From our August 2019 Newsletter

Publications

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

Publications

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.