The branches of the immune system work in concert to defend against pathogens and prevent tissue damage due to excessive inflammation. Uropathogens in general, and uropathogenic Escherichia coli (UPEC) in particular, have evolved a diverse range of virulence mechanisms to avoid detection and destruction by the mucosal immune system of the urinary tract. Research towards a vaccine active against UPEC continues but has yet to be successful. Orally administered immunomodulatory bacterial lysates both stimulate and modulate the immune response in the urinary tract via the integrated mucosal immune system. The 2018 European Association of Urology (EAU) guidelines on treating acute uncomplicated cystitis recommend aiming for rapid resolution of symptoms, reduction of morbidity, and prophylaxis against reinfection. Recommended short-term antibiotic therapy has the advantage of good compliance, low cost, few adverse events, and low impact on bacterial flora. Antibiotic treatment of asymptomatic bacteriuria is only indicated during pregnancy and before invasive interventions. For recurrent infection, prophylaxis using behavioral modification and counseling should be employed first, then nonantibiotic prophylaxis, and, finally, low-dose continuous or postcoital antibiotic prophylaxis. The 2018 EAU guidelines give a strong recommendation for the oral bacterial lysate immunomodulator OM-89. All other nonantibiotic prophylactic strategies require more data, except for topical estrogen for postmenopausal women. For last-resort antibiotic prophylaxis, nitrofurantoin or fosfomycin trometamol are recommended. Guidelines for Latin America are currently being drafted, taking into account the unique ethnicity, availability of medicines, prevalence of antibiotic resistance, and healthcare practices found throughout the region.