Treatment outcome of continuation of intravenous amikacin for Mycobacterium abscessus pulmonary disease with a persistent culture positivity after the treatment initiation.

INTRODUCTION: Whether prolonged intravenous amikacin treatment would lead to better treatment results in patients with Mycobacterium abscessus subspecies abscessus (M. abscessus) pulmonary disease (PD) is unknown. We investigated the efficacy of continued amikacin treatment for the microbiological outcome of M. abscessus PD patients with persistent culture positivity after treatment initiation. METHODS: We retrospectively evaluated 62 patients with M. abscessus PD who were treated with intravenous amikacin and beta-lactams along with a macrolide-based regimen at 3 tertiary referral centers in South Korea. The intravenous antibiotic treatment duration was determined by the attending physician. RESULTS: The median treatment durations with amikacin and beta-lactam in the 62 patients were 25.1 and 8.2 weeks, respectively. The overall microbiological cure rate was 29.0%. Among the 62 patients, 44 showed persistent culture positivity at 8 weeks after treatment with an amikacin-containing multidrug regimen. The median parenteral amikacin treatment duration after 8 weeks in these patients was 18.0 weeks. The conditional probability of microbiological cure with continuation of the amikacin-containing regimen in these patients was 18.2% (95% confidence interval 8.2-32.7). Additionally, the conditional probability of microbiological cure in the 34 patients with persistent culture positivity at 12 weeks was 8.8% (95% confidence interval 1.9-23.7). After 16 weeks, the conditional probability of microbiological cure decreased further, reaching 0% at 28 weeks after treatment initiation. CONCLUSION: The continuation of intravenous amikacin therapy was usually not followed by culture conversion in M. abscessus PD patients with persistent sputum culture positivity after treatment initiation.

Impact of Molecular Drug Susceptibility Testing on the Time to Multidrug-resistant Tuberculosis Treatment Initiation.

BACKGROUND: The purpose of this study was to evaluate the current status and trends in the coverage of molecular drug susceptibility testing (mDST), and the impact of mDST on the time to multidrug-resistant tuberculosis (MDR-TB) treatment initiation in Korea. METHODS: We included confirmed rifampin-resistant (RR)/MDR-TB patients who submitted application forms for novel drug uses to the National TB Expert Review Committee from September 1, 2016 to November 30, 2019. We retrospectively reviewed their medical records. RESULTS: Of the 621 MDR/RR-TB patients, mDST was performed in 442 (71.2%); Xpert MTB/RIF (Xpert) alone in 109 (17.6%), MTBDRplus line probe assay (LPA) alone in 199 (32.0%), and both Xpert and LPA in 134 (21.6%) patients. The coverage rate of mDST has gradually increased to 70% in 2015, 50.7% in 2016, 67.9% in 2017, 75.2% in 2018, and 79.4% in 2019 (P for trend < 0.001). Median time to MDR-TB treatment initiation was 35 days (interquartile range25-75 0-72), which has gradually decreased during the study period (P < 0.001). Independent predictors of shorter time to MDR-TB treatment initiation were retreatment case (adjusted hazard ratio [aHR], 1.30; 95% confidence interval [CI], 1.10-1.54), Xpert testing (aHR, 2.42; 95% CI, 2.03-2.88), and LPA testing (aHR, 1.83; 95% CI, 1.55-2.16). Transfer to another healthcare facility was inversely related to shorter time to treatment initiation (aHR, 0.74; 95% CI, 0.63-0.88). CONCLUSION: mDST coverage is gradually increasing and contributes to reducing the time to MDR-TB treatment initiation. Further efforts are needed to achieve universal access to mDST and to properly integrate mDST into routine clinical practice.

Interim treatment outcomes in multidrug-resistant tuberculosis using bedaquiline and/or delamanid in South Korea.

PURPOSE: The Korea Centers for Disease Control & Prevention has implemented a review process for the approval of new drugs used to treat patients with multidrug-resistant tuberculosis (MDR-TB) since September 2016. Therefore, this study aimed to evaluate the efficacy and safety of these new drugs bedaquiline (Bdq) and delamanid (Dlm). METHODS: A total of 318 patients with MDR-TB were reviewed by the committee from September 2016 to February 2018; 282 (88.7%) of them were treated with the new drugs (Bdq, 107 patients; Dlm, 108 patients; and both concurrently or sequentially, 67 patients) and retrospectively evaluated. Culture conversion rates, interim treatment outcomes at 12 months, and predictors of unfavorable outcomes were analyzed. Treatment efficacy was also compared between Bdq and Dlm. RESULTS: The mean age of the patients was 49.3 years, and 197 (69.9%) were male. Three patients were HIV seropositive and 151 (53.5%) were quinolone resistant. The culture conversion rates at 2 and 6 months were 57.4% (81/141) and 89.4% (126/141), respectively. A favorable outcome at 12 months was achieved in 84.8% of patients (239/282). Differences in the culture conversion rate or interim treatment outcomes were not statistically significant among the drug susceptibility test patterns or new drugs used. Multivariable analysis showed that age >60 years and body mass index of <18.5 kg/m2 were significant risk factors for unfavorable outcomes at 12 months. CONCLUSIONS: The use of new drugs resulted in satisfactory interim treatment results, without significant differences between them.

In Vitro MIC Values of Rifampin and Ethambutol and Treatment Outcome in Mycobacterium avium Complex Lung Disease.

Although it is known that the in vitro MICs of rifampin and ethambutol are poorly correlated with the clinical response in Mycobacterium avium complex (MAC) lung disease (MAC-LD), evidence for this is limited. This study investigated the association between treatment outcome and the in vitro MICs of rifampin and ethambutol in patients with MAC-LD. Among patients diagnosed with macrolide-susceptible MAC-LD between January 2008 and December 2013, 274 patients who were treated with a standard regimen for ≥12 months until August 2017 and whose in vitro MIC results were available were enrolled at a tertiary referral center in South Korea. The MICs of antimicrobial agents were determined using the broth microdilution method. The mean age of the included patients was 60.4 years. The overall treatment success rate was 79.6% (218/274 patients) and tended to decrease with increasing MICs of rifampin and ethambutol, particularly at MICs of ≥8 µg/ml. Treatment success rate was significantly different between MAC isolates with MICs of ≥8 µg/ml for rifampin and ethambutol and those with MICs of <8 µg/ml for rifampin and/or ethambutol (64.9% versus 85.3%, P < 0.001). Multivariate analysis showed that an MIC of ≥8 µg/ml for both drugs and initial sputum acid-fast bacillus (AFB) smear positivity were independent risk factors for an unfavorable response (adjusted odds ratio [OR] = 3.154, 95% confidence interval [CI] = 1.641 to 6.063, and P = 0.001 for an MIC of ≥8 µg/ml; adjusted OR = 2.769, 95% CI = 1.420 to 5.399, and P = 0.003 for initial sputum AFB smear positivity). These findings suggest that the in vitro MICs of rifampin and ethambutol may be related to treatment outcome in MAC-LD.

Choice between Levofloxacin and Moxifloxacin and Multidrug-Resistant Tuberculosis Treatment Outcomes.

RATIONALE: We previously showed that the choice of levofloxacin or moxifloxacin for the treatment of patients with fluoroquinolone-sensitive multidrug-resistant tuberculosis (MDR-TB) did not affect sputum culture conversion at 3 months of treatment. OBJECTIVES: To compare final treatment outcomes between patients with MDR-TB randomized to levofloxacin or moxifloxacin. METHODS: A total of 151 participants with MDR-TB who were included for the final analysis in our previous trial were followed through the end of treatment. Treatment outcomes were compared between 77 patients in the levofloxacin group and 74 in the moxifloxacin group, based on the 2008 World Health Organization definitions as well as 2013 revised definitions of treatment outcomes. In addition, the time to culture conversion was compared between the two groups. MEASUREMENTS AND MAIN RESULTS: Treatment outcomes were not different between the two groups, based on 2008 World Health Organization definitions as well as 2013 definitions. With 2008 definitions, cure was achieved in 54 patients (70.1%) in the levofloxacin group and 54 (73.0%) in the moxifloxacin group (P = 0.72). Treatment success rates, including cure and treatment completed, were not different between the two groups (87.0 vs. 81.1%, P = 0.38). With 2013 definitions, cure rates (83.1 vs. 78.4%, P = 0.54) and treatment success rates (84.4 vs. 79.7%, P = 0.53) were also similar between the levofloxacin and moxifloxacin groups. Time to culture conversion was also not different between the two groups (27.0 vs. 45.0 d, P = 0.11 on liquid media; 17.0 vs. 42.0 d, P = 0.14 on solid media). Patients in the levofloxacin group had more adverse events than those in the moxifloxacin group (79.2 vs. 63.5%, P = 0.03), especially musculoskeletal ones (37.7 vs. 14.9%, P = 0.001). CONCLUSIONS: The choice of levofloxacin or moxifloxacin made no difference to the final treatment outcome among patients with fluoroquinolone-sensitive MDR-TB. Clinical trial registered with www.clinicalrials.gov (NCT01055145).

A shorter treatment duration may be sufficient for patients with Mycobacterium massiliense lung disease than with Mycobacterium abscessus lung disease.

BACKGROUND: Mycobacterium abscessus complex is the second most common organism isolated from patients with nontuberculous mycobacterial (NTM) lung disease in South Korea. This study aimed to compare clinical features and treatment outcomes of M. abscessus and Mycobacterium massiliense lung disease. METHODS: We retrospectively identified stored clinical isolates of M. abscessus complex as either M. abscessus or M. massiliense and reviewed medical records to compare clinical characteristics and treatment responses. All patients were treated empirically over several months with multidrug regimens, including a macrolide and one or more parenteral agents. RESULTS: Of the 249 patient isolates tested, 128 (59 with M. abscessus and 69 with M. massiliense) met the American Thoracic Society diagnostic criteria for NTM pulmonary disease, and treatment outcomes were analyzed in 48 patients (26 with M. abscessus and 22 with M. massiliense). The clinical and radiologic findings were similar between the two groups. Although the durations of parenteral and total treatment were significantly shorter in patients with M. massiliense than in those with M. abscessus (4.7 months vs 7.4 months, P = .006, and 12.1 months vs 16.3 months, P = .043), the treatment success rate was significantly higher in patients with M. massiliense (95.5%) than in M. abscessus cases (42.3%, P < .001). CONCLUSION: Patients with M. massiliense pulmonary infection responded better to this antibiotic strategy than those with M. abscessus infection. A shortened duration of treatment may be sufficient for M. massiliense pulmonary infection.

Treatment outcomes of refractory MAC pulmonary disease treated with drugs with unclear efficacy.

We aimed to investigate the treatment outcomes of patients with refractory Mycobacterium avium complex (MAC) lung disease treated with regimens containing drugs with unclear efficacy. Of all patients diagnosed with MAC lung disease between April 2004 and September 2012 at a tertiary referral center in South Korea, the outcomes of 51 patients treated with regimens containing drugs with unclear efficacy (clofazimine, moxifloxacin, rifabutin, and linezolid) because of treatment failure after receiving standard treatment were retrospectively analyzed. The mean age (standard deviation) of the 51 patients was 59.0 (10.3) years and 29 (56.9%) were male. The etiologic agent was M. avium in 17 patients (33.3%) and Mycobacterium intracellulare in 34 patients (66.7%); 42 patients (82.4%) had the fibrocavitary form of the disease. Of the 51 patients, 26, 28, 35, and 7 received clofazimine-, moxifloxacin-, rifabutin-, and linezolid-containing regimens (numbers are not mutually exclusive), with median drug administration durations of 147, 128, 209, and 88 days, respectively. Overall, 8 patients (15.7%) had a favorable response. Treatment outcomes did not differ by drug regimen or even by the combination of more than 2 drugs. The treatment outcomes of patients with refractory MAC lung disease were unsatisfactory with regimens containing possibly effective drugs such as clofazimine, moxifloxacin, rifabutin and linezolid.

Comparison of levofloxacin versus moxifloxacin for multidrug-resistant tuberculosis.

RATIONALE: Levofloxacin (LFX) and moxifloxacin (MXF) are the two most frequently recommended fluoroquinolones for treatment of patients with multidrug-resistant tuberculosis (MDR-TB). However, studies comparing the effectiveness of LFX and MXF among patients with MDR-TB are lacking. OBJECTIVES: To compare the effectiveness of LFX and MXF in terms of culture conversion after 3 months of treatment for MDR-TB. METHODS: In this prospective multicenter randomized open label trial, we randomly assigned 182 patients with MDR-TB (sensitive to LFX and MXF) to receive either LFX (750 mg/day; 90 patients) or MXF (400 mg/day; 92 patients) with a background drug regimen. The primary outcome was the proportion of patients who achieved sputum culture conversion at 3 months of treatment. Secondary outcomes were time to culture conversion and time to smear conversion, with data censored at 3 months, and the proportions of adverse drug reactions. MEASUREMENTS AND MAIN RESULTS: At 3 months of treatment, 68 (88.3%) of the 77 patients in the LFX group and 67 (90.5%) of the 74 in the MXF group showed conversion to negative sputum cultures (odds ratio for LFX compared with MXF, 0.78; 95% confidence interval, 0.27-2.20). Adverse drug reactions were reported in six patients (7.7%) in the LFX group and four (5.2%) in the MXF group (P = 0.75). CONCLUSIONS: The choice of LFX or MXF for treatment of patients with MDR-TB may not affect sputum culture conversion at 3 months of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01055145).

The efficacy of rifabutin for rifabutin-susceptible, multidrug-resistant tuberculosis.

OBJECTIVE: We investigated the efficacy of rifabutin (RFB)-containing regimens for the treatment of RFB-susceptible, multidrug-resistant tuberculosis (MDR-TB). METHODS: From 146 patients diagnosed with MDR-TB between January 2006 and December 2009 at Asan Medical Center in South Korea, 31 patients (21.2%) were found to have RFB-susceptible MDR-TB. Of these 31 patients, 14 patients who had been treated with RFB for more than one month were included. Forty-two patients with RFB-resistant MDR-TB were selected as a control group, and the outcomes of both groups were retrospectively compared. RESULTS: Of 14 patients with RFB-susceptible MDR-TB, the mean age was 44.4 years and the proportion of extensively drug-resistant TB (XDR-TB) was 35.7% (5/14). Baseline characteristics and the drug resistance pattern (except RFB) did not differ between the two groups. Treatment success was achieved in 12 (85.7%) patients in the RFB group: cure in 10 (71.4%) and treatment completion in two (14.3%). The treatment success rate was 52.4% (22/42) in the control group (p = 0.032). Treatment failure was more common in patients of the control group (40.5% vs. 14.3%; p = 0.106). CONCLUSIONS: RFB is useful as an additional drug in the treatment of MDR-TB in patients with RFB-susceptible MDR-TB.

Treatment outcomes and survival based on drug resistance patterns in multidrug-resistant tuberculosis.

RATIONALE: Few large-scale studies have investigated multidrug-resistant tuberculosis (MDR-TB) treatment outcomes relative to drug-resistance patterns. OBJECTIVES: To assess the impact of additional drug resistances on treatment outcomes and long-term survival in a large HIV-negative MDR-TB cohort. METHODS: Treatment outcomes and long-term survival of patients with MDR-TB newly diagnosed or retreated in 2000 to 2002 were retrospectively analyzed based on drug-resistance patterns after 5-8 years of follow-up. MEASUREMENTS AND MAIN RESULTS: Of 1,407 patients with MDR-TB, 75 (5.3%) had extensively drug-resistant TB (XDR-TB(re)) by the revised definition; 159 (11.3%) had ofloxacin-resistant pre-XDR-TB (pre-XDR-TB(o)); and 117 (8.3%) had second-line injectable drug (SLID)-resistant pre-XDR-TB (pre-XDR-TB(s)). Patients with XDR-TB(re) showed the lowest treatment success rate (29.3%) and the poorest long-term survival, and XDR-TB(re) was more strongly associated with long-term mortality than XDR-TB as originally defined (hazards ratio [HR], 3.15; 95% confidence interval [CI], 2.06-4.83; P < 0.001 vs. HR, 2.15; 95% CI, 1.49-3.09; P < 0.001). Patients with either form of pre-XDR-TB showed poorer cumulative survival than those with ofloxacin-susceptible/SLID-susceptible MDR-TB (P < 0.05 for each comparison). Although streptomycin susceptibility did not affect the treatment outcomes of patients with pre-XDR-TB, streptomycin-resistant pre-XDR-TB was more strongly associated with long-term mortality than ofloxacin-susceptible/SLID-susceptible MDR-TB (HR, 2.17; 95% CI, 1.22-3.84; P < 0.008 for pre-XDR-TB(o); and HR, 2.69; 95% CI, 1.40-5.16; P = 0.003 for pre-XDR-TB(s)). CONCLUSIONS: The revised XDR-TB definition is appropriate for defining patients with MDR-TB with the poorest outcomes. Both pre-XDR-TB(o) and pre-XDR-TB(s) were independently associated with poor long-term survival in patients with MDR-TB. SM susceptibility was linked to better survival in patients with pre-XDR-TB.

Treatment outcomes and long-term survival in patients with extensively drug-resistant tuberculosis.

RATIONALE: The increasing worldwide incidence of extensively drug-resistant tuberculosis (XDR-TB) has emerged as a threat to public health and tuberculosis (TB) control. Treatment outcomes have varied among studies, and data on long-term survival are still scarce. OBJECTIVES: To retrospectively assess the burden, clinical characteristics, treatment outcomes, and long-term survival rate of patients with XDR-TB in a cohort of patients with HIV-negative multidrug-resistant tuberculosis (MDR-TB) in South Korea. METHODS: Medical records were reviewed of patients newly diagnosed with or retreated for MDR-TB from 2000 to 2002. The cohort was monitored for 3 to 7 years after the initiation of treatment. Initial treatment outcomes and cumulative survival rates were analyzed, and predictors of treatment success and survival were defined. MEASUREMENTS AND MAIN RESULTS: Of 1,407 patients with MDR-TB 75 (5.3%) had XDR-TB at treatment initiation. The default rate was high (453/1,407; 32%), and patients with XDR-TB had lower treatment success (29.3 vs. 46.2%; P = 0.004) and higher all-cause (49.3 vs. 19.4%; P < 0.001) and TB-related disease mortality (41.3 vs. 11.8%; P < 0.001) than other patients with MDR-TB. The presence of XDR-TB significantly affected treatment success (odds ratio, 0.23; 95% confidence interval [CI], 0.08-0.64; P = 0.005), all-cause mortality (hazards ratio, 3.25; 95% CI, 1.91-5.53; P < 0.001), and TB-related mortality (hazards ratio, 4.45; 95% CI, 2.48-8.00; P < 0.001) on multivariate analyses. CONCLUSIONS: XDR-TB occurred in a substantial proportion of patients with MDR-TB in South Korea, and was the strongest predictor of treatment outcomes and long-term survival in patients with MDR-TB. Adequate TB control policies should be implemented to prevent the further development and spread of drug resistance.

Green tea extract inhibits paraquat-induced pulmonary fibrosis by suppression of oxidative stress and endothelin-l expression.

Paraquat-induced pulmonary fibrosis involves two factors, direct injury by oxygen free radicals and indirect injury by inflammatory cells and fibroblasts. Endothelin-1 (ET-1) has been shown to act as a mediator of pulmonary fibrosis, and its formation increases during oxidative stress. We investigated whether green tea extract (GTE), which has antioxidant properties, inhibits paraquat-induced pulmonary fibrosis and whether ET-1 is involved in this process. Paraquat (0.3 mg/kg) was instilled into the right lungs of rats, following which the rats were either not further treated (Group P, n = 7), or they were administered 1% GTE mixed with feed (Group PG; n = 7) or the ET(A) receptor antagonist ZD2574 (10 mg/kg through gavage; Group PZ; n = 7) for two weeks. As control, we used rats instilled with saline (Group N; n = 6). Two weeks after paraquat instillation, we assayed the degree of pulmonary fibrosis by light microscopic morphometry and hydroxyproline content; lipid peroxidation as a marker of oxidative stresses by measurement of malondialdehyde (MDA); ET-1 by immunohistochemistry; and prepro-ET-1 mRNA expression by reverse transcription-polymerase chain reaction. Compared with Group N, significant pulmonary fibrosis was observed in Group P, accompanied by increases in MDA, ET-1, and prepro-ET-1 mRNA expression. Compared with Group P, Group PG showed significant decreases in pulmonary fibrosis, along with decreases in MDA, ET-1, and prepro-ET-1 mRNA expression. We also observed significant decreases in pulmonary fibrosis in Group PZ compared with Group P. These findings suggest that GTE inhibits paraquat-induced pulmonary fibrosis by suppression of oxidative stress and ET-1 expression.

Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs.

RATIONALE: In cigarette smoking-induced chronic obstructive pulmonary disease, structural and functional derangements are characterized by parenchymal destruction and pulmonary hypertension. Statins are 3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase inhibitors that have been used as lipid-lowering agents. These drugs also have additional pharmacologic properties, including antiinflammation, scavenging reactive oxygen species, restoring endothelial function, and antithrombogenesis, all of which can counteract the harmful effects of cigarette smoking. OBJECTIVE: We performed assays to determine whether simvastatin could attenuate lung damage induced by chronic cigarette smoking in rats. METHODS: In Sprague-Dawley rats exposed to cigarette smoke for 16 weeks, morphologic changes in the lungs and pulmonary arterial pressure were examined. MAIN RESULTS: Simvastatin inhibited lung parenchymal destruction and development of pulmonary hypertension, and also inhibited peribronchial and perivascular infiltration of inflammatory cells and induction of matrix metalloproteinase-9 activity in lung tissue. Simvastatin additionally prevented pulmonary vascular remodeling and the changes in endothelial nitric oxide synthase expression induced by smoking. In human lung microvascular endothelial cells, simvastatin increased expression of endothelial nitric oxide synthase mRNA. CONCLUSIONS: Simvastatin ameliorated the structural and functional derangements of the lungs caused by cigarette smoking, partly by suppressing inflammation and matrix metalloproteinase-9 induction and preventing pulmonary vascular abnormality. These findings indicate that statins may play a role in the treatment of cigarette smoking-induced chronic obstructive pulmonary disease.