From our October 2019 Newsletter

Publications

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

Publications

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

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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

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

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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

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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

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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

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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

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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

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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.

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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.

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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.

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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.