Fluoroquinolone resistance in Mycobacterium tuberculosis has become increasingly important. A review of mutations in DNA gyrase, the fluoroquinolone target, is needed to improve the molecular detection of resistance. We performed a systematic review of studies reporting mutations in DNA gyrase genes in clinical M. tuberculosis isolates. From 42 studies that met inclusion criteria, 1220 fluoroquinolone-resistant M. tuberculosis isolates underwent sequencing of the quinolone resistance-determining region (QRDR) of gyrA; 780 (64%) had mutations. The QRDR of gyrB was sequenced in 534 resistant isolates; 17 (3%) had mutations. Mutations at gyrA codons 90, 91 or 94 were present in 654/1220 (54%) resistant isolates. Four different GyrB numbering systems were reported, resulting in mutation location discrepancies. We propose a consensus numbering system. Most fluoroquinolone-resistant M. tuberculosis isolates had mutations in DNA gyrase, but a substantial proportion did not. The proposed consensus numbering system can improve molecular detection of resistance and identification of novel mutations.
Of all blood cultures positive for coagulase-negative staphylococci collected in 1 year at an academic hospital, 100 were selected randomly for review and designated true positives or contaminated. For the 85 patients whose cultures were determined to be contaminated, chart abstractions revealed substantial unnecessary antibiotic administration, additional laboratory tests and procedures, and hospital readmissions.
SUMMARY Setting A large tuberculosis clinic in Durban, South Africa. Objective To determine the association between isoniazid mono-resistant tuberculosis and treatment outcomes. Design We performed a retrospective longitudinal study of patients seen from 2000–2012 to compare episodes of isoniazid mono-resistant to drug-susceptible tuberculosis using logistic regression with robust standard errors. Isoniazid mono-resistant tuberculosis was treated with modified regimens. Results Among 18,058 TB patients, there were 19,979 TB episodes for which drug susceptibility tests were performed. Of these, 557 were INH mono-resistant and 16,311 were drug-susceptible. Loss to follow-up, transfer, and HIV co-infection (41% had known HIV serostatus) were similar between groups. Isoniazid mono-resistant episodes were more likely to result in treatment failure (4.1% versus 0.6%, P<0.001) and death (3.2% versus 1.8%, P=0.01) than drug-susceptible episodes. After adjusting for age, sex, race, retreatment status, and disease site, isoniazid mono-resistant episodes were more likely to have resulted in treatment failure (odds ratio [OR] 6.84; 95% confidence interval [CI] 4.29–10.89; P<0.001) and death (OR 1.81; 95% CI 1.11–2.95; P=0.02). Conclusion Isoniazid mono-resistance was associated with worse clinical outcomes compared to drug-susceptible tuberculosis. Our findings support the need for rapid diagnostic tests for isoniazid resistance and improved treatment regimens for isoniazid mono-resistant tuberculosis.
SUMMARY SETTING Fluoroquinolone (FQ) exposure before tuberculosis (TB) diagnosis is common, but its effect on outcomes, including mortality, is unclear. DESIGN Among TB patients reported to the Tennessee Department of Health from 2007 to 2009, we assessed FQ exposure within 6 months before TB diagnosis. The primary outcome was the combined endpoint of death at the time of TB diagnosis and during anti-tuberculosis treatment. RESULTS Among 609 TB cases, 214 (35%) received FQs within 6 months before TB diagnosis. A total of 71 (12%) persons died; 10 (2%) were dead at TB diagnosis and 61 (10%) died during anti-tuberculosis treatment. In multivariable logistic regression analysis, factors independently associated with death were older age (OR 1.05 per year, 95%CI 1.04–1.07), human immunodeficiency virus infection (OR 8.08, 95%CI 3.83–17.06), US birth (OR 3.03, 95%CI 1.03–9.09), and any FQ exposure before TB diagnosis (OR 1.82, 95%CI 1.05–3.15). Persons with FQ exposure before TB diagnosis were more likely to have culture- and smear-positive disease than unexposed persons. CONCLUSIONS Among this patient population, FQ exposure before TB diagnosis was associated with an increased risk of death. These findings underscore the need for cautious use of FQs in persons with possible TB.
Tuberculosis remains a leading cause of death globally despite curative treatment, partly due to the difficulty of identifying patients who will not respond to therapy. Simple host biomarkers that correlate with response to drug treatment would facilitate improvement in outcomes and the evaluation of novel therapies. In a prospective longitudinal cohort study, we evaluated neutrophil count and phenotype at baseline, as well as during TB treatment in 79 patients [50 (63%) HIV-positive] with microbiologically confirmed drug susceptible TB undergoing standard treatment. At time of diagnosis, blood neutrophils were highly expanded and surface expression of the neutrophil marker CD15 greatly reduced compared to controls. Both measures changed rapidly with the commencement of drug treatment and returned to levels seen in healthy control by treatment completion. Additionally, at the time of diagnosis, high neutrophil count, and low CD15 expression was associated with higher sputum bacterial load and more severe lung damage on chest x-ray, two clinically relevant markers of disease severity. Furthermore, CD15 expression level at diagnosis was associated with TB culture conversion after 2 months of therapy (OR: 0.14, 95% CI: 0.02, 0.89), a standard measure of early TB treatment success. Importantly, our data was not significantly impacted by HIV co-infection. These data suggest that blood neutrophil metrics could potentially be exploited to develop a simple and rapid test to help determine TB disease severity, monitor drug treatment response, and identify subjects at diagnosis who may respond poorly to treatment.
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