June 2019 Newsletter

News

FDA Antimicrobial Drugs Advisory Committee recommends approval of pretomanid

Investigational drug pretomanid is under regulatory review by FDA for treatment of XDR-TB and treatment-intolerant or non-responsive MDR-TB as part of a new investigational regimen. A decision regarding pretomanid approval is expected to be made by August of 2019.

Advocates call on TB Alliance to make public the pretomanid licensing agreement with Mylan

TB advocates sent an open letter to TB alliance requesting the organization toshare their recent agreement with Mylan.

Publications

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.

May 2019 Newsletter

News

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).

 

Publications

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.

April 2019 Newsletter


NEWS

Low-Level Delamanid and Bedaquiline Resistancein Extensively Drug-Resistant TB

In a brief report published in Clinical Infectious Diseases, researchers reported a case of drug resistance against 2 recently approved antitubercular medications: delamanid and bedaquiline. Researchers presented a patient with extensively drug-resistant tuberculosis (TB), and highlighted the potential for the emergence and transmission of resistant Mycobacterium tuberculosis complex strains with more frequent use of these relatively new drugs
Read the full article here.

PUBLICATIONS

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.


What will it take to eliminate drug-resistant tuberculosis?

This is the third article in our State of the Art series, with senior RESIST-TB editors Bob Horsburgh, Carole Mitnick and Christoph Lange.

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.

Read the full article here.

March 2019 Newsletter

NEWS ANNOUNCEMENTS

 

WHO consolidated guidelines on drug-resistant tuberculosis treatment
These Consolidated guidelines include a comprehensive set of WHO recommendations for the treatment and care of DR-TB, derived from these WHO guidelines documents. The consolidated guidelines include policy recommendations on treatment regimens for isoniazid-resistant TB (Hr-TB) and MDR/RR-TB, including longer and shorter regimens, culture monitoring of patients on treatment, the timing of antiretroviral therapy (ART) in MDR/RR-TB patients infected with the human immunodeficiency virus (HIV), use of surgery for patients receiving MDR-TB treatment, and optimal models of patient support and care.
Access the full guidelines and WHO report here.
Download the guidelines directly here.

Upcoming RESIST-TB Webinar
On Friday, April 12th from 08:30 to 9:30 EST (14:30-15:30 CEST and SAST), RESIST-TB will be hosting a webinar on two presentations from the 2019 Conference on Retroviruses and Opportunistic Infections (CROI):
THE INHindsight Trial
(Early bactericidal activity of high-dose isonizaid against multidrug-resistant TB)
by Kelly E. DooleyThe DELIBERATE Trial
(QT effects of bedaquiline, delamanid or both in MDR-TB patients)
by Gary Maartens*An announcement will sent out soon with details on how to join the webinar.

PUBLICATIONS

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.

The MDR-TB epidemic—a status report

RESIST-TB authored (C. R. Horsburgh, Jr, C. D. Mitnick, C. Lange) editorial in the International Journal of Tuberculosis and Lung Disease February edition:

 

Despite its recognition over 28 years ago, the magnitude of the impact of drug resistance of M. tuberculosis on TB control has long been under-appreciated. We now realize that MDR strains of M. tuberculosis are spreading by primary transmission and not merely developing through therapeutic misadventure, that cure rates are abysmal,4,5andthat the level of resistance to drugs in addition to INH and RMP is often astonishingly high.

Click here to access this article (download available for free).

 

February 2019 Newsletter

NEWS

TB activists for first time challenge TB drug patent in India
February 6, 2019 – Médecins Sans Frontières (MSF) is supporting a patent challenge filed in India this week by two tuberculosis survivors, to prevent pharmaceutical corporation Johnson & Johnson (J&J) from extending its monopoly on the tuberculosis drug bedaquiline.

The development of bedaquiline benefited from considerable public investment, and the evidence for its potential to improve cure rates with fewer side-effects was the result of a collective effort of the global TB community. MSF is urging J&J to refrain from attempts to extend its monopoly that will further delay the availability of quality-assured generic versions of bedaquiline in India, South Africa and other countries.

As patients challenge patent, J&J commits to tackling drug-resistant TB
February 17, 2019 – While Bedaquiline patent is contested, firm denies its monopoly would get extended.

Johnson & Johnson has tripled its commitment on tuberculosis drug Bedaquiline by offering 90,000 doseages to its global donation programme that ends in March, Paul Stoffels, J&J’s Vice-Chair of the Executive Committee and Chief Scientific Officer, said, on a programme that has given medicines to India as well.

 

PUBLICATIONS

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.

January 2019 Newsletter

NEWS AND ANNOUNCEMENTS

FIND WEBINAR SERIES 2019
FIND, the World Health Organization, the New Diagnostics Working Group and MSF Access Campaign are co-organizing a four-part webinar series on the use and implementation of next-generation sequencing (NGS) for drug-resistant TB (DR-TB). The series will take place on 5, 12, 19, and 26 February 2019. More information about these webinars and their specific times can be found here.

PUBLICATIONS

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

December 2018 Newsletter

NEWS AND ANNOUNCEMENTS

 

Upcoming Webinar

Managing Side Effects to Drug-resistant TB Treatment – Hosted by RESIST-TB and The Union’s NAPS
On January 16th at 08:30 EST (14:30 CET, 15:30 SAST), RESIST-TB and The Union’s Nurses and Allied Professionals Sub-Section (NAPS) will be hosting a webinar to discuss the ICN/CITC Nursing Guide for Management of Side Effects of DR-TB Treatment. Nurses are often the first to hear of a patient’s side effects during TB treatment, making them well positioned to intervene. The information presented in this guide, which will be the topic of this webinar, was developed to help nurses assess for and respond appropriately to side effects related to anti-TB medications.

For more information on how to join the webinar, continue to check our website.

 

PUBLICATIONS

1. Acceptability of a Novel Levofloxacin Dispersible Tablet Formulation in Young Children Exposed to Multidrug-Resistant Tuberculosis.
Pediatr Infect Dis J. 2018 Dec 13. doi: 10.1097/INF.0000000000002268. [Epub ahead of print]
Purchase SE, Garcia-Prats AJ, De Koker P, Draper HR, Osman M, Seddon JA, Schaaf HS, Hesseling AC.

ABSTRACT: 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.

This article is can be found here.

2. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment.
Clin Infect Dis. 2018 Nov 28;67(suppl_3):S327-S335. doi: 10.1093/cid/ciy625
Bolhuis MS, Akkerman OW, Sturkenboom MGG,  Ghimire S, Srivastava S, Gumbo T, Alffenaar JC.

ABSTRACT: Linezolid has been successfully used for treatment of multidrug-resistant tuberculosis (MDR-TB). However, dose- and duration-related toxicity limit its use. Here, our aim was to search relevant pharmacokinetics (PK)/pharmacodynamics (PD) literature to identify the effective PK/PD index and to define the optimal daily dose and dosing frequency of linezolid in MDR-TB regimens. The systematic search resulted in 8 studies that met inclusion criteria. A significant PK variability was observed. Efficacy of linezolid seems to be driven by area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC). Literature is inconclusive about the preferred administration of a daily dose of 600 mg. To prevent development of drug resistance, an AUC/MIC ratio of 100 in the presence of a companion drug at relevant exposure is required. A daily dose of 600 mg seems appropriate to balance between efficacy and toxicity. Being a drug with a very narrow therapeutic window, linezolid treatment may benefit from a more personalized approach, that is, measuring actual MIC values and therapeutic drug monitoring.

This article is can be found here.

3. Minimum inhibitory concentrations of fluoroquinolones and pyrazinamide susceptibility correlate to clinical improvement in MDR-TB patients – a nationwide Swedish cohort study over two decades.
Clin Infect Dis. 2018 Dec 18. doi: 10.1093/cid/ciy1068. [Epub ahead of print]
Davies Forsman L, Jonsson J, Wagrell C, Werngren J, Mansjö
M, Wijkander M, Groenheit R, Hammar U, Giske CG, Schön T,
Bruchfeld J.

INTRODUCTION: Minimum inhibitory concentration (MIC) testing, unlike routine drug susceptibility testing (DST) at a single critical concentration, quantifies drug resistance. The association of MICs and treatment outcome in multidrug-resistant
tuberculosis (MDR-TB) patients is unclear. Therefore, we correlated MICs of first-and second-line TB drugs with time to sputum culture conversion (tSCC) and treatment outcome in MDR-TB patients.
MATERIALS/METHODS: Clinical and demographic data of MDR-TB patients in Sweden 1992-2014 including DST results were retrieved from medical records. MIC determinations were performed retrospectively for the stored individual Mtb isolates using broth microdilution in Middlebrook 7H9. We fitted Cox proportional hazard models correlating MICs, DST results and clinical variables to tSCC and treatment outcome.                                                                                                                                                                                                                             RESULTS: Successful treatment outcome was observed in 83.5% (132/158) of MDR-TB patients. Increasing MICs of fluoroquinolones, diabetes and age > 40 years were significantly associated with unsuccessful treatment outcome. Patients treated with PZA had a significantly shorter tSCC compared to patients were not (median difference 27 days).
CONCLUSION: Increasing MICs of fluoroquinolones were correlated to unsuccessful treatment outcome in MDR-TB patients. Further studies, including MIC testing and clinical outcome data to define clinical Mtb breakpoints, are warranted. PZA treatmentwas associated with shorter tSCC, highlighting the importance of PZA DST.

This article can be found here.

4. Transmission of drug-resistant tuberculosis in HIV-endemic settings
Lancet Infect Dis. 2018 Dec 13. pii: S1473-3099(18)30537-1. doi: 10.1016/S1473-3099(18)30537-1. [Epub ahead of print]
Khan PY, Yates TA, Osman M, Warren RM, van der Heijden Y, Padayatchi N, Nardell EA, Moore D, Mathema B, Gandhi N, Eldholm V, Dheda K, Hesseling AC, Mizrahi V, Rustomjee R, Pym A.

ABSTRACT: The emergence and expansion of the multidrug-resistant tuberculosis epidemic is a threat to the global control of tuberculosis. Multidrug-resistant tuberculosis is the result of the selection of resistance-conferring mutations during inadequate antituberculosis treatment. However, HIV has a profound effect on the natural history of tuberculosis, manifesting in an increased rate of disease progression, leading to increased transmission and amplification of multidrug-resistant tuberculosis. Interventions specific to HIV-endemic areas are urgently needed to block tuberculosis transmission. These interventions should include a combination of rapid molecular diagnostics and improved chemotherapy to shorten the duration of infectiousness, implementation of infection control measures, and activescreening of multidrug-resistant tuberculosis contacts, with prophylactic regimens for individuals without evidence of disease. Development and improvement of the efficacy of interventions will require a greater understanding of the factors affecting the transmission of multidrug-resistant tuberculosis in HIV-endemic settings, including population-based molecular epidemiology studies. In this Series article, we review what we know about the transmission of multidrug-resistant tuberculosis in settings with high burdens of HIV and define the research priorities required to develop more effective interventions, to diminish ongoing transmission and the amplification of drug resistance.

This article can be accessed for free here. (With a registered Lancet account, also free)

Science-based Dosing of Second Line Antituberculosis Agents for TB Programs – IDSA Clinical Infectious Disease Volume 67, Supplement 3 

1.Pharmacokinetic/Pharmacodynamic Background and Methods and Scientific Evidence Base for Dosing of Second-line Tuberculosis Drugs

2. Gatifloxacin Pharmacokinetics/Pharmacodynamics–based Optimal Dosing for Pulmonary and Meningeal Multidrug-resistant Tuberculosis

3. Artificial intelligence–derived 3-Way Concentration-dependent Antagonism of Gatifloxacin, Pyrazinamide, and Rifampicin During Treatment of Pulmonary Tuberculosis

4. Levofloxacin Pharmacokinetics/Pharmacodynamics, Dosing, Susceptibility Breakpoints, and Artificial Intelligence in the Treatment of Multidrug-resistant Tuberculosis

5. Amikacin Dosing for MDR Tuberculosis: A Systematic Review to Establish or Revise the Current Recommended Dose for Tuberculosis Treatment

6. D-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

7. Ethionamide Pharmacokinetics/Pharmacodynamics-derived Dose, the Role of MICs in Clinical Outcome, and the Resistance Arrow of Time in Multidrug-resistant Tuberculosis

8. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment

9.  The Sterilizing Effect of Intermittent Tedizolid for Pulmonary Tuberculosis

10. Multiparameter Responses to Tedizolid Monotherapy and Moxifloxacin Combination Therapy Models of Children With Intracellular Tuberculosis

11. Transformation Morphisms and Time-to-Extinction Analysis That Map Therapy Duration From Preclinical Models to Patients With Tuberculosis: Translating From Apples to Oranges

12.  Efficacy Versus Hepatotoxicity of High-dose Rifampin, Pyrazinamide, and Moxifloxacin to Shorten Tuberculosis Therapy Duration: There Is Still Fight in the Old Warriors Yet!

13. The Role of Novel Approaches and New Findings in the Pharmacology of Tuberculosis Medicines in Improving Treatment Outcomes

*The above links provide abstracts to the articles

Nursing Guide for Managing Side Effects to Drug-resistant TB Treatment

This guide was developed by nurses with experience in the clinical care and programmatic management of TB and DR-TB in both high- and low-resource settings. Nursing and DR-TB literature were reviewed to establish best practice nursing assessment and intervention guidance. Nurses caring for patients with DR-TB field tested the job aid and provided feedback which was used to inform final content and format. A link to this guide online can be found here.

Citation: International Council of Nurses and Curry International Tuberculosis Center. Nursing guide for managing side effects to drug-resistant TB treatment. Geneva. 2018.