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LITERATURE AND PUBLICATIONS

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RECENT PUBLICATIONS

From our July 2022 Newsletter

1. Spatial heterogeneity of extensively drug resistant-tuberculosis in Western Cape Province, South Africa.
 
Sci Rep. 2022 Jun 27;12(1):10844. doi: 10.1038/s41598-022-14581-4. Sy KTL(1), Leavitt SV(2), de Vos M(3), Dolby T(4), Bor J(1)(2), Horsburgh CR Jr(1)(2)(5)(6), Warren RM(3), Streicher EM(3), Jenkins HE(2), Jacobson KR(7).
Tuberculosis (TB) remains a leading infectious disease killer globally. Treatment outcomes are especially poor among people with extensively drug-resistant (XDR) TB, until recently defined as rifampicin-resistant (RR) TB with resistance to an aminoglycoside (amikacin) and a fluoroquinolone (ofloxacin). We used laboratory TB test results from Western Cape province, South Africa between 2012 and 2015 to identify XDR-TB and pre-XDR-TB (RR-TB with resistance to one second-line drug) spatial hotspots. We mapped the percentage and count of individuals with RR-TB that had XDR-TB and pre-XDR-TB across the province and in Cape Town, as well as amikacin-resistant and ofloxacin-resistant TB. We found the percentage of pre-XDR-TB and the count of XDR-TB/pre-XDR-TB highly heterogeneous with geographic hotspots within RR-TB high burden areas, and found hotspots in both percentage and count of amikacin-resistant and ofloxacin-resistant TB. The spatial distribution of percentage ofloxacin-resistant TB hotspots was similar to XDR-TB hotspots, suggesting that fluoroquinolone-resistace is often the first step to additional resistance. Our work shows that interventions used to reduce XDR-TB incidence may need to be targeted within spatial locations of RR-TB, and further research is required to understand underlying drivers of XDR-TB transmission in these locations.

© 2022. The Author(s).
DOI: 10.1038/s41598-022-14581-4
PMCID: PMC9237070
PMID: 35760977 [Indexed for MEDLINE]
 
2. Bedaquiline, Delamanid, Linezolid and Clofazimine for Treatment of Pre-extensively Drug-Resistant Tuberculosis.

Clin Infect Dis. 2022 Jun 29:ciac528. doi: 10.1093/cid/ciac528. Online ahead of print.

Padmapriyadarsini C(1), Vohra V(2), Bhatnagar A(3), Solanki R(4), Sridhar R(5), Anande L(6), Muthuvijaylakshmi M(1), Bhatia M(2), Jeyadeepa B(1), Taneja G(3), Balaji S(1), Shah P(4), Saravanan N(1), Chauhan V(6), Kumar H(1), Ponnuraja C(1), Livchits V(7), Bahl M(8), Alavadi U(7), Sachdeva KS(9), Swaminathan S(10)(11); for BEAT India Team.

BACKGROUND: Treatment success rates for multidrug-resistant tuberculosis (MDR-TB) remain low globally. Availability of newer drugs has given scope to develop regimens that can be patient-friendly, less toxic, with improved outcomes. We proposed to determine the effectiveness of an entirely oral, short-course regimen with Bedaquiline and Delamanid in treating MDR-TB with additional resistance to fluoroquinolones (MDR-TBFQ+) or second-line injectable (MDR-TBSLI+).
METHODS: We prospectively determined the effectiveness and safety of combining two new drugs with two repurposed drugs - Bedaquiline, Delamanid, Linezolid, and Clofazimine for 24-36 weeks in adults with pulmonary MDR-TBFQ+ or/and MDR-TBSLI+. The primary outcome was a favorable response at end of treatment, defined as two consecutive negative cultures taken four weeks apart. The unfavorable outcomes included bacteriologic or clinical failure during treatment period.
RESULTS: Of the 165 participants enrolled, 158 had MDR-TBFQ+. At the end of treatment, after excluding 12 patients due to baseline drug susceptibility and culture negatives, 139 of 153 patients (91%) had a favorable outcome. Fourteen patients (9%) had unfavorable outcomes: four deaths, seven treatment changes, two bacteriological failures, and one withdrawal. During treatment, 85 patients (52%) developed myelosuppression, 69 (42%) reported peripheral neuropathy, and none had QTc(F) prolongation >500msec. At 48 weeks of follow-up, 131 patients showed sustained treatment success with the resolution of adverse events in the majority.
CONCLUSION: After 24-36 weeks of treatment, this regimen resulted in a satisfactory favorable outcome in pulmonary MDR-TB patients with additional drug resistance. Cardiotoxicity was minimal, and myelosuppression, while common, was detected early and treated successfully.

© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
DOI: 10.1093/cid/ciac528
PMID: 35767251
 
3. Addressing bedaquiline treatment interruptions in the treatment of drug-resistant TB.

Int J Tuberc Lung Dis. 2022 Jul 1;26(7):671-677. doi: 10.5588/ijtld.21.0678.

Kambili C(1), Rossenu S(2), Hoetelmans RMW(2), Birmingham E(3), Bakare N(4).

SETTING: The recommended dosing regimen for bedaquiline (BDQ), consisting of a 2-week loading phase (400 mg/day), followed by a maintenance phase (200 mg three times/week), might pose challenges when treatment is interrupted and needs to be reinitiated. Guidance on BDQ treatment re-initiation is, therefore, needed.
OBJECTIVE: This pharmacokinetic-based simulation study aimed to provide recommendations for re-initiating BDQ following treatment interruptions.
DESIGN: Simulations of treatment interruptions, defined as any time a patient misses ≥2 consecutive BDQ doses for up to 56 consecutive days (2 months), were assessed using the BDQ population-pharmacokinetic model.RESULTS: Any treatment interruption lasting ≤28 days prior to completing the 14-day loading phase can be managed by completing the remaining loading doses. Scenarios when it is sufficient to simply restart maintenance dosing are discussed. In some scenarios, treatment interruptions require reloading for 1 week prior to restarting maintenance dosing.
CONCLUSIONS: This simulation study provided recommendations for managing BDQ treatment interruptions and underscores the importance of having a robust population-pharmacokinetic model for TB drugs to inform clinical guidance. Such recommendations are valuable to help ensure optimal treatment with BDQ for treating multidrug-resistant TB.

DOI: 10.5588/ijtld.21.0678
PMCID: PMC9272739
PMID: 35768912 [Indexed for MEDLINE]
 
4. Practical and psychosocial challenges faced by caregivers influence the acceptability of multidrug-resistant tuberculosis preventive therapy for young children.

PLoS One. 2022 Jul 14;17(7):e0268560. doi: 10.1371/journal.pone.0268560. eCollection 2022.

Wademan DT(1), Hoddinott G(1), Purchase SE(1), Seddon JA(1)(2), Hesseling AC(1), Garcia-Prats AJ(1)(3), Reis R(4)(5)(6), Reynolds LJ(7)(8).

Drug-resistant (DR) strains of Mycobacterium tuberculosis (M. tb) are increasingly recognised as a threat to global tuberculosis (TB) control efforts. Identifying people with DR-TB exposure/ infection and providing TB preventive therapy (TPT) is a public health priority. TB guidelines advise the evaluation of household contacts of newly diagnosed TB cases, with the provision of TPT to vulnerable populations, including young children (<5 years). Many children become infected with TB through exposure in their household. Levofloxacin is under evaluation as TPT in children exposed to M. tb strains with resistance to rifampicin and isoniazid (multidrug-resistant TB; MDR-TB). Prior to opening a phase 3 prevention trial in children <5 years exposed to MDR-TB, the pharmacokinetics and safety of a novel formulation of levofloxacin given daily was evaluated as part of a lead-in study. We conducted an exploratory qualitative study of 10 caregivers' experiences of administering this formulation. We explored how the acceptability of levofloxacin as TPT is shaped by the broader impacts of MDR-TB on the overall psychological, social, and financial wellbeing of caregivers, many of whom also had experienced MDR-TB. Caregivers reported that the novel levofloxacin formulation was acceptable. However, caregivers described significant psychosocial challenges in the process of incorporating TPT administration to their children into their daily lives, including financial instability, withdrawal of social support and stigma. When caregivers themselves were sick, these challenges became even more acute. Although new child-friendly formulations can ameliorate some of the pragmatic challenges related to TPT preparation and administration, the overall psychosocial burden on caregivers responsible for administering TPT remains a major determinant of effective MDR-TB prevention in children.

DOI: 10.1371/journal.pone.0268560
PMCID: PMC9282439
PMID: 35834509 [Indexed for MEDLINE]

5. The global impact of household contact management for children on multidrug-resistant and rifampicin-resistant tuberculosis cases, deaths, and health-system costs in 2019: a modelling study.

Lancet Glob Health. 2022 Jul;10(7):e1034-e1044. doi: 10.1016/S2214-109X(22)00113-9. Epub 2022 May 18.

Dodd PJ(1), Mafirakureva N(2), Seddon JA(3), McQuaid CF(4).
Comment in Lancet Glob Health. 2022 Jul;10(7):e942-e943.

BACKGROUND: Estimates suggest that at least 30 000 children develop multidrug-resistant or rifampicin-resistant tuberculosis each year. Despite household contact management (HCM) being widely recommended, it is rarely done.
METHODS: We used mathematical modelling to evaluate the potential country-level and global effects and cost-effectiveness of multidrug-resistant or rifampicin-resistant tuberculosis HCM for children younger than 15 years who are living with a person with newly diagnosed multidrug-resistant or rifampicin-resistant tuberculosis. We compared a baseline of no HCM with several HCM strategies and tuberculosis preventive therapy regimens, calculating the effect on multidrug-resistant or rifampicin-resistant tuberculosis cases, deaths, and health-system costs. All HCM strategies involved the screening of children for prevalent tuberculosis disease but with tuberculosis preventive therapy either not given or targeted dependent on age, HIV status, and result of tuberculin skin test. We evaluated the use of fluoroquinolones (ie, levofloxacin and moxifloxacin), delamanid, and bedaquiline as tuberculosis preventive therapy.
FINDINGS: Compared with a baseline without HCM, HCM for all adults diagnosed with multidrug-resistant or rifampicin-resistant tuberculosis in 2019 would have entailed screening 227 000 children (95% uncertainty interval [UI]: 205 000-252 000) younger than 15 years globally, and averted 2350 tuberculosis deaths (1940-2790), costing an additional US$63 million (74-95 million). If all the children within the household who had been in contact with the person with multidrug-resistant or rifampicin-resistant tuberculosis received tuberculosis preventive therapy with levofloxacin, 5620 incident tuberculosis cases (95% UI 4540-6890) and an additional 1240 deaths (970-1540) would have been prevented. Incremental cost-effectiveness ratios were lower than half of per-capita gross domestic product for most interventions in most countries. Targeting only children younger than 5 years and those living with HIV reduced the number of incident cases and deaths averted, but improved cost-effectiveness. Tuberculosis preventive therapy with delamanid increased the effect, in terms of reduced incidence and mortality, compared with levofloxacin.
INTERPRETATION: HCM for patients with multidrug-resistant or rifampicin-resistant tuberculosis is cost-effective in most settings and could avert a substantial proportion of multidrug-resistant or rifampicin-resistant tuberculosis cases and deaths in children globally.
FUNDING: UK Medical Research Council.

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/S2214-109X(22)00113-9
PMCID: PMC9197775
PMID: 35597248 [Indexed for MEDLINE]

From our June 2022 Newsletter

1. 25 years of surveillance of drug-resistant tuberculosis: achievements,
challenges, and way forward.

 
Lancet Infect Dis. 2022 Jul;22(7):e191-e196. doi: 10.1016/S1473-3099(21)00808-2.
Epub 2022 Mar 3.
 
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.
 
DOI: 10.1016/S1473-3099(21)00808-2
PMCID: PMC8893725
PMID: 35248168

 
2. Proposed Linezolid Dosing Strategies to Minimize Adverse Events for Treatment of Extensively Drug-Resistant Tuberculosis.
 
Clin Infect Dis. 2022 May 30;74(10):1736-1747. doi: 10.1093/cid/ciab699.
 
Imperial MZ(1), Nedelman JR(2), Conradie F(3), Savic RM(1).
 
BACKGROUND: We evaluated Nix-TB trial data (NCT02333799, N = 109) to provide dosing recommendations to potentially minimize linezolid toxicity in patients with extensively drug-resistant tuberculosis.
METHODS: A pharmacokinetic model and toxicodynamic models for peripheral neuropathy, hemoglobin, and platelets were developed. Simulations compared safety outcomes for daily linezolid of 1200 and 600 mg, with and without dose adjustments for toxicity. Severe neuropathy was based on symptom scores from the Brief Peripheral Neuropathy Screen. Severe anemia and thrombocytopenia were defined as ≥ grade 3 adverse events according to the NIAID Division of Microbiology and Infectious Disease Adult Toxicity table.
RESULTS: Predicted concentration-time profiles were a major predictor in all toxicodynamic models. Simulations showed higher percentages of patients with severe neuropathy (median, 19%; 90% confidence interval [CI], 17%-22% vs 5%, 4%-7%) and severe anemia (15%, 12%-17% vs 1%, 0%-2%) between 1200 and 600 mg daily linezolid. No differences in severe thrombocytopenia were observed (median, <1% for both daily doses). Generally, neuropathy occurred after 3 to 6 months of treatment and, with protocol-specified management, reversed within 15 months after onset. Simulations indicated that a >10% decrease in hemoglobin level after 4 weeks of treatment would have maximum sensitivity (82%) and specificity (84%) for predicting severe anemia. Reducing the dose from 1200 to 600 mg triggered by this marker may prevent 60% (90% CI, 45%-72%) of severe anemia.
CONCLUSIONS: Simple neuropathy symptom and hemoglobin monitoring may guide linezolid dosing to avoid toxicities, but prospective testing is needed to confirm the benefit-to-risk ratio.
 
© The Author(s) 2021. Published by Oxford University Press for the Infectious
Diseases Society of America.
 
DOI: 10.1093/cid/ciab699
PMCID: PMC9155613
PMID: 34604901 [Indexed for MEDLINE]
 
3. Treatment outcomes 24 months after initiating short, all-oral bedaquiline-containing or injectable-containing rifampicin-resistant tuberculosis treatment regimens in South Africa: a retrospective cohort study.
 
Lancet Infect Dis. 2022 Jul;22(7):1042-1051. doi: 10.1016/S1473-3099(21)00811-2.
Epub 2022 May 2.
 
Ndjeka N(1), Campbell JR(2), Meintjes G(3), Maartens G(3), Schaaf HS(4), Hughes
J(4), Padanilam X(5), Reuter A(6), Romero R(7), Ismail F(8), Enwerem M(9),
Ferreira H(10), Conradie F(11), Naidoo K(12), Menzies D(2).
 
BACKGROUND: There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable
group).
METHODS: Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9-12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes.
FINDINGS: Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8-20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1-8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0-5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4-11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment.
INTERPRETATION: Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.
FUNDING: WHO Global TB Programme.
TRANSLATION: For the French translation of the abstract see Supplementary
Materials section.
 
This is an Open Access article published under the CC BY 3.0 IGO license which
permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited. In any use of this article, there should be
no suggestion that WHO endorses any specific organisation, products or services.
The use of the WHO logo is not permitted. This notice should be preserved along
with the article's original URL.
 
DOI: 10.1016/S1473-3099(21)00811-2
PMID: 35512718
 
4. Global availability of susceptibility testing for second-line anti-tuberculosis agents.
 
Int J Tuberc Lung Dis. 2022 Jun 1;26(6):524-528. doi: 10.5588/ijtld.21.0420.
 
Lazarchik A(1), Nyaruhirira AU(2), Chiang CY(3), Wares F(4), Horsburgh CR(5).
 
BACKGROUND: The continued development of new anti-TB agents brings with it a demand for accompanying treatment regimens to prevent the development of resistance. Effectively meeting this demand requires an understanding of the pathogen´s susceptibility to various treatment options, which in turn makes access to antibiotic susceptibility testing (AST) a paramount consideration in the global treatment of TB.
METHODS: A 12-question, quantitative and qualitative survey was developed to gauge global capacity and access to AST. The survey was disseminated to members of the Global Laboratory Initiative, Global Drug-resistant TB Initiative, and the TB section of the International Union Against Tuberculosis and Lung Disease to solicit responses from pertinent stakeholders.
RESULTS: A total of 323 complete responses representing 84 countries and all WHO Regions were collected. AST capacity for fluoroquinolones and second-line injectables was high in all WHO Regions. AST capacity for the new and repurposed drugs is highest in the European Region, Region of the Americas and the Western Pacific Region, but quite limited in the African and Eastern Mediterranean Regions. The AST turnaround time for second-line drugs was delayed compared to that for first-line drugs as samples needed to be sent farther for analysis. Common barriers to AST for second-line drugs were lack of specimen transportation infrastructure, high costs, and lack of specialised laboratory workers and specialised laboratory facilities.
CONCLUSION: Without expanding global access to AST, the growing availability of new treatment options will likely be threatened by accompanying increase in resistance. There is an earnest and pressing need to improve capacity and access to AST alongside treatment options.
 
DOI: 10.5588/ijtld.21.0420
PMID: 35650708 [Indexed for MEDLINE]

5. Keeping up with the guidelines: design changes to the STREAM stage 2 randomised controlled non-inferiority trial for rifampicin-resistant tuberculosis.
 
Trials. 2022 Jun 7;23(1):474. doi: 10.1186/s13063-022-06397-4.
 
Goodall RL(1), Sanders K(2), Bronson G(3), Gurumurthy M(4), Torrea G(5),
Meredith S(2), Nunn A(2), Rusen ID(3); STREAM Trial Team.
 
Collaborators: Bronson G, Gurumurthy M, Komrska J, Patel L, Qawiy I, Rusen ID,
Ali S, Bellenger K, Bennet D, Bennet R, Dodds W, Goodall R, Meredith S, Murphy
B, Nunn A, Roach C, Sanders K, Whitney J, Van Deun A, Torrea G, Chiang CY, Rosu
L, Squire B, Madan J.
 
Results from the STREAM stage 1 trial showed that a 9-month regimen for patients with rifampicin-resistant tuberculosis was non-inferior to the 20-month regimen recommended by the 2011 WHO treatment guidelines. Similar levels of severe adverse events were reported on both regimens suggesting the need for further research to optimise treatment. Stage 2 of STREAM evaluates two additional short-course regimens, both of which include bedaquiline. Throughout stage 2 of STREAM, new drug choices and a rapidly changing treatment landscape have necessitated changes to the trial's design to ensure it remains ethical and relevant. This paper describes changes to the trial design to ensure that stage 2 continues to answer important questions. These changes include the early closure to recruitment of two trial arms and an adjustment to the definition of the primary endpoint. If the STREAM experimental regimens are shown to be non-inferior or superior to the stage 1 study regimen, this would represent an important contribution to evidence about potentially more tolerable and more efficacious MDR-TB regimens, and a welcome advance for patients with rifampicin-resistant tuberculosis and tuberculosis control programmes globally. Trial registration: ISRCTN ISRCTN18148631. Registered 10 February
2016.
 
© 2022. The Author(s).
 
DOI: 10.1186/s13063-022-06397-4
PMCID: PMC9171092
PMID: 35672833 [Indexed for MEDLINE]
 
Conflict of interest statement: The authors declare that they have no competing
interests.

From Our May 2022 Newsletter

Cost of TB prevention and treatment in the Philippines in 2017

Int J Tuberc Lung Dis. 2022 May 1;26(5):392-398. doi: 10.5588/ijtld.21.0622.

Capeding TPJ(1), Rosa JD(1), Lam H(1), Gaviola DG(2), Garfin AMC(2), Hontiveros C(2), Cunnama L(3), Laurence YV(4), Kitson N(4), Vassall A(4), Sweeney S(4), Garcia-Baena I(5).

BACKGROUND: The Philippines aims to accelerate TB reduction through the provision of universally accessible and affordable services. The objectives of this paper are to estimate the costs of TB services and interventions using a health systems´ perspective, and to explore cost differences in service delivery via primary care facilities or hospitals.
METHODS: Data were collected from a multi-stage stratified random sampling of 28 facilities in accordance with Global Health Cost Consortium costing standards and analysis tools. Unit costs (in US$) estimated using top-down (TD) and bottom-up (BU) approaches, are summarised following Value TB reporting standards and by broad facility type.
RESULTS: Cost of delivering 32 TB services and eight interventions varied by costing method and delivery platform. Average BU costs ranged from US$0.38 for treatment support visits, US$2.5 for BCG vaccination, US$19.48 for the Xpert® MTB/RIF test to US$3,677 for MDR-TB treatment using the long regimen. Delivering TB care in hospitals was generally more costly than in primary care facilities, except for TB prevention in children and MDR-TB treatment using the long regimen.
CONCLUSION: Comprehensive costing data for TB care in the Philippines are now available to aid in the design, planning, and prioritisation of delivery models to End TB.

DOI: 10.5588/ijtld.21.0622
PMCID: PMC9067429
PMID: 35505478 [Indexed for MEDLINE]
 
Moxifloxacin Pharmacokinetics, Cardiac Safety, and Dosing for the Treatment of Rifampicin-Resistant Tuberculosis in Children
 
Clin Infect Dis. 2022 Apr 28;74(8):1372-1381. doi: 10.1093/cid/ciab641.

Radtke KK(1), Hesseling AC(2), Winckler JL(2), Draper HR(2), Solans BP(1), Thee S(2)(3), Wiesner L(4), van der Laan LE(2), Fourie B(2), Nielsen J(5), Schaaf HS(2), Savic RM(1), Garcia-Prats AJ(2)(6).

BACKGROUND: Moxifloxacin is a recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics and QT interval prolongation and evaluate optimal dosing in children with RR-TB.
METHODS: Pharmacokinetic data were pooled from 2 observational studies in South African children with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing.
RESULTS: Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8-15] years); 16 (19%) were aged <2 years, and 8 (9%) were living with human immunodeficiency virus (HIV). The median (range) moxifloxacin dose on pharmacokinetic sampling days was 11 mg/kg (6.1 to 17). Apparent clearance was 6.95 L/h for a typical 16-kg child. Stunting and HIV increased apparent clearance. Crushed or suspended tablets had faster absorption. The median (range) maximum change in QTcF after moxifloxacin administration was 16.3 (-27.7 to 61.3) ms. No child had QTcF ≥500 ms. The concentration-QTcF relationship was nonlinear, with a maximum drug effect (Emax) of 8.80 ms (interindividual variability = 9.75 ms). Clofazimine use increased Emax by 3.3-fold. Model-based simulations of moxifloxacin pharmacokinetics predicted that current dosing recommendations are too low in children.
CONCLUSIONS: Moxifloxacin doses above 10-15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when coadministered with other QT-prolonging agents.

© The Author(s) 2021. 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/ciab641
PMCID: PMC9049278
PMID: 34286843 [Indexed for MEDLINE]
 
Delamanid Added to an Optimized Background Regimen in Children with Multidrug-Resistant Tuberculosis: Results of a Phase I/II Clinical Trial
 
Antimicrob Agents Chemother. 2022 May 17;66(5):e0214421. doi:10.1128/aac.02144-21. Epub 2022 Apr 11.
 
Garcia-Prats AJ(1), Frias M(2), van der Laan L(1), De Leon A(3), Gler MT(2), Schaaf HS(1), Hesseling AC(1), Malikaarjun S(4), Hafkin J(4).
 
Delamanid has been demonstrated to be safe and effective for treatment of adult multidrug-resistant tuberculosis (MDR-TB) and has been approved by the European Commission for treatment of pediatric MDR-TB patients at least 10 kg in weight, making the drug no longer limited to adults. A 10-day phase I age deescalation study was conducted, followed by a 6-month phase II extension study, to assess the pharmacokinetics, safety, tolerability, and preliminary efficacy of delamanid when combined with optimized background regimen (OBR) in children (birth to 17 years) with MDR-TB. Delamanid administered at 100 mg twice-daily (BID), 50 mg BID, and 25 mg BID resulted in exposures in 12- to 17- (n = 7), 6- to 11- (n = 6), and 3- to 5-year-olds (n = 12), respectively, comparable with those in adults at the approved adult dosage (100 mg BID). Exposures in 0- to 2-year-olds (n = 12) following a weight-based dosing regimen (5 mg once daily [QD] to 10 mg BID) were lower than predicted from pharmacokinetic modeling of the older three age groups and below target exposures in adults. Overall, the safety profile of delamanid in children 0 to 17 years of age was similar to the adult profile. At 24 months after the first delamanid dose, 33/37 children (89.2%) had favorable treatment outcomes, as defined by the World Health Organization (15/37 [40.5%] cured and 18/37 [48.6%] completed treatment). A new pediatric delamanid formulation used in 0- to 2-year-olds and 3- to 5-year-olds was palatable per child/parent and nurse/investigator reports. Data from initial phase I/II studies inform our understanding of delamanid use in children and support its further assessment in the setting of pediatric MDR-TB. (This study has been registered at ClinicalTrials.gov under identifiers NCT01856634 [phase I trial] and NCT01859923 [phase II trial].).
 
DOI: 10.1128/aac.02144-21
PMCID: PMC9112969
PMID: 35404075 [Indexed for MEDLINE]
 
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 May 1;41(5):401-404. doi: 
10.1097/INF.0000000000003486.

Shah I(1), Antony S(1), Jaiswal A(1), Bodhanwala M(2), Shah D(3), Tipre P(3), 
Salve J(4), Parmar M(4)(5), Sachdeva KS(6).

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 [Indexed for MEDLINE]

Rapid molecular tests for tuberculosis and tuberculosis drug resistance: a qualitative evidence synthesis of recipient and provider views

Cochrane Database Syst Rev. 2022 Apr 26;4(4):CD014877. doi: 10.1002/14651858.CD014877.pub2.

Engel N(1), Ochodo EA(2)(3), Karanja PW(4), Schmidt BM(5), Janssen R(1), Steingart KR(6), Oliver S(7)(8).

Update of doi: 10.1002/14651858.CD014877.

BACKGROUND: Programmes that introduce rapid molecular tests for tuberculosis and tuberculosis drug resistance aim to bring tests closer to the community, and thereby cut delay in diagnosis, ensure early treatment, and improve health outcomes, as well as overcome problems with poor laboratory infrastructure and inadequately trained personnel. Yet, diagnostic technologies only have an impact if they are put to use in a correct and timely manner. Views of the intended beneficiaries are important in uptake of diagnostics, and their effective use also depends on those implementing testing programmes, including providers, laboratory professionals, and staff in health ministries. Otherwise, there is a risk these technologies will not fit their intended use and setting, cannot be made to work and scale up, and are not used by, or not accessible to, those in need.
OBJECTIVES: To synthesize end-user and professional user perspectives and experiences with low-complexity nucleic acid amplification tests (NAATs) for detection of tuberculosis and tuberculosis drug resistance; and to identify implications for effective implementation and health equity.
SEARCH METHODS: We searched MEDLINE, Embase, CINAHL, PsycInfo and Science Citation Index Expanded databases for eligible studies from 1 January 2007 up to 20 October 2021. We limited all searches to 2007 onward because the development of Xpert MTB/RIF, the first rapid molecular test in this review, was completed in 2009.
SELECTION CRITERIA: We included studies that used qualitative methods for data collection and analysis, and were focused on perspectives and experiences of users and potential users of low-complexity NAATs to diagnose tuberculosis and drug-resistant tuberculosis. NAATs included Xpert MTB/RIF, Xpert MTB/RIF Ultra, Xpert MTB/XDR, and the Truenat assays. Users were people with presumptive or confirmed tuberculosis and drug-resistant tuberculosis (including multidrug-resistant (MDR-TB)) and their caregivers, healthcare providers, laboratory technicians and managers, and programme officers and staff; and were from any type of health facility and setting globally. MDR-TB is tuberculosis caused by resistance to at least rifampicin and isoniazid, the two most effective first-line drugs used to treat tuberculosis.
DATA COLLECTION AND ANALYSIS: We used a thematic analysis approach for data extraction and synthesis, and assessed confidence in the findings using GRADE CERQual approach. We developed a conceptual framework to illustrate how the findings relate.
MAIN RESULTS: We found 32 studies. All studies were conducted in low- and middle-income countries. Twenty-seven studies were conducted in high-tuberculosis burden countries and 21 studies in high-MDR-TB burden countries. Only one study was from an Eastern European country. While the studies covered a diverse use of low-complexity NAATs, in only a minority of studies was it used as the initial diagnostic test for all people with presumptive tuberculosis. We identified 18 review findings and grouped them into three overarching categories. Critical aspects users value People with tuberculosis valued reaching diagnostic closure with an accurate diagnosis, avoiding diagnostic delays, and keeping diagnostic-associated cost low. Similarly, healthcare providers valued aspects of accuracy and the resulting confidence in low-complexity NAAT results, rapid turnaround times, and keeping cost to people seeking a diagnosis low. In addition, providers valued diversity of sample types (for example, gastric aspirate specimens and stool in children) and drug resistance information. Laboratory professionals appreciated the improved ease of use, ergonomics, and biosafety of low-complexity NAATs compared to sputum microscopy, and increased staff satisfaction. Challenges reported to realizing those values People with tuberculosis and healthcare workers were reluctant to test for tuberculosis (including MDR-TB) due to fears, stigma, or cost concerns. Thus, low-complexity NAAT testing is not implemented with sufficient support or discretion to overcome barriers that are common to other approaches to testing for tuberculosis. Delays were reported at many steps of the diagnostic pathway owing to poor sample quality; difficulties with transporting specimens; lack of sufficient resources; maintenance of low-complexity NAATs; increased workload; inefficient work and patient flows; over-reliance on low-complexity NAAT results in lieu of clinical judgement; and lack of data-driven and inclusive implementation processes. These challenges were reported to lead to underutilization.  Concerns for access and equity The reported concerns included sustainable funding and maintenance and equitable use of resources to access low-complexity NAATs, as well as conflicts of interest between donors and people implementing the tests. Also, lengthy diagnostic delays, underutilization of low-complexity NAATs, lack of tuberculosis diagnostic facilities in the community, and too many eligibility restrictions hampered access to prompt and accurate testing and treatment. This was particularly the case for vulnerable groups, such as children, people with MDR-TB, or people with limited ability to pay. We had high confidence in most of our findings.
AUTHORS' CONCLUSIONS: Low-complexity diagnostics have been presented as a solution to overcome deficiencies in laboratory infrastructure and lack of skilled professionals. This review indicates this is misleading. The lack of infrastructure and human resources undermine the added value new diagnostics of low complexity have for recipients and providers. We had high confidence in the evidence contributing to these review findings. Implementation of new diagnostic 
technologies, like those considered in this review, will need to tackle the challenges identified in this review including weak infrastructure and systems, and insufficient data on ground level realities prior and during implementation, as well as problems of conflicts of interest in order to ensure equitable use of resources.

Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

DOI: 10.1002/14651858.CD014877.pub2
PMCID: PMC9038447
PMID: 35470432 [Indexed for MEDLINE]

Treatment outcomes 24 months after initiating short, all-oralbedaquiline-containing or injectable-containing rifampicin-resistant tuberculosis treatment regimens in South Africa: a retrospective cohort study
 
Lancet Infect Dis. 2022 May 2:S1473-3099(21)00811-2. doi:10.1016/S1473-3099(21)00811-2. Online ahead of print.
 
Ndjeka N(1), Campbell JR(2), Meintjes G(3), Maartens G(3), Schaaf HS(4), HughesJ(4), Padanilam X(5), Reuter A(6), Romero R(7), Ismail F(8), Enwerem M(9), Ferreira H(10), Conradie F(11), Naidoo K(12), Menzies D(2).
 
BACKGROUND: There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group).
METHODS: Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9-12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of
treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus
death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes.
FINDINGS: Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8-20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1-8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0-5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4-11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment.
INTERPRETATION: Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.
FUNDING: WHO Global TB Programme.
TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
 
This is an Open Access article published under the CC BY 3.0 IGO license which
permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited. In any use of this article, there should be
no suggestion that WHO endorses any specific organisation, products or services.
The use of the WHO logo is not permitted. This notice should be preserved along
with the article's original URL.
 
DOI: 10.1016/S1473-3099(21)00811-2
PMID: 35512718

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 &gt; 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 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]

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