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Antimicrobial resistance is a serious public health concern across the world. Gram-negative resistance has propagated over the globe via various methods, the most challenging of which include extended-spectrum β-lactamases, carbapenemases, and AmpC enzymes. Gram-negative bacterial infections are difficult to treat in critically extremely sick persons. Resistance to different antibiotic treatments nearly always lowers the probability of proper empirical coverage, sometimes resulting in severe outcomes. Multidrug resistance can be combated with varying degrees of success using a combination of older drugs with high toxicity levels and novel therapeutics. The current therapies for multidrug-resistant Gram-negative bacteria are discussed in this review, which includes innovative medications, older pharmaceuticals, creative combinations of the two, and therapeutic targets.