The most common cause of acute epididymitis in men under 35 years is Chlamydia trachomatis. This is because sexually transmitted infections are the predominant etiology in this age group, with Chlamydia being the leading pathogen. It typically ascends from the urethra or prostate to involve the epididymis. Empiric antibiotic treatment should target Chlamydia and Neisseria gonorrhoeae due to their high prevalence in sexually active young men. Identifying the correct pathogen is crucial for effective management and preventing complications such as abscess or infertility.

Reference: Harrison's Principles of Internal Medicine, 20th Edition.