Download Is Antibiotic Cycling the Answer to Preventing the Emergence of

SUPPLEMENT ARTICLE
Is Antibiotic Cycling the Answer to Preventing
the Emergence of Bacterial Resistance in
the Intensive Care Unit?
Marin H. Kollef
Department of Internal Medicine, Pulmonary and Critical Care Division, Washington University School of Medicine, Barnes-Jewish Hospital,
St. Louis, Missouri
Antibiotic resistance has emerged as an important determinant of mortality for patients in the intensive care
unit (ICU) setting. This is largely due to the increasing presence of pathogenic microorganisms with resistance
to existing antibiotic agents, resulting in the administration of inappropriate treatment. Escalating antibiotic
resistance has also been associated with greater overall health care costs, as a result of prolonged hospitalizations
and convalescence associated with failure of antibiotic treatment, the need to develop new antibiotic agents,
and the implementation of broader infection control and public health interventions aimed at curbing the
spread of antibiotic-resistant pathogens. Antibiotic cycling has been advocated as a tool to reduce the occurrence
of antibiotic resistance, especially in the ICU setting. Unfortunately, the cumulative evidence to date suggests
that antibiotic cycling has limited efficacy for preventing antibiotic resistance. Nevertheless, a strategy whereby
multiple or all classes of antibiotics are available for use (i.e., antibiotic heterogeneity) can be part of a broader
effort aimed at curtailing antibiotic resistance within ICUs. Such efforts should be routine, given the limited
availability of new antibiotic drug classes for the foreseeable future.
Resistance to antibiotics has emerged as an important
variable influencing patient mortality and overall resource use in the intensive care unit (ICU) setting [1–
3]. ICUs worldwide are faced with increasingly rapid
emergence and spread of antibiotic-resistant bacteria.
Both antibiotic-resistant gram-negative bacteria and
gram-positive bacteria have been reported as important
causes of hospital-acquired infections [4–12]. In many
circumstances, particularly with methicillin-resistant
Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and gram-negative bacteria producing extended-spectrum b-lactamases with resistance to multiple other antibiotics, few antibiotic agents remain for
effective treatment [13–19]. The ICU is an important
area for the emergence of antibiotic resistance, because
Reprints or correspondence: Dr. Marin H. Kollef, Pulmonary and Critical Care
Division, Campus Box 8052, 660 S. Euclid Ave., St. Louis, MO 63110 (mkollef
@im.wustl.edu).
Clinical Infectious Diseases 2006; 43:S82–8
2006 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2006/4305S2-0008$15.00
S82 • CID 2006:43 (Suppl 2) • Kollef
of the frequent use of broad-spectrum antibiotics; the
crowding of patients with high levels of disease acuity
within relatively small specialized areas; reductions in
nursing staff and other support staff due to economic
pressures, which increase the likelihood of person-toperson transmission of microorganisms; and the presence of more chronically and acutely ill patients, who
require prolonged hospitalization and often harbor antibiotic-resistant bacteria [2, 20, 21].
Many strategies have been advocated to prevent the
emergence of antibiotic resistance in the ICU setting
[22]. These strategies also have applications outside of
ICUs and for nonbacterial pathogens. It is important
to note that these interventions attempt to balance the
somewhat competing goals of providing appropriate
antibiotic treatment to critically ill patients while avoiding the unnecessary administration of antibiotics. Antibiotic cycling, or antibiotic rotation, is an approach
that has been used to reduce the occurrence of antibiotic resistance. Here, I describe the evidence for and
against the routine use of this intervention.
RISK FACTORS FOR INFECTIONS WITH
ORGANISMS RESISTANT TO ANTIBIOTICS
A brief description of risk factors promoting antibiotic resistance is needed to understand the rationale for prevention strategies such as antibiotic cycling. Antibiotic use drives the emergence of resistance. Therefore, use of strategies aimed at limiting
or modifying the administration of antibiotic agents has the
greatest likelihood of preventing resistance to these agents [21].
A number of investigators have demonstrated a close association between the prior use of antibiotics and the emergence
of subsequent antibiotic resistance in both gram-negative and
gram-positive bacteria [23–34]. Other factors promoting antibiotic resistance include prolonged hospitalization, the presence of invasive devices such as endotracheal tubes and intravascular catheters (possibly because of the formation of biofilms
on the surfaces of these devices), residence in long-term-treatment facilities, and inadequate infection control practices [21].
However, the prolonged administration of antibiotic regimens,
especially with a single or predominant antibiotic or drug class,
appears to be the most important factor promoting the emergence of antibiotic resistance that is potentially amenable to
intervention [31, 35, 36].
IMPLICATIONS OF INCREASING BACTERIAL
RESISTANCE TO ANTIBIOTICS
Previous investigations have shown that antibiotic regimens
lacking activity against microorganisms identified as causing
serious infections (e.g., hospital-acquired pneumonia and
bloodstream infections) are associated with greater hospital
mortality [37–46]. More recently, the same finding has been
demonstrated for patients with severe sepsis [47–50]. Unfortunately, changing antibiotic therapy to an appropriate regimen
after susceptibility data become available has not been demonstrated to improve clinical outcomes [39, 43, 45]. These
studies suggest that clinicians should strive to administer appropriate initial antibiotic treatment to patients with serious
infections, especially those infected with potentially high-risk
antibiotic-resistant pathogens (e.g., Pseudomonas aeruginosa,
Acinetobacter species, and methicillin-resistant S. aureus), to
minimize the risk of mortality. In addition, optimal dosing, the
interval of drug administration, and duration of treatment are
factors that must be considered for antibiotic efficacy, for limitation of toxicity, and to prevent the emergence of bacterial
resistance [21].
STRATEGIES FOR PREVENTING ANTIBIOTIC
RESISTANCE
The most commonly used antibiotic-modification strategies
aimed at limiting antibiotic resistance are provided here, to
place antibiotic cycling in the proper context of these other
interventions. It is assumed that, whenever antibiotics are prescribed, they will be used in doses and administered at time
intervals aimed at optimizing their pharmacokinetic and pharmacodynamic properties [21].
Formal Protocols and Guidelines
Antibiotic practice guidelines or protocols have emerged as a
potentially effective means of both avoiding unnecessary antibiotic administration and increasing the effectiveness of prescribed antibiotics. Automated antibiotic use guidelines have
been successfully used to identify and minimize the occurrence
of adverse effects of drugs administered and to improve antibiotic selection [51, 52]. Their use has also been associated with
stable antibiotic susceptibility patterns for both gram-positive
and gram-negative bacteria, possibly as a result of promoting
antibiotic heterogeneity and specific end points for discontinuation of antibiotic treatment [53, 54]. Antibiotic guidelines
have also been applied to reduce the overall use of antibiotics
and to limit the use of inappropriate antibiotic treatment, both
of which could affect the development of antibiotic resistance
[40, 55, 56]. One way these guidelines limit the unnecessary
use of antibiotic agents is by recommending that therapy be
modified when initial empirical broad-spectrum antibiotics are
prescribed and results of culture reveal that more narrow-spectrum antibiotics can be used [56].
Hospital Antibiotic Prescription Restrictions
Restricted use of specific antibiotics or antibiotic classes has
been used as a strategy to reduce the occurrence of antibiotic
resistance and to reduce costs of antibiotics [21]. Such an
approach has been shown to achieve reductions in pharmacy
expenses and in adverse reactions to the restricted drugs [57].
Restricted use of specific antibiotics has generally been applied
to those drugs with a broad spectrum of action (e.g., carbapenems), rapid emergence of antibiotic resistance (e.g.,
cephalosporins), and readily identified toxicity (e.g., aminoglycosides). To date, it has been difficult to demonstrate that
antibiotic prescription restrictions are effective in curbing the
overall emergence of antibiotic resistance among bacterial
species. This may be due, in large part, to methodological
problems. However, their use has been successful in specific
outbreaks of infection with antibiotic-resistant bacteria, particularly in conjunction with infection control practices and
educational activities regarding antibiotics [31, 58–60]. Of
note, this type of intervention will be successfully implemented only if such outbreaks are recognized by monitoring
patient surveillance cultures and clinical cultures.
Antibiotic Cycling • CID 2006:43 (Suppl 2) • S83
Use of Narrow-Spectrum Antibiotics
Antibiotic Cycling
Another proposed strategy to curtail the development of
antibiotic resistance, in addition to the judicious overall use
of antibiotics, is to use drugs with a narrow antibiotic spectrum. Several investigations suggest that infections such as
community-acquired pneumonia can usually be successfully
treated with narrow-spectrum antibiotics, especially if the infections are not life-threatening [61, 62]. Similarly, the avoidance of broad-spectrum antibiotics (e.g., cephalosporins) and
the reintroduction of narrow-spectrum agents (e.g., penicillin,
trimethoprim, and gentamicin) along with infection control
practices have been successful in reducing the occurrence of
infections with Clostridium difficile [63]. Unfortunately, patients in ICUs often have already received antibiotic treatment, making it more likely that they will be infected with
an antibiotic-resistant pathogen [34]. Therefore, initial empirical treatment with broad-spectrum agents is often necessary to avoid inappropriate treatment until culture results
become available [41, 42].
Studies supporting antibiotic cycling. Antibiotic class cycling
has been suggested as a potential strategy for reducing the
emergence of antibiotic resistance [70]. In theory, a class of
antibiotics or a specific antibiotic drug is withdrawn from use
for a defined period and reintroduced at a later point in time
in an attempt to limit bacterial resistance to the cycled antibiotic
agents. This offers the potential for antibiotic classes to be used
that possess greater overall activity against the predominant
ICU pathogens, resulting in more-effective treatment of nosocomial infections. Antibiotic cycling is one method of achieving antibiotic heterogeneity, a practice whereby multiple antibiotic classes are used in an environment such as the ICU to
reduce the emergence of resistance that might occur as a result
of using a single or limited number of antibiotic classes. Other
methods include mixing of antibiotic classes, scheduled changes
of antibiotic classes, and the rotation of antibiotics (figure 1).
Rahal et al. [31] introduced an antibiotic guideline in their
hospital that significantly restricted the clinical use of cephalosporins. This was done to combat an outbreak of infection
with extended-spectrum b-lactamase–producing Klebsiella
pneumoniae. The restriction of cephalosporin use was successful, with an 80.1% reduction in their hospital-wide use, which
was accompanied by a 44.0% reduction in infection and colonization with the extended-spectrum b-lactamase–producing
K. pneumoniae [31]. However, the use of imipenem increased
by 140.6% during the intervention year and was associated with
a 68.7% increase in the incidence of imipenem-resistant P. aeruginosa throughout the medical center. Although the number of
multiply resistant pathogens decreased with this formulary restriction, its overall effectiveness can be questioned. This experience illustrates the potential limitations of substituting homogenous use of one antibiotic class with that of another.
Gerding et al. [71] first evaluated the cycling of aminoglycosides over a 10-year period at the Minneapolis Veterans Affairs Medical Center, cycling amikacin and gentamicin. The
cycling of aminoglycosides was introduced in response to increasing levels of resistance to gentamicin among gram-negative
bacteria. Using cycles of 12–51 months, these investigators
found significantly reduced resistance to gentamicin when amikacin was used but a return of resistance with the rapid reintroduction of gentamicin; this was followed by more-gradual
reintroduction of gentamicin a second time, without increased
levels of resistance occurring. This experience suggested that
the cycling of antibiotics within the same drug class, in some
circumstances, could be an effective strategy for curbing antibiotic resistance. However, the overall use of aminoglycosides
also decreased during the 10-year course of this investigation,
potentially contributing to the reduced resistance.
My group [72] first examined the influence of a scheduled
antibiotic change on the incidence of nosocomial infections
Combination Antibiotic Therapy
The use of combination antibiotic therapy has been proposed
as a strategy to reduce the emergence of bacterial resistance, as
has been used for Mycobacterium tuberculosis infection. Unfortunately, no convincing data exist to validate this strategy’s
effectiveness for nosocomial infections. Several recent metaanalyses recommend the use of monotherapy with a b-lactam
antibiotic for the definitive treatment of neutropenic fever and
severe sepsis, once antibiotic susceptibilities are known [64, 65].
Additionally, there is no definitive evidence that the emergence
of resistance to antibiotics is reduced by the use of combination
antibiotic therapy. However, empirical combination therapy directed against high-risk pathogens such as P. aeruginosa should
be encouraged until the results of antibiotic susceptibility testing become available. Such an approach to empirical treatment
can increase the likelihood of providing appropriate initial antibiotic therapy with improved outcomes [46, 66].
Shorter Courses of Antibiotic Treatment
Prolonged administration of antibiotics to patients in ICUs has
been shown to be an important risk factor for the emergence
of colonization and infection with antibiotic-resistant bacteria
[36, 40]. Therefore, recent attempts have been made to reduce
the duration of antibiotic treatment for specific bacterial infections. Several clinical trials have found that antibiotic treatment for 7–8 days is acceptable for most patients with ventilator-associated pneumonia who do not have bacteremia [35,
40, 56]. Similarly, shorter courses of antibiotic treatment have
been successfully used for patients at low risk for ventilatorassociated pneumonia [67], patients with pyelonephritis [68],
and patients with community-acquired pneumonia [69].
S84 • CID 2006:43 (Suppl 2) • Kollef
Figure 1. Strategies for achieving antibiotic heterogeneity. Each arrow denotes a unit of time. B, b-lactam; CA, carbapenem; CE, cephalosporin; Q,
quinolone.
among patients undergoing cardiac surgery. This was done because of high rates of resistance to the third-generation cephalosporins, particularly among Klebsiella and Pseudomonas species. During 6 months, the traditional practice of prescribing
a third-generation cephalosporin (ceftazidime) for the empirical treatment of gram-negative bacterial infections was used,
which was followed by a 6-month period during which a fluoroquinolone (ciprofloxacin) was used. Unexpectedly, the overall incidence of ventilator-associated pneumonia was significantly reduced in the second 6-month period, compared with
that in the first 6-month period. This was primarily due to a
significant reduction in the incidence of ventilator-associated
pneumonia attributed to antibiotic-resistant gram-negative
bacteria.
In a subsequent similar investigation, we cycled different
antibiotic classes for the treatment of suspected or documented
gram-negative bacterial infections during 3 consecutive 6month periods among patients (n p 3668 ) admitted to a medical and surgical ICU [73]. Again, this was done to evaluate
the influence of scheduled drug changes on outcomes after a
period of prolonged use of cephalosporins in the ICU setting.
The overall administration of inappropriate antibiotic treatment for nosocomial infections was decreased during the course
of this study, primarily because of a statistically significant decrease in the administration of inappropriate antibiotic treatment for gram-negative bacterial infections. Additionally, we
found that the hospital mortality rate significantly decreased
during our third antibiotic cycle period for patients with greater
severity of illness. The data from these 2 studies suggest that
scheduled changes of antibiotic classes, away from a drug class
used as the predominant empirical choice for treatment, can
reduce the short-term occurrence of infections with antibioticresistant organisms [72, 73].
Gruson et al. [74] developed an antibiotic intervention program in their ICU because of high levels of resistance to the
quinolone and cephalosporin classes of antibiotics among
gram-negative bacteria. The program consisted of restricting
the use of ceftazidime and ciprofloxacin along with cycling
other antibiotics directed against gram-negative bacteria. Antibiotic consumption and resistance profiles were monitored
monthly to help determine the antibiotics to be used during
each subsequent time cycle. The occurrence of ventilator-associated pneumonia significantly decreased during the 2-year
intervention period, compared with that in the 2-year control
period, when cycling and restriction of quinolones and cephalosporins were not used. The reduction in ventilator-associated
Antibiotic Cycling • CID 2006:43 (Suppl 2) • S85
pneumonia was primarily attributable to a decreased incidence
of infection with antibiotic-resistant gram-negative bacteria. Indeed, it appeared that part of the explanation for these findings
was the greater administration of effective antibiotic regimens
during the cycling periods, as was also demonstrated in our
own study [73].
Gruson et al. [75] also evaluated the long-term benefits of
antibiotic cycling. The long-term effect of their cycling program
was studied by comparing the incidence of gram-negative bacilli
responsible for ventilator-associated pneumonia during a 3year period of routine use of this strategy after the period of
investigation. They found that there was a sustained decrease
in the occurrence of early-onset ventilator-associated pneumonia but that the occurrence of late-onset ventilator-associated pneumonia increased. Overall, the potential antibioticresistant gram-negative bacilli identified were more susceptible
to most b-lactam antibiotics than were gram-negative bacilli
identified during the precycling period.
Raymond et al. [76] conducted a 2-year before-and-after
study in a surgical ICU, to evaluate the influence of an antibiotic
rotation strategy on clinical outcomes [76]. Specific antibiotic
rotation schedules were developed for pneumonia and intraabdominal infections. Outcome analysis revealed significant
reductions in the incidence of gram-positive bacterial infections, antibiotic-resistant gram-negative bacterial infections,
and mortality associated with infection. This same group of
investigators subsequently demonstrated that this strategy of
antibiotic rotation in the ICU setting was associated with a
reduction in infection-related morbidity (rates of hospital-acquired and antibiotic-resistant hospital-acquired infection) on
non-ICU wards to which patients were transferred [77]. Unfortunately, as was seen in the studies by Gruson et al. [74, 75],
these antibiotic rotation studies had methodological limitations.
First, they used historical control groups to determine the influence of antibiotic cycling on clinical outcomes. Second, modifications in other practices, including infection control and
antibiotic-specific changes (e.g., de-escalation of antibiotic
treatment on the basis of subsequent culture results), may have
contributed to the observed outcome differences.
Studies rebutting the benefits of antibiotic cycling. Unfortunately, mathematical modeling suggests that the use of
antibiotic cycling will be inferior to “mixing” of antibiotics as
a strategy to reduce the emergence of antibiotic resistance [78].
At the scale relevant to bacterial populations, mixing of antibiotic classes imposes greater heterogeneity than does cycling
[78]. Consequently, antibiotic cycling is unlikely to be effective
and may even promote the emergence of resistance. This is
supported by several more-recent clinical experiences.
van Loon et al. [79] cycled 2 different antibiotic classes (fluoroquinolone and b-lactam) in a surgical ICU during four 4month cycling periods, obtaining respiratory aspirates and recS86 • CID 2006:43 (Suppl 2) • Kollef
tal swabs for culture. In all, 388 patients were evaluated along
with 2520 culture results. There was good adherence to the
antibiotic protocol, but overall antibiotic use increased by 24%.
Acquisition of resistant bacteria was highest during use of levofloxacin and piperacillin-tazobactam. The potential for selection of antibiotic-resistant gram-negative bacteria during periods of homogenous exposure increased from cefpirome to
piperacillin-tazobactam to levofloxacin.
Similarly, Warren et al. [80] cycled 4 classes of antibiotics
with gram-negative activity over 3- to 4-month intervals for
24 months after a 5-month baseline period of uncontrolled
antibiotic use. Acquisition of resistance was evaluated by culture
of Enterobacteriaceae and P. aeruginosa obtained from rectal
swabs on admission, weekly in the ICU, and at discharge.
Among study patients who were not already identified by culture as having a resistant organism, the rate of acquisition of
enteric colonization with an organism resistant to any of the
target drugs remained stable during the cycling period: (P. aeruginosa: relative rate, 0.96; 95% CI, 0.47–2.16; Enterobacteriaceae: relative rate, 1.57; 95% CI, 0.80–3.34). However, the
proportion of P. aeruginosa resistant to the target drugs increased hospital-wide during the cycling period but decreased
in the ICU in which antibiotic cycling was used [80].
It is important to note that these last 2 studies were performed in unique situations. The study by van Loon et al. [79]
was performed in the Netherlands, where baseline rates of antibiotic-resistant gram-negative bacteria are low. Warren et al.
[80] conducted their trial in an ICU that was already using
aggressive infection control practices and strategies aimed at
minimizing unnecessary antibiotic use [40, 46, 56]. Therefore,
antibiotic cycling appeared to be less effective in these rigorous
investigations than in earlier studies, in which cycling was introduced as a potential “fix” for problematic antibiotic practices
[72–77, 81].
Summary
Clinicians working in the ICU setting should routinely use
antibiotic strategies aimed at limiting the emergence of resistance [21]. Antibiotic cycling appears to be of limited value as
a stand-alone intervention. Nevertheless, strategies incorporating multiple interventions, including antibiotic heterogeneity,
shorter courses of treatment, and narrowing or de-escalation
of antibiotics on the basis of culture results, are most likely to
be successful.
Acknowledgments
Potential conflicts of interest. M.H.K.: no conflicts.
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