ObjectiveTo investigate the predominant pathogen distribution in malignant pleural effusion (MPE) complicated by pleural infection and analyze the antimicrobial resistance, thereby providing data support for the empirical use of antibiotics in clinical practice. MethodsClinical data from patients with MPE at the Second Affiliated Hospital of Harbin Medical University between January 2021 and September 2024 were collected and analyzed to identify common pathogens and their antimicrobial resistance in MPE-associated infections. ResultsRetrospective analysis included 240 patients, with 120 cases being pathogen-positive and 120 pathogen-negative. Among the pathogen-positive cases, 62 were female (51.67%) and 58 were male (48.33%), with a mean age of 65.25 ± 12.23 years. A total of 138 pathogen strains were isolated, including 137 bacterial strains (99.28%) and only 1 fungal strain (0.72%). Gram-positive bacteria predominated (99 strains, 72.26%), comprising Streptococcus spp. (60 strains, 60.61%; including 20 Streptococcus mitis), Staphylococcus spp. (31 strains, 31.31%; including 20 Staphylococcus epidermidis), Enterococcus spp. (4 strains, 4.04%), and others (4 strains, 4.04%). Gram-negative bacteria accounted for 38 strains (27.74%), including Enterobacterales (16 strains, 42.11%; including 5 Enterobacter cloacae), Acinetobacter spp. (15 strains, 39.47%; including 9 Acinetobacter baumannii), Pseudomonas spp. (6 strains, 15.79%), and others (1 strain, 2.63%). Gram-positive bacteria exhibited high resistance to erythromycin and clindamycin. However, they are susceptible to vancomycin, linezolid, and tigecycline. Streptococcus demonstrated favorable antimicrobial activity against penicillin, third-generation cephalosporins (cefotaxime), and fourth-generation cephalosporins (cefepime). Gram-negative bacteria were generally more sensitive to antibiotics, though elevated resistance rates were observed for certain third-generation cephalosporins (ceftazidime) and quinolones (levofloxacin). ConclusionsBacterial pathogens, particularly Gram-positive cocci, remain the primary causative agents in MPE-associated pleural infections. For empirical treatment, third-generation cephalosporins or third-/fourth-generation quinolones are recommended. Vancomycin or linezolid may be used for penicillin-allergic patients, while carbapenems should be reserved for refractory cases.