Antibiotic Cycling, Mixing Does Not Prevent Gram-Negative Antibiotic Resistance

Pseudomonas aeruginosa, petri dish
Pseudomonas aeruginosa, petri dish
Findings do not provide evidence that antibiotic mixing, compared with antibiotic cycling with 6-week cycling periods, with third-generation or fourth-generation cephalosporins, piperacillin-tazobactam, and carbapenems reduces the prevalence of carriage with antibiotic-resistant, Gram-negative bacteria in the ICU.

Cycling and mixing of antibiotic prescriptions for Gram-negative bacteria may not reduce antibiotic resistance in intensive care units (ICUs), according to a study recently published in the Lancet Infectious Diseases.

In an international, multicenter, cluster-randomized, crossover study ( identifier: NCT01293071), eligible European ICUs were included, which included medical, surgical, or mixed ICUs with at least 8 ventilator beds. During a 4-month baseline period, ICUs applied standard care treatment practices. Then, ICUs were randomly assigned a 9-month intervention period (either mixing or cycling), followed by a 1-month washout period and another 9-month intervention period of the opposite strategy to that used in the first intervention period. During intervention periods, the preferred treatment choices for ICU-acquired infections in which Gram-negative bacteria were covered were third- or fourth-generation cephalosporins, piperacillin-tazobactam, and carbapenems.

Eight ICUs were included from June 2011 to February 2014. Of the 10,980 patients admitted during the study period, 745 during cycling and 853 during mixing were present during the monthly point-prevalence surveys for respiratory and perineal swabs and were included in the main analysis.

The average volume of antibiotic use was 1.51 defined daily dose (DDD)/patient-day during baseline, 1.59 DDD/patient-day during cycling, and 1.53 DDD/patient-day during mixing. The difference between mixing and cycling was 0.053 DDD/patient-day (P =.93). However, there was substantial variation in antibiotic use between ICUs. Study antibiotics accounted for 39% of all antibiotics during baseline, 42% during cycling, and 43% during mixing. Carbapenems were used most frequently (0.33 DDD/patient-day during cycling vs 0.31 DDD/patient-day during mixing), followed by third-generation and fourth-generation cephalosporins (0.21 DDD/patient-day vs 0.22 DDD/patient-day) and piperacillin-tazobactam (0.13 DDD/patient-day in both study periods).

Overall, 9-month periods of antibiotic cycling and mixing did not change the unit-wide prevalence of antibiotic-resistant, Gram-negative bacteria. The mean prevalence of the composite primary endpoint was 23% (168/745) during cycling and 22% (184/853) during mixing (P =.64). There was no difference in all-cause in-ICU mortality between intervention periods: ICU mortality was 11% during baseline, 11% during cycling, and 12% during mixing (P =.38).

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On the basis of the results, study authors concluded that “neither strategy [antibiotic cycling and mixing] can be recommended in ICUs” to control the emergence of antibiotic-resistant, Gram-negative bacteria.


van Duijn PJ, Verbrugghe W, Jorens PG, et al; SATURN consortium. The effects of antibiotic cycling and mixing on antibiotic resistance in intensive care units: a cluster-randomised crossover trialLancet Infect Dis. 2018;18(4):401-409.