The devil's advocacy: when and why inhaled therapies for tuberculosis may not work.

Factors that are inimical to the success of inhaled therapies for tuberculosis (TB) include: (i) lack of access of inhaled therapies to poorly-aerated areas of the tubercular lung; (ii) limited ability to penetrate biofilms formed by extracellular bacilli; (iii) selection for resistant bacilli on account of administration of low doses of anti-TB agents; (iv) induction of inflammation and/or immunopathology in the airways and lungs; and (v) anomalies in antigen processing and presentation of vaccines delivered to the lungs. Further, the claim that inhaled therapies rescue alternatively-activated macrophages may not be applicable to all individuals. Fortunately, there are ways and means to address each of the above factors.