Once-daily dosing of amikacin for treatment of Mycobacterium abscessus lung disease.

SETTING: Tertiary referral centre, Samsung Medical Center, South Korea. OBJECTIVE: To evaluate the pharmacokinetic parameters and toxicities of once-daily amikacin (AMK) dosing for lung disease due to Mycobacterium abscessus. DESIGN: A retrospective review of 48 patients with M. abscessus lung disease who received once-daily AMK for 4 weeks between January 2012 and June 2015. RESULTS: With a starting dose of 15 mg/kg/day and adjustment of AMK dose according to the peak serum level (Cmax), the Cmax target of 55-65 µg/ml was achieved in 31.3% (15/48) of patients in the first week, 68.8% (33/48) in week 2, 91.7% (44/48) in week 3 and 95.8% (46/48) in week 4. Transient nephrotoxicity developed in 6.3% (3/48) of patients and ototoxicity in 25.0% (6/24), which was determined by audiogram as hearing loss, asymptomatic in five patients and tinnitus in one. Multivariate analysis revealed that the highest drug concentration 12 h after administration was significantly associated with the development of toxicities (adjusted odds ratio 1.862, P = 0.047). CONCLUSION: Our results suggest that once-daily AMK for 4 weeks with a target Cmax of 55-65 µg/ml can be used in patients with M. abscessus lung disease, with careful monitoring of toxicity.

The 100 most-cited articles on non-tuberculous mycobacterial infection from 1995 to 2015.

SETTING: Citation analyses aid in assessing quality, trends and future directions of research fields. OBJECTIVE: To identify the most influential articles on infections caused by non-tuberculous mycobacteria (NTM) in the last 20 years. DESIGN: We performed a cited reference search of the Web of Science database from 1995 to 2015. The 100 most cited articles on NTM infections were analysed. RESULTS: The top 100 articles were cited 114-1471 times, and were published from 1995 to 2013. Sixty-five were laboratory-based, basic science articles, with the major topics being pathophysiology (n = 20) and molecular methods for NTM identification (n = 15). Among the 35 non-laboratory studies, major topics were clinical management (n = 15) and epidemiology (n = 14). The top article was a clinical treatise on the management of NTM disease, published in 2007. Although there was a correlation between article rank and journal impact factor (P = 0.043, ρ = -0.202), the five articles from the journals with highest impact factors did not rank among the top 10 articles. CONCLUSION: A large proportion of influential articles on NTM infection are basic scientific studies, and the most influential articles are not always published in high-impact journals.

Liquid culture enhances diagnosis of patients with milder forms of non-tuberculous mycobacterial lung disease.

OBJECTIVE: To evaluate the proportion and clinical characteristics of patients with non-tuberculous mycobacteria (NTM) lung disease diagnosed based on positive culture results in liquid medium only. METHODS: We reviewed the medical records of 978 patients diagnosed with NTM lung disease. All clinical samples were cultured in both solid and liquid media. RESULTS: Of the 978 patients, 111 (11.3%) were culture-positive in liquid medium only (liquid culture group), and 867 (88.7%) (solid culture group) on solid medium, regardless of the culture results in liquid medium. At the time of diagnosis, the liquid culture group was less likely than the solid culture group to have haemoptysis (11.7% vs. 20.0%, P = 0.04), positive sputum smear for acid-fast bacilli (14.4% vs. 50.2%, P < 0.001) or the fibrocavitary form of NTM lung disease (3.6% vs. 14.6%, P = 0.001). During the median follow-up period of 28.9 months (interquartile range 19.1-41.6), the proportion of patients requiring antibiotic treatment was lower in the liquid culture group than in the solid culture group (44.1% vs. 61.6%, P < 0.001). CONCLUSIONS: Liquid media culture is helpful in the diagnosis of patients with less severe forms of NTM lung disease.

Implication of vitamin D-associated factors in patients with non-tuberculous mycobacterial lung disease.

BACKGROUND: Little information is available regarding vitamin D-associated factors in patients with non-tuberculous mycobacteria (NTM) lung disease. OBJECTIVE: To determine the association between vitamin D-related factors and susceptibility to NTM lung disease. DESIGN: The relative gene expression levels of cathelicidin (CAMP), defensin (DEFB4), vitamin D receptor (VDR) and 1-hydroxylase (CYP27B1), as well as the serum levels of 25-hydroxyvitamin D (25[OH]D), cathelicidin (LL-37), defensin (hBD-2) and vitamin D-binding protein (DBP) from 82 patients with NTM lung disease and 28 control subjects were analysed. RESULTS: Gene expression of CAMP and DEFB4 was significantly higher, and gene expression of VDR and CYP27B1 was significantly lower, in NTM patients than controls. Serum LL-37 and hBD-2 levels were not significantly different between NTM patients and controls; however, the serum DBP level was higher in NTM patients than controls. The serum vitamin D status of patients did not correlate with serum LL-37, hBD-2, or DBP concentration or gene expression of CAMP, DEFB4, VDR or CYP27B1. CONCLUSION: A higher level of gene expression for antimicrobial peptide is more likely to be associated with NTM lung disease than serum vitamin D status.

The prevalence of bronchiectasis in patients with Marfan syndrome.

An association has been suggested between Marfan syndrome (MFS) and the nodular bronchiectatic form of lung disease caused by non-tuberculous mycobacteria (NTM). We evaluated the prevalence of bronchiectasis in 79 adult patients with MFS using computed tomography (CT) imaging. Airway dilation indicative of bronchiectasis (22/79, 28%) and bronchioloectasis (10/79, 13%) were relatively common, although the extent of dilation was not severe and was frequently confined to a single lobe. However, bronchiolitis was evident in only three patients (4%), and no patient was diagnosed with NTM lung disease.

Identification of Mycobacterium species in direct respiratory specimens using reverse blot hybridisation assay.

BACKGROUND: The early diagnosis of mycobacterial infections is a critical step for initiating treatment and curing the patient. OBJECTIVE: To evaluate the performance of the reverse blot hybridisation assay (REBA) Myco-ID for the rapid identification of Mycobacterium species in acid-fast bacilli (AFB) smear-positive respiratory specimens. DESIGN: A total of 148 AFB smear-positive respiratory specimens were used for the identification of Mycobacterium species using polymerase chain reaction (PCR) REBA, and the results were compared with the gold standard method as well as culture, PCR-restriction fragment length polymorphism analysis (PRA) and rpoB sequence analysis. RESULTS: The results of this assay showed that 59/148 samples were positive for M. tuberculosis and 87 were positive for non-tuberculous mycobacteria (NTM); one sample had mixed infection with both M. tuberculosis and NTM. One case was negative for both M. tuberculosis and NTM and was identified as Nocardia farcinica using PRA and sequence analysis. Of a total of 89 cases, the most frequently identified NTM species were M. intracellulare (n = 28, 31.5%), M. avium (n = 21, 23.6%), M. massiliense (n = 19, 21.3%) and M. abscessus (n = 16, 18.0%). CONCLUSION: The PCR-REBA assay is an efficient tool for the rapid identification of the main Mycobacterium species in clinical specimens. The PCR-REBA assay can therefore provide useful information to physicians for appropriate treatment by clearly identifying Mycobacterium species.

Advances in the management of pulmonary disease due to Mycobacterium abscessus complex.

Mycobacterium abscessus complex is a group of rapidly growing mycobacteria, and an emerging cause of non-tuberculous mycobacterial lung disease in patients with cystic fibrosis and chronic lung diseases, such as bronchiectasis. M. abscessus complex is the most drug-resistant of the mycobacterial pathogens, resulting in limited therapeutic options and a high treatment failure rate. M. abscessus complex is comprised of three closely related subspecies: M. abscessus (sensu stricto), M. massiliense and M. bolletii. M. abscessus encodes a functional erythromycin ribosomal methylase gene, erm(41), which modifies the binding site for macrolide antibiotics, causing inducible macrolide resistance. However, this inducible macrolide resistance is not seen in M. massiliense, as the erm(41) gene of this subspecies is non-functional. Accordingly, treatment success rates with macrolide-based antibiotic treatment are much higher in patients with M. massiliense infections than in those infected with M. abscessus. Precise speciation of M. abscessus complex is important for predicting antibiotic susceptibilities and patient outcome.

Changes in serum immunomolecules during antibiotic therapy for Mycobacterium avium complex lung disease.

Little information is available regarding changes in immune status for patients with Mycobacterium avium complex (MAC) lung disease during antibiotic therapy. Serum immunomolecules from 42 patients with MAC lung disease were assayed comparatively using an array-based system according to (i) patients with MAC lung disease at the time of diagnosis versus healthy controls and (ii) alterations after 12 months of antibiotic therapy in the MAC lung disease group. In addition, cytokine analyses were performed to determine whether cytokine responses were associated specifically with the disease phenotype, treatment outcome and aetiological agent. Notably, the serum concentrations of type 1 cytokine-associated molecules, such as CD40L, interferon (IFN)-γ, interleukin (IL)-8 and IL-23, were decreased significantly in patients at the time of diagnosis, suggesting that these molecules may serve as indicators of host susceptibility to MAC disease. Although the overall serum level of T helper type 1 (Th1)-related molecules, such as CD40L and IFN-γ, was restored after treatment, Th17-related cytokines, such as IL-17 and IL-23, were down-regulated significantly at 12 months post-treatment compared to pretreatment. Furthermore, these cytokine patterns differed among patient subgroups. Decreased serum concentrations of IL-17 and/or IL-23 were associated with failure of sputum conversion, the fibrocavitary disease phenotype and M. intracellulare lung disease. Thus, the reciprocal balance between Th1 and Th17 immunity during antibiotic therapy for MAC lung disease is critical for dictating the treatment response. In conclusion, a low level of Th1-related immunomolecules may perpetuate MAC lung disease, and the serum concentrations of Th17-related cytokines can reflect the treatment outcome, disease phenotype and aetiological agent.

Genotyping of Mycobacterium intracellulare isolates and clinical characteristics of lung disease.

BACKGROUND: Variable number of tandem repeats (VNTR) loci were recently identified in Japanese isolates of Mycobacterium intracellulare. We hypothesised that some mycobacterial genotypes are more virulent than others, resulting in particular genotypes being associated with disease phenotype and progression. OBJECTIVE: To evaluate the VNTR loci of M. intracellulare in clinical isolates from Korean patients, and investigate the association between mycobacterial genotype and disease phenotype and progression. DESIGN: In total, 70 M. intracellulare clinical isolates were genotyped using 16 M. intracellulare VNTR loci. RESULTS: VNTR typing showed strong discriminatory power and genetic diversity for molecular epidemiological studies of M. intracellulare. In a phylogenetic tree, the M. intracellulare clinical isolates were divided into two clusters (A and B). Cluster A was observed more frequently (77%) than Cluster B; however, there was no association between the clinical characteristics, disease progression, drug susceptibility and clusters based on VNTR genotyping. CONCLUSIONS: VNTR typing could be used for epidemiological studies of M. intracellulare lung disease; however, no association was found between the specific VNTR genotypes of M. intracellulare and the clinical characteristics of Korean patients.

Toxocariasis as a cause of new pulmonary infiltrates.

SETTING: Patients with new pulmonary infiltrates on chest computed tomography (CT) scans at a tertiary centre in South Korea. OBJECTIVE: To demonstrate associations among radiological changes, blood eosinophilia (E) and Toxocara (T) seropositivity. DESIGN: We retrospectively reviewed blood eosinophilia, Toxocara seropositivity, history of raw meat intake and radiological features, and divided study patients into four groups according to blood eosinophilia and Toxocara seropositivity. RESULTS: Among 150 patients, 62 were E- and T-positive (E+T+), 45 were E-negative and T-positive (E-T+), 7 were E-positive and T-negative (E+T-), and 36 were E- and T-negative (E-T-). History of raw meat intake was found in 95 (63%) patients. The type and number of lesions on CT did not show any significant differences among the four groups. Among 119 patients who were not diagnosed with a specific disease, transient or migrating lesions were seen in 93% of E+T+, 93% of E-T+, 80% of E+T- and 52% of E-T- patients (P < 0.0001). Furthermore, the frequencies of migrating or new lesions and improvement were significantly higher in the Toxocara-positive group (88/95, 93%) than in the Toxocara-negative group (14/24, 58%; P = 0.002). CONCLUSION: Transient and migratory pulmonary infiltrates on chest CT scans were associated with blood eosinophilia and Toxocara seropositivity. Clinicians should consider asymptomatic toxocariasis as a cause of unexplained new pulmonary infiltrates in countries with dietary habits of raw meat intake.

Clinical significance of mycobacterial genotyping in Mycobacterium avium lung disease in Korea.

SETTING: A recent study in Japan found that mycobacterial genotyping was associated with disease progression and susceptibility to certain drugs in Mycobacterium avium lung disease. However, it is not known whether this association is true in other populations. OBJECTIVE: To investigate the association between mycobacterial genotype, clinical characteristics and the progression of M. avium lung disease in Korean patients. DESIGN: A total of 102 M. avium clinical isolates were genotyped using M. avium tandem repeats-variable number of tandem repeats (MATR-VNTR). RESULTS: MATR-VNTR typing demonstrated a high discriminatory power and genetic diversity for molecular epidemiological studies of M. avium. In the phylogenetic tree, the M. avium clinical isolates were divided into three major clusters: A, B and C. Cluster A was observed most frequently (64/102, 63%), whereas cluster C was found in a minor proportion of the isolates (8/102, 8%). However, there was no association between the clinical characteristics, disease progression and drug susceptibility and the phylogenetic tree based on VNTR genotyping. CONCLUSIONS: MATR-VNTR genotyping may be useful for epidemiological studies of M. avium lung disease; however, no association was found between the specific VNTR genotypes of M. avium and the clinical characteristics of Korean patients.

Initial lactate level and mortality in septic shock patients with hepatic dysfunction.

An elevated serum lactate level is associated with morbidity and mortality in patients with severe sepsis and septic shock. In patients with hepatic dysfunction, however an elevated serum lactate level may be due to either impaired lactate clearance or excessive production. Thus, we evaluated whether the initial serum lactate level was also associated with mortality in septic shock patients with hepatic dysfunction. A retrospective observational study enrolled 307 patients with septic shock admitted to the intensive care unit (ICU) between May 2007 and July 2009. Hepatic dysfunction was defined as a serum total bilirubin > 34.2 micromol/l (2 mg/dl). Selected patients were divided into high (> or = 4 mmol/l) and low (< 4 mmol/l) lactate groups, according to the initial serum lactate level. Of 307 patients with septic shock, 118 (38%) patients with hepatic dysfunction were eligible for this study. The median lactate levels were 5.9 (interquartile range 4.7 to 9.0) and 2.6 (interquartile range 1.7 to 3.2) mmol/l for the high and low lactate groups respectively (P < 0.001). The initial serum lactate level was strongly associated with in hospital mortality in a univariate analysis (P < 0.001). After adjusting for potential confounding factors, the initial serum lactate level remained significantly associated with in-hospital mortality (odds ratio 1.281, 95% confidence interval 1.097 to 1.496, P = 0.002). In conclusion, the serum lactate level could be useful in predicting the outcome of patients with septic shock regardless of hepatic dysfunction.

Pulmonary paragonimiasis mimicking lung cancer in a tertiary referral centre in Korea.

OBJECTIVE AND DESIGN: To determine how pulmonary paragonimiasis may be confused with lung cancer, we retrospectively analysed the clinical and radiological characteristics of 47 patients (27 males, median age 55 years; interquartile range 49-61) with serologically or histopathologically confirmed pulmonary paragonimiasis seen between October 2004 and December 2009. RESULTS: Respiratory symptoms were present in 29 (62%) patients; the remaining 18 (38%) were asymptomatic. Chest radiography (CXR) revealed intrapulmonary parenchymal lesions (n = 35, 75%) more frequently than pleural lesions (n = 11, 23%). Of the 47 patients, 28 (60%) were referred for suspected lung cancer. The majority of these patients had no symptoms, and 22 (79%) patients with suspected lung cancer had nodular or mass lesions on CXR. As a result, additional diagnostic procedures were performed to make an accurate diagnosis in these patients, including bronchoscopy in 20, transthoracic lung biopsy in 11 and fluorodeoxyglucose positron emission tomography in seven. Surgical lung resection was performed unnecessarily in six patients. CONCLUSIONS: Pulmonary paragonimiasis presenting with nodular or mass lesions on CXR is common. Clinicians should therefore include pulmonary paragonimiasis in the differential diagnosis of asymptomatic nodular lesions in the lung in patients who have lived in or travelled to paragonimiasis-endemic areas.

Direct application of the PCR restriction analysis method for identifying NTM species in AFB smear-positive respiratory specimens.

The early differentiation of Mycobacterium tuberculosis from non-tuberculous mycobacteria (NTM) and the identification of NTM species are crucial for the proper management of patients with smear-positive sputum. We evaluated the usefulness of a polymerase chain reaction restriction analysis (PRA) method based on the rpoB gene for identifying NTM species in a study of 121 smear-positive respiratory specimens with presumed NTM. The PRA method amplified mycobacterial DNA in 72 specimens (60%) and differentiated NTM species correctly in 68 (94%). The PRA method could be a useful and rapid method for identifying NTM species in smear-positive respiratory specimens when urgent clinical decisions are required.

Safety and usefulness of bronchoscopy in ventilator-dependent patients with severe thrombocytopenia.

Flexible bronchoscopy is a useful diagnostic procedure in patients with respiratory failure due to unexplained pulmonary infiltrates, but its safety and usefulness in ventilator-dependent patients with severe thrombocytopenia have not been established. A retrospective review of the medical records of all patients who underwent bronchoscopy while receiving mechanical ventilation support at Samsung Medical Centre, Seoul, Korea between January 2002 and July 2006 was conducted. The medical records of 37 patients with severe thrombocytopenia (platelet count <50,000 /microl) at the time of bronchoscopy were analysed. Mean platelet count was 27,300+/-12,500 /microl. The most common underlying condition was haematologic malignancy, which occurred in 21(56.7%) patients, followed by severe sepsis in five (13.6%) and post-liver transplantation complications and autoimmune disease in four each (10.8%). The procedures performed were bronchoalveolar lavage in 33 patients, washing in three and transbronchial lung biopsy in five. Two patients died within 24 hours of completing the procedure. In patients surviving longer than 24 hours, there was no significant decline in oxygenation index (PaO2/FiO2), sequential organ failure assessment score or simplified acute physiological score II after the procedure. Lung compliance significantly decreased at two hours post-bronchoscopy but recovered to the pre-bronchoscopy level by 24 hours. Intensive care unit mortality was 51.4% (19 of 37 patients). Bronchoscopy was helpful in confirming the diagnosis in 17 patients (45.9%). Therapeutic modifications were made in 14 patients (37.8%) after bronchoscopy. Severe thrombocytopenia per se should not preclude bronchoscopy, even in patients receiving mechanical ventilation.

Vitamin D-receptor polymorphisms and non-tuberculous mycobacterial lung disease in Korean patients.

This study investigated the potential role of vitamin D-receptor (VDR) gene polymorphisms in susceptibility to lung disease caused by non-tuberculous mycobacteria (NTM). TaqI and FokI polymorphisms were compared in 124 patients and 127 controls. The genotype, allele and haplotype frequencies did not differ between patients and controls. TaqI and FokI polymorphisms of the VDR gene do not appear to be responsible for host susceptibility to NTM lung disease, at least in this Korean population. An association cannot, however, be completely ruled out, as only two single nucleotide polymorphisms of the VDR gene were studied in this report.