LITERATURE AND PUBLICATIONS

From our November 2022 Newsletter

1. Adherence trajectory as an on-treatment risk indicator among drug-resistant TB patients in the Philippines

PLoS One. 2022 Nov 8;17(11):e0277078. doi: 10.1371/journal.pone.0277078.
eCollection 2022.
 
Huddart S(1)(2), Geocaniga-Gaviola DM(3), Crowder R(1)(2), Lim AR(3), Lopez E(3), Valdez CL(3), Berger CA(1)(2), Destura R(4), Kato-Maeda M(1)(2), Cattamanchi A(1)(2), Garfin AMC(3).
 
INTRODUCTION: High levels of treatment adherence are critical for achieving
optimal treatment outcomes among patients with tuberculosis (TB), especially for drug-resistant TB (DR TB). Current tools for identifying high-risk non-adherence are insufficient. Here, we apply trajectory analysis to characterize adherence behavior early in DR TB treatment and assess whether these patterns predict treatment outcomes.
METHODS: We conducted a retrospective analysis of Philippines DR TB patients treated between 2013 and 2016. To identify unique patterns of adherence, we performed group-based trajectory modelling on adherence to the first 12 weeks of
treatment. We estimated the association of adherence trajectory group with six-month and final treatment outcomes using univariable and multivariable logistic regression. We also estimated and compared the predictive accuracy of adherence trajectory group and a binary adherence threshold for treatment outcomes.
RESULTS: Of 596 patients, 302 (50.7%) had multidrug resistant TB, 11 (1.8%)
extremely drug-resistant (XDR) TB, and 283 (47.5%) pre-XDR TB. We identified three distinct adherence trajectories during the first 12 weeks of treatment: a high adherence group (n = 483), a moderate adherence group (n = 93) and a low adherence group (n = 20). Similar patterns were identified at 4 and 8 weeks. Being in the 12-week moderate or low adherence group was associated with unfavorable six-month (adjusted OR [aOR] 3.42, 95% CI 1.90-6.12) and final (aOR 2.71, 95% 1.73-4.30) treatment outcomes. Adherence trajectory group performed similarly to a binary threshold classification for the prediction of final treatment outcomes (65.9% vs. 65.4% correctly classified), but was more accurate for prediction of six-month treatment outcomes (79.4% vs. 60.0% correctly classified).
CONCLUSIONS: Adherence patterns are strongly predictive of DR TB treatment outcomes. Trajectory-based analyses represent an exciting avenue of research into TB patient adherence behavior seeking to inform interventions which rapidly identify and support patients with high-risk adherence patterns.
 
Copyright: © 2022 Huddart et al.
 
DOI: 10.1371/journal.pone.0277078
PMCID: PMC9642894
PMID: 36346814 [Indexed for MEDLINE]

2. Effectiveness and Safety of Bedaquiline-based, Modified All-oral 9-11-month Treatment Regimen for Rifampicin-Resistant Tuberculosis in Vietnam.
 
Int J Infect Dis. 2022 Nov 10:S1201-9712(22)00592-6. doi: 10.1016/j.ijid.2022.11.007. Online ahead of print.
 
Mai Phuong NT(1), Hai Minh LT(1), Collette Merle CS(2), Pedrazzoli D(3), Linh NN(3), Decroo T(4), Hoa NB(1), Thuy HTT(1), Nhung NV(5).
 
BACKGROUND: WHO recommends a 7-drug 9-11-month rifampicin-resistant tuberculosis (RR-TB) short treatment regimen (STR). To reduce the pill burden, we assessed the safety and effectiveness of a 5-drug 9-11-month modified STR (mSTR).
METHODS: Prospective cohort study of an all-oral mSTR (comprising bedaquiline, levofloxacin, linezolid, clofazimine and/or pyrazinamide) for RR-TB patients
without confirmed fluoroquinolone resistance, enrolled in Vietnam between 2020-2021.
RESULTS: One hundred eight patients were enrolled. Sixty-three of 74 (85%) achieved culture conversion at 2 months. Of 106 evaluated, 95 (90%) were successfully treated, 6 (6%) were lost-to-follow-up, 1 (1%) died and 4 (4%) had
treatment failure, including 3 with permanent regimen change due to adverse events (AE) and 1 with culture reversion. Thirty-two (30% of 108) patients encountered at least one AE. Of 45 AEs recorded, 13 (29%) were serious (hospitalization, life threatening or death). The median time to AE was 3 months (IQR:2-5). Twenty-six AEs led to regimen adaptation: either dose reduction (N=1), drug temporary interruption (N=19), or drug permanent discontinuation (N=6, 4 attributed to linezolid).
CONCLUSION: The high treatment success 5-drug mSTR may replace the 7-drug regimen in routine care. AEs were frequent, but manageable in most patients. Active AEs monitoring is essential, particularly when using linezolid throughout.
 
Copyright © 2022. Published by Elsevier Ltd.
 
DOI: 10.1016/j.ijid.2022.11.007
PMID: 36372364
 
3. Selection bias in multidrug-resistant tuberculosis cohort studies assessing  sputum culture conversion.

PLoS One. 2022 Nov 10;17(11):e0276457. doi: 10.1371/journal.pone.0276457. 
eCollection 2022.

Rodriguez CA(1)(2), Lodi S(3), Horsburgh CR(1), Bastard M(4), Hewison C(5), 
Huerga H(4), Khan M(6), Khan PY(7)(8), Khan U(7), Oyewusi L(9), Padayachee S(6), Mitnick CD(2), Franke MF(2).

BACKGROUND: Conversion of sputum culture from positive to negative for M. tuberculosis is a key indicator of treatment response. An initial positive culture is a pre-requisite to observe conversion. Consequently, patients with a missing or negative initial culture are excluded from analyses of conversion outcomes. To identify the initial, or "baseline" culture, researchers must define a sample collection interval. An interval extending past treatment initiation can increase sample size but may introduce selection bias because patients without a positive pre-treatment culture must survive and remain in care to have a culture in the post-treatment interval.
METHODS: We used simulated data and data from the endTB observational cohort to investigate the potential for bias when extending baseline culture intervals past treatment initiation. We evaluated bias in the proportion with six-month conversion.
RESULTS: In simulation studies, the potential for bias depended on the proportion of patients missing a pre-treatment culture, proportion with conversion, proportion culture positive at treatment initiation, and proportion of patients missing a pre-treatment culture who would have been observed to be culture positive, had they had a culture. In observational data, the maximum potential for bias when reporting the proportion with conversion reached five percentage points in some sites.
CONCLUSION: Extending the allowable baseline interval past treatment initiation may introduce selection bias. If investigators choose to extend the baseline collection interval past treatment initiation, the proportion missing a pre-treatment culture and the number of deaths and losses to follow up during the post-treatment allowable interval should be clearly enumerated.

Copyright: © 2022 Rodriguez et al. 

DOI: 10.1371/journal.pone.0276457
PMCID: PMC9648724
PMID: 36355658 [Indexed for MEDLINE]

4. In silico evaluation of WHO-endorsed molecular methods to detect drug resistant tuberculosis.

Sci Rep. 2022 Oct 22;12(1):17741. doi: 10.1038/s41598-022-21025-6.

Brankin A(1)(2), Seifert M(2)(3), Georghiou SB(2), Walker TM(1)(4), Uplekar S(2), Suresh A(2), Colman RE(5)(6).

Universal drug susceptibility testing (DST) for tuberculosis is a major goal of the END TB strategy. PCR-based molecular diagnostic tests have been instrumental in increasing DST globally and several assays have now been endorsed by the World Health Organization (WHO) for use in the diagnosis of drug resistance. These endorsed assays, however, each interrogate a limited number of mutations associated with resistance, potentially limiting their sensitivity compared to sequencing-based methods. We applied an in silico method to compare the sensitivity and specificity of WHO-endorsed molecular based diagnostics to the mutation set identified by the WHO mutations catalogue using phenotypic DST as the reference. We found that, in silico, the mutation sets used by probe based molecular diagnostic tests to identify rifampicin, isoniazid, pyrazinamide, levofloxacin, moxifloxacin, amikacin, capreomycin and kanamycin resistance produced similar sensitivities and specificities to the WHO mutation catalogue. PCR-based diagnostic tests were most sensitive for drugs where mechanisms of resistance are well established and localised to small genetic regions or a few prevalent mutations. Approaches using sequencing technologies can provide advantages for drugs where our knowledge of resistance is limited, or where complex resistance signatures exist.

© 2022. The Author(s).

DOI: 10.1038/s41598-022-21025-6
PMCID: PMC9587982
PMID: 36273016 [Indexed for MEDLINE]
 
5. Pharmacokinetics and Safety of Bedaquiline in Human Immunodeficiency Virus (HIV)-Positive and Negative Older Children and Adolescents With Rifampicin-Resistant Tuberculosis.

Clin Infect Dis. 2022 Nov 14;75(10):1772-1780. doi: 10.1093/cid/ciac252.

Hughes JA(1), Solans BP(2), Draper HR(1), Schaaf HS(1), Winckler JL(1), van der Laan L(1), Radtke KK(2), Fourie B(3), Wiesner L(4), Hesseling AC(1), Savic 
RM(2), Garcia-Prats AJ(1)(5).

BACKGROUND: Pharmacokinetic data for bedaquiline in children are limited. We 
described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care.
METHODS: In this observational cohort study, children aged 6-17 years receiving 
bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modeling performed. Pediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µg ⋅ h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described.
RESULTS: Fifteen children (3 human immunodeficiency virus [HIV]-positive) with median age 13.3 years (range 6.5-16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centered in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, and AUC reference attainment was achieved in only 3 (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and 2 children had mild QT interval corrected for heart rate using Fridericia's formula (QT) prolongation.
CONCLUSIONS: The evaluated doses of bedaquiline in children ≥ 6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.

© The Author(s) 2022. Published by Oxford University Press for the Infectious 
Diseases Society of America. All rights reserved. For permissions, e-mail: 
journals.permissions@oup.com.

DOI: 10.1093/cid/ciac252
PMCID: PMC9662178
PMID: 35377434 [Indexed for MEDLINE]

6. Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial

BACKGROUND: The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen.
METHODS: We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631.
FINDINGS: Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9–19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1–31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss.
INTERPRETATION: Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss.
FUNDING: USAID and Janssen Research & Development.
 
Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S0140-6736(22)02078-5
PMID: 36368336 [Indexed for MEDLINE]
 

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From our October 2022 Newsletter

Mutation detection and minimum inhibitory concentration determination against linezolid and clofazimine in confirmed XDR-TB clinical isolates. 

BMC Microbiol. 2022 Oct 3;22(1):236. doi: 10.1186/s12866-022-02622-x. 

Singh K(1), Sharma S(1), Banerjee T(1), Gupta A(2), Anupurba S(3).
 
BACKGROUND: The emergence of multidrug-resistant tuberculosis (MDR-TB) has complicated the situation due to the decline in potency of second-line anti-tubercular drugs. This limits the treatment option for extensively drug-resistant tuberculosis (XDR-TB). The aim of this study was to determine and compare the minimum inhibitory concentration (MIC) by agar dilution and resazurin microtiter assay (REMA) along with the detection of mutations against linezolid and clofazimine in confirmed XDR-TB clinical isolates.
RESULTS: A total of 169 isolates were found positive for Mycobacterium tuberculosis complex (MTBC). The MIC was determined by agar dilution and REMA methods. The isolates which showed non-susceptibility were further subjected to mutation detection by targeting rplC gene (linezolid) and Rv0678 gene (clofazimine). The MIC for linezolid ranged from 0.125 µg/ml to > 2 µg/ml and for clofazimine from 0.25 µg/ml to > 4 µg/ml. The MIC50 and MIC90 for linezolid were 0.5 µg/ml and 1 µg/ml respectively while for clofazimine both were 1 µg/ml. The essential and categorical agreement for linezolid was 97.63% and 95.26% and for clofazimine, both were 100%. The sequencing result of the rplC gene revealed a point mutation at position 460 bp, where thymine (T) was substituted for cytosine (C) while seven mutations were noted between 46 to 220 bp in Rv0678 gene.
CONCLUSION: REMA method has been found to be more suitable in comparison to the agar dilution method due to lesser turnaround time. Mutations in rplC and Rv0678 genes were reasons for drug resistance against linezolid and clofazimine respectively.
 
© 2022. The Author(s).
 
DOI: 10.1186/s12866-022-02622-x
PMCID: PMC9531458
PMID: 36192704 [Indexed for MEDLINE]

2. Caregiver willingness to give TPT to children living with drug-resistant TB patients. 

Int J Tuberc Lung Dis. 2022 Oct 1;26(10):949-955. doi: 10.5588/ijtld.21.0760.
 
Rouzier V(1), Murrill M(2), Kim S(3), Naini L(4), Shenje J(5), Mitchell E(6), Raesi M(7), Lourens M(8), Mendoza A(9), Conradie F(10), Suryavanshi N(11), Hughes M(12), Shah S(13), Churchyard G(14), Swindells S(15), Hesseling A(16), Gupta A(1).
 
BACKGROUND Pediatric household contacts (HHCs) of patients with multidrug-resistant TB (MDR-TB) are at high risk of infection and active disease. Evidence of caregiver willingness to give MDR-TB preventive therapy (TPT) to children is limited.
METHODS This was a cross-sectional study of HHCs of patients with MDR-TB to assess caregiver willingness to give TPT to children aged <13 years.
RESULTS Of 743 adult and adolescent HHCs, 299 reported caring for children aged <13 years of age. The median caregiver age was 35 years (IQR 27-48); 75% were women. Among caregivers, 89% were willing to give children MDR TPT. In unadjusted analyses, increased willingness was associated with TB-related knowledge (OR 5.1, 95% CI 2.3-11.3), belief that one can die of MDR-TB (OR 5.2, 95% CI 1.2-23.4), concern for MDR-TB transmission to child (OR 4.5, 95% CI 1.6-12.4), confidence in properly taking TPT (OR 4.5, 95% CI 1.6-12.6), comfort telling family about TPT (OR 5.5, 95% CI 2.1-14.3), and willingness to take TPT oneself (OR 35.1, 95% CI 11.0-112.8).
CONCLUSIONS A high percentage of caregivers living with MDR- or rifampicin-resistant TB patients were willing to give children a hypothetical MDR TPT. These results provide important evidence for the potential uptake of effective MDR TPT when implemented.
 
DOI: 10.5588/ijtld.21.0760
PMCID: PMC9524515
PMID: 36163664 [Indexed for MEDLINE]
 
3. Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort. 

Clin Infect Dis. 2022 Sep 29;75(6):1006-1013. doi: 10.1093/cid/ciac019.
 
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), Kamene Kimenye M(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).
 
Comment in doi: 10.1093/cid/ciac347.
 
BACKGROUND: Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion. 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 (AESIs) among 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 (26.4%), electrolyte depletion (26.0%), and hearing loss (13.2%) with an incidence per 1000 person months of treatment, 1000 person-months of treatment 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 receiving 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: AEs often related to linezolid and injectable drugs were more common than those frequently attributed to bedaquiline and delamanid. MDR-TB treatment monitoring and drug durations should reflect expected safety profiles of drug combinations.
CLINICAL TRIALS REGISTRATION: NCT02754765.
 
© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.
 
DOI: 10.1093/cid/ciac019
PMCID: PMC9522425
PMID: 35028659 [Indexed for MEDLINE]
 
4. Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis Treatment (SMARTT): a study protocol for a phase IV pragmatic randomized controlled patient management strategy trial. 

Trials. 2022 Oct 8;23(1):864. doi: 10.1186/s13063-022-06793-w.
 
Van Rie A(1), De Vos E(2), Costa E(3), Verboven L(2), Ndebele F(4), Heupink TH(2), Abrams S(2); SMARTT team, Fanampe B(5), Van der Spoel Van Dyk A(6), Charalambous S(4), Churchyard G(4), Warren R(3).
 
Collaborators: Maraba N, Makkan H, Beattie T, Sibeko ZR, Bohlela S, Segwaba P, Ogunbayo EA, Mhlambi N, Wells F, Rigouts L, Maartens G, Conradie F, Black J, Potgieter S.
 
BACKGROUND: Rifampicin-resistant tuberculosis (RR-TB) remains an important global health problem. Ideally, the complete drug-resistance profile guides individualized treatment for all RR-TB patients, but this is only practised in high-income countries. Implementation of whole genome sequencing (WGS) technologies into routine care in low and middle-income countries has not become a reality due to the expected implementation challenges, including translating WGS results into individualized treatment regimen composition.
METHODS: This trial is a pragmatic, single-blinded, randomized controlled medical device trial of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Subjects are 18 years or older and diagnosed with pulmonary RR-TB in four of the five health districts of the Free State province in South Africa. Participants are randomized in a 1:1 ratio to either the intervention (a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB) or control (RR-TB treatment according to the national South African guidelines). The primary effectiveness outcome is the bacteriological response to treatment measured as the rate of change in time to liquid culture positivity during the first 6 months of treatment. Secondary effectiveness outcomes include cure rate, relapse rate (recurrence of RR-TB disease) and TB free survival rate in the first 12 months following RR-TB treatment completion. Additional secondary outcomes of interest include safety, the feasibility of province-wide implementation of the strategy into routine care, and health economic assessment from a patient and health systems perspective.
DISCUSSION: This trial will provide important real-life evidence regarding the feasibility, safety, cost, and effectiveness of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Given the pragmatic nature, the trial will assist policymakers in the decision-making regarding the integration of next-generation sequencing technologies into routine RR-TB care in high TB burden settings.
TRIAL REGISTRATION: ClinicalTrials.gov NCT05017324. Registered on August 23, 2021.
 
© 2022. The Author(s).
 
DOI: 10.1186/s13063-022-06793-w
PMCID: PMC9548157
PMID: 36209235 [Indexed for MEDLINE]
 
5. Patient and health-care provider experience of a person-centred, multidisciplinary, psychosocial support and harm reduction programme for patients with harmful use of alcohol and drug-resistant tuberculosis in Minsk, Belarus. 

BMC Health Serv Res. 2022 Sep 30;22(1):1217. doi: 10.1186/s12913-022-08525-x.
 
Harrison RE(1), Shyleika V(1), Falkenstein C(1), Garsevanidze E(1), Vishnevskaya O(1), Lonnroth K(2), Sayakci Ö(1), Sinha A(3), Sitali N(4), Skrahina A(5), Stringer B(3), Tan C(6), Mar HT(1), Venis S(3), Vetushko D(5), Viney K(2)(7), Vishneuski R(1), Carrion Martin AI(8).
 
BACKGROUND: Tuberculosis (TB) often concentrates in groups of people with complex health and social issues, including alcohol use disorders (AUD). Risk of TB, and poor TB treatment outcomes, are substantially elevated in people who have AUD. Médecins sans Frontières and the Belarus Ministry of Health have worked to improve treatment adherence in patients with multi-drug or rifampicin resistant (MDR/RR)-TB and harmful use of alcohol. In 2016, a person-centred, multidisciplinary, psychosocial support and harm reduction programme delivered
by TB doctors, counsellors, psychiatrists, health-educators, and social workers was initiated. In 2020, we described patient and provider experiences within the programme as part of a wider evaluation.
METHODS: We recruited 12 patients and 20 health-care workers, using purposive sampling, for in-depth individual interviews and focus group discussions. We used a participant-led, flexible, exploratory approach, enabling participants and the interviewer to shape topics of conversation. Qualitative data were coded manually and analysed thematically. As part of the analysis process, identified themes were shared with health-care worker participants to enable their reflections to be incorporated into the findings.
RESULTS: Key themes related to the patients' and practitioners experience of having and treating MDRTB with associated complex health and social issues were: fragility and despair and guidance, trust and health. Prejudice and marginalisation were global to both themes. Counsellors and other health workers built a trusting relationship with patients, enabling guidance through a multi-disciplinary approach, which supported patients to achieve their vision of health. This guidance was achieved by a team of social workers, counsellors, doctors and health-educators who provided professional and individualised help for patients' illnesses, personal or interpersonal problems, administrative tasks, and job searches.
CONCLUSIONS: Patients with MDR/RR-TB and harmful use of alcohol faced complex issues during treatment. Our findings describe how person-centred, multi-disciplinary, psychosocial support helped patients in this setting to cope with these challenges and complete the treatment programme. We recommend that these findings are used to: i) inform programmatic changes to further boost the person-centred care nature of this program; and ii) advocate for this type of person-centred care approach to be rolled out across Belarus, and in contexts that face similar challenges.
 
© 2022. The Author(s).
 
DOI: 10.1186/s12913-022-08525-x
PMCID: PMC9523183
PMID: 36180873 [Indexed for MEDLINE]
 
6. 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 Oct 12;75(8):1307-1314. doi: 10.1093/cid/ciac176.
 
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), Rafi Siddiqui M(15), Grium Tefera D(16), Vetushko D(17), Yeghiazaryan L(18), Holtzman D(19), Islam S(11), Kumsa A(20), Jacques Leblanc G(21), Leonovich O(22), Mamsa S(11), Manzur-Ul-Alam M(23), Myint Z(24), Padayachee S(25), Franke MF(3), Hewison C(9).
 
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 patients (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
PMCID: PMC9555840
PMID: 35243494 [Indexed for MEDLINE]

 

From our September 2022 Newsletter

1. High clustering rate and genotypic drug-susceptibility screening for the newly recommended anti-tuberculosis drugs among global extensively drug-resistant Mycobacterium tuberculosis isolates

Emerg Microbes Infect. 2022 Dec;11(1):1857-1866. doi: 10.1080/22221751.2022.2099304.

Trisakul K(1)(2), Nonghanphithak D(1)(2), Chaiyachat P(1)(2), Kaewprasert O(1)(2), Sakmongkoljit K(3), Reechaipichitkul W(1)(2), Chaiprasert A(4), Blair D(5), Clark TG(6), Faksri K(1)(2).

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) make TB difficult to control. Global susceptibility data for six newly recommended anti-TB drugs against M/XDR-TB are still limited. Using publicly available whole-genome sequences, we determined the proportion of 513 phenotypically XDR-TB isolates that carried mutations associated with resistance against these drugs (bedaquiline, clofazimine, linezolid, delamanid, pretomanid and cycloserine). Mutations of Rv0678 and Rv1979c were detected in 69/513 isolates (13.5%) for bedaquiline resistance and 79/513 isolates (15.4%)
for clofazimine resistance with additional mmpL5 mutations. Mutations conferring resistance to delamanid were detected in fbiB and ddn genes for 11/513 isolates (2.1%). For pretomanid, a mutation was detected in the ddn gene for 3/513 isolates (0.6%). Nineteen mutations of pykA, cycA, ald, and alr genes, conferring resistance to cycloserine, were found in 153/513 isolates (29.8%). No known mutations associated with linezolid resistance were detected. Cluster analysis showed that 408/513 isolates fell within 99 clusters and that 354 of these isolates were possible primary drug-resistant TB (292 XDR-TB, 57 pre-XDR-TB and 5 MDR-TB). Clonal transmission of primary XDR isolates might contribute significantly to the high prevalence of DR-TB globally.

DOI: 10.1080/22221751.2022.2099304
PMCID: PMC9336503
PMID: 35792049 [Indexed for MEDLINE]
 
2. Investigating resistance in clinical Mycobacterium tuberculosis complex isolates with genomic and phenotypic antimicrobial susceptibility testing: a multicentre observational study.

Lancet Microbe. 2022 Sep;3(9):e672-e682. doi: 10.1016/S2666-5247(22)00116-1. Epub 2022 Jul 27.

Finci I(1), Albertini A(2), Merker M(3), Andres S(4), Bablishvili N(5), Barilar I(6), Cáceres T(7), Crudu V(8), Gotuzzo E(7), Hapeela N(9), Hoffmann H(10), Hoogland C(2), Kohl TA(6), Kranzer K(11), Mantsoki A(2), Maurer FP(12), Nicol MP(13), Noroc E(8), Plesnik S(14), Rodwell T(15), Ruhwald M(2), Savidge T(16), Salfinger M(17), Streicher E(18), Tukvadze N(5), Warren R(18), Zemanay W(9), Zurek A(19), Niemann S(6), Denkinger CM(20).

BACKGROUND: Whole-genome sequencing (WGS) of Mycobacterium tuberculosis complex has become an important tool in diagnosis and management of drug-resistant tuberculosis. However, data correlating resistance genotype with quantitative phenotypic antimicrobial susceptibility testing (AST) are scarce.
METHODS: In a prospective multicentre observational study, 900 clinical M tuberculosis complex isolates were collected from adults with drug-resistant tuberculosis in five high-endemic tuberculosis settings around the world (Georgia, Moldova, Peru, South Africa, and Viet Nam) between Dec 5, 2014, and Dec 12, 2017. Minimum inhibitory concentrations (MICs) and resulting binary phenotypic AST results for up to nine antituberculosis drugs were determined and correlated with resistance-conferring mutations identified by WGS.
FINDINGS: Considering WHO-endorsed critical concentrations as reference, WGS had high accuracy for prediction of resistance to isoniazid (sensitivity 98·8% [95% CI 98·5-99·0]; specificity 96·6% [95% CI 95·2-97·9]), levofloxacin (sensitivity 94·8% [93·3-97·6]; specificity 97·1% [96·7-97·6]), kanamycin (sensitivity 96·1%
[95·4-96·8]; specificity 95·0% [94·4-95·7]), amikacin (sensitivity 97·2% [96·4-98·1]; specificity 98·6% [98·3-98·9]), and capreomycin (sensitivity 93·1% [90·0-96·3]; specificity 98·3% [98·0-98·7]). For rifampicin, pyrazinamide, and ethambutol, the specificity of resistance prediction was suboptimal (64·0% [61·0-67·1], 83·8% [81·0-86·5], and 40·1% [37·4-42·9], respectively). Specificity for rifampicin increased to 83·9% when borderline mutations with MICs overlapping with the critical concentration were excluded. Consequently, we highlighted mutations in M tuberculosis complex isolates that are often falsely identified as susceptible by phenotypic AST, and we identified potential novel resistance-conferring mutations.
INTERPRETATION: The combined analysis of mutations and quantitative phenotypes shows the potential of WGS to produce a refined interpretation of resistance, which is needed for individualised therapy, and eventually could allow differential drug dosing. However, variability of MIC data for some M tuberculosis complex isolates carrying identical mutations also reveals limitations of our understanding of the genotype and phenotype relationships (eg, including epistasis and strain genetic background).
FUNDING: Bill &amp; Melinda Gates Foundation, German Centre for Infection Research,

German Research Foundation, Excellence Cluster Precision Medicine of Inflammation (EXC 2167), and Leibniz ScienceCampus EvoLUNG. Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S2666-5247(22)00116-1
PMCID: PMC9436784
PMID: 35907429 [Indexed for MEDLINE]
 
3. Pharmacokinetics and Safety of WHO-Recommended Dosage and Higher Dosage of Levofloxacin for Tuberculosis Treatment in Children: a Pilot Study.

Int J Infect Dis. 2022 Sep;122:603-608. doi: 10.1016/j.ijid.2022.07.029. Epub
2022 Jul 13.

Jantarabenjakul W(1), Suntarattiwong P(2), Wacharachaisurapol N(3), Supradish Na Ayudhya P(2), Phaisal W(4), Tawan M(5), Moonwong J(5), Sudjaritruk T(6), Chariyavilaskul P(4), Puthanakit T(7).

OBJECTIVES: To evaluate the pharmacokinetic parameters of the 2020 World Health Organization (WHO)-recommended pediatric dosage of levofloxacin and the higher-than-WHO dosage.
METHODS: Children aged 1-15 years with tuberculosis who received levofloxacin-based treatment for at least 7 days were enrolled. First, five children were enrolled to receive the WHO-recommended dosage (15-20 mg/kg/day), then an additional five children received a dosage higher than the WHO-recommended dosage (20-30 mg/kg/day). Blood samples were collected at predose and postdose 1, 2, 4, 6, 8, and 12 hours. A target of the ratio of the free area under the concentration-time curve to minimum inhibitory concentration (fAUC/MIC) was 100.
RESULTS: The median (interquartile range) age was 9.6 (4.9-10.5) and 12.0 (10.1-12.3) years in the WHO dosage and higher-than-WHO dosage groups, respectively. The median (interquartile range) duration of antituberculosis treatment was 24 (8-24) weeks. The geometric mean (95% confidence interval) of fAUC/MIC was 60.4 (43.5-84.0) and 103.2 (70.1-151.8) in the WHO and higher-than-WHO dosage groups, respectively. There was no adverse event of QT prolongation or any other grade 3 or 4 adverse events.
CONCLUSION: Levofloxacin at a higher dose of 20-30 mg/kg/day could achieve the fAUC/MIC target in children.

Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.ijid.2022.07.029
PMID: 35842213 [Indexed for MEDLINE] 

4. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.

N Engl J Med. 2022 Sep 1;387(9):810-823. doi: 10.1056/NEJMoa2119430.

Conradie F(1), Bagdasaryan TR(1), Borisov S(1), Howell P(1), Mikiashvili L(1), Ngubane N(1), Samoilova A(1), Skornykova S(1), Tudor E(1), Variava E(1), Yablonskiy P(1), Everitt D(1), Wills GH(1), Sun E(1), Olugbosi M(1), Egizi E(1), Li M(1), Holsta A(1), Timm J(1), Bateson A(1), Crook AM(1), Fabiane SM(1), Hunt R(1), McHugh TD(1), Tweed CD(1), Foraida S(1), Mendel CM(1), Spigelman M(1); ZeNix Trial Team.
Collaborators: Bagdasaryan T, Conradie F, Ngubane N, Howell P, Borisov S,
Mikiashvili L, Variava E, Samoilova A, Yablonskiy P, Tudor E, Skornyakov S,
Thompson L, Canseco JO, Paleckyte A, Solanki P, Choo L, Witney AA.

Comment in N Engl J Med. 2022 Sep 1;387(9):842-843.

BACKGROUND: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear.
METHODS: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated.
RESULTS: A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups.
CONCLUSIONS: A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).

Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2119430
PMID: 36053506 [Indexed for MEDLINE]

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From our August 2022 Newsletter

1. Population Pharmacokinetics of Delamanid and its Main Metabolite DM-6705 in Drug-Resistant Tuberculosis Patients Receiving Delamanid Alone or Coadministered with Bedaquiline.

Clin Pharmacokinet. 2022 Aug;61(8):1177-1185. doi: 10.1007/s40262-022-01133-2. Epub 2022 Jun 7.

Tanneau L(1), Karlsson MO(1), Diacon AH(2), Shenje J(3), De Los Rios J(4), Wiesner L(5), Upton CM(2), Dooley KE(6), Maartens G(5), Svensson EM(7)(8).

BACKGROUND AND OBJECTIVE: Delamanid is a nitroimidazole, a novel class of drug for treating tuberculosis, and is primarily metabolized by albumin into the metabolite DM-6705. The aims of this analysis were to develop a population pharmacokinetic (PK) model to characterize the concentration-time course of delamanid and DM-6705 in adults with drug-resistant tuberculosis and to explore a potential drug-drug interaction with bedaquiline when coadministered.

METHODS: Delamanid and DM-6705 concentrations after oral administration, from 52 participants (of whom 26 took bedaquiline concurrently and 20 were HIV-1 positive) enrolled in the DELIBERATE trial were analyzed using nonlinear mixed-effects modeling.

RESULTS: Delamanid PK were described by a one-compartment disposition model with transit compartment absorption (mean absorption time of 1.45 h [95% confidence interval 0.501-2.20]) and linear elimination, while the PK of DM-6705 metabolite were described by a one-compartment disposition model with delamanid clearance as input and linear elimination. Predicted terminal half-life values for delamanid and DM-6705 were 15.1 h and 7.8 days, respectively. The impact of plasma albumin concentrations on delamanid metabolism was not significant. Bedaquiline coadministration did not affect delamanid PK. Other than allometric scaling with body weight, no patients' demographics were significant (including HIV).
CONCLUSIONS: This is the first joint PK model of delamanid and its DM-6705 metabolite. As such, it can be utilized in future exposure-response or exposure-safety analyses. Importantly, albumin concentrations, bedaquiline coadministration, and HIV co-infection (dolutegravir coadministration) did not have an effect on delamanid and DM-6705 PK.

© 2022. The Author(s).

DOI: 10.1007/s40262-022-01133-2
PMCID: PMC9349160
PMID: 35668346 [Indexed for MEDLINE]
 
2. Integrative analysis of clinical health records, imaging and pathogen genomics identifies personalized predictors of disease prognosis in tuberculosis.

medRxiv. 2022 Jul 21:2022.07.20.22277862. doi: 10.1101/2022.07.20.22277862. Preprint.

Sambarey A, Smith K, Chung C, Arora HS, Yang Z, Agarwal P, Chandrasekaran S.

Tuberculosis (TB) afflicts over 10 million people every year and its global burden is projected to increase dramatically due to multidrug-resistant TB (MDR-TB). The Covid-19 pandemic has resulted in reduced access to TB diagnosis and treatment, reversing decades of progress in disease management globally. It is thus crucial to analyze real-world multi-domain information from patient health records to determine personalized predictors of TB treatment outcome and drug resistance. We conduct a retrospective analysis on electronic health records of 5060 TB patients spanning 10 countries with high burden of MDR-TB including Ukraine, Moldova, Belarus and India available on the NIAID-TB portals database. We analyze over 200 features across multiple host and pathogen modalities representing patient social demographics, disease presentations as seen in cChest X rays and CT scans, and genomic records with drug susceptibility features of the pathogen strain from each patient. Our machine learning model, built with diverse data modalities outperforms models built using each modality alone in predicting treatment outcomes, with an accuracy of 81% and AUC of 0.768. We determine robust predictors across countries that are associated with unsuccessful treatmentclinical outcomes, and validate our predictions on new patient data from TB Portals. Our analysis of drug regimens and drug interactions suggests that synergistic drug combinations and those containing the drugs Bedaquiline, Levofloxacin, Clofazimine and Amoxicillin see more success in treating MDR and XDR TB. Features identified via chest imaging such as percentage of abnormal volume, size of lung cavitation and bronchial obstruction are associated significantly with pathogen genomic attributes of drug resistance. Increased disease severity was also observed in patients with lower BMI and with comorbidities. Our integrated multi-modal analysis thus revealed significant associations between radiological, microbiological, therapeutic, and demographic data modalities, providing a deeper understanding of personalized responses to aid in the clinical management of TB.

DOI: 10.1101/2022.07.20.22277862
PMCID: PMC9327630
PMID: 35898335

 
3. A data compendium associating the genomes of 12,289 Mycobacterium tuberculosis isolates with quantitative resistance phenotypes to 13 antibiotics.

PLoS Biol. 2022 Aug 9;20(8):e3001721. doi: 10.1371/journal.pbio.3001721. eCollection 2022 Aug.

The CRyPTIC Consortium.

Comment in
    Genome-wide association studies of global Mycobacterium tuberculosis resistance to thirteen antimicrobials in 10,228 genomes identify new resistance mechanisms.

The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) presents here a data compendium of 12,289 Mycobacterium tuberculosis global clinical isolates, all of which have undergone whole-genome sequencing and have had their minimum inhibitory concentrations to 13 antitubercular drugs measured in a single assay. It is the largest matched phenotypic and genotypic dataset for M. tuberculosis to date. Here, we provide a summary detailing the breadth of data collected, along with a description of how the isolates were selected, collected, and uniformly processed in CRyPTIC partner laboratories across 23 countries. The compendium contains 6,814 isolates resistant to at least 1 drug, including 2,129 samples that fully satisfy the clinical definitions of rifampicin resistant (RR), multidrug resistant (MDR), pre-extensively drug resistant (pre-XDR), or extensively drug resistant (XDR). The data are enriched for rare resistance-associated variants, and the current limits of genotypic prediction of resistance status (sensitive/resistant) are presented by using a genetic mutation catalogue, along with the presence of suspected resistance-conferring mutations for isolates resistant to the newly introduced drugs bedaquiline, clofazimine, delamanid, and linezolid. Finally, a case study of rifampicin monoresistance demonstrates how this compendium could be used to advance our genetic understanding of rare resistance phenotypes. The data compendium is fully open source and it is hoped that it will facilitate and inspire future research for years to come.

DOI: 10.1371/journal.pbio.3001721
PMCID: PMC9363010
PMID: 35944069 [Indexed for MEDLINE]
 

4. Investigating resistance in clinical Mycobacterium tuberculosis complex isolates with genomic and phenotypic antimicrobial susceptibility testing: a multicentre observational study.

Lancet Microbe. 2022 Jul 27:S2666-5247(22)00116-1. doi: 10.1016/S2666-5247(22)00116-1. Online ahead of print.

Finci I(1), Albertini A(2), Merker M(3), Andres S(4), Bablishvili N(5), Barilar I(6), Cáceres T(7), Crudu V(8), Gotuzzo E(7), Hapeela N(9), Hoffmann H(10), Hoogland C(2), Kohl TA(6), Kranzer K(11), Mantsoki A(2), Maurer FP(12), Nicol MP(13), Noroc E(8), Plesnik S(14), Rodwell T(15), Ruhwald M(2), Savidge T(16), Salfinger M(17), Streicher E(18), Tukvadze N(5), Warren R(18), Zemanay W(9), Zurek A(19), Niemann S(6), Denkinger CM(20).

BACKGROUND: Whole-genome sequencing (WGS) of Mycobacterium tuberculosis complex has become an important tool in diagnosis and management of drug-resistant tuberculosis. However, data correlating resistance genotype with quantitative phenotypic antimicrobial susceptibility testing (AST) are scarce.
METHODS: In a prospective multicentre observational study, 900 clinical M tuberculosis complex isolates were collected from adults with drug-resistant tuberculosis in five high-endemic tuberculosis settings around the world (Georgia, Moldova, Peru, South Africa, and Viet Nam) between Dec 5, 2014, and Dec 12, 2017. Minimum inhibitory concentrations (MICs) and resulting binary phenotypic AST results for up to nine antituberculosis drugs were determined and correlated with resistance-conferring mutations identified by WGS.
FINDINGS: Considering WHO-endorsed critical concentrations as reference, WGS had high accuracy for prediction of resistance to isoniazid (sensitivity 98·8% [95% CI 98·5-99·0]; specificity 96·6% [95% CI 95·2-97·9]), levofloxacin (sensitivity 94·8% [93·3-97·6]; specificity 97·1% [96·7-97·6]), kanamycin (sensitivity 96·1% [95·4-96·8]; specificity 95·0% [94·4-95·7]), amikacin (sensitivity 97·2% [96·4-98·1]; specificity 98·6% [98·3-98·9]), and capreomycin (sensitivity 93·1% [90·0-96·3]; specificity 98·3% [98·0-98·7]). For rifampicin, pyrazinamide, and ethambutol, the specificity of resistance prediction was suboptimal (64·0% [61·0-67·1], 83·8% [81·0-86·5], and 40·1% [37·4-42·9], respectively). Specificity for rifampicin increased to 83·9% when borderline mutations with MICs overlapping with the critical concentration were excluded. Consequently, we highlighted mutations in M tuberculosis complex isolates that are often falsely identified as susceptible by phenotypic AST, and we identified potential novel resistance-conferring mutations.
INTERPRETATION: The combined analysis of mutations and quantitative phenotypes shows the potential of WGS to produce a refined interpretation of resistance, which is needed for individualised therapy, and eventually could allow differential drug dosing. However, variability of MIC data for some M 
tuberculosis complex isolates carrying identical mutations also reveals limitations of our understanding of the genotype and phenotype relationships (eg, including epistasis and strain genetic background).
FUNDING: Bill & Melinda Gates Foundation, German Centre for Infection Research, German Research Foundation, Excellence Cluster Precision Medicine of Inflammation (EXC 2167), and Leibniz ScienceCampus EvoLUNG.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open 
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All 
rights reserved.

DOI: 10.1016/S2666-5247(22)00116-1
PMID: 35907429