To combat the global challenge of antimicrobial resistance, many different strategies are required. In an attempt to reserve antibiotics such as meropenem, clinical studies have been conducted to examine patient outcomes with alternative antibiotics, such as piperacillin-tazobactam. However, the need to study the relative effects of these antibiotics on the gut microbiome has been identified, given the gut microbiome serves as a reservoir for antimicrobial resistance and pathogenic organisms. We used a shotgun metagenomics approach to study the effects of antibiotics on the gut microbiome in critically ill patients, with a focus on meropenem and piperacillin-tazobactam. Our research examined the gut microbiome alteration between samples collected at baseline and following antibiotics within individuals and between different groups. The impact of different antibiotics on the alpha- and beta-diversity, and the selective pressure for Clostridioides difficile, Candida species and certain ESKAPE pathogens, as well as antimicrobial resistance genes was demonstrated. Interindividual variation highlighted the need for gut microbiome monitoring as part of personalised medicine and antimicrobial stewardship strategies.