Kyeongman Jeon

Clinical Significance of Differentiation of Mycobacterium massiliense from Mycobacterium abscessus

RATIONALE Mycobacterium massiliense has been recognized as a separate species from Mycobacterium abscessus; however, little is known regarding the clinical impact of this differentiation. OBJECTIVES To compare clinical features and treatment outcomes between patients with M. abscessus lung disease and those with M. massiliense lung disease. METHODS We performed molecular identification of stored clinical isolates of M. abscessus complex and compared clinical characteristics and treatment outcomes between 64 patients with M. abscessus lung disease and 81 patients with M. massiliense lung disease. MEASUREMENTS AND MAIN RESULTS The clinical and radiographic manifestations of disease caused by each species were similar. Standardized combination antibiotic therapy, including a clarithromycin-containing regimen in combination with an initial 4-week course of cefoxitin and amikacin, was given to 57 patients (24 with M. abscessus and 33 with M. massiliense) for more than 12 months. The proportion of patients with sputum conversion and maintenance of negative sputum cultures was higher in patients with M. massiliense infection (88%) than in those with M. abscessus infection (25%; P < 0.001). Inducible resistance to clarithromycin (minimal inhibitory concentrations ≥ 32 μg/ml) was found in all tested M. abscessus isolates (n = 19), but in none of the M. massiliense isolates (n = 28). CONCLUSIONS Treatment response rates to combination antibiotic therapy including clarithromycin were much higher in patients with M. massiliense lung disease than in those with M. abscessus lung disease. The inducible resistance to clarithromycin could explain the lack of efficacy of clarithromycin-containing antibiotic therapy against M. abscessus lung disease.

Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65 patients.

RATIONALE The optimal therapeutic regimen and duration of treatment for Mycobacterium abscessus lung disease is not well established. OBJECTIVES To assess the efficacy of a standardized combination antibiotic therapy for the treatment of M. abscessus lung disease. METHODS Sixty-five patients (11 males, 55 females, median age 55 yr) with M. abscessus lung disease were treated with clarithromycin, ciprofloxacin, and doxycycline, together with an initial regimen of amikacin and cefoxitin for the first 4 weeks of hospitalization. MEASUREMENTS AND MAIN RESULTS Treatment response rates were 83% for symptoms and 74% for high-resolution computed tomography. Sputum conversion and maintenance of negative sputum cultures for more than 12 months was achieved in 38 (58%) patients. These rates were significantly lower in patients whose isolates were resistant to clarithromycin (17%, 2/12) compared with those whose isolates were susceptible or intermediate to clarithromycin (64%, 21/33; P = 0.007). Neutropenia and thrombocytopenia associated with cefoxitin developed in 33 (51%) and 4 (6%) patients, respectively. Drug-induced hepatotoxicity occurred in 10 (15%) patients. Because of these adverse reactions, cefoxitin was discontinued in 39 (60%) patients after treatment for a median of 22 days. CONCLUSIONS Standardized combination antibiotic therapy was moderately effective in treating M. abscessus lung disease. However, frequent adverse reactions and the potential for long-duration hospitalization are important problems that remain to be solved.

Macrolide Treatment for Mycobacterium abscessus and Mycobacterium massiliense Infection and Inducible Resistance

RATIONALE Macrolides, such as clarithromycin (CLR) and azithromycin (AZM), are frequently the only oral antibiotics that are active against Mycobacterium abscessus and M. massiliense infections. OBJECTIVES To compare the activity of CLR and AZM in experimental models. METHODS We compared the treatment efficacies of CLR and AZM and determined the correlation between efficacy and induced erythromycin ribosome methyltransferase gene (erm)(41) expression in experimental models of M. abscessus and M. massiliense infections. MEASUREMENTS AND MAIN RESULTS In all tested M. abscessus isolates, a high level of inducible CLR resistance developed (minimal inhibitory concentration [MIC] on Day 3 versus Day 14; P < 0.001). Whereas the AZM MIC increased on Day 14 (P < 0.01 versus Day 3), the level was significantly lower than the CLR MIC on Day 14 (P < 0.001). However, the MICs of CLR and AZM for the M. massiliense isolates did not change. Compared with CLR, AZM presented greater antibiotic activity against M. abscessus in vitro, ex vivo, and in vivo (P < 0.05), whereas both macrolides were comparably effective against M. massiliense. In M. abscessus infection, the level of erm(41) expression was higher after exposure to CLR than after exposure to AZM (P < 0.001). Experiments using an erm(41)-knockout M. abscessus mutant and an M. massiliense transformant expressing M. abscessus erm(41) confirmed that erm(41) was responsible for inducible CLR resistance. CONCLUSIONS CLR induces greater erm(41) expression and thus higher macrolide resistance than AZM in M. abscessus infection. AZM may be more effective against M. abscessus, whereas both macrolides appear to be equally effective against M. massiliense.

Clinical characteristics and treatment outcomes of chronic necrotizing pulmonary aspergillosis: a review of 43 cases

OBJECTIVES Chronic necrotizing pulmonary aspergillosis (CNPA) is uncommon, and the optimal therapeutic regimen has not been established. In a retrospective cohort study, we investigated the clinical characteristics and treatment outcomes of patients with CNPA. METHODS We reviewed the medical records of all patients who had been diagnosed with CNPA at our institution over the last 10 years. RESULTS Forty-three patients were identified. Their median age was 60 years (interquartile range (IQR) 45-65 years), and 34 (79%) of the patients were men. The most common underlying lung disease was pulmonary tuberculosis (n=40, 93%). After CNPA was diagnosed, all patients were treated with antifungal drugs, including oral itraconazole (n=39, 91%) or intravenous amphotericin B (n=4, 9%). Seventeen (40%) patients discontinued therapy early (<3 months), 14 patients due to death and three to loss of follow-up. Twenty-six (60%) patients received oral itraconazole at a daily dose of 200-400mg for more than 3 months. The median treatment duration was 6 months (IQR 6-12 months). In these 26 patients, clinical improvement was observed in 15 (58%) and radiological improvement was observed in 11 (42%). Ten (38%) patients showed no improvement. Twenty-two (51%) patients died, including 18 (42%) CNPA-related deaths, during a median follow-up of 15 months (IQR 2.5-32 months). The median survival time was 62 months. CONCLUSIONS CNPA is difficult to treat and often has a poor outcome. Further studies with more patients are needed to identify the optimal therapy for patients with CNPA.

Clinical Significance of the Differentiation Between Mycobacterium avium and Mycobacterium intracellulare in M avium Complex Lung Disease

BACKGROUND Mycobacterium avium and Mycobacterium intracellulare are grouped together as the M avium complex; however, little is known about the clinical impact of this species differentiation. This study compared the clinical features and prognoses of patients with M avium and M intracellulare lung disease. METHODS From 2000 to 2009, 590 patients were given a new diagnosis of M avium complex lung disease; 323 (55%) had M avium lung disease, and 267 (45%) had M intracellulare lung disease. RESULTS Compared with the patients with M avium lung disease, the patients with M intracellulare lung disease were more likely to have the following characteristics: older age (64 vs 59 years, P = .002), a lower BMI (19.5 kg/m² vs 20.6 kg/m², P < .001), respiratory symptoms such as cough (84% vs 74%, P = .005), a history of previous treatment for TB (51% vs 31%, P < .001), the fibrocavitary form of the disease (26% vs 13%, P < .001), smear-positive sputum (56% vs 38%, P < .001), antibiotic therapy during the 24 months of follow-up (58% vs 42%, P < .001), and an unfavorable microbiologic response after combination antibiotic treatment (56% vs 74%, P = .001). CONCLUSIONS Patients with M intracellulare lung disease exhibited a more severe presentation and had a worse prognosis than patients with M avium lung disease in terms of disease progression and treatment response. Therefore, species differentiation between M avium and M intracellulare may have prognostic and therapeutic implications.

Repeated derecruitments accentuate lung injury during mechanical ventilation.

OBJECTIVES The aim of our study was to assess whether repeated derecruitments induced by the repetitive withdrawal of high positive end-expiratory pressure could induce lung injury in a swine model. DESIGN Prospective, randomized, experimental animal study. SETTING University laboratory. SUBJECTS Specific pathogen-free pigs (Choong-Ang Laboratory Animals, Seoul, Korea) weighing around 30 kg. INTERVENTIONS After lung injury was induced by repeated saline lavage, pigs were ventilated in pressure-limited mode with the highest possible positive end-expiratory pressure with a tidal volume of 8 mL/kg and maximum inspiratory pressure of 30 cm H2O. With this initial ventilator setting, the control group (n = 5) received ventilation without derecruitments for 4 hours, and in the derecruitment group (n = 5), derecruitments were repeatedly induced by intentional disconnection of the ventilatory circuit for 30 seconds every 5 minutes for 4 hours. MEASUREMENTS AND MAIN RESULTS After the initial increase in positive end-expiratory pressure, the PaO2 increased to greater than 450 mm Hg in both groups. The PaO2 remained at greater than 450 mm Hg in the control group persistently, but in the derecruitment group, PaO2 significantly decreased to 427.7 mm Hg (adjusted p = 0.03) after 2 hours and remained significant for the rest of the study. PaCO2, oxygenation index, and alveolar-arterial oxygen gradient also significantly increased after 2 hours compared with the control group. However, the variables of respiratory mechanics except for minute volume at 2-hour point showed no difference between the two groups for the duration of the study. Histologically, significant bronchiolar injury was observed in the dependent portion of the derecruitment group compared with the controls (p = 0.03), but not in the nondependent area of the lung. CONCLUSIONS Repeated derecruitments exacerbated lung injury, particularly at the bronchiolar level in the dependent portion. Strategies to minimize this type of injury should be incorporated when designing optimal ventilator strategies in acute respiratory distress syndrome patients.Objectives:The aim of our study was to assess whether repeated derecruitments induced by the repetitive withdrawal of high positive end-expiratory pressure could induce lung injury in a swine model. Design:Prospective, randomized, experimental animal study. Setting:University laboratory. Subjects:Specific pathogen-free pigs (Choong–Ang Laboratory Animals, Seoul, Korea) weighing around 30 kg. Interventions:After lung injury was induced by repeated saline lavage, pigs were ventilated in pressure-limited mode with the highest possible positive end-expiratory pressure with a tidal volume of 8 mL/kg and maximum inspiratory pressure of 30 cm H2O. With this initial ventilator setting, the control group (n = 5) received ventilation without derecruitments for 4 hours, and in the derecruitment group (n = 5), derecruitments were repeatedly induced by intentional disconnection of the ventilatory circuit for 30 seconds every 5 minutes for 4 hours. Measurements and Main Results:After the initial increase in positive end-expiratory pressure, the PaO2 increased to greater than 450 mm Hg in both groups. The PaO2 remained at greater than 450 mm Hg in the control group persistently, but in the derecruitment group, PaO2 significantly decreased to 427.7 mm Hg (adjusted p = 0.03) after 2 hours and remained significant for the rest of the study. PaCO2, oxygenation index, and alveolar-arterial oxygen gradient also significantly increased after 2 hours compared with the control group. However, the variables of respiratory mechanics except for minute volume at 2-hour point showed no difference between the two groups for the duration of the study. Histologically, significant bronchiolar injury was observed in the dependent portion of the derecruitment group compared with the controls (p = 0.03), but not in the nondependent area of the lung. Conclusions:Repeated derecruitments exacerbated lung injury, particularly at the bronchiolar level in the dependent portion. Strategies to minimize this type of injury should be incorporated when designing optimal ventilator strategies in acute respiratory distress syndrome patients.

Intermittent Antibiotic Therapy for Nodular Bronchiectatic Mycobacterium avium Complex Lung Disease

RATIONALE Although intermittent, three-times-weekly therapy is recommended for the initial treatment of noncavitary nodular bronchiectatic Mycobacterium avium complex (MAC) lung disease, supporting data are limited. OBJECTIVES To evaluate the clinical efficacy of intermittent therapy compared with daily therapy for nodular bronchiectatic MAC lung disease. METHODS A retrospective cohort study of 217 patients with treatment-naive noncavitary nodular bronchiectatic MAC lung disease. All patients received either daily (n = 99) or intermittent therapy (n = 118) that included clarithromycin or azithromycin, rifampin, and ethambutol. MEASUREMENTS AND MAIN RESULTS Modification of the initial antibiotic therapy occurred more frequently in the daily therapy group than in the intermittent therapy group (46 vs. 21%; P < 0.001); in particular, ethambutol was more frequently discontinued in the daily therapy group than in the intermittent therapy group (24 vs. 1%; P ≤ 0.001). However, the rates of symptomatic improvement, radiographic improvement, and sputum culture conversion were not different between the two groups (daily therapy vs. intermittent therapy: 75 vs. 82%, P = 0.181; 68 vs. 73%, P = 0.402; 76 vs. 67%, P = 0.154, respectively). In addition, the adjusted proportion of sputum culture conversion was similar between the daily therapy (71.3%; 95% confidence interval, 59.1-81.1%) and the intermittent therapy groups (73.6%; 95% confidence interval, 62.9-82.2%; P = 0.785). CONCLUSIONS These results suggest that intermittent three-times-weekly therapy with a macrolide, rifampin, and ethambutol is a reasonable initial treatment regimen for patients with noncavitary nodular bronchiectatic MAC lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00970801).

Increasing Recovery of Nontuberculous Mycobacteria from Respiratory Specimens over a 10-Year Period in a Tertiary Referral Hospital in South Korea

Background The number of patients with pulmonary disease caused by nontuberculous mycobacteria (NTM) has been increasing worldwide. The aim of this study was to evaluate long-term trends in the NTM recovery rate from respiratory specimens over a 10-year period in a tertiary referral hospital in South Korea. Methods We retrospectively reviewed the records of mycobacterial cultures of respiratory specimens at Samsung Medical Center from January 2001 to December 2011. Results During the study period, 32,841 respiratory specimens from 10,563 patients were found to be culture-positive for mycobacteria. These included 12,619 (38%) Mycobacterium tuberculosis and 20,222 (62%) NTM isolates. The proportion of NTM among all positive mycobacterial cultures increased from 43% (548/1,283) in 2001 to 70% (3,341/4,800) in 2011 (p<0.001, test for trend). The recovery rate of NTM isolates from acid-fast bacilli smear-positive specimens increased from 9% (38/417) in 2001 to 64% (1,284/1,997) in 2011 (p<0.001, test for trend). The proportion of positive liquid cultures was higher for NTM than for M. tuberculosis (p<0.001). The most frequently isolated NTM were Mycobacterium avium-intracellulare complex (53%) and Mycobacterium abscessus-massiliense complex (25%). Conclusion The recovery rate of NTM from respiratory specimens in South Korea has increased steadily.

Clinical characteristics of health care-associated pneumonia in a Korean teaching hospital.

BACKGROUND Health care-associated pneumonia (HCAP) has been proposed as a new category of respiratory infection. ATS/IDSA guidelines state that all patients with HCAP should receive empirical therapy directed at multidrug-resistant pathogens. However, recent data from other countries have reported a different picture of HCAP. METHODS We conducted a retrospective observational study of patients with HCAP and CAP who were hospitalized through the emergency department in January-December 2008 at Samsung Medical Center, Seoul, Korea, and compared clinical characteristics, severity, distribution of pathogen, and outcomes. RESULTS In total, 345 patients hospitalized with pneumonia were eligible, 182 (52.8%) with HCAP and 163 (47.2%) with CAP. Patients with HCAP had greater comorbidity and higher Pneumonia Severity Index (PSI) score (P < 0.001). Although Streptococcus pneumoniae was the most frequently isolated pathogen in HCAP and CAP patients, the occurrence of potentially drug-resistant pathogens (29.3% vs. 13.0%; P = 0.044) and inappropriate initial antimicrobial treatment (24.6% vs. 8.7%; P = 0.032) were significantly higher in HCAP patients. Patients with HCAP had a longer duration of hospital stay (13 [8-18] vs. 8 [6-12] days; P < 0.001), and higher in-hospital mortality (19.2% vs. 7.4%; P = 0.001). In a multiple logistic regression analysis, however, in-hospital mortality was independently associated with higher PSI class (OR 2.82, 95% CI 1.19-6.70) and ICU admission (OR 15.37, 95% CI 3.58-66.05). CONCLUSIONS Severity of illness, rather than type of pneumonia, was the main predicting factor for in-hospital mortality among patients with pneumonia hospitalized through the emergency department.

Occult nodal metastasis in patients with non-small cell lung cancer at clinical stage IA by PET/CT

Background and objective:  The introduction of 18F‐FDG PET/CT has enhanced the diagnostic accuracy of nodal staging for non‐small cell lung cancer (NSCLC). We analysed risk factors for occult nodal metastasis in patients with clinical stage IA NSCLC as determined by 18F‐FDG PET/CT.