Recent Publications (From our June 2020 Newsletter)

Tuberculosis Publications

1. Bedaquiline resistance in drug-resistant tuberculosis HIV co-infected patients.
 Eur Respir J. 2020 Jun 4;55(6):1902383. doi: 10.1183/13993003.02383-2019. Print 2020 Jun.

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). 
Genetic mutations linked to bedaquiline resistance were found before starting treatment and acquired during treatment in patients with drug-resistant TB and HIV in KwaZulu-Natal, South Africa. Routine bedaquiline resistance testing needs to be accelerated. http://bit.ly/2vnL4VY

Global tuberculosis (TB) control is threatened by drug resistance, with over 500 000 cases resistant to first line drugs in 2018 [1]. Bedaquiline is a highly effective TB drug and has improved drug-resistant TB (DR-TB) outcomes in trial and programmatic settings [2, 3]. The World Health Organization (WHO) recommends its inclusion in most DR-TB regimens [4] and it is under further evaluation in clinical trials. There have been several reports of clinical bedaquiline resistance [5–8]. Resistance-associated variants (RAVs) in clinical isolates identified to date are almost exclusively caused by Rv0678 mutations which can raise Mycobacterium tuberculosis minimum inhibitory concentrations (MICs) for bedaquiline and clofazimine [9].

DOI: 10.1183/13993003.02383-2019
PMCID: PMC7270361
PMID: 32060065

2. Ambulatory management of pre- and extensively drug resistant tuberculosis  patients with imipenem delivered through port-a-cath: A mixed methods study on  treatment outcomes and challenges.

PLoS One. 2020 Jun 16;15(6):e0234651. doi: 10.1371/journal.pone.0234651. eCollection 2020.

Chavan VV(1), Dalal A(2), Nagaraja S(3), Thekkur P(4)(5), Mansoor H(1), Meneguim A(1), Paryani R(1), Singh P(1), Kalon S(1), Das M(1), Ferlazzo G(6), Isaakidis P(6).

BACKGROUND: Imipenem, an intravenous antibiotic is recommended for use in drug resistant tuberculosis (DR-TB) when an effective regimen with combination of other second line drugs is not possible. Though the treatment success rates with carbapenems are promising, the twice daily injection of Imipenem usually requires patients to be hospitalized. The Médecins Sans Frontières independent clinic in Mumbai, India implemented ambulatory and home based management of patients receiving Imipenem through the use of port-a-cath.
OBJECTIVE: We aimed to describe the adverse events and treatment outcomes of ambulatory pre- and XDR-TB patients initiated on imipenem through port-a-cath between January 2015 and June 2018 and to explore the challenges with this regimen as perceived by healthcare providers and patients.
METHODS: A convergent mixed methods study with quantitative (longitudinal descriptive study using the routine data) and qualitative (descriptive study) part conducted concurrently. For the quantitative component, all XDR-TB and pre-XDR-TB initiated on imipenem containing regimen during January 2015-June 2018 were included. For qualitative component, interviews were carried out including patients who initiated on imipenem (n = 5) and healthcare providers (n = 7) involved in providing treatment. Treatment outcomes, culture conversion and adverse events during treatment were described. Thematic analysis was carried
out for qualitative component.
RESULTS: Of the 70 patients included, the mean age was 28.1 (standard deviation: 11.2) years and 36 (51.4%) were females. Fifty one (72.9%) had XDR-TB. All patients were resistant to fluoroquinilone, levofloxacin. Vomiting was reported by 55 (78.6%) patients and at least one episode of QTC prolongation (more than 500 msec by Fredrecia method) was detected in 25 (35.7%). Port-a-cath block and
infection was seen in 11 (15.7%) and 20 (28.6%) patients respectively. Favourable outcomes were seen in 43 (61.4%) patients. Mortality was seen in 22 (31.4%) patients, 2 (2.9%) were lost-to-follow-up and 3 (4.3%) were declared as treatment failure. The overarching theme of the qualitative analysis was: Challenges in delivering Imipenem via port-a-cath device in ambulatory care. Major challenges identified were difficulties in adhering to drug dose timelines, vomiting, restricted mobility due to port-a-cath, paucity of infection control and space constraints at patients’ home for optimal care.
CONCLUSION: Administration of imipenem was feasible through port-a-cath. Though outcomes with ambulatory based imipenem containing regimens were promising, there were several challenges in providing care. The feasibility of infusion at day care facilities needs to explored to overcome challenges in infusion at
patients home.

DOI: 10.1371/journal.pone.0234651
PMCID: PMC7297304
PMID: 32544174

3. Concordance of drug resistance profiles between persons with drug-resistant tuberculosis and their household contacts: a systematic review and meta-analysis.

Clin Infect Dis. 2020 May 25:ciaa613. doi: 10.1093/cid/ciaa613. Online ahead of print.

Chiang SS(1)(2), Brooks MB(3), Jenkins HE(4), Rubenstein D(1), Seddon JA(5)(6), van de Water BJ(3), Lindeborg MM(3), Becerra MC(3)(7), Yuen CM(3)(7).

BACKGROUND: Household contacts of patients with drug-resistant tuberculosis are at high risk for being infected with Mycobacterium tuberculosis and for developing tuberculosis disease. To guide regimen composition for the empirical treatment of tuberculosis infection and disease in these household contacts, we estimated drug resistance profile concordance between index patients with drug-resistant tuberculosis and their household contacts.
METHODS: We performed a systematic review and meta-analysis of studies published through July 24, 2018 and reported resistance profiles of drug-resistant tuberculosis index and secondary cases within their households. Using a random-effects meta-analysis, we estimated resistance profile concordance, defined as the percentage of secondary cases whose M. tuberculosis strains were resistant to the same drugs as strains from their index cases. We also estimated isoniazid/rifampin concordance, defined as whether index and secondary cases had identical susceptibilities for isoniazid and rifampin only.
RESULTS: We identified 33 eligible studies, which evaluated resistance profile concordance between 484 secondary cases and their household index cases. Pooled resistance profile concordance was 54.3% (95% confidence interval [CI]: 40.7-67.6, I2=85%). Pooled isoniazid/rifampin concordance was 82.6% (95% CI: 72.3-90.9; I2=73%). Concordance estimates were similar in a sub-analysis of 16 studies from high tuberculosis-burden countries. There were insufficient data to perform a sub-analysis among pediatric secondary cases.
CONCLUSION: Household contacts of drug-resistant TB patients should receive treatment for TB infection and disease that assumes that they, too, are infected with a drug-resistant M. tuberculosis strain. Whenever possible, drug susceptibility testing should be performed for secondary cases to optimize regimen composition.

© 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/ciaa613
PMID: 32448887

4. Isoniazid Preventive Therapy in Contacts of Multidrug-resistant Tuberculosis.

Am J Respir Crit Care Med. 2020 Jun 17. doi: 10.1164/rccm.201908-1576OC. Online ahead of print.

Huang CC(1)(2), Becerra MC(2), Calderon R(3), Contreras C(3), Galea J(4), Grandjean L(5)(6)(7), Lecca L(3), Yataco R(3), Zhang Z(1), Murray M(2)(8).

RATIONALE: The World Health Organization recommends the use of isoniazid alone or in combination with rifapentine to treat latent tuberculosis infection. The recent rise of drug-resistant tuberculosis has complicated the choice of latent tuberculosis infection treatment regimen.
OBJECTIVES: To evaluate the effects of isoniazid preventive therapy on contacts of multidrug-resistant tuberculosis patients Methods: In a prospective cohort study conducted between September 2009 and August 2012, we identified 4,500 index tuberculosis patients and 14,044 tuberculosis-exposed household contacts whom we followed for one year for the occurrence of incident tuberculosi disease. Although Peruvian national guidelines specify that isoniazid preventive therapy should be provided to contacts aged 19 and under, only half this group received isoniazid preventive therapy.
MEASUREMENTS AND MAIN RESULTS: Among 4,216 contacts under 19 years of age, 2,106
(50%) initiated isoniazid preventive therapy at enrollment. The protective effect of isoniazid was more extreme in contacts exposed to drug-sensitive (adjusted hazard ratio, 0.30 [95% confidence interval, 0.18-0.48]) and to multidrug-resistant tuberculosis (0.19 [0.05-0.66]) compared to those exposed to mono-isoniazid-resistant (0.80 [0.23-2.80]). In the second independent study, tuberculosis occurred in none of the 76 household contacts who received isoniazid preventive therapy compared to 3% (8/273) of those who did not.
CONCLUSION: Household contacts who received isoniazid preventive therapy had a lower incidence of tuberculosis disease even when they had been exposed to an index patient with multidrug-resistant tuberculosis. Isoniazid may have a role in the management of latent multidrug-resistant tuberculosis infection.

DOI: 10.1164/rccm.201908-1576OC
PMID: 32551948

Tuberculosis and COVID-19 Publications

1. Challenges in Tuberculosis Clinical Trials in the Face of the COVID-19 Pandemic:  A Sponsor’s Perspective.

Trop Med Infect Dis. 2020 May 27;5(2):E86. doi: 10.3390/tropicalmed5020086.

Rusen ID(1).

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.

DOI: 10.3390/tropicalmed5020086
PMID: 32471274

2. Responding to SARS-CoV-2 in South Africa: What can we learn from drug-resistant tuberculosis?

Eur Respir J. 2020 May 29:2001369. doi: 10.1183/13993003.01369-2020. Online ahead of print.

Ndjeka N(1)(2), Conradie F(3)(2), Meintjes G(4), Reuter A(5), Hughes J(6), Padanilam X(7), Ismail N(8), Kock Y(1), Master I(9), Romero R(10), Te Riele J(11), Enwerem M(12), Ferreira H(13), Maartens G(4).

Rapid adoption of new diagnostic tools, parallel process of research and implementation, decentralization of services, the use of personal protective equipment as well as strong partnership and collaboration could strengthen the fight against COVID-19.

The novel coronavirus strain, SARS-CoV-2, was first reported from China in December 2019 [1]. As of the 14th May 2020, more than 4.4 million individuals have tested positive for SARS-COV-2 globally [2]. More than 300,000 individuals have died globally due to SARS-COV-2 [2].

DOI: 10.1183/13993003.01369-2020
PMCID: PMC7257618
PMID: 32471936

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.

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

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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

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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

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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
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

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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.