Mouse Model for Efficacy Testing of Antituberculosis Agents via Intrapulmonary Delivery

Abstract

Here we describe an experimental murine model that allows for aerosolized antituberculosis drug efficacy testing. Intrapulmonary aerosol delivery of isoniazid, capreomycin, and amikacin to mice with pulmonary infection of Mycobacterium tuberculosis demonstrated efficacy in reducing pulmonary bacterial loads similar to that seen by standard drug delivery methods, even when lower concentrations of drugs and fewer doses were used in the aerosolized drug regimens. Interestingly, intrapulmonary delivery of isoniazid also reduced the bacterial load in the spleen.T uberculosis (TB) is a chronic infectious disease with increasing incidence of drug resistance. Patients with drug-susceptible TB receive 6 to 9 months of combination drug treatment consisting of isoniazid (INH), rifampin (RIF), pyrazinamide, and ethambutol by the oral route for 2 months followed by INH and RIF for another 4 to 6 months. For patients with multidrug-resistant tuberculosis (MDR-TB) infection, current guidelines still recommend prolonged (up to 2 years) therapy using second-line TB drugs. Of the second-line drugs, parenterally administered antimicrobials of initial choice are amikacin, kanamycin, and capreomycin (1). The optimal duration for the treatment of MDR-TB with injectable agents is not known, and treatment with these agents is associated with substantial toxicity. New drugs that have the potential to shorten therapy, can be easily administered, and have low toxicity would be a great advance in TB drug development. An alternative approach is to use an aerosolized method to deliver high concentrations of anti-TB drugs locally to the site of the infection. Aerosolized drugs, unlike injectable agents, are easy to administer and provide higher concentrations at the local site of infection, thereby reducing systemic levels of exposure to the drug (4, 10-12, 14, 21). There have been several attempts to deliver aerosols of anti-TB drugs using microparticles, dry powder, and nebulized forms of drugs, but these approaches are also subject to inherent problems with formulation and delivery of the carrier vehicle (8,9,11,13,20,(22)(23)(24)(25). An experimental murine model that utilizes intrapulmonary aerosol delivery of drugs and allows for local pulmonary administration of anti-TB drugs and efficacy testing will facilitate the development of new agents for anti-TB aerosol drug delivery. In addition, the murine model could be a tool for early experimental compounds with limited oral bioavailability to obtain an in vivo proof of concept, especially for natural product compounds (with high molecular weights) or those of peptide origin.These studies compare the efficacies of commonly used anti-TB drugs when delivered by intrapulmonary aerosol delivery, oral administration, or the subcutaneous injection route using a lowdose aerosol infection of Mycobacterium tuberculosis in an immunocompetent murine model. INH, an orally administered drug, and the parenteral anti-TB drugs capreomycin and amikacin were chosen to validate the efficacy of intrapulmonary...

The Activity of a Hexameric M17 Metallo-Aminopeptidase Is Associated With Survival of Mycobacterium tuberculosis

“…Otherwise, urinary elimination is slower in humans (Ueda et al, 1994). Moreover, intrapulmonary delivery of isoniazid, capreomycin, or amikacin to mice has resulted in a better reduction of pulmonary mycobacterial loads than that seen by standard drug delivery methods when lower concentrations of drugs and fewer doses have been used (Gonzalez-Juarrero et al, 2012; Pham et al, 2015). Thus, in our study, intranasal administration of bestatin may have extended drug effects in the lungs, the main TB target organ, bypassing the problem of its rapid urinary elimination and thus showing efficacy to reduce M. tuberculosis loads in mice lungs.…”

Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents

“…In addition, we did note that two MtB‐active HPs do not have the 2‐position halogenated, which is likely offset by the chlorine atoms in the 6‐ and 7‐position(s). Multiple animal models can determine the efficacy of investigational drugs for MtB infections, including lung‐infection models that deliver test compounds via aerosolized formulations . Collectively, HPs could serve as great starting points for new treatment options against persistent MtB infections.…”

“…Multiple animal modelsc an determine the efficacy of investigational drugs for MtB infections, [126] including lung-infection models that deliver test compounds via aerosolized formulations. [127,128] Collectively,H Ps could serve as great starting points for new treatment options against persistent MtB infections. Figure 10.…”

Computational pharmacokinetics/pharmacodynamics of rifampin in a mouse tuberculosis infection model

“…PBPK modeling is becoming established in drug development through it’s increasing use for in vitro in vivo extrapolation and interspecies scaling [45]. Additionally, the physiologically based framework described here contains basic modeling elements for novel anti-TB drug therapies such as those related to host-directed adjunct therapies [46] and alternate routes of administration [47]. …”