April 2019 Newsletter


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
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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.

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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.

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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.

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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.

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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.

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