Plague, one of the most devastating diseases of human history, is caused by Yersinia pestis . In this study, we analyzed the population genetic structure of Y. pestis and the two other pathogenic Yersinia species, Y. pseudotuberculosis and Y. enterocolitica . Fragments of five housekeeping genes and a gene involved in the synthesis of lipopolysaccharide were sequenced from 36 strains representing the global diversity of Y. pestis and from 12–13 strains from each of the other species. No sequence diversity was found in any Y. pestis gene, and these alleles were identical or nearly identical to alleles from Y. pseudotuberculosis . Thus, Y. pestis is a clone that evolved from Y. pseudotuberculosis 1,500–20,000 years ago, shortly before the first known pandemics of human plague. Three biovars (Antiqua, Medievalis, and Orientalis) have been distinguished by microbiologists within the Y. pestis clone. These biovars form distinct branches of a phylogenetic tree based on restriction fragment length polymorphisms of the locations of the IS 100 insertion element. These data are consistent with previous inferences that Antiqua caused a plague pandemic in the sixth century, Medievalis caused the Black Death and subsequent epidemics during the second pandemic wave, and Orientalis caused the current plague pandemic.
BACKGROUNDCohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011. METHODSWe conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority. RESULTSOf 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group -a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], −7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, −10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively. CONCLUSIONSIn persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety.
; Coordination Provinciale Lèpre/Tuberculose, Kinshasa, Democratic Republic of Congo dThe rapid diagnosis of rifampin resistance is hampered by a reported insufficient specificity of molecular techniques for detection of rpoB mutations. Our objective for this study was to document the prevalence and prognostic value of rpoB mutations with unclear phenotypic resistance. The study design entailed sequencing directly from sputum of first failure or relapse patients without phenotypic selection and comparison of the standard retreatment regimen outcome, according to the mutation present. We found that among all rpoB mutations, the best-documented "disputed" rifampin resistance mutations (511Pro, 516Tyr, 526Asn, 526Leu, 533Pro, and 572Phe) made up 13.1% and 10.6% of all mutations in strains from Bangladesh and Kinshasa, respectively. Except for the 511Pro and 526Asn mutations, most of these strains with disputed mutations tested rifampin resistant in routine Löwenstein-Jensen medium proportion method drug susceptibility testing (DST; 78.7%), but significantly less than those with common, undisputed mutations (96.3%). With 63% of patients experiencing failure or relapse in both groups, there was no difference in outcome of first-line retreatment between patients carrying a strain with disputed versus common mutations. We conclude that rifampin resistance that is difficult to detect by the gold standard, phenotypic DST, is clinically and epidemiologically highly relevant. Sensitivity rather than specificity is imperfect with any rifampin DST method. Even at a low prevalence of rifampin resistance, a rifampin-resistant result issued by a competent laboratory may not warrant confirmation, although the absence of a necessity for confirmation needs to be confirmed for molecular results among new cases. However, a result of rifampin susceptibility should be questioned when suspicion is very high, and further DST using a different system (i.e., genotypic after phenotypic testing) would be fully justified.
BackgroundIn contrast to drug-sensitive tuberculosis, the guidelines for the treatment of multi-drug-resistant tuberculosis (MDR-TB) have a very poor evidence base; current recommendations, based on expert opinion, are that patients should be treated for a minimum of 20 months. A series of cohort studies conducted in Bangladesh identified a nine-month regimen with very promising results. There is a need to evaluate this regimen in comparison with the currently recommended regimen in a randomized controlled trial in a variety of settings, including patients with HIV-coinfection.Methods/DesignSTREAM is a multi-centre randomized trial of non-inferiority design comparing a nine-month regimen to the treatment currently recommended by the World Health Organization in patients with MDR pulmonary TB with no evidence on line probe assay of fluoroquinolone or kanamycin resistance. The nine-month regimen includes clofazimine and high-dose moxifloxacin and can be extended to 11 months in the event of delay in smear conversion. The primary outcome is based on the bacteriological status of the patients at 27 months post-randomization. Based on the assumption that the nine-month regimen will be slightly more effective than the control regimen and, given a 10% margin of non-inferiority, a total of 400 patients are required to be enrolled. Health economics data are being collected on all patients in selected sites.DiscussionThe results from the study in Bangladesh and cohorts in progress elsewhere are encouraging, but for this regimen to be recommended more widely than in a research setting, robust evidence is needed from a randomized clinical trial. Results from the STREAM trial together with data from ongoing cohorts should provide the evidence necessary to revise current recommendations for the treatment for MDR-TB.Trial registrationThis trial was registered with clincaltrials.gov (registration number: ISRCTN78372190) on 14 October 2010.
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