October 2017 Newsletter

1. The Physicochemical Basis of Clofazimine-Induced Skin Pigmentation.
J Invest Dermatol. 2017 Oct 14. pii: S0022-202X(17)33040-3. doi: 10.1016/j.jid.2017.09.031. [Epub ahead of print]
Murashov MD(1), LaLone V(1), Rzeczycki PM(1), Keswani RK(1), Yoon GS(1), Sud S(1), Rajeswaran W(2), Larsen S(2), Stringer KA(3), Rosania GR(4).

ABSTRACT: Clofazimine is a weakly basic, FDA-approved antibiotic recommended by the World Health Organization to treat leprosy and multi-drug-resistant tuberculosis. Upon prolonged treatment, clofazimine extensively bioaccumulates and precipitates throughout the organism, forming crystal-like drug inclusions (CLDIs). Because of the drug’s red color, it is widely believed that clofazimine bioaccumulation results in skin pigmentation, its most common side effect. To test whether clofazimine-induced skin pigmentation is due to CLDI formation, we synthesized a closely related clofazimine analog that does not precipitate under physiological pH and chloride conditions that are required for CLDI formation. Despite the absence of detectable CLDIs in mice, administration of this analog still led to significant skin pigmentation. In clofazimine treated mice, skin cryosections revealed no evidence of CLDIs when analyzed with a microscopic imaging system specifically designed for detecting clofazimine aggregates. Rather, the reflectance spectra of the skin revealed a signal corresponding to the soluble, free base form of the drug. Consistent with the low concentrations of clofazimine in the skin, these results suggest that clofazimine-induced skin pigmentation is not due to clofazimine precipitation and CLDI formation, but rather to the partitioning of the circulating, free base form of the drug into subcutaneous fat.

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2. Bilateral cavitary multidrug- or extensively drug-resistant tuberculosis: role of surgery.
Eur J Cardiothorac Surg. 2017 Oct 10. doi:10.1093/ejcts/ezx350.
Marfina GY(1), Vladimirov KB(2), Avetisian AO(1), Starshinova AA(1), Kudriashov GG(1), Sokolovich EG(1), Yablonskii PK(1)(3).

OBJECTIVES: Cavitary disease and bilateral lesions are among the risk factors for poor outcome of pulmonary tuberculosis (TB). Our aim was to explore the value and limits of surgery in patients with advanced TB.
METHODS: A retrospective study of 57 consecutive patients who underwent thoracic surgery for culture-positive bilateral cavitary pulmonary TB was performed. Forty-four (77.2%) patients were men and 13 (22.8%) patients were women; their ages were in the range of 18-61 years. Twenty-two (38.6%) patients had multidrug-resistant (MDR) TB and 35 (61.4%) patients had extensively drug-resistant (XDR) TB confirmed with cultures. On admission, 49 (86.0%) patients had sputum smear microscopy positive for acid-fast bacilli. The main indication for surgery was treatment failure manifested as contagious persisting cavities despite best available therapy. The surgical procedures included combinations of pulmonary resections of different levels, selective thoracoplasties and/or endobronchial valve treatment. The operations were performed consecutively, starting with the most affected side. TB therapy preceded the operation for a minimum of 6 months and was continued after the operation on the basis of the patient’s susceptibility to drugs for Mycobacterium tuberculosis.
RESULTS: We performed 121 operations: 42 in 22 patients with MDR TB (1.9 operations per patient) and 79 procedures in 35 patients with XDR TB (2.3 operations per patient). No deaths occurred in the 1st year. Two late deaths followed, 1 unrelated to and 1 due to TB progression. Ten major complications (1 complication per patient) developed: main bronchus stump fistula (n = 4), prolonged air leak (n = 3), respiratory failure (n = 2) and wound seroma (n = 1). At the 1-month follow-up visit, sputum smear conversion was observed in 11(68.8%) patients with MDR and in 15 (45.5%) patients with XDR TB. At the late (20-36 months) follow-up visit, culture negativity was achieved in 21 (95.5%) patients with MDR TB and in 23 (65.7%) patients with XDR TB (P = 0.015).
CONCLUSIONS: Thoracic surgery may significantly improve patients’ outcomes and even result in a cure in a good portion of patients with bilateral cavitary MDR and XDR TB and should be considered as the essential element of multimodality treatment for MDR and XDR TB, even in patients with bilateral cavitary disease and borderline respiratory reserves.

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3. A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance.
BMC Genomics. 2017 Oct 11;18(1):769. doi: 10.1186/s12864-017-4146-z.
Sheen P(1), Requena D(1), Gushiken E(1), Gilman RH(2), Antiparra R(1), Lucero B(1), Lizárraga P(1), Cieza B(1), Roncal E(1), Grandjean L(3), Pain A(4), McNerney R(5), Clark TG(5)(6), Moore D(5), Zimic M(7).

BACKGROUND: Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.
RESULTS: We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes. We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.
CONCLUSIONS: These results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.

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4. Fluoroquinolone Resistance Mutation Detection Is Equivalent to Culture-Based Drug Sensitivity Testing for Predicting Multidrug-Resistant Tuberculosis Treatment Outcome: A Retrospective Cohort Study.
Clin Infect Dis. 2017 Oct 15;65(8):1364-1370. doi: 10.1093/cid/cix556.
Farhat MR(1)(2), Jacobson KR(3), Franke MF(4), Kaur D(5), Murray M(4)(6), Mitnick CD(4)(7).

BACKGROUND: Molecular diagnostics that rapidly and accurately predict fluoroquinolone (FQ) resistance promise to improve treatment outcomes for individuals with multidrug-resistant (MDR) tuberculosis (TB). Mutations in the gyr genes, though, can cause variable levels of in vitro FQ resistance, and some in vitro resistance remains unexplained by gyr mutations alone, but the implications of these discrepancies for treatment outcome are unknown.
METHODS: We performed a retrospective cohort study of 172 subjects with MDR/extensively drug-resistant TB subjects and sequenced the full gyrA and gyrB open reading frames in their respective sputum TB isolates. The gyr mutations were classified into 2 categories: a set of mutations that encode high-level FQ resistance and a second set that encodes intermediate resistance levels. We constructed a Cox proportional model to assess the effect of the gyr mutation type on the time to death or treatment failure and compared this with in vitro FQ resistance, controlling for host and treatment factors.
RESULTS: Controlling for other host and treatment factors and compared with patients with isolates without gyr resistance mutations, “high-level” gyr mutations significantly predict poor treatment outcomes with a hazard ratio of 2.6 (1.2-5.6). We observed a hazard of death and treatment failure with “intermediate-level” gyr mutations of 1.3 (0.6-3.1), which did not reach statistical significance. The gyr mutations were not different than culture-based FQ drug susceptibility testing in predicting the hazard of death or treatment failure and may be superior.
CONCLUSIONS: FQ molecular-based diagnostic tests may better predict treatment response than traditional drug susceptibility testing and open avenues for personalizing TB therapy.

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5. The devil we know: is the use of injectable agents for the treatment of MDR-TB justified?
Int J Tuberc Lung Dis. 2017 Nov 1;21(11):1114-1126. doi: 10.5588/ijtld.17.0468.
Reuter A(1), Tisile P(2), von Delft D(2), Cox H(3), Cox V(4), Ditiu L(5), Garcia-Prats A(6), Koenig S(7), Lessem E(8), Nathavitharana R(9), Seddon JA(10), Stillo J(11), von Delft A(12), Furin J(7).

ABSTRACT: For decades, second-line injectable agents (IAs) have been the cornerstone of treatment for multidrug-resistant tuberculosis (MDR-TB). Although evidence on the efficacy of IAs is limited, there is an expanding body of evidence on the serious adverse events caused by these drugs. Here, we present the results of a structured literature review of the safety and efficacy of IAs. We review the continued widespread use of these agents in the context of therapeutic alternatives-most notably the newer TB drugs, bedaquiline and delamanid-and from the context of human rights, ethics and patient-centered care. We conclude that there is limited evidence of the efficacy of IAs, clear evidence of the risks of these drugs, and that persons living with MDR-TB should be informed about these risks and provided with access to alternative therapeutic options.

Read full IJTLD article here