Antibiotic data for COVID-19 patients (n = 145).

AMR is a growing concern in viral infections, where microbiome shifts contribute to resistance gene dissemination. While dengue and COVID-19, caused by ssRNA viruses, are not bacterial-driven, their resistome and microbial communities influence disease progression and AMR burden. This study analyzes the resistome and microbiome in 251 COVID-19 and 112 dengue patients using non-canonical metatranscriptomics. By mapping antimicrobial resistance genes (ARGs) and their transcriptionally active microbes (TAMs) hosts, we uncover greater ARG burden in COVID-19, particularly during mortality, with a diverse set of associated TAMs compared to dengue. MDR genes were prevalent, with beta-lactamase ARGs commonly detected in both infections. COVID-19 exhibited higher carbapenemase resistance genes (NDM, OXA, VIM), while dengue was associated with TEM variants. Escherichia coli and Klebsiella pneumoniae were dominant ARG hosts, with Acinetobacter baumannii in COVID-19 mortality and Bacillus cereus in severe dengue. These findings highlight resistome dynamics and emphasize the need for AMR surveillance in high-burden infections.