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Summary: Objectives: To determine the current spectrum of Gram-positive bloodstream infections (BSI) in patients with hematologic malignancies at our institution, and to determine the in vitro activity of various fluoroquinolones against clinical Gram-positive isolates collected from such patients. Methods: Institutional microbiology records from 493 consecutive episodes of Gram-positive BSI were reviewed. The in vitro activity of six fluoroquinolones against 477 clinical isolates was determined using an NCCLS approved, broth-dilution method. Results: The most common Gram-positive organisms isolated from the bloodstream of patients with hematological malignancies were coagulase-negative staphylococci (33%), Staphylococcus aureus (15%), viridans group streptococci (10%), and the enterococci (8%). Acute leukemias were the most common underlying malignancies, and 73% of patients were neutropenic when they developed their BSI. The newer generation quinolones – moxifloxacin and gatifloxacin – had the best overall in vitro activity against the Gram-positive isolates tested, and were at least 2 to 8-fold more potent than the early generation quinolones (ofloxacin and ciprofloxacin). Of the 477 isolates tested, 405 (85%) were from patients receiving quinolone (ciprofloxacin or levofloxacin) prophylaxis. Conclusions: In patients with hematologic malignancies, Gram-positive BSI are caused by a large number of bacterial species and many occur despite antimicrobial prophylaxis. The newer generation quinolones – moxifloxacin and gatifloxacin – have better in vitro activity against these organisms than early generation agents (ciprofloxacin and ofloxacin). [Copyright &y& Elsevier]