Abstract
Tuberculosis resistant cases have been estimated to grow every year. Besides Mycobacterium tuberculosis, other mycobacterial species are responsible for an increasing number of difficult-to-treat infections. To increase efficacy of pulmonary treatment of mycobacterial infections an inhalable antibiotic powder targeting infected alveolar macrophages (AMs) and including an efflux pump inhibitor was developed. Low molecular weight sodium hyaluronate sub-micron particles were efficiently loaded with rifampicin, isoniazid and verapamil, and transformed in highly respirable microparticles (mean volume diameter: 1 μm) by spray drying. These particles were able to regenerate their original size upon contact with aqueous environment with mechanical stirring or sonication. The in vitro drugs release profile from the powder was characterized by a slow release rate, favorable to maintain a high drug level inside AMs. In vitro antimicrobial activity and ex vivo macrophage infection assays employing susceptible and drug resistant strains were carried out. No significant differences were observed when the powder, which did not compromise the AMs viability after a five-day exposure, was compared to the same formulation without verapamil. However, both preparations achieved more than 80% reduction in bacterial viability irrespective of the drug resistance profile. This approach can be considered appropriate to treat mycobacterial respiratory infections, regardless the level of drug resistance.
Highlights
Tuberculosis (TB), a bacterial infection caused by Mycobacterium tuberculosis (Mtb), is a major communicable disease
The effect of hyaluronic acid sodium salt (HA) concentration and water: ethanol ratio on the HA nanoparticle formation were investigated by turbidimetry
In the present work we have developed and tested a new platform for lung delivery of antibiotics aiming at efficiently treating mycobacterial infections and tackling the multidrug resistance phenomenon
Summary
Tuberculosis (TB), a bacterial infection caused by Mycobacterium tuberculosis (Mtb), is a major communicable disease. According to the World Health Organization (WHO), 10 million new TB cases were estimated in 2017, and 1.3 million people died among HIV-negative people. 9% of all the new cases occurred in HIV infected patients, among which TB is the leading cause of death, especially in Africa. Apart from Mtb, other mycobacterial species are getting a great deal of attention for public health in many geographical regions, as they cause very difficult-to-treat infections in immunocompromised as well as in immunocompetent patients. Lymphadenitis, skin and soft tissue infections are the most common expressions of the disease. Concerning pulmonary infections, nontuberculous mycobacteria (NTM) are, to some extent, similar to Mtb, as they start by infecting macrophages [2]. Whereas Mtb interactions with the immune system have been extensively studied, in particular, with respect to the role played by alveolar macrophages (AMs), limited information about the immune response against NTM is available [3]
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