Compliance with new drug use and the effect of discrepant drug susceptibility testing on MDR/RR-TB treatment.

BACKGROUND: Following the WHO???s announcement in 2018, the use of new drugs was recommended for all patients with multidrug-resistant TB (MDR-TB) in Korea. This study aimed to evaluate adherence to new anti-TB drug regimens and implementation of molecular drug susceptibility testing (mDST) in Korea.METHODS: Nationwide, 560 patients were reported as having MDR-TB in 2021. The implementation of mDST and new anti-TB drug use were analysed. The discrepancy between mDST and phenotypic DST (pDST) results and their implications on the use of new anti-TB drugs were also analysed. The use of novel anti-TB drugs has been approved by the National TB Expert Committee.RESULTS: The non-adherence rate in MDR-TB patients was 14.3%. The mDST implementation rate was 96.1%. Of the 459 patients who underwent both mDST and pDST, the discordance rate for rifampicin (RIF) resistance was 22.6% (n = 104), of which 72.1% (n = 75) were resistant on mDST but susceptible on pDST. The discrepancy in mDST and pDST results related to RIF resistance was found to be the main cause of non-adherence to new drug regimen.CONCLUSION: Comprehensive training on how to interpret conflicting results between mDST and pDST could enhance the utilisation of new drugs in the treatment of MDR/RIF-resistant TB.

Treatment outcome, recurrence and safety of multidrug-resistant TB treated with low-dose linezolid.

BACKGROUND: Linezolid (LZD) is a key treatment option for patients with multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We investigated the long-term treatment outcomes and safety of MDR/RR-TB treatment using low-dose LZD.METHODS: Medical records of patients with MDR/RR-TB treated with LZD ≥4 weeks between 2004 and 2018 at the Asan Medical Center, Seoul, Republic of Korea, were reviewed. Standard-dose and low-dose LZD groups were defined as patients initially administered LZD ≥600 mg/day or 300 mg/day, respectively.RESULTS: Among 94 patients, 65 were included in the low-dose LZD group; mean age was 43.1 ± 15.6 years, 53 (56.4%) were men and 77 (83.7%) were resistant to fluoroquinolone. The low-dose LZD group showed features of less severe disease, such as limited MDR-TB history and less severe radiological findings. There was no difference in treatment outcomes, relapse and safety between groups. In the low-dose LZD group, 54 (83.1%) succeeded treatment, of whom 48 (88.9%) were followed-up for a median of 38 months; there was no recurrence. Adverse drug reactions were reported in 41 (63.1%); peripheral neuropathy was most frequently reported (n = 31, 47.7%), while myelosuppression was reported in 12 (18.5%).CONCLUSION: Low-dose LZD in selected patients with less severe disease is both effective in the long-term and safe for the treatment of MDR/RR-TB.

Treatment outcomes of multidrug-resistant TB with selective use of new drugs.

SETTING: This was a nationwide cohort study.OBJECTIVE: To assess the treatment outcomes in patients with multidrug-resistant TB (MDR-TB) who underwent treatment guided by a national TB expert review committee in South Korea.DESIGN: We enrolled all patients with MDR-TB submitted for approval for the use of new TB drugs, including bedaquiline and delamanid, from 2016 to 2019. Patients were classified into two groups: those on new TB drugs and those not on new TB drugs. We compared the final treatment outcomes between the groups and analysed the prognostic factors.RESULTS: Of a total of 785 patients, respectively 754 (96.1%) and 31 (3.9%) were classified into the "new TB drugs" group and "no new TB drugs" group. The new TB drugs group had a higher acid-fast bacilli smear positivity rate and higher resistance rate to second-line injectable drugs or fluoroquinolones. Of all the patients, 97.8% achieved culture conversion (97.7% vs. 100%), and 80.4% achieved treatment success (80.2% vs. 86.7%); there was no difference between the two groups.CONCLUSIONS: New drugs are currently recommended for use in all MDR-TB treatment regimens, and the use of new drugs, as determined by an expert committee, in mainly quinolone-susceptible MDR-TB, did not compromise the treatment success rate.

Adverse events and development of tuberculosis after 4 months of rifampicin prophylaxis in a tuberculosis outbreak.

We screened tuberculosis (TB) contacts as an outbreak investigation with tuberculin skin test (TST) and interferon-gamma release assay (IGRA). We evaluated adverse events and TB incidence in all persons screened after rifampicin (RFP) prophylaxis, and specifically assessed the new TB cases in relation to initial TST and IGRA results. The 180 contacts were divided into four groups: TST+/IGRA+ (n = 101), TST+/IGRA- (n = 22), TST-/IGRA+ (n = 16), and TST-/IGRA- (n = 41). RFP treatment (4 months) was prescribed only to the TST+/IGRA+ group. Of 87 contacts who initiated prophylaxis, adverse events occurred in 21 contacts (24.1%) including hepatotoxicity (11.5%), flu-like syndrome (5.7%), and thrombocytopenia (3.4%). TB developed in two TST+/IGRA+ subjects after completion of prophylaxis, including one multidrug-resistant (MDR)-TB case during 21.8 months of follow-up. Adverse events were frequent, and development of TB including MDR-TB occurred after RFP prophylaxis.

Treatment outcomes in multidrug-resistant tuberculosis according to pyrazinamide susceptibility.

BACKGROUND: Pyrazinamide (PZA) is an important anti-tuberculosis drug for multidrug-resistant tuberculosis (MDR-TB). However, PZA has recently been demoted within the hierarchy of TB drugs used for MDR-TB.METHODS: We conducted a retrospective cohort study to investigate treatment outcomes for simple MDR-TB (susceptible to both second-line injectable drugs and fluoroquinolones) according to PZA susceptibility.RESULTS: Among 216 pulmonary MDR-TB patients included in the study, 68 (31.5%) were PZA-resistant (PZA-R). The mean age was 41.8 years, and 63.4% were male. Baseline characteristics such as comorbidity, previous TB history, acid-fast bacilli (AFB) smear positivity and cavitation were similar in PZA-susceptible (PZA-S) and PZA-R patients. The number of potentially effective drugs was slightly higher among PZA-S patients than among the PZA-R (5.1 vs. 4.8, respectively; P = 0.003). PZA was more frequently used in PZA-S patients (73.0%) than in the PZA-R (14.7%), while para-aminosalicylic acid was more frequently used in PZA-R than in PZA-S patients (76.5% vs. 50.7%). The treatment success rate was similar in PZA-S (77.7%) and PZA-R (75.0%) patients. PZA resistance was not associated with treatment success in multivariate analysis.CONCLUSIONS: PZA-resistant simple MDR-TB patients had the same treatment success rate as the PZA-susceptible group even without using novel anti-TB drugs.

Clinical course and lung function change of idiopathic nonspecific interstitial pneumonia.

Most studies of idiopathic nonspecific interstitial pneumonia (NSIP) have primarily studied mortality. In order to clarify the detailed outcome and prognostic markers in idiopathic NSIP, the clinical course with initial radiological and clinical features was analysed. The clinical course of 83 patients who were classified with idiopathic NSIP (72 fibrotic, 11 cellular; 27 males and 56 females; mean+/-sd age 54.4+/-10.1 yrs) was retrospectively analysed. In fibrotic NSIP, 16 (22%) patients died of NSIP-related causes with a median (range) follow-up of 53 (0.3-181) months. Despite the favourable survival (5-yr 74%), patients with fibrotic NSIP were frequently hospitalised with recurrence rate of 36%. Reduced forced vital capacity at 12 months was a predictor of mortality. On follow-up, lung function was improved or stable in approximately 80% of the patients. The extent of consolidation and ground-glass opacity on initial high-resolution computed tomography correlated significantly with serial changes of lung function, and the presence of honeycombing was a predictor of poor prognosis. During follow-up, eight (10%) patients developed collagen vascular disease. In conclusion, the overall prognosis of fibrotic nonspecific interstitial pneumonia was good; however, there were significant recurrences despite initial improvement and a subset of the patients did not respond to therapy. Some patients developed collagen vascular diseases at a later date.

Combined use of QuantiFERON-TB Gold assay and chest computed tomography in a tuberculosis outbreak.

OBJECTIVE: To evaluate the value of the QuantiFERON-TB Gold (QFT-G) assay and chest computed tomography (CT), in addition to the conventional use of the tuberculin skin test (TST) and chest radiography (CXR), in a contact investigation of a tuberculosis (TB) outbreak. DESIGN: In a contact investigation of a TB outbreak in a high school, TST and CXR were performed on all 1044 employees and students. QFT-G was performed on TST-positive subjects, and CT on QFT-G-positive subjects and students with TST > or =20 mm. RESULTS: TST was positive in 388 subjects (37.2%), while QFT-G was positive in 7.6% (30/394). CXR showed abnormal findings suggestive of TB in 10 (1.0%) subjects, all of whom were TST-positive and six of whom were QFT-G-positive. Findings suggestive of active TB were noted in 17 (32.7%) of 52 subjects by CT. Collectively, among 21 (1.1%) TB patients, all were TST-positive, 12 (57.1%) were QFT-G-positive and active TB was diagnosed by CT, and not by CXR, in 11 subjects. CONCLUSION: Compared to the conventional approach, the additional use of QFT-G in TST-positive subjects and chest CT in subgroups with a high probability of infection was found to be more effective in the differentiation between active TB, latent TB and non-infected subjects in a contact investigation.

Pulmonary tuberculosis with acute respiratory failure.

The aim of the present study was to evaluate the clinical characteristics, prognoses and predictors of mortality of patients with pulmonary tuberculosis (TB) with acute respiratory failure (ARF), and to investigate the adjunctive use of corticosteroids in such cases. TB patients with ARF requiring mechanical ventilation (n = 90) were enrolled retrospectively during 1989-2006. The patients were divided into two groups: tuberculous pneumonia (TBP; n = 66), and miliary TB (MTB; n = 24). The TBP patients were older than the MTB patients (mean age 68.0 versus 54.5 yrs), and the mean+/-SD interval from hospital admission to start of anti-TB treatment was longer for the TBP than for the MTB group (5.0+/-7.0 versus 2.8+/-2.5 days). However, there was no difference in in-hospital mortality rate between the two groups (68.2 versus 58.3%). In the TBP patients, multivariate analysis showed that advanced age and shock unrelated to sepsis were associated with poor outcomes. Even though corticosteroid use was a predictor of survival in TBP patients, it was difficult to conclusively determine the efficacy of corticosteroids in TBP with ARF because of the retrospective study design. The present study reveals the need for randomised controlled trials to clarify the role of corticosteroids as adjunctive therapy in the management of tuberculous pneumonia with acute respiratory failure.

Incidence of tuberculosis among health care workers at a private university hospital in South Korea.

SETTING: A private university hospital in South Korea. OBJECTIVE: To investigate the incidence of tuberculosis (TB) among health care workers (HCWs) employed at a university hospital in South Korea. DESIGN: The occurrence of TB cases among HCWs over a 6-year period (2001-2006) was reviewed. The prevalence of TB was compared with that of the general population using a prevalence ratio (PR) adjusted by age and sex. RESULTS: The study involved 8433 people. TB developed in 61 HCWs (0.72%). The prevalence ratio among all HCWs was 1.05 (95%CI 0.80-1.35). In occupational subgroups, the PRs for doctors, nurses and employees in other departments were respectively 0.58 (95%CI 0.30-1.01), 1.81 (95%CI 1.21-2.59) and 0.95 (95% CI 0.58-1.46). For nurses working in TB-related departments, the relative risk of developing TB was 3.4 times higher (95%CI 1.52-8.25) than for employees in other departments (P=0.005). The PR for nurses working in TB-related department was 5.1 (95%CI 3.23-8.42). CONCLUSION: Among HCWs, nurses working in TB-related departments were at increased risk of developing TB. This suggests that some TB develops via in-hospital infection.

First Report of the Korean Lung Transplantation Registry.

BACKGROUND: The Korean Organ Transplantation Registry (KOTRY) began to register lung transplants in 2015. This is an initial report on the status of patients receiving lung transplants over the past 2 years. METHODS: We analyzed a total of 69 patients who received lung transplants in 2015 and 2016 and who registered with the KOTRY. RESULTS: The 69 patients were treated in 5 institutions. The average (SD) donor age was 39.2 (12.6) years; there were 40 male patients. The average (SD) recipient age was 55.7 (10.0) years, and the number of male recipients was 46. A total of 66 patients underwent bilateral lung transplantation, 3 underwent single-lung transplantation, and 1 underwent simultaneous heart-lung transplantation. The most frequent indication for lung transplantation was idiopathic pulmonary fibrosis (35 patients), followed by connective tissue disease-related interstitial lung disease (9) and acute respiratory failure (8). Prior to transplantation, 23 patients required ventilator care, and 12 required extracorporeal membrane oxygenation while on the waiting list. Episodes of acute rejection during follow-up were reported in 4, 2, 1, and 1 patients at 3, 6, 9, and 12 months, respectively. Infections requiring hospitalization were reported in 27, 10, 4, and 3 patients at 3, 6, 9, and 12 months, respectively. CONCLUSION: The establishment of KOTRY renders it possible to collect nationwide data on lung transplantation, improving research on the topic and clarifying clinical feasibility.

Impact of short-term exposure to fluoroquinolones on ofloxacin resistance in HIV-negative patients with tuberculosis.

SETTING: Seoul, Korea, a country with an intermediate tuberculosis (TB) burden and low prevalence of human immunodeficiency virus (HIV) infection. OBJECTIVES: To determine the frequency of ofloxacin (OFX) resistance in Mycobacterium tuberculosis, and to assess whether short-term use of fluoroquinolones (FQNs) induces ofloxacin-resistant M. tuberculosis. DESIGN: The subject cohort consisted of 2788 patients with culture-confirmed TB with drug susceptibility testing data; only four were HIV-positive. The patients were divided into two groups: those who were or were not recently exposed to FQNs. RESULTS: Of the 2788 isolates, the rates of OFX resistance were 1.1% and 8.5% in initially treated and retreated patients, respectively (P < 0.05). Of the 94 OFX-resistant isolates, 83 (88.3%) were multidrug-resistant (MDR). There was no difference in rates of OFX resistance throughout the study period, or between the FQN-exposed (1/39, 2.6%) and control groups (93/2749, 3.4%). The median duration of FQN treatment was 7 days (range 1-47 days). One OFX-resistant isolate in the FQN-exposed group was MDR. CONCLUSION: The rate of OFX-resistant M. tuberculosis was low and stationary throughout the study period in Korea. Most OFX resistance was accompanied by MDR, and the frequency of OFX-resistant M. tuberculosis was low in subjects taking short-term FQNs.

Clinical significance of QT-prolonging drug use in patients with MDR-TB or NTM disease.

SETTING: Many drugs with potential QT prolongation effects (QT drugs) have already been used for decades in patients with multidrug-resistant TB (MDR-TB) or non-tuberculous mycobacterial (NTM) disease, but without a common consensus. OBJECTIVE: To investigate the effects of QT drugs on cardiac events in patients with MDR-TB or NTM disease. METHODS: We retrospectively reviewed 373 patients (mean age: 56.4 years) with MDR-TB or NTM disease treated for >1 month with clofazimine (CFZ), moxifloxacin (MFX), bedaquiline (BDQ), delamanid (DLM) or macrolides (clarithromycin or azithromycin). Adverse cardiac events, death and QTcF changes were evaluated. RESULTS: Forty-four per cent had MDR-TB; 165 (44%), 315 (85%), 10 (3%), 229 (61%) and 1 patient received CFZ, MFX, BDQ, macrolides and DLM, respectively. Except for three patients (0.8%) lost to follow-up with unknown cause of death, 3 (0.8%, 95%CI 0.2-2.4) adverse cardiac events were documented: atrial fibrillation, cardiac tamponade due to TB pericarditis and cardiac arrest, which was determined to not have been caused by QT drugs. Clinically significant QTcF changes (QTcF > 500 msec or an increase > 60 msec) were observed in 10/60 patients (17%, 95%CI 8.0-30.7) without clinical events. CONCLUSION: The use of QT drugs, alone or in combination, in the treatment of MDR-TB or NTM disease is relatively safe.

Deep tracheal laceration after balloon dilation for benign tracheobronchial stenosis: case reports of two patients.

We report two cases of deep tracheal laceration in female patients after balloon dilation for benign tracheobronchial stenosis. Immediate post-procedure bronchoscopy and CT including 3D reconstructions showed deep lacerations in the posterior tracheal wall. Clinically, the patients' dyspnoea subsided and there has been no recurrence during follow-up after balloon dilation. On the follow-up 3D-reconstructed CT scans obtained 2 months and 8 months following balloon dilation, respectively, the lacerations had healed completely and there was considerable improvement in lumen size.

Subspecies distribution and macrolide and fluoroquinolone resistance genetics of Mycobacterium abscessus in Korea.

BACKGROUND: Treating Mycobacterium abscessus infections with antimicrobials remains difficult, possibly due to drug resistance. OBJECTIVE: To investigate the subspecies distribution of M. abscessus and its correlation with antibiotic susceptibility and the genetics of antibiotic resistance, focusing on macrolides and fluoroquinolones, in the Republic of Korea. DESIGN: A total of 53 M. abscessus isolates were identified to the subspecies level by sequencing of hsp65 and erm(41). The minimal inhibitory concentrations (MICs) of clarithromycin (CLM) and ciprofloxacin (CFX) were determined using Sensititre™ RAPMYCO plates. The rrl, gyrA and gyrB genes were sequenced to elucidate the molecular mechanisms of macrolide and fluoroquinolone resistance. RESULTS: Isolates included 22 M. abscessus subsp. abscessus and 31 M. abscessus subsp. bolletii. erm(41) sequences showing subspecies-specific deletions and sequence variations in the 28th nucleotide were concordant with inducible CLM resistance; however, mutations in rrl were not detected. Low- and high-level CFX resistance was observed in respectively 19 (35.8%) and 10 (18.9%) of the 53 clinical isolates, regardless of subspecies. However, no non-synonymous mutations were detected in gyrA or gyrB. CONCLUSION: Sequencing of the erm gene and subspeciation of M. abscessus may be used to predict inducible macrolide susceptibility. Further studies of the relationship between specific mutations in gyrA or gyrB to MIC change are required.

Conventional and real-time PCR targeting 16S ribosomal RNA for the detection of Mycobacterium tuberculosis complex.

SETTING: Conventional diagnostic methods for tuberculosis (TB) have limited sensitivity and specificity or are time-consuming. OBJECTIVE: 16S rDNA and 16S rRNA of Mycobacterium tuberculosis complex (MTC) were used as targets to develop sensitive and specific polymerase chain reactions (PCRs) to improve the diagnosis of MTC. DESIGN: We developed conventional and real-time PCRs targeting 16S rDNA and rRNA of MTC. RESULTS: PCRs targeting 16S rRNA had a 10-100 times lower limit of detection for M. tuberculosis than PCRs targeting 16S rDNA. The sensitivities of the 16S rDNA PCR, 16S rRNA reverse transcription PCR (RT-PCR), 16S rDNA real-time PCR and 16S rRNA real-time RT-PCR for sputum specimens were respectively 92%, 94.6%, 96% and 100%. Real-time PCR showed no cross-reactivity, but conventional PCR had cross-reactivity to M. avium, M. gastri and M. nonchromogenicum. CONCLUSION: PCRs targeting the 16S rRNA of MTC were more sensitive than those targeting 16S rDNA; 16S rRNA real-time RT-PCR showed the highest sensitivity and specificity for MTC.

Comparison of LTBI treatment regimens for patients receiving anti-tumour necrosis factor therapy.

SETTING: A tertiary referral centre in South Korea. OBJECTIVE: To compare the completion rates and adverse drug reactions of three latent tuberculous infection (LTBI) treatment regimens for patients receiving anti-tumour necrosis factor (anti-TNF) therapy. DESIGN: A total of 408 patients were diagnosed with LTBI before receiving anti-TNF therapy between December 2004 and December 2013. Nine months of isoniazid (9H), 4 months of rifampicin (4H) or 3 months of isoniazid/rifampicin (3HR) were prescribed. The results were analysed retrospectively. RESULTS: The mean age of the 408 study subjects was 44 years; 258 (63.2%) were male. The 9H, 4R and 3HR treatment regimens were given to respectively 61 (15.0%), 139 (34.1%) and 208 (51.0%) patients. A total of 362 (88.7%) patients completed the treatment. The treatment completion rate was highest in patients receiving 3HR (94.2%). Of the 408 patients, 54 (13.2%) had one or more adverse drug reactions; their frequency was similar in the three groups. CONCLUSIONS: In patients receiving anti-TNF therapy, 3HR seems to be the most acceptable treatment regimen for LTBI, given its high completion rate and acceptable rate of adverse drug reactions.

Toll-like receptor 4 plays no role in susceptibility of mice to Mycobacterium tuberculosis infection.

Although various members of the pattern recognition Toll-like receptor (TLR) family have been implicated in host resistance to Mycobacterium tuberculosis infection, it remains unclear if the TLR4 receptor plays an important role. We demonstrate here that infection of TRL4-competent and TLR4-deficient mice on the C3H inbred mouse strain background had similar outcomes, measured in terms of the course of the disease, cell accumulation patterns in the lungs, and lung histopathology. These data argue against a significant role for TLR4 in immunity to tuberculosis in the mouse model.