Formulation Design Dictates the Pulmonary Delivery and Antimicrobial Efficacy of Clofazimine−Amikacin Combinations against Mycobacterium abscessus

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Abstract Intracellular infections impose fundamental physicochemical barriers that can disrupt antibiotic synergy observed under well-mixed in vitro conditions. Mycobacterium abscessus, a macrophage-resident pathogen, exemplifies this challenge, as co-administered drugs must traverse multiple membrane barriers and achieve coordinated intracellular exposure. The combination of clofazimine (CFZ) and amikacin (AMK) exhibits robust, time-dependent synergy in broth, yet their divergent physicochemical properties (lipophilic versus hydrophilic) predict differential intracellular access. Here, we evaluated whether formulation architecture can mitigate this spatial and temporal separation. CFZ and AMK were engineered either as physical mixtures of micronized powders or as spray-dried composite particles across multiple drug ratios and compared in terms of aerosol performance and intracellular efficacy in a THP-1 macrophage infection model. Neither drug alone achieved meaningful intracellular killing despite activity in broth. In contrast, combination efficacy was strongly formulation-dependent and exhibited a non-monotonic relationship with composition. Physical mixtures were most effective at CFZ-rich ratios, whereas spray-dried composites achieved superior killing at an intermediate mass ratio (1:4 CFZ/AMK) and displayed a delayed-onset kinetic profile consistent with architecture-dependent temporal drug availability. Aerosol studies showed that composite particles generally improved dispersibility and reduced bulk aerodynamic fractionation between the two drugs relative to physical mixtures, although this effect was condition-dependent. Together, these findings indicate that intracellular efficacy is governed not solely by drug identity or dose, but by formulation-controlled spatial and temporal drug presentation. This work establishes formulation architecture as a critical design variable for translating antibiotic synergy into biologically constrained environments.

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