May 2019 Newsletter


Advocates raise serious concerns about errors in the WHO guidelines for the treatment of drug-resistant TB
On 23 April 2019, TB advocates sent an open letter to Dr. Tedros Adhanom Ghebreyesus, Director-General of the World Health Organization (WHO), expressing their serious concerns about the WHO Global TB Program’s ability to issue evidence-based guidelines for the treatment of drug-resistant TB.

Community capacity building modules to accelerate DR-TB response
Affected communities and community-based organizations can play a crucial role and work with national programmes in ensuring a person-centred and human rights-based approach in the management of drug-resistant TB in countries in the South-East Asia Region, provided their capacity is built with appropriate training to understand the science and management of DR-TB. This article explores the recent developments made at the WHO South-East Asia Regional Meeting of National TB Program Managers and Partners.

It’s Time to End Drug-Resistant Tuberculosis: The Case for Action
NEW BRUNSWICK, N.J., MAY 7, 2019 — A new report published today by The Economist Intelligence Unit (EIU), and with support from Johnson & Johnson, emphasizes the urgent need for focused global action to address the growing threat of drug-resistant tuberculosis (DR-TB). DR-TB is the leading contributor to deaths from antimicrobial resistance (AMR).



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
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.