Top

Trials

Published in:

Open Access 01-12-2014 | Study protocol

Antibiotic rotation strategies to reduce antimicrobial resistance in Gram-negative bacteria in European intensive care units: study protocol for a cluster-randomized crossover controlled trial

Authors: Pleun J van Duijn, Marc JM Bonten

Published in: Trials | Issue 1/2014

Abstract

Background

Intensive care units (ICU) are epicenters for the emergence of antibiotic-resistant Gram-negative bacteria (ARGNB) because of high rates of antibiotic usage, rapid patient turnover, immunological susceptibility of acutely ill patients, and frequent contact between healthcare workers and patients, facilitating cross-transmission.

Antibiotic stewardship programs are considered important to reduce antibiotic resistance, but the effectiveness of strategies such as, for instance, antibiotic rotation, have not been determined rigorously. Interpretation of available studies on antibiotic rotation is hampered by heterogeneity in implemented strategies and suboptimal study designs. In this cluster-randomized, crossover trial the effects of two antibiotic rotation strategies, antibiotic mixing and cycling, on the prevalence of ARGNB in ICUs are determined. Antibiotic mixing aims to create maximum antibiotic heterogeneity, and cycling aims to create maximum antibiotic homogeneity during consecutive periods.

Methods/Design

This is an open cluster-randomized crossover study of mixing and cycling of antibiotics in eight ICUs in five European countries. During cycling (9 months) third- or fourth-generation cephalosporins, piperacillin-tazobactam and carbapenems will be rotated during consecutive 6-week periods as the primary empiric treatment in patients suspected of infection caused by Gram-negative bacteria. During mixing (9 months), the same antibiotics will be rotated for each consecutive antibiotic course. Both intervention periods will be preceded by a baseline period of 4 months. ICUs will be randomized to consecutively implement either the mixing and then cycling strategy, or vice versa. The primary outcome is the ICU prevalence of ARGNB, determined through monthly point-prevalence screening of oropharynx and perineum. Secondary outcomes are rates of acquisition of ARGNB, bacteremia and appropriateness of therapy, length of stay in the ICU and ICU mortality. Results will be adjusted for intracluster correlation, and patient- and ICU-level variables of case-mix and infection-prevention measures using advanced regression modeling.

Discussion

This trial will determine the effects of antibiotic mixing and cycling on the unit-wide prevalence of ARGNB in ICUs.

Trial registration

ClinicalTrials.gov NCT01293071 December 2010.

Available only for authorised users

Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno R, Lipman J, Gomersall C, Sakr Y, Reinhart K: International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009, 302: 2323-2329.CrossRefPubMed

Sarraf-Yazdi S, Sharpe M, Bennett KM, Dotson TL, Anderson DJ, Vaslef SN: A 9-Year retrospective review of antibiotic cycling in a surgical intensive care unit. J Surg Res. 2012, 176: e73-e78.CrossRefPubMedPubMedCentral

Gerding DN, Larson TA, Hughes RA, Weiler M, Shanholtzer C, Peterson LR: Aminoglycoside resistance and aminoglycoside usage: ten years of experience in one hospital. Antimicrob Agents Chemother. 1991, 35: 1284-1290.CrossRefPubMedPubMedCentral

Cadena J, Taboada CA, Burgess DS, Ma JZ, Lewis JS, Freytes CO, Patterson JE: Antibiotic cycling to decrease bacterial antibiotic resistance: a 5-year experience on a bone marrow transplant unit. Bone Marrow Transplant. 2007, 40: 151-155.CrossRefPubMed

van Loon HJ, Vriens MR, Fluit AC, Troelstra A, van der Werken C, Verhoef J, Bonten MJ: Antibiotic rotation and development of gram-negative antibiotic resistance. Am J Respir Crit Care Med. 2005, 171: 480-487.CrossRefPubMed

Craig M, Cumpston AD, Hobbs GR, Devetten MP, Sarwari AR, Ericson SG: The clinical impact of antibacterial prophylaxis and cycling antibiotics for febrile neutropenia in a hematological malignancy and transplantation unit. Bone Marrow Transplant. 2007, 39: 477-482.CrossRefPubMed

Martinez JA, Nicolas JM, Marco F, Horcajada JP, Garcia-Segarra G, Trilla A, Codina C, Torres A, Mensa J: Comparison of antimicrobial cycling and mixing strategies in two medical intensive care units. Crit Care Med. 2006, 34: 329-336.CrossRefPubMed

Warren DK, Hill HA, Merz LR, Kollef MH, Hayden MK, Fraser VJ, Fridkin SK: Cycling empirical antimicrobial agents to prevent emergence of antimicrobial-resistant Gram-negative bacteria among intensive care unit patients. Crit Care Med. 2004, 32: 2450-2456.CrossRefPubMed

Ginn AN, Wiklendt AM, Gidding HF, George N, O’Driscoll JS, Partridge SR, O’Toole BI, Perri RA, Faoagali J, Gallagher JE, Lipman J, Iredell JR: The ecology of antibiotic use in the ICU: homogeneous prescribing of cefepime but not tazocin selects for antibiotic resistant infection. PLoS One. 2012, 7: e38719-CrossRefPubMedPubMedCentral

10.

Sandiumenge A, Lisboa T, Gomez F, Hernandez P, Canadell L, Rello J: Effect of antibiotic diversity on ventilator-associated pneumonia caused by ESKAPE Organisms. Chest. 2011, 140: 643-651.CrossRefPubMed

11.

Toltzis P, Dul MJ, Hoyen C, Salvator A, Walsh M, Zetts L, Toltzis H: The effect of antibiotic rotation on colonization with antibiotic-resistant bacilli in a neonatal intensive care unit. Pediatrics. 2002, 110: 707-711.CrossRefPubMed

12.

Nijssen S, Fluit A, van de Vijver D, Top J, Willems R, Bonten MJ: Effects of reducing beta-lactam antibiotic pressure on intestinal colonization of antibiotic-resistant gram-negative bacteria. Intensive Care Med. 2010, 36: 512-519.CrossRefPubMed

13.

Raymond DP, Pelletier SJ, Crabtree TD, Gleason TG, Hamm LL, Pruett TL, Sawyer RG: Impact of a rotating empiric antibiotic schedule on infectious mortality in an intensive care unit. Crit Care Med. 2001, 29: 1101-1108.CrossRefPubMed

14.

Sandiumenge A, Diaz E, Rodriguez A, Vidaur L, Canadell L, Olona M, Rue M, Rello J: Impact of diversity of antibiotic use on the development of antimicrobial resistance. J Antimicrob Chemother. 2006, 57: 1197-1204.CrossRefPubMed

15.

Bennett KM, Scarborough JE, Sharpe M, Dodds-Ashley E, Kaye KS, Hayward TZ, Vaslef SN: Implementation of antibiotic rotation protocol improves antibiotic susceptibility profile in a surgical intensive care unit. J Trauma. 2007, 63: 307-311.CrossRefPubMed

16.

Evans HL, Milburn ML, Hughes MG, Smith RL, Chong TW, Raymond DP, Pelletier SJ, Pruett TL, Sawyer RG: Nature of gram-negative rod antibiotic resistance during antibiotic rotation. Surg Infect (Larchmt). 2005, 6: 223-231.CrossRef

17.

Hedrick TL, Schulman AS, McElearney ST, Smith RL, Swenson BR, Evans HL, Truwit JD, Scheld WM, Sawyer RG: Outbreak of resistant Pseudomonas aeruginosa infections during a quarterly cycling antibiotic regimen. Surg Infect (Larchmt). 2008, 9: 139-152.CrossRef

18.

Dominguez EA, Smith TL, Reed E, Sanders CC, Sanders WE: A pilot study of antibiotic cycling in a hematology-oncology unit. Infect Control Hosp Epidemiol. 2000, 21 (1 Suppl): S4-S8.CrossRefPubMed

19.

Gruson D, Hilbert G, Vargas F, Valentino R, Bebear C, Allery A, Gbikpi-Benissan G, Cardinaud JP: Rotation and restricted use of antibiotics in a medical intensive care unit: impact on the incidence of ventilator-associated pneumonia caused by antibiotic-resistant gram-negative bacteria. Am J Respir Crit Care Med. 2000, 162 (3 Pt 1): 837-843.CrossRefPubMed

20.

Raineri E, Crema L, Dal Zoppo S, Acquarolo A, Pan A, Carnevale G, Albertario F, Candiani A: Rotation of antimicrobial therapy in the intensive care unit: impact on incidence of ventilator-associated pneumonia caused by antibiotic-resistant Gram-negative bacteria. Eur J Clin Microbiol Infect Dis. 2010, 29: 1015-1024.CrossRefPubMed

21.

Damas P, Canivet JL, Ledoux D, Monchi M, Melin P, Nys M, De Mol P: Selection of resistance during sequential use of preferential antibiotic classes. Intensive Care Med. 2006, 32: 67-74.CrossRefPubMed

22.

Gruson D, Hilbert G, Vargas F, Valentino R, Bui N, Pereyre S, Bebear C, Bebear CM, Gbikpi-Benissan G: Strategy of antibiotic rotation: long-term effect on incidence and susceptibilities of Gram-negative bacilli responsible for ventilator-associated pneumonia. Crit Care Med. 2003, 31: 1908-1914.CrossRefPubMed

23.

Takesue Y, Nakajima K, Ichiki K, Ishihara M, Wada Y, Takahashi Y, Tsuchida T, Ikeuchi H: Impact of a hospital-wide programme of heterogeneous antibiotic use on the development of antibiotic-resistant Gram-negative bacteria. J Hosp Infect. 2010, 75: 28-32.CrossRefPubMed

24.

Nijssen S, Bootsma M, Bonten M: Potential confounding in evaluating infection-control interventions in hospital settings: changing antibiotic prescription. Clin Infect Dis. 2006, 43: 616-623.CrossRefPubMed

25.

Campbell MK, Piaggio G, Elbourne DR, Altman DG: Consort 2010 statement: extension to cluster randomised trials. BMJ. 2012, 345: e5661-CrossRefPubMed

26.

de Smet AM, Kluytmans JA, Blok HE, Mascini EM, Benus RF, Bernards AT, Kuijper EJ, Leverstein-van Hall MA, Jansz AR, de Jongh BM, van Asselt GJ, Thijsen SF, Conijn SN, Kaan JA, Arends JP, Sturm PD, Bootsma MC, Bonten MJ: Selective digestive tract decontamination and selective oropharyngeal decontamination and antibiotic resistance in patients in intensive-care units: an open-label, clustered group-randomised, crossover study. Lancet Infect Dis. 2011, 11: 372-380.CrossRefPubMed

27.

Gerding DN: Antimicrobial cycling: lessons learned from the aminoglycoside experience. Infect Control Hosp Epidemiol. 2000, 21 (1 Suppl): S12-S17.CrossRefPubMed

28.

Bonhoeffer S, Lipsitch M, Levin BR: Evaluating treatment protocols to prevent antibiotic resistance. Proc Natl Acad Sci U S A. 1997, 94: 12106-12111.CrossRefPubMedPubMedCentral

29.

Bergstrom CT, Lo M, Lipsitch M: Ecological theory suggests that antimicrobial cycling will not reduce antimicrobial resistance in hospitals. Proc Natl Acad Sci U S A. 2004, 101: 13285-13290.CrossRefPubMedPubMedCentral

30.

Magee JT: The resistance ratchet: theoretical implications of cyclic selection pressure. J Antimicrob Chemother. 2005, 56: 427-430.CrossRefPubMed

31.

Reluga TC: Simple models of antibiotic cycling. Math Med Biol. 2005, 22: 187-208.CrossRefPubMed

32.

Chow K, Wang X, Curtiss R, Castillo-Chavez C: Evaluating the efficacy of antimicrobial cycling programmes and patient isolation on dual resistance in hospitals. J Biol Dyn. 2011, 5: 27-43.CrossRefPubMed

33.

Sun HR, Lu X, Ruan S: Qualitative analysis of models with different treatment protocols to prevent antibiotic resistance. Math Biosci. 2010, 227: 56-67.CrossRefPubMedPubMedCentral

34.

Beardmore RE, Pena-Miller R: Rotating antibiotics selects optimally against antibiotic resistance, in theory. Math Biosci Eng. 2010, 7: 527-552.CrossRefPubMed

35.

Bonhoeffer S, Wiesch PA, Kouyos RD: Rotating antibiotics does not minimize selection for resistance. Math Biosci Eng. 2010, 7: 919-922.CrossRefPubMed

36.

Beardmore RE, Pena-Miller R: Antibiotic cycling versus mixing: the difficulty of using mathematical models to definitively quantify their relative merits. Math Biosci Eng. 2010, 7: 923-933.CrossRefPubMed

37.

Kouyos RD, Abel Zur Wiesch P, Bonhoeffer S: Informed switching strongly decreases the prevalence of antibiotic resistance in hospital wards. PLoS Comput Biol. 2011, 7: e1001094-CrossRefPubMedPubMedCentral

38.

ClinicalTrials.gov.http://clinicaltrials.gov/,

Title: Antibiotic rotation strategies to reduce antimicrobial resistance in Gram-negative bacteria in European intensive care units: study protocol for a cluster-randomized crossover controlled trial
Authors: Pleun J van Duijn
Marc JM Bonten
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Trials / Issue 1/2014
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/1745-6215-15-277

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Antibiotic rotation strategies to reduce antimicrobial resistance in Gram-negative bacteria in European intensive care units: study protocol for a cluster-randomized crossover controlled trial

Abstract

Background

Methods/Design

Discussion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods/Design

Discussion

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2014

National Adolescent Treatment Trial for Obesity in Kuwait (NATTO): project design and results of a randomised controlled trial of a good practice approach to treatment of adolescent obesity in Kuwait

Toward onset prevention of cognitive decline in adults with Down syndrome (the TOP-COG study): study protocol for a randomized controlled trial

Variability in research ethics review of cluster randomized trials: a scenario-based survey in three countries

Disappointment and adherence among parents of newborns allocated to the control group: a qualitative study of a randomized clinical trial

Effect of a structured psycho-oncological screening and treatment model on mental health in cancer patients (STEPPED CARE): study protocol for a cluster randomized controlled trial

A combination of ascorbic acid and α-tocopherol to test the effectiveness and safety in the fragile X syndrome: study protocol for a phase II, randomized, placebo-controlled trial