Aerosol Infection Model of Tuberculosis in Wistar Rats

Abstract

We explored suitability of a rat tuberculosis aerosol infection model for investigating the pharmacodynamics of new antimycobacterial agents. Infection of rats via the aerosol route led to a reproducible course of M. tuberculosis infection in the lungs. The pulmonary bacterial load increased logarithmically during the first six weeks, thereafter, the infection stabilized for the next 12 weeks. We observed macroscopically visible granulomas in the lungs with demonstrable acid-fast bacilli and associated histopathology. Rifampicin (RIF) at a dose range of 30 to 270 mg/kg exhibited a sharp dose response while isoniazid (INH) at a dose range of 10 to 90 mg/kg and ethambutol (EMB) at 100 to 1000 mg/kg showed shallow dose responses. Pyrazinamide (PZA) had no dose response between 300 and 1000 mg/kg dose range. In a separate time kill study at fixed drug doses (RIF 90 mg/kg, INH 30 mg/kg, EMB 300 mg/kg, and PZA 300 mg/kg) the bactericidal effect of all the four drugs increased with longer duration of treatment from two weeks to four weeks. The observed infection profile and therapeutic outcomes in this rat model suggest that it can be used as an additional, pharmacologically relevant efficacy model to develop novel antitubercular compounds at the interface of discovery and development.

1,4-Azaindole, a Potential Drug Candidate for Treatment of Tuberculosis

“…The 1,4-azaindole series was identified by a scaffold morphing approach as described previously (15). The potency of these compounds against M. tuberculosis was mainly improved through the MICbased SAR with three points of diversification (amide side chain, a hydrophobic group, and core ring substitutions).…”

“…Methods used for determining the pharmacokinetics (PK) in mice and rats after intravenous (IVPK) and/or oral administration (POPK) of the drug and the in vivo efficacy in mouse and rat models of aerosol infection with TB were described earlier (11,15). In these models, treatment was initiated after 4 weeks of infection, and the total duration of treatment was 4 weeks (6 days/week).…”

One Size Fits All? Not in In Vivo Modeling of Tuberculosis Chemotherapeutics

“…In the search for an ideal TB model, investigators continue to test other animal species as models for TB and TB chemotherapy including various rats, the minipig, and the Chinese tree shrew among others ( Sugawara et al., 2004 ; Elwood et al., 2007 ; Gaonkar et al., 2010 ; Gil et al., 2010 ; Zhan et al., 2014 ). Of these, the Wistar rat is perhaps the most well characterized, because it is a common species used for PK/PD characterization and toxicity assessment of potential therapeutics, and it would be more economical to be able to use the same species for drug efficacy studies ( Gaonkar et al., 2010 ; Singhal et al., 2011 ; Foo et al., 2011 ; Ramani et al., 2012 ; Kondreddi et al., 2013 ; Kumar et al., 2014 ).…”

“…In the search for an ideal TB model, investigators continue to test other animal species as models for TB and TB chemotherapy including various rats, the minipig, and the Chinese tree shrew among others ( Sugawara et al., 2004 ; Elwood et al., 2007 ; Gaonkar et al., 2010 ; Gil et al., 2010 ; Zhan et al., 2014 ). Of these, the Wistar rat is perhaps the most well characterized, because it is a common species used for PK/PD characterization and toxicity assessment of potential therapeutics, and it would be more economical to be able to use the same species for drug efficacy studies ( Gaonkar et al., 2010 ; Singhal et al., 2011 ; Foo et al., 2011 ; Ramani et al., 2012 ; Kondreddi et al., 2013 ; Kumar et al., 2014 ). The Wistar rat and Lewis rats lacked lesions with central necrosis when infected with the Mtb strains chosen by the investigators, but the two species of Cotton rat developed necrotic lesions and higher bacterial loads despite being exposed to a low dose of Mtb H37Rv ( Sugawara et al., 2004 ; Swaim et al., 2006 ; Elwood et al., 2007 ; Singhal et al., 2011 ).…”

The current state of animal models and genomic approaches towards identifying and validating molecular determinants ofMycobacterium tuberculosisinfection and tuberculosis disease

“…Rats have been used successfully as an animal model for testing drug efficacy (Gaonkar et al . 2010; Foo et al . 2011) and antigen-specific T cell responses (Cardona et al .…”