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LITERATURE AND PUBLICATIONS

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RECENT PUBLICATIONS

From Our April 2022 Newsletter

Disadvantage and the Experience of Treatment for Multidrug-Resistant Tuberculosis (MDR-TB).
 
SSM Qual Res Health. 2022 Dec;2:100042. doi: 10.1016/j.ssmqr.2022.100042. Epub 2022 Jan 28.
 
Taylor HA(1), Dowdy DW(2), Searle AR(3), Stennett AL(3), Dukhanin V(1), Zwerling AA(4), Merritt MW(5).

In the present research, we aimed to demonstrate how exploring patients’ treatment experiences may help decision makers better understand and pay attention to social impacts of health interventions. We take multi-drug-resistant tuberculosis (MDR-TB) as a paradigm case of a disease that disproportionately affects people already living with disadvantage and for which treatment itself is extremely burdensome. We conducted a total of 140 in-depth interviews with 53 patients, 56 health care providers, and 31 community members.We found that the burdens of MDR-TB treatment described by respondents fell into two categories: those related to managing the medications (n=77) and those related to other aspects of completing treatment (n=52). Respondents also identified social support (n=121), access to essential goods and services (n=74), personal motivation (n=52), and patient knowledge about the relationship between treatment completion and potential cure (n=44) as factors that may either lighten treatment burdens and facilitate completion or add to treatment burdens and inhibit completion. When asked specifically about preferences for MDR-TB treatment advances, respondents favored a shorter course of treatment (n=52) and fewer pills (n=51) over fewer side effects (n=18). According a pattern analysis applied across the data using the core dimensions of social justice we found that experiencing the side effects of MDR-TB treatment tends uniformly to erode all three dimensions. Our findings demonstrate how systematic collection of data about patients’ lived experience can inform decision-making regarding the social impacts of health interventions in at-risk community living with a high-burden of disease from the perspective of disadvantage.
 
DOI: 10.1016/j.ssmqr.2022.100042
PMCID: PMC8896740
PMID: 35252955

Investigation of Clofazimine Resistance and Genetic Mutations in Drug-Resistant Mycobacterium tuberculosis Isolates.
 

J Clin Med. 2022 Mar 30;11(7):1927. doi: 10.3390/jcm11071927.
 
Park S(1), Jung J(1), Kim J(1), Han SB(2), Ryoo S(1).
 
Recently, as clofazimine (CFZ) showed a good therapeutic effect in treating multi-drug-resistant tuberculosis (MDR-TB), the anti-tuberculosis activity and resistance were re-focused. Here, we investigated the CFZ resistance and genetic mutations of drug-resistant Mycobacterium tuberculosis (DR-Mtb) isolates to improve the diagnosis and treatment of drug-resistant TB patients. The minimal inhibitory concentration (MIC) of CFZ was examined by resazurin microtiter assay (REMA) with two reference strains and 122 clinical isolates from Korea. The cause of CFZ resistance was investigated in relation to the therapeutic history of patients. Mutations of Rv0678, Rv1979c and pepQ of CFZ resistant isolates were analyzed by PCR and DNA sequencing. The rate of CFZ resistance with MIC > 1 mg/L was 4.1% in drug-resistant Mtb isolates. The cause of CFZ resistance was not related to treatment with CFZ or bedaquiline. A CFZ susceptibility test should be conducted regardless of dugs use history. The four novel mutation sites were identified in the Rv0678 and pepQ genes related to CFZ resistance in this study.
 
DOI: 10.3390/jcm11071927
PMCID: PMC9000149
PMID: 35407536
 
Delamanid or pretomanid? A Solomonic judgement!
 
J Antimicrob Chemother. 2022 Mar 31;77(4):880-902. doi: 10.1093/jac/dkab505.
 
Mudde SE(1), Upton AM(2), Lenaerts A(3), Bax HI(1)(4), De Steenwinkel JEM(1).
 
Given the low treatment success rates of drug-resistant tuberculosis (TB), novel TB drugs are urgently needed. The landscape of TB treatment has changed considerably over the last decade with the approval of three new compounds: bedaquiline, delamanid and pretomanid. Of these, delamanid and pretomanid belong to the same class of drugs, the nitroimidazoles. In order to close the knowledge gap on how delamanid and pretomanid compare with each other, we summarize the main findings from preclinical research on these two compounds. We discuss the compound identification, mechanism of action, drug resistance, in vitro activity, in vivo pharmacokinetic profiles, and preclinical in vivo activity and efficacy. Although delamanid and pretomanid share many similarities, several differences could be identified. One finding of particular interest is that certain Mycobacterium tuberculosis isolates have been described that are resistant to either delamanid or pretomanid, but with preserved susceptibility to the other compound. This might imply that delamanid and pretomanid could replace one another in certain regimens. Regarding bactericidal activity, based on in vitro and preclinical in vivo activity, delamanid has lower MICs and higher mycobacterial load reductions at lower drug concentrations and doses compared with pretomanid. However, when comparing in vivo preclinical bactericidal activity at dose levels equivalent to currently approved clinical doses based on drug exposure, this difference in activity between the two compounds fades. However, it is important to interpret these comparative results with caution knowing the variability inherent in preclinical in vitro and in vivo models.
 
© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.
 
DOI: 10.1093/jac/dkab505
PMCID: PMC8969540
PMID: 35089314 [Indexed for MEDLINE]
 
Linezolid toxicity in patients with drug-resistant tuberculosis: a prospective cohort study.
 
J Antimicrob Chemother. 2022 Mar 31;77(4):1146-1154. doi: 10.1093/jac/dkac019.
 
Wasserman S(1)(2), Brust JCM(3), Abdelwahab MT(4), Little F(5), Denti P(4), Wiesner L(4), Gandhi NR(6)(7), Meintjes G(1)(8), Maartens G(1)(4).
 
BACKGROUND: Linezolid is recommended for treating drug-resistant TB. Adverse events are a concern to prescribers but have not been systematically studied at the standard dose, and the relationship between linezolid exposure and clinical toxicity is not completely elucidated.
PATIENTS AND METHODS: We conducted an observational cohort study to describe the incidence and determinants of linezolid toxicity, and to determine a drug exposure threshold for toxicity, among patients with rifampicin-resistant TB in South Africa. Linezolid exposures were estimated from a population  pharmacokinetic model. Mixed-effects modelling was used to analyse toxicity outcomes.
RESULTS: One hundred and fifty one participants, 63% HIV positive, were enrolled and followed for a median of 86 weeks. Linezolid was permanently discontinued for toxicity in 32 (21%) participants. Grade 3 or 4 linezolid-associated adverse events occurred in 21 (14%) participants. Mean haemoglobin concentrations increased with time on treatment (0.03 g/dL per week; 95% CI 0.02-0.03). Linezolid trough concentration, male sex and age (but not HIV positivity) were independently associated with a decrease in haemoglobin >2 g/dL. Trough 
linezolid concentration of 2.5 mg/L or higher resulted in optimal model performance to describe changing haemoglobin and treatment-emergent anaemia (adjusted OR 2.9; 95% CI 1.3-6.8). SNPs 2706A > G and 3010G > A in mitochondrial DNA were not associated with linezolid toxicity.
CONCLUSIONS: Permanent discontinuation of linezolid was common, but linezolid-containing therapy was associated with average improvement in toxicity measures. HIV co-infection was not independently associated with linezolid toxicity. Linezolid trough concentration of 2.5 mg/L should be evaluated as a target for therapeutic drug monitoring.
 
© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
 
DOI: 10.1093/jac/dkac019
PMCID: PMC7612559
PMID: 35134182 [Indexed for MEDLINE]
 
Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment.
 
Eur Respir J. 2022 Apr 14;59(4):2200166. doi: 10.1183/13993003.00166-2022. Print 2022 Apr.
 
Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti- TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance.
 
DOI: 10.1183/13993003.00166-2022
PMID: 35422426 [Indexed for MEDLINE]

Assessment of epidemiological and genetic characteristics and clinical outcomes of resistance to bedaquiline in patients treated for rifampicin-resistant tuberculosis: a cross-sectional and longitudinal study.
 
Lancet Infect Dis. 2022 Apr;22(4):496-506. doi: 10.1016/S1473-3099(21)00470-9. Epub 2021 Nov 12.
 
Ismail NA(1), Omar SV(2), Moultrie H(3), Bhyat Z(3), Conradie F(4), Enwerem M(5), Ferreira H(6), Hughes J(7), Joseph L(3), Kock Y(8), Letsaolo V(3), Maartens G(9), Meintjes G(9), Ngcamu D(3), Okozi N(3), Padanilam X(10), Reuter A(11), Romero R(12), Schaaf S(7), Te Riele J(13), Variava E(14), van der Meulen M(3), Ismail F(15), Ndjeka N(8).
 
BACKGROUND: Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated 
with bedaquiline resistance, using data from South Africa (2015-19).
METHODS: Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes.
FINDINGS: Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR.
INTERPRETATION: Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential.
FUNDING: National Institute for Communicable Diseases of South Africa.
 
Copyright © 2022 Elsevier Ltd. All rights reserved.
 
DOI: 10.1016/S1473-3099(21)00470-9
PMID: 34780706 [Indexed for MEDLINE]

From Our March 2022 Newsletter

25 years of surveillance of drug-resistant tuberculosis: achievements, challenges, and way forward.
 

Lancet Infect Dis. 2022 Mar 3:S1473-3099(21)00808-2. doi: 10.1016/S1473-3099(21)00808-2. Online ahead of print.
 
Dean AS(1), Tosas Auguet O(2), Glaziou P(2), Zignol M(2), Ismail N(2), Kasaeva T(2), Floyd K(2).
 
Tuberculosis is second only to COVID-19 as a cause of death from a single infectious agent. In 2020, almost 10 million people were estimated to have developed tuberculosis and it caused 1·5 million deaths. Around a quarter of deaths caused by antimicrobial resistance are due to rifampicin-resistant tuberculosis. Antimicrobial resistance surveillance systems for many bacterial pathogens are still in the early stages of implementation in many countries, and do not yet allow for the estimation of disease burden at the national level. In this Personal View, we present the achievements, challenges, and way forward for the oldest and largest global antimicrobial resistance surveillance system. Hosted by WHO since 1994, the Global Project on Anti-Tuberculosis Drug Resistance Surveillance has served as a platform for the evaluation of the trends in anti-tuberculosis drug resistance for over 25 years at country, regional, and global levels. With an estimated 465 000 incident cases of multidrug-resistant and rifampicin-resistant tuberculosis in 2019, drug-resistant tuberculosis remains a public health crisis. The COVID-19 pandemic has reversed years of progress in providing essential tuberculosis services and reducing disease burden. The number of people diagnosed with drug-resistant tuberculosis has dropped by 22% since before the pandemic, and the number of patients provided with treatment for drug-resistant tuberculosis has dropped by 15%. Now more than ever, closing gaps in the detection of drug-resistant tuberculosis requires investment in research and development of new diagnostic tools and their rollout, expansion of sample transport systems, and the implementation of data connectivity solutions.
 
Copyright © 2022 World Health Organization. Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/S1473-3099(21)00808-2
PMCID: PMC8893725
PMID: 35248168
 
Treatment outcomes among childhood extensively drug-resistant tuberculosis patients in Pakistan.
 

ERJ Open Res. 2022 Feb 21;8(1):00551-2021. doi: 10.1183/23120541.00551-2021. eCollection 2022 Jan.
 
Abubakar M(1), Ahmad N(1), Atif M(2), Hayat Khan A(3), Ghafoor A(4).
 
Treatment outcomes of childhood XDR-TB patients in Pakistan are better than in adult patients but still disappointing https://bit.ly/3rkQ9sw.
 
Copyright ©The authors 2022.
 
DOI: 10.1183/23120541.00551-2021
PMCID: PMC8859504
PMID: 35198629
 
Safety and effectiveness outcomes from a 14-country cohort of patients with multi-drug resistant tuberculosis treated concomitantly with bedaquiline, delamanid and other second-line drugs.
 
Clin Infect Dis. 2022 Mar 4:ciac176. doi: 10.1093/cid/ciac176. Online ahead of print.
 
Huerga H(1), Khan U(2), Bastard M(1), Mitnick CD(3)(4)(5), Lachenal N(6), Khan PY(2)(7), Seung KJ(3)(4)(5), Melikyan N(1), Ahmed S(8), Rich ML(3)(4)(5), Varaine F(9), Osso E(3)(6), Rashitov M(10), Salahuddin N(11), Salia G(12), Sánchez E(13), Serobyan A(14), Siddiqui MR(15), Tefera DG(16), Vetushko D(17), Yeghiazaryan L(18), Holtzman D(19), Islam S(20), Kumsa A(21), Leblanc GJ(22), Leonovich O(23), Mamsa S(20), Manzur-Ul-Alam M(24), Myint Z(25), Padayachee S(26), Franke MF(3), Hewison C(9); endTB study observational study team.
 
BACKGROUND: Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet, this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.
METHODS: We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.
RESULTS: Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died and 7.2% experienced treatment failure.
CONCLUSIONS: Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.
 
© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.
 
DOI: 10.1093/cid/ciac176
PMID: 35243494
 
Bedaquiline adherence measured by electronic dose monitoring predicts clinical outcomes in the treatment of patients with multidrug-resistant tuberculosis and HIV/AIDS.
 
J Acquir Immune Defic Syndr. 2022 Feb 21. doi: 10.1097/QAI.0000000000002940. Online ahead of print.
 
O'Donnell MR(1), Padayatchi N, Wolf A, Zelnick J, Daftary A, Orrell C, Nimmo C, Baldwin M, Boodhram R, Maharaj B, Amico KR, Naidoo K, Friedland G.
 
BACKGROUND: Novel regimens have revolutionized multidrug-resistant tuberculosis (MDR-TB) treatment; however, medication adherence remains challenging and poorly characterized. We hypothesized that bedaquiline adherence, measured using electronic dose monitoring, would predict MDR-TB treatment outcomes.
SETTING: Prospective cohort study in KwaZulu-Natal, South Africa.
METHODS: Adults with MDR-TB and HIV initiating bedaquiline and on antiretroviral therapy (ART) were eligible. Separate electronic dose monitoring devices measured bedaquiline and ART adherence through six months, calculated as observed versus expected doses. Whole genome sequencing was performed to identify bedaquiline resistance-associated variants.
RESULTS: From November 2016 through February 2018, 199 participants with MDR-TB and HIV were enrolled and followed through treatment completion (median 17.2 months IQR 12.2-19.6). Median bedaquiline adherence was higher than ART adherence (97 vs. 89%, p<0.001), but correlated (r2=0.68, p<0.001). High bedaquiline adherence (≥90%) compared to lower adherence was associated with improved rates of end of treatment successful outcome (83.4% vs. 46.3%, p<0.001), decreased mortality (11.0% vs. 29.6% p=0.004), and improved retention in care through end of treatment (94.5% vs. 79.6% p=0.002). Modelling identified a highly significant, but linear association between bedaquiline adherence and outcome. On multivariable analysis, bedaquiline adherence was independently associated with mortality and outcome. Bedaquiline resistance-associated variants were seen in 12% (7/57) of sequenced isolates (7% baseline, 5% emergent) with only 28.6% experiencing successful treatment outcome.
CONCLUSIONS: Bedaquiline adherence through 6-months independently predicted end of MDR-TB treatment outcome, but a specific bedaquiline adherence threshold was not identified. Interventions to optimize bedaquiline adherence are urgently needed to improve MDR-TB HIV treatment outcomes.
 
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
 
DOI: 10.1097/QAI.0000000000002940
PMID: 35195572

 

From Our February 2022 Newsletter

 

Delamanid or pretomanid? A Solomonic judgement!
 
J Antimicrob Chemother. 2022 Jan 28:dkab505. doi: 10.1093/jac/dkab505. Online 
ahead of print.
 
Mudde SE(1), Upton AM(2), Lenaerts A(3), Bax HI(1)(4), De Steenwinkel JEM(1).
 
Given the low treatment success rates of drug-resistant tuberculosis (TB), novel TB drugs are urgently needed. The landscape of TB treatment has changed considerably over the last decade with the approval of three new compounds: bedaquiline, delamanid and pretomanid. Of these, delamanid and pretomanid belong to the same class of drugs, the nitroimidazoles. In order to close the knowledge gap on how delamanid and pretomanid compare with each other, we summarize the main findings from preclinical research on these two compounds. We discuss the compound identification, mechanism of action, drug resistance, in vitro activity, in vivo pharmacokinetic profiles, and preclinical in vivo activity and efficacy. Although delamanid and pretomanid share many similarities, several differences could be identified. One finding of particular interest is that certain Mycobacterium tuberculosis isolates have been described that are resistant to either delamanid or pretomanid, but with preserved susceptibility to the other compound. This might imply that delamanid and pretomanid could replace one another in certain regimens. Regarding bactericidal activity, based on in vitro and preclinical in vivo activity, delamanid has lower MICs and higher mycobacterial load reductions at lower drug concentrations and doses compared with pretomanid. However, when comparing in vivo preclinical bactericidal activity at dose levels equivalent to currently approved clinical doses based on drug exposure, this difference in activity between the two compounds fades. However, it is important to interpret these comparative results with caution knowing the variability inherent in preclinical in vitro and in vivo models.
 
© The Author(s) 2022. Published by Oxford University Press on behalf of British 
Society for Antimicrobial Chemotherapy.
 
DOI: 10.1093/jac/dkab505
PMID: 35089314

Model-Based Efficacy and Toxicity Comparisons of Moxifloxacin for Multidrug-Resistant Tuberculosis.

Open Forum Infect Dis. 2021 Dec 29;9(3):ofab660. doi: 10.1093/ofid/ofab660. 
eCollection 2022 Mar.
 
Yun HY(1), Chang V(2), Radtke KK(2), Wang Q(2), Strydom N(2), Chang MJ(3)(4)(5), Savic RM(2).
 
BACKGROUND: Moxifloxacin (MOX) is used as a first-choice drug to treat multidrug-resistant tuberculosis (MDR-TB); however, evidence-based dosing optimization should be strengthened by integrative analysis. The primary goal of this study was to evaluate MOX efficacy and toxicity using integrative model-based approaches in MDR-TB patients.
METHODS: In total, 113 MDR-TB patients from 5 different clinical trials were analyzed for the development of a population pharmacokinetics (PK) model. A final population PK model was merged with a previously developed lung-lesion distribution and QT prolongation model. Monte Carlo simulation was used to calculate the probability target attainment value based on concentration. An area under the concentration-time curve (AUC)-based target was identified as the minimum inhibitory concentration (MIC) of MOX isolated from MDR-TB patients.
RESULTS: The presence of human immunodeficiency virus (HIV) increased clearance by 32.7% and decreased the AUC by 27.4%, compared with HIV-negative MDR-TB patients. A daily dose of 800 mg or a 400-mg, twice-daily dose of MOX is expected to be effective in MDR-TB patients with an MIC of ≤0.25 µg/mL, regardless of PK differences resulting from the presence of HIV. The effect of MOX in HIV positive MDR-TB patients tended to be decreased dramatically from 0.5 µg/mL, in contrast to the findings in HIV-negative patients. A regimen of twice-daily doses of 400 mg should be considered safer than an 800-mg once-daily dosing regimen, because of the narrow fluctuation of concentrations.
CONCLUSIONS: Our results suggest that a 400-mg, twice-daily dose of MOX is an optimal dosing regimen for MDR-TB patients because it provides superior efficacy and safety.
 
© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
 
DOI: 10.1093/ofid/ofab660
PMCID: PMC8825669
PMID: 35146045
 
Increased Moxifloxacin Dosing Among Patients With Multidrug-Resistant Tuberculosis With Low-Level Resistance to Moxifloxacin Did Not Improve Treatment Outcomes in a Tertiary Care Center in Mumbai, India.
 

Open Forum Infect Dis. 2021 Dec 23;9(2):ofab615. doi: 10.1093/ofid/ofab615. 
eCollection 2022 Feb.
 
Tornheim JA(1), Udwadia ZF(2), Arora PR(3), Gajjar I(3), Sharma S(3), Karane 
M(3), Sawant N(3), Kharat N(3), Blum AJ(4), Shivakumar SVBY(5), Gupte AN(1), 
Gupte N(1)(5), Mullerpattan JB(2), Pinto LM(2), Ashavaid TF(3), Gupta A(1)(6), 
Rodrigues C(7).
 
BACKGROUND: Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available.
METHODS: We conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5 µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600 mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable Cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes.
RESULTS: Of 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200 [56.5%]), which was similar between groups (56.7% vs 54.0%, P = .74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted (hazard ratio [HR], 1.2 [95% confidence interval {CI}, .6-2.4]) or adjusted (HR, 0.8 [95% CI, .5-1.4]) models but was associated with joint pain (HR, 3.2 [95% CI, 1.2-8.8]).
CONCLUSIONS: In a large observational cohort, adding high-dose (600 mg) moxifloxacin to a drug susceptibility test-based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin-resistant MDR-TB.
 
© The Author(s) 2021. Published by Oxford University Press on behalf of 
Infectious Diseases Society of America.
 
DOI: 10.1093/ofid/ofab615
PMCID: PMC8794589
PMID: 35097152

An All-Oral 6-Month Regimen for Multidrug-Resistant TB (the NExT Study): A Multicenter, Randomized Controlled Trial.
 
Am J Respir Crit Care Med. 2022 Feb 17. doi: 10.1164/rccm.202107-1779OC. Online ahead of print.
 
Esmail A(1)(2), Oelofse S(3)(2), Lombard C(4)(5), Perumal R(3)(2), Mbuthini 
L(3), Goolam Mahomed A(6), Variava E(7)(8), Black J(9), Oluboyo P(10), Gwentshu 
N(11), Ngam E(11), Ackerman T(12), Marais L(13), Mottay L(3)(2), Meier S(14)(2), 
Pooran A(3)(2), Tomasicchio M(3)(15), Te Riele J(16), Derendinger B(17), Ndjeka 
N(18), Maartens G(19), Warren R(20), Martinson N(21)(22), Dheda K(23)(2)(24).
 
Rationale/objectives: Improving treatment outcomes, reducing drug toxicity, avoiding injectable agents, and shortening the treatment duration to 6-months (approximating that of rifampicin-susceptible tuberculosis) remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB).
METHODS: We conducted a multicentre randomised controlled trial in adults with MDR/RR-TB (i.e. without resistance to fluoroquinolones or aminoglycosides). Participants were randomly assigned (1:1 ratio) to a ~6-month all-oral regimen that included levofloxacin, bedaquiline and linezolid, or the standard-of-care ≥ 9-month WHO-approved injectable-based regimen. The primary endpoint was a favourable WHO-defined treatment outcome 24 months after treatment initiation.
MAIN RESULTS: 93 of 111 participants randomised were included in the modified intention-to-treat analysis; 51 (55%) were HIV co-infected (median CD4 count 158 cells/mL). Participants in the intervention arm were 2.2 times more likely to experience a favourable 24-month outcome than participants in the standard-of-care arm [RR 2.2 (1.2-4.1); p=0.006]. Toxicity-related drug substitution occurred more frequently in the standard-of-care arm [(65·9% (29/44) versus 36·7% (18/49), p= 0·001)]; 79.3% (23/29) due to kanamycin (mainly hearing loss; replaced by bedaquiline) in the standard-of-care arm, and 83·3% (15/18) due to linezolid (mainly anaemia) in the interventional arm. Culture conversion was significantly better in the intervention arm [HR 2.6 (1.4-4.9); p= 0.003] after censoring those with bedaquiline replacement in the standard-of-care arm.
CONCLUSIONS: An all-oral 6-month levofloxacin, bedaquiline and linezolid-containing MDR/RR-TB regimen was associated with significantly improved 24-month treatment outcomes compared with traditional injectable-containing regimens. However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02454205.
 
DOI: 10.1164/rccm.202107-1779OC
PMID: 35175905
 
Feasibility of a "Salvage Regimen" Using Home-based Intravenous Meropenem Therapy With a Delamanid/Bedaquilline Containing Regimen in the Management of MDR/XDR Pediatric Tuberculosis.
 

Pediatr Infect Dis J. 2022 Feb 10. doi: 10.1097/INF.0000000000003486. Online 
ahead of print.
 
Shah I(1), Antony S, Jaiswal A, Bodhanwala M, Shah D, Tipre P, Salve J, Parmar 
M, Sachdeva KS.
 
INTRODUCTION: The prevalence of multidrug resistant (MDR) tuberculosis (TB) with additional resistance to fluoroquinolones or second-line injectables (MDRFQ/SLI)/extensively drug-resistant TB (XDR-TB) in children is high in Mumbai. There are limited therapeutic options available in management of such children. Carbapenems, although approved for this indication, requires 2 to 3 daily injections, which are cumbersome. Bedaquilline (Bdq) and Delamanid (Dlm), the new antitubercular drugs still remain inaccessible to this subset of patients caused by conditional approvals. Hence, newer strategies to combat MDRFQ/SLI/XDR-TB needs to be explored.
OBJECTIVES: To study feasibility and interim outcomes of a "salvage regimen" using home-based carbapenem therapy through peripherally inserted central catheter as part of a longer (18-20 months) optimized background regimen including Dlm or Bdq or both in pediatric MDRFQ/SLI/XDR-TB patients who failed a standard MDR-TB regimen under the National Tuberculosis Elimination Programme in Mumbai, India.
DESIGN AND METHODS: Retrospective descriptive analysis study. National Tuberculosis Elimination Programme medical records of all MDRFQ/SLI/XDR-TB patients enrolled at the pediatric TB clinic at BJ Wadia Hospital for Children, Mumbai who were initiated on such "salvage regimen" during the period between April 2018 and December 2020 were retrospectively studied. Treatment outcomes and adverse events were described.
RESULTS: Of the 15 patients enrolled, mean age of the patient population was 12.53 ± 2.47 years and the female:male ratio was 13:2. Seven patients had XDR-TB while 8 patients had MDRFQ/SLI. Most common adverse event noted was dyselectrolytemia (3 patients). Catheter-related complications were reported in 5 patients and included catheter blockage, leak, and thrombosis. Sputum culture conversion was reported in all of the patients. One child mortality was reported and 2 patients were lost to follow up during study period.
CONCLUSIONS: Home-based meropenem therapy using peripherally inserted central catheter is feasible with few adverse effects. This can be a promising strategy in the management of MDRFQ/SLI/XDR-TB when an effective oral regimen cannot be otherwise constituted and needs to be explored further.
 
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
 
DOI: 10.1097/INF.0000000000003486
PMID: 35153288

 

From Our January 2022 Newsletter

Confronting and Coping with Multidrug-Resistant Tuberculosis: Life Experiences in Thailand.
 
Qual Health Res. 2022 Jan;32(1):159-167. doi: 10.1177/10497323211049777. Epub 2021 Nov 30.
 
Numpong S(1), Kengganpanich M(2), Kaewkungwal J(1), Pan-Ngum W(1), Silachamroon U(3), Kasetjaroen Y(4), Lawpoolsri S(1).
 
In this article, we aimed to understand the life experiences of Thai persons diagnosed with multi-drug-resistant tuberculosis (MDR-TB). A qualitative study using a face-to-face in-depth interview was conducted at a hospital in Thailand which has the highest prevalence of MDR-TB in the country between January and February 2019. Twenty persons living with MDR-TB in Thailand were purposively selected to represent a variety of experiences based on different gender, ages, and treatment phases. Qualitative data were transcribed and thematic analysis was applied to identify common themes and sub-themes. The results indicated that all participants faced emotional difficulties, such as fear of death, fear of stigmatization, confusion, and sadness when first knowing of their diagnosis. Family and social support were the main ways that the patients coped with difficult situations. Suicidal ideas were more prevalent among patients with poor family support. Screening for mental health problems should be routinely performed in MDR-TB patients. Proper health education should be provided to patients and families to reduce emotional difficulties and stigmatization.
 
DOI: 10.1177/10497323211049777
PMCID: PMC8739603
PMID: 34845946 [Indexed for MEDLINE]


Bedaquiline Drug Resistance Emergence Assessment in Multidrug-Resistant Tuberculosis (MDR-TB): a 5-Year Prospective In Vitro Surveillance Study of Bedaquiline and Other Second-Line Drug Susceptibility Testing in MDR-TB Isolates.
 
J Clin Microbiol. 2022 Jan 19;60(1):e0291920. doi: 10.1128/JCM.02919-20. Epub 2021 Oct 27.
 
Kaniga K(1), Hasan R(2)(3), Jou R(4), Vasiliauskienė E(5), Chuchottaworn C(6), Ismail N(7), Metchock B(8), Miliauskas S(9), Viet Nhung N(10), Rodrigues C(11), Shin S(12), Simsek H(13)(14), Smithtikarn S(15), Ngoc ALT(10), Boonyasopun J(16), Kazi M(11), Kim S(12), Kamolwat P(15), Musteikiene G(9), Sacopon CA(17), Tahseen S(18), Vasiliauskaitė L(5), Wu MH(4), Vally Omar S(7).
 
Bedaquiline Drug Resistance Emergence Assessment in Multidrug-resistant tuberculosis (MDR-TB) (DREAM) was a 5-year (2015 to 2019) phenotypic drug resistance surveillance study across 11 countries. DREAM assessed the susceptibility of 5,036 MDR-TB isolates of bedaquiline treatment-naive patients to bedaquiline and other antituberculosis drugs by the 7H9 broth microdilution (BMD) and 7H10/7H11 agar dilution (AD) MIC methods. Bedaquiline AD MIC quality control (QC) range for the H37Rv reference strain was unchanged, but the BMD MIC QC range (0.015 to 0.12 μg/ml) was adjusted compared with ranges from a multilaboratory, multicountry reproducibility study conforming to Clinical and Laboratory Standards Institute Tier-2 criteria. Epidemiological cutoff values of 0.12 μg/ml by BMD and 0.25 μg/ml by AD were consistent with previous bedaquiline breakpoints. An area of technical uncertainty or intermediate category was set at 0.25 μg/ml and 0.5 μg/ml for BMD and AD, respectively. When applied to the 5,036 MDR-TB isolates, bedaquiline-susceptible, -intermediate, and -resistant rates were 97.9%, 1.5%, and 0.6%, respectively, for BMD and 98.8%, 0.8%, and 0.4% for AD. Resistance rates were the following: 35.1% ofloxacin, 34.2% levofloxacin, 33.3% moxifloxacin, 1.5% linezolid, and 2% clofazimine. Phenotypic cross-resistance between bedaquiline and clofazimine was 0.4% in MDR-TB and 1% in pre-extensively drug-resistant (pre-XDR-TB)/XDR-TB populations. Coresistance to bedaquiline and linezolid and clofazimine and linezolid were 0.1% and 0.3%, respectively, in MDR-TB and 0.2% and 0.4%, respectively, in pre-XDR-TB/XDR-TB populations. Resistance rates to bedaquiline appear to be low in the bedaquiline-treatment-naive population. No treatment-limiting patterns for cross-resistance and coresistance have been identified with key TB drugs to date.
 
DOI: 10.1128/JCM.02919-20
PMID: 34705538


Tuberculosis Pathways to Care and Transmission of Multidrug Resistance in India.
 
Am J Respir Crit Care Med. 2022 Jan 15;205(2):233-241. doi: 10.1164/rccm.202012-4333OC.
 
Atre SR(1), Jagtap JD(1), Faqih MI(1), Dumbare YK(1), Sawant TU(1), Ambike SL(1), Bhawalkar JS(1), Bharaswadkar SK(2), Jogewar PK(3), Adkekar RS(3), Hodgar BP(4), Jadhav V(5), Mokashi ND(6), Golub JE(7), Dixit A(8)(9), Farhat MR(8)(10).
 
Rationale: India is experiencing a regional increase in cases of multidrug-resistant tuberculosis (MDR-TB). Objectives: Given the complexity of MDR-TB diagnosis and care, we sought to address key knowledge gaps in MDR risk factors, care delays, and drivers of delay to help guide disease control. 
Methods: From January 2018 to September 2019, we conducted interviews with adults registered with the National TB Elimination Program for MDR (n = 128) and non-MDR-TB (n = 269) treatment to quantitatively and qualitatively study care pathways. We collected treatment records and GeneXpert-TB/RIF diagnostic 
reports.
Measurements and Main Results: MDR-TB was associated with young age and crowded residence. GeneXpert rifampicin resistance diversity was measured at 72.5% Probe E. Median time from symptom onset to diagnosis of MDR was 90 days versus 60 days for non-MDR, Wilcoxon P < 0.01. Delay decreased by a median of 30 days among non-MDR patients with wider access to GeneXpert, Wilcoxon P = 0.02. Pathways to care were complex, with a median (interquartile range) of 4 (3-5) and 3 (2-4) encounters for MDR and non-MDR, respectively. Of patients with 
MDR-TB, 68% had their first encounter in the private sector, and this was associated with a larger number of subsequent healthcare encounters and catastrophic expenditure. Conclusions: The association of MDR with young age, crowding, and low genotypic diversity raises concerns of ongoing MDR transmission fueled by long delays in care. Delays are decreasing with GeneXpert use, suggesting the need for routine use in presumptive TB. Qualitatively, we identify the need to improve patient retention in the National TB Elimination Program and highlight patients' trust relationship with private providers.
 
DOI: 10.1164/rccm.202012-4333OC
PMID: 34706203


Safety of treatment regimens containing bedaquiline and delamanid in the endTB cohort.
 

Clin Infect Dis. 2022 Jan 13:ciac019. doi: 10.1093/cid/ciac019. Online ahead of print.
 
Hewison C(1), Khan U(2), Bastard M(3), Lachenal N(4), Coutisson S(4), Osso E(5), Ahmed S(6), Khan P(2), Franke MF(5), Rich ML(5)(7), Varaine F(1), Melikyan N(3), Seung KJ(5)(7), Adenov M(8), Adnan S(9), Danielyan N(10), Islam S(11), Janmohamed A(6), Karakozian H(12), Kimenye MK(13), Kirakosyan O(14), Kholikulov B(15), Krisnanda A(16), Kumsa A(17), Leblanc G(18), Lecca L(19), Nkuebe M(20), Mamsa S(9), Padayachee S(21), Thit P(22), Mitnick CD(5)(7), Huerga H(3); endTB study observational study team.
 
RATIONALE: Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion.
OBJECTIVES: Evaluate safety of longer MDR/RR-TB regimens containing bedaquiline and/or delamanid.
METHODS: Multicentre (16 countries), prospective, observational study, reporting incidence and frequency of clinically relevant adverse events of special interest (AESI) amongst patients who received MDR/RR-TB treatment containing bedaquiline and/or delamanid. The AESIs were defined a priori as important events caused by bedaquiline, delamanid, linezolid, injectables, and other 
commonly used drugs. Occurrence of these events was also reported by exposure to the likely causative agent.
RESULTS: Among 2296 patients, the most common clinically relevant AESIs were: peripheral neuropathy in 26.4%, electrolyte depletion in 26.0%, and hearing loss in 13.2% of patients. Per 1000 person-months of treatment, the incidence of these events was 21.5 (95% confidence interval [CI]: 19.8-23.2), 20.7 (95% CI: 19.1-22.4), and 9.7 (95% CI: 8.6-10.8), respectively. QT interval was prolonged in 2.7% or 1.8 (95% CI: 1.4-2.3)/1000 person-months of treatment. Patients who received injectables (N=925) and linezolid (N=1826) were most likely to experience events during exposure: Hearing loss, acute renal failure, or electrolyte depletion occurred in 36.8% or 72.8 (95%CI: 66.0-80.0) times/1000 person-months of injectable drug exposure. Peripheral neuropathy, optic neuritis and/or myelosuppression occurred in 27.8% or 22.8 (95% CI: 20.9-24.8) times/1000 patient-months of linezolid exposure.
CONCLUSIONS: Adverse events often related to linezolid and injectable drugs were more common than those frequently attributed to bedaquiline and delamanid. MDR-TB treatment monitoring schedules and individual drug durations should reflect expected safety profiles of drug combinations.
 
© The Author(s) 2022. Published by Oxford University Press for the Infectious 
Diseases Society of America.
 
DOI: 10.1093/cid/ciac019
PMID: 35028659


Safety, Tolerability, and Pharmacokinetics of Telacebec (Q203), a New Antituberculosis Agent, in Healthy Subjects.

Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0143621. doi: 10.1128/AAC.01436-21. Epub 2021 Oct 25.
 
Kim J(1)(2), Choi J(2), Kang H(2), Ahn J(2), Hutchings J(2), van Niekerk C(2), Park D(2), Kim J(2), Jeon Y(2), Nam K(2), Shin S(#)(3), Shin BS(#)(1).
 
Telacebec (Q203) is a potent drug candidate under clinical development for the treatment of drug-naïve and drug-resistant tuberculosis. The first-in-human randomized, placebo-controlled, double-blind, dose-escalation Phase 1A trial (Q203-TB-PI-US001) was conducted to evaluate the safety, tolerability, and pharmacokinetics of telacebec. A total of 56 normal, healthy, male and female subjects (42 active and 14 placebo) were enrolled in the study. The doses of telacebec were 10 mg (Cohort 1), 30 mg (Cohort 2), 50 mg (Cohort 3), 100 mg (Cohort 4), 200 mg (Cohort 5), 400 mg (Cohort 6), and 800 mg (Cohort 7) in a fasted state. Subjects participating in Cohort 4 were also enrolled in Cohort 8 
to investigate the food effect on the pharmacokinetics of telacebec after a high-fat meal. In all subjects dosed with telacebec (10 to 800 mg), telacebec was well tolerated and did not lead to any significant or serious adverse events. Following a single oral administration of telacebec (10 to 800 mg), telacebec plasma concentration reached the maximal plasma concentration (Cmax) 
in average 2.0 to 3.5 h and showed multi-exponential decline thereafter. The area under the plasma concentration versus time curve (AUC) was approximately dose-proportional. A significant increase in plasma concentrations was observed in the fed condition compared with the fasted condition with the geometric mean ratio of 3.93 for Cmax. Moderate delay in Tmax (4.5 h) was also observed in the fed condition. These results, combined with the demonstrated activity against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support further investigation of telacebec for the treatment of tuberculosis.
 
DOI: 10.1128/AAC.01436-21
PMID: 34694872