Antibiotic cycles: Wasted motion or novel weapon?

New CDC study may shed light on ICU practice

Antibiotic "cycling" approaches that periodically switch out drugs to thwart the rise of resistant pathogens are showing both promise and problems in ongoing research. While current data are mixed, a new research project by the Centers for Disease Control and Prevention may shed more light on what many hope is a solution for the rising tide of antibiotic resistance.

"Many hospital epidemiologists are intrigued — in dealing with their ICU resistance problems — [with] scheduled antibiotic changes, or cycling of antimicrobials," said Scott Fridkin, MD, medical epidemiologist in the Centers for Disease Control and Prevention hospital infections program. The concept of scheduled antimicrobial changes, or cycling, refers to the premeditated cyclic introduction or removal of select classes of agents, he told attendees at the CDC 4th Decennial International Conference on Nosocomial and Healthcare-Associated Infections, held in Atlanta in March.

"The goal of cycling . . . is not just the reduction of a current resistance problem, but the prevention of emergence of a new problem," Fridkin noted. "Because of several issues regarding the feasibility of such strict control of . . . antimicrobials and controlling for patient mix, it’s thought that the intensive care unit may be the best place to institute this type of program. However, the efficacy of such programs is unknown, and the harmful effects are also not known."

Multicenter studies using similar measurements and methodologies are needed to show that antibiotic cycling is a safe and effective means to reduce dramatically increasing drug resistance in intensive care unit (ICU) patients, he said. "In an attempt to do this, the CDC has begun funding a small network to reduce resistance through cycling in medical ICUs," Fridkin noted. "Three sites have been funded for a program to assess the impact of changing empirical therapy through a cycling program," he said. "The emphasis of this program will be to measure the protective effect of cycling on the patient level, to see if there is a protective effect in the acquisition of colonization or infection with resistant gram negatives."

Other approaches, such as physician education, computer-assisted prescribing, drug utilization evaluations, and performance feedback must continue, he said. "However, cycling may be one way to force prescribing changes by prescribers," he added. ". . . The preliminary data available are very hopeful that cycling may be a powerful tool in the ICU population in which patient outcomes and quality of care delivered will not be compromised."

There are several issues to consider when doing a cycling program, and many of them underscore the need for monitoring, Fridkin said, citing a recent review article on the practice.¹ "Monitoring the quality of care delivered in the unit cannot be overemphasized," he said. "There are lots of possibilities for compromising quality of patient care whenever we manipulate what it is that prescribers want to prescribe. Some system needs to be in place during a cycling program to at least monitor the quality of care by some process measurements." By the same token, monitoring antimicrobial use is essential to be sure that the program actually does affect prescribing patterns in the ICU, he said. "There needs to be rational choice of cycling agents, as well as support for the cycling program by the ICU staff or the clinicians and prescribers that go through there," he emphasized. Likewise, monitoring infection control during the cycling program is essential to ascertain if there are changes in practice or other aspects that may be important.

Although antimicrobial resistance is a global concern across patient populations, ICU patients may be at greatest risk for acquiring the organisms because many are immune-compromised and have invasive devices. In addition to such host factors, they are subjected to intense exposures to antibiotics. Thus, it is not surprising that data from the CDC National Nosocomial Infections Surveillance (NNIS) system for nosocomial pneumonia indicate that antibiotic-resistant pathogens are increasingly a source of infection in ICUs. Citing NNIS data and other sources, Fridkin estimated that there are about 126,000 cases of nosocomial pneumonia in ICU patients annually in the United States. "It’s quite a great burden, and something that definitely needs to be addressed by novel methods," he said.

Pathogens of concern include methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci, and vancomycin-resistant enterococci (VRE). "There has been a dramatic increase [of these pathogens] in the past five years in the ICU population," he said. "Most notably, in 1999 [for] the first time ever, the [MRSA] rate increased above 50%. So one out of every two Staph aureus [isolates] associated with nosocomial infection in [NNIS hospital] ICU patients appears to be MRSA. Of note, the VRE rate has broken 25% as well for the first time."

Fridkin outlined several studies of efforts to stave off such trends through antibiotic controls, including one that showed promising results with a "single switch approach."² The researchers decreased the number of patients exposed to ceftazidime but increased the amount that were exposed to ciprofloxacin. "They concluded that there was a decrease in the incidence [of] ventilator-associated pneumonia caused by antimicrobial-resistant gram-negative rods, which they classified as a gram-negative resistance to greater than one class of the antibiotics that are usually used to treat the organism," Fridkin said. "So, these results are somewhat encouraging."

Other researchers found that after restricting third-generation cephalosporins, the number of infections with Klebsiella pneumoniae dropped significantly.³ "That’s quite reassuring," he said. "However, they noticed that there was a dramatic increase in the amount of imipenem resistance in Pseudomonas-causing infections. . . . They attributed this increase to a doubling in the amount of imipenem that was used as an alternative agent." Such an unintended consequence has been described as "squeezing the balloon" of antimicrobial resistance, as efforts to limit one antibiotic may result in rising resistance to another.⁴

References

1. Gerding DN. Antimicrobial cycling: Lessons learned from the aminoglycoside experience. Infect Control Hosp Epidemiol 2000; 21 (suppl):S12-S17.

2. Kollef MH, Vlasnik J, Sharpness L, et al. Scheduled change of antibiotic classes. A strategy to decrease the incidence of ventilator-associated pneumonia. Am J Respir Crit Care Med 1997; 156 (4 pt. 1):1,040-1,048.

3. Rahal JJ, Urban C, Horn D, et al. Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella. JAMA 1998;280:1,233-1,237.

4. Burke JP. Antibiotic resistance — squeezing the balloon. JAMA 1998;240: 1,270-1,271.