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.