scholarly journals Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis.

1996 ◽  
Vol 40 (12) ◽  
pp. 2809-2812 ◽  
Author(s):  
B P Kelly ◽  
S K Furney ◽  
M T Jessen ◽  
I M Orme
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Low Dose ◽  
Bacterial Load ◽  
Lung Model ◽  
Exposure Model ◽  
Infection Model ◽  
High Dose ◽  
Level Of Activity ◽  
Days Of Therapy ◽  
Aerosol Infection

As a paradigm for chronic infectious diseases, tuberculosis exhibits a variety of clinical presentations, ranging from primary pulmonary tuberculosis to reactivation tuberculosis and cavitary disease. To date, the animal models used in evaluating chemotherapy of tuberculosis have been high-dose intravenous models that mimic the disseminated forms of the disease. In the present study, we have used a low-dose aerosol exposure model which we feel better reflects newly diagnosed tuberculosis in patients converting to tuberculin positivity. As appropriate examples of chemotherapy, four rifamycins (rifampin, rifabutin, rifapentine, and KRM-1648) were tested, first in an in vitro murine macrophage model and then in the low-dose aerosol infection model, for their activity against Mycobacterium tuberculosis. In both models, KRM-1648 had the highest level of activity of the four compounds. In the infected-lung model, rifabutin, rifapentine, and KRM-1648 all had sterilizing activity when given orally at 5 mg/kg of body weight per day. When given at 2.5 mg/kg/day, KRM-1648 had the highest level of activity of the four drugs, reducing the bacterial load by 2.7 logs over 35 days of therapy.

scholarly journals Effect of Coadministration of Moxifloxacin and Rifampin on Mycobacterium tuberculosis in a Murine Aerosol Infection Model

2012 ◽  
Vol 56 (6) ◽  
pp. 3054-3057 ◽  
Author(s):  
V. Balasubramanian ◽  
S. Solapure ◽  
S. Gaonkar ◽  
K. N. Mahesh Kumar ◽  
R. K. Shandil ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Hollow Fiber ◽  
Lung Model ◽  
Control Group ◽  
Infection Model ◽  
Content Type ◽  
Days Of Therapy ◽  
Cell Kill ◽  
Aerosol Infection

ABSTRACTCoadministration of moxifloxacin and rifampin was evaluated in a murine model ofMycobacterium tuberculosispulmonary infection to determine whether the finding of antagonism documented in a hollow-fiber infection model could be recapitulatedin vivo. Colony counts were followed in a no-treatment control group, groups administered moxifloxacin or rifampin monotherapy, and a group administered a combination of the two agents. Following 18 days of once-daily oral administration to mice infected withM. tuberculosis, there was a reduction in the plasma exposure to rifampin that decreased further when rifampin was coadministered with moxifloxacin. Pharmacodynamic analysis demonstrated a mild antagonistic interaction between moxifloxacin and rifampin with respect to cell kill in the mouse model for tuberculosis (TB). No emergence of resistance was noted over 28 days of therapy, even with monotherapy. This was true even though one of the agents in the combination (moxifloxacin) induces error-prone replication. The previously noted antagonism with respect to cell kill shown in the hollow-fiber infection model was recapitulated in the murine TB lung model, although to a lesser extent.

scholarly journals Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs againstMycobacterium tuberculosis

2010 ◽  
Vol 55 (3) ◽  
pp. 1237-1247 ◽  
Author(s):  
Mary A. De Groote ◽  
Janet C. Gilliland ◽  
Colby L. Wells ◽  
Elizabeth J. Brooks ◽  
Lisa K. Woolhiser ◽  
...  
Keyword(s):  
Mouse Models ◽  
Low Dose ◽  
Drug Regimen ◽  
Drug Combinations ◽  
Infection Model ◽  
High Dose ◽  
Standard Drug ◽  
Experimental Drugs ◽  
Infection Models ◽  
Aerosol Infection

ABSTRACTMethodologies for preclinical animal model testing of drugs againstMycobacterium tuberculosisvary from laboratory to laboratory; however, it is unknown if these variations result in different outcomes. Thus, a series of head-to-head comparisons of drug regimens in three commonly used mouse models (intravenous, a low-dose aerosol, and a high-dose aerosol infection model) and in two strains of mice are reported here. Treatment with standard tuberculosis (TB) drugs resulted in similar efficacies in two mouse species after a low-dose aerosol infection. When comparing the three different infection models, the efficacies in mice of rifampin and pyrazinamide were similar when administered with either isoniazid or moxifloxacin. Relapse studies revealed that the standard drug regimen showed a significantly higher relapse rate than the moxifloxacin-containing regimen. In fact, 4 months of the moxifloxacin-containing combination regimen showed similar relapse rates as 6 months of the standard regimen. The intravenous model showed slower bactericidal killing kinetics with the combination regimens tested and a higher relapse of infection than either aerosol infection models. All three models showed similar outcomes forin vivoefficacy and relapse of infection for the drug combinations tested, regardless of the mouse infection model used. Efficacy data for the drug combinations used also showed similar results, regardless of the formulation used for rifampin or timing of the drugs administered in combination. In all three infection models, the dual combination of rifampin and pyrazinamide was less sterilizing than the standard three-drug regimen, and therefore the results do not support the previously reported antagonism between standard TB agents.

scholarly journals Evaluation of Once-Weekly Therapy for Tuberculosis Using Isoniazid plus Rifamycins in the Mouse Aerosol Infection Model

1998 ◽  
Vol 42 (11) ◽  
pp. 3047-3048 ◽  
Author(s):  
Jason V. Brooks ◽  
Ian M. Orme
Keyword(s):  
Animal Model ◽  
Mycobacterium Tuberculosis ◽  
Low Dose ◽  
Infection Model ◽  
Model Data ◽  
Highly Effective ◽  
Clinical Conditions ◽  
Aerosol Infection ◽  
Weekly Therapy

ABSTRACT Once-weekly therapy with combinations of isoniazid plus a rifamycin was tested in the mouse low-dose aerosol infection model against two strains of Mycobacterium tuberculosis. Combinations of isoniazid and rifalizil and isoniazid and rifapentine were both highly effective. These animal model data thus support the evaluation of these regimens under clinical conditions.

scholarly journals SWR Mice Are Highly Susceptible to Pulmonary Infection with Mycobacterium tuberculosis

2003 ◽  
Vol 71 (9) ◽  
pp. 5266-5272 ◽  
Author(s):  
Oliver C. Turner ◽  
Robert G. Keefe ◽  
Isamu Sugawara ◽  
Hiroyuki Yamada ◽  
Ian M. Orme
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Low Dose ◽  
Pulmonary Infection ◽  
Inflammatory Cell ◽  
Inbred Mice ◽  
Bacterial Load ◽  
Lower Percentage ◽  
Effector Memory ◽  
Aerosol Infection ◽  
Lung Surface Area

ABSTRACT Inbred mice differ in their abilities to control the growth of Mycobacterium tuberculosis in the lung and can as a result be regarded as either resistant or susceptible strains. In this study we report that the SWR mouse is both highly susceptible and in addition appears incapable of establishing a characteristic state of chronic disease after low-dose aerosol infection. In comparison to C57BL/6 mice, SWR mice were unable to contain the bacterial load in the lungs, resulting in progressive fatal disease. Histologic analysis of the lung tissue revealed evidence of a florid inflammatory cell response in the SWR mice leading to degeneration and necrosis and consolidation of a large percentage of the lung surface area. Digestion of infected lungs and analysis by flow cytometry demonstrated an initially similar but eventually higher number of lymphocytes accumulating in the SWR mice. Additionally, in contrast to the C57BL/6 mice, SWR mice had a significantly lower percentage of CD4 T cells in the lungs showing evidence of proliferation and positive intracellular staining for gamma interferon during the first two months of infection, and a lower percentage of both CD4 and CD8T cells exhibiting differentiation to an effector/memory phenotype during the first month of infection. We propose that further investigation of the SWR mouse may provide a new animal model for immunocompetent individuals apparently unable to effectively control the growth of M. tuberculosis in the lung.

scholarly journals Expression of the Nitric Oxide Synthase 2 Gene Is Not Essential for Early Control of Mycobacterium tuberculosis in the Murine Lung

2000 ◽  
Vol 68 (12) ◽  
pp. 6879-6882 ◽  
Author(s):  
Andrea M. Cooper ◽  
John E. Pearl ◽  
Jason V. Brooks ◽  
Stefan Ehlers ◽  
Ian M. Orme
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Nitric Oxide Synthase ◽  
Low Dose ◽  
Interleukin 12 ◽  
Infection Model ◽  
Rapid Progression ◽  
Ifn Γ ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

ABSTRACT The interleukin-12 and gamma interferon (IFN-γ) pathway of macrophage activation plays a pivotal role in controlling tuberculosis. In the murine model, the generation of supplementary nitric oxide by the induction of the nitric oxide synthase 2 (NOS2) gene product is considered the principal antimicrobial mechanism of IFN-γ-activated macrophages. Using a low-dose aerosol-mediated infection model in the mouse, we have investigated the role of nitric oxide in controllingMycobacterium tuberculosis in the lung. In contrast to the consequences of a systemic infection, a low dose of bacteria introduced directly into the lungs of mice lacking the NOS2 gene is controlled almost as well as in intact animals. This is in contrast to the rapid progression of disease in mice lacking IFN-γ or a key member of the IFN signaling pathway, interferon regulatory factor 1. Thus while IFN-γ is pivotal in early control of bacterial growth in the lung, this control does not completely depend upon the expression of the NOS2 gene. The absence of inducible nitric oxide in the lung does, however, result in increased polymorphonuclear cell involvement and eventual necrosis in the pulmonary granulomas of the infected mice lacking the NOS2 gene.

Calcitriol Exerts Prophylactic Anti-Mycobacterium Effect In A Dose-Dependent Manner

2021 ◽  
Author(s):  
Jianguo Li ◽  
Zhen Li ◽  
Zefeng Gao ◽  
Juan Xia ◽  
Jia Cui ◽  
...  
Keyword(s):  
Vitamin D ◽  
1H Nmr ◽  
Low Dose ◽  
Bacterial Load ◽  
High Dose ◽  
Dependent Manner ◽  
Prophylactic Effect ◽  
Moderate Dose ◽  
Metabolism Pathway ◽  
Dose Dependent

Abstract Vitamin D was empirically applied for Tuberculosis (TB) treatment in the past, and is currently used as an adjuvant for TB therapy. Although an increasing pile of evidences suggests that vitamin D has no therapeutic effect against TB infection, the prophylactic effect of vitamin D in preventing TB remains largely undetermined. To experimentally valuate the potential prophylactic effect of calcitriol (the active form of vitamin D) against mycobacterium infection, we performed dose-gradient calcitriol soaking in 30-day-old zebrafish before Mycobacterium marinum (M. marinum) challenge through tail vein injection. 1H-NMR metabolomics analysis was further performed for illustration of potential mechanisms underlying the prophylactic effect of calcitriol against M. marinum. The results suggested that calcitriol exerts dose-dependent prophylactic anti-mycobacterium effects, i.e., the bacterial load and the corresponding inflammatory factors (IL-1β, TNF-α, and IFN-γ) expressions in M. marinum challenged zebrafish were reduced by low-dose (25 µg/L) or high-dose (2500 µg/L) calcitriol soaking, rather than by moderate-dose (250 µg/L) calcitriol soaking. Body weight of the M. marinum challenged zebrafish was recovered by high-dose prophylactic calcitriol soaking rather than by low-dose or moderate-dose calcitriol. The 1H-NMR metabolomic profiling identified 29 metabolites with altered abundance among the dose-gradient calcitriol groups, among which 22 metabolites were co-varied with the dose of calcitriol, the rest 7 metabolites were co-varied with the bacterial load and the inflammatory response in term of cytokine expression. Further pathway analysis indicated that the glycine, serine, and threonine metabolism pathway was the activated in both of the two metabolite groups, indicating that the pathway was altered by dose-gradient of calcitriol and was in response to M. marinum infection in zebrafish. The results of the present study suggested that the activation of glycine, serine and threonine metabolism pathway may play a potential role for the dose-dependent anti-mycobacterium effect induced by prophylactic calcitriol soaking.

scholarly journals Ultra-low Dose Aerosol Infection of Mice with Mycobacterium tuberculosis More Closely Models Human Tuberculosis

2020 ◽  
Author(s):  
Courtney R. Plumlee ◽  
Fergal J. Duffy ◽  
Benjamin H. Gern ◽  
Jared L. Delahaye ◽  
Sara B. Cohen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Low Dose ◽  
Aerosol Infection

scholarly journals Mycobacterial Antigens Exacerbate Disease Manifestations in Mycobacterium tuberculosis-Infected Mice

2002 ◽  
Vol 70 (4) ◽  
pp. 2100-2107 ◽  
Author(s):  
Andre L. Moreira ◽  
Liana Tsenova ◽  
Melles Haile Aman ◽  
Linda-Gail Bekker ◽  
Sherry Freeman ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Pulmonary Disease ◽  
Bacterial Load ◽  
Subcutaneous Administration ◽  
Mycobacterial Antigen ◽  
Lung Pathology ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Aerosol Infection ◽  
Mycobacterial Antigens

ABSTRACT To control tuberculosis worldwide, the burden of adult pulmonary disease must be reduced. Although widely used, Mycobacterium bovis BCG vaccination given at birth does not protect against adult pulmonary disease. Therefore, postexposure vaccination of adults with mycobacterial antigens is being considered. We examined the effect of various mycobacterial antigens on mice with prior M. tuberculosis infection. Subcutaneous administration of live or heat-treated BCG with or without lipid adjuvants to infected mice induced increased antigen-specific T-cell proliferation but did not reduce the bacterial load in the lungs and caused larger lung granulomas. Similarly, additional mycobacterial antigen delivered directly to the lungs by aerosol infection with viable M. tuberculosis mixed with heat-killed Mycobacterium tuberculosis (1:1) also did not reduce the bacillary load but caused increased expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), which was associated with larger granulomas in the lungs. When M. tuberculosis-infected mice were treated with recombinant BCG that secreted cytokines shown to reduce disease in a preinfection vaccine model, the BCG secreting TNF-α, and to a lesser extent, IL-2 and gamma interferon (IFN-γ), caused a significant increase in granuloma size in the lungs. Moreover, treatment of M. tuberculosis-infected mice with recombinant murine TNF-α resulted in increased inflammation in the lungs and accelerated mortality without affecting the bacillary load. Taken together, these studies suggest that administration of mycobacterial antigens to mice with prior M. tuberculosis infection leads to immune activation that may exacerbate lung pathology via TNF-α-induced inflammation without reducing the bacillary load.

scholarly journals Mycobacterium tuberculosis in Chemokine Receptor 2-Deficient Mice: Influence of Dose on Disease Progression

2002 ◽  
Vol 70 (11) ◽  
pp. 5946-5954 ◽  
Author(s):  
Holly M. Scott ◽  
JoAnne L. Flynn
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Cell Migration ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Low Dose ◽  
High Dose ◽  
Long Term Effects ◽  
Spread Of Infection ◽  
Oxide Synthase

ABSTRACT Within a Mycobacterium tuberculosis-induced granuloma, lymphocytes and macrophages work together to control bacterial growth and limit the spread of infection. Chemokines and chemokine receptors are involved in cell migration and are logical candidates for a role in granuloma formation. In the present study we addressed the role of CC chemokine receptor 2 (CCR2) in M. tuberculosis infection. In previous studies (W. Peters et al., Proc. Natl. Acad. Sci. USA 98:7958-7963, 2001), CCR2−/− mice were found to be highly susceptible to a moderate or high dose of H37Rv administered intravenously (i.v.). We have expanded those studies to demonstrate that the susceptibility of CCR2−/− mice is dose dependent. After low-dose aerosol or i.v. infection of CCR2−/− mice with M. tuberculosis, there was a substantial delay in cell migration to the lungs and delayed expression of gamma interferon and inducible nitric oxide synthase. The CCR2−/− mice had a severe and prolonged deficiency in the number of macrophages in the lungs and an early increase in the number of neutrophils. Despite these deficiencies in cell migration, the CCR2−/− mice did not have increased bacterial loads in the lungs compared to wild-type (C57BL/6) mice and successfully formed granulomas. This finding is in contrast to CCR2−/− mice infected with a high dose of M. tuberculosis administered i.v. These results indicate that with low-dose infection, a delay in immune response in the lungs does not necessarily have detrimental long-term effects on the progression of the disease. The fact that CCR2−/− mice survive with substantially fewer macrophages in the low-dose models implies that the immune response to low-dose M. tuberculosis infection in mice is more robust than necessary to control the infection. Finally, these data demonstrate that, in cases of infectious disease in knockout models, clear phenotypes may not be evident when one is solely evaluating bacterial numbers and survival. Functional assays may be necessary to reveal roles for components of the multifactorial immune system.

scholarly journals Examination of Mycobacterium tuberculosis sigma factor mutants using low-dose aerosol infection of guinea pigs suggests a role for SigC in pathogenesis

Microbiology ◽  
2006 ◽  
Vol 152 (6) ◽  
pp. 1591-1600 ◽  
Author(s):  
Russell K. Karls ◽  
Jeannette Guarner ◽  
David N. McMurray ◽  
Kristin A. Birkness ◽  
Frederick D. Quinn
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Sigma Factor ◽  
Guinea Pigs ◽  
Low Dose ◽  
Sigma Factors ◽  
Respiratory Pathogen ◽  
Growth Deficiency ◽  
Aerosol Infection

Secondary sigma factors in bacteria direct transcription of defence regulons in response to specific stresses. To identify which sigma factors in the human respiratory pathogen Mycobacterium tuberculosis are important for adaptive survival in vivo, defined null mutations were created in individual sigma factor genes. In this study, in vitro growth virulence and guinea pig pathology of M. tuberculosis mutants lacking functional sigma factors (SigC, SigF, or SigM) were compared to the parent strain, H37Rv. None of the mutant strains exhibited a growth deficiency in Middlebrook 7H9 broth, nor were any impaired for intracellular replication in the human monocytic macrophage cell-line THP-1. Following low-dose aerosol infection of guinea pigs, however, differences could be detected. While a SigM mutant resulted in lung and spleen granulomas of comparable composition to those found in H37Rv-infected animals, a SigF mutant was partially attenuated, exhibiting necrotic spleen granulomas and ill-defined lung granulomas. SigC mutants exhibited attenuation in the lung and spleen; notably, necrotic granulomas were absent. These data suggest that while SigF may be important for survival in the lung, SigC is likely a key regulator of pathogenesis and adaptive survival in the lung and spleen. Understanding how SigC mediates survival in the host should prove useful in the development of anti-tuberculosis therapies.

Sign in / Sign up

Export Citation Format

Share Document