Clofazimine and QT prolongation in the treatment of rifampicin-resistant tuberculosis: Findings of aDSM in Taiwan.

BACKGROUND: Bedaquiline, delamanid and fluoroquinolones are associated with increased QTcF. Whether clofazimine is associated with QTcF prolongation is less clear. METHODS: All patients with rifampicin-resistant TB enrolled between May 2017 and Dec 2019 were included. ECGs were performed at baseline, month 1, month 3 and month 6 for patients treated with conventional regimens, and at additional timepoint for patients treated with bedaquiline, delamanid and short regimen. We estimated the maximum increase of QTcF and constructed cox proportional hazards models to assess factors associated with QTcF≥501ms. RESULTS: Among 321 patients, 59 (18.4%) patients had QTcF≥501ms during a mean follow-up of 242 days (median 189, range 4-1091). The median maximum increase of QTcF was 43.4 ms (IQR 31.3-65.9) in patients treated with clofazimine. Treatment with clofazimine was significantly associated with QTcF≥501ms as compared to without clofazimine (adjusted hazards ratio (adjHR) 4.35, 95% confidence interval (CI) 2.01-9.44). Among patients not treated with bedaquiline and delamanid, those treated with clofazimine and a fluoroquinolone (adjHR 3.43, 95% CI 1.61-7.34) and those treated with clofazimine and high dose moxifloxacin (adjHR 6.54, 95% CI 2.43-17.60) had a significantly higher risk of QTcF≥501ms as compared to those treated with a fluoroquinolone without other QTcF prolonging agents. Four (1.6%) patients had documented ventricular tachycardia, in which one was Torsade de pointes. One patient was found to have sudden death during hospitalization. CONCLUSIONS: Clofazimine was significantly associated with an increased risk of QTcF prolongation. QTcF≥501ms was potentially associated with fatal event and needed to be managed cautiously.

Enhancing the sequence coverage of nanodiamond-extracted early secretory proteins from the Mycobacterium tuberculosis complex.

The unambiguous identification of protein species requires high sequence coverage. In this study, we successfully improved the sequence coverage of early secretory 10 kDa cell filtrate protein (CFP-10) and 6 kDa early secretory antigenic target (ESAT-6) proteins from the Mycobacterium tuberculosis complex (MTC) in broth culture media with the use of the 4-chloro-α-cyanocinnamic acid (Cl-CCA) matrix. Conventional matrices, α-cyano-hydroxy-cinnamic acid (CHCA) and 2,5-dihydroxybenzoic acid (DHB), were also used for comparison. After nanodiamond (ND) extraction, the sequence coverage of the CFP-10 protein was 87% when CHCA and DHB matrices were used, and the ESAT-6 protein was not detected. On the other hand, the sequence coverage for ND-extracted CFP-10 and ESAT-6 could reach 94% and 100%, respectively, when the Cl-CCA matrix was used and with the removal of interference from bovine serum albumin (BSA) protein and α-crystallin (ACR) protein. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) was also adopted to analyze the protein mass spectra. A total of 6 prominent ion signals were observed, including ESAT-6 protein peaks at mass-to-charge ratios (m/z) of ∼7931, ∼7974, ∼9768, and ∼9813 and CFP-10 protein peaks at m/z of ∼10 100 and ∼10 660. The ESAT-6 ion signals were always detected concurrently with CFP-10 ion signals, but CFP-10 ion signals could be detected alone without the ESAT-6 ion signals. Furthermore, the newly found ESAT-6 peaks were also confirmed using a Mag-Beads-Protein G kit with an ESAT-6 antibody to capture the ESAT-6 protein, which was also consistent with the sequence coverage analysis.

Mitigating treatment failure of pulmonary pre-extensively drug-resistant tuberculosis: The role of new and repurposed drugs.

BACKGROUND: Pre-extensively drug-resistant tuberculosis (pre-XDR-TB), defined as multidrug-resistant TB (MDR-TB) with additional resistance to any fluoroquinolone (FQ) is difficult to treat. We assessed whether the use of new or repurposed drugs (bedaquiline, delamanid, linezolid, carbapenem, clofazimine, pretomanid) mitigated treatment failure of pre-XDR-TB. METHODS: MDR-TB patients managed in the Taiwan MDR-TB consortium between July 2009-December 2019 were eligible. Treatment outcomes at 30 months were assessed. Logistic regression models were constructed to investigate factors associated with treatment outcomes. RESULTS: 109 patients with FQ-resistant MDR-TB and 218 patients with FQ-susceptible MDR-TB were included. 60 (55.1%) patients with FQ-resistant MDR-TB and 63 (28.9%) patients with FQ-susceptible MDR-TB have been treated with new or repurposed drugs (p < 0.01). Of the 218 patients with FQ-susceptible MDR-TB, 187 (85.8%) had treatment success, 30 (13.8%) died, no treatment failure, and 1 (0.5%) was loss-to-follow-up; of the 109 patients with FQ-resistant MDR-TB, 78 (71.6%) had treatment success, 21 (19.3%) died, 9 (8.3%) had treatment failure, and 1 (0.9%) was loss-to-follow-up (p < 0.01). The use of new or repurposed drugs was not associated with treatment outcomes among patients with FQ-susceptible MDR-TB. No patients with FQ-resistant MDR-TB treated with ≥2 new or repurposed drugs within 6 months of treatment initiation had treatment failure (p = 0.03). Patients with FQ-resistant MDR-TB treated with 1 new or repurposed drugs was more likely to have treatment failure as compared with patients not treated with new or repurposed drugs (adjOR 7.06, 95% CI 1.72-29.06). CONCLUSIONS: Proper use of new or repurposed anti-TB drugs can mitigate treatment failure in FQ-resistant MDR-TB.

Incremental yield of serial sputum examinations in the diagnosis of pulmonary tuberculosis in Taiwan: Findings of a pragmatic trial.

BACKGROUND: Presumptive tuberculosis (TB) cases commonly had two to three sputum examinations in Taiwan. The incremental yield of serial sputum examinations has not been assessed before. METHODS: In a pragmatic trial, presumptive TB patients with a frontline nucleic acid amplification test (NAAT) were classified as group A. Those without a frontline NAAT were randomized into group B frontline NAAT as intervention, and group C usual care. We investigated expected incremental yields and the number of examinations required for detection of one additional TB case from each serial sputum smear and culture. RESULTS: Of 6835 presumptive TB cases, 395 (5.8%) were smear positive for acid-fast bacilli, and 195 (2.8%) culture positive for M tuberculosis. The expected incremental yield from a third smear was 3.5% and examination of 1712 (95% credibility interval 586-4706) third smears was required to detected one additional TB case. Sensitivity of one smear with an NAAT in group B was 46.8% (95% confidence interval 32.1%-61.9%), and that of two smears in Group C 40.0% (95% confidence interval 25.7%-55.7%). The expected incremental yield from a third culture was 8.4%, and the number of third cultures required to detect one additional TB case was 394 (95% credibility interval 231-670). CONCLUSIONS: The incremental yield of the third sputum smear was negligible. It may be reasonable to perform an NAAT, smear and culture on the first specimen and culture alone on the second. The utility of the third serial culture for the detection of additional TB case is debatable.

Nucleic acid amplification tests reduce delayed diagnosis and misdiagnosis of pulmonary tuberculosis.

The clinical impact of nucleic acid amplification (NAA) tests on reducing delayed diagnosis and misdiagnosis of pulmonary TB (PTB) has rarely been investigated. PTB patients were classified into a frontline NAA group, an add-on NAA group, and a no NAA group. The outcomes of interest were the proportion of PTB case died before anti-TB treatment, the interval between sputum examination and initiation of treatment, and misdiagnosis of PTB. A total of 2192 PTB patients were enrolled, including 282 with frontline NAA, 717 with add-on NAA, and 1193 with no NAA tests. Patients with NAA tests had a lower death rate before treatment initiation compared to those without NAA tests (1.6% vs. 4.4%, p < 0.001) in all cases. Patients with frontline NAA compared to those with add-on NAA and those without NAA, had a shorter interval between sputum examination and treatment initiation in all cases (3 days vs. 6 days (p < 0.001), vs 18 days (p < 0.001)), and less misdiagnosis in smear-positive cases (1.8% vs. 5.6% (p = 0.039), vs 6.5% (p = 0.026)). In conclusion, NAA tests help prevent death before treatment initiation. Frontline NAA tests perform better than add-on NAA and no NAA in avoiding treatment delay in all cases, and misdiagnosis of PTB in smear-positive cases.

Performance of Nucleic Acid Amplification Tests in Patients with Presumptive Pulmonary Tuberculosis in Taiwan.

INTRODUCTION: Several nucleic acid amplification tests (NAATs) for detection of Mycobacterium tuberculosis (TB) complex (MTBC) are available in Taiwan; however, their performances may differ and have not been extensively evaluated. Therefore, we aimed to explore the accuracy of NAATs overall followed by comparison between platforms commonly used in Taiwan. METHODS: This study enrolled presumptive pulmonary TB patients with NAATs throughout Taiwan. The diagnostic performance of smear microscopy and NAATs was assessed using sputum culture as a reference standard. To investigate the performance of NAATs in excluding non-tuberculous mycobacteria (NTM), we quantified the false-positive proportion of NAATs in patients infected with NTM. RESULTS: Of the 4126 enrollees, 860 (20.8%) had positive NAATs. The sensitivity and specificity of NAATs were 83.2% and 96.7%, respectively, compared to 81.5% and 55.3% for smear. There was no significant difference in sensitivity between the NAATs and smear; however, the specificity of smear was significantly lower than that of the NAATs [difference 41.4%, 95% confidence interval (CI) 39.6-43.2%]. There was no significant difference in sensitivity among Roche Cobas Amplicor Mycobacterium tuberculosis assay (Amplicor), Xpert MTB/RIF assay (Xpert) and in-house polymerase chain reaction (in-house PCR) (82.2% versus 83.8% versus 82.4%); however, in-house PCR was significantly less specific than Amplicor (difference 5.3%, 95% CI 2.4-8.2%) and Xpert (difference 5.8%, 95% CI 3.1-8.5%). The sensitivity of NAATs among smear-negative cases was 33.1% (95% CI 26.0-40.3%). In-house PCR had a significantly higher false-positive rate among specimens that were culture positive for NTM than Amplicor (7.7% versus 0.3%; difference 7.4%, 95% CI 3.4-11.5%) and Xpert (7.7% versus 0.7%; difference 7.0%, 95% CI 2.9-11.0%). CONCLUSION: The NAATs overall had a relatively high sensitivity and specificity in detecting MTBC while Amplicor and Xpert performed better than in-house PCR in excluding NTM. Our findings will be useful for the development of national policy.

A program to improve the quality of dental unit water in a medical center.

ABSTRACT: The water quality of dental unit waterlines (DUWLs) is associated with patient safety. No program for DUWL water quality improvement has been formulated since the time they were established 20 years ago. This study provides an improvement program for the quality of dental unit water. The improvement program was implemented step by step: discharge of DUWLs for 5 minutes in the morning before clinical service to flush out the water left in the pipeline overnight; weekly disinfection of the handpiece connector with 75% alcohol and replacement of the old connector when the water quality of the same dental chair unit (DCU) was continuously found to be unqualified; monthly disinfection of the water supply system and pipeline; and establishment of DCU maintenance work standards and staff education and training. From 2016 to 2018, the water quality of 18 DCUs was tested by microorganism culture. The colonies >200 colony forming unit were categorized as unqualified. This program was divided into a pre-test phase, Phase 1, a maintenance phase, and Phase 2. A Chi-square test was used to calculate the difference of unqualified water quality numbers between each phase of the improvement program. In the pre-test phase, the water quality rate (high quality number/high-quality number + low-quality number) was 58.3%. In Phase 1, the quality rate before and after the intervention was 64.8% (35/54) and 92.2% (83/90) (P < .001), respectively. After Phase 1, the quality rate reached 100%. However, the quality rate dropped to 75% during the maintenance phase. Then, we proceeded into Phase 2 of the improvement program by further monthly disinfection to DUWLs. In Phase 2, the quality rate was 62/73 (84.9%) and improved to 142/144 (98.6%) after the intervention (P < .001). The quality rate reached 100% once again and was maintained at 100% thereafter. In conclusion, the 4 steps of the improvement program improved the water quality of the DUWL, which is important for patient safety.

Lymphocyte percentage and platelet count correlate with the treatment outcome to tyrosine kinase inhibitors in epidermal growth factor receptor-mutated lung adenocarcinoma.

This observational study evaluated the treatment outcomes of clinical factors on the patients with lung adenocarcinoma with epidermal growth factor receptor mutations who received tyrosine kinase inhibitors as first-line treatment.Patients with stage IIIb or IV lung adenocarcinoma with mutated epidermal growth factor receptor were enrolled retrospectively between March 2010 and December 2017. The hematologic markers on progression-free survival (PFS) and overall survival (OS) were analyzed.Totally 190 patients were enrolled. In univariate analysis by hematologic markers, lower lymphocyte percentage and higher platelet count were associated with significantly poor PFS and OS. Multivariate analysis showed lower lymphocyte percentage was independent poor prognostic factors for PFS and OS. Higher platelet count was an independent poor prognostic factor for OS only.Patients with lung adenocarcinoma receiving tyrosine kinase inhibitors with lower lymphocyte percentage and higher platelet count had poorer prognoses compared with other patients.

Impact of universal drug susceptibility testing and effective management of multidrug-resistant tuberculosis in Taiwan.

BACKGROUND: The treatment outcomes of multidrug-resistant tuberculosis (MDR-TB) patients in the 1990s in Taiwan was not satisfactory. To strengthen programmatic management of drug-resistant tuberculosis (PMDT), Taiwan MDR-TB Consortium (TMTC) was established in 2007. We assess the performance and epidemiologic impact of TMTC. METHODOLOGY/PRINCIPLE FINDINGS: We analyzed the trends of proportion of TB cases with drug susceptibility testing, enrollment of MDR-TB patients into TMTC and outcomes of treatment of all MDR-TB patients in Taiwan from 2007-2016. We computed the trends of both incidence and prevalence of MDR-TB from 2007-2016. We assessed the trends of MDR-TB among both new and recurrent TB cases. The proportion of TB cases with drug susceptibility testing results increased from 24.2% in 2007 to 97.9% in 2016. Of the 1,452 MDR-TB patients who were eligible for TMTC care, 1,197 (82.4%) were enrolled in TMTC, in whom 82.9% had treatment success. MDR-TB incidence was 9.0 cases per million in 2007, which declined to 4.6 cases per million in 2016 (p<0.0001). MDR-TB prevalence decreased from 19.4 cases per million in 2007 to 8.4 cases per million in 2016 (p<0.0001). The proportion of MDR-TB among new TB cases decreased from 1.4% in 2010 to 1.0% in 2016 (p = 0.039); and that among recurrent TB cases from 9.0% in 2010 to 1.8% in 2016 (p<0.0001). CONCLUSIONS: We concluded that effective PMDT have had a significant impact on the epidemic of drug-resistant TB in Taiwan.

Treatment outcomes for multidrug-resistant tuberculosis in Eastern Taiwan.

OBJECTIVES: The objective of this study is to evaluate the treatment outcomes of patients with multidrug-resistant tuberculosis (MDR-TB) under special programmatic management in Eastern Taiwan over the past 10 years. MATERIALS AND METHODS: All newly diagnosed MDR-TB patients and MDR-TB patients enrolled previously with persistent positive cultures were included in this study, from May 2007 to April 2017, in Eastern Taiwan. A panel of pulmonologists designed the initial MDR-TB regimens. Subsequently, regimens were adjusted according to drug susceptibility test results for second-line drugs. Mobile teams were organized for treatment support, and several measures were adapted to safeguard effective treatment support. RESULTS: A total of 178 patients with bacteriological confirmed pulmonary MDR-TB were identified, of whom 167 had treatment outcomes when the study was conducted. Of these 167 patients, 120 (71.9%) were cured, 11 (6.5%) completed therapy (78.4% had successful treatment), 25 (15.0%) died, 9 (5.4%) had treatment failure, none were transferred out, and 2 (1.2%) were lost to follow-up. Surgery was performed on 8 (4.8%). CONCLUSIONS: This is an analysis of the treatment outcomes after adopting the Directly Observed Treatment, Short-course Plus program to treat MDR-TB patients in Eastern Taiwan. We had a low proportion of loss-to-follow-up, resulting in a high treatment success rate. This program serves as an effective model in providing quality care to patients with MDR-TB.