Objective: To describe the effect of a combination prophylactic regimen of levofloxacin, a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class, with either penicillin or doxycycline on the changing epidemiology of bacterial infections and antimicrobial resistance patterns of isolated organisms in the allogeneic hematopoietic stem cell transplant (HSCT) patient population. Patients and MethOds:We conducted a single-center, retrospective cohort study of all allogeneic HSCT recipients from January 1, 20031, , through August 31, 2008, who received prophylactic levofloxacin in combination with penicillin (or with doxycycline in penicillin-allergic patients) from allogeneic stem cell infusion until neutrophil engraftment.Results: Of the 258 patients who underwent allogeneic HSCT during the study period, 231 received levofloxacin prophylaxis, 76 (33%) of whom developed an infection within 3 months after transplant. Over time, the ratio of gram-positive to gram-negative (GN) infections decreased from 2.11 in 2004, the first year that GN organisms were isolated, to 1.11 in 2008 (P=.20). Emergence of fluoroquinolone-resistant GN bacteria was observed (P=.02), whereas resistance to extended-spectrum β-lactams did not change over time. Combined vancomycin-resistant enterococci colonization and infection rates increased during the study period (P=.04). Clostridium difficile colitis was uncommon. individual reprints of this article are not available. address correspondence to bridgette l. therriault, Pharmd, at her current affiliation: Wesley Medical center, 550 n hillside, Wichita, Ks 67214 (bridgettet8@yahoo.com).