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Breast discharge and breast abscesses are common clinical presentations with heterogeneous etiologies. When infection is suspected, culture with antimicrobial susceptibility testing (AST) is essential to guide targeted therapy, particularly in settings where antimicrobial resistance and antibiotic misuse may influence empirical choices. We aimed to characterize the microbiologic spectrum and cumulative susceptibility patterns of breast-associated secretion and drainage specimens submitted for culture in a private central microbiology laboratory in Damascus, Syria, and to assess annual MSSA susceptibility trends. We performed a retrospective, laboratory-based analysis of breast-associated secretion and drainage specimens from female patients processed between 1 January 2022 and 31 December 2024. To minimize duplicate-sampling bias, only the first culture per patient per calendar year was included, and annual cohorts represented unique patients. Organisms were categorized as Gram-positive or Gram-negative. Susceptibility was summarized as S/I/R with explicit reporting of numbers tested per antibiotic. An annual MSSA trend analysis across 2022–2024 was conducted for selected clinically relevant agents using Pearson’s chi-square test. We included 122 cultures (2022: 42; 2023: 35; 2024: 45; mean age 37.4 years). Gram-positive organisms predominated (74.6%). All Staphylococcus aureus isolates were phenotypically methicillin susceptible by direct MIC-based testing, making MSSA the most common isolate (84/122, 68.9%), followed by E. coli (14/122, 11.5%). MSSA showed universal susceptibility to methicillin and vancomycin and high susceptibility to linezolid, with lower susceptibility to fluoroquinolones, TMP-SMX, and fusidic acid. E. coli and pooled Enterobacterales showed highest activity to carbapenems and amikacin, with variable fluoroquinolone activity and low cephalosporin activity. These Gram-negative findings should be interpreted cautiously because of the small organism-specific and pooled denominators. MSSA minocycline susceptibility increased significantly over time (Pearson’s chi-square test, p = 0.006); other agents showed no significant annual change. This three-year cumulative antibiogram provides locally relevant susceptibility data for breast-associated secretion and drainage specimens submitted for culture in Syria, supporting context-specific empiric therapy, culture-guided refinement, early de-escalation, and stewardship, with careful interpretation of low-denominator estimates. Question: What are the microbiologic spectrum, cumulative antimicrobial susceptibility patterns, and annual MSSA susceptibility trends among breast-associated secretion and drainage specimens submitted for culture from female patients processed in a private central microbiology laboratory in Damascus, Syria, receiving physician-referred specimens from multiple Syrian governorates, during 2022–2024? Findings: In this retrospective, laboratory-based study including 122 breast-associated secretion and drainage specimens (one culture per patient per year; unique patients across years), Gram-positive organisms predominated (74.6%), and all Staphylococcus aureus isolates were phenotypically methicillin susceptible by direct MIC-based testing, making MSSA the leading isolate (68.9%), followed by E. coli (11.5%). MSSA retained 100% susceptibility to methicillin and vancomycin and very high susceptibility to linezolid, while showing lower susceptibility to several commonly used outpatient agents, including fluoroquinolones, trimethoprim-sulfamethoxazole, and fusidic acid. Among Gram-negative isolates, organism-specific (E. coli) and pooled-group analyses showed the highest activity for carbapenems and amikacin, with lower cephalosporin activity in pooled Enterobacterales. These Gram-negative findings should be interpreted cautiously because of the small organism-specific and pooled denominators. Annual MSSA trend analysis showed a significant increase in minocycline susceptibility over 2022–2024, with no significant year-to-year changes for the other evaluated agents. Meaning: These findings provide a locally relevant cumulative antibiogram for breast-associated secretion and drainage specimens submitted for culture in Syria, supporting context-specific empiric therapy, culture-guided refinement, early de-escalation, and antimicrobial stewardship, while emphasizing transparent denominators and cautious interpretation of low-count estimates.