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From Our May 2021 Newsletter


Multidrug-resistant tuberculosis imported into low-incidence countries-a GeoSentinel analysis, 2008-2020.

J Travel Med. 2021 May 12:taab069. doi: 10.1093/jtm/taab069. Online ahead of 
Eimer J(1), Patimeteeporn C(2), Jensenius M(3), Gkrania-Klotsas E(4), Duvignaud 
A(5), Barnett ED(6), Hochberg NS(7), Chen LH(8), Trigo-Esteban E(9), Gertler 
M(10), Greenaway C(11), Grobusch MP(12)(13), Angelo KM(2), Hamer DH(7)(14), 
Caumes E(15)(16), Asgeirsson H(1)(17).
BACKGROUND: Early detection of imported multidrug-resistant tuberculosis (MDR-TB) is crucial, but knowledge gaps remain about migration- and travel-associated MDR-TB epidemiology. The aim was to describe epidemiologic characteristics among international travelers and migrants with MDR-TB. METHODS: Clinician-determined and microbiologically confirmed MDR-TB diagnoses deemed to be related to travel or migration were extracted from GeoSentinel, a global surveillance network of travel and tropical medicine clinics, from January 2008 through December 2020. MDR-TB was defined as resistance to both isoniazid and rifampicin. Additional resistance to either a fluoroquinolone or a second-line injectable drug was categorized as pre-extensively drug-resistant (pre-XDR) TB, and as extensively drug-resistant (XDR) TB when resistance was detected for both. Sub-analyses were performed based on degree of resistance and country of origin.
RESULTS: Of 201 patients, 136 had MDR-TB (67.7%), 25 had XDR-TB (12.4%), 23 had pre-XDR TB (11.4%), and 17 had unspecified MDR- or XDR-TB (8.5%); 196 (97.5%) were immigrants, of which 92 (45.8%) originated from the former Soviet Union. The median interval from arrival to presentation was 154 days (interquartile range [IQR]: 10-751 days); 34.3% of patients presented within 1 month after immigration, 30.9% between 1 and 12 months, and 34.9% after ≥1 year. Pre-XDR- and XDR-TB patients from the former Soviet Union other than Georgia presented earlier than those with MDR-TB (26 days [IQR: 8-522] vs. 369 days [IQR: 84-827]) while patients from Georgia presented very early, irrespectively of the level of resistance (8 days [IQR: 2-18] vs. 2 days [IQR: 1-17]). 
CONCLUSIONS: MDR-TB is uncommon in traditional travellers. Purposeful medical migration may partly explain differences in time to presentation among different groups. Public health resources are needed to better understand factors contributing to cross-border MDR-TB spread and to develop strategies to optimize care of TB-infected patients in their home countries before migration.
© International Society of Travel Medicine 2021. Published by Oxford University 
Press. All rights reserved. For Permissions, please e-mail:
DOI: 10.1093/jtm/taab069
PMID: 33987682

Emergence of additional drug resistance during treatment of multidrug-resistant tuberculosis in China: a prospective cohort study.
Clin Microbiol Infect. 2021 Apr 23:S1198-743X(21)00169-5. doi: 
10.1016/j.cmi.2021.04.001. Online ahead of print.
Hu Y(1), Zheng X(1), Davies Forsman L(2), Ning Z(3), Chen C(4), Gao Y(1), Zhang 
Z(3), Lu W(4), Werngren J(5), Bruchfeld J(2), Hoffner S(6), Xu B(7).
OBJECTIVES: Little is known about how additional second-line drug resistance emerges during multidrug resistant tuberculosis (MDR-TB) treatment. The present study aimed to investigate the influence of microevolution, exogenous reinfection and mixed infection on second-line drug resistance during the 
recommended 2-year MDR-TB treatment. 
METHODS: Individuals with MDR-TB were enrolled between 2013 and 2016 in a multicentre prospective observational cohort study and were followed up for 2 years until treatment completion. Whole-genome sequencing (WGS) was applied for serial Mycobacterium tuberculosis isolates from study participants throughout the treatment, to study the role of microevolution, exogenous reinfection and mixed infection in the development of second-line drug resistance. 
RESULTS: Of the 286 enrolled patients with MDR-TB, 63 (22.0%) M. tuberculosis isolates developed additional drug resistance during the MDR-TB treatment, including 5 that fulfilled the criteria of extensively drug-resistant TB. By comparing WGS data of serial isolates retrieved from the patients throughout treatment, 41 (65.1%) of the cases of additional second-line drug resistance were the result of exogenous reinfection, 18 (28.6%) were caused by acquired drug resistance, i.e. microevolution, while the remaining 4 (6.3%) were caused by mixed infections with drug-resistant and drug-susceptible strains. In multivariate analysis, previous TB treatment (adjusted hazard ratio (aHR) 2.51, 95% CI 1.51-4.18), extensive disease on chest X-ray (aHR 3.39, 95% CI 2.03-5.66) and type 2 diabetes mellitus (aHR 4.00, 95% CI 2.22-7.21) were independent risk factors associated with the development of additional second-line drug resistance. CONCLUSIONS: A large proportion of additional second-line drug resistance emerging during MDR-TB treatment was attributed to exogenous reinfection, indicating the urgency of infection control in health facilities as well as the need for repeated drug susceptibility testing throughout MDR-TB treatment.
Copyright © 2021 European Society of Clinical Microbiology and Infectious 
Diseases. Published by Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.cmi.2021.04.001
PMID: 33895338

Tuberculosis, COVID-19 and hospital admission: Consensus on pros and cons based on a review of the evidence.
Pulmonology. 2021 May-Jun;27(3):248-256. doi: 10.1016/j.pulmoe.2020.12.016. Epub 
2021 Jan 28.
Migliori GB(1), Visca D(2), van den Boom M(3), Tiberi S(4), Silva DR(5), Centis 

R(6), D'Ambrosio L(7), Thomas T(8), Pontali E(9), Saderi L(10), Schaaf HS(11), 

Sotgiu G(10); contributing members of the Global Tuberculosis Network.
The scientific debate on the criteria guiding hospitalization of tuberculosis (TB) and COVID-19 patients is ongoing. The aim of this review is to present the available evidence on admission for TB and TB/COVID-19 patients and discuss the criteria guiding hospitalization. Furthermore, recommendations are made as derived from recently published World Health Organization documents, based on Global Tuberculosis Network (GTN) expert opinion. The core published documents and guidelines on the topic have been reviewed. The proportion of new TB cases admitted to hospital ranges between 50% and 100% while for multidrug-resistant (MDR) TB patients it ranges between 85 and 100% globally. For TB patients with COVID-19 the proportion of cases admitted is 58%, probably reflecting different scenarios related to the diagnosis of COVID-19 before, after or at the same time of the active TB episode. The hospital length of stay for drug-susceptible TB ranges from 20 to 60 days in most of countries, ranging from a mean of 10 days (USA) to around 90 days in the Russian Federation. Hospitalization is longer for MDR-TB (50-180 days). The most frequently stated reasons for recommending hospital admission include: severe TB, infection control concerns, co-morbidities and drug adverse events which cannot be managed at out-patient level. The review also provides suggestions on hospital requirements for safe admissions as well as patient discharge criteria, while underlining the relevance of patient-centred care through community/home-based care.
Copyright © 2021 Sociedade Portuguesa de Pneumologia. Published by Elsevier 
España, S.L.U. All rights reserved.
DOI: 10.1016/j.pulmoe.2020.12.016
PMCID: PMC7843149
PMID: 33547028 [Indexed for MEDLINE]

Diagnostic accuracy of the FluoroType MTB and MTBDR VER 2.0 assays for the centralised high throughput detection of Mycobacterium tuberculosis complex DNA and isoniazid and rifampicin resistance.
Clin Microbiol Infect. 2021 Apr 29:S1198-743X(21)00209-3. doi: 
10.1016/j.cmi.2021.04.022. Online ahead of print.
Dippenaar A(1), Derendinger B(1), Dolby T(2), Beylis N(3), van Helden PD(1), 
Theron G(1), Warren RM(1), de Vos M(4).
OBJECTIVES: To evaluate the accuracy of two new molecular diagnostic tests for the detection of drug resistant tuberculosis, the FluoroType MTB and MTBDR VER 2.0 assays, in combination with manual and automated DNA extraction methods.
METHODS: Sputa from 360 Xpert Ultra Mycobacterium tuberculosis complex (MTBC)-positive patients and 250 Xpert Ultra MTBC-negative patients were tested. GenoType MTBDRplus served as reference for MTBC and drug resistance detection. Sanger sequencing was used to resolve discrepancies.
RESULTS: FluoroType MTB VER 2.0 showed similar MTBC sensitivity compared to FluoroType MTBDR VER 2.0 [manual DNA extraction: 91.6% (294/321) vs. 89.8% (291/324) (p=0.4); automated DNA extraction: 92.1% (305/331) vs 87.7% (291/332) (p=0.05)]. FluoroType MTBDR VER2.0 showed comparable diagnostic accuracy to FluoroType MTBDR VER1.0 as previously reported for the detection of MTBC and rifampicin and isoniazid resistance.
CONCLUSIONS: The FluoroType MTB and MTBDR VER 2.0 assays together with an automated DNA extraction and PCR set-up platform may improve laboratory operational efficiency for the diagnosis of MTBC and resistance to rifampicin and isoniazid and show promise for the implementation in a centralised molecular drug susceptibility testing model.
Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.cmi.2021.04.022
PMID: 33933566
Rapid Tuberculosis Diagnostics Including Molecular First- and Second-Line Resistance Testing Based on a Novel Microfluidic DNA Extraction Cartridge.
J Mol Diagn. 2021 May;23(5):643-650. doi: 10.1016/j.jmoldx.2021.02.004. Epub 
2021 Feb 23.
Beutler M(1), Homann AR(2), Mihalic M(3), Plesnik S(3), Niebling L(2), Eckart 
M(4), Allerheiligen V(4), Czurratis D(5), Maharjan B(6), Shrestha B(6), Parpieva 
N(7), Turaev L(7), Sayfutdinov Z(7), Hofmann-Thiel S(8), Grasse W(9), 
Metzger-Boddien C(9), Paust N(2), Hoffmann H(10).
Xpert MTB/RIF testing has improved tuberculosis (TB) diagnostics and rifampicin (Rif) resistance testing worldwide. However, it has weaknesses, such as its restriction to Rif resistance testing and the inability to use extracted DNA for further testing. Herein, a holistic diagnostic workflow, including TB detection 
and resistance testing toward Rif, isoniazid, and important second-line drugs (SLDs), based on a novel microfluidic DNA extraction cartridge (TB-Disk), is presented. DNA from 73 precharacterized sputum samples was extracted with TB-Disk, including 45 clinical and bacteriologically confirmed TB samples, nine TB-negative samples, and 19 sputum samples spiked with twofold dilutions of TB bacteria. The extracted DNA was subjected to further testing with FluoroType MTB (FT-MTB), GenoType MTBDRplus (GT-plus), and GenoType MTBDRsl. A total of 100% (20/20) and 72% (18/25) of smear-positive and smear-negative TB samples were identified as Mycobacterium tuberculosis complex positive. A total of 79% (33/42) of subsequently GT-plus tested samples yielded a valid result. Eight samples were identified as multidrug-resistant TB by GT-plus and further tested for resistance toward SLDs using GenoType MTBDRsl, yielding 75% (6/8) valid results. FT-MTB with cartridge-based DNA extraction (Disk-DNA) and DNA extracted with FluoroLyse yielded similar analytical sensitivities. FT-MTB with Disk-DNA was 100% specific. TB-Disk in combination with FT-MTB enables sensitive TB detection. The Disk-DNA can be further  used for screening resistance toward first-line drugs and SLDs.
Copyright © 2021 Association for Molecular Pathology and American Society for 
Investigative Pathology. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jmoldx.2021.02.004
PMID: 33636391

From Our March 2021 Newsletter

Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis.
J Antimicrob Chemother. 2021 Mar 12;76(4):1019-1024. doi: 10.1093/jac/dkaa550.
Alghamdi WA(1), Al-Shaer MH(2), Kipiani M(3), Barbakadze K(3), Mikiashvili L(3), Kempker RR(4), Peloquin CA(2).
BACKGROUND: Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use.
OBJECTIVES: To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis.
METHODS: A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4-6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored.
RESULTS: Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0-24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0-12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine.
CONCLUSIONS: We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.
© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email:
DOI: 10.1093/jac/dkaa550
PMCID: PMC7953320
PMID: 33378452

Dynamic needs and challenges of people with drug-resistant tuberculosis and HIV  in South Africa: a qualitative study.

Lancet Glob Health. 2021 Apr;9(4):e479-e488. doi: 10.1016/S2214-109X(20)30548-9.
Daftary A(1), Mondal S(2), Zelnick J(3), Friedland G(4), Seepamore B(5), Boodhram R(6), Amico KR(7), Padayatchi N(6), O'Donnell MR(8).
BACKGROUND: There is little evidence of patient acceptability for drug-resistant tuberculosis (DRTB) care in the context of new treatment regimens and HIV co-infection. We aim to describe experiences of DRTB-HIV care among patients in KwaZulu-Natal province, South Africa.
METHODS: In this qualitative study using Bury's framework for chronic illness, we conducted 13 focus groups at a tertiary hospital with 55 patients co-infected with DRTB and HIV (28 women, 27 men) who were receiving new bedaquiline-based treatment for DRTB, concurrent with antiretroviral therapy. Eligible patients were consenting adults (aged >18 years) with confirmed DRTB and HIV who were enrolled into the PRAXIS study within 2 weeks of initiating bedaquiline-based treatment for DRTB. Participants were recruited from the PRAXIS cohort to participate in a focus group based on their time in DRTB treatment: early (2-6 weeks after treatment initiation), middle (2-6 months after discharge or treatment initiation if never hospitalised), and late (>6 months after treatment initiation). Focus groups were carried out in isiZulu language, audio recorded, and translated to English within 4 weeks. Participants were asked about their experiences of DRTB and HIV care and treatment, and qualitative data were coded and thematically analysed.
FINDINGS: From March, 2017, to June, 2018, distinctive patient challenges were identified at four critical stages of DRTB care: diagnosis, marked by centralised hospitalisation, renunciation from routine life, systemic stigmatisation and, for patients with longstanding HIV, renewed destabilisation; treatment initiation, marked by side-effects, isolation, and social disconnectedness; discharge, marked by brief respite and resurgent therapeutic and social disruption; and continuity, marked by deepening socioeconomic challenges despite clinical recovery. The periods of diagnosis and discharge into the community were particularly difficult. Treatment information and agency in decision making was a persistent gap. Sources of stigmatisation shifted with movement between the hospital and community. Resilience was built by connecting to peers, self-isolating, financial and material security, and a focus on recovery.
INTERPRETATION: People with DRTB and HIV undergo disruptive, life-altering experiences. The lack of information, agency, and social protections in DRTB care and treatment causes wider-reaching challenges for patients compared with HIV. Decentralised, community, peer-support, and differentiated care models for DRTB might be ameliorative and help to maximise the promise of new regimens. FUNDING: US National Institutes of Health. TRANSLATION: For the isiZulu translation of the abstract see Supplementary Materials section.
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/S2214-109X(20)30548-9
PMID: 33740409

Neuropsychiatric toxicity and cycloserine concentrations during treatment for  multidrug-resistant tuberculosis.
Int J Infect Dis. 2021 Mar 5:S1201-9712(21)00206-X. doi: 10.1016/j.ijid.2021.03.001. Online ahead of print.
Court R(1), Centner CM(2), Chirehwa M(3), Wiesner L(4), Denti P(5), de Vries N(6), Harding J(7), Gumbo T(8), Maartens G(9), McIlleron H(10).
BACKGROUND: Cycloserine, or its structural analogue terizidone, has been associated with neuropsychiatric toxicity (psychosis, depression, and neuropathy). There are limited prospective clinical data on the incidence and risk factors for neuropsychiatric toxicity in TB patients treated with cycloserine.
METHOD: We prospectively evaluated neuropsychiatric toxicity using validated screening tools in patients with multi-drug resistant tuberculosis treated with terizidone. Cox proportional hazard modelling was performed to explore the effects of clinical variables and measures of cycloserine pharmacokinetics in plasma.
RESULTS: We recruited 144 participants: 78 men; median age 35.2 years; 91 (63%) HIV-infected. Fifty-five (38%) participants developed at least one neuropsychiatric event (30 cases per 100 person-months): 50 (35%) neuropathy, 14 (10%) depression, and 11 (8%) psychosis. Neuropathy was independently associated with cycloserine clearance (aHR:0.34, p:0.03) and high-dose pyridoxine (200 mg vs. 150 mg daily).
CONCLUSION: We observed a high incidence of early neuropsychiatric toxicity in this cohort of patients treated with terizidone. Cycloserine clearance and higher doses of pyridoxine are associated with incident or worsening peripheral neuropathy.
Copyright © 2021. Published by Elsevier Ltd.
DOI: 10.1016/j.ijid.2021.03.001
PMID: 33684562

Drug susceptibility patterns of Mycobacterium tuberculosis from adults with  multidrug-resistant tuberculosis and implications for a household contact  preventive therapy trial.
BMC Infect Dis. 2021 Feb 24;21(1):205. doi: 10.1186/s12879-021-05884-4.
Demers AM(1), Kim S(2), McCallum S(3), Eisenach K(4), Hughes M(3), Naini L(5), Mendoza-Ticona A(6), Pradhan N(7), Narunsky K(8), Poongulali S(9), Badal-Faesen S(10), Upton C(11), Smith E(12), Shah NS(13), Churchyard G(14)(15), Gupta A(7)(16), Hesseling A(1), Swindells S(17); ACTG A5300/IMPAACT I2003 PHOENIx Feasibility study team.
BACKGROUND: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs).
METHODS: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability.
RESULTS: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens.
CONCLUSIONS: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.
DOI: 10.1186/s12879-021-05884-4
PMCID: PMC7903693
PMID: 33627075 [Indexed for MEDLINE]

Targeted next generation sequencing directly from sputum for comprehensive  genetic information on drug resistant Mycobacterium tuberculosis.
Tuberculosis (Edinb). 2021 Mar;127:102051. doi: 10.1016/ Epub 2021 Jan 8.
Kambli P(1), Ajbani K(2), Kazi M(3), Sadani M(4), Naik S(5), Shetty A(6), Tornheim JA(7), Singh H(8), Rodrigues C(9).
BACKGROUND: Timely drug resistance detection is essential to global tuberculosis management. Unfortunately, rapid molecular tests assess resistance to only a few drugs, with culture required for comprehensive susceptibility test results.
METHODS: We evaluated targeted next generation sequencing (tNGS) for tuberculosis on 40 uncultured sputum samples. Resistance profiles from tNGS were compared with profiles from Xpert MTB/RIF, line probe assay (LPA), pyrosequencing (PSQ), and phenotypic testing. Concordance, sensitivity, specificity, and overall test agreement were compared across assays.
RESULTS: tNGS provided results for 39 of 40 samples (97.5%) with faster turnaround than phenotypic testing (median 3 vs. 21 days, p = 0.0068). Most samples were isoniazid and rifampin resistant (N = 31, 79.5%), 21 (53.8%) were fluoroquinolone resistant, and 3 (7.7%) were also resistant to Kanamycin. Half were of the Beijing lineage (N = 20, 51.3%). tNGS from uncultured sputum identified all resistance to isoniazid, rifampin, fluoroquinolones, and second-line injectable drugs that was identified by other methods. Agreement between tNGS and existing assays was excellent for isoniazid, rifampin, and SLDs, very good for levofloxacin, and good for moxifloxacin.
CONCLUSION: tNGS can rapidly identify tuberculosis, lineage, and drug resistance with faster turnaround than phenotypic testing. tNGS is a potential alternative to phenotypic testing in high-burden settings.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/
PMID: 33450448

 Effectiveness of Preventive Therapy for Persons Exposed at Home to  Drug-Resistant Tuberculosis, Karachi, Pakistan.
Emerg Infect Dis. 2021 Mar;27(3):805-812. doi: 10.3201/eid2703.203916.
Malik AA, Gandhi NR, Lash TL, Cranmer LM, Omer SB, Ahmed JF, Siddiqui S, Amanullah F, Khan AJ, Keshavjee S, Hussain H, Becerra MC.
In Karachi, Pakistan, a South Asian megacity with a high prevalence of tuberculosis (TB) and low HIV prevalence, we assessed the effectiveness of fluoroquinolone-based preventive therapy for drug-resistant (DR) TB exposure. During February 2016–March 2017, high-risk household contacts of DR TB patients began a 6-month course of preventive therapy with a fluoroquinolone-based, 2-drug regimen. We assessed effectiveness in this cohort by comparing the rate and risk for TB disease over 2 years to the rates and risks reported in the literature. Of 172 participants, TB occurred in 2 persons over 336 person-years of observation. TB disease incidence rate observed in the cohort was 6.0/1,000 person-years. The incidence rate ratio ranged from 0.29 (95% CI 0.04–1.3) to 0.50 (95% CI 0.06–2.8), with a pooled estimate of 0.35 (95% CI 0.14–0.87). Overall, fluoroquinolone-based preventive therapy for DR TB exposure reduced risk for TB disease by 65%.
Fluoroquinolone-based preventive therapy reduced risk for tuberculosis disease by 65%.
DOI: 10.3201/eid2703.203916
PMCID: PMC7920671
PMID: 33624580

From Our February 2021 Newsletter

QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial.

Lancet Infect Dis. 2021 Feb 12:S1473-3099(20)30770-2. doi: 10.1016/S1473-3099(20)30770-2. Online ahead of print.

Dooley KE(1), Rosenkranz SL(2), Conradie F(3), Moran L(4), Hafner R(5), von Groote-Bidlingmaier F(6), Lama JR(7), Shenje J(8), De Los Rios J(7), Comins K(6), Morganroth J(9), Diacon AH(10), Cramer YS(2), Donahue K(11), Maartens G(12); AIDS Clinical Trials Group (ACTG) A5343 DELIBERATE Study Team.

Collaborators: Alli O, Gottesman J, Guevara M, Hikuam C, Hovind L, Karlsson M, McClaren J, McIlleron H, Murtaugh W, Rolls B, Shahkolahi A, Stone L, Tegha G, Tenai J, Upton C, Wimbish C.

BACKGROUND: Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established. Our aim was to characterise the effects of bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6 months of multidrug treatment, among patients with multidrug-resistant or rifampicin-resistant tuberculosis taking multidrug background therapy.
METHODS: ACTG A5343 is a phase 2, open-label, randomised, controlled trial in which adults with multidrug-resistant or rifampicin-resistant tuberculosis receiving multidrug background treatment were randomly assigned 1:1:1 by centrally, computer-generated randomisation, by means of permuted blocks to receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru. Individuals with QTc greater than 450 ms were excluded. HIV-positive participants received dolutegravir-based antiretroviral therapy. Clofazimine was disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum cultures were done fortnightly. The primary endpoint was mean QTcF change from baseline (averaged over weeks 8-24); cumulative culture conversation at week 8-24 was an exploratory endpoint. Analyses included all participants who initiated study tuberculosis treatment (modified intention-to-treat population). This trial is registered with, NCT02583048 and is ongoing.
FINDINGS: Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84 participants (28 in each treatment group, and 31 in total with HIV) were enrolled. Two participants did not initiate study treatment (one in the delamanid group withdrew consent and one in the bedaquiline plus delamanid group) did not meet the eligibility criterion). Mean change in QTc from baseline was 12·3 ms (95% CI 7·8-16·7; bedaquiline), 8·6 ms (4·0-13·1; delamanid), and 20·7 ms (16·1-25·3) (bedaquiline plus delamanid). There were no grade 3 or 4 adverse QTc prolongation events and no deaths during study treatment. Cumulative culture conversion by week 8 was 21 (88%) of 24 (95% CI 71-97; bedaquiline), 20 (83%) of 24 (65-95; delamanid), and 19 (95%) of 20 (79-100; bedaquiline plus delamanid) and was 92% (77-99) for bedaquiline, 91% (76-99), for delamanid, and 95% (79-100) for bedaquiline plus delamanid at 24 weeks.
INTERPRETATION: Combining bedaquiline and delamanid has a modest, no more than additive, effect on the QTc interval, and initial microbiology data are encouraging. This study provides supportive evidence for use of these agents together in patients with multidrug-resistant or rifampicin-resistant tuberculosis with normal baseline QTc values.
FUNDING: Division of AIDS, National Institutes of Health.

Copyright © 2021 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(20)30770-2
PMID: 33587897

Multidrug-resistant tuberculosis in children and adolescents: current strategies for prevention and treatment.
Expert Rev Respir Med. 2021 Feb;15(2):221-237. doi: 10.1080/17476348.2021.1828069. Epub 2020 Oct 10.
Seddon JA(1)(2), Johnson S(1)(2), Palmer M(1), van der Zalm MM(1), Lopez-Varela E(1)(3), Hughes J(1), Schaaf HS(1).
INTRODUCTION: An estimated 30,000 children develop multidrug-resistant (MDR) tuberculosis (TB) each year, with only a small proportion diagnosed and treated. This field has historically been neglected due to the perception that children with MDR-TB are challenging to diagnose and treat. Diagnostic and therapeutic developments in adults have improved pediatric management, yet further pediatric-specific research and wider implementation of evidence-based practices are required.
AREAS COVERED: This review combines the most recent data with expert opinion to highlight best practice in the evaluation, diagnosis, treatment, and support of children and adolescents with MDR-TB disease. A literature search of PubMed was carried out on topics related to MDR-TB in children. This review provides practical advice on MDR-TB prevention and gives updates on new regimens and novel treatments. The review also addresses host-directed therapy, comorbid conditions, special populations, psychosocial support, and post-TB morbidity, as well as identifying outstanding research questions.
EXPERT OPINION: Increased availability of molecular diagnostics has the potential to aid with the diagnosis of MDR-TB in children. Shorter MDR-TB disease treatment regimens have made therapy safer and shorter and further developments with novel agents and repurposed drugs should lead to additional improvements. The evidence base for MDR-TB preventive therapy is increasing.
DOI: 10.1080/17476348.2021.1828069
PMID: 32965141

Systematic Review of Mutations Associated with Isoniazid Resistance Points to  Continuing Evolution and Subsequent Evasion of Molecular Detection, and  Potential for Emergence of Multidrug Resistance in Clinical Strains of  Mycobacterium tuberculosis.
Antimicrob Agents Chemother. 2021 Feb 17;65(3):e02091-20. doi:
10.1128/AAC.02091-20. Print 2021 Feb 17.
Valafar SJ(1).
Molecular testing is rapidly becoming an integral component of global tuberculosis (TB) control. Uncommon mechanisms of resistance escape detection by these platforms and undermine our ability to contain outbreaks. This article is a systematic review of published articles that reported isoniazid (INH) resistance-conferring mutations between September 2013 and December 2019. The genes katG, inhA, and fabG1, and the intergenic region oxyR'-ahpC were considered in this review. Fifty-two articles were included that described 9,306 clinical isolates (5,804 INH resistant [INHr] and 3,502 INH susceptible [INHs]) from 31 countries. The three most frequently mutated loci continue to be locus 315 of katG (katG315; n = 4,271), locus -15 of inhA (inhA-15; n = 787), and locus -8 of inhA (inhA-8; 106). However, the diagnostic value of inhA-8 is far lower than previously thought, as it only appears in 25 (0.4%) of the INHr isolates lacking the first two mutations. I catalogued 45 new loci (29 katG, nine inhA, and seven ahpC) associated with INH resistance and identified 59 loci (common to this and previous reviews) as a reliable basis for molecular diagnostics. Including all observed mutations provides a cumulative sensitivity of 85.6%. In 14.4% of resistant isolates, no mechanism of resistance was detected, making them likely to escape molecular detection, and in the case of INH monoresistance, likely to convert to multidrug-resistant TB (MDR-TB). Integrating the information cataloged in this study into current diagnostic tools is essential for combating the emergence of MDR-TB, and its exclusion can lead to an unintended selection against common mechanisms and to diversifying evolution. Observation of many low-frequency resistance-conferring mutations points to an advantage of whole-genome sequencing (WGS) for diagnostics. Finally, I provide five recommendations for future diagnostic platforms.
Copyright © 2021 American Society for Microbiology.
DOI: 10.1128/AAC.02091-20
PMID: 33361298

4. Evaluating Integrated Care for People Living With HIV and Multidrug-Resistant  Tuberculosis in South Africa: A Case-Based Approach Using the Chronic Care Model.
J Assoc Nurses AIDS Care. 2021 Feb 15. doi: 10.1097/JNC.0000000000000242. Online ahead of print.
Geiger K(1), Bergman A, Farley JE.
In South Africa, tuberculosis (TB) and multidrug-resistant TB (MDR-TB) frequently occur in people living with HIV. World Health Organization guidelines recommend the integration of MDR-TB and HIV care but, in practice, fully integrated care is difficult to achieve. In this article, we use five elements of the Chronic Care Model as a framework for evaluating a case of integrated. MDR-TB/HIV care and to highlight opportunities for nurses to improve care delivery and patient outcomes. We apply the Chronic Care Model framework to a concrete example by examining the case of a 33-year-old man who developed MDR-TB treatment failure while concurrently taking a powerful new MDR-TB antiretroviral therapy regimen for his HIV.
Copyright © 2021 Association of Nurses in AIDS Care.
DOI: 10.1097/JNC.0000000000000242
PMID: 33595985

5. Should treatment of low-level rifampicin mono-resistant tuberculosis be different?
J Clin Tuberc Other Mycobact Dis. 2021 Jan 29;23:100222. doi:
10.1016/j.jctube.2021.100222. eCollection 2021 May.
Gopie FA(1)(2), Commiesie E(3), Baldi S(4), Kamst M(5), Kaur D(6), de Lange WCM(7), Pinas PS(4), Stijnberg D(3), Wongsokarijo M(4), Zijlmans CWR(2), de Zwaan R(5), van Soolingen D(5), Vreden SGS(1), de Vries G(8).
BACKGROUND: Rifampicin resistant tuberculosis (RR-TB) was frequently detected in Suriname after the introduction of Xpert MTB/RIF in 2012. Subsequent phenotypic drug-susceptibility testing (DST) was not conclusive at that moment, while RR-TB patients treated with first-line tuberculostatics had good treatment outcome. In our study, we analysed this interesting observation.
METHODS: We collected demographic and clinical characteristics and treatment outcome of TB patients from May 2012-December 2018 and performed a univariate and multivariate analysis to assess possible associations with resistance to rifampicin. Secondly, we conducted whole genome sequencing on all available Mycobacterium tuberculosis isolates that had a rifampicin resistance in the Xpert MTB/RIF test and performed phenotypic DST on selected isolates.
FINDINGS: RR-TB was detected in 59 (9.6%) patients confirmed by Xpert. These patients were treated with rifampicin-containing regimens in most (88%) of the cases. In all 32 samples examined, a D435Y mutation in the rpoB gene was identified; only one isolate revealed an additional isoniazid mutation. Phenotypic DST indicated low-level rifampicin resistance. In multivariate analysis, the Creole ethnicity was a factor associated with rifampicin resistance (aOR 3.5; 95%CI 1.9-6.4). The treatment success rate for patients with RR-TB (78.0%) was comparable to the treatment outcome in non-RR-TB patients 77.8%.
INTERPRETATION: This study confirms a low-level rifampicin mono-resistance in TB patients of Suriname. These patients could benefit from a first-line regimen with high dose rifampicin (or rifabutin), rather than from the lengthy treatment. regimens for rifampicin-resistant and multi-drug resistant TB, a concept of stratified medicine also advocated for the treatment of TB.
© 2021 The Authors. Published by Elsevier Ltd.
DOI: 10.1016/j.jctube.2021.100222
PMCID: PMC7869001
PMID: 33598570

From Our January 2021 Newsletter

 Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with
multidrug-resistant tuberculosis.

J Antimicrob Chemother. 2020 Dec 30:dkaa550. doi: 10.1093/jac/dkaa550. Online ahead of print.
Alghamdi WA(1), Al-Shaer MH(2), Kipiani M(3), Barbakadze K(3), Mikiashvili L(3), Kempker RR(4), Peloquin CA(2).
BACKGROUND: Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use.
OBJECTIVES: To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis.
METHODS: A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4-6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored.
RESULTS: Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0-24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0-12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine.
CONCLUSIONS: We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.
© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email:
DOI: 10.1093/jac/dkaa550
PMID: 33378452

HIV infection and multidrug resistant tuberculosis: a systematic review and

BMC Infect Dis. 2021 Jan 11;21(1):51. doi: 10.1186/s12879-020-05749-2.
Sultana ZZ(1), Hoque FU(2), Beyene J(3), Akhlak-Ul-Islam M(4), Khan MHR(5), Ahmed S(6), Hawlader DH(7), Hossain A(8)(9)(10).
Erratum in BMC Infect Dis. 2021 Jan 20;21(1):86.
BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) in HIV infected individuals is a serious threat to global efforts to combat tuberculosis. Inconsistent findings on the association between HIV infection and MDR-TB were present in many studies. We aimed to review existing data on the relationship
between HIV infection and MDR-TB systematically to assess the contribution of HIV on MDR-TB worldwide. We also investigated the patterns of MDR-TB by age, country-wise income, study designs, and global regions.
METHODS: We utilized PubMed, Google Scholar, and ScienceDirect databases to select eligible studies for meta-analysis that were published between January 12,010, and July 30, 2020. The random-effects model was used to obtain the pooled odds ratio of the crude association between HIV and MDR-TB with a 95%
confidence interval. We investigated the potential publication-bias by checking funnel plot asymmetry and using the Egger's test. Moreover, we assessed the heterogeneity using the I2 statistic. Sensitivity analysis was performed based on sample size and adjustment factors. The protocol was registered with PROSPERO-CRD42019132752.
RESULTS: We identified 1603 studies through a database search, and after subsequent eliminations we selected 54 studies including 430,534 TB patients. The pooled odds of MDR-TB was 1.42 times higher in HIV-positive patients than HIV-negative patients (OR=1.42,CI=1.17-1.71, I2=75.8%). Subgroup analysis revealed that the estimated pooled odds for South-East Asian countries was 1.86, which is the highest in WHO regions (OR=1.86,CI=1.30-2.67, I2=0.00%), followed by Europe and Africa. The effect estimate was found to be higher for primary MDR-TB (OR=2.76,CI=1.70-4.46, I2=0.00%). There was also a trend towards increased odds of MDR-TB for HIV patients older than 40 years (OR=1.56,CI=1.17-2.06). The association was found to be significant in high-burden TB countries (OR=1.75, CI=1.39-2.19) and in high-income countries
(OR=1.55, CI=1.06-2.27).
CONCLUSION: Such findings indicate that HIV infection raises the risk of MDR-TB, and after contrasting it with the results of the earlier pooled study, it appeared to be an upward risk trend. Moreover, we found that the risk is the highest in the South-East Asian region. A balanced allocation of resources is needed to halt both primary and secondary MDR-TB, particularly in HIV infected people with 40 years of age and older.
DOI: 10.1186/s12879-020-05749-2
PMCID: PMC7802168
PMID: 33430786 [Indexed for MEDLINE]

"Take the treatment and be brave": Care experiences of pregnant women with
rifampicin-resistant tuberculosis.

PLoS One. 2020 Dec 21;15(12):e0242604. doi: 10.1371/journal.pone.0242604.
eCollection 2020.
Loveday M(1)(2), Hlangu S(1), Furin J(3).
BACKGROUND: There are few data on the on the care experiences of pregnant women with rifampicin-resistant TB.
OBJECTIVE: To describe the treatment journeys of pregnant women with RR-TB-including how their care experiences shape their identities-and identify areas in which tailored interventions are needed.
METHODS: In this qualitative study in-depth interviews were conducted among a convenience sample from a population of pregnant women receiving treatment for RR-TB. This paper follows COREQ guidelines. A thematic network analysis using an inductive approach was performed to analyze the interview transcripts and notes. The analysis was iterative and a coding system developed which focused on the
care experiences of the women and how these experiences affected their perceptions of themselves, their children, and the health care system in which treatment was received.
RESULTS: Seventeen women were interviewed. The women described multiple challenges in their treatment journeys which required them to demonstrate sustained resilience (i.e. to "be brave"). Care experiences required them to negotiate seemingly contradictory identities as both new mothers-"givers of
life"-and RR-TB patients facing a complicated and potentially deadly disease. In terms of their "pregnancy identity" and "RR-TB patient identity" that emerged as part of their care experiences, four key themes were identified that appeared to have elements that were contradictory to one another (contradictory areas).
These included: 1) the experience of physical symptoms or changes; 2) the experience of the "mothering" and "patient" roles; 3) the experience of the care they received for their pregnancy and their RR-TB; and 4) the experience of community engagement. There were also three areas that overlapped with both
roles and during which identity was negotiated/reinforced and they included: 1) faith; 2) socioeconomic issues; and 3) long-term concerns over the child's health. At times, the health care system exacerbated these challenges as the women were not given the support they needed by health care providers who were
ill-informed or angry and treated the women in a discriminatory fashion. Left to
negotiate this confusing time period, the women turned to faith, their own mothers, and the fathers of their unborn children.
CONCLUSION: The care experiences of the women who participated in this study highlight several gaps in the current health care system that must be better addressed in both TB and perinatal services in order to improve the therapeutic journeys for pregnant women with RR-TB and their children. Suggestions for
optimizing care include the provision of integrated services, including specialized counseling as well as training for health care providers; engagement of peer support networks; provision of socioeconomic support; long-term medical care/follow-up for children born to women who were treated for RR-TB; and inclusion of faith-based services in the provision of care.
DOI: 10.1371/journal.pone.0242604
PMCID: PMC7751874
PMID: 33347448 [Indexed for MEDLINE]

Lesion Heterogeneity Coincides With Long-Term Heteroresistance in MDR-TB.
J Infect Dis. 2021 Jan 12:jiab011. doi: 10.1093/infdis/jiab011. Online ahead of
Chen Y(1)(2), Ji L(2), Liu Q(1)(3), Li J(2), Hong C(2), Jiang Q(1)(2), Gan M(4), Takiff HE(5)(6)(7), Yu W(2), Tan W(2), Gao Q(1)(2).
Tuberculosis (TB) heteroresistance, in which only a fraction of the bacteria in a TB patient contains drug-resistant mutations, has been a rising concern. However, its origins and prevalence remain elusive. Here, whole-genome sequencing was performed on 83 serial isolates from 31 MDR-TB patients and heteroresistance was detected in isolates from 21 (67.74%) patients. Heteroresistance persisted in the host for long periods, spanning months to years, and was associated with having multiple tubercular lesions. Our findings indicate that heteroresistance is common and persistent in MDR-TB patients and
may affect the success of their treatment regimens.
© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail:
DOI: 10.1093/infdis/jiab011
PMID: 33433601

Culture Conversion in Patients Treated with Bedaquiline and/or Delamanid. A
Prospective Multicountry Study.

Am J Respir Crit Care Med. 2021 Jan 1;203(1):111-119. doi: 10.1164/rccm.202001-0135OC.
Franke MF(1)(2), Khan P(3), Hewison C(4), Khan U(3), Huerga H(5), Seung KJ(2)(6), Rich ML(2)(6), Zarli K(7), Samieva N(8), Oyewusi L(9), Nair P(10), Mudassar M(3), Melikyan N(5), Lenggogeni P(11), Lecca L(12), Kumsa A(13), Khan M(14), Islam S(15), Hussein K(16), Docteur W(17), Chumburidze N(18), Berikova
E(19), Atshemyan H(20), Atwood S(6), Alam M(15), Ahmed S(3), Bastard M(5), Mitnick CD(1)(2)(6).
Comment in Am J Respir Crit Care Med. 2021 Jan 1;203(1):11-13.
Rationale: Bedaquiline and delamanid offer the possibility of more effective and less toxic treatment for multidrug-resistant (MDR) tuberculosis (TB). With this treatment, however, some patients remain at high risk for an unfavorable treatment outcome. The endTB Observational Study is the largest multicountry
cohort of patients with rifampin-resistant TB or MDR-TB treated in routine care with delamanid- and/or bedaquiline-containing regimens according to World Health Organization guidance.Objectives: We report the frequency of sputum culture conversion within 6 months of treatment initiation and the risk factors for
Methods: We included patients with a positive baseline culture who initiated a first endTB regimen before April 2018. Two consecutive negative cultures collected 15 days or more apart constituted culture conversion. We used generalized mixed models to derive marginal predictions for the probability of culture conversion in key subgroups.Measurements and Main Results: A total of 1,109 patients initiated a multidrug treatment containing bedaquiline (63%), delamanid (27%), or both (10%). Of these, 939 (85%) experienced culture
conversion within 6 months. In adjusted analyses, patients with HIV had a lower probability of conversion (0.73; 95% confidence interval [CI], 0.62-0.84) than patients without HIV (0.84; 95% CI, 0.79-0.90; P = 0.03). Patients with both cavitary disease and highly positive sputum smear had a lower probability of conversion (0.68; 95% CI, 0.57-0.79) relative to patients without either (0.89; 95% CI, 0.84-0.95; P = 0.0004). Hepatitis C infection, diabetes mellitus or glucose intolerance, and baseline resistance were not associated with
Conclusions: Frequent sputum conversion in patients with rifampin-resistant TB or MDR-TB who were treated with bedaquiline and/or delamanid underscores the need for urgent expanded access to these drugs. There is a need to optimize treatment for patients with HIV and extensive disease.
DOI: 10.1164/rccm.202001-0135OC
PMCID: PMC7781121
PMID: 32706644

From Our December 2020 Newsletter

Compassionate Use of Delamanid in Adults and Children for Drug-resistant TB:  5-year Update.
Eur Respir J. 2020 Nov 26:2002483. doi: 10.1183/13993003.02483-2020. Online ahead of print.
Ghosh S(1), Breitscheidel L(1), Lazarevic N(1), Martin A(1), Hafkin J(2), Hittel N(1).
BACKGROUND: Although delamanid has been approved for the treatment of multidrug-resistant tuberculosis (MDR-TB) in numerous regions, in areas where it is not yet registered, it can be accessed as part of salvage therapy-in particular, for those patients with limited treatment options-via the Otsuka Compassionate Use (CU) programme. Here we present the analysis of interim treatment outcomes by 24 weeks of more than 200 multidrug-resistant tuberculosis (MDR-TB) patients globally who received delamanid under the Otsuka CU programme.
METHODS: We evaluated the treatment efficacy, with respect to culture negativity at 24 weeks, and safety profile of delamanid in a MDR-TB cohort of patients treated under CU between 2014 and 2019.
RESULTS: Among patients who received delamanid as part of a multidrug regimen, 123/202 (61%) had extensively drug-resistant tuberculosis (XDR-TB), 66/202 (33%) had HIV co-infection, and 34/202 (17%) were children ages between 6 and 17 years. Of those patients who were culture positive at delamanid treatment initiation and completed 24 weeks of delamanid treatment in combination with other anti-TB drugs, culture negativity was achieved in 116/147 (79%). The corresponding rates of culture negativity for patients with XDR-TB, HIV co-infection, and the paediatric subgroup were 69/90 (77%), 44/48 (92%), and 20/25 (80%), respectively. QT interval prolongation was the most frequently observed serious adverse event (reported in 8% of patients receiving delamanid). Overall, treatment safety outcomes did not reveal any new or unidentified risks.
CONCLUSIONS: The use of delamanid combined with other active drugs has the potential to achieve high rates of culture negativity in difficult-to-treat drug-resistant tuberculosis cases, with a favourable safety profile.
Copyright ©ERS 2020.
DOI: 10.1183/13993003.02483-2020
PMID: 33243846

From Our November 2020 Newsletter

 Clinical perspectives on treatment of rifampicin-resistant/multidrug-resistant TB.

Int J Tuberc Lung Dis. 2020 Nov 1;24(11):1134-1144. doi: 10.5588/ijtld.20.0330.
Cox V(1), McKenna L(2), Acquah R(3), Reuter A(3), Wasserman S(4), Vambe D(5), Ustero P(6), Udwadia Z(7), Triviño-Duran L(8), Tommasi M(9), Skrahina A(10), Seddon JA(11), Rodolfo R(12), Rich M(13), Padanilam X(14), Oyewusi L(15), Ohler L(16), Lungu P(17), Loveday M(18), Khan U(19), Khan P(20), Hughes J(21), Hewison C(22), Guglielmetti L(22), Furin J(23).
Rapid diagnostics, newer drugs, repurposed medications, and shorter regimens have radically altered the landscape for treating rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB). There are multiple ongoing clinical trials aiming to build a robust evidence base to guide RR/MDR-TB treatment, and both observational studies and programmatic data have contributed to advancing the treatment field. In December 2019, the WHO issued their second 'Rapid Communication´ related to RR-TB management. This reiterated their prior recommendation that a majority of people with RR/MDR-TB receive all-oral treatment regimens, and now allow for specific shorter duration regimens to be used programmatically as well. Many TB programs need clinical advice as they seek to roll out such regimens in their specific setting. In this Perspective,
we highlight our early experiences and lessons learned from working with National TB Programs, adult and pediatric clinicians and civil society, in optimizing treatment of RR/MDR-TB, using shorter, highly-effective, oral regimens for the majority of people with RR/MDR-TB.
DOI: 10.5588/ijtld.20.0330
PMID: 33172520

Population Pharmacokinetic Analysis of Delamanid in Patients with Pulmonary Multi-Drug Resistant Tuberculosis.

Antimicrob Agents Chemother. 2020 Oct 26:AAC.01202-20. doi: 10.1128/AAC.01202-20. Online ahead of print.
Wang X(1), Mallikaarjun S(2), Gibiansky E(3).
A population pharmacokinetic (PopPK) model of delamanid in patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) was developed using data from four delamanid clinical trials. The final PopPK dataset contained 20,483 plasma samples from 744 patients with MDR-TB receiving an optimized background regimen (OBR). Delamanid PK was adequately described for all observed dosing regimens and subpopulations by a two-compartment model with first-order elimination and absorption, an absorption lag time, and decreased relative bioavailability with increasing dose. Relative bioavailabilities of 200 mg and higher doses (250 and 300 mg) were 76% and 58% of a 100 mg dose, respectively. Relative bioavailability was 26% higher after evening doses than morning doses and 9% higher in outpatient settings than inpatient settings. The rate of absorption was faster, and lag time shorter, following a morning dose compared to an evening dose. Relative bioavailabilities in patients in North-East Asian and South-East Asian regions were 53% and 40% higher, respectively, than patients in non-Asian regions. Apparent clearance was higher (to the power of -0.892) in patients with hypoalbuminemia (albumin < 3.4 g/dL). Co-administration of efavirenz in patients with HIV increased delamanid clearance by 35%. Delamanid exposure was not affected by age (18-64 years), mild/moderate renal impairment, anti-TB antibiotic resistance status, HIV status or markers of hepatic dysfunction; nor by concomitant administration of OBR, lamivudine, tenofovir, pyridoxine, CYP 3A4 inhibitors and inducers or antacids. Model evaluation suggested reasonable model fit and predictive power, indicating the model should prove reliable to derive PK metrics for subsequent PK/PD analyses.
Copyright © 2020 Wang et al.
DOI: 10.1128/AAC.01202-20
PMID: 33106258

Changes in treatment for multidrug-resistant tuberculosis according to national income.

Eur Respir J. 2020 Nov 5;56(5):2001394. doi: 10.1183/13993003.01394-2020. Print 2020 Nov.
Kwak N(1), Winters N(2), Campbell JR(2), Chan ED(3)(4), Gegia M(5), Lange C(6)(7)(8)(9), Lee M(10), Milanov V(11), Menzies D(2), Yim JJ(1).
The aim of this study was to analyse temporal changes in treatments for and outcomes of multidrug-resistant (MDR)/rifampin-resistant (RR)-tuberculosis (TB) in the context of national economic status.We analysed data collected by the Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB Treatment on MDR/RR-TB patients from 37 countries. The data were stratified by three national income levels (low-/lower-middle, upper-middle and high) and grouped by time of treatment initiation (2001-2003, 2004-2006, 2007-2009, 2010-2012 and 2013-2015). Temporal trends over the study period were analysed. The probability of treatment success in different income groups over time was calculated using generalised linear mixed models with random effects.In total, 9036 patients were included in the analysis. Over the study period, use of group
A drugs (levofloxacin/moxifloxacin, bedaquiline and linezolid) recommended by the World Health Organization increased and treatment outcomes improved in all income groups. Between 2001-2003 and 2013-2015, treatment success rates increased from 60% to 78% in low-/lower-middle-income countries, from 40% to 67%
in upper-middle-income countries, and from 73% to 81% in high-income countries. In earlier years, the probability of treatment success in upper-middle-income countries was lower than that in low-/lower-middle-income countries, but no difference was observed after 2010. However, high-income countries had persistently higher probability of treatment success compared to upper-middle income countries.Improved treatment outcomes and greater uptake of group A drugs were observed over time for patients with MDR/RR-TB at all income levels. However, treatment outcomes are still unsatisfactory, especially in
upper-middle-income countries.
Copyright ©ERS 2020.
DOI: 10.1183/13993003.01394-2020
PMID: 32586878

Molecular evaluation of fluoroquinolone resistance in serial Mycobacterium  tuberculosis isolates from individuals diagnosed with multidrug-resistant  tuberculosis.

Antimicrob Agents Chemother. 2020 Oct 26:AAC.01663-20. doi: 10.1128/AAC.01663-20. Online ahead of print.
Willby M(1), Chopra P(1), Lemmer D(2), Klein K(1), Dalton TL, Engelthaler DM(2), Cegielski P(3), Posey JE(4); Global PETTS Investigators.
Fluoroquinolones (FQ) are crucial components of multidrug-resistant tuberculosis (MDR TB) treatment. Varying levels of resistance are associated with specific mutations within the Quinolone Resistance Determining Region (QRDR) of gyrA We sequenced the QRDR from serial isolates of MDR TB patients in the Preserving Effective TB Treatment Study (PETTS) with baseline (FQR) or acquired FQ resistance (FQACQR) using the IonTorrent™ Personal Genome Machine to a depth of 10,000x and reported single nucleotide polymorphisms in ≥1% of reads. FQR isolates harbored 15 distinct alleles with 1.3 (max=6) on average per isolate. Eighteen alleles were identified in FQACQR isolates with an average of 1.6 (max=9) per isolate. Isolates from 78% of FQACQR individuals had mutant alleles identified within 6 months of treatment initiation. Asp94Gly followed by
Ala90Val were the predominant alleles in initial FQ-resistant isolates. Seventy-seven percent (36/47) of FQACQR group patients had isolates with FQ resistance alleles prior to changes to the FQ component of their treatment. Unlike individuals treated initially with other FQs, none of the 21 individuals treated initially with levofloxacin developed genotypic or phenotypic FQ resistance, although, country of residence is likely a contributing factor since 69% of these individuals were from a single country. Initial detection of phenotypic and genotypic resistance occurred simultaneously for most; however, phenotypic resistance occurred earlier in isolates harboring mixtures of very low-abundance (<1% of reads) alleles while genotypic resistance often occurred earlier for low-level resistance-associated alleles. Understanding factors influencing acquisition and evolution of FQ resistance could reveal strategies for improved treatment success.
Copyright © 2020 American Society for Microbiology.
DOI: 10.1128/AAC.01663-20
PMID: 33106264