Abstract by Junwei Wang

Lower respiratory tract infections are a widespread health issue since it is associated with a variety of lung diseases. The increasing cases of multidrug-resistant (MDR) bacteria and the lack of new antibiotics make lower respiratory tract infections even challenging to treat. The antibiotic combination is regarded as a resort to treat severe infections caused by MDR pathogens since it can afford an enhanced antibacterial effect and reduced resistance development. In addition, the delivery of antibiotics to the lung is considered to be an efficient means to combat lower respiratory tract infections because the antibiotics can be directly applied to the site of infection. Compared to oral and parenteral administration routes, pulmonary administration of antibiotics shows the potential to reduce the dose required and diminish systemic side effects.

This PhD project aims to explore formulation strategies to design inhalable dry powder formulations with improved antibacterial activity to treat lower respiratory tract infections. In the first part of this PhD project, the relationship between dissolution rate and antibacterial efficacy of thiamphenicol (TAP), a poorly water-soluble antibiotic, was investigated, after TAP was micronized into micro and nano ranges particles with the same crystalline form. A dissolution-efficacy model was established to describe the relationship between the antibacterial efficacy and dissolution rate of TAP, which revealed that the in vitro bacteria-killing effect of TAP was increased with an increase in the dissolution rate. The relationship between the dissolution rate and the in vitro bacteria-killing effect of TAP became less apparent when TAP concentration exceeded a certain level. It implies that the improvement of the dissolution rate might be a critical formulation strategy to reduce failure treatment risk caused by insufficient doses.

Antibiotic combinations with synergistic effects are thought to afford superior killing efficacy against MDR pathogens over mono-therapy. However, there is no inhalable antibiotic combination formulation available on the market. In the second part of this PhD project, it was attempted to formulate a combination of aztreonam (Azt) and tobramycin (Tob) into a fixed-dose inhalable dry powder formulation, which exhibited a synergistic effect against MDR P. aeruginosa and A. baumannii. The addition of L-leucine to the fixed-dose dry powder formulations could largely improve their aerodynamic performance and physical stability, which did not compromise the in vitro bacteria-killing effect against those MDR pathogens.

In the third part of this PhD project, a dry powder formulation consisted of a combination of ciprofloxacin (CIP) and polymyxin B (PMB) was attempted to combat MDR A. baumannii, a “superbug”. This fixed-dose dry powder combination exhibited adequate aerosol performance and an improved bacteria-killing effect against resistance A. baumannii compared to CIP or PMB used alone. Moreover, the combination of CIP and PMB exerted a superior suppression of the bacteria’s resistance evolution over the mono-treatment of PMB and CIP.

This thesis demonstrates that the dissolution rate is an important factor influencing the antibacterial effect of poorly water-soluble antibiotics when formulating inhalable antibiotic dry powders. Fixed-dose antibiotic combinations formulated into a dry powder for inhalation may retain the synergistic effect as the drug pairs in a liquid form. Enhanced antibacterial activity and inhibition on resistance development could be achieved simultaneously via the rational selection of antibiotic combination pairs and formulating them into inhalable dry powders.