Max Salfinger

Selection of a Moxifloxacin Dose That Suppresses Drug Resistance in Mycobacterium tuberculosis, by Use of an In Vitro Pharmacodynamic Infection Model and Mathematical Modeling

BACKGROUNDnMoxifloxacin is a quinolone antimicrobial that has potent activity against Mycobacterium tuberculosis. To optimize moxifloxacin dose and dose regimen, pharmacodynamic antibiotic-exposure targets associated with maximal microbial kill and complete suppression of drug resistance in M. tuberculosis must be identified.nnnMETHODSnWe used a novel in vitro pharmacodynamic infection model of tuberculosis in which we exposed M. tuberculosis to moxifloxacin with a pharmacokinetic half-life of decline similar to that encountered in humans. Data obtained from this model were mathematically modeled, and the drug-exposure breakpoint associated with the suppression of drug resistance was determined. Monte-Carlo simulations were performed to determine the probability that 10,000 clinical patients taking different doses of moxifloxacin would achieve or exceed the drug-exposure breakpoint needed to suppress resistance to moxifloxacin in M. tuberculosis.nnnRESULTSnThe ratio of the moxifloxacin-free (non-protein-bound) area under the concentration-time curve from 0 to 24 h to the minimum inhibitory concentration associated with complete suppression of the drug-resistant mutant population was 53. For patients taking moxifloxacin doses of 400, 600, or 800 mg/day, the calculated target-attainment rates to suppress drug resistance were 59%, 86%, and 93%, respectively.nnnCONCLUSIONnA moxifloxacin dose of 800 mg/day is likely to achieve excellent M. tuberculosis microbial kill and to suppress drug resistance. However, tolerability of this higher dose is still unknown.

Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis.

The inhA and kasA genes of Mycobacterium tuberculosis have each been proposed to encode the primary target of the antibiotic isoniazid (INH). Previous studies investigating whether overexpressed inhA or kasA could confer resistance to INH yielded disparate results. In this work, multicopy plasmids expressing either inhA or kasA genes were transformed into M. smegmatis, M. bovis BCG and three different M. tuberculosis strains. The resulting transformants, as well as previously published M. tuberculosis strains with multicopy inhA or kasAB plasmids, were tested for their resistance to INH, ethionamide (ETH) or thiolactomycin (TLM). Mycobacteria containing inhA plasmids uniformly exhibited 20‐fold or greater increased resistance to INH and 10‐fold or greater increased resistance to ETH. In contrast, the kasA plasmid conferred no increased resistance to INH or ETH in any of the five strains, but it did confer resistance to thiolactomycin, a known KasA inhibitor. INH is known to increase the expression of kasA in INH‐susceptible M. tuberculosis strains. Using molecular beacons, quantified inhA and kasA mRNA levels showed that increased inhA mRNA levels corre‐lated with INH resistance, whereas kasA mRNA levels did not. In summary, analysis of strains harbouring inhA or kasA plasmids yielded the same conclusion: overexpressed inhA, but not kasA, confers INH and ETH resistance to M. smegmatis, M. bovis BCG and M. tuberculosis. Therefore, InhA is the primary target of action of INH and ETH in all three species.

Universal Genotyping in Tuberculosis Control Program, New York City, 2001–2003

Real-time universal genotyping decreased unnecessary treatment.

Diagnostic tools in tuberculosis: Present and future

Leadership will play a major role in the management of tuberculosis in the future. Many populations, such as immunocompromised patients and immigrants from countries with a higher prevalence of tuberculosis, create a challenge for care and diagnosis. Mycobacterial laboratory testing has undergone many changes in the past 10 years with the advent of nucleic acid probes for identification of Mycobacterium tuberculosis, and more recently nucleic acid amplification and beyond where computer technology meets molecular biology. In the past, changes for tuberculosis testing were not incorporated rapidly, sometimes taking 20 years or more to be fully implemented. The dynamics of acceptance of change and more rapid implementation need to be understood. With the use of such programs as Fast Track for Tuberculosis Testing, this can be accomplished more readily. New technologies can be provided to all users of such a network within a short amount of time and health care providers can equally benefit from this novel approach. The tuberculosis laboratory cannot stand alone. It must work together with other players, in order to eliminate tuberculosis.

Susceptibility Testing for Nontuberculous Mycobacteria: Should it be Performed?

With the resurgence of tuberculosis, there has been an estimated 70,000 excess cases since its steady decline ceased in 1985. Topped with public fear of acquiring multidrug-resistant tuberculosis, the field of mycobacteriology once again entered the limelight 50 yr after the discovery of streptomycin. Although they are not contagious, nontuberculous mycobacteria are also being recovered more frequently, compared with one or two decades ago, in HIVnegative (1) as well as in HIV-positive individuals (2,3). These organisms produce morbidity and mortality from their resultant mycobacteriosis (disease caused by nontuberculous mycobacteria) in transplant recipients (4), in elderly patients (5,6), in cystic fibrosis patients (7), and following accidental trauma (8). This article covers only a snapshot of these organisms and presents some basic rules for the microbiology laboratory. The reader may consult the many excellent reviews for further details on the subject (9-15).

Coming Out of the Darkness

A solution to get the problem off, have you found it? Really? What kind of solution do you resolve the problem? From what sources? Well, there are so many questions that we utter every day. No matter how you will get the solution, it will mean better. You can take the reference from some books. And the coming out of darkness is one book that we really recommend you to read, to get more solutions in solving this problem.