From our November 2019 Newsletter

PUBLICATIONS

1. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.
Am J Respir Crit Care Med. 2019 Nov 15;200(10):e93-e142. doi:
10.1164/rccm.201909-1874ST.

Nahid P, Mase SR, Migliori GB, Sotgiu G, Bothamley GH, Brozek JL, Cattamanchi A,
Cegielski JP, Chen L, Daley CL, Dalton TL, Duarte R, Fregonese F, Horsburgh CR
Jr, Ahmad Khan F, Kheir F, Lan Z, Lardizabal A, Lauzardo M, Mangan JM, Marks SM,
McKenna L, Menzies D, Mitnick CD, Nilsen DM, Parvez F, Peloquin CA, Raftery A,
Schaaf HS, Shah NS, Starke JR, Wilson JW, Wortham JM, Chorba T, Seaworth B.

Background: The American Thoracic Society, U.S. Centers for Disease Control and
Prevention, European Respiratory Society, and Infectious Diseases Society of
America jointly sponsored this new practice guideline on the treatment of
drug-resistant tuberculosis (DR-TB). The document includes recommendations on the
treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but
rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and
a new individual patient data meta-analysis from 12,030 patients, in 50 studies,
across 25 countries with confirmed pulmonary rifampin-resistant TB were used for
this guideline. Meta-analytic approaches included propensity score matching to
reduce confounding. Each recommendation was discussed by an expert committee,
screened for conflicts of interest, according to the Grading of Recommendations,
Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one
Population, Intervention, Comparator, and Outcomes questions were addressed,
generating 25 GRADE-based recommendations. Certainty in the evidence was judged
to be very low, because the data came from observational studies with significant
loss to follow-up and imbalance in background regimens between comparator groups.
Good practices in the management of MDR-TB are described. On the basis of the
evidence review, a clinical strategy tool for building a treatment regimen for
MDR-TB is also provided.Conclusions: New recommendations are made for the choice
and number of drugs in a regimen, the duration of intensive and continuation
phases, and the role of injectable drugs for MDR-TB. On the basis of these
recommendations, an effective all-oral regimen for MDR-TB can be assembled.
Recommendations are also provided on the role of surgery in treatment of MDR-TB
and for treatment of contacts exposed to MDR-TB and treatment of
isoniazid-resistant TB.

DOI: 10.1164/rccm.201909-1874ST
PMID: 31729908

Read the full article here.

2. Clinical Outcomes among Patients with Drug-resistant Tuberculosis receiving Bedaquiline or Delamanid Containing Regimens.
Clin Infect Dis. 2019 Nov 12. pii: ciz1107. doi: 10.1093/cid/ciz1107. [Epub ahead
of print]

Kempker RR(1), Mikiashvili L(2), Zhao Y(3), Benkeser D(3), Barbakadze K(2),
Bablishvili N(2), Avaliani Z(2), Peloquin CA(4), Blumberg HM(1)(5), Kipiani M(2).

BACKGROUND: Bedaquiline and delamanid are newly available drugs for treating
multidrug-resistant tuberculosis (MDR TB); however, there is limited data guiding
their use and no comparison studies.
METHODS: We conducted a prospective observational study among patients with MDR
TB in Georgia receiving a bedaquiline or delamanid-based treatment regimen.
Monthly sputum cultures, minimal inhibitory concentration testing, and adverse
event monitoring were performed. Primary outcomes were culture conversion rates
and clinical outcomes. Targeted maximum likelihood estimation (TMLE) and
superlearning were utilized to produce a covariate-adjusted proportion of
outcomes for each regimen.
RESULTS: Among 156 patients with MDR TB, 100 were enrolled and 95 were receiving
a bedaquiline (n=64) or delamanid (n=31) based regimen. Most were male (82%) and
the median age was 38 years. Rates of previous treatment (56%) and cavitary
disease (61%) were high. The most common companion drugs included linezolid,
clofazimine, cycloserine and a fluoroquinolone. Median effective drugs received
among patients on bedaquiline (4, IQR 4-4) and delamanid (4, IQR 3.5-5) based
regimens were similar. Rates of acquired drug resistance were significantly
higher among patients receiving delamanid versus bedaquiline (36% vs. 10%, p
<0.01). Adjusted rates of sputum culture conversion at two months (67 vs. 47%,
p=0.10) and six months (95 vs. 74%, p<0.01) and favorable clinical outcomes (96
vs. 72%, p<0.01) were higher among patients receiving bedaquiline versus
delamanid.
CONCLUSIONS: Among patients with MDR TB, bedaquiline-based regimens were
associated with higher rates of sputum culture conversion and favorable outcomes
and a lower rate of acquired drug resistance versus delamanid-based regimens.

© 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/ciz1107
PMID: 31712809

This article is not available via open access.

3. Culture conversion at six months in patients receiving delamanid-containing regimens for the treatment of multidrug-resistant tuberculosis.
Clin Infect Dis. 2019 Nov 2. pii: ciz1084. doi: 10.1093/cid/ciz1084. [Epub ahead
of print]

Seung KJ(1), Khan P(2), Franke MF(3), Ahmed S(2), Aiylchiev S(4), Alam M(5),
Putri FA(6), Bastard M(7), Docteur W(8), Gottlieb G(9), Hewison C(10), Islam
S(5), Khachatryan N(11), Kotrikadze T(12), Khan U(13), Kumsa A(14), Lecca L(15),
Tassew YM(16), Melikyan N(16), Naing YY(17), Oyewusi L(18), Rich M(1), Wanjala
S(19), Yedilbayev A(1), Huerga H(7), Mitnick CD(3); endTB Study Group.

Delamanid should be effective against highly resistant strains of M.
tuberculosis, but uptake has been slow globally. In the endTB Observational
Study, which enrolled one of the largest, most heterogeneous cohorts of patients
receiving delamanid as part of a multidrug regimen, 80% experienced sputum
culture conversion within six months.

© 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/ciz1084
PMID: 31676905

This article is not available via open access.

4. Transmissibility and potential for disease progression of drug resistant Mycobacterium tuberculosis: prospective cohort study.
BMJ. 2019 Oct 24;367:l5894. doi: 10.1136/bmj.l5894.

Becerra MC(1), Huang CC(2), Lecca L(3), Bayona J(4), Contreras C(3), Calderon
R(3), Yataco R(3), Galea J(5), Zhang Z(2), Atwood S(2), Cohen T(6), Mitnick
CD(1), Farmer P(1)(2), Murray M(7)(2).

OBJECTIVE: To measure the association between phenotypic drug resistance and the
risk of tuberculosis infection and disease among household contacts of patients
with pulmonary tuberculosis.
SETTING: 106 district health centers in Lima, Peru between September 2009 and
September 2012.
DESIGN: Prospective cohort study.
PARTICIPANTS: 10 160 household contacts of 3339 index patients with tuberculosis
were classified on the basis of the drug resistance profile of the patient: 6189
were exposed to drug susceptible strains of Mycobacterium tuberculosis, 1659 to
strains resistant to isoniazid or rifampicin, and 1541 to strains that were
multidrug resistant (resistant to isoniazid and rifampicin).
MAIN OUTCOME MEASURES: Tuberculosis infection (positive tuberculin skin test) and
the incidence of active disease (diagnosed by positive sputum smear or chest
radiograph) after 12 months of follow-up.
RESULTS: Household contacts exposed to patients with multidrug resistant
tuberculosis had an 8% (95% confidence interval 4% to 13%) higher risk of
infection by the end of follow-up compared with household contacts of patients
with drug sensitive tuberculosis. The relative hazard of incident tuberculosis
disease did not differ among household contacts exposed to multidrug resistant
tuberculosis and those exposed to drug sensitive tuberculosis (adjusted hazard
ratio 1.28, 95% confidence interval 0.9 to 1.83).
CONCLUSION: Household contacts of patients with multidrug resistant tuberculosis
were at higher risk of tuberculosis infection than contacts exposed to drug
sensitive tuberculosis. The risk of developing tuberculosis disease did not
differ among contacts in both groups. The evidence invites guideline producers to
take action by targeting drug resistant and drug sensitive tuberculosis, such as
early detection and effective treatment of infection and disease.
TRIAL REGISTRATION: ClinicalTrials.gov NCT00676754.

Published by the BMJ Publishing Group Limited. For permission to use (where not
already granted under a licence) please go to
http://group.bmj.com/group/rights-licensing/permissions.

DOI: 10.1136/bmj.l5894
PMCID: PMC6812583
PMID: 31649017  [Indexed for MEDLINE]

Read the full article here.

5. Daily Dosing for Bedaquiline in Patients with Tuberculosis.
Antimicrob Agents Chemother. 2019 Oct 22;63(11). pii: e00463-19. doi:
10.1128/AAC.00463-19. Print 2019 Nov.

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

The bedaquiline regimen for the treatment of multidrug-resistant tuberculosis
(MDR-TB) in adults is a loading dose of 400 mg QD for 2 weeks followed by 200 mg
thrice weekly (TIW) 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
PMCID: PMC6811417
PMID: 31451504

Read the full article here.

6. Treatment Outcomes of Patients Switching From an Injectable Drug to Bedaquiline During Short Standardized Treatment for Multidrug-resistant Tuberculosis in Mozambique.
Clin Infect Dis. 2019 Oct 30;69(10):1809-1811. doi: 10.1093/cid/ciz196.

Bastard M(1), Molfino L(2), Mutaquiha C(3), Galindo MA(2), Zindoga P(3), Vaz
D(2), Mahinça I(3), DuCros P(4), Rusch B(2), Telnov A(2).

Bedaquiline was recommended by the World Health Organization as the preferred
option in treatment of multidrug-resistant tuberculosis (MDR-TB) with long
regimens. However, no recommendation was given for the short MDR-TB regimen. Data
from our small cohort of patients who switched from injectable drug to
bedaquiline suggest that a bedaquiline-based short regimen is effective and safe.

© 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/ciz196
PMID: 30901021

This article is not available via open access.