1. Treatment outcomes of rifabutin-containing regimens for rifabutin-sensitive multidrug-resistant pulmonary tuberculosis.

Int J Infect Dis. 2017 Dec;65:135-141. doi: 10.1016/j.ijid.2017.10.013.

Lee H(1), Ahn S(2), Hwang NY(2), Jeon K(1), Kwon OJ(1), Huh HJ(3), Lee NY(3), Koh WJ(4).

OBJECTIVES: The aim of this study was to evaluate whether rifabutin can improve treatment outcomes in patients with rifabutin-sensitive MDR-TB.

METHODS: A retrospective cohort study was performed on 76 patients with rifabutin-sensitive MDR-TB who were treated with or without rifabutin between 2006 and 2011.

RESULTS: Overall, 75% (57/76) of patients achieved favorable outcomes, including cure (53/76, 70%) and treatment completion (4/76, 5%). In contrast, 25% (19/76) had unfavorable treatment outcomes, which included treatment failure (6/76, 8%), death (2/76, 3%), loss to follow-up (4/76. 5%), and no evaluation due to transfer to other institutions (7/76, 9%). Rifabutin was given to 52 (68%) of the 76 patients with rifabutin-sensitive MDR-TB. Although favorable treatment outcomes were more frequent in patients who received rifabutin [81% (42/52)] than in those who did not receive rifabutin [63% (15/24)], this difference was not statistically significant (P=0.154). However, in multivariable regression logistic analysis, use of rifabutin was significantly associated with favorable treatment outcomes in patients with rifabutin-sensitive MDR-TB (adjusted odds ratio=9.80, 95% confidence interval=1.65-58.37, P=0.012).

CONCLUSIONS: These results suggest that the use of rifabutin can improve treatment outcomes in patients with rifabutin-sensitive MDR-TB.

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2. Rapid Microarray-based Detection of Rifampicin-, Isoniazid- and Fluoroquinolone Resistance in Mycobacterium tuberculosis using a Single Cartridge.

J Clin Microbiol. 2017 Dec 6. pii: JCM.01249-17. doi: 10.1128/JCM.01249-17.

Havlicek J(1), Dachsel B(1), Slickers P(1), Andres S(2), Beckert P(3)(4), Feuerriegel S(3)(4), Niemann S(3)(4), Merker M(5)(4), Labugger I(1).

ABSTRACT: Rapid and robust identification of mutations in Mycobacterium tuberculosis complex (MTBC) strains mediating multidrug and extensively drug-resistant (M/XDR) phenotypes is crucial to combat the MDR tuberculosis (TB) epidemic. Currently available molecular TB drug susceptibility tests are either restricted to single targets/drugs (i.e. Xpert MTB/RIF) or aid the risk of cross-contaminations due to the design limitations of the open platform (i.e. line probe assays).With a good understanding of the technical and commercial boundaries we designed a test cartridge with an introduction of dried reagents, based on an oligonucleotide array, which has the ability to identify MTBC strains resistant to isoniazid, rifampicin and the fluoroquinolones. The melting curve assay interrogates in a closed cartridge system within 90 minutes 43 different mutations in the rifampicin resistance determining region (RRDR) of rpoB, rpoB codon 572, katG codon 315, the inhA promoter region, and the quinolone resistance determining region (QRDR) of gyrA The assay performance was evaluated with 265 clinical MTBC isolates from Swaziland including MDR/XDR, non-MDR, and fully susceptible isolates from a drug resistance survey performed in 2009/2010. In 99.5% of the cases, the results were consistent with the previously acquired data utilizing Sanger sequencing. By means of the closed cartridge system in combination with the battery-powered Alere™ q analyzer and with the potential to extent the current gene target panel the assay could serve as a rapid and robust point-of-care test in settings lacking comprehensive molecular laboratory infrastructure to differentiate MDR and non-MDR TB-patients and to assist clinicians in early treatment decisions.

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3. Limited Effect of Later-generation Fluoroquinolones in the Treatment of Ofloxacin-resistant and Moxifloxacin-susceptible Multidrug-resistant Tuberculosis.

Antimicrob Agents Chemother. 2017 Dec 4. pii: AAC.01784-17. doi: 10.1128/AAC.01784-17. [Epub ahead of print]

Lee H(1), Ahn S(2), Hwang NY(2), Jeon K(1), Kwon OJ(1), Huh HJ(3), Lee NY(3), Kim CK(4), Koh WJ(5).

ABSTRACT: Recent data conflict on the clinical efficacy of later-generation fluoroquinolones, such as moxifloxacin or levofloxacin, for the treatment of multidrug-resistant tuberculosis (MDR-TB) that is resistant to ofloxacin but susceptible to moxifloxacin. The purpose of the present study was to evaluate whether later-generation fluoroquinolones can improve treatment outcomes in patients with ofloxacin-resistant/moxifloxacin-susceptible MDR-TB. A retrospective cohort study was performed on 208 patients with moxifloxacin-susceptible MDR-TB who were treated between 2006 and 2011. Later-generation fluoroquinolones were used in all patients. Overall, 171 patients (82%) had ofloxacin-susceptible/moxifloxacin-susceptible MDR-TB (ofloxacin-susceptible group) and 37 (18%) had ofloxacin-resistant/moxifloxacin-susceptible MDR-TB (ofloxacin-resistant group). Compared to the ofloxacin-susceptible group, the ofloxacin-resistant group was more likely to have a previous history of MDR-TB treatment (P < 0.001) and cavitary lesions on chest radiography (P < 0.001). In addition, the ofloxacin-resistant group was more likely than the ofloxacin-susceptible group to have drug resistance to pyrazinamide (P = 0.003), streptomycin (P = 0.015), prothionamide (P < 0.001), and para-aminosalicylic acid (P < 0.001). Favorable outcomes were more frequently achieved in the ofloxacin-susceptible group than in the ofloxacin-resistant group [91% (156/171) vs. 57% (21/37), respectively; P < 0.001]. In multivariable regression logistic analysis, the ofloxacin-susceptible group was about 5.36 (95% confidence interval = 1.55-18.53) times more likely than the ofloxacin-resistant group (P < 0.001) to have favorable outcomes. Despite in vitro moxifloxacin susceptibility, favorable treatment outcomes for ofloxacin-resistant MDR-TB were significantly lower than for ofloxacin-susceptible MDR-TB, even when later-generation fluoroquinolones were used, indicating that more aggressive therapies may be needed for ofloxacin-resistant MDR-TB.

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4. Population implications of the use of bedaquiline in people with extensively drug-resistant tuberculosis: are fears of resistance justified?

Lancet Infect Dis. 2017 Dec;17(12):e429-e433. doi: 10.1016/S1473-3099(17)30299-2. Epub 2017 May 19.

Kunkel A(1), Furin J(2), Cohen T(3).

ABSTRACT: Global rollout of the new antituberculosis drug bedaquiline has been slow, in part reflecting concerns about spread of bedaquiline resistance. Acquired resistance to bedaquiline is especially likely in patients with extensively

drug-resistant (XDR) tuberculosis. However, the very high mortality rates of patients with XDR not receiving bedaquiline, and promising cohort study results, suggest these patients also have greatest need for the drug. In this Personal View, we argue that resistance concerns should not forestall use of bedaquiline

in patients with XDR tuberculosis. Our position in favour of increased access to bedaquiline for these patients is based on three arguments. First, the use of drug combinations that include bedaquiline might prevent spread of XDR disease to others in the community. Second, until new combination regimens of novel drugs for XDR tuberculosis become available, patients with XDR disease and their infected contacts will face equivalent outcomes if bedaquiline is either not provided because of policy, or not effective because of resistance. Finally, because resistance to bedaquiline and other antituberculosis drugs is caused by mutations within a single bacterial chromosome, use of bedaquiline in patients with XDR tuberculosis will not substantially increase the risk of bedaquiline resistance in patients with drug-susceptible or multidrug-resistant (non‑XDR) tuberculosis strains.

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