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Background: Rising antibiotic resistance poses a challenge to the management of febrile neutropenia in patients with haematological malignancies receiving chemotherapy., Aim: We studied an alternating first-line antibiotic strategy to determine its impact on all-cause mortality and bacteremia rates in patients with febrile neutropenia., Methods: An alternating first-line antibiotic strategy was established in mid-2013. Data for 2012 (before strategy implementation) and 2014 (post-strategy implementation) were compared. Antibiotic Heterogeneity Index (AHI) for each of the two time-periods was also calculated., Findings: There were 2012 admissions (26082 patient-days) in 2012 and 1843 admissions (24331 patient-days) in 2014. There was no significant difference in the baseline characteristics of patients in the two groups. The defined daily doses (DDD) of cefepime (CEF) fell while the DDD of piperacillin-tazobactam (PTZ) rose in 2014 compared with 2012. Vancomycin DDD fell in 2014. The AHI was 0.466 in 2012 and 0.582 in 2014. The difference in all-cause mortality was not statistically significant. There was no difference in rates of bacteremia with CEF-resistant, PTZ-resistant and carbapenem-resistant gram-negative organisms in the two groups. Rates of new cases of Methicillin-resistant Staphylococcus aureus (MRSA) were 2.38/1000 and 2.59/1000 patient-days in 2012 and 2014 respectively. Rates of new cases of Vancomycin-resistant Enterococcus (VRE) were 1.84/1000 and 1.81/1000 patient-days in 2012 and 2014 respectively. There was no Carbapenem-resistant Enterobacteriaceae (CRE) bacteremia in 2012 and 1 in 2014., Conclusion: An alternating first-line antibiotic strategy resulted in an increase in antibiotic heterogeneity, without increasing mortality. There was also no significant increase in bacteremia rates., Competing Interests: The authors have declared that no competing interests exist.