February Newsletter: New Articles Highlight Emergence of Resistance to Bedaquiline and underline the need for improved susceptibility testing

1. Bedaquiline resistance in drug-resistant tuberculosis HIV co-infected patients.
Eur Respir J. 2020 Feb 14. pii: 1902383. doi: 10.1183/13993003.02383-2019. [Epub
ahead of print]
Nimmo C(1)(2)(3), Millard J(3)(4)(5), Brien K(3), Moodley S(3), van Dorp L(2),
Lutchminarain K(6), Wolf A(7), Grant AD(3)(8), Balloux F(2), Pym AS(3),
Padayatchi N(9), O’Donnell M(10)(11).
DOI: 10.1183/13993003.02383-2019
PMID: 32060065

Read the full article here.

2. Bedaquiline-resistant Tuberculosis: Dark Clouds on the Horizon.
Am J Respir Crit Care Med. 2020 Feb 13. doi: 10.1164/rccm.201909-1819LE. [Epub
ahead of print]
Andres S(1), Merker M(2), Heyckendorf J(3), Kalsdorf B(3), Rumetshofer R(4),
Indra A(5), Hofmann-Thiel S(6), Hoffmann H(7)(8), Lange C(9), Niemann S(10),
Maurer FP(11).
DOI: 10.1164/rccm.201909-1819LE
PMID: 32053752

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3. Validation of Bedaquiline Phenotypic Drug Susceptibility Testing Methods and Breakpoints: A Multi-Laboratory, Multi-Country Study.
J Clin Microbiol. 2020 Jan 22. pii: JCM.01677-19. doi: 10.1128/JCM.01677-19.
[Epub ahead of print]
Kaniga K(1), Aono A(2), Borroni E(3), Cirillo DM(3), Desmaretz C(4), Hasan
R(5)(6), Joseph L(7), Mitarai S(2), Shakoor S(5), Torrea G(4), Ismail
NA(7)(8)(9), Omar SV(7).

Drug-resistant tuberculosis persists as a major public health concern. Alongside
efficacious treatments, validated and standardized drug susceptibility testing
(DST) is required to improve patient care. This multi-country, multi-laboratory
external quality assessment (EQA) study aimed to validate the sensitivity,
specificity, and reproducibility of provisional bedaquiline minimal inhibitory
concentration (MIC), breakpoints and World Health Organization interim critical
concentrations (CCs), for categorising clinical Mycobacterium tuberculosis
isolates as susceptible/resistant to the drug.Three methods were used:
Middlebrook 7H11 agar proportion (AP) assay, broth microdilution (BMD), and
mycobacterial growth indicator tube (MGIT). Each of the five laboratories tested
the 40-isolate (20 unique isolates, duplicated) EQA panel at three time points.
The study validated the sensitivity and specificity of bedaquiline MIC
susceptible breakpoint of 0.12 μg/mL for BMD method, and WHO interim CCs of 1
μg/mL for MGIT and 0.25 μg/mL for 7H11 AP methods.Categorical agreements between
observed and expected results, and sensitivities/specificities for correctly
identifying an isolate as susceptible/resistant were highest at the 0.25, 0.12,
and 1 μg/mL bedaquiline concentrations, for the AP method, BMD (frozen or dry
plates), and MGIT960 respectively. At these concentrations, very major error
rates for erroneously labelling an isolate ‘susceptible’ when it was resistant
were the lowest and within CLSI guidelines. The most reproducible bedaquiline DST
methods were MGIT960 and BMD using dry plates.These findings validate
standardized DST methodologies and interpretative criteria to facilitate routine
phenotypic bedaquiline DST, and monitor the emergence of bedaquiline resistance.

Copyright © 2020 Kaniga et al.

DOI: 10.1128/JCM.01677-19
PMID: 31969421

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4. Should we worry about bedaquiline exposure in the treatment of multidrug-resistant and extensively drug-resistant tuberculosis?
Eur Respir J. 2020 Feb 12;55(2). pii: 1901908. doi: 10.1183/13993003.01908-2019.
Print 2020 Feb.
Alffenaar JC(1)(2)(3), Akkerman OW(4)(5), Tiberi S(6), Sotgiu G(7), Migliori
GB(8)(9); Global Tuberculosis Network Bedaquiline study group.
DOI: 10.1183/13993003.01908-2019
PMID: 31699843

Read the full article here.

5. Clarity with INHindsight: High-Dose Isoniazid for Drug-Resistant Tuberculosis with inhA Mutations.
Am J Respir Crit Care Med. 2020 Feb 20. doi: 10.1164/rccm.202002-0264ED. [Epub
ahead of print]
Wasserman S(1), Furin J(2).
DOI: 10.1164/rccm.202002-0264ED
PMID: 32078783

Read the full article here.

6. MDR/XDR-TB management of patients and contacts: Challenges facing the new decade. The 2020 clinical update by the Global Tuberculosis Network.
Int J Infect Dis. 2020 Feb 4. pii: S1201-9712(20)30045-X. doi:
10.1016/j.ijid.2020.01.042. [Epub ahead of print]
Migliori GB(1), Tiberi S(2), Zumla A(3), Petersen E(4), Chakaya JM(5), Wejse
C(6), Muñoz Torrico M(7), Duarte R(8), Alffenaar JW(9), Schaaf HS(10), Marais
BJ(11), Cirillo DM(12), Alagna R(13), Rendon A(14), Pontali E(15), Piubello
A(16), Figueroa J(17), Ferlazzo G(18), García-Basteiro A(19), Centis R(20), Visca
D(21), D’Ambrosio L(22), Sotgiu G(23); members of the Global Tuberculosis

The continuous flow of new research articles on MDR-TB diagnosis, treatment,
prevention and rehabilitation requires frequent update of existing guidelines.
This review is aimed at providing clinicians and public health staff with an
updated and easy-to-consult document arising from consensus of Global
Tuberculosis Network (GTN) experts. The core published documents and guidelines
have been reviewed, including the recently published MDR-TB WHO rapid advice and
ATS/CDC/ERS/IDSA guidelines. After a rapid review of epidemiology and risk
factors, the clinical priorities on MDR-TB diagnosis (including whole genome
sequencing and drug-susceptibility testing interpretations) and treatment
(treatment design and management, TB in children) are discussed. Furthermore, the
review comprehensively describes the latest information on contact tracing and
LTBI management in MDR-TB contacts, while providing guidance on post-treatment
functional evaluation and rehabilitation of TB sequelae, infection control and
other public health priorities.

Copyright © 2020. Published by Elsevier Ltd.

DOI: 10.1016/j.ijid.2020.01.042
PMID: 32032752

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7. Isoniazid- and Rifampin-Resistance Mutations Associated with Resistance to Second-line Drugs and with Sputum Culture Conversion.
J Infect Dis. 2020 Jan 31. pii: jiaa042. doi: 10.1093/infdis/jiaa042. [Epub ahead
of print]

Click ES(1), Kurbatova E(2), Alexander H(1), Dalton TL(2), Chen MP(2), Posey
JE(2), Ershova JJ(1), Cegielski P(1).

BACKGROUND: Mutations in the genes inhA, katG and rpoB confer resistance to
anti-tuberculosis (TB) drugs isoniazid and rifampin. We questioned whether
specific mutations in these genes were associated with different clinical and
microbiological characteristics.
METHODS: In a multi-country prospective cohort study of MDR-TB, we identified
inhA, katG and rpoB mutations in sputum isolates using the Hain MTBDRplus line
probe assay. For specific mutations, we performed bivariate analysis to determine
relative risk of baseline or acquired resistance to other TB drugs. We compared
time-to-sputum-culture-conversion (TSCC) using Kaplan-Meier curves and stratified
Cox regression.
RESULTS: In total, 447 participants enrolled January 2005-December 2008 from
seven countries were included. Relative to rpoB S531L, isolates with rpoB D516V
had less cross-resistance to rifabutin, increased baseline resistance to other
drugs, and increased acquired fluoroquinolone resistance.Relative to mutation of
katG only, mutation of inhA promoter and katG was associated with increased
acquired fluoroquinolone resistance and slower TSCC (125.5 vs. 89.0 days).
CONCLUSIONS: Specific mutations in inhA and katG are associated with differences
in resistance to other drugs and TSCC. Molecular testing may make it possible to
tailor treatment and assess additional drug resistance risk according to specific
mutation profile.

Published by Oxford University Press for the Infectious Diseases Society of
America 2020. This work is written by (a) US Government employee(s) and is in the
public domain in the US.

DOI: 10.1093/infdis/jiaa042
PMID: 32002554

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8. Population Pharmacokinetics and Dosing of Ethionamide in Children with Tuberculosis.
Antimicrob Agents Chemother. 2020 Feb 21;64(3). pii: e01984-19. doi:
10.1128/AAC.01984-19. Print 2020 Feb 21.

Bjugård Nyberg H(1), Draper HR(2), Garcia-Prats AJ(2), Thee S(3), Bekker A(2),
Zar HJ(4)(5), Hooker AC(1), Schaaf HS(2), McIlleron H(6), Hesseling AC(2), Denti

Ethionamide has proven efficacy against both drug-susceptible and some
drug-resistant strains of Mycobacterium tuberculosis Limited information on its
pharmacokinetics in children is available, and current doses are extrapolated
from weight-based adult doses. Pediatric doses based on more robust evidence are
expected to improve antituberculosis treatment, especially in small children. In
this analysis, ethionamide concentrations in children from 2 observational
clinical studies conducted in Cape Town, South Africa, were pooled. All children
received ethionamide once daily at a weight-based dose of approximately 20 mg/kg
of body weight (range, 10.4 to 25.3 mg/kg) in combination with other first- or
second-line antituberculosis medications and with antiretroviral therapy in cases
of HIV coinfection. Pharmacokinetic parameters were estimated using nonlinear
mixed-effects modeling. The MDR-PK1 study contributed data for 110 children on
treatment for multidrug-resistant tuberculosis, while the DATiC study contributed
data for 9 children treated for drug-susceptible tuberculosis. The median age of
the children in the studies combined was 2.6 years (range, 0.23 to 15 years), and
the median weight was 12.5 kg (range, 2.5 to 66 kg). A one-compartment, transit
absorption model with first-order elimination best described ethionamide
pharmacokinetics in children. Allometric scaling of clearance (typical value,
8.88 liters/h), the volume of distribution (typical value, 21.4 liters), and
maturation of clearance and absorption improved the model fit. HIV coinfection
decreased the ethionamide bioavailability by 22%, rifampin coadministration
increased clearance by 16%, and ethionamide administration by use of a
nasogastric tube increased the rate, but the not extent, of absorption. The
developed model was used to predict pediatric doses achieving the same drug
exposure achieved in 50- to 70-kg adults receiving 750-mg once-daily dosing.
Based on model predictions, we recommend a weight-banded pediatric dosing scheme
using scored 125-mg tablets.

Copyright © 2020 American Society for Microbiology.

DOI: 10.1128/AAC.01984-19
PMID: 31871093

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9. Preventing drug-resistant tuberculosis transmission.
Lancet Infect Dis. 2020 Feb;20(2):157-158. doi: 10.1016/S1473-3099(19)30613-9.
Epub 2019 Nov 26.
Koch A(1), Cox H(2).
DOI: 10.1016/S1473-3099(19)30613-9
PMID: 31784368

Read the full article here.