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Antibiotic Rotation and Development of Gram-Negative Antibiotic Resistance

Departments of Surgery, Medical Microbiology, and Internal Medicine and Infectious Diseases, and Hospital Hygiene and Infection Prevention, Eijkman-Winkler Institute for Microbiology, Infectious Disease and Inflammation, University Medical Center Utrecht, Utrecht, The Netherlands

Correspondence and requests for reprints should be addressed to H. J. van Loon, M.D., Dept. Surgery, Room G04-228 University Medical Center Utrecht, Heidelberglaan 100, PO Box 3508 GA, Utrecht, The Netherlands. E-mail: hjvloon{at}yahoo.com

To attain a better understanding of antibiotic cycling and its effects on the epidemiology of antibiotic resistance in gram-negative microorganisms, two different antibiotic classes (quinolone and ß-lactam) were cycled during four 4-month periods in a surgical intensive care unit. Respiratory aspirates and rectal swabs were obtained and DNA fingerprinting was performed. Primary endpoint of the study was the acquisition rate with gram-negative bacteria resistant to the antibiotic of choice during each cycle. Secondary endpoints were changes in endemic prevalence of resistant bacteria and the relative importance of cross-transmission. In all, 388 patients were included and 2,520 cultures analyzed. Adherence to antibiotic protocol was 96%. Overall antibiotic use increased with 24%. Acquisition rates with resistant bacteria were highest during levofloxacin exposure (relative risk [RR] 3.2; 95% confidence interval [CI]: 1.4–7.1) and piperacillin/tazobactam exposure (RR 2.4; 95% CI 1.2–4.8). The relative importance of cross-transmission decreased during the study. For individual patients, treatment with levofloxacin was the only independent risk factor for acquisition of levofloxacin-resistant bacteria (hazard ratio 12.6; 95% CI 3.8–41.6). Potential for selection of antibiotic-resistant gram-negative bacteria during periods of homogeneous exposure increased from cefpirome to piperacillin/tazobactam to levofloxacin. Cycling of homogeneous antibiotic exposure is unlikely to control the emergence of gram-negative antimicrobial resistance in intensive care units.

Key Words: antibiotic resistance • antibiotic rotation • antimicrobial therapy • cycling antibiotics • gram-negative microorganisms

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