. 91 different NTM species were isolated. Mycobacterium avium complex (MAC) bacteria predominated in most countries, followed by M. gordonae and M. xenopi. Important differences in geographical distribution of MAC species as well as M. xenopi, M. kansasii and rapid-growing mycobacteria were observed. This snapshot demonstrates that the species distribution among NTM isolates from pulmonary specimens in the year 2008 differed by continent and differed by country within these continents. These differences in species distribution may partly determine the frequency and manifestations of pulmonary NTM disease in each geographical location. Species distribution among nontuberculous mycobacteria isolates from pulmonary specimens is geographically diverse http://ow.ly/npu6r

Clinical relevance of non-tuberculous mycobacteria isolated in the Nijmegen-Arnhem region, The Netherlands

Background: The frequency of clinical isolation of non-tuberculous mycobacteria (NTM) in the Netherlands is increasing, but its clinical relevance is often uncertain. Objective: To assess the frequency and clinical relevance of isolation of NTM in four associated hospitals in a single region in the Netherlands. Methods: Medical files of all patients from whom NTM were isolated between January 1999 and January 2005 were reviewed retrospectively. Diagnostic criteria for non-tuberculous mycobacterial disease published by the American Thoracic Society (ATS) were used to determine clinical relevance. Results: 232 patients were found, from whom NTM were isolated from the respiratory tract in 91% of cases. Patients were mostly white men, with an average age of 60 years and pre-existing pulmonary disease. Fifty-three of 212 patients (25%) with pulmonary isolates met the ATS diagnostic criteria for pulmonary NTM disease; this percentage differed by species. Most patients were treated with rifampicin, ethambutol and clarithromycin. Treatment outcome for pulmonary NTM disease was suboptimal but differed by species: overall, improvement was seen in 67% of treated patients, but in only 50% of those with pulmonary M avium disease. Lymphadenitis was the most common extrapulmonary disease type. Conclusions: Twenty-five per cent of all patients with pulmonary NTM isolates met the ATS criteria. Clinical relevance differs by species. NTM isolation increases over time. Species distribution differs from that of neighbouring countries and the M avium complex isolates have traits different from those reported in the USA. Adherence to diagnostic and treatment guidelines can be improved.

Clinical relevance of Mycobacterium malmoense isolation in the Netherlands

Uncertainty exists about the clinical relevance of Mycobacterium malmoense isolation, especially in pulmonary samples. We therefore determined clinical relevance, treatment and outcome of M. malmoense isolation in the Netherlands. A retrospective medical file study was conducted for all patients in the Netherlands from whom Mycobacterium malmoense had been isolated between January 2002 and January 2006. Diagnostic criteria for nontuberculous mycobacterial (NTM) disease published by the American Thoracic Society (ATS) were used to determine clinical relevance. Treatment was compared with guidelines published by the British Thoracic Society. In total, 51 patients were found from whom M. malmoense was isolated. Of these, 40 (78%) patients had pulmonary isolates and 32 (80%) of them met the ATS diagnostic criteria. Cavitary disease was most common (n = 28; 88%). Patients with pulmonary disease were mostly males, with an average age of 56 yrs and pre-existing chronic obstructive pulmonary disease. Cervical lymphadenitis was the most common extrapulmonary disease type. Adherence to treatment guidelines was poor. A good clinical response to treatment was observed in 70% and 73% of patients treated for pulmonary and extrapulmonary disease, respectively. In conclusion, M. malmoense is a clinically highly relevant NTM in the Netherlands causing serious pulmonary morbidity. Adherence to treatment guidelines is not satisfactory.

Mycobacterium xenopi clinical relevance and determinants, the Netherlands.

Clinical isolation of M. xenopi represents true infection in 51% of cases; genotype is a major determinant.

Drug treatment of pulmonary nontuberculous mycobacterial disease in HIV-negative patients: the evidence.

Pulmonary disease (PD) caused by nontuberculous mycobacteria is an emerging infection mainly in countries where the incidence of tuberculosis is in decline. It affects an elderly population, often with underlying chronic lung diseases, but its epidemiology shows significant regional variation. Guidelines and recommendations for treatment of these infections exist, but build strongly on expert opinion, as very few good quality clinical trials have been performed in this field. Only for the most frequent causative agents, the Mycobacterium avium complex, Mycobacterium kansasii and Mycobacterium abscessus, a reasonable number of trials and case series is now available. For the less frequent causative agents of pulmonary nontuberculous mycobacterial (NTM) disease (Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium fortuitum, Mycobacterium chelonae) data is mostly limited to a few very small case series. Within this review, we have collected and combined evidence from all available trials and case series. From the data of these trials and case series, we reconstruct a more evidence-based overview of possible drug treatment regimens and their outcomes.

Mycobacterium genavense in the Netherlands: an opportunistic pathogen in HIV and non-HIV immunocompromised patients. An observational study in 14 cases

Mycobacterium genavense is an opportunistic non-tuberculous mycobacterium previously mostly associated with HIV-infected patients with CD4 counts below 100/μL. In this retrospective observational study of medical charts we studied all Dutch patients in whom M. genavense was detected between January 2002 and January 2010. Of the 14 patients identified, 13 (93%) showed clinically relevant M. genavense disease. All patients with M. genavense disease were severely immunocompromised, including HIV-infected patients, solid organ transplant recipients, those with chronic steroid use in combination with other immune modulating drugs, recipients of chemotherapy for non-Hodgkin lymphoma, and those with immunodeficiency syndromes. Two patients had non-disseminated pulmonary M. genavense disease. Of the 12 patients treated, eight (75%) showed a favourable outcome. Four patients died in this study, three despite treatment for M. genavense disease. We conclude that M. genavense is a clinically relevant pathogen in severely immunocompromised patients that causes predominantly disseminated disease with serious morbidity and mortality. M. genavense is increasingly seen among non-HIV immunocompromised patients.

Synergistic activity of rifampicin and ethambutol against slow-growing nontuberculous mycobacteria is currently of questionable clinical significance

A key issue in the treatment of disease caused by slow-growing nontuberculous mycobacteria is the limited association between in vitro minimum inhibitory concentrations (MICs) of rifampicin and ethambutol alone and the in vivo outcome of treatment with these drugs. Combined susceptibility testing to rifampicin and ethambutol could provide a more realistic view of the efficacy of these drugs. In this study, Mycobacterium avium (n = 5), Mycobacterium chimaera (n = 6), Mycobacterium intracellulare (n = 4), Mycobacterium xenopi (n = 4), Mycobacterium malmoense (n = 3) and Mycobacterium simiae (n = 2) clinical isolates were selected and the MICs of rifampicin and ethambutol alone and in combination were measured using the Middlebrook 7H10 agar dilution method. Synergy was defined as a fractional inhibitory concentration index ≤ 0.5. Rifampicin and ethambutol showed synergistic activity against the majority of M. avium (4/5), M. chimaera (5/6) and M. intracellulare (3/4) isolates and 1 of 2 eligible M. malmoense isolates. No synergistic activity was measured against M. xenopi and M. simiae. Synergy was neither universal for all species nor for all isolates of one species; it thus needs to be tested for rather than assumed. Even if this synergy exists in vivo, it is questionable whether the MICs to the combined drugs can be overcome by the drug exposure attained by current regimens at the recommended dosages. New dosing strategies for rifampicin and ethambutol should be studied to increase the exposure to these drugs and thus maximise their impact.

Prevalence of nontuberculous mycobacteria in COPD patients with exacerbations

Hoefsloot, Wouter van Ingen, Jakko Magis-Escurra, Cecile Reijers, Monique H van Soolingen, Dick Dekhuijzen, Richard P N Boeree, Martin J Comment Letter England J Infect. 2013 Jun;66(6):542-5. doi: 10.1016/j.jinf.2012.12.011. Epub 2013 Jan 5.

Characterization of a novel variant of Mycobacterium chimaera

In this study, nonchromogenic mycobacteria were isolated from pulmonary samples of three patients in the Netherlands. All isolates had identical, unique 16S rRNA gene and 16S-23S ITS sequences, which were closely related to those of Mycobacterium chimaera and Mycobacterium marseillense. The biochemical features of the isolates differed slightly from those of M. chimaera, suggesting that the isolates may represent a possible separate species within the Mycobacterium avium complex (MAC). However, the cell-wall mycolic acid pattern, analysed by HPLC, and the partial sequences of the hsp65 and rpoB genes were identical to those of M. chimaera. We concluded that the isolates represent a novel variant of M. chimaera. The results of this analysis have led us to question the currently used methods of species definition for members of the genus Mycobacterium, which are based largely on 16S rRNA or rpoB gene sequencing. Definitions based on a single genetic target are likely to be insufficient. Genetic divergence, especially in the MAC, yields strains that cannot be confidently assigned to a specific species based on the analysis of a single genetic target.

High definition bronchoscopy: a randomized exploratory study of diagnostic value compared to standard white light bronchoscopy and autofluorescence bronchoscopy

BackgroundVideobronchoscopy is an essential diagnostic procedure for evaluation of the central airways and pivotal for the diagnosis and staging of lung cancer. Technological improvements have resulted in high definition (HD) images with advanced real time image enhancement techniques (i-scan).ObjectivesIn this study we aimed to explore the sensitivity of HD+ i-scan bronchoscopy for detection of epithelial changes like vascular abnormalities and suspicious preinvasive lesions, and tumors.MethodsIn patients scheduled for a therapeutic or diagnostic procedure under general anesthesia videos of the bronchial tree were made using 5 videobronchoscopy modes in random order: normal white light videobronchoscopy (WLB), HD-bronchoscopy (HD), HD bronchoscopy with surface enhancement technique (i-scan1), HD with surface- and tone enhancement technique (i-scan2) and dual mode autofluorescence videobronchoscopy (AFB). The videos were scored in random order by two independent and blinded expert bronchoscopists.ResultsIn 29 patients all videos were available for analysis. Vascular abnormalities were scored most frequently in HD + i-scan2 bronchoscopy (1.33 ± 0.29 abnormal or suspicious sites per patient) as compared to 0.12 ± 0.05 site for AFB (P = 0.003). Sites suspicious for preinvasive lesions were most frequently reported using AFB (0.74 ± 0.12 sites per patient) as compared to 0.17 ± 0.06 for both WLB and HD bronchoscopy (P = 0.003). Tumors were detected equally by all modalities. The preferred modality was HD bronchoscopy with i-scan (tone- plus surface and surface enhancement in respectively 38% and 35% of cases P = 0.006).ConclusionsThis study shows that high definition bronchoscopy with image enhancement technique may result in better detection of subtle vascular abnormalities in the airways. Since these abnormalities may be related to preneoplastic lesions and tumors this is of clinical relevance. Further investigations using this technique relating imaging to histology are warranted.