Person: Sloutsky, Alexander
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Sloutsky
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Alexander
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Sloutsky, Alexander
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Publication Aggressive Regimens for Multidrug-Resistant Tuberculosis Decrease All-Cause Mortality(Public Library of Science, 2013) Mitnick, Carole; Franke, Molly; Rich, Michael; Alcantara Viru, Felix A.; Appleton, Sasha C.; Atwood, Sidney S.; Bayona, Jaime; Bonilla, Cesar; Chalco, Katiuska; Fraser, Hamish S. F.; Furin, Jennifer; Guerra, Dalia; Hurtado, Rocio; Joseph, Keith; Llaro, Karim; Mestanza, Lorena; Mukherjee, Joia; Muñoz, Maribel; Palacios, Eda; Sanchez, Epifanio; Seung, Kwonjune; Shin, Sonya; Sloutsky, Alexander; Tolman, Arielle W.; Becerra, MercedesRationale: A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen. Objectives: This study assessed the impact of an aggressive regimen–one containing at least five likely effective drugs, including a fluoroquinolone and injectable–on treatment outcomes in a large MDR-TB patient cohort. Methods: This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death. Measurements and Main Results: In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93). Conclusions: The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB.Publication Multiple Introductions of Multidrug-Resistant Tuberculosis into Households, Lima, Peru(Centers for Disease Control and Prevention, 2011) Cohen, Ted; Murray, Megan; Abubakar, Ibrahim; Zhang, Zibiao; Sloutsky, Alexander; Arteaga, Fernando; Chalco, Katiuska; Franke, Molly; Becerra, MercedesTwo cases of multidrug-resistant tuberculosis (MDR TB) in a household are assumed to reflect within-household transmission. However, in high-incidence areas of MDR TB, secondary cases may arise through exposure to MDR TB in the community. To estimate the frequency of multiple introductions of MDR TB into households, we used spoligotyping and 24-loci mycobacterial interspersed repetitive unit–variable number tandem repeats to classify isolates from 101 households in Lima, Peru, in which >1 MDR TB patient received treatment during 1996–2004. We found different MDR TB strains in \(\geq\)10% of households. Alternate approaches for classifying matching strains produced estimates of multiple introductions in \(\leq\)38% of households. At least 4% of MDR TB patients were reinfected by a second strain of MDR Mycobacterium tuberculosis. These findings suggest that community exposure to MDR TB in Lima occurs frequently. Rapid drug sensitivity testing of strains from household contacts of known MDR TB patients is needed to identify optimal treatment regimens.Publication Independent Large Scale Duplications in Multiple M. tuberculosis Lineages Overlapping the Same Genomic Region(Public Library of Science, 2012) Weiner, Brian; Victor, Thomas C.; Warren, Robert M.; Plikaytis, Bonnie B.; Posey, James E.; van Helden, Paul D.; Gey van Pittius, Nicolass C.; Koehrsen, Michael; Sisk, Peter; Stolte, Christian; White, Jared; Gagneux, Sebastien; Birren, Bruce; Gomez, James; Sloutsky, Alexander; Hung, Deborah; Murray, Megan; Galagan, James E.Mycobacterium tuberculosis, the causative agent of most human tuberculosis, infects one third of the world's population and kills an estimated 1.7 million people a year. With the world-wide emergence of drug resistance, and the finding of more functional genetic diversity than previously expected, there is a renewed interest in understanding the forces driving genome evolution of this important pathogen. Genetic diversity in M. tuberculosis is dominated by single nucleotide polymorphisms and small scale gene deletion, with little or no evidence for large scale genome rearrangements seen in other bacteria. Recently, a single report described a large scale genome duplication that was suggested to be specific to the Beijing lineage. We report here multiple independent large-scale duplications of the same genomic region of M. tuberculosis detected through whole-genome sequencing. The duplications occur in strains belonging to both M. tuberculosis lineage 2 and 4, and are thus not limited to Beijing strains. The duplications occur in both drug-resistant and drug susceptible strains. The duplicated regions also have substantially different boundaries in different strains, indicating different originating duplication events. We further identify a smaller segmental duplication of a different genomic region of a lab strain of H37Rv. The presence of multiple independent duplications of the same genomic region suggests either instability in this region, a selective advantage conferred by the duplication, or both. The identified duplications suggest that large-scale gene duplication may be more common in M. tuberculosis than previously considered.