There are limited therapeutic options for extensively drug-resistant tuberculosis. In this study from South Korea, linezolid was shown to have some activity in treating resistant tuberculosis; ...however, its use was associated with clinically significant toxicity.
Linezolid (Zyvox, Pfizer) was approved in 2000 for drug-resistant, gram-positive bacterial infections.
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A member of the oxazolidinone antibiotic class, linezolid inhibits protein synthesis by binding the 23S ribosomal RNA (rRNA) portion of the bacterial 50S ribosomal subunit.
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In adults, linezolid is administered at a dose of 600 mg twice daily, with phase 3 and postmarketing trials showing an acceptable side-effect and adverse-event profile during the FDA-approved 28 days of therapy.
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Data on longer-term use are limited, but serious neuropathies (e.g., peripheral and optic neuropathies), myelosuppression, and hyperlactatemia have been observed
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and are considered to be related to the inhibition . . .
Early bactericidal activity studies monitor daily sputum bacterial counts in individuals with tuberculosis (TB) for 14 days during experimental drug treatment. The rate of change in sputum bacterial ...load over time provides an informative, but imperfect, estimate of drug activity and is considered a critical step in development of new TB drugs. In this clinical study, 160 participants with TB received isoniazid, pyrazinamide, or rifampicin, components of first-line chemotherapy, and moxifloxacin individually and in combination. In addition to standard bacterial enumeration in sputum, participants underwent 2-deoxy-2-
Ffluoro-d-glucose positron emission tomography and computerized tomography (
FFDG-PET/CT) at the beginning and end of the 14-day drug treatment. Quantitating radiological responses to drug treatment provided comparative single and combination drug activity measures across lung lesion types that correlated more closely with established clinical outcomes when combined with sputum enumeration compared to sputum enumeration alone. Rifampicin and rifampicin-containing drug combinations were most effective in reducing both lung lesion volume measured by CT imaging and lesion-associated inflammation measured by PET imaging. Moxifloxacin was not superior to rifampicin in any measure by PET/CT imaging, consistent with its performance in recent phase 3 clinical trials. PET/CT imaging revealed synergy between isoniazid and pyrazinamide and demonstrated that the activity of pyrazinamide was limited to lung lesion, showing the highest FDG uptake during the first 2 weeks of drug treatment.
FFDG-PET/CT imaging may be useful for measuring the activity of single drugs and drug combinations during evaluation of potential new TB drug regimens before phase 3 trials.
Tuberculosis remains an important health concern in many countries. The aim of this study was to identify predictors of unfavorable outcomes at the end of treatment (EOT) and at the end of study ...(EOS; 40 months after EOT) in South Korea.
New or previously treated tuberculosis patients were recruited into a prospective observational cohort study at two hospitals in South Korea. To identify predictors of unfavorable outcomes at EOT and EOS, logistic regression analysis was performed.
The proportion of multidrug-resistant tuberculosis (MDR-TB) was 8.2% in new cases and 57.9% in previously treated cases. Of new cases, 68.6% were cured, as were 40.7% of previously treated cases. At EOT, diabetes, ≥3 previous TB episodes, ≥1 significant regimen change, and MDR-TB were significantly associated with treatment failure or death. At EOS, age ≥35, body-mass index (BMI) <18.5, diabetes, and MDR-TB were significantly associated with treatment failure, death, or relapse. Among cases that were cured at EOT, age ≥50 and a BMI <18.5 were associated with subsequent death or relapse during follow-up to EOS. Treatment interruption was associated with service sector employees or laborers, bilateral lesions on chest X-ray, and previous treatment failure or treatment interruption history.
Risk factors for poor treatment outcomes at EOT and EOS include both patient factors (diabetes status, age, BMI) and disease factors (history of multiple previous treatment episodes, MDR-TB). In this longitudinal, observational cohort study, diabetes mellitus and MDR-TB were risk factors for poor treatment outcomes and relapse. Measures to help ensure that the first tuberculosis treatment episode is also the last one may improve treatment outcomes.
ClinicalTrials.gov ID: NCT00341601.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Long-term linezolid use is limited by mitochondrial toxicity-associated adverse events (AEs). Within a prospective, randomized controlled trial of linezolid to treat chronic extensively ...drug-resistant tuberculosis, we serially monitored the translational competence of mitochondria isolated from peripheral blood of participants by determining the cytochrome c oxidase/citrate synthase activity ratio. We compared this ratio with AEs associated with mitochondrial dysfunction. Linezolid trough concentrations were determined for 38 participants at both 600mg and 300mg doses. Those on 600mg had a significantly higher risk of AE than those on 300mg (HR 3·10, 95% CI 1·23–7·86). Mean mitochondrial function levels were significantly higher in patients before starting linezolid compared to their concentrations on 300mg (P=0·004) or 600mg (P<0·0001). Increasing mean linezolid trough concentrations were associated with lower mitochondrial function levels (Spearman's ρ=−0.48; P=0.005). Mitochondrial toxicity risk increased with increasing linezolid trough concentrations, with all patients with mean linezolid trough >2μg/ml developing an AE related to mitochondrial toxicity, whether on 300mg or 600mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use.
•Linezolid is increasingly being used to treat drug-resistant tuberculosis.•Long-term use of linezolid is limited by mitochondrial toxicity-associated adverse events.•We examined linezolid trough concentrations in chronic XDR-TB patients on linezolid.•Mitochondrial toxicity risk increased with increasing linezolid trough concentrations.•Therapeutic drug monitoring may help avoid mitochondrial toxicities in long-term linezolid treatment.
Linezolid is increasingly being used to treat drug resistant tuberculosis, with the beneficial effect of linezolid tempered by the mitochondrial toxicity-associated adverse events seen with long-term use. Within a prospective, randomized controlled trial of linezolid for the treatment of chronic, extensively drug-resistant tuberculosis, we found that the risk of mitochondrial toxicity increased with increasing linezolid trough concentrations, with all patients with a mean trough >2μg/ml developing an adverse event related to mitochondrial toxicity. If our results are confirmed by other studies, therapeutic drug monitoring may become an important component of long-term linezolid treatment to prevent mitochondrial toxicity-related adverse events.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Definitive clinical trials of new chemotherapies for treating tuberculosis (TB) require following subjects until at least 6 months after treatment discontinuation to assess for durable cure, making ...these trials expensive and lengthy. Surrogate endpoints relating to treatment failure and relapse are currently limited to sputum microbiology, which has limited sensitivity and specificity. We prospectively assessed radiographic changes using 2-deoxy-2-(18)F-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) at 2 and 6 months (CT only) in a cohort of subjects with multidrug-resistant TB, who were treated with second-line TB therapy for 2 years and then followed for an additional 6 months. CT scans were read semiquantitatively by radiologists and were computationally evaluated using custom software to provide volumetric assessment of TB-associated abnormalities. CT scans at 6 months (but not 2 months) assessed by radiologist readers were predictive of outcomes, and changes in computed abnormal volumes were predictive of drug response at both time points. Quantitative changes in FDG uptake 2 months after starting treatment were associated with long-term outcomes. In this cohort, some radiologic markers were more sensitive than conventional sputum microbiology in distinguishing successful from unsuccessful treatment. These results support the potential of imaging scans as possible surrogate endpoints in clinical trials of new TB drug regimens. Larger cohorts confirming these results are needed.
Background. Extensively drug‐resistant (XDR) tuberculosis (TB) is a major public health threat in South Korea. Methods. We analyzed baseline epidemiological data for 250 patients enrolled in an ...ongoing prospective observational study of TB at a large tertiary referral hospital in South Korea. Results. Twenty‐six subjects with XDR TB were identified; all were patients who had previously received TB therapy. Cumulative previous treatment duration (range, 18–34 months; odds ratio OR, 5.6; 95% confidence interval CI, 1.0–59), number of previously received second‐line anti‐TB drugs (OR, 1.3; 95% CI, 1.1–1.5), and female sex (OR, 3.2; 95% CI, 1.1–8.3) were significantly associated with XDR TB in crude analyses. After controlling for other factors in a multivariable model, cumulative previous treatment duration remained significantly associated with XDR TB (OR, 5.8; 95% CI, 1.0–61). Subjects with XDR TB were more likely to produce culture‐positive sputum at 6 months, compared with patients with non—multidrug resistant TB (risk ratio, 13; 95% CI, 5.1–53). Kanamycin resistance was found to be predictive of 6‐month culture positivity after adjustment for ofloxacin and streptomycin resistance (risk ratio, 3.9; 95% CI, 1.9–11). Conclusions. XDR TB was found to be associated with the cumulative duration of previous treatment with second‐line TB drugs among subjects in a tertiary care TB hospital. Patients with XDR TB were more likely to not respond to therapy, and successful conversion of sputum culture results to negative was correlated with initial susceptibility to both fluoroquinolones and kanamycin but not to streptomycin.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Tuberculosis (TB) remains an immense public health problem in the Republic of Korea despite a more than fivefold decrease in the prevalence of the disease over the last 3 decades. The rise in ...drug-resistant TB has compounded the situation. We analyzed 208 clinical isolates of M. tuberculosis from the National Masan Tuberculosis Hospital by spoligotyping, IS6110 restriction fragment length polymorphism (RFLP), and 24-locus-based mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing to assess the diversity and transmission dynamics of the tubercle bacilli in the Republic of Korea. The majority of the isolates (97.1%) belonged to the Beijing genotype. Cluster analysis by MIRU-VNTR yielded a low clustering rate of 22.3%, with most of the clusters comprising isolates with diverse drug resistance patterns. The discriminatory capacity of the typing methods was high for RFLP and MIRU-VNTR (allelic diversity h = 0.99) but low for spoligotyping (h = 0.31). Although analysis of 19 MIRU-VNTR loci was needed to achieve maximum discrimination, an informative set of 8 loci (960, 1955, 2163b, 2165, 2996, 3192, 4052, and 4348) (h = 0.98) that was able to differentiate most of the closely related strains was identified. These findings suggest that 24-locus-based MIRU-VNTR typing is a likely suitable alternative to RFLP to differentiate clinical isolates in this setting, which is dominated by M. tuberculosis Beijing strains. Within the study limits, our results also suggest that the problem of drug-resistant TB in the Republic of Korea may be largely due to acquired resistance as opposed to transmission.
Direct bronchial spread of tuberculosis was extensively described in pre-antibiotic human pathology literature but this description has been overlooked in the post-antibiotic era, in which most ...pathology data come from animal models that emphasise the granuloma. Modern techniques, such as 18F2-fluoro-2-deoxy-D-glucose (FDG) PET-CT scans, might provide further insight. Our aim was to understand normal early tuberculosis resolution patterns on pulmonary PET-CT scans in treated patients with tuberculosis who were subsequently cured.
In this observational analysis, we analysed data from PredictTB, an ongoing, prospective, randomised clinical trial that examined sequential baseline and week 4 FDG-PET-CT scans from participants successfully treated (sputum culture negative 18 months after enrolment) for drug-susceptible pulmonary tuberculosis in South Africa and China. Participants who were aged 18–75 years, GeneXpert MTB/RIF positive for tuberculosis and negative for rifampicin resistance, had not yet started tuberculosis treatment, had not been treated for active tuberculosis within the previous 3 years, and met basic safety laboratory criteria were included and participants with diabetes, HIV infection, or with extrapulmonary tuberculosis including pleural tuberculosis were excluded. Scans were assessed by two readers for the location of tuberculosis lesions (eg, cavities and consolidations), bronchial thickening patterns, and changes from baseline to week 4 of treatment.
Among the first 124 participants (enrolled from June 22, 2017, to Sept 27, 2018) who were successfully treated, 161 primarily apical cavitary lesions were identified at baseline. Bronchial thickening and inflammation linking non-cavitary consolidative lesions to cavities were observed in 121 (98%) of 124 participants' baseline PET-CT scans. After 4 weeks of treatment, 21 (17%) of 124 participants had new or expanding lesions linked to cavities via bronchial inflammation that were not present at baseline, particularly participants with two or more cavities at baseline and participants from South Africa.
In participants with pulmonary tuberculosis who were subsequently cured, the location of cavitary and non-cavitary lesions at baseline and new lesions at week 4 of treatment suggest a cavitary origin of disease and bronchial spread through the lungs. Bronchial spread from cavities might play a larger role in the spread of pulmonary tuberculosis than has been appreciated. Elucidating cavity lesion dynamics and Mycobacterium tuberculosis viability within cavities might better explain treatment outcomes and why some patients are cured and others relapse.
Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials Partnership, China Ministry of Science and Technology, National Natural Science Foundation of China, and National Institutes of Health.
For the Chinese, Afrikaans and Xhosa translations of the abstract see Supplementary Materials section.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
: By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms ...consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01). We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment.
: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C.
: Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified.
NCT02821832.
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