Antibiotics were firstly used for the treatment of critical infections in the 1940s. They could save patients’ lives and increased life spans by improving the outcome of serious infections. Antibiotics are the most commonly used drugs in a healthcare environment. However, antibiotics are not correctly prescribed, due to improper antibiotic selection, not suitable dosing, inappropriate treatment duration, and wrong treatment in nonbacterial conditions. Consequently, the rapid emergence of resistant bacteria occurs worldwide because they could adapt and compete with environmental stress. There are 4 primary mechanisms of resistance to counter the antibiotics: (i) modification of the target, (ii) enzymatic inhibition of the antibiotics, (iii) active efflux of the antibiotics, and (iv) changing membrane permeability. Carbapenem-resistant Pseudomonas aeruginosa (CR-PA), CR Acinetobacter baumannii (CR-AB), and CR Enterobacteriaceae were declared by World Health Organization (WHO) as the three most important pathogens that pose the greatest threat to human health. Moreover, they are also multidrug-resistant (MDR) and usually resist almost all of the most effective antibiotics, including carbapenem and fourthgeneration cephalosporin. There is an urgent need to develop new strategies to combat antibiotic resistance and preserve the existing antibiotics. Numerous approaches, including host-directed, antibiotic-adjuvant combination, and antibiotic-antibiotic combination therapy, have been put forward to bring about antibiotic efficacy against MDR pathogens.