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:

DOI: 10.1093/cid/ciaa327
PMID: 32266942

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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:

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

DOI: 10.3390/antibiotics9030133
PMID: 32209979

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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
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

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