The higher rate of antibiotic resistance among bacteria isolated from infections has become one of the key problems among hospitalized patients, particularly those treated in the ICU. A wide variety of methods to reduce these rates have been proposed, including those that are relatively non-specific, such as better hand hygiene, and others that are more specific, such as restricting the use of specific antimicrobials associated with specific pathogens, such as third-generation cephalosporins. Although it is acknowledged widely that antimicrobials exert selective pressure on bacteria, leading to resistance, whether it is possible to manipulate this pressure to improve resistance rates is unclear.
One controversial technique to alter antibiotic pressure beneficially in a geographically defined area involves cycling or rotating the antimicrobials used to treat infections. To date, studies of cycling have had inconsistent results, although some have demonstrated benefits, as judged by various outcomes [3
]. On the other hand, mathematical models suggest that a strategy of greater antibiotic heterogeneity might lead to better outcomes [8
], although one clinical study specifically testing this hypothesis suggested otherwise [9
]. Probably because of the wide variety of classes of agents available, all clinical studies to date have analyzed the utility of cycling to improve the rates of resistance among gram-negative pathogens. However, the introduction of linezolid enabled cycling of this drug and vancomycin for the empiric treatment of gram-positive infections in critically ill patients. We report here the first study of cycling of agents active against gram-positive organisms in an attempt to alter the resistance rates for two problematic pathogens, MRSA and VRE.
Although the study was designed to reduce the incidence of VRE in the ICU, this goal was not achieved. Rather, a marked reduction in the rate of infection with MRSA was noted after the introduction of cycling with no change in the rate of recovery of MSSA, leading to a significant reduction in the percentage of S. aureus that were MRSA. These changes appeared to be isolated to the ICU, where cycling was practiced, because there was no change in either the number of MRSA or MSSA infections treated or the percentage of all S. aureus that were MRSA outside the ICU on the same surgical services during the same six-year period.
The mechanism of the near-eradication of MRSA from the ICU under study is unclear. It is possible that the intermittent use of linezolid allowed the environmental deletion of S. aureus clones subclinically less susceptible to vancomycin that persisted during the four years of baseline data collection. There are no direct data to support this hypothesis, because isolates were not tested for heteroresistance, and, in fact, there was never any evidence of MiC “creep” that might have been expected with a relative loss of vancomycin sensitivity. On the other hand, the in-hospital mortality rate in patients infected with S. aureus who were treated with any agent decreased after the introduction of cycling (although the numbers were too small to confirm statistical significance), perhaps implying the environmental loss of one or more virulent clones.
It is possible that the reduction in the rate of MRSA infection was related to other changes in care unrelated to cycling. No systematic changes in infection control practice were made between the two periods studied, however. The same isolation procedures, use of alcohol-based hand hygiene, infection prevention techniques (such as full barrier precautions for the placement of central venous catheters and semirecumbency for mechanical ventilation), and methods for the diagnosis of infection were used throughout. It is possible, of course, that compliance with all of these preventive steps improved over time; this was not measured. If this was the case, however, one would have expected to see a reduction in all infections and no change in the ratio of MRSA to MSSA infections. We did note a decrease in the rate of pneumonia caused by gram-negative organisms during the same period (data not shown), but to a much lesser degree than seen for MRSA, and did not find a significant decline in gram-negative catheter-related blood stream infections. In addition, any undocumented changes in infection control or prevention process would have been expected to affect the rates of non-iCU acquired infection similarly, as they would have been prescribed by the same protocols, but this result was not observed. Finally, another possible explanation for changes in the prevalence of MRSA is undocumented changes in the usage of other antimicrobial agents. For example, changes in the use of cephalosporins with activity against MSSA might change selection for MRSA. Although there was no documented change in the therapeutic use of cephalosporins between the periods studied, alterations in prophylactic use (which was not tracked) may have occurred.
Several weaknesses of the current study deserve mention. First, it was carried out in a single iCU, and the applicability to other iCUs or patient populations is unproved. Second, the overall approach was a before–after design, rather than randomization, a design forced by the lack of availability of an appropriate control unit. Theoretically, a follow-up period without cycling demonstrating a return to baseline rate of MRSA infections would have strengthened the results, but the authors instead have undertaken a second study examining daily cycling as a model of heterogeneity, the results of which are being analyzed. Third, these data do not address the supposition that completely heterogeneous use of linezolid and vancomycin would improve results further, as predicted by mathematical models. As noted, a two-year analysis of this question has been completed, and the data from this intervention are being analyzed. Fourth, subtle or undocumented changes in the usage of other antibiotics (therapeutic or prophylactic) may have occurred, leading to variations in MRSA selection pressures that were not taken into account. Finally, the cost of linezolid is greater than that of vancomycin, and specific antibiotic cost data for these patients in our ICU are not available. However, the significant reduction in the empiric use of either vancomycin or linezolid attributable to a decrease in the number of all gram-positive infections, as well as the ability to de-escalate more frequently to betalactam antibiotics with a reduction in the number of MRSA infections, probably led to relative cost neutrality with cycling.
It is interesting that quarterly cycling of classes of antimicrobials for infections with gram-negative bacteria has been relatively unsuccessful in changing resistance rates, at least in medical ICUs [10
]. There could be several reasons, including the fact that the number of gram-negative pathogens targeted is greater than for cycling of drugs against gram-positive organisms, and that the relative representation of various sites of infection is different in medical and surgical ICUs. In addition, the rapidity with which relevant gram-positive bacteria, including MRSA, become resistant to either vancomycin or linezolid probably is less than for gram-negative pathogens against the antimicrobial agents used to treat them. Thus, it is possible a three-month cycle of a gram-negative agent will lead to resistance more frequently than will a three-month cycle of either linezolid or vancomycin.
Overall, the data suggest that quarterly cycling of linezolid and vancomycin for the empiric treatment of gram-positive infections in the ICU may be effective in reducing the frequency of infections with MRSA. Further studies will be needed in other ICUs with high rates of isolation of this pathogen to confirm these findings.