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.

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.

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.

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.

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.

The 'either test positive' strategy for latent tuberculous infection before anti-tumour necrosis factor treatment.

SETTING: A ttertiary referral centre in South Korea. OBJECTIVES: The 'either test positive' strategy, incorporating both the tuberculin skin test (TST) and the T-SPOT(®).TB(T-SPOT) assay, was evaluated as a novel method for diagnosing latent tuberculous infection (LTBI) before treatment with anti-tumour necrosis factor (TNF) in patients with immune-mediated inflammatory diseases. DESIGN: From June 2008 to April 2012, 430 patients received anti-TNF treatment at our institution. TST and T-SPOT were performed simultaneously at baseline. LTBI was defined as a positive TST or a positive T-SPOT result. RESULTS: The positivity rates for the TST and T-SPOT assays were respectively 19.1% (82/430) and 44.2% (190/430), yielding an LTBI-positive rate of 48.6% (209/430). LTBI treatment was initiated in 46.0% (198/430) of patients and was completed by 89.4% (177/198). During follow-up (median 884 days), 0.9% (4/430) of the patients developed active tuberculosis (TB). All four TB patients were TST-negative at baseline, although two received LTBI treatment based on the baseline positive T-SPOT assay results. CONCLUSIONS: The either test positive strategy is a valid method for diagnosing LTBI before anti-TNF treatment, although it is not clear whether it is superior to other strategies.

Treatment outcomes and moxifloxacin susceptibility in ofloxacin-resistant multidrug-resistant tuberculosis.

SETTING: A tertiary referral centre in Seoul, South Korea. OBJECTIVE: To investigate the effect of moxifloxacin (MFX) susceptibility and later-generation fluoroquinolone (FQ) use on the treatment outcomes of ofloxacin (OFX) resistant multidrug-resistant tuberculosis (MDR-TB). DESIGN: Of 223 patients diagnosed with MDR-TB between January 2006 and December 2012, 70 (31.4%) patients with OFX-resistant MDR-TB were enrolled in this retrospective cohort study. Their treatment outcomes were analysed. RESULTS: The mean age (standard deviation) of the 70 patients was 40.6 (12.9) years; 43 (61.4%) were male and 26 (37.1%) had extensively drug-resistant TB. Of the 70 patients, 22 (31.4%) had MFX-susceptible TB, while the remaining 48 (68.6%) were MFX-resistant. The MFX-susceptible and -resistant groups were comparable in terms of baseline characteristics (including age, sex and radiological severity), and respectively 90.9% (20/22) and 70.8% (34/48) were treated with later-generation FQ-containing regimens (P = 0.074; mainly MFX [40/54, 74.1%]). Treatment success was achieved in 72.7% (16/22) of the MFX-susceptible patients and in 41.7% (20/48) of the MFX-resistant patients (P = 0.021). Treatment failure was significantly higher in the MFX-resistant group (41.7% [20/48] vs. 9.1% [2/22]; P = 0.006). CONCLUSION: Patients with OFX-resistant MDR-TB had significantly better treatment outcomes when susceptible to MFX. This probably reflects the effect of later-generation FQ treatment.

CT findings of pulmonary non-tuberculous mycobacterial infection in non-AIDS immunocompromised patients: a case-controlled comparison with immunocompetent patients.

OBJECTIVE: To describe CT findings of non-tuberculous mycobacteria (NTM) pulmonary infection in non-AIDS immunocompromised patients (ICPs) and to compare these findings with those in immunocompetent patients. METHODS: From July 2000 to August 2007, 369 patients (mean age 58.3 years; 169 males and 200 females) with pulmonary NTM infection were retrospectively reviewed. Of these 369 patients, 24 ICPs (mean age 64.8 years; 15 males and 9 females) were identified. 16 patients had diabetes mellitus, and 6 patients had received long-term steroid therapy. One had received solid organ transplantation and one had received high-dose chemotherapy for haematological disease. 24 age- and sex-matched immunocompetent patients (mean age 64.6 years; 15 males and 9 females) were selected as the control group from the same registry. CT images were reviewed in consensus by three chest radiologists, who were blinded to immune status. Each lung lobe was evaluated in terms of extent of the lesion, bronchiectasis, parenchymal opacity and the presence of ancillary findings. results: A total of 287 lobes were evaluated in ICPs and the control group. The ICPs showed a higher prevalence of ill-defined nodules, with cavities and large opacity >2 cm with/without cavity (p=0.03, 0.04 and 0.02, respectively). Regardless of the immune status, the most common CT findings were bronchiectasis and ill-defined nodules without cavity. CONCLUSION: The most common CT findings of pulmonary NTM infection in ICPs were bronchiectasis and ill-defined nodules, similar to those in the control group. Ill-defined nodules with cavity and large opacity >2 cm with/without cavity were more frequently found in ICPs. ADVANCES IN KNOWLEDGE: In patients affected by NTM infection, large opacities and cavitation in pulmonary nodules are more frequent in ICPs than in immunocompetent patients.

GenoType® MTBDRplus assay detection of drug-resistant tuberculosis in routine practice in Korea.

SETTING: Korea is an intermediate-burden country with high rates of tuberculosis (TB) drug resistance. OBJECTIVE: To evaluate the performance of the GenoType® MTBDRplus (MTBDR) assay in diagnosing drug-resistant TB in routine practice in Korea. DESIGN: The MTBDR assay was performed on 428 samples, and the results were retrospectively compared with the results of conventional drug susceptibility testing (DST). The interval between treatment and diagnosis of drug resistance was also compared. RESULTS: The sensitivity, specificity and positive and negative predictive values of the MTBDR assay were respectively 96.6%, 98.9%, 93.4% and 99.5% for the detection of rifampicin (RMP) resistance; 93.8%, 98.3%, 92.7% and 98.6% for isoniazid (INH) resistance; and 91.1%, 99.2%, 99.4% and 98.7% for multidrug-resistant TB (MDR-TB). The median interval between the start of anti-tuberculosis chemotherapy and the reporting of results was 88.9 days for conventional DST and 19.8 days for MTBDR using clinical specimens. CONCLUSION: The specificity of the MTBDR assay in detecting MDR-TB was very high, although the sensitivity in detecting INH resistance and MDR-TB was not optimal (<95%). Although the turnaround time in detecting drug resistance was dramatically reduced with MTBDR compared to conventional DST, more effort is needed to shorten the turnaround time.

Combined use of a TST and the T-SPOT®.TB assay for latent tuberculosis infection diagnosis before anti-TNF-α treatment.

BACKGROUND: Diagnosis of latent tuberculosis infection (LTBI) before anti-tumour-necrosis factor (anti-TNF) treatment is important. However, the tuberculin skin test (TST) has limitations, and the role of interferon-gamma release assays has not yet been determined. OBJECTIVE: To evaluate the combined use of TST and the T-SPOT(®).TB (T-SPOT) assay prior to anti-TNF treatment. METHODS: From July 2004 to March 2008, 281 patients were treated with anti-TNF agents. TST and T-SPOT were performed simultaneously at baseline. LTBI was defined as a positive TST of ≥10 mm induration or as a positive T-SPOT if TST was ≥5 mm but <10 mm. LTBI treatment was initiated, and patients were followed until August 2010. RESULTS: Positivity rates for TST and T-SPOT were respectively 33.6% (94/280) and 69.1% (186/269). LTBI treatment was initiated in 35.9% (101/281) of the patients, and active TB developed in 2.1% (6/281). Among the six TB patients, three were TST-negative at baseline and received no LTBI treatment, whereas all four who underwent T-SPOT showed positive results at baseline. CONCLUSION: In a TB-prevalent country, TST-defined LTBI diagnosis and treatment seem to be limited in preventing the development of TB before anti-TNF treatment. Further studies for T-SPOT alone or the combined use of TST and T-SPOT (either test positive strategy) for detecting LTBI are necessary.

Diagnostic sensitivity of culture and drug resistance patterns in Korean patients with intestinal tuberculosis.

SETTING: It is challenging to differentiate between intestinal tuberculosis (ITB) and Crohn's disease in areas where TB is still prevalent. The use of diagnostic tools and verifying the drug resistance patterns of ITB can be helpful for its correct diagnosis. OBJECTIVE: To determine the diagnostic sensitivity of a culture assay using colonoscopic biopsy specimens and the drug resistance patterns of Mycobacterium tuberculosis isolated from ITB. DESIGN: Data from 400 patients diagnosed with ITB were retrospectively analysed. RESULTS: Of the 400 patients, 170 (42.5%) were males; the median age at diagnosis was 40 years. The sensitivity of culture was 44.1% (145/329). Resistance to at least one anti-tuberculosis drug was identified in 13 (17.6%) and multidrug-resistant TB (MDR-TB) was diagnosed in two (2.7%) of the 74 patients for whom drug susceptibility testing was performed. Including M. tuberculosis isolated from respiratory specimens, the proportion of MDR-TB was 4.4% (5/113); previous anti-tuberculosis treatment was an independent risk factor for MDR-TB (26.7% vs. 1.0%, P < 0.01). CONCLUSION: Culture of colonoscopic biopsy specimens shows substantial diagnostic sensitivity; the frequency of MDR-TB is higher in previously treated cases than in new cases.

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.

Distinguishing tuberculosis from Mycobacterium avium complex disease using an interferon-gamma release assay.

SETTING: The QuantiFERON-TB Gold (QFT-G) test can be used to distinguish between tuberculosis (TB) and non-tuberculous mycobacterial disease, but a high background TB infection rate may pose a problem. Although the QuantiFERON-TB (QFT) test, the first-generation QFT-G test, employs a non-specific PPD antigen, avium sensitin is also used as a stimulating antigen. OBJECTIVE: To evaluate the utility of these two interferon gamma release assays (IGRAs), QFT-G and QFT, and the tuberculin skin test (TST), to differentiate TB from Mycobacterium avium complex (MAC) disease in an intermediate TB burden country. METHODS: We compared the diagnostic performance of these three tests in 38 prospectively enrolled patients with TB and 40 with MAC lung disease. RESULTS: The TST yielded positive results in 70.6% of TB and 47.5% of MAC patients; the proportions were respectively 89.5% and 34.3% for QFT-G and 86.8% and 35.3% for QFT. The three tests were of similar accuracy, sensitivity and specificity in diagnosing TB. CONCLUSION: Our findings indicate that the TST and IGRAs could not discriminate between active TB and MAC disease or latent TB infection in a TB-endemic area.