While new generations of existing classes of antibiotics have predominated pipelines, novel nonantibiotic approaches such as antitoxins are gradually taking a more prominent position to address today’s most challenging issues in the field, notably the threatening rise of resistant strains and the unacceptably high rates of treatment failure and mortality despite the best of care. This review presents the clinical stage broad-spectrum antitoxin agent CAL02, which is active against both gram-positive and gram-negative bacteria including ESKAPE pathogens. CAL02 neutralizes bacterial pore-forming toxins, enzymes, and toxin-effector virulent appendages that play a vital and upstream role in pathogenic processes responsible for the progress and severity of infections such as severe pneumonia, bacteremia, and sepsis. The present overview underlines how combination therapies with antimicrobial agents operating in synergy with antibiotics, via unprecedented mechanisms of action, hold promise to dramatically improve standard of care and overturn the morbidity and mortality associated with resistant pathogens. The concerted efforts of academia, industry, clinicians, and regulatory agencies are contributing to a more accurate understanding of the various nontraditional approaches in development. Novel antitoxin treatments help reshape the antibiotic-driven set of mind.