The discovery of antibiotics marked a golden age in the revolution of human medicine. However, decades later, bacterial infections remain a global healthcare threat, and a return to the pre-antibiotic era seems inevitable if stringent measures are not adopted to curb the rapid emergence and spread of multidrug resistance and the indiscriminate use of antibiotics. In hospital settings, multidrug resistant (MDR) pathogens, including carbapenem-resistant Pseudomonas aeruginosa
, vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus
(MRSA), and extended-spectrum β-lactamases (ESBL) bearing Acinetobacter baumannii
, Escherichia coli
, and Klebsiella pneumoniae
are amongst the most problematic due to the paucity of treatment options, increased hospital stay, and exorbitant medical costs. Antimicrobial peptides (AMPs) provide an excellent potential strategy for combating these threats. Compared to empirical antibiotics, they show low tendency to select for resistance, rapid killing action, broad-spectrum activity, and extraordinary clinical efficacy against several MDR strains. Therefore, this review highlights multidrug resistance among nosocomial bacterial pathogens and its implications and reiterates the importance of AMPs as next-generation antibiotics for combating MDR superbugs.