Testing of Experimental Compounds in a Relapse Model of Tuberculosis Using Granulocyte-Macrophage Colony-Stimulating Factor Gene-Disrupted Mice

Woolhiser, Lisa K.; Hoff, Donald R.; Marietta, Karen S.; Orme, Ian M.; Lenaerts, Anne J.

doi:10.1128/aac.01346-07

Cited by 7 publications

(7 citation statements)

References 31 publications

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“…The virulent M. tuberculosis strain Erdman (TMC 107; ATCC 35801) was used as the standard strain for drug testing in all animal studies (53). Drug susceptibility testing of the M. tuberculosis Erdman strain used was recently performed for PZA and moxifloxacin at the Mycobacteriology Laboratory at the National Jewish Health, Denver, CO, by Bactec (17,18).…”

Section: Methodsmentioning

confidence: 99%

“…There are various infection protocols based on the route of infection in mice. In the low-dose aerosol (LDA) infection method, reported studies generally aim at expected implantations in lungs of 30 to 100 CFU per mouse (5,6,53), versus 3,000 to 10,000 CFU for high-dose aerosol (HDA) infections (37, 39-41, 45, 47, 51, 52). The LDA method aims for an infection with few bacilli, leading to a chronic infection.…”

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confidence: 99%

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Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosis

Groote

Gilliland

Wells

et al. 2011

Antimicrob Agents Chemother

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Methodologies for preclinical animal model testing of drugs against Mycobacterium tuberculosis vary 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 for in vivo efficacy 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.For the first time in many years, there is a portfolio of promising new compounds at every level of tuberculosis (TB) drug discovery and development (4; www.tballiance.org). However, careful selection of new drug candidates is imperative, and efficient screening models for new drugs, including pertinent animal models, need to be further developed and studied. Preclinical testing in animals of newly discovered agents alone, and in combination with new and old agents, prior to being tested in humans is a crucial but lengthy process. These drug regimens include agents that provide bactericidal activities against rapidly growing bacilli, but they especially aim to include those that possess potent sterilizing activities and hence prevent relapse (8). The most commonly used animal species in TB drug development is the mouse, mainly because of economical and practical reasons, but also because of the limited requirement of compound (26).Various mouse Mycobacterium tuberculosis infection models are utilized by both industry and academia, and they differ in the route of infection with M. tuberculosis, inoculum and strain of M. tuberculosis, strain of mice, timing of the start of treatment after infection, the length of treatment, etc. A model where therapy is started immediately after in...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosis

Groote

Gilliland

Wells

et al. 2011

Antimicrob Agents Chemother

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“…This was confirmed experimentally in a laboratory setting, 21 cured animals having subsequently developed a transient specific antigenic immune response that decreased over time. This transient resistance appears to prevent hematogenous spread of new bacilli and, consequently, a second episode of tuberculosis caused by early exogenous infection.…”

Section: Discussionmentioning

confidence: 64%

Tuberculosis recurrence in a priority city in the state of São Paulo, Brazil

2017

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Objective: To describe cases of tuberculosis recurrence (TBR), stratified by temporal classification (early or late TBR), and to identify possible predictors of such recurrence. Methods:This was an analytical retrospective observational epidemiological study involving a cohort of 963 new cases of pulmonary tuberculosis, reported and treated via the Tuberculosis Control Program in the city of Carapicuíba, Brazil. The study period was from 2000 to 2010. All of the pulmonary tuberculosis patients who successfully completed the treatment (with or without confirmation of cure) were selected and followed until December 31, 2012. Results: Of the 963 cases, TBR occurred in 47 (4.88%). The mean time between the first and second tuberculosis episodes was 36.12 months. Of the 47 TBR cases, 16 (34.04%) occurred within the first 18 months after the completion of the initial treatment (early TBR) and 31 (65.96%) occurred thereafter (late TBR). There were statistically significant differences between the early and late TBR groups only regarding level of education (≤ 3 vs. > 3 years of schooling; p < 0.004) and weight gain at completion of the initial treatment (1.78 kg vs. 5.31 kg; p < 0.045)-not regarding any of the other variables studied. Conclusions: A low level of education might translate to poor treatment adherence, which impedes the killing of bacilli and facilitates their survival in a latent state, making it appear as if the treatment was effective. Minimal or no weight gain at completion of the initial treatment might be a reliable biomarker to be used by health care facilities that provide tuberculosis treatment.

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“…The availability of IFNγ gene-disrupted mice provided a rapidly progressive infection model (66), which had the benefit of substantially reducing the amount of compound needed for evaluation, as well as a rapid readout of effectiveness. Similarly, the highly reproducible reactivation of disease seen in granulocytemacrophage colony-stimulating factor knockout mice allowed the screening of compounds to prevent this (67). More recently, the C3HeB/FeJ mutant mouse model has been used to evaluate drugs in a model of severe lung necrosis (68).…”

Section: Assessment Of New Drugsmentioning

confidence: 99%

Animal Models of Tuberculosis: An Overview

Williams¹,

Orme

2016

Microbiol Spectr

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This article provides an overview of the animal models currently used in tuberculosis research, both for understanding the basic science of the disease process and also for practical issues such as testing new vaccine candidates and evaluating the activity of potential new drugs. Animals range in size, from zebrafish to cattle, and in degrees of similarity to the human disease from both an immunological and pathologic perspective. These models have provided a great wealth of information (impossible to obtain simply from observing infected humans), but we emphasize here that one must use care in interpreting or applying this information, and indeed the true art of animal modeling is in deciding what is pertinent information and what might not be. These ideas are discussed in the context of current approaches in vaccine and drug development, including a discussion of certain limitations the field is currently facing in such studies.

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Testing of Experimental Compounds in a Relapse Model of Tuberculosis Using Granulocyte-Macrophage Colony-Stimulating Factor Gene-Disrupted Mice

Cited by 7 publications

References 31 publications

Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosis

Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosis

Tuberculosis recurrence in a priority city in the state of São Paulo, Brazil

Animal Models of Tuberculosis: An Overview

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