Secondary bacterial infections, including ventilator associated pneumonia (VAP), lead to worse clinical outcomes and increased mortality following viral respiratory infections . Critically ill patients with coronavirus disease 2019 (COVID-19) face an elevated risk of VAP, although susceptibility varies widely . Because mechanisms underlying VAP predisposition remained unknown, we assessed lower respiratory tract host immune responses and microbiome dynamics in 36 patients, including 28 COVID-19 patients , 15 of whom developed VAP, and eight critically ill controls . We employed a combination of tracheal aspirate bulk and single cell RNA sequencing (scRNA-seq). Two days before VAP onset, a lower respiratory transcriptional signature of bacterial infection was observed, characterized by increased expression of neutrophil degranulation, toll-like receptor and cytokine signaling pathways . When assessed at an earlier time point following endotracheal intubation, more than two weeks prior to VAP onset, we observed a striking early impairment in antibacterial innate and adaptive immune signaling that markedly differed from COVID-19 patients who did not develop VAP . scRNA-seq further demonstrated suppressed immune signaling across monocytes/macrophages, neutrophils and T cells . While viral load did not differ at an early post-intubation timepoint, impaired SARS-CoV-2 clearance and persistent interferon signaling characterized the patients who later developed VAP . Longitudinal metatranscriptomic analysis revealed disruption of lung microbiome community composition in patients who developed VAP, providing a connection between dysregulated immune signaling and outgrowth of opportunistic pathogens . Together, these findings demonstrate that COVID-19 patients who develop VAP have impaired antibacterial immune defense weeks before secondary infection onset.