More studies needed to define potential role of antibiotic cycling

September 2005

Consequences of serious infections caused by antimicrobial-resistant pathogens include increased morbidity, mortality and health care-related costs. As a result, health care institutions have employed numerous strategies to reduce the effect of such resistance. Many of these focus on appropriate antibiotic selection and promotion of optimal infection control practices.

Among the most significant factors in the development of antimicrobial resistance is the presence of antibiotics within the environment. Numerous studies have reported associations between antibiotic use and resistance at both the patient and health care institution levels of use. Withdrawal of an antibiotic or antibiotic class, which pathogens have demonstrated increasing resistance, has resulted in recovery of in vitro activity of the antibiotic in some cases. Therefore, scheduled withdrawal of an antibiotic or antibiotic class from general use may be an effective strategy to reduce the incidence and effect of antibiotic resistance.

For the strategy commonly known as “antibiotic cycling” or “antibiotic rotation,” a selected antibiotic or antibiotic class is withdrawn from general use. Removal is done either within a patient care ward or institution. The withdrawn antibiotic is substituted with another antibiotic, ideally from a different chemical class that has a comparable spectrum of activity but different mechanisms of antimicrobial resistance. Examples may include the substitution of select ß-lactams with either fluoroquinolones or aminoglycosides. The reintroduction of the withdrawn agent is then performed on a schedule, thus “cycled” back in use. Changes in hospital formulary antibiotics and/or antibiotic restrictions do not constitute true antibiotic cycling, as rotation is scheduled.

Does cycling work?

Mathematical modeling to predict the effect of antibiotic cycling on antimicrobial resistance has raised doubt as to its potential effectiveness. Single antibiotic use, antibiotic mixing (equal proportions of the population each receive two different antibiotics at all times) and cycling have been compared using various cycling durations, mixing proportion and hospital unit settings. Results of these simulations infrequently predicted cycling as the most beneficial approach in reducing the theoretical spread of resistant microorganisms.

The clinical data examining the effect of antibiotic cycling on resistance has been extensively summarized elsewhere (Masterson, et al). Many studies were performed in response to the increasing incidence of gram-negative resistance. Most studies involve adult patients in the ICU. A reduction in the isolation of gram-negative pathogens has been the endpoint most frequently used. Clinical outcomes are rarely examined.

Resistant pathogens. A study that cycled antibiotics within the aminoglycoside class observed a significant decrease in gram-negative resistance when gentamicin (or tobramycin) use was replaced with amikacin, but saw an increase in such resistance once gentamicin (or tobramycin) was reintroduced.

Colonization. Two investigations in pediatric ICUs found no significant effect of cycling between antibiotic classes on colonization with resistant organisms (Toltzis, et al). In contrast, a decrease in rectal colonization with glycopeptide-resistant Enterococcus was observed when piperacillin/tazobactam replaced ceftazidime in a hematology unit (Bradley, et al).

Clinical outcomes.. With a significant decrease in the incidence of ventilator-associated pneumonia and increase in ß-lactam susceptibility in gram-negative organisms (Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia and Burkholderia cepacia), no effect on mortality was found after cycling various ß-lactam antibiotics in a medical ICU (Gruson, et al). Another study found a decrease in infectious mortality following the rotation of fluoroquinolones and ß-lactams in a surgical ICU; however, antibiotic cycles were not repeated (Raymond, et al).

Unanswered questions remain

Because of the limited number of adequately controlled clinical trials examining the effect of antibiotic cycling on resistance, numerous questions remain. The optimal cycle duration is yet to be determined. Reports of cycles vary in published reports from one to 51 months. Since reports have described both hospital-wide and unit-specific antibiotic cycling strategies, it is not known which of these strategies is best. The optimal time to employ cycling as a strategy for control of antibiotic resistance is also unknown. Cycling has often been introduced in response to a serious resistance problem. Conceivably, antibiotic cycling would offer the most benefit if used before the development of a resistance problem. However, routine sequential antibiotic exposure could potentially add new resistance determinants to an already active resistance environment, only aggravating the problem.

Numerous issues surround the successful implementation of cycling programs within institutions. Effective communication as to the current “cycle” is essential. Even with such communication, compliance (ranging from 8% to 97% in published reports) may have a significant effect on effectiveness. Studies have infrequently examined antibiotic costs as outcomes in antibiotic cycling studies. While one study reported no significant change in total antibiotic costs, other pilot studies documented increased antibiotic costs associated with cycling programs.

If cycling programs are effective, another question would be how long could the effects on resistance be sustained. Cycling’s effect on resistance assumes that antibiotic selection and pressure are the major determinants of resistance. However, nonantimicrobial contributors to resistance (such as lack of adherence to adequate infection control measures) should be considered as well. A number of available studies reported re-emergence of resistance once the antibiotic or antibiotic class was reintroduced.

Antibiotic cycling has been employed as a method of decreasing resistance with variable success. Numerous issues regarding the effect of such a strategy are outstanding. Additional adequately controlled studies are needed to better define the potential role of antibiotic cycling as an effective strategy.

For more information:

• Brown EM, Nathwani D. Antibiotic cycling or rotation: a systematic review of the evidence of efficacy. J Antimicrob Chemother. 2005;55(1):6-9.
• Masterton RG. Antibiotic cycling: more than it might seem? J Antimicrob Chemother. 2005;55(1):1-5.
• Gruson D, Hilbert G, Vargas F, et al. 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(7):1908-1914.
• Moss WJ, Beers MC, Johnson E, et al. Pilot study of antibiotic cycling in a pediatric intensive care unit. Crit Care Med. 2002;30(8):1877-1882.
• Toltzis P, Dul MJ, Hoyen C, et al. The effect of antibiotic rotation on colonization with antibiotic-resistant bacilli in a neonatal intensive care unit. Pediatrics. 2002;110(4):707-711.
• Raymond DP, Pelletier SJ, Crabtree TD, et al. Impact of a rotating empiric antibiotic schedule on infectious mortality in an intensive care unit. Crit Care Med. 2001;29(6):1101-1108.
• Gerding DN. Antimicrobial cycling: lessons learned from the aminoglycoside experience. Infect Control Hosp Epidemiol. 2000; 21(1 Suppl):S12-S17.
• Bradley SJ, Wilson ALT, Allen MC, et al. The control of hyperendemic glycopeptide-resistant Enterococcus spp. on a haematology unit by changing antibiotic usage. J Antimicrob Chemother. 1999;43(2):261-266.