Evaluation of clinical isolates of Mycobacterium tuberculosis in the murine and guinea pig infection models, The

2011 Fall.Includes bibliographical references.Globally the tuberculosis epidemic continues unabated, affecting over nine million people a year, with more than half a million of these cases being resistant to multiple drugs. Multiple drug resistant tuberculosis (MDR-TB) is becoming a growing problem to the world's population. Despite this growing problem, very little research is being focused on MDR-TB. One basic question not yet addressed is how drug resistance affects virulence levels. A hypothesis, originating from classical studies of Mitchison, is that drug resistance results in a lower virulence level. Using the murine and guinea pig models of infection, I studied the ability of multiple isogenic pairs of Mycobacterium tuberculosis to grow in these particular animal models, in order to determine if acquired drug resistance increased or decreased the virulence of the drug resistant strain. In the murine model there was no discernable relationship between the drug resistance of a given strain and its virulence. Instead, isogenic drug resistant strains exhibited a range of virulence. Interestingly, the opposite was seen in the guinea pig infection model. In this model, it was observed that the drug resistant strain of the isogenic pair caused less severe disease and pathology. Drug resistance is not the only cause for concern in the ever continuing tuberculosis epidemic. Many strains that are associated with outbreaks around the world are being classified as either high or low transmission strains. High transmission strains are thought to be associated with increased rates of infections and higher virulence, the latter driving the former. Low transmission strains are the opposite; while they have been known to cause disease the numbers of cases where these strains have been identified appear to be fewer. I examined the virulence and pathogenicity of two strains selected for apparent high versus low transmission patterns, recently seen in a tuberculosis outbreak within the Chinese community of San Francisco, CA, USA that were typed as being W - Beijing strains. My studies did not support the hypothesis that high transmission strains have a higher virulence level

Metronidazole Lacks Antibacterial Activity in Guinea Pigs Infected with Mycobacterium tuberculosis▿

Metronidazole, which is used for the treatment of infections caused by anaerobic organisms, was evaluated in Mycobacterium tuberculosis-infected guinea pigs. M. tuberculosis can adapt to hypoxia, which is present in the primary lesions of infected guinea pigs. Metronidazole treatment (for 6 weeks at 100 mg/kg of body weight) resulted in no reduction in the bacillary burden and significantly worsened lesion inflammation

Activities of TMC207, Rifampin, and Pyrazinamide against Mycobacterium tuberculosis Infection in Guinea Pigs▿

The experimental compound TMC207 is showing promise against infections caused by Mycobacterium tuberculosis both in a variety of animal studies and in the field. In this study, we used the guinea pig model, a species that shows several similarities to human tuberculosis, including the hallmark of primary granuloma necrosis, to determine the efficacy of a combination regimen combining TMC207 with rifampin and pyrazinamide. This drug regimen rapidly reduced the bacterial load in the lungs to undetectable levels by 8 weeks of treatment. This reduction was associated with a substantial improvement in lung pathology, but despite this effect areas of residual necrosis still remained. In the draining lymph nodes, however, tissue damage was rapid and not significantly reversed by the drug treatment. Approximately 10 to 11 months after the treatment had ended, the animals began to trigger a Karnovsky scale indicating bacterial regrowth and potential relapse, an event confirmed by the new development of both pulmonary and extrapulmonary granulomatous lesions. Interestingly, a similar rate of relapse was also seen in animals receiving 24 weeks of rifampin, pyrazinamide, and isoniazid standard chemotherapy. These data indicate that TMC207 could be a useful addition to current treatment regimens for tuberculosis

Evaluation of Standard Chemotherapy in the Guinea Pig Model of Tuberculosis ▿

The purpose of this study was 2-fold. First, we evaluated standard chemotherapy in the guinea pig model of tuberculosis to determine if this animal species could productively be used for this purpose. Second, given the similarities of the pathology of disease in guinea pigs and humans, we wished to evaluate additional parameters, including magnetic resonance imaging, microscopy, and cytokine expression and lymphocyte phenotypes, in response to an infection treated with drug therapy. This study shows that conventional rifampin-isoniazid-pyrazinamide chemotherapy significantly decreased the numbers of the highly virulent Erdman K01 strain of Mycobacterium tuberculosis, with most of the bacilli being eliminated in a month. Despite this result, bacteria could still be detected in the lungs and other tissues for at least another 3 to 4 months. Resolution of the nonnecrotic granulomas in the lungs and lymph nodes could be clearly visualized by magnetic resonance imaging at the macroscopic level. Microscopically, the majority of the pulmonary and extrapulmonary inflammation resolved spontaneously, leaving residual lesions composed of dystrophic calcification and fibrosis marking the site of necrosis of the primary lesion. Residual calcified lesions, which were also associated with pulmonary lymphangitis, contained acid-fast bacilli even following aggressive chemotherapy. The presence of intact extracellular bacilli within these lesions suggests that these could serve as the primary sites of disease reactivation. The chemotherapy reduced the level of T-cell influx into infected tissues and was accompanied by a large and sustained increase in TH1 cytokine expression. Chemotherapy also prevented the emergence in lung tissues of high levels of interleukin-10 and Foxp3-positive cells, known markers of regulatory T cells