The prevalence of difficult-to-treat infections is increasing worldwide, despite regional variations in the etiological pathogens. This report provides an extensive overview of the use of antibiotics in Brazil and Mexico, with a special focus on complicated hospital-treated infections (HTIs) due to methicillin-resistant Staphylococcus aureus (MRSA) and gram-negative pathogens. Such multi-drug resistant pathogens are becoming increasingly life-threatening and burdensome to local healthcare economies, which are overflowing with generics from a broad range of antibiotic classes. However, governments are keen to regulate the use of antibiotics so that forthcoming multi-drug resistance can be restrained. Healthcare providers struggle to employ more effective and costly antibiotics that address complicated infections caused by resistant pathogens in these cost-constrained markets. Thus, novel antibiotics, such as Actavis/AstraZeneca’s Avycaz, The Medicines Company’s Carbavance, Tetraphase’s eravacycline, and Merck’s Zerbaxa, must overcome stringent clinical and reimbursement challenges.