January 2017 e-Newsletter

1. Drug regimens identified and optimized by output-driven platform markedly reduce tuberculosis treatment time.
Nat Commun. 2017 Jan 24;8:14183. doi: 10.1038/ncomms14183.
Lee BY(1), Clemens DL(1), Silva A(2), Dillon BJ(1), Masleša-Galić S(1), Nava S(1), Ding X(3), Ho CM(2,)(4), Horwitz MA(1).

ABSTRACT: The current drug regimens for treating tuberculosis are lengthy and onerous, and hence complicated by poor adherence leading to drug resistance and disease relapse. Previously, using an output-driven optimization platform and an in vitro macrophage model of Mycobacterium tuberculosis infection, we identified several experimental drug regimens among billions of possible drug-dose combinations that outperform the current standard regimen. Here we use this platform to optimize the in vivo drug doses of two of these regimens in a mouse model of pulmonary tuberculosis. The experimental regimens kill M. tuberculosis much more rapidly than the standard regimen and reduce treatment time to relapse-free cure by 75%. Thus, these regimens have the potential to provide a markedly shorter course of treatment for tuberculosis in humans. As these regimens omit isoniazid, rifampicin, fluoroquinolones and injectable aminoglycosides, they would be suitable for treating many cases of multidrug and extensively drug-resistant tuberculosis.

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2. Reasons for Non-Enrollment in Treatment among Multi-Drug Resistant Tuberculosis Patients in Hunan Province, China.
PLoS One. 2017 Jan 23;12(1):e0170718. doi: 10.1371/journal.pone.0170718. eCollection 2017.
Xu Z(1), Xiao T(1), Li Y(1), Yang K(2), Tang Y(1), Bai L(3).

ABSTRACT: In 2015, only 49% of notified multi-drug resistant tuberculosis (MDR-TB) patients in China were estimated to have initiated treatment, compared with 90% of those worldwide. A case-control study was conducted to identify the reasons for non-enrollment in treatment among MDR-TB patients in Hunan province, China. All detected MDR-TB patients registered in designated MDR-TB hospitals in Hunan province from 2011 to 2014 were included and followed until June 2015 to determine their treatment status. Approximately 33.8% (482/1425) of patients were not enrolled in standardized treatment. Factors associated with lower enrollment rate were: age greater than 60 years, living in rural area, unemployed or occupation unreported. Of those who were not enrolled in MDR-TB treatment, the primary reasons for non-enrollment included economic hardship (23.0%), out-migration for work (18.0%), concerns about work and studies (13.7%), and the belief that they were cured after undergoing drug-sensitive TB treatment (12.4%).
Therefore, comprehensive strategies targeting priority populations, especially those enhancing treatment affordability and availability, need to be implemented to improve MDR-TB control.

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3. Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance.
Nat Genet. 2017 Jan 16. doi: 10.1038/ng.3767. [Epub ahead of print]
Manson AL(1), Cohen KA(1,)(2,)(3), Abeel T(1,)(4), Desjardins CA(1), Armstrong DT(5), Barry CE 3rd(6), Brand J(7); TBResist Global Genome Consortium, Chapman SB(1), Cho SN(8), Gabrielian A(9), Gomez J(1), Jodals AM(10), Joloba M(11), Jureen P(12), Lee JS(8), Malinga L(7), Maiga M(13), Nordenberg D(14), Noroc E(15), Romancenco E(15), Salazar A(1,)(4), Ssengooba W(11), Velayati AA(16), Winglee K(5), Zalutskaya A(17), Via LE(6), Cassell GH(18), Dorman SE(5), Ellner J(19), Farnia P(16), Galagan JE(1,)(20), Rosenthal A(9), Crudu V(15), Homorodean D(10), Hsueh PR(21), Narayanan S(22), Pym AS(2), Skrahina A(17), Swaminathan S(22), Van der Walt M(7), Alland D(23), Bishai WR(2,)(5), Cohen T(24,)(25), Hoffner S(12), Birren BW(1), Earl AM(1).
COLLABORATORS: Brand J, Jureen P, Malinga L, Nordenberg D, Velayati AA, Cassell GH, Farnia P, Homorodean D, Van der Walt M, Hoffner S.

ABSTRACT: Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome sequences from 5,310 M. tuberculosis isolates from five continents. Despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. We have identified harbinger mutations that often precede multidrug resistance. In particular, the katG mutation encoding p.Ser315Thr, which confers resistance to isoniazid, overwhelmingly arose before mutations that conferred rifampicin resistance across all of the lineages, geographical regions and time periods. Therefore, molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of polymorphisms that occur before the emergence of multidrug resistance, particularly katG p.Ser315Thr, into molecular diagnostics should enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB.

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4. Estimated generic prices for novel treatments for drug-resistant tuberculosis.
J Antimicrob Chemother. 2017 Jan 10. pii: dkw522. doi: 10.1093/jac/dkw522. [Epub ahead of print]
Gotham D(1), Fortunak J(2), Pozniak A(3), Khoo S(4), Cooke G(5), Nytko FE 3rd(2), Hill A(3).

BACKGROUND: The estimated worldwide annual incidence of MDR-TB is 480 000, representing 5% of TB incidence, but 20% of mortality. Multiple drugs have recently been developed or repurposed for the treatment of MDR-TB. Currently, treatment for MDR-TB costs thousands of dollars per course.
OBJECTIVES: To estimate generic prices for novel TB drugs that would be achievable given large-scale competitive manufacture.
METHODS: Prices for linezolid, moxifloxacin and clofazimine were estimated based on per-kilogram prices of the active pharmaceutical ingredient (API). Other costs were added, including formulation, packaging and a profit margin. The projected costs for sutezolid were estimated to be equivalent to those for linezolid, based on chemical similarity. Generic prices for bedaquiline, delamanid and pretomanid were estimated by assessing routes of synthesis, costs/kg of chemical reagents, routes of synthesis and per-step yields. Costing algorithms reflected variable regulatory requirements and efficiency of scale based on demand, and were validated by testing predictive ability against widely available TB medicines.
RESULTS: Estimated generic prices were US$8-$17/month for bedaquiline, $5-$16/month for delamanid, $11-$34/month for pretomanid, $4-$9/month for linezolid, $4-$9/month for sutezolid, $4-$11/month for clofazimine and $4-$8/month for moxifloxacin. The estimated generic prices were 87%-94% lower than the current lowest available prices for bedaquiline, 95%-98% for delamanid and 94%-97% for linezolid. Estimated generic prices were $168-$395 per course for the STREAM trial modified Bangladesh regimens (current costs $734-$1799), $53-$276 for pretomanid-based three-drug regimens and $238-$507 for a delamanid-based four-drug regimen.
CONCLUSIONS: Competitive large-scale generic manufacture could allow supplies of treatment for 5-10 times more MDR-TB cases within current procurement budgets.

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5. Reduced chance of hearing loss associated with Therapeutic Drug Monitoring of Aminoglycosides in the treatment of Multidrug Resistant Tuberculosis.
Antimicrob Agents Chemother. 2017 Jan 9. pii: AAC.01400-16. doi: 10.1128/AAC.01400-16. [Epub ahead of print]
van Altena R(1,)(2), Dijkstra JA(3), van der Meer ME(3), Borjas Howard JF(4), Kosterink JG(3,)(5), van Soolingen D(6,)(7), van der Werf TS(2,)(4), Alffenaar JW(8).

ABSTRACT: Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our Tuberculosis Center, we have employed therapeutic drug monitoring (TDM) targeting pre-set pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto-) toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of TB patients treated with amikacin or kanamycin in the period 2000 – 2012. Patients with culture-confirmed multi- or extensively drug resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study. Clinical data, including Cmax, Cmin and audiometry data were extracted from the patients’ medical charts. 80 patients met the inclusion criteria. The mean weighted Cmax/MIC ratio obtained from 57 patients was 31.2 for amikacin and 12.3 for kanamycin. The extent of hearing loss was limited and correlated with the cumulative drug dose per kg body weight during daily administration. At follow-up, 35 (67.3%) of all patients had successful outcome; there were no relapses. At a median dose of 6.5 mg/kg a correlation was found between the dose per kg bodyweight during daily dosing and the extent of hearing loss in dB at 8000 Hz. This study suggests that the efficacy at this lower dosage is maintained with limited toxicity. A randomized controlled trial should provide final proof of the safety and efficacy of TDM-guided use of aminoglycosides in MDR-TB treatment.

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