Recent Publications (from our May 2020 newsletter)

1. Progress in the roll-out of multidrug-resistant tuberculosis (MDR-TB) treatments.
Int J Tuberc Lung Dis. 2020 May 1;24(5):535-536. doi: 10.5588/ijtld.19.0717.

Heng M(1), Allmendinger S(1), Chiang CY(2), Trébucq A(2), Horsburgh CR(1).

Please see this document. Corrections to this publication are in-press for next month’s IJTLD issue.

2. Challenges in TB regimen development: preserving evidentiary standards for regulatory decisions and policymaking.
Expert Rev Anti Infect Ther. 2020 Apr 28:1-3. doi:
10.1080/14787210.2020.1756776. Online ahead of print.

Guglielmetti L(1)(2)(3), Low M(4)(5)(6), McKenna L(5)(7).

DOI: 10.1080/14787210.2020.1756776
PMID: 32345064

Read the full article here.

3. High prevalence of hepatitis C infection among multidrug-resistant tuberculosis patients.
J Hepatol. 2020 May;72(5):1028-1029. doi: 10.1016/j.jhep.2019.10.018. Epub 2020
Mar 6.

Seung KJ(1), Franke MF(2), Hewison C(3), Huerga H(4), Khan U(5), Mitnick CD(6);
end TB Study Group.

DOI: 10.1016/j.jhep.2019.10.018
PMID: 32147086

Conflict of interest statement: Conflict of interest The endTB Consortium
coordinated donations of delamanid (Otsuka Pharmaceutical) and bedaquiline
(Janssen) to be used for treatment by some of the patients included in the endTB
Observational Study. All authors report no additional potential conflicts of
interest. Please refer to the accompanying ICMJE disclosure forms for further
details. 

Read the full article here.
4. Challenges in Tuberculosis Clinical Trials in the Face of the COVID-19 Pandemic: A Sponsor’s PerspectiveTrop. Med. Infect. Dis.20205(2), 86; https://doi.org/10.3390/tropicalmed5020086 (registering DOI)

I.D. Rusen

The COVID-19 pandemic has caused unforeseen and extreme changes in societal and health system functioning not previously experienced in most countries in a lifetime. The impact of the pandemic on clinical trials can be especially profound given their complexities and operational requirements. The STREAM Clinical Trial is the largest trial for MDR-TB ever conducted. Currently operating in seven countries, the trial had 126 participants on treatment and 312 additional participants in active follow up as of March 31, 2020. Areas of particular concern during this global emergency include treatment continuity, supply chain management and participant safety monitoring. This commentary highlights some of the challenges faced due to the pandemic and the steps taken to protect the safety of trial participants and the integrity of the trial.

Read the full article here.

5. Neurocognitive functioning in MDR-TB patients with and without HIV in KwaZulu-Natal, South Africa.
Trop Med Int Health. 2020 May 19. doi: 10.1111/tmi.13444. Online ahead of print.

Ramlall S(1), Lessells RJ(2)(3), Naidu T(4), Sandra Mthembu S(5), Padayachi
N(3), Burns JK(1)(6), Tomita A(2)(7).

OBJECTIVES: Optimizing medication adherence is one of the essential factors in
reversing the tide of a TB-HIV syndemic in sub-Saharan Africa, especially South
Africa. Impairment in key neurocognitive domains may impair patients’ ability to
maintain adherence to treatment, but the level of cognition and its relationship
to HIV status has not been examined in individuals with drug-resistant TB. We
therefore investigated performance on several key neurocognitive domains in
relationship to HIV status in a sample of multi-drug resistant (MDR-TB).
METHODS: We enrolled microbiologically confirmed MDR-TB inpatients at a
TB-specialist referral hospital in KwaZulu-Natal province, South Africa. We
collected cross-sectional data on sociodemographic, clinical, and neurocognitive
function (e.g. attention, memory, executive functioning, language fluency,
visual-spatial, eye-hand coordination). For the primary analysis, we excluded
participants with major depressive episode/substance use disorder (MDE/SUD). We
fitted adjusted Poisson regression models to explore the association between HIV
and neurocognitive function.
RESULTS: We enrolled 200 people with MDR-TB; 33 had MDE/SUD, and data of 167
were analyzed (151 HIV+, 16 HIV-). The mean age of participants was 34.2 years;
the majority were female (83%), and 53% had not completed secondary school.
There was evidence of impaired neurocognitive functioning across all domains in
both HIV+/- study participants. Based on the regression analyses, individuals
with co-infection (MDR-TB/HIV+), as well as those who had longer duration of
hospital stays experienced significantly lower cognitive performance in several
domains. Poor cognitive performance was significantly related to older age and
lower educational attainment. The presence of major depression or substance use
disorders did not influence the significance of the findings.
CONCLUSIONS: Adults with MDR-TB have significant neurocognitive impairment,
especially if HIV positive. An integrated approach is necessary in the
management of MDR-TB as cognitive health influences the ability to adhere to
chronic treatment, clinical outcomes and functionality.

This article is protected by copyright. All rights reserved.

DOI: 10.1111/tmi.13444
PMID: 32428324

This article is not available via OpenAccess.

6. Pattern of InhA and KatG mutations in isoniazid monoresistant Mycobacterium tuberculosis isolates.
Lung India. 2020 May-Jun;37(3):227-231. doi: 10.4103/lungindia.lungindia_204_19.

Charan AS(1), Gupta N(1), Dixit R(1), Arora P(1), Patni T(2), Antony K(1), Singh
M(3).

AIMS AND OBJECTIVES: The aim of the study is to detect the pattern of genetic
mutation, i.e., Inh A or Kat G or both (Inh A and kat G) in isoniazid (INH)
monoresistant mycobacteria and to correlate with the pattern in
multidrug-resistant (MDR) isolates.
MATERIALS AND METHODS: In this study, a quantitative research approach was used.
The research design was descriptive observational study. The study was conducted
at the Department of Respiratory Medicine, JLN Medical College, Ajmer,
Rajasthan, and Intermediate Referral Laboratory, State TB Demonstration Centre,
Ajmer. A total of 298 samples found to have resistant strains of Mycobacterium
tuberculosis were enrolled with purposive sampling.
RESULTS: The mean age of patients was 40.27 ± 13.82 years. There were 250
(83.9%) males, while 48 (16.1%) were females. One hundred ninety-two (64.4%)
were resistant for INH only, while the rest were resistant to both INH as well
as rifampicin (MDR-tuberculosis). The most common mutation in INH monoresistance
was kat G (125; 65.1%) as compared to inh A (54; 28.1%) and both inh A and kat G
(13; 6.7%). Among kat G mutations, the most common gene pattern was the absence
of WT (S315T) and the presence of MUT1 (S315T1).
CONCLUSION: Knowledge about mutation patterns of different INH resistant strains
is important in the present era where there is a provision of separate regimens
for INH monoresistant TB. Since these mutations are very closely related to
high- or low-degree resistance to INH, the therapeutic regimens cannot be
generalized.

DOI: 10.4103/lungindia.lungindia_204_19
PMID: 32367844

Read the full article here.

Recent Publications from our April Newsletter

1. Risk factors for adverse events in household contacts prescribed preventive treatment for drug-resistant TB exposure.
Clin Infect Dis. 2020 Apr 8. pii: ciaa327. doi: 10.1093/cid/ciaa327. [Epub ahead
of print]

Malik AA(1)(2)(3), Becerra MC(4)(5)(6), Lash TL(1), Cranmer LM(7), Omer
SB(8)(9)(10), Fuad J(2), Siddiqui S(2), Amanullah F(11), Jaswal M(2), Salahuddin
N(11), Keshavjee S(4)(5)(6), Hussain H(3), Gandhi NR(1).

BACKGROUND: Completion of TB preventive treatment is important to optimize
efficacy; treatment-related adverse events sometimes result in discontinuation.
This study describes the occurrence of adverse events and their risk factors
during a 6-month 2-drug fluoroquinolone-based preventive treatment for household
contacts of drug-resistant TB patients in Karachi, Pakistan.
METHODS: The primary outcome was development of any clinical adverse event during
preventive treatment. Adverse events were categorized using the adverse events
grading tables of National Institute of Health. Time to event analysis with
Kaplan-Meier curves and Cox proportional hazards models accounting for recurrence
were used to analyze associated risk factors.
RESULTS: Of the 172 household contacts on preventive treatment, 36 (21%)
developed 64 adverse events during 813 months of treatment. The incidence of
adverse events over 6-months treatment was 7.9 per 100 person-months (p-m); 16
per 100 p-m with a fluoroquinolone and ethionamide and 4.4 per 100 p-m with a
fluoroquinolone and ethambutol. There were 53 (83%) grade 1 and 11 grade 2
adverse events with no grade 3 or 4 adverse event. In multivariable analysis, the
risk of adverse events was higher in contacts prescribed ethionamide as compared
to ethambutol adjusting for age, sex and BMI (aHR: 2.1 [95% CI: 1.2-3.6]).
Overall, there was no notable difference in treatment completion amongst the
contacts who experienced an adverse event and those who did not (cOR: 1.1 [95%
CI: 0.52-2.5]).
CONCLUSION: A fluoroquinolone-based preventive treatment regimen for DR-TB
exposure is well tolerated. Regimens with ethionamide are more likely to result
in adverse events.

© The Author(s) 2020. 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/ciaa327
PMID: 32266942

Read the full article here.

2. Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid.
Antibiotics (Basel). 2020 Mar 23;9(3). pii: E133. doi:
10.3390/antibiotics9030133.

Nieto Ramirez LM(1), Quintero Vargas K(2), Diaz G(3)(4).

Tuberculosis (TB) remains the deadliest Infectious disease worldwide, partially
due to the increasing dissemination of multidrug and extensively drug-resistant
(MDR/XDR) strains. Drug regimens containing the new anti-TB drugs bedaquiline
(BDQ) and delamanid (DLM) appear as a last resort for the treatment of MDR or
XDR-TB. Unfortunately, resistant cases to these drugs emerged just one year after
their introduction in clinical practice. Early detection of resistant strains to
BDQ and DLM is crucial to preserving the effectiveness of these drugs. Here, we
present a systematic review aiming to define all available genotypic variants
linked to different levels of resistance to BDQ and DLM that have been described
through whole genomic sequencing (WGS) and the available drug susceptibility
testing methods. During the review, we performed a thorough analysis of 18
articles. BDQ resistance was associated with genetic variants in Rv0678 and atpE,
while mutations in pepQ were linked to a low-level of resistance for BDQ. For
DLM, mutations in the genes ddn, fgd1, fbiA, and fbiC were found in
phenotypically resistant cases, while all the mutations in fbiB were reported
only in DLM-susceptible strains. Additionally, WGS analysis allowed the detection
of heteroresistance to both drugs. In conclusion, we present a comprehensive
panel of gene mutations linked to different levels of drug resistance to BDQ and
DLM.

DOI: 10.3390/antibiotics9030133
PMID: 32209979

Read the full article here.

3. Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis.
Lancet Respir Med. 2020 Apr;8(4):383-394. doi: 10.1016/S2213-2600(20)30047-3.
Epub 2020 Mar 17.

Lan Z(1), Ahmad N(2), Baghaei P(3), Barkane L(4), Benedetti A(1), Brode SK(5),
Brust JCM(6), Campbell JR(1), Chang VWL(7), Falzon D(8), Guglielmetti L(9),
Isaakidis P(10), Kempker RR(11), Kipiani M(12), Kuksa L(4), Lange C(13),
Laniado-Laborín R(14), Nahid P(15), Rodrigues D(16), Singla R(17), Udwadia
ZF(18), Menzies D(19); Collaborative Group for the Meta-Analysis of Individual
Patient Data in MDR-TB treatment 2017.

BACKGROUND: Treatment of multidrug-resistant tuberculosis requires long-term
therapy with a combination of multiple second-line drugs. These drugs are
associated with numerous adverse events that can cause severe morbidity, such as
deafness, and in some instances can lead to death. Our aim was to estimate the
absolute and relative frequency of adverse events associated with different
tuberculosis drugs to provide useful information for clinicians and tuberculosis
programmes in selecting optimal treatment regimens.
METHODS: We did a meta-analysis using individual-level patient data that were
obtained from studies that reported adverse events that resulted in permanent
discontinuation of anti-tuberculosis medications. We used a database created for
our previous meta-analysis of multidrug-resistant tuberculosis treatment and
outcomes, for which we did a systematic review of literature published between
Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual
patient-level information from authors. We also considered for this analysis
studies contributing patient-level data in response to a public call made by WHO
in 2018. Meta-analysis for proportions and arm-based network meta-analysis were
done to estimate the incidence of adverse events for each tuberculosis drug.
FINDINGS: 58 studies were identified, including 50 studies from the updated
individual patient data meta-analysis for multidrug-resistant tuberculosis
treatment. 35 of these studies, with 9178 patients, were included in our
analysis. Using meta-analysis of proportions, drugs with low risks of adverse
event occurrence leading to permanent discontinuation included levofloxacin (1·3%
[95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]),
and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events
leading to permanent discontinuation was seen with three second-line injectable
drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2%
[6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1%
[9·9-19·6]). Risk of bias in selection of studies was judged to be low because
there were no important differences between included and excluded studies.
Variability between studies was significant for most outcomes analysed.
INTERPRETATION: Fluoroquinolones, clofazimine, and bedaquiline had the lowest
incidence of adverse events leading to permanent drug discontinuation, whereas
second-line injectable drugs, aminosalicylic acid, and linezolid had the highest
incidence. These results suggest that close monitoring of adverse events is
important for patients being treated for multidrug-resistant tuberculosis. Our
results also underscore the urgent need for safer and better-tolerated drugs to
reduce morbidity from treatment itself for patients with multidrug-resistant
tuberculosis.
FUNDING: Canadian Institutes of Health Research, Centers for Disease Control and
Prevention (USA), American Thoracic Society, European Respiratory Society, and
Infectious Diseases Society of America.

Copyright © 2020 World Health Organization. Published by Elsevier Ltd. All rights
reserved. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S2213-2600(20)30047-3
PMID: 32192585

This article is not available via Open Access.

4. Validation of Bedaquiline Phenotypic Drug Susceptibility Testing Methods and Breakpoints: a Multilaboratory, Multicountry Study.
J Clin Microbiol. 2020 Mar 25;58(4). pii: e01677-19. doi: 10.1128/JCM.01677-19.
Print 2020 Mar 25.

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 multicountry, multilaboratory
external quality assessment (EQA) study aimed to validate the sensitivity,
specificity, and reproducibility of provisional bedaquiline MIC breakpoints and
World Health Organization interim critical concentrations (CCs) for categorizing
clinical Mycobacterium tuberculosis isolates as susceptible/resistant to the
drug. Three methods were used: Middlebrook 7H11 agar proportion (AP) assay, broth
microdilution (BMD) assay, and mycobacterial growth indicator tube (MGIT) assay.
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 a bedaquiline MIC susceptibility breakpoint of 0.12 μg/ml for
the BMD method and WHO interim CCs of 1 μg/ml for MGIT and 0.25 μg/ml for the
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, the very major error rates for erroneously
categorizing an isolate as susceptible when it was resistant were the lowest and
within CLSI guidelines. The most highly reproducible bedaquiline DST methods were
MGIT960 and BMD using dry plates. These findings validate the use of standardized
DST methodologies and interpretative criteria to facilitate routine phenotypic
bedaquiline DST and to monitor the emergence of bedaquiline resistance.

Copyright © 2020 Kaniga et al.

DOI: 10.1128/JCM.01677-19
PMCID: PMC7098739
PMID: 31969421

Read the full article here.

From our March Newsletter!

1. Triumph and Tragedy of 21st Century Tuberculosis Drug Development.
N Engl J Med. 2020 Mar 5;382(10):959-960. doi: 10.1056/NEJMe2000860.

Thwaites G(1), Nahid P(1).

Comment on
    N Engl J Med. 2020 Mar 5;382(10):893-902.

DOI: 10.1056/NEJMe2000860
PMID: 32130819  [Indexed for MEDLINE]

This article is not available via open access. 

2. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis.
N Engl J Med. 2020 Mar 5;382(10):893-902. doi: 10.1056/NEJMoa1901814.

Conradie F(1), Diacon AH(1), Ngubane N(1), Howell P(1), Everitt D(1), Crook
AM(1), Mendel CM(1), Egizi E(1), Moreira J(1), Timm J(1), McHugh TD(1), Wills
GH(1), Bateson A(1), Hunt R(1), Van Niekerk C(1), Li M(1), Olugbosi M(1),
Spigelman M(1); Nix-TB Trial Team.

Collaborators: Mvuna N, Upton C, Vanker N, Greyling L, Eriksson M, Fabiane SM,
Canseco JO, Solanki P.

Comment in
    N Engl J Med. 2020 Mar 5;382(10):959-960.

BACKGROUND: Patients with highly drug-resistant forms of tuberculosis have
limited treatment options and historically have had poor outcomes.
METHODS: In an open-label, single-group study in which follow-up is ongoing at
three South African sites, we investigated treatment with three oral drugs –
bedaquiline, pretomanid, and linezolid – that have bactericidal activity against
tuberculosis and to which there is little preexisting resistance. We evaluated
the safety and efficacy of the drug combination for 26 weeks in patients with
extensively drug-resistant tuberculosis and patients with multidrug-resistant
tuberculosis that was not responsive to treatment or for which a second-line
regimen had been discontinued because of side effects. The primary end point was
the incidence of an unfavorable outcome, defined as treatment failure
(bacteriologic or clinical) or relapse during follow-up, which continued until 6
months after the end of treatment. Patients were classified as having a favorable
outcome at 6 months if they had resolution of clinical disease, a negative
culture status, and had not already been classified as having had an unfavorable
outcome. Other efficacy end points and safety were also evaluated.
RESULTS: A total of 109 patients were enrolled in the study and were included in
the evaluation of efficacy and safety end points. At 6 months after the end of
treatment in the intention-to-treat analysis, 11 patients (10%) had an
unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had
a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during
treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent
during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The
expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of
patients) and myelosuppression (48%), although common, were manageable, often
leading to dose reductions or interruptions in treatment with linezolid.
CONCLUSIONS: The combination of bedaquiline, pretomanid, and linezolid led to a
favorable outcome at 6 months after the end of therapy in a high percentage of
patients with highly drug-resistant forms of tuberculosis; some associated toxic
effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov
number, NCT02333799.).

Copyright © 2020 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa1901814
PMCID: PMC6955640
PMID: 32130813  [Indexed for MEDLINE]

Read the full article here.
 
3. Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis.

Lancet Respir Med. 2020 Mar 16. pii: S2213-2600(20)30047-3. doi:
10.1016/S2213-2600(20)30047-3. [Epub ahead of print]

Lan Z(1), Ahmad N(2), Baghaei P(3), Barkane L(4), Benedetti A(1), Brode SK(5),
Brust JCM(6), Campbell JR(1), Chang VWL(7), Falzon D(8), Guglielmetti L(9),
Isaakidis P(10), Kempker RR(11), Kipiani M(12), Kuksa L(4), Lange C(13),
Laniado-Laborín R(14), Nahid P(15), Rodrigues D(16), Singla R(17), Udwadia
ZF(18), Menzies D(19); Collaborative Group for the Meta-Analysis of Individual
Patient Data in MDR-TB treatment 2017.

Collaborators: Ahmad N, Baghaei P, Barkane L, Benedetti A, Brode SK, Brust J,
Campbell JR, Chang V, Falzon D, Guglielmetti L, Isaakidis P, Kempker RR, Kipiani
M, Kuksa L, Lan Z, Lange C, Laniado-Laborín R, Nahid P, Rodrigues D, Singla R,
Udwadia ZF, Menzies D.

BACKGROUND: Treatment of multidrug-resistant tuberculosis requires long-term
therapy with a combination of multiple second-line drugs. These drugs are
associated with numerous adverse events that can cause severe morbidity, such as
deafness, and in some instances can lead to death. Our aim was to estimate the
absolute and relative frequency of adverse events associated with different
tuberculosis drugs to provide useful information for clinicians and tuberculosis
programmes in selecting optimal treatment regimens.
METHODS: We did a meta-analysis using individual-level patient data that were
obtained from studies that reported adverse events that resulted in permanent
discontinuation of anti-tuberculosis medications. We used a database created for
our previous meta-analysis of multidrug-resistant tuberculosis treatment and
outcomes, for which we did a systematic review of literature published between
Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual
patient-level information from authors. We also considered for this analysis
studies contributing patient-level data in response to a public call made by WHO
in 2018. Meta-analysis for proportions and arm-based network meta-analysis were
done to estimate the incidence of adverse events for each tuberculosis drug.
FINDINGS: 58 studies were identified, including 50 studies from the updated
individual patient data meta-analysis for multidrug-resistant tuberculosis
treatment. 35 of these studies, with 9178 patients, were included in our
analysis. Using meta-analysis of proportions, drugs with low risks of adverse
event occurrence leading to permanent discontinuation included levofloxacin (1·3%
[95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]),
and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events
leading to permanent discontinuation was seen with three second-line injectable
drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2%
[6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1%
[9·9-19·6]). Risk of bias in selection of studies was judged to be low because
there were no important differences between included and excluded studies.
Variability between studies was significant for most outcomes analysed.
INTERPRETATION: Fluoroquinolones, clofazimine, and bedaquiline had the lowest
incidence of adverse events leading to permanent drug discontinuation, whereas
second-line injectable drugs, aminosalicylic acid, and linezolid had the highest
incidence. These results suggest that close monitoring of adverse events is
important for patients being treated for multidrug-resistant tuberculosis. Our
results also underscore the urgent need for safer and better-tolerated drugs to
reduce morbidity from treatment itself for patients with multidrug-resistant
tuberculosis.
FUNDING: Canadian Institutes of Health Research, Centers for Disease Control and
Prevention (USA), American Thoracic Society, European Respiratory Society, and
Infectious Diseases Society of America.

Copyright © 2020 World Health Organization. Published by Elsevier Ltd. All rights
reserved. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S2213-2600(20)30047-3
PMID: 32192585

This article is not available via open access.

4. Sources of multi-drug resistance in patients with previous isoniazid resistant tuberculosis identified using whole genome sequencing: A longitudinal cohort study.
Clin Infect Dis. 2020 Mar 13. pii: ciaa254. doi: 10.1093/cid/ciaa254. [Epub ahead
of print]

Srinivasan V(1)(2), Ha VTN(1), Vinh DN(1), Thai PVK(3), Ha DTM(3), Lan NH(3), Hai
HT(1), Walker TM(2), Thu DDA(1), Dunstan SJ(4), Thwaites GE(1)(2), Ashton
PM(1)(2), Caws M(5), Thuong NTT(1).

BACKGROUND: Meta-analysis of patients with isoniazid-resistant tuberculosis given
standard first-line anti-tuberculosis treatment indicated an increased risk of
multi-drug resistant tuberculosis (MDR-TB) emerging (8%), compared to
drug-sensitive tuberculosis (0.3%). Here we use whole genome sequencing (WGS) to
investigate whether treatment of patients with pre-existing isoniazid resistant
disease with first-line anti-tuberculosis therapy risks selecting for rifampicin
resistance, and hence MDR-TB.
METHODS: Patients with isoniazid-resistant pulmonary TB were recruited and
followed up for 24 months. Drug-susceptibility testing was performed by
Microscopic observation drug-susceptibility assay (MODS), Mycobacterial Growth
Indicator Tube (MGIT) and by WGS on isolates at first presentation and in the
case of re-presentation. Where MDR-TB was diagnosed, WGS was used to determine
the genomic relatedness between initial and subsequent isolates. De novo
emergence of MDR-TB was assumed where the genomic distance was five or fewer
single nucleotide polymorphisms (SNPs) whereas reinfection with a different
MDR-TB strain was assumed where the distance was 10 or more SNPs.
RESULTS: 239 patients with isoniazid-resistant pulmonary tuberculosis were
recruited. Fourteen (14/239, 5.9%) patients were diagnosed with a second episode
of tuberculosis that was multi-drug resistant. Six (6/239, 2.5%) were identified
as having evolved MDR-TB de novo and six as having been re-infected with a
different strain. In two cases the genomic distance was between 5-10 SNPs and
therefore indeterminate.
CONCLUSIONS: In isoniazid-resistant TB, de novo emergence and reinfection of
MDR-TB strains equally contributed to MDR development. Early diagnosis and
optimal treatment of isoniazid resistant TB are urgently needed to avert the de
novo emergence of MDR-TB during treatment.

© The Author(s) 2020. Published by Oxford University Press for the Infectious
Diseases Society of America.

DOI: 10.1093/cid/ciaa254
PMID: 32166306

Read the full article here.

5. Improving Quality of Patient Data for Treatment of Multidrug- or Rifampin-Resistant Tuberculosis.
Emerg Infect Dis. 2020 Mar;26(3). doi: 10.3201/eid2603.190997. Epub 2020 Mar 17.

Campbell JR, Falzon D, Mirzayev F, Jaramillo E, Migliori GB, Mitnick CD, Ndjeka
N, Menzies D.

International policy for treatment of multidrug- and rifampin-resistant
tuberculosis (MDR/RR TB) relies largely on individual patient data (IPD) from
observational studies of patients treated under routine conditions. We prepared
guidance on which data to collect and what measures could improve consistency and
utility for future evidence-based recommendations. We highlight critical stages
in data collection at which improvements to uniformity, accuracy, and
completeness could add value to IPD quality. Through a repetitive development
process, we suggest essential patient- and treatment-related characteristics that
should be collected by prospective contributors of observational IPD in MDR/RR
TB.

DOI: 10.3201/eid2603.190997
PMCID: PMC7045826
PMID: 31922953

Read the full article here.

6. Standardised shorter regimens versus individualised longer regimens for rifampin- or multidrug-resistant tuberculosis.
Eur Respir J. 2020 Mar 20;55(3). pii: 1901467. doi: 10.1183/13993003.01467-2019.
Print 2020 Mar.

Abidi S(1)(2), Achar J(3), Assao Neino MM(4), Bang D(5), Benedetti A(1)(2)(6),
Brode S(7), Campbell JR(1)(2), Casas EC(8), Conradie F(9), Dravniece G(10), du
Cros P(3)(11), Falzon D(12), Jaramillo E(12), Kuaban C(13), Lan Z(1)(2), Lange
C(14)(15)(16)(17), Li PZ(2), Makhmudova M(18), Maug AKJ(19), Menzies D(1)(2),
Migliori GB(20), Miller A(21), Myrzaliev B(22), Ndjeka N(23), Noeske J(24),
Parpieva N(25), Piubello A(19)(26), Schwoebel V(26), Sikhondze W(27), Singla
R(28), Souleymane MB(19), Trébucq A(26), Van Deun A(29), Viney K(30)(31)(32),
Weyer K(12), Zhang BJ(1)(2), Ahmad Khan F(33)(2).

Comment in
    Eur Respir J. 2020 Mar 20;55(3):.

We sought to compare the effectiveness of two World Health Organization
(WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant
(RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the “shorter
regimen”) and individualised regimens of ≥20 months (“longer regimens”).We
collected individual patient data from observational studies identified through
systematic reviews and a public call for data. We included patients meeting WHO
eligibility criteria for the shorter regimen: not previously treated with
second-line drugs, and with fluoroquinolone- and second-line injectable
agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects
meta-regression to calculate adjusted odds ratios and adjusted risk differences
(aRDs) for failure or relapse, death within 12 months of treatment initiation and
loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine
studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53
studies of longer regimens. Treatment success was higher with the shorter regimen
than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less
loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk
difference for failure or relapse was slightly higher with the shorter regimen
overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline
resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16),
prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09,
95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised
shorter regimen was associated with substantially less loss to follow-up during
treatment compared with individualised longer regimens and with more failure or
relapse in the presence of resistance to component medications. Our findings
support the need to improve access to reliable drug susceptibility testing.

The content of this work is copyright of the authors or their employers. Design
and branding are copyright ©ERS 2020.

DOI: 10.1183/13993003.01467-2019
PMID: 31862767

Read the full article here.

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

Read the full article here.

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

Read the full article here.

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
Network.

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

Read the full article here.

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

Read the full article here.

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
P(7).

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

Read the full article here.

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.

From our January 2020 Newsletter!

1. Early Bactericidal Activity of Different Isoniazid Doses for Drug Resistant TB (INHindsight): A Randomized Open-label Clinical Trial.
Am J Respir Crit Care Med. 2020 Jan 16. doi: 10.1164/rccm.201910-1960OC. [Epub
ahead of print]

Dooley KE(1), Miyahara S(2), von Groote-Bidlingmaier F(3), Sun X(2), Hafner R(4),
Rosenkranz SL(2)(5), Ignatius EH(6), Nuermberger EL(7), Moran L(8), Donahue K(5),
Swindells S(9), Vanker N(10), Diacon AH(11); A5312 Study Team.

RATIONALE: High-dose isoniazid is recommended in short-course regimens for
multidrug-resistant TB (MDR-TB). The optimal dose of isoniazid and its individual
contribution to efficacy against TB strains with inhA or katG mutations are
unknown.
OBJECTIVE: Define the optimal dose of isoniazid for patients with
isoniazid-resistant TB mediated by inhA mutations.
METHODS: AIDS Clinical Trials Group A5312 is a Phase 2A, open-label trial in
which individuals with smear-positive pulmonary TB with isoniazid resistance
mediated by an inhA mutation were randomized to receive isoniazid 5, 10 or 15
mg/kg daily for 7 days (inhA group), and controls with drug-sensitive TB received
standard dose (5 mg/kg/day). Overnight sputum cultures were collected daily. The
7-day early bactericidal activity of isoniazid was estimated as the average daily
change in log10 colony forming units on solid media (EBACFU0-7) or as time to
positivity in liquid media in hours (EBATTP0-7) using nonlinear mixed effects
models.
MEASUREMENTS AND MAIN RESULTS: Fifty-nine participants, 88% with cavitary
disease, 20% HIV-positive, 16 with isoniazid-sensitive and 41 with isoniazid
mono-resistant or MDR TB, were enrolled at one site in South Africa. Mean
EBACFU0-7 at doses of 5, 10 and 15 mg/kg in the inhA group was 0.07, 0.17 and
0.22 log10CFU/mL/day, respectively, and 0.16 log10CFU/mL/day in controls.
EBATTP0-7 patterns were similar. There were no drug-related Grade >3 adverse
events.
CONCLUSIONS: Isoniazid 10-15 mg/kg daily had similar activity against TB strains
with inhA mutations as 5 mg/kg against drug-sensitive strains. The activity of
high-dose isoniazid against strains with katG mutations will be explored next.
Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01936831.

DOI: 10.1164/rccm.201910-1960OC
PMID: 31945300

Read the full article here.

2. “A very humiliating illness”: a qualitative study of patient-centered Care for Rifampicin-Resistant Tuberculosis in South Africa

Jennifer Furin, Marian Loveday, Sindisiwe Hlangu, Lindy Dickson-Hall, Sacha le Roux, Mark Nicol and Helen Cox

Background: Patient-centered care is pillar 1 of the “End TB” strategy, but little has been documented in the literature about what this means for people living with rifampicin-resistant (RR-TB). Optimizing care for such individuals requires a better understanding of the challenges they face and the support they need.
Methods: A qualitative study was done among persons living with RR-TB and members of their support network. A purposive sample was selected from a larger study population and open-ended interviews were conducted using a semi-standard interview guide. Interviews were recorded and transcribed and the content analyzed using an iterative thematic analysis based in grounded theory.
Results: 16 participants were interviewed from three different provinces. Four distinct periods in which support was needed were identified: 1) pre-diagnosis; 2) pre-treatment; 3) treatment; and 4) post-treatment. Challenges common in all four periods included: socioeconomic issues, centralized care, and the need for better counseling at multiple levels.
Conclusions: Beyond being a “very humiliating illness”, RR-TB robs people of their physical, social, economic, psychological, and emotional well-being far beyond the period when treatment is being administered. Efforts to tackle these issues are as important as new drugs and diagnostics in the fight against TB. Keywords: South Africa, Costs, Challenges, Social support, Counseling

DOI https://doi.org/10.1186/s12889-019-8035-z

Read the full article here.

3. Outcomes of Community-Based Systematic Screening of Household Contacts of Patients with Multidrug-Resistant Tuberculosis in Myanmar.
Trop Med Infect Dis. 2019 Dec 25;5(1). pii: E2. doi: 10.3390/tropicalmed5010002.

Kyaw NTT(1), Sithu A(1), Satyanarayana S(2)(3), Kumar AMV(2)(3)(4), Thein S(5),
Thi AM(1), Wai PP(1), Lin YN(1), Kyaw KWY(1), Tun MMT(1), Oo MM(1), Aung ST(5),
Harries AD(3)(6).

Screening of household contacts of patients with multidrug-resistant tuberculosis
(MDR-TB) is a crucial active TB case-finding intervention. Before 2016, this
intervention had not been implemented in Myanmar, a country with a high MDR-TB
burden. In 2016, a community-based screening of household contacts of MDR-TB
patients using a systematic TB-screening algorithm (symptom screening and chest
radiography followed by sputum smear microscopy and Xpert-MTB/RIF assays) was
implemented in 33 townships in Myanmar. We assessed the implementation of this
intervention, how well the screening algorithm was followed, and the yield of
active TB. Data collected between April 2016 and March 2017 were analyzed using
logistic and log-binomial regression. Of 620 household contacts of 210 MDR-TB
patients enrolled for screening, 620 (100%) underwent TB symptom screening and
505 (81%) underwent chest radiography. Of 240 (39%) symptomatic household
contacts, 71 (30%) were not further screened according to the algorithm. Children
aged <15 years were less likely to follow the algorithm. Twenty-four contacts
were diagnosed with active TB, including two rifampicin- resistant cases (yield
of active TB = 3.9%, 95% CI: 2.3%-6.5%). The highest yield was found among
children aged <5 years (10.0%, 95% CI: 3.6%-24.7%). Household contact screening
should be strengthened, continued, and scaled up for all MDR-TB patients in
Myanmar.

DOI: 10.3390/tropicalmed5010002
PMID: 31881646

Read the full article here.

4. Population pharmacokinetics and dosing of ethionamide in children with tuberculosis.
Antimicrob Agents Chemother. 2019 Dec 23. pii: AAC.01984-19. doi:
10.1128/AAC.01984-19. [Epub ahead of print]

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

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

Copyright © 2019 American Society for Microbiology.

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

Read the full article here.

5. Feasibility of Identifying Household Contacts of Rifampin-and Multidrug-resistant Tuberculosis Cases at High Risk of Progression to Tuberculosis Disease.
Clin Infect Dis. 2020 Jan 16;70(3):425-435. doi: 10.1093/cid/ciz235.

Gupta A(1)(2), Swindells S(3), Kim S(4), Hughes MD(5), Naini L(6), Wu X(5),
Dawson R(7), Mave V(1)(2), Sanchez J(8), Mendoza A(9), Gonzales P(8), Kumarasamy
N(10), Comins K(11), Conradie F(12), Shenje J(13), Fontain SN(14), Garcia-Prats
A(15), Asmelash A(16), Nedsuwan S(17), Mohapi L(18), Lalloo UG(19), Ferreira
ACG(20), Mugah C(21), Harrington M(22), Jones L(4), Cox SR(1), Smith B(23), Shah
NS(24), Hesseling AC(15), Churchyard G(25)(26)(27).

BACKGROUND: We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their
household contacts (HHCs) to inform the development of an interventional clinical
trial.
METHODS: We conducted a cross-sectional study of adult MDR-TB cases and their
HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings,
chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing
(tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human
immunodeficiency virus (HIV) testing.
RESULTS: From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were
enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli
sputum smears and 43% had cavitary disease; at study entry, 35% remained smear
positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs
that were diagnosed with TB prior to entry and excluded. Of the remaining 1007
HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs
that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable,
and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA
positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775
(77%) were considered high-risk per these mutually exclusive groups: 102 (10%)
were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610
(61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and
were TBI positive. Only 21 (2%) HHCs were on preventive therapy.
CONCLUSIONS: The majority of HHCs in these high-burden countries were at high
risk of TB disease and infection, yet few were receiving routine preventive
therapy. Trials of novel, preventive therapies are urgently needed to inform
treatment policy and practice.

© The Author(s) 2019. 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/ciz235
PMID: 30942853

Read the full article here.