PREVIOUS LITERATURE IN DR-TB

FROM OUR December 2019 Newsletter

1. Projecting the impact of variable MDR-TB transmission efficiency on long-term epidemic trends in South Africa and Vietnam.
Sci Rep. 2019 Dec 2;9(1):18099. doi: 10.1038/s41598-019-54561-9.

Salvatore PP(1), Kendall EA(2), Seabrook D(3), Brown J(3), Durham GH(3), Dowdy
DW(4)(5).

Whether multidrug-resistant tuberculosis (MDR-TB) is less transmissible than
drug-susceptible (DS-)TB on a population level is uncertain. Even in the absence
of a genetic fitness cost, the transmission potential of individuals with MDR-TB
may vary by infectiousness, frequency of contact, or duration of disease. We used
a compartmental model to project the progression of MDR-TB epidemics in South
Africa and Vietnam under alternative assumptions about the relative transmission
efficiency of MDR-TB. Specifically, we considered three scenarios: consistently
lower transmission efficiency for MDR-TB than for DS-TB; equal transmission
efficiency; and an initial deficit in the transmission efficiency of MDR-TB that
closes over time. We calibrated these scenarios with data from drug resistance
surveys and projected epidemic trends to 2040. The incidence of MDR-TB was
projected to expand in most scenarios, but the degree of expansion depended
greatly on the future transmission efficiency of MDR-TB. For example, by 2040, we
projected absolute MDR-TB incidence to account for 5% (IQR: 4-9%) of incident TB
in South Africa and 14% (IQR: 9-26%) in Vietnam assuming consistently lower
MDR-TB transmission efficiency, versus 15% (IQR: 8-27%)and 41% (IQR: 23-62%),
respectively, assuming shrinking transmission efficiency deficits. Given future
uncertainty, specific responses to halt MDR-TB transmission should be
prioritized.

DOI: 10.1038/s41598-019-54561-9
PMID: 31792289

Read the full article here.

2. Drug-resistant tuberculosis in eastern Europe and central Asia: a time-series analysis of routine surveillance data.
Lancet Infect Dis. 2019 Nov 26. pii: S1473-3099(19)30568-7. doi:
10.1016/S1473-3099(19)30568-7. [Epub ahead of print]

Dadu A(1), Hovhannesyan A(1), Ahmedov S(2), van der Werf MJ(3), Dara M(4).

BACKGROUND: Among all WHO regions, the WHO European Region has the highest
proportion of drug-resistant tuberculosis among new and retreated cases. The 18
high-priority countries in eastern Europe and central Asia account for 85% of the
tuberculosis incidence and more than 90% of drug-resistant tuberculosis cases
emerging in the region. We aimed to analyse time-series trends in notification
rates of drug-resistant tuberculosis among new tuberculosis cases in the 18
high-priority countries in the WHO European Region.
METHODS: We used country data stored in WHO's global tuberculosis database. For
each country, we calculated annual notification rates per 100 000 population of
new tuberculosis cases and of drug-resistant tuberculosis among new cases
reported from Jan 1, 2000, to Dec 31, 2017. We computed annual percentage changes
of notification rates and identified time-points of significant change in trends
using the joinpoint regression method.
FINDINGS: All 17 countries with data (no data available from Turkmenistan) showed
a significant decline in new tuberculosis notification rates in the most recent
years since the last joinpoint if one was identified. Notification rates of
drug-resistant tuberculosis showed diverse trends, with substantial year-to-year
variation. In the most recent years, notification rates of drug-resistant
tuberculosis among new tuberculosis cases were decreasing in two countries
(Estonia and Latvia), increasing in eight countries (Azerbaijan, Kyrgyzstan,
Moldova [Republic of Moldova], Romania, Russia [Russian Federation], Tajikistan,
Ukraine, and Uzbekistan), and stable in seven countries (Armenia, Belarus,
Bulgaria, Georgia, Kazakhstan, Lithuania, and Turkey).
INTERPRETATION: Our findings suggest that countries in the WHO European Region
are more successful in controlling drug-susceptible tuberculosis than
drug-resistant forms, and as a result, the proportion of drug-resistant strains
among newly notified patients with tuberculosis is increasing in many settings.
Two countries showed that it is possible to decrease incidence of both
drug-susceptible and drug-resistant tuberculosis. If no additional efforts are
made in prevention and care of patients with drug-resistant tuberculosis, further
decline of the tuberculosis burden will be halted. Further studies are needed to
investigate the success stories and document the most effective interventions to
reach the target to end tuberculosis by 2030.


FUNDING: United States Agency for International Development.

Copyright © 2019 World Health Organization. Published by Elsevier Ltd. All rights
reserved. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S1473-3099(19)30568-7
PMID: 31784371

This article is not available via open access.

3. Clinical Characteristics of Active Tuberculosis Diagnosed after Starting Treatment for Latent Tuberculosis Infection.
Clin Infect Dis. 2019 Nov 27. pii: ciz1157. doi: 10.1093/cid/ciz1157. [Epub ahead
of print]

Flynn AG(1)(2), Aiona K(3), Haas MK(2)(3), Reves R(2), Belknap R(2)(3).

BACKGROUND: Efforts to expand treatment of latent tuberculosis infection (LTBI)
raise concerns for missed subclinical active tuberculosis (TB) and acquired
drug-resistance.
METHODS: We conducted a retrospective cohort review of patients who began LTBI
therapy between January 1, 2006 and December 31, 2017 at the Denver Metro TB
Clinic, Colorado, USA. Electronic databases and chart review were used for data
collection. Subsequent active TB diagnoses in this cohort were determined using
the state of Colorado TB database through June 30, 2018.
RESULTS: 8472 patients started LTBI treatment during the study period with 46%
prescribed nine months of isoniazid and 43% four months of rifampin. 24 (0.28%)
developed active TB, 10 during and 14 after LTBI therapy. Culture confirmation
was obtained for 13 (54%) and none had acquired drug-resistance. Patients
diagnosed during (n=10) versus after treatment (n=14) were less likely to be
culture-confirmed (30% versus 71%) and less likely to have pulmonary disease (20%
vs 57%).
CONCLUSIONS: Subclinical TB missed by symptom screening and chest radiography was
rare in our mostly HIV-negative cohort. Culture negative, extrapulmonary disease
was more common with TB diagnosed during than after LTBI treatment. We found no
evidence for acquired drug resistance in LTBI patients subsequently diagnosed
with active TB.

© 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/ciz1157
PMID: 31773132

This article is not available via open access.

4. Treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules.
Eur Respir J. 2019 Dec 4;54(6). pii: 1900580. doi: 10.1183/13993003.00580-2019.
Print 2019 Dec.

Bolhuis MS(1), van der Werf TS(2)(3), Kerstjens HAM(2)(4), de Lange WCM(2)(4),
Alffenaar JC(5)(6), Akkerman OW(2)(4).

Despite all our efforts, the disease burden of tuberculosis (TB) is not falling fast enough to reach the 2030 milestone of the End TB strategy [1]. Multidrug-resistant tuberculosis (MDR-TB) remains a public health crisis, with low treatment success rates [1]. The repurposed drug linezolid has emerged as a core drug in MDR-TB treatment regimens [2, 3], despite its toxicity, e.g. anaemia, peripheral neuropathy and gastrointestinal disorders, optic neuritis, and thrombocytopenia [4, 5]. Currently, linezolid is used off-label, as part of Group A “Medicines to be prioritised” of the World Health Organization (WHO) MDR-TB treatment guideline [2] and in several large trials [6], such as the NIX-TB and END-TB trials.

DOI: 10.1183/13993003.00580-2019
PMID: 31439686

This article is not available via open access.

From our November 2019 Newsletter

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.

From our October 2019 Newsletter

1. Progress in global rollout of new multidrug-resistant tuberculosis treatments
This is an article published by The International Union Against Tuberculosis and Lung Disease (The Union) collaborating with RESIST-TB to demonstrate the implementation of new MDR-TB regimens among WHO regions.

2. Effect of tablet crushing on drug exposure in the treatment of multidrug-resistant tuberculosis.
Int J Tuberc Lung Dis. 2019 Oct 1;23(10):1068-1074. doi: 10.5588/ijtld.18.0775.

Court R(1), Chirehwa MT(1), Wiesner L(1), de Vries N(2), Harding J(3), Gumbo
T(4), Maartens G(1), McIlleron H(1).

SETTING: Treatment outcomes in multidrug-resistant tuberculosis (MDR-TB) are
poor. Due to drug toxicity and a long treatment duration, approximately half of
patients are treated successfully. Medication is often crushed for patients who
have difficulty swallowing whole tablets. Whether crushing tablets affects drug
exposure in MDR-TB treatment is not known.OBJECTIVE AND DESIGN: We performed a
sequential pharmacokinetic study in patients aged >18 years on MDR-TB treatment
at two hospitals in Cape Town, South Africa. We compared the bioavailability of
pyrazinamide, moxifloxacin, isoniazid (INH), ethambutol and terizidone when the
tablets were crushed and mixed with water before administration vs. swallowed
whole. We sampled blood at six time points over 10 h under each condition
separated by 2 weeks. Non-compartmental analysis was used to derive the key
pharmacokinetic measurements.RESULTS: Twenty participants completed the study: 15
were men, and the median age was 31.5 years. There was a 42% reduction in the
area under the curve AUC0-10 of INH when the tablets were crushed compared with
whole tablets (geometric mean ratio 58%; 90%CI 47-73). Crushing tablets of
pyrazinamide, moxifloxacin, ethambutol and terizidone did not affect the
bioavailability significantly.CONCLUSION: We recommend that crushing of INH
tablets in the MDR-TB treatment regimen be avoided. Paediatric INH formulations
may be a viable alternative if the crushing of INH tablets is indicated.

DOI: 10.5588/ijtld.18.0775
PMID: 31627771

Read the full article here.

3. What is the best culture conversion prognostic marker for patients treated for multidrug-resistant tuberculosis?
Int J Tuberc Lung Dis. 2019 Oct 1;23(10):1060-1067. doi: 10.5588/ijtld.18.0649.

Bastard M(1), Sanchez-Padilla E(1), Hayrapetyan A(2), Kimenye K(3), Khurkhumal
S(4), Dlamini T(5), Fadul Perez S(6), Telnov A(7), Hewison C(8), Varaine F(8),
Bonnet M(9).

INTRODUCTION: Identification of good prognostic marker for tuberculosis (TB)
treatment response is a necessary step on the path towards a surrogate marker to
reduce TB trial duration.METHODS: We performed a retrospective analysis on
routinely collected data in 6 drug-resistant TB (DRTB) programs. Culture
conversion, defined as two consecutive negative cultures, was assessed, and
performance of culture conversion at Month 2 and Month 6 to predict treatment
success were explored. To explore factors associated with positive predicted
value (PPV) and the specificity of culture conversion, a multinomial logistic
regression was fitted.RESULTS: This study included 634 patients: 68.5% were
males; the median age was 35 years, 75.2% were previously treated for TB, 59.4%
were resistant only to isoniazid and rifampicin and 18.1% resistant to
fluoroquinolones. Culture conversion at Month 2 and 6 showed similar PPV while
specificity was much higher for culture conversion at Month 2: 91.3% (95%CI
86.1-95.1). PPV of culture conversion at Month 2 did not vary strongly according
to patients' characteristics, while specificity was slightly higher among
patients with fluoroquinolone-resistant strains.CONCLUSION: Culture conversion at
Month 2 is an acceptable prognostic marker for MDR-TB treatment. Considering the
advantage of using an earlier marker, further evaluation as a surrogate marker is
warranted to shorten TB trials.

DOI: 10.5588/ijtld.18.0649
PMID: 31627770

Read the full article here.

4. Advances in clinical trial design for development of new TB treatments-Translating international tuberculosis treatment guidelines into national strategic plans: Experiences from Belarus, South Africa, and Vietnam.
PLoS Med. 2019 Oct 18;16(10):e1002896. doi: 10.1371/journal.pmed.1002896.
eCollection 2019 Oct.

Brigden G(1), Nhung NV(2), Skrahina A(3), Ndjeka N(4), Falzon D(5), Zignol M(5).

DOI: 10.1371/journal.pmed.1002896
PMID: 31626628

Read the full article here.

5. Use of Second-line Medications and Treatment Outcomes in Children With Tuberculosis in a Single Center From 2007 to 2018.
Pediatr Infect Dis J. 2019 Oct;38(10):1027-1034. doi:
10.1097/INF.0000000000002410.

Chiappini E(1), Matucci T, Lisi C, Petrolini C, Venturini E, Tersigni C, de
Martino M, Galli L.

BACKGROUND: The incidence of drug-resistant forms of tuberculosis (DR-TB) and the
number of children treated with second-line drugs (SLDs) are increasing. However,
limited amount of information is available regarding the use of SLDs in this
population.
METHODS: To describe the treatment of pediatric TB with SLDs and factors
associated with use of SLDs in children with and without documented DR-TB,
records of pediatric TB patients referred to a center in Italy from 2007 to 2018
were reviewed retrospectively.
RESULTS: Of 204 children diagnosed with active TB during the study period, 42
were treated with SLDs because of confirmed or probable drug resistance (42.8%),
adverse reactions to first-line drugs (7.1%), central nervous system involvement
(11.9%) or unconfirmed possible drug resistance (38.1%). There were no deaths or
adverse reactions to SLDs reported. Treatment was successful in 85.2% children
treated with first-line drugs and 92.9% children treated with SLDs. After
adjusting for calendar period, the only factor associated with DR-TB was <2 years
old [odds ratio (OR): 5.24 for <2 years vs. 5-18 years; P = 0.008]. Factors
associated with treatment with SLDs were TB at 2 or more sites (OR: 11.30; P <
0.001), extrapulmonary TB (OR: 8.48; P < 0.001) or adverse reactions to
first-line drugs (OR: 7.48; P = 0.002). No differences were noted in age or
region of origin.
CONCLUSIONS: A substantial proportion of TB children were treated with SLDs. The
main reason for using SLDs was failure of a first-line drug regimen, suggesting
possible DR-TB and underestimation of DR-TB in children. The use of SLD regimens
was associated with a high success rate and good tolerability profile.

DOI: 10.1097/INF.0000000000002410
PMID: 31397749

Read the full article here.

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
Jr(6).

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
investigation.
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:
journals.permissions@oup.com.

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

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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.

From our August 2019 Newsletter

1. Outcomes of Bedaquiline Treatment in Patients with Multidrug-Resistant Tuberculosis.
Emerg Infect Dis. 2019 May;25(5):936-943. doi: 10.3201/eid2505.181823.

Mbuagbaw L, Guglielmetti L, Hewison C, Bakare N, Bastard M, Caumes E,
Fréchet-Jachym M, Robert J, Veziris N, Khachatryan N, Kotrikadze T, Hayrapetyan
A, Avaliani Z, Schünemann HJ, Lienhardt C.

Bedaquiline is recommended by the World Health Organization for the treatment of
multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB).
We pooled data from 5 cohorts of patients treated with bedaquiline in France,
Georgia, Armenia, and South Africa and in a multicountry study. The rate of
culture conversion to negative at 6 months (by the end of 6 months of treatment)
was 78% (95% CI 73.5%-81.9%), and the treatment success rate was 65.8% (95% CI
59.9%-71.3%). Death rate was 11.7% (95% CI 7.0%-19.1%). Up to 91.1% (95% CI
82.2%-95.8%) of the patients experienced >1 adverse event, and 11.2% (95% CI
5.0%-23.2%) experienced a serious adverse event. Lung cavitations were
consistently associated with unfavorable outcomes. The use of bedaquiline in MDR
and XDR TB treatment regimens appears to be effective and safe across different
settings, although the certainty of evidence was assessed as very low.

DOI: 10.3201/eid2505.181823
PMCID: PMC6478224
PMID: 31002070

Access the article here.

2. Long-Term Effects on QT prolongation of Pretomanid, Alone and in Combinations, in Patients with Tuberculosis.
Antimicrob Agents Chemother. 2019 Jul 29. pii: AAC.00445-19. doi:
10.1128/AAC.00445-19. [Epub ahead of print]

Li H(1), Salinger DH(1), Everitt D(2), Li M(2), Del Parigi A(2), Mendel C(2),
Nedelman JR(3).

Concentration-QTc modeling was applied to pretomanid, a new nitroimidazooxazine
anti-tuberculosis drug. Data came from eight phase 2 and phase 3 studies. Besides
pretomanid alone, various combinations with bedaquiline, linezolid, moxifloxacin,
and pyrazinamide were considered; special attention was given to the
bedaquiline-pretomanid-linezolid (BPaL) regimen that has demonstrated efficacy in
the Nix-TB study in subjects with extensively drug resistant or
treatment-intolerant or nonresponsive multi-drug-resistant tuberculosis.Three
heart-rate corrections to QT were considered: Fridericia's QTcF, Bazett's QTcB,
and a population-specific correction, QTcN.QTc increased with the plasma
concentrations of pretomanid, bedaquiline's M2 metabolite, and moxifloxacin in a
manner described by a linear model, where the three slope coefficients were
constant across studies, visits within study, and times-post-dose within visit,
but where the intercept varied across those dimensions. The intercepts tended to
increase on treatment to a plateau after several weeks, a pattern termed the
secular trend The slope terms were similar for the three QTc corrections, but the
secular trends differed, suggesting that at least some of the secular trend was
due to the elevated heart rates of tuberculosis patients decreasing to normal
levels on treatment.For pretomanid 200 mg QD alone, a typical steady-state Cmax
resulted in a mean change from baseline of QTcN of 9.1 ms, with an upper 90% CI
limit of 10.2 ms. For the BPaL regimen, due to the additional impact of the
bedaquiline M2 metabolite, the corresponding values were 13.6 ms and 15.0 ms. The
contribution to these values from the secular trend was 4.0 ms.

Copyright © 2019 Li et al.

DOI: 10.1128/AAC.00445-19
PMID: 31358590

Access the article here.

3. A safety evaluation of bedaquiline for the treatment of multi-drug resistant tuberculosis.
Expert Opin Drug Saf. 2019 Aug 5:1-8. doi: 10.1080/14740338.2019.1648429. [Epub
ahead of print]

Cohen K(1), Maartens G(1).

Introduction: Outcomes of treatment for resistant tuberculosis are poor, with
long treatment duration and poor tolerability. Bedaquiline is a novel
anti-mycobacterial drug, which has a very long terminal elimination half-life.
Bedaquiline was approved in 2012 for drug-resistant tuberculosis following
improved time to culture conversion and cure rates in a phase 2b study; but
mortality was higher in the bedaquiline arm, resulting in a black box warning
despite the fact that almost all deaths occurred after bedaquiline was stopped.
Areas covered: The authors review safety data of bedaquiline used for
rifampicin-resistant tuberculosis from the phase 2 studies, and from case series
and observational cohorts. The authors focus on QT interval prolongation,
hepatotoxicity, and mortality. Expert opinion: Bedaquiline markedly reduced
mortality and improved treatment success in observational studies, resulting in
bedaquiline being strongly recommended for rifampicin-resistant tuberculosis by
the World Health Organization. In the phase 2 studies participants randomised to
bedaquiline had higher rates of liver enzyme elevation and modest QT interval
prolongation. Severe QT prolongation was an infrequent cause of bedaquiline
interruption despite the frequent use of concomitant drugs that also prolong the
QT interval. While awaiting results of phase 3 randomised controlled trials,
tuberculosis treatment programmes should strengthen pharmacovigilance.

DOI: 10.1080/14740338.2019.1648429
PMID: 31339384

Access the article here.

4. Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling.
Lancet Infect Dis. 2019 Aug;19(8):903-912. doi: 10.1016/S1473-3099(19)30307-X.
Epub 2019 Jul 4.

Knight GM(1), McQuaid CF(2), Dodd PJ(3), Houben RMGJ(2).

BACKGROUND: To end the global tuberculosis epidemic, latent tuberculosis
infection needs to be addressed. All standard treatments for latent tuberculosis
contain drugs to which multidrug-resistant (MDR) Mycobacterium tuberculosis is
resistant. We aimed to estimate the global burden of multidrug-resistant latent
tuberculosis infection to inform tuberculosis elimination policy.
METHODS: By fitting a flexible statistical model to tuberculosis drug resistance
surveillance and survey data collated by WHO, we estimated national trends in the
proportion of new tuberculosis cases that were caused by MDR strains. We used
these data as a proxy for the proportion of new infections caused by MDR M
tuberculosis and multiplied trends in annual risk of infection from previous
estimates of the burden of latent tuberculosis to generate trends in the annual
risk of infection with MDR M tuberculosis. These estimates were used in a cohort
model to estimate changes in the global and national prevalence of latent
infection with MDR M tuberculosis. We also estimated recent infection levels (ie,
in 2013 and 2014) and made predictions for the future burden of MDR tuberculosis
in 2035 and 2050.
FINDINGS: 19·1 million (95% uncertainty interval [UI] 16·4 million-21·7 million)
people were latently infected with MDR tuberculosis in 2014-a global prevalence
of 0·3% (95% UI 0·2-0·3). MDR strains accounted for 1·2% (95% UI 1·0-1·4) of the
total latent tuberculosis burden overall, but for 2·9% (95% UI 2·6-3·1) of the
burden among children younger than 15 years (risk ratio for those younger than 15
years vs those aged 15 years or older 2·65 [95% UI 2·11-3·25]). Recent latent
infection with MDR M tuberculosis meant that 1·9 million (95% UI 1·7 million-2·3
million) people globally were at high risk of active MDR tuberculosis in 2015.
INTERPRETATION: We estimate that three in every 1000 people globally carry latent
MDR tuberculosis infection, and prevalence is around ten times higher among those
younger than 15 years. If current trends continue, the proportion of latent
tuberculosis caused by MDR strains will increase, which will pose serious
challenges for management of latent tuberculosis-a cornerstone of tuberculosis
elimination strategies.
FUNDING: UK Medical Research Council, Bill & Melinda Gates Foundation, and
European Research Council.

Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access
article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights
reserved.

DOI: 10.1016/S1473-3099(19)30307-X
PMCID: PMC6656782
PMID: 31281059

Access the article here.

5. Linezolid interruption in patients with fluoroquinolone-resistant tuberculosis receiving a bedaquiline-based treatment regimen.
Int J Infect Dis. 2019 Aug;85:74-79. doi: 10.1016/j.ijid.2019.04.028. Epub 2019
May 14.

Olayanju O(1), Esmail A(1), Limberis J(1), Gina P(1), Dheda K(2).

BACKGROUND: Treatment outcomes of patients with extensively drug-resistant
tuberculosis (XDR-TB) are suboptimal and treatment options remain limited.
Linezolid is associated with improved outcomes but also substantial toxicity, and
details about the relationship between these are lacking from resource-poor
HIV-endemic settings.
METHODS: This was a prospective follow-up study of 63 South African XDR-TB
patients (58.7% HIV-infected; median CD4 131 cells/μl) between 2014 and 2018. The
frequency and severity of linezolid-associated adverse events and the impact on
treatment outcomes were compared between linezolid interrupters and
non-interrupters.
RESULTS: Twenty-two patients (34.9%) discontinued or underwent dose reduction due
to presumed linezolid-associated toxicity. Anaemia (77.3% vs. 7.3%; p< 0.001),
peripheral neuropathy (63.6% vs. 14.6%; p= 0.003), and optic neuritis (18.2% vs.
9.8%; p= 0.34) occurred more frequently in linezolid interrupters than in
non-interrupters. Anaemia, peripheral neuropathy, and optic neuritis occurred at
a median of 5, 18, and 23 weeks, respectively, after treatment initiation.
Linezolid interruption was not associated with unfavourable outcomes but was
strongly associated with HIV co-infection (adjusted hazard ratio 4.831, 95%
confidence interval 1.526-15.297; p= 0.007) and bacterial load (culture days to
positivity; adjusted hazard ratio 0.824, 95% confidence interval 0.732- 0.927; p=
0.001).
CONCLUSIONS: Linezolid-related treatment interruption is common, is strongly
associated with HIV co-infection, and system-specific toxicity occurs within
predictable time frames. These data inform the clinical management of patients
with drug-resistant TB.

Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/j.ijid.2019.04.028
PMID: 31100421

Access the article here.

6. Linezolid resistance in patients with drug-resistant TB and treatment failure in South Africa.
J Antimicrob Chemother. 2019 Aug 1;74(8):2377-2384. doi: 10.1093/jac/dkz206.

Wasserman S(1)(2), Louw G(3), Ramangoaela L(4), Barber G(4), Hayes C(5), Omar
SV(6), Maartens G(1)(7), Barry C(3), Song T(3), Meintjes G(1)(2).

OBJECTIVES: Limited data exist on clinical associations and genotypic correlates
of linezolid resistance in Mycobacterium tuberculosis. We aimed to describe
mutations and clinical factors associated with phenotypic linezolid resistance
from patients with drug-resistant TB at two public sector facilities in South
Africa.
METHODS: Adults and adolescents with treatment failure (culture positivity
≥4 months) on a linezolid-containing regimen were retrospectively identified.
Phenotypic resistance, as defined by a linezolid MIC >1 mg/L, was assessed for
retrieved isolates using broth microdilution. Targeted sequencing of rrl and rplC
was performed, irrespective of growth on subculture.
RESULTS: Thirty-nine patients with linezolid-based treatment failure were
identified, 13 (33%) of whom had phenotypic or genotypic linezolid resistance
after a median duration of 22 months (range = 7-32) of linezolid therapy. Paired
MIC testing and genotyping was performed on 55 unique isolates. All isolates with
phenotypic resistance (n = 16) were associated with known resistance mutations,
most frequently due to the T460C substitution in rplC (n = 10); rrl mutations
included G2814T, G2270C/T and A2810C. No mutations were detected in isolates with
MICs at or below the critical concentration.
CONCLUSIONS: Linezolid resistance occurred in a third of patients with
drug-resistant TB and treatment failure. Resistance occurred late and was
predicted by a limited number of mutations in rrl and rplC. Screening for
genotypic resistance should be considered for patients with a positive culture
after 4 months of linezolid therapy in order to optimize treatment and avoid the
toxicity of ineffective linezolid therapy.

© The Author(s) 2019. Published by Oxford University Press on behalf of the
British Society for Antimicrobial Chemotherapy.

DOI: 10.1093/jac/dkz206
PMCID: PMC6640298
PMID: 31081017

Access the article here.

7. Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing.
Am J Respir Crit Care Med. 2019 Aug 1;200(3):370-380. doi:
10.1164/rccm.201807-1361OC.

Dheda K(1)(2), Lenders L(1), Srivastava S(3)(4), Magombedze G(3), Wainwright
H(5), Raj P(4), Bush SJ(3), Pollara G(6), Steyn R(7), Davids M(1), Pooran A(1),
Pennel T(8), Linegar A(8), McNerney R(1), Moodley L(8), Pasipanodya JG(3), Turner
CT(6), Noursadeghi M(6), Warren RM(9), Wakeland E(4), Gumbo T(1)(3).

Rationale: There is poor understanding about protective immunity and the
pathogenesis of cavitation in patients with tuberculosis.Objectives: To map
pathophysiological pathways at anatomically distinct positions within the human
tuberculosis cavity.Methods: Biopsies were obtained from eight predetermined
locations within lung cavities of patients with multidrug-resistant tuberculosis
undergoing therapeutic surgical resection (n = 14) and healthy lung tissue from
control subjects without tuberculosis (n = 10). RNA sequencing,
immunohistochemistry, and bacterial load determination were performed at each
cavity position. Differentially expressed genes were normalized to control
subjects without tuberculosis, and ontologically mapped to identify a spatially
compartmentalized pathophysiological map of the cavity. In silico perturbation
using a novel distance-dependent dynamical sink model was used to investigate
interactions between immune networks and bacterial burden, and to integrate these
identified pathways.Measurements and Main Results: The median (range) lung cavity
volume on positron emission tomography/computed tomography scans was 50 cm3
(15-389 cm3). RNA sequence reads (31% splice variants) mapped to 19,049 annotated
human genes. Multiple proinflammatory pathways were upregulated in the cavity
wall, whereas a downregulation "sink" in the central caseum-fluid interface
characterized 53% of pathways including neuroendocrine signaling, calcium
signaling, triggering receptor expressed on myeloid cells-1, reactive oxygen and
nitrogen species production, retinoic acid-mediated apoptosis, and RIG-I-like
receptor signaling. The mathematical model demonstrated that neuroendocrine,
protein kinase C-θ, and triggering receptor expressed on myeloid cells-1
pathways, and macrophage and neutrophil numbers, had the highest correlation with
bacterial burden (r > 0.6), whereas T-helper effector systems did
not.Conclusions: These data provide novel insights into host immunity to
Mycobacterium tuberculosis-related cavitation. The pathways defined may serve as
useful targets for the design of host-directed therapies, and transmission
prevention interventions.

DOI: 10.1164/rccm.201807-1361OC
PMCID: PMC6680310
PMID: 30694692

Access the article here.

From our July 2019 Newsletter

1. Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling.
Lancet Infect Dis. 2019 Jul 4. pii: S1473-3099(19)30307-X. doi:
10.1016/S1473-3099(19)30307-X. [Epub ahead of print]

Knight GM(1), McQuaid CF(2), Dodd PJ(3), Houben RMGJ(2).

BACKGROUND: To end the global tuberculosis epidemic, latent tuberculosis
infection needs to be addressed. All standard treatments for latent tuberculosis
contain drugs to which multidrug-resistant (MDR) Mycobacterium tuberculosis is
resistant. We aimed to estimate the global burden of multidrug-resistant latent
tuberculosis infection to inform tuberculosis elimination policy.
METHODS: By fitting a flexible statistical model to tuberculosis drug resistance
surveillance and survey data collated by WHO, we estimated national trends in the
proportion of new tuberculosis cases that were caused by MDR strains. We used
these data as a proxy for the proportion of new infections caused by MDR M
tuberculosis and multiplied trends in annual risk of infection from previous
estimates of the burden of latent tuberculosis to generate trends in the annual
risk of infection with MDR M tuberculosis. These estimates were used in a cohort
model to estimate changes in the global and national prevalence of latent
infection with MDR M tuberculosis. We also estimated recent infection levels (ie,
in 2013 and 2014) and made predictions for the future burden of MDR tuberculosis
in 2035 and 2050.
FINDINGS: 19·1 million (95% uncertainty interval [UI] 16·4 million-21·7 million)
people were latently infected with MDR tuberculosis in 2014-a global prevalence
of 0·3% (95% UI 0·2-0·3). MDR strains accounted for 1·2% (95% UI 1·0-1·4) of the
total latent tuberculosis burden overall, but for 2·9% (95% UI 2·6-3·1) of the
burden among children younger than 15 years (risk ratio for those younger than 15
years vs those aged 15 years or older 2·65 [95% UI 2·11-3·25]). Recent latent
infection with MDR M tuberculosis meant that 1·9 million (95% UI 1·7 million-2·3
million) people globally were at high risk of active MDR tuberculosis in 2015.
INTERPRETATION: We estimate that three in every 1000 people globally carry latent
MDR tuberculosis infection, and prevalence is around ten times higher among those
younger than 15 years. If current trends continue, the proportion of latent
tuberculosis caused by MDR strains will increase, which will pose serious
challenges for management of latent tuberculosis-a cornerstone of tuberculosis
elimination strategies.


FUNDING: UK Medical Research Council, Bill & Melinda Gates Foundation, and
European Research Council.

Read the article here.

2. Analysis of loss to follow-up in 4099 multidrug-resistant pulmonary tuberculosis patients.
Eur Respir J. 2019 Jul 11;54(1). pii: 1800353. doi: 10.1183/13993003.00353-2018.
Print 2019 Jul.

Walker IF(1), Shi O(2)(3), Hicks JP(4), Elsey H(4), Wei X(2), Menzies D(5), Lan
Z(5), Falzon D(6), Migliori GB(7), Pérez-Guzmán C(8)(9), Vargas MH(9)(10),
García-García L(11), Sifuentes Osornio J(12), Ponce-De-León A(13), van der Walt
M(14), Newell JN(4).

Loss to follow-up (LFU) of ≥2 consecutive months contributes to the poor levels
of treatment success in multidrug-resistant tuberculosis (MDR-TB) reported by TB
programmes. We explored the timing of when LFU occurs by month of MDR-TB
treatment and identified patient-level risk factors associated with LFU.We
analysed a dataset of individual MDR-TB patient data (4099 patients from 22
countries). We used Kaplan-Meier survival curves to plot time to LFU and a Cox
proportional hazards model to explore the association of potential risk factors
with LFU.Around one-sixth (n=702) of patients were recorded as LFU. Median
(interquartile range) time to LFU was 7 (3-11) months. The majority of LFU
occurred in the initial phase of treatment (75% in the first 11 months). Major
risk factors associated with LFU were: age 36-50 years (HR 1.3, 95% CI 1.0-1.6;
p=0.04) compared with age 0-25 years, being HIV positive (HR 1.8, 95% CI 1.2-2.7;
p<0.01) compared with HIV negative, on an individualised treatment regimen (HR
0.7, 95% CI 0.6-1.0; p=0.03) compared with a standardised regimen and a recorded
serious adverse event (HR 0.5, 95% CI 0.4-0.6; p<0.01) compared with no serious
adverse event.Both patient- and regimen-related factors were associated with LFU,
which may guide interventions to improve treatment adherence, particularly in the
first 11 months.

Read the article here.

3. Fluoroquinolones in Drug-Resistant Tuberculosis: Culture Conversion and Pharmacokinetic/Pharmacodynamic Target Attainment To Guide Dose Selection.
Antimicrob Agents Chemother. 2019 Jun 24;63(7). pii: e00279-19. doi:
10.1128/AAC.00279-19. Print 2019 Jul.

Al-Shaer MH(1), Alghamdi WA(1)(2), Alsultan A(3), An G(4), Ahmed S(5), Alkabab
Y(6), Banu S(5), Barbakadze K(7), Houpt E(6), Kipiani M(7), Mikiashvili L(7),
Cegielski JP(8), Kempker RR(9), Heysell SK(6), Peloquin CA(10).

Fluoroquinolones are group A drugs in tuberculosis guidelines. We aim to compare
the culture conversion between new-generation (levofloxacin and moxifloxacin) and
old-generation (ciprofloxacin and ofloxacin) fluoroquinolones, develop
pharmacokinetic models, and calculate target attainment for levofloxacin and
moxifloxacin. We included three U.S. tuberculosis centers. Patients admitted
between 1984 and 2015, infected with drug-resistant tuberculosis, and who had
received fluoroquinolones for ≥28 days were included. Demographics, sputum
cultures and susceptibility, treatment regimens, and serum concentrations were
collected. A time-to-event analysis was conducted, and Cox proportional hazards
model was used to compare the time to culture conversion. Using additional data
from ongoing studies, pharmacokinetic modelling and Monte Carlo simulations were
performed to assess target attainment for different doses. Overall, 124 patients
received fluoroquinolones. The median age was 40 years, and the median weight was
60 kg. Fifty-six patients (45%) received old-generation fluoroquinolones.
New-generation fluoroquinolones showed a faster time to culture conversion
(median 16 versus 40 weeks, P = 0.012). After adjusting for isoniazid and
clofazimine treatment, patients treated with new-generation fluoroquinolones were
more likely to have culture conversion (adjusted hazards ratio, 2.16 [95%
confidence interval, 1.28 to 3.64]). We included 178 patients in the
pharmacokinetic models. Levofloxacin and moxifloxacin were best described by a
one-compartment model with first-order absorption and elimination. At least 1,500
to 1,750 mg levofloxacin and 800 mg moxifloxacin may be needed for maximum kill
at the current epidemiologic cutoff values. In summary, new-generation
fluoroquinolones showed faster time to culture conversion compared to the old
generation. For optimal target attainment at the current MIC values, higher doses
of levofloxacin and moxifloxacin may be needed.

Read the article here.

4. Characterization of linezolid-resistance-associated mutations in Mycobacterium tuberculosis through WGS.
J Antimicrob Chemother. 2019 Jul 1;74(7):1795-1798. doi: 10.1093/jac/dkz150.

Pi R(1)(2), Liu Q(1)(2), Jiang Q(1)(2), Gao Q(1)(2).

OBJECTIVES: Linezolid is becoming an important antibiotic for treating MDR/XDR
TB, but the mutations conferring resistance to linezolid remain inadequately
characterized. Herein, we investigated the linezolid-resistance-associated
mutations on a whole-genome scale through parallel selections of resistant
isolates in vitro.
METHODS: Ten parallel Mycobacterium tuberculosis H37Rv cultures were subjected to
spontaneous mutant selection on 7H11 agar plates containing 2.5 mg/L linezolid.
The linezolid resistance of resulting colonies was confirmed by growth on a
second linezolid plate. WGS was then performed to identify mutations associated
with linezolid resistance.
RESULTS: Of 181 colonies appearing on the initial linezolid plates, 154 were
confirmed to be linezolid resistant. WGS showed that 88.3% (136/154) of these
isolates had a T460C mutation in rplC, resulting in a C154R substitution. The
other 18 isolates harboured a single mutation in the rrl gene, with G2814T and
G2270T mutations accounting for 7.8% (12/154) and 3.9% (6/154), respectively.
CONCLUSIONS: No mutations in novel genes were associated with linezolid
resistance in a whole-genome investigation of 154 linezolid-resistant isolates
selected in vitro. These results emphasize that rrl and rplC genes should be the
major targets for molecular detection of linezolid resistance.

This article is not available via open access.

From our June 2019 Newsletter

1. TB Preventive Therapy for individuals exposed to drug-resistant tuberculosis: feasibility and safety of a community-based delivery of
fluoroquinolone-containing preventive regimen.


Clin Infect Dis. 2019 Jun 12. pii: ciz502. doi: 10.1093/cid/ciz502. [Epub ahead
of print]


Malik AA, Fuad J, Siddiqui S, Amanullah F, Jaswal M, Pmdcp ZB, Jabeen F, Fatima R, Yuen CM, Salahuddin N, Khan AJ, Keshavjee S, Becerra MC, Hussain H.

BACKGROUND: Observational studies have demonstrated the effectiveness of a
fluoroquinolone-based regimen to treat individuals exposed to or presumed to be
infected with drug-resistant (DR)-TB. We sought to assess the feasibility of this
approach in an urban setting in South Asia.
METHODS: From February 2016 until March 2017, all household contacts of DR-TB
patients enrolled at The Indus Hospital were screened for TB symptoms at home.
Children 0-17 years, symptomatic adults and those with an immunocompromising
condition (HIV, diabetes or malnutrition) were evaluated for TB disease. Contacts
diagnosed with TB disease were started on treatment. Contacts without TB disease
(i) younger than 5 years; (ii) between 5 and 17 years old with either a positive
TST or an immunocompromising condition; or (iii) 18 years and older with an
immunocompromising conditionwere offered six month treatment with a
fluoroquinolone.
RESULTS: One hundred households with 800 contacts were enrolled: 353 (44·1%)
individuals age 17 years or younger with a median age of 19 years (IQR: 10-32);
423 (52·9%) were males. In total, 737 (92·1%) individuals were screened, of which
eight were already on treatment for TB (1·1%), and another three (0·4%) contacts
were diagnosed with TB disease and started on treatment. Of 215 eligible for
infection treatment, 172 (80·0%) contacts initiated and 121 (70·3%) completed
treatment. No TB disease nor significant adverse events were observed during 12
months of follow up in any group.
CONCLUSIONS: Fluoroquinolone-based treatment for contacts with presumed DR-TB
infection is feasible and well tolerated in a high TB burden setting.

This article is not available via open access.

2. Direct detection of pyrazinamide resistance of Mycobacterium tuberculosis using pncA PCR Sequencing.
J Clin Microbiol. 2019 Jun 12. pii: JCM.00145-19. doi: 10.1128/JCM.00145-19.
[Epub ahead of print]


Tam KK, Leung KS, Siu GK, Chang KC, Wong SS, Ho PL, Leung EK, Yam WC.

An in-house-developed pncA sequencing for pyrazinamide (PZA) resistance was
evaluated using 162 archived Mycobacterium tuberculosis complex (MTBC) isolates
with well-defined phenotypic PZA susceptibility profile by BACTEC MGIT 960 PZA
kit and PZase activities. Preliminary results showed 100% concordance between
pncA sequencing and phenotypic PZA drug susceptibility test (DST) among archived
isolates. Meanwhile, 637 respiratory specimens were prospectively collected with
158 reported as MTBC-positive by Abbott Realtime MTB Assay (96.3% sensitivity
[95% Cl: 92.2-98.7%]; 100% specificity [95% CI: 99.2-100.0%]). Genotypic and
phenotypic PZA resistance profiles of these 158 MTBC-positive specimens were
analysed by pncA sequencing and BACTEC MGIT 960 PZA kit, respectively. For PZA
resistance, pncA sequencing detected pncA mutations in 5/5(100%) phenotypic PZA
resistant respiratory specimens within four working days. No pncA mutations were
detected among PZA susceptible specimens. Combining archived isolates with
prospective specimens, 27 were identified as phenotypic PZA resistant with pncA
mutation. Among these 27 samples, 6/27 (22.2%) phenotypic PZA resistant strains
carried novel pncA mutations without rpsA and panD mutations. These included 5
with mutations (Del383T, Del380-390, A-Ins at 127, A-Ins at 407 and G-Ins at 508)
in pncA structural gene, and 1 with mutation (T-12C) at pncA promoter region. All
these six strains had no or reduced PZase activities, indicating the novel
mutations might confer PZA resistance. Additionally, 25/27 phenotypic PZA
resistant strains were confirmed multidrug-resistant tuberculosis (MDR-TB). As
PZA is commonly used in MDR-TB treatment regimen, direct pncA sequencing will
rapidly detect PZA resistance and facilitate judicious use of PZA in treating
PZA-susceptible MDR-TB.

This article is not available via open access.

3. Surveillance of adverse events in the treatment of drug-resistant tuberculosis: A global feasibility study.
Int J Infect Dis. 2019 Jun;83:72-76. doi: 10.1016/j.ijid.2019.03.036. Epub 2019 Apr 3.


Members of the International Study Group on new anti-tuberculosis drugs and
adverse events monitoring.

The World Health Organization launched a global initiative, known as aDSM (active
TB drug safety monitoring and management) to better describe the safety profile
of new treatment regimens for drug-resistant tuberculosis (TB) in real-world
settings. However, comprehensive surveillance is difficult to implement in
several countries. The aim of the aDSM project is to demonstrate the feasibility
of implementing national aDSM registers and to describe the type and the
frequency of adverse events (AEs) associated with exposure to the new anti-TB
drugs. Following a pilot study carried out in 2016, official involvement of TB
reference centres/countries into the project was sought and cases treated with
bedaquiline- and/or delamanid-containing regimens were consecutively recruited.
AEs were prospectively collected ensuring potential attribution of the AE to a
specific drug based on its known safety profile. A total of 309 cases were fully
reported from 41 centres in 27 countries (65% males; 268 treated with
bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781
cases the participating countries had committed to report by the first quarter of
2019.

Read the article here.

4. Acceptability of a Novel Levofloxacin Dispersible Tablet Formulation in Young Children Exposed to Multidrug-resistant Tuberculosis.
Pediatr Infect Dis J. 2019 Jun;38(6):608-610. doi: 10.1097/INF.0000000000002268.


Purchase SE, Garcia-Prats AJ, De Koker P, Draper HR, Osman M, Seddon JA, Schaaf HS, Hesseling AC.

Levofloxacin is used for the treatment and prevention of multidrug-resistant
tuberculosis in children, but current adult formulations are poorly palatable. A
questionnaire administered to caregivers of 27 children taking a novel 100 mg
dispersible taste-masked levofloxacin tablet found the new formulation to be more
palatable (69%) and easier to prepare (81%) than the adult formulation. This
formulation may assist children to better adhere to anti-tuberculous therapy.

Read the article here.

From our May 2019 Newsletter

1. What will it take to eliminate drug-resistant tuberculosis?
Int J Tuberc Lung Dis. 2019 May 1;23(5):535-546. doi: 10.5588/ijtld.18.0217.


Kendall EA, Sahu S, Pai M, Fox GJ, Varaine F, Cox H, Cegielski JP, Mabote L, Vassall A, Dowdy DW.

ABSTRACT: Drug-resistant tuberculosis (DR-TB) is challenging to diagnose, treat, and prevent, but this situation is slowly changing. If the world is to drastically reduce the incidence of DR-TB, we must stop creating new DR-TB as an essential first step. The DR-TB epidemic that is ongoing should also be directly addressed. First-line drug resistance must be rapidly detected using universal molecular testing for resistance to at least rifampin and, preferably, other key drugs at initial TB diagnosis. DR-TB treatment outcomes must also improve dramatically. Effective use of currently available, new, and repurposed drugs, combined with patient-centered treatment that aids adherence and reduces catastrophic costs, are essential. Innovations within sight, such as short, highly effective, broadly indicated regimens, paired with point-of-care drug susceptibility testing, could accelerate progress in treatment outcomes. Preventing or containing resistance to second-line and novel drugs is also critical and will require high-quality systems for diagnosis, regimen selection, and treatment monitoring. Finally, earlier detection and/or prevention of DR-TB is necessary, with particular attention to airborne infection control, case finding, and preventive therapy for contacts of patients with DR-TB. Implementing these strategies can overcome the barrier that DR-TB represents for global TB elimination efforts, and could ultimately make global elimination of DR-TB (fewer than one annual case per million population worldwide) attainable. There is a strong cost-effectiveness case to support pursuing DR-TB elimination; however, achieving this goal will require substantial global investment plus political and societal commitment at national and local levels.

This article is not available via open access.

2. Improved treatment outcomes with bedaquiline when substituted for second-line injectable agents in multidrug resistant tuberculosis: a retrospective cohort study.
Clin Infect Dis. 2018 Aug 24. doi: 10.1093/cid/ciy727.


Zhao Y, Fox T, Manning K, Stewart A, Tiffin N, Khomo N, Leslie J, Boulle A, Mudaly V, Kock Y, Meintjes G, Wasserman S.

BACKGROUND: Bedaquiline is used as a substitute for second-line injectable (SLI) intolerance in the treatment of multidrug-resistant tuberculosis (MDR-TB), butthe efficacy and safety of this strategy is unknown.
METHODS: We performed a retrospective cohort study to evaluate treatment outcomes for MDR-TB patients who substituted bedaquiline for SLIs. Adults receiving bedaquiline substitution for MDR-TB therapy, plus a matched control group who did not receive bedaquiline, were identified from the electronic TB register in the Western Cape Province, South Africa. The primary outcome measure was the proportion of patients with death, loss to follow up, or failure to achieve sustained culture conversion at 12 months of treatment.
RESULTS: Data from 162 patients who received bedaquiline substitution and 168 controls were analyzed; 70.6% were HIV-infected. Unfavorable outcomes occurred in 35/146 (23.9%) patients in the bedaquiline group versus 51/141 (36.2%) in the control group (relative risk, 0.66; 95% confidence interval [CI], 0.46 to 0.95). The number of patients with culture reversion was lower in those receiving bedaquiline (1 patient, 0.8%) compared to controls (12 patients, 10.3%; P = 0.001). Delayed initiation of bedaquiline was independently associated with failure to achieve sustained culture conversion (adjusted odds ratio, 1.5; 95% CI, 1.1 - 1.9, for every 30-day delay). Mortality was similar at 12 months (11 deaths in each group; P = 0.973).
CONCLUSIONS: Substituting bedaquiline for SLIs in MDR-TB treatment resulted in improved outcomes at 12 months compared with patients who remained on SLIs, supporting the use of bedaquiline for MDR-TB treatment in programmatic settings.

Read the full article here.

3. Linezolid interruption in patients with fluoroquinolone-resistant tuberculosis receiving a bedaquiline-based treatment regimen. 
Int J Infect Dis. 2019 May 14. pii: S1201-9712(19)30199-7. doi: 10.1016/j.ijid.2019.04.028.


Olayanju O, Esmail A, Limberis J, Gina P, Dheda K.

BACKGROUND: Treatment outcomes of extensively drug-resistant tuberculosis (XDR-TB) patients are sub-optimal and treatment options remain limited. Linezolid is associated with improved outcomes but also substantial toxicity, and details about the relationship between these are lacking from resource-poor HIV-endemic
settings.
METHODS: We prospectively followed up 63 South African XDR-TB patients (58.7% HIV-infected; median CD4 131 cells/µl) between 2014 and 2018. The frequency and severity of linezolid-associated adverse events and the impact on treatment outcomes were compared between linezolid interrupters and non-interrupters.
RESULTS: Twenty-two patients (34.9%) discontinued or underwent dose reduction due to presumed linezolid-associated toxicity. Anaemia (77.3% versus 7.3%; p < 0.001), peripheral neuropathy (63.6% versus 14.6%; p = 0.003), and optic neuritis (18.2% versus 9.8%; p = 0.34) occurred more frequently in linezolid interrupters than in non-interrupters. Anaemia, peripheral neuropathy, and optic neuritis occurred at a median of 5, 18 and 23 weeks, respectively, after treatment initiation. Linezolid interruption was not associated with unfavourable outcomes but was strongly associated with HIV co-infection (aHR 4.831 (1.526-15.297); p = 0.007) and bacterial load (culture days to positivity; aHR = 0.824 (0.732- 0.927); p = 0.001).
CONCLUSION: Linezolid-related treatment interruption is common, is strongly associated with HIV co-infection, and system-specific toxicity occurs within predictable time frames. These data inform the clinical management of patients with drug resistant TB.

Read the full article here.

4. Pharmacokinetics, optimal dosing, and safety of linezolid in children with multidrug-resistant tuberculosis: Combined data from two prospective observational studies.
PLoS Med. 2019 Apr 30;16(4):e1002789. doi: 10.1371/journal.pmed.1002789. eCollection 2019 Apr.


Garcia-Prats AJ, Schaaf HS, Draper HR, Garcia-Cremades M, Winckler J, Wiesner L, Hesseling AC, Savic RM.

BACKGROUND: Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB.
METHODS AND FINDINGS: Children routinely treated for MDR-TB in 2 observational studies (2011-2015, 2016-2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data.
CONCLUSIONS: Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated.

Read the full article here.

5. Bedaquiline and delamanid in combination for treatment of drug-resistant tuberculosis.
Lancet Infect Dis. 2019 May;19(5):470. doi: 10.1016/S1473-3099(19)30168-9.


Mohr E, Ferlazzo G, Hewison C, De Azevedo V, Isaakidis P.

SUMMARY: Here we report on the final outcomes for the cohort of 28 patients from Armenia, India, and South Africa who initiated regimens containing the combination of bedaquiline and delamanid from January to August, 2016, for the treatment of multidrug-resistant tuberculosis in our cohort study.

 

Read the full article here.

From our April 2019 Newsletter

1. Feasibility of Identifying Household Contacts of Rifampin- and Multidrug-Resistant Tuberculosis Cases at High Risk of Progression to Tuberculosis Disease.
Clin Infect Dis. 2019 Mar 28. pii: ciz235. doi: 10.1093/cid/ciz235.


Gupta A, Swindells S, Kim S, Hughes MD, Naini L, Wu X, Dawson R, Mave V, Sanchez J, Mendoza A, Gonzales P, Kumarasamy N, Comins K,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 eight high-TB-burden  countries. HHCs underwent symptom screening, chest radiography (CXR), sputum TB bacteriology, TB infection (TBI) testing (tuberculin skin test and interferon gamma release assay) and 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 acid fast bacilli sputum smear-positive and 43% had cavitary disease; at study entry 35% remained smear-positive after a median MDR-TB treatment duration of 8.8 weeks. Nine HHCs were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. 121 (12%) HHC had new TB identified: 17 (2%) were confirmed; 33 (3%) probable; and 71 (7%) possible TB. 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%) <5 years; 63 (6%) 5 and HIV-infected; and 610 (61%) 5 years, HIV-negative/unknown, and 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.

 

This article is unavailable via open access.

2. Gridlock from diagnosis to treatment of multidrug-resistant tuberculosis in Tanzania: low accessibility of molecular diagnostic services and lack of healthcare worker empowerment in 28 districts of 5 high burden TB regions with mixed methods evaluation.
BMC Public Health. 2019 Apr 11;19(1):395. doi: 10.1186/s12889-019-6720-6.


Mpagama SG, Mbelele PM, Chongolo AM, Lekule IA, Lyimo JJ, Kibiki GS, Heysell SK.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) outcomes are adversely
impacted by delay in diagnosis and treatment.
METHODS: Mixed qualitative and quantitative approaches were utilized to identify
healthcare system related barriers to implementation of molecular diagnostics for
MDR-TB. Randomly sampled districts from the 5 highest TB burden regions were
enrolled during the 4th quarter of 2016. District TB & Leprosy Coordinators
(DTLCs), and District AIDS Coordinators (DACs) were interviewed, along with staff
from all laboratories within the selected districts where molecular diagnostics
tests for MDR-TB were performed. Furthermore, the 2015 registers were audited for
all drug-susceptible but retreatment TB cases and TB collaborative practices in
HIV clinics, as these patients were in principal targeted for drug susceptibility
testing by rapid molecular diagnostics.
RESULTS: Twenty-eight TB districts from the 5 regions had 399 patients reviewed
for retreatment with a drug-susceptible regimen. Only 160 (40%) had specimens
collected for drug-susceptibility testing, and of those specimens only 120 (75%)
had results communicated back to the clinic. MDR-TB was diagnosed in 16 (13.3%)
of the 120 specimens but only 12 total patients were ultimately referred for
treatment. Furthermore, among the HIV/AIDS clinics served in 2015, the median
number of clients with TB diagnosis was 92 cases [IQR 32-157] yet only 2 people
living with HIV were diagnosed with MDR-TB throughout the surveyed districts.
Furthermore, the districts generated 53 front-line healthcare workers for
interviews. DTLCs with intermediate or no knowledge on the clinical application
of XpertMTB/RIF were 3 (11%), and 10 (39%), and DACs with intermediate or no
knowledge were 0 (0%) and 2 (8%) respectively (p = 0.02). Additionally, 11 (100%)
of the laboratories surveyed had only the 4-module XpertMTB/RIF equipment. The
median time that XpertMTB/RIF was not functional in the 12 months prior to the
investigation was 2 months (IQR 1-4).
CONCLUSIONS: Underutilization of molecular diagnostics in high-risk groups was a
function of a lack of front-line healthcare workforce empowerment and training,
and a lack of equipment access, which likely contributed to the observed delay in
MDR-TB diagnosis in Tanzania.

Read the full article here.

3. Impact of universal drug susceptibility testing and effective management of multidrug-resistant tuberculosis in Taiwan.
PLoS One. 2019 Apr 2;14(4):e0214792. doi: 10.1371/journal.pone.0214792. eCollection 2019.


Lee PH, Chan PC, Peng YT, Chu PW, Wu MH, Jou R, Yu MC, Lin CJ, Huang YW, Chien ST, Lee JJ, Chiang CY.

BACKGROUND: The treatment outcomes of multidrug-resistant tuberculosis (MDR-TB) patients in the 1990s in Taiwan was not satisfactory. To strengthen programmatic management of drug-resistant tuberculosis (PMDT), Taiwan MDR-TB Consortium (TMTC) was established in 2007. We assess the performance and epidemiologic impact of TMTC.
METHODOLOGY/PRINCIPLE FINDINGS: We analyzed the trends of proportion of TB cases with drug susceptibility testing, enrollment of MDR-TB patients into TMTC and outcomes of treatment of all MDR-TB patients in Taiwan from 2007-2016. We computed the trends of both incidence and prevalence of MDR-TB from 2007-2016. We assessed the trends of MDR-TB among both new and recurrent TB cases. The proportion of TB cases with drug susceptibility testing results increased from 24.2% in 2007 to 97.9% in 2016. Of the 1,452 MDR-TB patients who were eligible for TMTC care, 1,197 (82.4%) were enrolled in TMTC, in whom 82.9% had treatment success. MDR-TB incidence was 9.0 cases per million in 2007, which declined to 4.6 cases per million in 2016 (p<0.0001). MDR-TB prevalence decreased from 19.4 cases per million in 2007 to 8.4 cases per million in 2016 (p<0.0001). The proportion of MDR-TB among new TB cases decreased from 1.4% in 2010 to 1.0% in 2016 (p = 0.039); and that among recurrent TB cases from 9.0% in 2010 to 1.8% in 2016 (p<0.0001).
CONCLUSIONS: We concluded that effective PMDT have had a significant impact on the epidemic of drug-resistant TB in Taiwan.

 

Read the full article here.

4. Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations.
Antimicrob Agents Chemother. 2019 Apr 25;63(5). pii: e02516-18. doi: 10.1128/AAC.02516-18.


Sarathy J, Blanc L, Alvarez-Cabrera N, O'Brien P, Dias-Freedman I, Mina M, Zimmerman M, Kaya F, Ho Liang HP, Prideaux B, Dietzold J, Salgame P, Savic RM, Linderman J, Kirschner D, Pienaar E, Dartois V.

ABSTRACT: Fluoroquinolones represent the pillar of multidrug-resistant tuberculosis (MDR-TB) treatment, with moxifloxacin, levofloxacin, or gatifloxacin being prescribed to MDR-TB patients. Recently, several clinical trials of "universal" drug regimens, aiming to treat drug-susceptible and drug-resistant TB, have included a fluoroquinolone. In the absence of clinical data comparing their side-by-side efficacies in controlled MDR-TB trials, a pharmacological rationale is needed to guide the selection of the most efficacious fluoroquinolone. The present studies were designed to test the hypothesis that fluoroquinolone concentrations (pharmacokinetics) and activity (pharmacodynamics) at the site of infection are better predictors of efficacy than the plasma concentrations and potency measured in standard growth inhibition assays and are better suited to determinations of whether one of the fluoroquinolones outperforms the others in rabbits with active TB. We first measured the penetration of these fluoroquinolones in lung lesion compartments, and their potency against bacterial populations that reside in each compartment, to compute lesion-centric pharmacokinetic-pharmacodynamic (PK/PD) parameters. PK modeling methods were used to quantify drug penetration from plasma to tissues at human-equivalent doses. On the basis of these metrics, moxifloxacin emerged with a clear advantage, whereas plasma-based PK/PD favored levofloxacin (the ranges of the plasma AUC/MIC ratio [i.e., the area under the concentration-time curve over 24 h in the steady state divided by the MIC] are 46 to 86 for moxifloxacin and 74 to 258 for levofloxacin). A comparative efficacy trial in the rabbit model of active TB demonstrated the superiority of moxifloxacin in reducing bacterial burden at the lesion level and in sterilizing cellular and necrotic lesions. Collectively, these results show that PK/PD data obtained at the site of infection represent an adequate predictor of drug efficacy against TB and constitute the baseline required to explore synergies, antagonism, and drug-drug interactions in fluoroquinolone-containing regimens.

 

Read the full article here.

5. Treatment as prevention and other interventions to reduce transmission of multidrug-resistant tuberculosis.
Int J Tuberc Lung Dis. 2019 Apr 1;23(4):396-404. doi: 10.5588/ijtld.18.0276.


Nathavitharana RR, Lederer P, Tierney DB, Nardell E.

ABSTRACT: Drug-resistant tuberculosis (DR-TB) represents a major programmatic challenge at the national and global levels. Only ∼30% of patients with multidrug-resistant TB (MDR-TB) were diagnosed, and ∼25% were initiated on treatment for MDR-TB in 2016. Increasing evidence now points towards primary transmission of DR-TB, rather than inadequate treatment, as the main driver of the DR-TB epidemic. The cornerstone of DR-TB transmission prevention should be earlier diagnosis and prompt initiation of effective treatment for all patients with DR-TB. Despite the extensive scale-up of Xpert® MTB/RIF testing, major implementation barriers continue to limit its impact. Although there is longstanding evidence in support of the rapid impact of treatment on patient infectiousness, delays in the initiation of effective DR-TB treatment persist, resulting in ongoing transmission. However, it is also imperative to address the burden of latent drug-resistant tuberculous infection because it is estimated that many DR-TB patients will become infectious before seeking care and encounter various diagnostic delays before treatment. Addressing latent DR-TB primarily consists of identifying, treating and following the contacts of patients with MDR-TB, typically through household contact evaluation. Adjunctive measures, such as improved ventilation and use of germicidal ultraviolet technology can further reduce TB transmission in high-risk congregate settings. Although many gaps remain in our biological understanding of TB transmission, implementation barriers to early diagnosis and rapid initiation of effective DR-TB treatment can and must be overcome if we are to impact DR-TB incidence in the short and long term.

This article is unavailable via open access.

From our March 2019 Newsletter

1. Treatment outcomes of patients switching from an injectable drug to bedaquiline during short standardized MDR-TB treatment in Mozambique
Clin Infect Dis. 2019 Mar 11. pii: ciz196. doi: 10.1093/cid/ciz196.


Bastard M, Molfino L, Mutaquiha C, Galindo MA, Zindoga P, Vaz D, Mahinça I, du Cros P, Rusch B, Telnov A

ABSTRACT: Bedaquiline was recommended by WHO as the preferred option in treatment of MDR-TB patients with long regimen. However, no recommendation was given for the short MDR-TB regimen. Data from our small cohort of patients who switched injectable dug to bedaquiline suggest that bedaquiline based short regimen is effective and safe.

This article is unavailable via open access.

2. A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis.
N Engl J Med. 2019 Mar 13. doi: 10.1056/NEJMoa1811867.


Nunn AJ, Phillips PPJ, Meredith SK, et. al.

BACKGROUND: Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011.
METHODS: We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive
a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority.
RESULTS: Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively.
CONCLUSIONS: In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety.

Read the full article here.

3. Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis.
Antimicrob Agents Chemother. 2019 Mar 11. pii: AAC.00055-19. doi: 10.1128/AAC.00055-19.


Alghamdi WA, Alsultan A, Al-Shaer MH, An G, Ahmed S, Alkabab Y, Banu S, Barbakadze K, Houpt E, Kipiani M, Mikiashvili L, Schmidt S, Heysell SK, Kempker RR, Cegielski JP, Peloquin CA.

BACKGROUND: Limited pharmacokinetic/pharmacodynamic (PK/PD) data exist on
cycloserine in tuberculosis (TB) patients. We pooled several studies into a large
PK dataset to estimate the population PK parameters for cycloserine in TB
patients. We also performed simulations to provide insight into optimizing the
dosing of cycloserine.
METHODS: TB patients were included from Georgia, Bangladesh, and four U.S. sites. Monolix and mlxR package were used for population PK modeling and simulation. We used PK/PD targets for time above MIC ≥30% and ≥64%, representing bactericidal activity and 80% of the maximum kill, to calculate the probability of target attainment (PTA). Optimal PK/PD breakpoints were defined as the highest MIC to achieve ≥90% of PTA.
RESULTS: Data from 247 subjects, including 205 patients with drug-resistant TB, were included. The data were best described by a one-compartment model. In most cases, the PK/PD breakpoints for the simulated regimens were similar for both PK/PD targets. Higher PTA was achieved as the total daily dose was increased. The
highest PK/PD breakpoint that resulted from the use of 250 mg dosages was 16 mg/L. For MICs >16 mg/L, doses of at least 500 mg three times daily or 750 mg twice daily were needed.
CONCLUSIONS: The current dosing for cycloserine, 250 to 500 mg once or twice daily, is not sufficient for MICs >16mg/L. Further studies are needed regarding the efficacy and tolerability of daily doses >1000 mg. Dividing the dose minimally affected the PK/PD breakpoints while optimized exposure, which can potentially reduce the drug adverse effects.

Read the full article here.

4. Antiretroviral switching and bedaquiline treatment of drug-resistant tuberculosis HIV co-infection.
Lancet HIV. 2019 Mar;6(3):e201-e204. doi: 10.1016/S2352-3018(19)30035-9.


O'Donnell MR, Padayatchi N, Daftary A, Orrell C, Dooley KE, Rivet Amico K, Friedland G.

ABSTRACT: Bedaquiline, a potent new therapy for drug-resistant tuberculosis, results in improved survival including in HIV patients with multidrug and extensively drug-resistant tuberculosis. In line with WHO recommendations, in South Africa
and other low-income and middle-income settings, antiretroviral therapy is switched from generic fixed-dose combination efavirenz-containing regimens to twice-daily nevirapine with separate companion pills because of interactions between efavirenz and bedaquiline. Early data suggest a signal for low antiretroviral therapy adherence after this antiretroviral therapy switch. Mortality and other tuberculosis-specific benefits noted with bedaquiline treatment in multidrug and extensively drug-resistant tuberculosis HIV might be compromised by HIV viral failure, and emergent antiretroviral resistance. Programmatic responses, such as adherence support and dual pharmacovigilance, should be instituted; antiretroviral therapy initiation with fixed-dose combinations without bedaquiline drug interactions should be strongly considered.

Read the full article here (will require a free Lancet account).

 

5. Health care gaps in the global burden of drug-resistant tuberculosis.

Int J Tuberc Lung Dis. 2019 Feb 1;23(2):125-135. doi: 10.5588/ijtld.18.0866. 

                                                                                                     

Cox V, Cox H, Pai M, Stillo J, Citro B, Brigden G.

ABSTRACT: The drug-resistant tuberculosis (DR-TB) cascade-from estimated or incident cases to numbers successfully treated or disease-free survival-has long been characterised by sharp declines at each step in the cascade. The losses along the cascade vary across different settings, and the reasons why some countries have a higher burden of DR-TB are complex and multifactorial; broadly, weak health systems, inadequate financing and poverty all impact differential access to DR-TB care. Within a human rights framework that mandates the right to health and the right to benefit from scientific progress, the aim of this review is to focus on describing inequities in access to DR-TB care at critical points in the cascade.

From our February 2019 Newsletter

1.  Major depression and household food insecurity among individuals with multidrug-resistant tuberculosis (MDR-TB) in South Africa.
Soc Psychiatry Psychiatr Epidemiol. 2019 Feb 13. doi: 10.1007/s00127-019-01669-y.


Tomita A, Ramlall S, Naidu T, Mthembu SS, Padayatchi N, Burns JK.

PURPOSE: Household food insecurity in South Africa is a pervasive public health challenge. Although its link to chronic health conditions is well established, its relationship to mental illness, particularly major depression, is not well-understood. Despite KwaZulu-Natal Province being the epicenter of the drug-resistant tuberculosis (MDR-TB) epidemic, and having the largest share of poverty in South Africa, this relationship remains unexamined. This study investigated the association between major depressive episode (MDE) and household food insecurity among individuals with MDR-TB.
METHODS: We enrolled and interviewed 141 newly admitted microbiologically confirmed MDR-TB inpatients at a specialized TB hospital in KwaZulu-Natal Province, South Africa. Logistic regression models were fitted to assess the relationship between MDE and household food insecurity, while accounting for socio-demographic status (e.g., age, gender, education, marital status, social grant status, income, and preference for living in one's community).
RESULTS: The prevalence of MDE and household food insecurity was 11.35% and 21.01%, respectively. MDE was significantly associated with household food insecurity (aOR 4.63, 95% CI 1.17-18.38). Individuals who are female (aOR 6.29, 95% CI 1.13-35.03), young (aOR 8.86, 95% CI 1.69-46.34), have low educational attainment (aOR 6.19, 95% CI 1.70-22.59) and receive social grants (aOR 7.60, 95% CI 2.36-24.48) were most at risk of household food insecurity.
CONCLUSIONS: MDE in individuals with MDR-TB was significantly associated with household food insecurity, independent of socio-economic status. Although MDR-TB is not exclusively a disease of the poor, individuals from socio-economically disadvantaged backgrounds (e.g., female, young adults, low education, and social grant recipients) were more likely to experience household food insecurity. Our study underscores the need to address the co-occurring cycles of food insecurity and untreated MDE in South Africa.

This article is available with open access here.

2. Underestimated pyrazinamide resistance may compromise outcomes of pyrazinamide containing regimens for treatment of drug susceptible and multi-drug-resistant tuberculosis in Tanzania.
BMC Infect Dis. 2019 Feb 7;19(1):129. doi: 10.1186/s12879-019-3757-1.


Juma SP, Maro A, Pholwat S, Mpagama SG, Gratz J, Liyoyo A, Houpt ER, Kibiki GS, Mmbaga BT, Heysell SK.

BACKGROUND: Tuberculosis (TB) is the leading cause of death from an infectious
disease and the roll-out of rapid molecular diagnostics for rifampin resistance has resulted in a steady rise in the number of patients with multidrug-resistant (MDR)-TB referred for treatment. Pyrazinamide is used in susceptible TB treatment for 6 months when used in combination with rifampin, isoniazid and ethambutol and is an important companion drug in novel MDR-TB trials. This study was undertaken to determine the prevalence of pyrazinamide resistance by either phenotypic or pncA testing among patients admitted to a referral hospital in Tanzania for
drug-susceptible and MDR-TB treatment.
METHODS: Surveillance sputa were sent among subjects beginning TB therapy at the national MDR-TB referral hospital during a 6 month period in 2013-2014. Mycobacterial cultures of pretreatment sputa were performed at the Kilimanjaro Clinical Research Institute (KCRI) in the BACTEC mycobacterial growth indicator tubes (MGIT) 960 system. Speciation of M. tuberculosis complex was confirmed by MTBc assay. Isolates were sub-cultured on to Lowenstein-Jensen (LJ) slants. Phenotypic resistance to pyrazinamide was performed in the MGIT system while a
real-time PCR with High Resolution Melt (HRM) technique was used to determine mutation in the pncA gene from the same pure subculture. Sputa were then collected monthly to determine the time to culture negativity. Final treatment outcome was determined.
RESULTS: Ninety-one M. tuberculosis isolates from individual patients were available for analysis of which 30 (32.9%) had MDR-TB, the mean (±SD) age was 33 ± 10 years, and the majority 23 (76.7%) were males. Of the 30 MDR-TB patients, 15(50%) had isolates with pyrazinamide resistance by conventional MGIT testing. This proportion expectedly exceeded the number with pyrazinamide resistance in the 61 patients without MDR-TB, 13 (21.3%) (p = 0.008). Six (20%) of MDR-TB patients had a poor outcome including treatment failure. Among patients with treatment failure, 5 (83%) had pyrazinamide resistance compared to only 10 (41.6%) with treatment success (p = 0.08). Two patients died, and both had isolates with pyrazinamide resistance. No other pretreatment characteristic was associated with treatment outcome.
CONCLUSION: Pyrazinamide susceptibility appears to be important in clinical outcomes for MDR-TB patients, and susceptibility testing appears to be a critical adjunct to TB care. The high proportion of PZA resistance in non-MDR TB cases calls for further local investigation.

This article is available with open access here.

3. Using Changes in Weight-for-Age z Score to Predict Effectiveness of Childhood Tuberculosis Therapy.
J Pediatric Infect Dis Soc. 2019 Feb 1. doi: 10.1093/jpids/piy138.


Chiang SS, Park S, White EI, Friedman JF, Cruz AT, Del Castillo H, Lecca L, Becerra MC, Seddon JA.

BACKGROUND: International guidelines recommend monitoring weight as an indicator of therapeutic response in childhood tuberculosis (TB) disease. This recommendation is based on observations in adults. In the current study, we evaluated the association between weight change and treatment outcome, the accuracy of using weight change to predict regimen efficacy, and whether successfully treated children achieve catch-up weight gain.
METHODS: We enrolled children treated for drug-susceptible TB disease (group 1) and multidrug-resistant TB disease (group 2) in Peru. We calculated the change in weight-for-age z score (ΔWAZ) between baseline and the end of treatment months 2-5 for group 1, and between baseline and months 2-8 for group 2. We used logistic regression and generalized estimating equation models to evaluate the relationship between ΔWAZ and outcome. We plotted receiver operating characteristic curves to determine the accuracy of ΔWAZ for predicting treatment
failure or death.
RESULTS: Groups 1 and 2 included 100 and 94 children, respectively. In logistic regression, lower ΔWAZ in months 3-5 and month 7 was associated with treatment failure or death in groups 1 and 2, respectively. In generalized estimating equation models, children in both groups who experienced treatment failure or death had lower ΔWAZ than successfully treated children. The ΔWAZ predicted treatment failure or death with 60%-90% sensitivity and 60%-86% specificity in months 2-5 for group 1 and months 7-8 for group 2. All successfully treated children-except group 2 participants with unknown microbiologic confirmation status-achieved catch-up weight gain.
CONCLUSIONS: Weight change early in therapy can predict the outcome of childhood TB treatment.

This article is not available for open access.

4. Effect of financial support on reducing the incidence of catastrophic costs among tuberculosis-affected households in Indonesia: eight simulated scenarios.
Infect Dis Poverty. 2019 Feb 2;8(1):10. doi: 10.1186/s40249-019-0519-7.


Fuady A, Houweling TAJ, Mansyur M, Burhan E, Richardus JH.

BACKGROUND: The World Health Organization's End Tuberculosis Strategy states that no tuberculosis (TB)-affected households should endure catastrophic costs due to TB. To achieve this target, it is essential to provide adequate social protection. As only a few studies in many countries have evaluated social-protection programs to determine whether the target is being reached, we assessed the effect of financial support on reducing the incidence of catastrophic costs due to TB in Indonesia.
METHODS: From July to September 2016, we interviewed adult patients receiving treatment for TB in 19 primary health centres in urban, sub-urban and rural area of Indonesia, and those receiving multidrug-resistant (MDR) TB treatment in an Indonesian national referral hospital. Based on the needs assessment, we developed eight scenarios for financial support. We assessed the effect of each simulated scenario by measuring reductions in the incidence of catastrophic costs.
RESULTS: We analysed data of 282 TB and 64 MDR-TB patients. The incidences of catastrophic costs in affected households were 36 and 83%, respectively. Patients' primary needs for social protection were financial support to cover costs related to income loss, transportation, and food supplements. The optimum scenario, in which financial support would be provided for these three items, would reduce the respective incidences of catastrophic costs in TB and MDR-TB-affected households to 11 and 23%. The patients experiencing catastrophic costs in this scenario would, however, have to pay high remaining costs (median of USD 910; [interquartile range (IQR) 662] in the TB group, and USD 2613; [IQR3442] in the MDR-TB group).
CONCLUSIONS: Indonesia's current level of social protection is not sufficient to mitigate the socioeconomic impact of TB. Financial support for income loss, transportation costs, and food-supplement costs will substantially reduce the incidence of catastrophic costs, but financial support alone will not be sufficient to achieve the target of 0% TB-affected households facing catastrophic costs. This would require innovative social-protection policies and higher levels of domestic and external funding.

This article is available via open access here.

5. Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing.
Am J Respir Crit Care Med. 2019 Jan 29. doi: 10.1164/rccm.201807-1361OC.


Dheda K, Lenders L, Srivastava S, Magombedze G, Wainwright H, Raj P, Bush SJ, Pollara G, Steyn R, Davids M, Pooran A, Pennel T, Linegar A, McNerney R, Moodley L, Pasipanodya JG, Turner CT, Noursadeghi M, Warren RM, Wakeland E, Gumbo T.

RATIONALE: There is poor understanding about protective immunity and the pathogenesis of cavitation in tuberculosis patients.
OBJECTIVES: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity.
METHODS: Biopsies were obtained from eight pre-determined locations within lung cavities of multidrug-resistant tuberculosis patients undergoing therapeutic surgical resection (n=14) and healthy lung tissue from non-tuberculosis controls (n=10). RNA sequencing, immunohistochemistry, and bacterial load determination was performed at each cavity position. Differentially expressed genes were normalized to non-tuberculosis controls, and ontologically mapped to identify a spatially compartmentalized pathophysiological map of the cavity. In silico perturbation using a novel distance-dependent dynamical sink model was used to investigate interactions between immune networks and bacterial burden, and to integrate these identified pathways.
RESULTS: The median (range) lung cavity volume on PET-CT scans was 50cm3 (15-389cm3). RNA sequence reads (31% splice variants) mapped to 19,049 annotated human genes. Multiple pro-inflammatory pathways were upregulated in the cavity wall, while a downregulation 'sink' in the central caseum-fluid interface characterized 53% of pathways including neuroendocrine signaling, calcium signaling, TREM-1, reactive oxygen and nitrogen species production, retinoic acid-mediated apoptosis, and RIG-I-like receptor signaling. The mathematical model demonstrated that neuroendocrine, protein kinase C-θ, and TREM-1 pathways, as well as macrophage and neutrophil numbers, had the highest correlation with bacterial burden (r>0.6), while T-helper effector systems did not.
CONCLUSION: These data provide novel insights into host immunity to drug-resistant Immune Mycobacterium tuberculosis-related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions.

This article can be found via open access here.

6. DeepAMR for predicting co-occurrent resistance of Mycobacterium tuberculosis.
Bioinformatics. 2019 Jan 28. doi: 10.1093/bioinformatics/btz067.


Walker TM, Walker AS, Wilson DJ, Peto TEA, Crook DW, Shamout F; CRyPTIC consortium, Zhu T, Clifton DA.

MOTIVATION: Resistance co-occurrence within first-line anti-tuberculosis (TB) drugs is a common phenomenon. Existing methods based on genetic data analysis of Mycobacterium tuberculosis (MTB) have been able to predict resistance of MTB to individual drugs, but have not considered the resistance co-occurrence and cannot capture latent structure of genomic data that corresponds to lineages.
METHODS: We used a large cohort of TB patients from 16 countries across six continents where whole-genome sequences for each isolate and associated phenotype to anti-TB drugs were obtained using drug susceptibility testing recommended by the World Health Organization. We then proposed an end-to-end multi-task model with deep denoising auto-encoder (DeepAMR) for multiple drug classification and developed DeepAMR_cluster, a clustering variant based on DeepAMR, for learning clusters in latent space of the data.
RESULTS: The results showed that DeepAMR outperformed baseline model and four machine learning models with mean AUROC from 94.4% to 98.7% for predicting resistance to four first-line drugs (i.e., isoniazid (INH), ethambutol (EMB), rifampicin (RIF), pyrazinamide (PZA)), multi-drug resistant TB (MDR-TB) and pan-susceptible TB (PANS-TB: MTB that is susceptible to all four first-line anti-TB drugs). In the case of INH, EMB, PZA, and MDR-TB, DeepAMR achieved its best mean sensitivity of 94.3%, 91.5%, 87.3% and 96.3%, respectively. While in the case of RIF and PANS-TB, it generated 94.2% and 92.2% sensitivity, which were lower than baseline model by 0.7% and 1.9%, respectively. T-SNE visualisation shows that DeepAMR_cluster captures lineage-related clusters in the latent space.


AVAILABILITY: The details of source code are provided at http://www.robots.ox.ac.uk/∼davidc/code.php.

This article is available via open access here.

From our January 2019 Newsletter

1. Ambient air pollution exposures and risk of drug-resistant tuberculosis.
Environ Int. 2019 Jan 11;124:161-169. doi: 10.1016/j.envint.2019.01.013. [Epub ahead of print]


Yao L, LiangLiang C, JinYue L, WanMei S, Lili S, YiFan L, HuaiChen L.

BACKGROUND: Few epidemiological studies have explored the effects of air pollution on the risk of drug-resistant tuberculosis (DR-TB).
OBJECTIVE: To investigate the short and long term residential concentrations of ambient air pollutants (particulate matter <10 μm in diameter (PM10) and particulate matter≤2.5 μm in diameter (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO)) in relation to the risk of DR-TB in a typical air pollution city, Jinan city, China.
METHODS: A total of 752 new culture-confirmed TB cases reported in TB prevention and control institutions of Jinan from January 1, 2014 to December 31, 2015 were included. Average individual-level concentrations of air pollution for 5 different exposure windows, vary from 90 days to 720 days to diagnosis were estimated using measurements from monitor closest to the patient home addresses. Logistic regression model adjusted for potential confounders was employed to evaluate correlation between air pollution and DR-TB risk at different five exposure windows individually.
RESULTS: There were substantially increased mono-drug resistance and poly-drug resistance risks for ambient PM2.5, PM10, O3, and CO exposures. High exposure to PM2.5, PM10, and CO was also significantly associated with increased incidence of multi-drug resistance (MDR) both in the single- and multi-pollutants regression models. The dominant positive associations for PM2.5was observed at 540 days exposure, for O3 was observed at 180 days exposure, and for PM10 and CO was observed from 90 days to 540 days exposures.
CONCLUSIONS: Our finding suggest that exposure to ambient air pollution (PM2.5, PM10, O3, and CO) are associated with increased risk of DR-TB. We provided epidemiological evidence of association between pollution exposure and mono-, poly- and multi-drug resistance.

This article is available for open access here.

2. Interventions to improve retention-in-care and treatment adherence among patients with drug-resistant tuberculosis: a systematic review.
Eur Respir J. 2019 Jan 10;53(1). pii: 1801030. doi: 10.1183/13993003.01030-2018. Print 2019 Jan.


Law S, Daftary A, O'Donnell M, Padayatchi N, Calzavara L, Menzies D.

ABSTRACT: The global loss to follow-up (LTFU) rate among drug-resistant tuberculosis (DR-TB) patients remains high at 15%. We conducted a systematic review to explore interventions to reduce LTFU during DR-TB treatment.We searched for studies published between January 2000 and December 2017 that provided any form of psychosocial or material support for patients with DR-TB. We estimated point estimates and 95% confidence intervals of the proportion LTFU. We performed subgroup analyses and pooled estimates using an exact binomial likelihood approach.We included 35 DR-TB cohorts from 25 studies, with a pooled proportion LTFU of 17 (12-23)%.  Cohorts that received any form of psychosocial or material support had lower LTFU rates than those that received standard care. Psychosocial support throughout treatment, via counselling sessions or home visits, was associated with lower LTFU rates compared to when support was provided through a limited number of visits or not at all.Our review suggests that psychosocial support should be provided throughout DR-TB treatment in order to reduce treatment LTFU. Future studies should explore the potential of providing self-administered therapy complemented with psychosocial support during the continuation phase.

This article is available for open access here.

3. Such a long journey: What health seeking pathways of patients with drug resistant tuberculosis in Mumbai tell us.
PLoS One. 2019 Jan 17;14(1):e0209924. doi: 10.1371/journal.pone.0209924. eCollection 2019.


Bhattacharya Chakravarty A, Rangan S, Dholakia Y, Rai S, Kamble S, Raste T, Shah S, Shah S, Mistry N.

INTRODUCTION: The Indian Tuberculosis (TB) Programme currently faces the dual challenges of tackling increasing numbers of drug resistant (DR) TB cases and regulating practices of a pluralistic private sector catering to TB patients. A study of health seeking behaviour of DR-TB patients in such a situation, offers an opportunity to understand the problems patients face while interacting with health systems.
METHODOLOGY: Forty-six DR-TB patients drawn from 15 high TB burden wards in Mumbai were interviewed using an open ended interview tool. Interviews were audio recorded and transcribed. Pathway schematics developed from analysis of patient records, were linked to transcripts. Open coding was used to analyse these units and themes were derived after collating the codes.
RESULTS AND DISCUSSION: The paper presents themes interwoven with narratives in the discussions. These include awareness-action gap among patients, role of neighbourhood providers, responsiveness of health systems, the not-such a 'merry go round' that patients go/are made to go on while seeking care, costs of diagnostics and treatment, and how DR-TB is viewed as the 'big TB'.
CONCLUSION: The recommendations are based on a preventative ethos which is sustainable, compared to interventions with top-down approaches, which get piloted, but fail to sustain impact when scaled up.

This article is available for open access here.

4. Pharmacokinetics, safety, and dosing of novel pediatric levofloxacin dispersible  tablets in children with multidrug-resistant tuberculosis exposure.
Antimicrob Agents Chemother. 2019 Jan 22. pii: AAC.01865-18. doi: 10.1128/AAC.01865-18. [Epub ahead of print]


Garcia-Prats AJ, Purchase SE, Osman M, Draper HR, Schaaf HS, Wiesner L, Denti P, Hesseling AC.

ABSTRACT: This study characterized the pharmacokinetics of novel 100 mg levofloxacin dispersible tablets in 24 children aged <5 years with household MDR-TB exposure. Data was pooled with previously published data from children (n=109) with MDR-TB receiving adult (250 mg) levofloxacin tablets, using nonlinear mixed-effect modelling. The adult 250 mg tablets had 41% lower bioavailability compared to thenovel dispersible tablets, resulting in much higher exposures with the dispersible tablets with the same mg/kg dose.

This article is available for open access here.

5. Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial.
Lancet Respir Med. 2019 Jan 7. pii: S2213-2600(18)30426-0. doi: 10.1016/S2213-2600(18)30426-0. [Epub ahead of print]


von Groote-Bidlingmaier F, Patientia R, Sanchez E, Balanag V Jr, Ticona E, Segura P, Cadena E, Yu C, Cirule A, Lizarbe V, Davidaviciene E, Domente L, Variava E, Caoili J, Danilovits M, Bielskiene V, Staples S, Hittel N, Petersen C, Wells C, Hafkin J, Geiter LJ, Gupta R.

BACKGROUND: Delamanid is one of two recently approved drugs for the treatment of multidrug-resistant tuberculosis. We aimed to evaluate the safety and efficacy of delamanid in the first 6 months of treatment.

METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done at 17 sites in seven countries (Estonia, Latvia,  Lithuania, Moldova, Peru, the Philippines, and South Africa). We enrolled eligible adults (>18 years) with pulmonary multidrug-resistant tuberculosis to receive, in combination with an optimised background regimen developed according to WHO and national guidelines, either oral delamanid (100 mg twice daily) for 2 months followed by 200 mg once daily for 4 months or placebo (same regimen). Patients were centrally randomised (2:1) and stratified by risk category for delayed sputum culture conversion. Primary outcomes were the time to sputum culture conversion over 6 months and the difference in the distribution of time to sputum culture conversion over 6 months between the two groups, as assessed in the modified intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424670.

FINDINGS: Between Sept 2, 2011, and Nov 27, 2013, we screened 714 patients, of whom 511 were randomly assigned (341 to delamanid plus optimised background regimen [delamanid group] and 170 to placebo plus optimised background regimen
[placebo group]) and formed the safety analysis population. 327 patients were culture-positive for multidrug-resistant tuberculosis at baseline and comprised the efficacy analysis population (226 in the delamanid group and 101 in the
placebo group). Median time to sputum culture conversion did not differ between the two groups (p=0·0562; modified Peto-Peto), with 51 days (IQR 29-98) in the delamanid group and 57 days (43-85) in the placebo group; the hazard ratio was 1·17 (95% CI 0·91-1·51, p=0·2157). 501 (98·0%) of 511 patients had at least one treatment-emergent adverse event. 136 (26·6%) of 511 patients had at least one
serious treatment-emergent adverse event; the incidence was similar between treatment groups (89 [26·1%] of 341 patients for delamanid and 47 [27·6%] of 170 for placebo). Deaths related to treatment-emergent adverse events were similar between groups (15 [4·4%] of 341 for delamanid and six [3·5%] of 170 for placebo). No deaths were considered to be related to delamanid.
INTERPRETATION: The reduction in median time to sputum culture conversion over 6 months was not significant in the primary analysis. Delamanid was well tolerated with a highly characterised safety profile. Further evaluation of delamanid is needed to determine its role in a rapidly evolving standard of care.

 

FUNDING: Otsuka Pharmaceutical.

This article is not available for open access.

6. Compassionate use of delamanid in combination with bedaquiline for the treatment of multidrug-resistant tuberculosis.
Eur Respir J. 2019 Jan 10;53(1). pii: 1801154. doi: 10.1183/13993003.01154-2018. Print 2019 Jan. Hafkin J, Hittel N, Martin A, Gupta R.

SUMMARY: Updated data from the Otsuka compassionate use program show that regimens combining delamanid and bedaquiline appear effective in MDR-TB cases with limited treatment options.This article is available here

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