From our September 2019 Newsletter


1. Management of drug-resistant tuberculosis.
Lancet. 2019 Sep 14;394(10202):953-966. doi: 10.1016/S0140-6736(19)31882-3.

Lange C(1), Dheda K(2), Chesov D(3), Mandalakas AM(4), Udwadia Z(5), Horsburgh CR

Drug-resistant tuberculosis is a major public health concern in many countries.
Over the past decade, the number of patients infected with Mycobacterium
tuberculosis resistant to the most effective drugs against tuberculosis (ie,
rifampicin and isoniazid), which is called multidrug-resistant tuberculosis, has
continued to increase. Globally, 4·6% of patients with tuberculosis have
multidrug-resistant tuberculosis, but in some areas, like Kazakhstan, Kyrgyzstan,
Moldova, and Ukraine, this proportion exceeds 25%. Treatment for patients with
multidrug-resistant tuberculosis is prolonged (ie, 9-24 months) and patients with
multidrug-resistant tuberculosis have less favourable outcomes than those treated
for drug-susceptible tuberculosis. Individualised multidrug-resistant
tuberculosis treatment with novel (eg, bedaquiline) and repurposed (eg,
linezolid, clofazimine, or meropenem) drugs and guided by genotypic and
phenotypic drug susceptibility testing can improve treatment outcomes. Some
clinical trials are evaluating 6-month regimens to simplify management and
improve outcomes of patients with multidrug-resistant tuberculosis. Here we
review optimal diagnostic and treatment strategies for patients with
drug-resistant tuberculosis and their contacts.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S0140-6736(19)31882-3
PMID: 31526739

Read the article here.

2. Citywide transmission of MDR-TB under China’s rapid urbanization: a retrospective population-based genomic spatial epidemiological study.
Clin Infect Dis. 2019 Aug 28. pii: ciz790. doi: 10.1093/cid/ciz790. [Epub ahead
of print]

Jiang Q(1)(2), Liu Q(1)(2), Ji L(1), Li J(1), Zeng Y(1), Meng L(1), Luo G(2),
Yang C(3), Takiff HE(4)(5), Yang Z(1), Tan W(1), Yu W(1), Gao Q(1)(2).

BACKGROUND: Population movement could extend multidrug-resistant tuberculosis
(MDR-TB) transmission and complicate its global prevalence. We sought to identify
the high-risk populations and geographic sites of MDR-TB transmission in
Shenzhen, the most common destination for internal migrants in China.
METHODS: We performed a population-based, retrospective study of patients who
were diagnosed with MDR-TB in Shenzhen during 2013-2017. By defining genomic
clusters with a threshold of 12 SNP distance based on whole-genome sequencing
their clinical strains, the clustering rate was calculated to evaluate the level
of recent transmission. Risk factors for MDR-TB transmission were identified by
multivariable logistic regression. To further delineate the epidemiological
links, we invited the genomic-clustered patients to an in-depth social network
RESULTS: In total, 105 (25.2%) of the 417 enrolled MDR-TB patients were grouped
into 40 genome clusters, suggesting recent transmission of MDR strains. The
adjusted risk for students to have a clustered strain was 4.05 (95% confidential
intervals [CI], 1.06-17.0) times greater than other patients. The majority (70%,
28/40) of the genomic clusters involved patients who lived in different
districts, with residences separated by an average of 8.76 kilometers. Other than
household members, confirmed epidemiological links were also identified among
classmates and workplace colleagues.
CONCLUSIONS: These findings demonstrate that local transmission of MDR-TB is a
serious problem in Shenzhen city. While most transmission occurred between people
who lived distant from each other, there was clear evidence that transmission
occurred in schools and workplaces, which should be included as targeted sites
for active case finding.

© The Author(s) 2019. Published by Oxford University Press for the Infectious
Diseases Society of America. All rights reserved. For permissions, e-mail:

DOI: 10.1093/cid/ciz790
PMID: 31504306

Read the article here.

3. The Lancet Respiratory Medicine Commission: 2019 update: epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant and  incurable tuberculosis.
Lancet Respir Med. 2019 Sep;7(9):820-826. doi: 10.1016/S2213-2600(19)30263-2.

Dheda K(1), Gumbo T(2), Maartens G(3), Dooley KE(4), Murray M(5), Furin J(6),
Nardell EA(7), Warren RM(8); Lancet Respiratory Medicine drug-resistant
tuberculosis Commission group.

Collaborators: Dheda K, Gumbo T, Maartens G, Dooley KE, Esmail A, Murray M, Furin
J, Nardell E, London L, Lessem E, Limberis J, Theron G, McNerney R, Niemann S,
Dowdy D, Van Rie A, Pasipanodya JG, Rodrigues C, Clark TG, Sirgel FA, Schaaf HS,
Chang KC, Lange C, Nahid P, Fourie B, Ndjeka N, Nunn A, Migliori GB, Udwadia ZF,
Horsburgh CR Jr, Churchyard GJ, Menzies D, Hesseling AC, Seddon JA, Low M,
Keshavjee S, Nuermberger E, McIlleron H, Fennelly KP, Jindani A, Jaramillo E,
Padayatchi N, Barry CE 3rd, Warren RM.

The Lancet Respiratory Medicine Commission on drug-resistant tuberculosis was
published in 2017, which comprehensively reviewed and provided recommendations on
various aspects of the disease. Several key new developments regarding
drug-resistant tuberculosis are outlined in this Commission Update. The WHO
guidelines on treating drug-resistant tuberculosis were updated in 2019 with a
reclassification of second line anti-tuberculosis drugs. An injection-free MDR
tuberculosis treatment regimen is now recommended. Over the past 3 years,
advances in treatment include the recognition of the safety and mortality benefit
of bedaquiline, the finding that the 9-11 month injectable-based ‘Bangladesh’
regimen was non-inferior to longer regimens, and promising interim results of a
novel 6 month 3-drug regimen (bedaquiline, pretomanid, and linezolid). Studies of
explanted lungs from patients with drug-resistant tuberculosis have shown
substantial drug-specific gradients across pulmonary cavities, suggesting that
alternative dosing and drug delivery strategies are needed to reduce functional
monotherapy at the site of disease. Several controversies are discussed including
the optimal route of drug administration, optimal number of drugs constituting a
regimen, selection of individual drugs for a regimen, duration of the regimen,
and minimal desirable standards of antibiotic stewardship. Newer rapid nucleic
acid amplification test platforms, including point-of-care systems that
facilitate active case-finding, are discussed. The rapid diagnosis of resistance
to other drugs, (notably fluoroquinolones), and detection of resistance by
targeted or whole genome sequencing will probably change the diagnostic landscape
in the near future.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S2213-2600(19)30263-2
PMID: 31486393

Read the article here.

4. Daily Dosing for Bedaquiline in Patients with Tuberculosis.
Antimicrob Agents Chemother. 2019 Aug 26. pii: AAC.00463-19. doi:
10.1128/AAC.00463-19. [Epub ahead of print]

Salinger DH(1), Nedelman JR(2), Mendel C(2), Spigelman M(2), Hermann DJ(3).

The bedaquiline regimen for the treatment of MDR-TB in adults is a loading dose
of 400 mg QD for 2 weeks followed by 200 mg t.i.w. for 22 weeks. Most TB
antibiotics administered with bedaquiline are given QD. Using pharmacokinetic
simulations, we explored alternative QD bedaquiline regimens and determined that
200 mg QD for 8 weeks followed by 100 mg QD provides comparable exposures to the
approved regimen. This simpler regimen is under clinical evaluation.

Copyright © 2019 Salinger et al.

DOI: 10.1128/AAC.00463-19
PMID: 31451504

Read the article here.

5. Acquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in Pakistan.
Antimicrob Agents Chemother. 2019 Aug 23;63(9). pii: e00915-19. doi:
10.1128/AAC.00915-19. Print 2019 Sep.

Ghodousi A(1), Rizvi AH(2), Baloch AQ(3), Ghafoor A(3), Khanzada FM(2), Qadir
M(2), Borroni E(1), Trovato A(1), Tahseen S(#)(2), Cirillo DM(#)(4).
We report on the first six cases of acquired resistance to bedaquiline in
Pakistan. Seventy sequential isolates from 30 drug-resistant-tuberculosis
patients on bedaquiline-containing regimens were retrospectively tested for
bedaquiline resistance by MIC testing and by the detection of mutations in
relevant genes. We documented cases failing therapy that developed specific
mutations in Rv0678 and had increased MICs associated with cross-resistance to
clofazimine during treatment. This study underlines the relevance of surveillance
programs following the introduction of new drugs.

Copyright © 2019 Ghodousi et al.

DOI: 10.1128/AAC.00915-19
PMCID: PMC6709449
PMID: 31262765

Read the article here.