Evaluation of Azithromycin-Bicarbonate against Multidrug-Resistant Pathogens in Topical Murine Models of Infection

Abstract

Multidrug-resistant pulmonary infections pose significant therapeutic challenges as treatment options continue to dwindle in the face of rising antimicrobial resistance. Similar challenges arise in the management of wound infections such as those resulting from burn and blast injuries, where resistant pathogens severely limit treatment options. These wounds are further complicated by high microbial loads that exacerbate tissue damage, delay healing, and increase the risk of systemic infection. The escalating threat of antimicrobial resistance highlights the urgent need for innovative therapeutic strategies. This study evaluates the therapeutic potential of a novel topical formulation, azithromycin-bicarbonate (AZM-BIC), for addressing drug-resistant infections in both pulmonary and wound settings. Using murine models of infection in bicarbonate-depleted environments, including lung, blast injury, and burn wound models, topical administration of AZM-BIC enabled the localized delivery of therapeutic concentrations of bicarbonate. In the pulmonary model, AZM-BIC significantly reduced the bacterial burden. In vitro and ex vivo studies revealed AZM-BIC's ability to inhibit biofilm formation, a critical factor in managing chronic infections. In wound infection models, AZM-BIC reduced the bacterial burden and enhanced wound healing. These findings establish AZM-BIC as a promising therapeutic approach, offering a targeted, effective solution for pulmonary infection management and wound care amid the growing threat of antimicrobial resistance. Furthermore, given that azithromycin is a well-established antibiotic and bicarbonate is a physiological component that is safe and well-tolerated, AZM-BIC represents a readily translatable strategy for clinical implementation.

Keywords: azithromycin-bicarbonate; biofilm formation; mortality; multidrug-resistant pathogen; murine lung infection; pathogens.