Antimicrobial resistance is one of the greatest threats to human health worldwide. The rate of development of newer antibiotics is much slower than the rate of development of antibiotic resistance. A survey reported that it takes 15 years and US$800 million (including preclinical and clinical costs) to bring a single drug to the market, whereas the reuse of the older drugs for antimicrobial use takes $17 million, thereby circumventing 40% of the overall cost. The first case is a patient with nosocomial pyrexia of unknown origin who was given treatment with tigecycline and cefepime/tazobactam but failed to respond to the same. However, the patient responded to the treatment with cotrimoxazole. The second case is a patient with meningitis caused by an atypical zoonotic pathogen, Staphylococcus chromogenes. This is the first report of human infection with S. chromogenes, this being a common cause of bovine mastitis. The isolate was obtained from a patient of neurotrauma who developed meningitis after decompressive craniotomy. The strain was obtained from cerebrospinal fluid, blood, and shunt chamber pus. Cotrimoxazole was given for the treatment, and the patient improved after the treatment. Although the newer antibiotics have replaced sulfonamides in the treatment of many infections, they are still of great value and are the agents of choice in many infections. Sulfonamides have wide antimicrobial activity against both Gram-positive and Gram-negative bacteria, but their usefulness has diminished with the emergence of resistant strains. This paper reports cases of two different kinds of infections from a level 1 trauma center, who failed to respond to the newer antibiotics but showed a response to administration of cotrimoxazole.