Search

Tuberculosis is a global pandemic, with 9 million new cases of the disease and approximately 2 million deaths each year. More than 98% of patients treated for tuberculosis in the United States between 1993 and 2007 had drug-susceptible strains. The standard treatment regimen for drug-susceptible tuberculosis has not changed in decades and was developed on the basis of empiric observations of different treatment regimens. Only recently has the veracity of the scientific basis for standard therapy been examined. The backbone of therapy is still isoniazid, rifampin, and pyrazinamide, although fluoroquinolones are being investigated as a replacement for isoniazid. Recent population pharmacokinetic studies have demonstrated the importance of individualized dosing of isoniazid, pyrazinamide, and rifampin. Isoniazid serum clearance differs depending on the patient's number of N-acetyltransferase 2 gene *4 (NAT2*4) alleles. Pyrazinamide serum clearance has been shown to increase with increases in body weight. Rifampin's volume of distribution, clearance, and absorption have wide between-patient and within-patient variability. Microbial pharmacokinetic-pharmacodynamic (PK-PD) indexes and targets to optimize microbial killing and minimize resistance have been identified for rifampin, isoniazid, pyrazinamide, and the fluoroquinolones. These PK-PD indexes suggest that different doses and dosing schedules than those currently recommended could optimize therapy and perhaps shorten duration of therapy. Efflux pump inhibition is also being investigated to enhance first-line antituberculosis drug therapy. Comorbid conditions such as diabetes mellitus and genetically determined iron overload syndromes have been associated with significantly worse patient outcomes. Therapy for these and other patient groups needs further improvement. These patient factors, the covariates for pharmacokinetic variability, and PK-PD factors suggest the need to individualize therapy for patients with tuberculosis in order to optimize outcomes and reduce the duration of therapy. [ABSTRACT FROM AUTHOR]

Background: Efflux of antibiotics is an effective resistance mechanism among antibiotic-resistant Staphylococcus aureus. This systematic review aims to evaluate the frequency and expression of efflux pump genes in S.aureus around the world., Method: A comprehensive literature search of several databases (Medline Pub Med, ISI, Scopus, Google Scholar, ISC, Science direct and Persian Journals Online, and citation lists) was performed. We considered published studies from 2001 to 2018. Articles reporting the prevalence and expression of efflux pump genes were selected., Result: Among 183 articles, 36 studies were selected. Of the 36, 23 articles were conducted in Asia.6 in Europe, 5 in America and 2 in African countries. In most of these studies norA, norB, qacA/B genes were commonly evaluated by molecular methods. The presence of efflux pump genes such as norA, norB, norC, mepA, mdeA, qacA/B was detected by PCR in 21 studies and over-expression of genes were reported in 13 studies. The most frequently reported genes in Asia were norA (75%), norB (60%), mepA (35%), mdeA (33%) and qacA/B (20.8%). In European studies, the prevalence of norB was mostly reported among S.aureus isolates and norA and qacA/B were commonly found in similar studies in America. The investigation of gene expression patterns showed that norA was most frequent single-pattern in Asia and America, norB or mdeA in Europe., Conclusion: According to this study MDR efflux pumps not only cause high-level resistance but also it considerably associated with over-expression of these genes. Due to the selective pressure on MRSA isolate, the enormous diversity of plasmid-encoded genes had been recorded in different regions, owing to the various numbers and types of isolates in each study or types of disinfectants for general use., (Copyright © 2019 Elsevier Ltd. All rights reserved.)