Antibiotic failure: Beyond antimicrobial resistance.

Despite significant progress in antibiotic discovery, millions of lives are lost annually to infections. Surprisingly, the failure of antimicrobial treatments to effectively eliminate pathogens frequently cannot be attributed to genetically-encoded antibiotic resistance. This review aims to shed light on the fundamental mechanisms contributing to clinical scenarios where antimicrobial therapies are ineffective (i.e., antibiotic failure), emphasizing critical factors impacting this under-recognized issue. Explored aspects include biofilm formation and sepsis, as well as the underlying microbiome. Therapeutic strategies beyond antibiotics, are examined to address the dimensions and resolution of antibiotic failure, actively contributing to this persistent but escalating crisis. We discuss the clinical relevance of antibiotic failure beyond resistance, limited availability of therapies, potential of new antibiotics to be ineffective, and the urgent need for novel anti-infectives or host-directed therapies directly addressing antibiotic failure. Particularly noteworthy is multidrug adaptive resistance in biofilms that represent 65 % of infections, due to the lack of approved therapies. Sepsis, responsible for 19.7 % of all deaths (as well as severe COVID-19 deaths), is a further manifestation of this issue, since antibiotics are the primary frontline therapy, and yet 23 % of patients succumb to this condition.