Advantages and drawbacks of antibiotic cycling in the critical care setting

Therapeutics

Advantages and drawbacks of antibiotic cycling in the critical care setting J.A. Martínez Department of Infectious Diseases, Hospital Clínic, IDIBAPS — University of Barcelona, Spain. Correspondance: J.A. MARTÍNEZ, Department of Infectious Diseases, Hospital Clínic Villarroel 170, 08036 Barcelona, Spain. e-mail: [email protected]

Résumé/Abstract ■■ ■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■ Advantages and drawbacks of antibiotic cycling in the critical care setting J.A. Martínez Cycling or rotation consists of the sequential or periodic use of two or more antibiotics not sharing a common mechanism of resistance. Cycling has been proposed as a putative tool for decreasing current resistance rates or deterring the emergence of resistance, particularly in the ICU setting. Perhaps the most remarkable hallmarks of cycling literature continue to be heterogeneity and flaws in individual studies which seriously compromise the interpretation of outcomes. Although as a strategy of antibiotic cycling use has, as a whole, a favorable record regarding resistance and clinical outcomes in the ICU setting, doubts still persist about this strategy being the best option. Further well-designed clinical trials must clarify whether other strategies able to promote a higher heterogeneity in antibiotic use, such as mixing, will ultimately be more effective. In this article, the pertinent theoretical basis and clinical experience concerning cycling are reviewed. Key words: intensive care unit, antibiotic cycling, antibiotic mixing, antimicrobial resistance, nosocomial infection.

Avantages et difficultés dans l’application du cycling (rotation) des antibiotiques dans les unités de soins intensifs J.A. Martínez L’usage de la rotation (cycling) des antibiotiques chez des patients de réanimation est représenté par des périodes séquentielles d’utilisation de deux ou plus de deux antibiotiques vis-àvis desquels les mécanismes de résistance diffèrent. Le cycling a été proposé comme un outil potentiellement efficace pour diminuer les taux actuels de résistance ou au moins limiter l’émergence de nouveaux mécanismes en Unité de soins intensifs (USI). Ce qui domine dans la littérature consacrée au cycling est l’hétérogénéité et la variabilité des données dans les études individuelles, ce qui compromet l’interprétation des résultats. Bien que la stratégie utilisant le cycling semble globalement offrir un résultat favorable quant à la résistance bactérienne ainsi que pour l’évolution clinique, des doutes persistent sur la notion selon laquelle le cycling est la meilleure stratégie. Plus récemment des essais cliniques bien construits devraient permettre d’observer de meilleures stratégies dans l’hétérogénéité des antibiotiques utilisés, et le concept du « mixing » pourrait à terme s’avérer plus efficace. Dans ce travail, sont revues sous un angle critique les bases théoriques et l’expérience clinique de l’usage de la rotation des antibiotiques chez les patients de réanimation. Mots-clés : unité de soins intensifs, rotation des antibiotiques (cycling), associations d’antibiotiques (mixing), résistance aux antibiotiques, infections nosocomiales. Antibiotiques 2007 ; 8 : 25-33

© 2007. Elsevier Masson SAS. Tous droits réservés

Introduction Cycling or rotation consists of the sequential or periodic use of two or more antibiotics not sharing a common mechanism of resistance. During the time span of a cycle, a given antibiotic is predominantly used and then substituted for another, usually from a different class. However, what defines an antibiotic as different from the previous one is not the class to which it belongs but the underlying determinant of resistance. When cycling is used as an intended intervention, the selection of drugs, the order of administration, the duration of cycles and the population on which the procedure is applied follow some pre-established schedule. This differentiate cycling as a strategy of antibiotic use from other non-planned changes in antibiotic administration, that may occur as a consequence of seasonal variations in disease incidence, outbreaks or the loss of efficacy due to resistance to a drug previously used. Cycling has been proposed as a putative tool for decreasing current resistance rates Abreviations ICU VAP

: intensive care unit : ventilator-associated pneumonia GNB : Gram-negative bacilli MRSA : methicillin-resistant Staphylococcus aureus ESBL : Extended Spectrum beta-lactamase y : year 4th-g : fourth-generation Piper-tazo : piperacillin-tazobactam Ticar-cla : ticarcillin-clavulanate TMP/SMX : trimethoprimsulfamethoxazole CVC : central venous catheter

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Advantages and drawbacks of antibiotic cycling in the critical care setting

or deterring the emergence of resistance. Before evaluating the clinical experience, the discussion of some theoretical concepts may be useful to gain insight into the basic understanding of the link connecting antibiotic pressure and resistance and the effect that cycling and other strategies may have on it.

Theoretical considerations SELECTIVE PRESSURE EXERTED BY ANTIBIOTICS

26

Selective pressure exerted by antibiotics on a community may increase the prevalence of people colonized by a given resistant microorganism in either one or both of the following ways: 1. By selecting resistant mutants from a predominantly susceptible bacterial population already colonizing or infecting the patient. The risk of selection may depend on the particular drug considered, microorganism and genetic basis of resistance. It can be assumed, for example, that spontaneous mutations in the target of quinolones occur at a sufficiently high frequency in most bacterial species as to endow this drug class with a significant potential for selecting resistant mutants from almost any susceptible bacterial population settled on the patient. In a similar manner, it may be considered that a susceptible P. aeruginosa, when detected in a patient, contains sub-populations of mutants resistant to most, if not all, available antibiotics which can be selected upon specific drug administration. Conversely, selection of mutants is irrelevant for microorganisms whose genetic determinants of resistance do not arise from single point mutations, such as usual methicillin-resistance in staphylococci or vancomycin-resistance in enterococci. 2. By predominantly directing transmission of resistant bacteria to patients treated with a given antibiotic who are initially colonized by susceptible organisms or not colonized by the considered pathogen. This assumption is consistent with clinical and experimental observations showing that antibiotics have always some positive effect in clearing susceptible organisms, while conditioning mucosal surfaces for the settlement of exogenous resistant flora. This mechanism will be operative for any pair of antibiotic-resistant organism as long as there are some individuals carrying the resistant version of

the microbe in the community and there is ongoing person-to-person transmission. Both circumstances are prevalent in the hospital, and certainly in the ICU setting. Selection of resistant mutants by antibiotics given to infected or colonized patients and admission of patients already colonized by resistant organisms guarantee the constant presence in the hospital of people carrying pathogens resistant to many available antibiotics. DETERMINISTIC MATHEMATICAL MODELS

Several deterministic mathematical models have evaluated the eventual relationship between the prevalence of use of an antibiotic (average proportion of patients in a community who receive a given antibiotic at any time) and the prevalence of individuals that will carry a pathogen resistant to it, as well as the time kinetics of this process in the hospital [1-3]. In these models, only transmission dynamics have been considered (the second mechanism discussed above), hence the impact of the prevalence of antibiotic use on resistance represents a minimum on top of which the selection of resistant mutants should be added when extrapolating data to the clinical scenario. All these models predict that under conditions of constant antibiotic pressure, prevalence of resistance will increase, when the prevalence of use of a given antibiotic goes beyond some threshold. The increasing prevalence of resistance will eventually reach a plateau at a level that correlates with the prevalence of antibiotic use. The pace of increasing resistance is expected to be particularly rapid in the hospital where the process can be completed in several weeks to few months. The good news are that, in the hospital setting, curtailing the use of a given antibiotic will diminish the prevalence of resistance and that changes in response to restrictive policies are expected to occur, over the span of weeks to few months. Ceasing the administration of an antibiotic is expected to reduce in a rather short time the prevalence of resistance to the rate of admission of patients already colonized by the resistant pathogen. This decline in the prevalence of resistance after withdrawing the antibiotic will occur whenever admitted patients enter the hospital generally colonized by sensitive bacteria, which will

J.A. Martínez

ultimately displace non-susceptible organisms if there is not sufficient selective pressure to maintain resistance. Therefore, when a decrease in resistance is not observed weeks or months after discontinuation of an antibiotic, it might be suspected that a reservoir (environment or colonized patients with prolonged length of stay) may be maintaining the prevalence of resistance at high levels. After cessation of an antibiotic, the expected decline in resistance will proceed unobstructed as long as drugs not showing cross-resistance with the restricted one are used. In due time, the prevalence of resistance to the restricted antibiotic will come back to low levels and the clinical usefulness of the drug restored. PREDICTABLE OSCILLATING PREVALENCE OF RESISTANCE

Derived from the predominant use and subsequent restriction of an antibiotic, it may turn cycling into a potential aid for the control of resistance in comparison with more traditional approaches to antibiotic management. In fact, cycling regimens in which the use of each drug is high enough and the periods long enough as to reach a clinically worrisome prevalence of resistance, would work like the rather obsolete approach of reserving an alternative effective antibiotic until the previous one is “burned out”. On the other hand, a planned cycling allows the manipulation of the cycles’ duration, hence withdrawal of any of the antibiotics under intervention can (and probably should) be done before an undesirable level of resistance is expected to be reached. In optimal conditions, a well designed cycling strategy could maintain the maximum prevalence of resistance to each one of the antibiotics under intervention below unsafe clinical levels and under the plateau that would correspond to their prevalence of use during the period of preferential administration. In order to preserve the clinical usefulness of any previously used drug over time, it may be important not to reintroduce the antibiotic before resistance has dropped to levels equal or lower than those present at the onset of the last cycle of predominant use. Otherwise, a ratchet effect will result in a progressive increase of resistance with each reintroduction [4].

ANTIBIOTIQUES, 2006 ; 8 : 25-33 © 2007. ELSEVIER MASSON SAS. TOUS DROITS RÉSERVÉS

OTHER OUTCOMES OF CYCLING

They have been subjected to mathematical modeling, the most interesting one being the eventual effect of this strategy on the average rate of patients carrying pathogens resistant to at least one of the rotated antibiotics [5]. According to these models, cycling will increase the average fraction of patients colonized by resistant bacteria as the duration of cycles goes up, and this prevalence will always be higher than that produced by a strategy in which equal fractions of the population receive at any time each one of the antibiotics. In this regard, the latter modality of antibiotic use, called mixing, would act like a cycling strategy with a zero duration of cycles. In addition, the ecological theory has also suggested that in most instances, cycling may be inferior to mixing in barring the generation of multiple resistance.

Cycling in the clinical setting HETEROGENEITY OF CLINICAL TRIALS

The clinical trials that have specifically addressed the subject of antibiotic cycling or so-called scheduled changes of antibiotics in the critical care setting are shown in table 1 [6-20]. Several reviews on the topic have also been published [21-26]. Perhaps the most remarkable hallmark of cycling literature is heterogeneity which seriously compromises interpretation of outcomes. The studies differ in almost all possible characteristics, such as purpose, design, measurements (including outcomes), number and duration of cycles, number of antibiotics cycled, comparison groups and, to some extent, setting and population on which the intervention is applied. Two studies focused in the substitution of a single antibiotic for another of different class [6, 9], one in the substitution of two antibiotics [11] and the rest cycled several antibiotics of different classes in a single tandem cycle [7, 10, 16-20] or multiple tandems [8, 12-15]. In few studies, multiple tandem cycles over periods of 1 year or longer were applied as to ascertain the long-term effect of interventions [8, 12-15]. Comparisons were done between different cycles of preferential usage of a given antibiotic [6, 7, 9, 11, 17, 18], successive baseline

and post-intervention periods [8, 10, 14, 15], simultaneous cohorts subjected and non-subjected to the intervention [13] and different strategies [16, 19, 20]. Each particular study has its own drawbacks but some general issues are of note. Firstly, those studies in which a change of a single antibiotic or a single tandem cycle were done, could only evaluate the putative effect of scheduled changes of antibiotics rather than cycling itself. The main advantage of cycling as a general strategy of use of antibiotics, lies in its potential for maintaining unchanged the level of resistance over time (and lower than other strategies) thanks to the programmed periodic introduction and withdrawal of a limited number of antimicrobials. For analytical purposes, at least three phases of preferential use and removal of each of the antibiotics under intervention should be ideally evaluated [26], which has been done in only four studies [8, 13-15]. SEQUENTIAL DESIGNS

Secondly, all investigations except one [13] used a sequential design, and it is well acknowledged that the outcomes in these kind of studies may be influenced by time-dependant confounders. Although some expected secular trends, such as the progressive increase in the severity of illness of ICU patients, would not bias the outcome towards a favorable effect of any strategy of antibiotic use, other events can make it very difficult to unequivocally attribute a given beneficial outcome to the studied intervention. This is particularly true for additional interventions that can effectively cut down antibiotic pressure (for instance throughout restriction of some antimicrobial agents plus de-escalation) [8] or the rate of pathogen transmission (usually by implementing new infection-control measures) [10, 15, 20]. Conversely, some secular trends can negatively affect the measured outcomes independently of the intervention itself. This could happen if during a given period more patients already colonized by resistant bacteria are admitted, if usage of antibiotics increases as a consequence of admission of sicker patients with a greater risk of infection, and if the length of stay is prolonged. In two studies [16, 17], there was a heavier use of antibiotics during one

Therapeutics of the intervention periods which may have conditioned the observed results. HAZARD VARIABILITY

There is a last consideration regarding the shortcomings of the cycling literature: even if transmission variables, such as compliance with barrier precaution, or cohorting of health care worker-patient contacts do not vary, non-negligible fluctuations in the prevalence of patients colonized by resistant organisms can be expected [27]. Hence, this chance variability can be wrongly attributed to the intervention. The reason for such fluctuations lies in the usually small size of ICUs, which imposes (through the dynamics of patient admissions and discharges) important random changes in relevant transmission variables, such as colonization pressure (proportion of patients that at any given time are colonized by a particular organism) [28, 29]. The fact that the risk of acquisition of resistant microorganisms may be enhanced by the colonization pressure makes less reliable the value of statistical differences, based on usual tests presuming outcome independence among patients. None of the cycling studies used alternative analysis based on stochastic models capable to assess most of the chance variability [27, 30]. The lack of adjustment for the above mentioned potential confounders cast a shade of doubt on most studies about the causal relationship between cycling and the observed outcomes. However the work done can not be entirely dismissed and some general conclusions may be drawn. RELATIONSHIPS BETWEEN SCHEDULED CHANGES OF ANTIBIOTICS AND RESISTANCE: CASE STUDIES

Several clinical studies have confirmed the theoretical predictions that: a) changing an antibiotic for another to which there is no significant cross-resistance is associated with a decrease in the prevalence of resistance to the first drug; b) reintroduction of a previously withdrawn antibiotic is again associated with an increase in resistance; c) changes in resistance after variation in the prevalence of use occur quickly, although not necessarily as fast as predicted by mathematical models.

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Advantages and drawbacks of antibiotic cycling in the critical care setting

J.A. Martínez

Study 1

crease in resistance to imipenem. However, no significant changes in the prevalence of resistance to ß-lactamase-inhibitor combinations or cephalosporins were noted during their respective periods of predominant usage. This study also showed that there was no change in the global prevalence of resistance over time: due to the study design, it is not clear whether the stability in the rates of resistance was the result of rotation in each of the three ICU subunits or of the preferential usage of different antibiotic classes at any given time in these subunits. In the third study [20], an outbreak of a carbapenem-resistant A. baumannii ensued during the 4-month prioritization period of carbapenems that apparently continued even after the decline in the use of this antibiotic class. It was not reported whether this epidemic strain was resistant to all β-lactams, which could have explained its persistence. An increase in ESBL-producing Enterobacteriaceae was also observed during the prioritization period that apparently originated within the cycle of preferential cephalosporin use. However, no changes in the susceptibility of P. aeruginosa were observed during the whole year of three successive 4-month rotation of carbapenems, cefepime and piperacillin-tazobactam.

In an early 6-month before-and-after study [6], (table 1) substitution of ciprofloxacin for ceftazidime in a cardiothoracic ICU led to a decrease in the prevalence of patients exposed to ceftazidime from 20% to 7% and to an increase in ciprofloxacin exposure from 3% to 19%. The rate of ceftazidime resistance among infecting gram-negative bacilli causing ventilatorassociated pneumonia (VAP) or bacteremia dropped from 32% during the ceftazidime period to 10% in the ciprofloxacin period. There was not a corresponding increase in the prevalence of resistance to ciprofloxacin, which remained at 10-12% in both periods. Study 2

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Another 6-months before-and-after study carried out in a medical-surgical ICU [11] (table 1) also showed that a substitution of trimethoprim-sulfamethoxazole for amoxicillin-clavulanate and of imipenem or cefepime plus metronidazole (depending on the type of infection) for piperacillin-tazobactam led to a lower incidence of both MRSA and P. aeruginosa resistant to piperacillin-tazobactam among isolates involved in clinical infections. A trend towards an increase in resistance to imipenem during the period of preferential use of this antibiotic was also observed. Study 3 In a more recent investigation [17], carried out in a surgical ICU, prevalence of resistance was assessed along four successive 4-month rotation scheme of levofloxacin, then cefpirome, then again levofloxacin and then piperacillin-tazobactam. Acquisition of resistant strains was evaluated by obtaining cultures of respiratory secretions and rectal swabs on admission and once weekly thereafter. A 96% adherence to the program was achieved. Prevalence of patients carrying gram-negative bacilli resistant to the scheduled antibiotic of the period, clearly went up and down according to the prevalence of use with some exceptions. Prevalence of resistance to levofloxacin peaked (50%) after three months of predominant use, then dropped to less than 10% at the end of the cefpirome period, to rise again up to 30% upon reintroduction of levofloxacin. Prevalence of resistance to both cefpirome and piperacillin-tazobactam

peaked during the periods of preferential use of one or the other ß-lactam and was low or went down during the levofloxacin cycles. The most striking exception was that the prevalence of levofloxacin resistance did not decrease again during the last period of piperacillin-tazobactam predominant use, despite the fact that the acquisition rate of levofloxacinresistant isolates was significantly lower than during the cycles of predominant levofloxacin usage. This discrepancy was probably due to the longer stay of patients during that period. The study also showed that homogeneous exposure to a given antibiotic class did not prevent the development of resistance to the other classes and that withdrawal of exposure may not necessarily be followed by a decrease in resistance as rapid as predicted by mathematical models. The latter observation may, in fact, be a direct consequence of the continuous presence in the unit of patients colonized by multipledrug resistant strains. Studies 4, 5, 6 At least three other studies have shown that priority given to a single antibiotic class during periods of ≥3 months may not only promote resistance to the drug in question, but have prolonged effects and foster multiple-drug resistance [16, 18, 20]. In one of them [16], a scheduled change of carbapenems, cefepime, ciprofloxacin and piperacillin/tazobactam at 3-month intervals during one year, led to a significant increase in the rates of resistance to cefepime and piperacillintazobactam among GNB which occurred mainly during the periods of preferential use of these antibiotics (18%-22% in comparison to 1%-4% in the beforeperiod). Also a 21% rate of organisms resistant to more than one drug (compared with 5% in the before-period) was observed. However, the increase in resistance to ciprofloxacin and carbapenems was not notorious and did not reach statistical significance. Similar findings for Gramnegative bacilli were obtained in another study where cephalosporins, ß-lactamaseinhibitor combinations and fluoroquinolones were rotated at 8 month intervals [18]. In regards to P. aeruginosa, there was a marked drop in susceptibility to ciprofloxacin during prioritization of both quinolones and ß-lactamaseinhibitor combinations. In addition, quinolone periods were associated with an in-

LESSONS RESULTING FROM STUDIES (AS DESCRIBED ABOVE)

The first lesson learnt from these studies is that for most antibiotics cycling is very effective in promoting resistance in Gramnegative bacilli to the scheduled drug, when predominantly administered during periods as short as 3 months. However, this is not a specific drawback of cycling but just what it should be expected. The second lesson is that the real microbial world tends to be more complex than mathematical models, because some assumptions are hardly fulfilled. The presumption of independence among different classes of antibiotics on selection of resistance is obviously too simplistic. Piperacillin-tazobactam and antiPseudomonas cephalosporins can both exert similar pressure for the selection of de-repressed inducible chromosomal β-lactamase producers among nonfermentative and enteric Gram-negative bacilli. Similarly, quinolones and several β-lactams can favor the emergence of

ANTIBIOTIQUES, 2006 ; 8 : 25-33 © 2007. ELSEVIER MASSON SAS. TOUS DROITS RÉSERVÉS

Therapeutics

Table 1 Clinical trials of antibiotic cycling. Études cliniques utilisant la rotation d’antibiotiques.

Ref.

Setting/Indication /Inclusion criteria /Primary outcome measurement

Cycle description [cycle duration] /no. of patients included per period

Adhesion to the scheduled regimen

Outcome/Weaknesses of the study

6 (1)*

• Cardiothoracic ICU • Empiric treatment of GNB infections • Patients undergoing cardiac surgery • Incidence of VAP and of VAP due to resistant GNB

• Ceftazidime (baseline) to ciprofloxacin [6 mo.] • 353/327

Estimated >71%

• Decrease in the incidence of VAP due to a significant reduction in the incidence of VAP due to antibiotic-resistant GNB • Before-and-after design. Only one antibiotic changed and one period of antibiotic change. Relative small sample to have statistical power to identify all important risk factors for the outcomes examined or to identify all significant outcome differences between the study groups. No colonization studies performed

7

• A medical and a surgical ICU • Empiric treatment of GNB infections • All admitted patients • Rates of inadequate antimicrobial therapy for nosocomial infections

• Ceftazidime (baseline) to ciprofloxacin to cefepime [6/6/5 mo.] • 1323/1243/1102

Estimated ≥58%

• Decrease in the administration of inadequate antibiotic treatment for GNB infections. Decreased mortality rate in patients with APACHE II ≥15 in period 3 (cefepime). During the cefepime period there were more infections (including VAP) than during other cycles • Sequential design. Only one tandem of cycling. No information about possible heterogeneity of effects by type of ICU. The lower mortality on patients with more severe disease during cycle 3 (cefepime) was apparently not explained by the reduction in the frequency of inappropriate treatment, hence the relationship between the presumed effect of the scheduled change of antibiotics and mortality remained uncertain

8

• Medical ICU. • Treatment of VAP • Patients requiring MV for more than 48 h • Incidence of VAP and involvement of potentially resistant GNB

• 2 y before-intervention period, then 2 y cycling period: cefepime (±amikacin) to piper-tazo (±tobramycin) to imipenem (±netilmycin) to ticar-cla [1 mo]. • 1004/1029 • Other interventions: restriction of ceftazidime and ciprofloxacin, de-escalation

Not stated

• Reduction in the incidence of VAP and a trend towards less involvement of potentially resistant GNB. Increase in the susceptibility of P. aeruginosa to cephalosporins, aminoglycosides and almost significantly to ciprofloxacin. Increase in susceptibility of B. cepacea to cefepime and ciprofloxacin and of A. baumannii to Ciprofloxacin. Decreased incidence of MRSA • Before-and-after design. Cycling was one of several strategies leading to a reduction of antibiotic usage in general and quinolones in particular, hence it was difficult to define the intrinsic effect of the rotation program. No colonization studies performed

9

• Medical ICU. • Treatment of infections due to GNB • Patients staying >24 h • Incidence of enteric VRE colonization based on surveillance cultures

• Ceftazidime to ciprofloxacin [6 mo.] • 389/351

Not stated

• No effect in the risk of acquiring VRE after adjustment for known risk factors. No change in the incidence of C. difficile infection, P. aeruginosa bacteremia nor MRSA bacteremia. • Before-and-after design. Only one antibiotic changed. Relative small sample size to detect significant differences in the rate of C. difficile infection and P. aeruginosa bacteremia.

10

• Surgery-trauma ICU. • Empiric treatment of pneumonia, peritonitis, sepsis of unknown origin • All admitted patients • Incidence of ICUacquired infections, infections due to antibioticresistant organisms, mortality associated with infection.

• 1 y of non-protocol, then 1 y of dual-antibiotic rotation (Pneumonia: cefepime to ciprofloxacin to piper/tazo to carbapenem. Other infections: piper-tazo to carbapenem to cefepime to ciprofloxacin) [3 mo.] • 699/757

≥62%

• Reductions in the incidence of antibiotic-resistant Gram-positive coccal infection, antibiotic-resistant GNB infections and mortality attributable to infection • Before-and-after design. Only one tandem of cycling. Change of ceftazidime for cefepime and introduction of alcohol handrub that affected mainly the rotation period.

11 (2)

• Medical-surgical ICU. • Therapy of common bacterial infection • Patients staying >48 h • Prevalence of resistance in most common pathogens involved in clinical infections

• 6 mo. of non-intervention (preferential usage of amoxicillin-clavulanic and piper-tazo), then 6 mo. of preferential use of TMP/ SMX (instead of amoxicillinclavulanic), and imipenem for pneumonia and cefepime plus metronidazol for peritonitis (both instead of piper-tazo) • 197/200

Not stated

• Significant decrease in methicillin-resistance in both S. aureus and coagulase-negative staphylococci. Significant decrease in piper-tazo resistance in P. aeruginosa together with a trend in resistance to imipenem. No significant difference in the incidence of ICU-acquired infections • Before-and-after study. Only one period of antibiotic change. Small sample size to assess differences in clinical outcomes.

* Figures in parentheses refer to studies selected for description in the text.

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Advantages and drawbacks of antibiotic cycling in the critical care setting

J.A. Martínez

Table 1 Clinical trials of antibiotic cycling. Études cliniques utilisant la rotation d’antibiotiques.

Setting/Indication /Inclusion criteria /Primary outcome measurement

Cycle description [cycle duration] /no. of patients included per period

12

• Pediatric medicalsurgical ICU. • Empiric therapy of any bacterial infection • Admitted patients except those with meningitis • Acquired resistant bacteria as assessed by surveillance cultures (nasopharynx and rectum)

• Imipenem to piper-tazo to ceftazidime plus clindamycin or cefepime, repeated over 18 months [3 mo.]* • 411 (total)

Stated as “common”

• No change over time in the risk of colonization by antibiotic-resistant organisms. • Sequential design. No comparison with other strategies of use of antibiotics. Low power to detect a possibly significant 5% decrease in prevalence of children colonized with antibiotic-resistant bacteria. Acquisition of resistant bacteria was only an estimation because of the few sampling surveillance points (twice per month).

13

• Neonatal ICU with 2 geographically separated care teams. • Therapy of infections due to GNB • All admitted patients • Acquired resistant bacteria as assessed by thrice-weekly sampling of naso-pharynx and rectum

• Control team: antibiotics selected according to physician preference. Rotation team: gentamicin to Piper-tazo to ceftazidime [1 mo.] • Duration: 1 y • 548/514

84%

• No effect on the rate of colonization by resistant gram-negative bacilli (albeit a non-significant trend against rotation was noted, p=0.09). No apparent effect on the incidence of the principal nosocomial infections (albeit the incidence of pneumonia was almost 2 times more common during rotation). • Low power to detect possible clinically significant differences in the rate of infections other than bacteremia.

14

• Same setting and criteria as in ref. 13.

• 2 y before-intervention period, then 2 y of protocolized cycling period, then 3 y of routine cycling (same schedule as in ref. 13) • 1004/1029/823

Not stated

• During routine cycling the incidence of VAP remained stable and was lower than during the before-intervention period. Prevalence of resistance in P. aeruginosa, S. maltophilia y A. baumanii remained stable or steadily diminished despite the reintroduction during the last period of ciprofloxacin and ceftazidime • Before-and-after design. No colonization studies performed

15

• Medical ICU • Therapy of infections due to GNB • Patients staying >48 h • Acquisition of GNB (as assessed by weekly rectal cultures) resistant to the antibiotics under intervention

• 5-month observation period, then 2 y rotation period: 4th-g cephalosporins to quinolones to carbapenems to piper/tazo and back [34 mo] • 242/930

Variable from 45 to 60%

• No difference between periods nor over time during cycling in the acquisition of resistant GNB. No differences in the incidence of VAP or ICU-acquired bloodstream infections. There was a trend towards increased mortality during cycling and a significant increase in the length of stay. • Before-and-after study. There were differences between periods in several markers of severity of illness which may explain the trend towards a higher and length of stay during cycling. There was an infection-control intervention on respiratory therapists during cycling. Due to a less than expected rate of acquisition of resistant GNB, the power to detect a significant reduction in this outcome was low.

16 (4)

• Same setting and criteria as in ref. 15.

• 1 y of dual antibiotic rotation (same schedule as in ref. 15), then 6 month offrotation, then 1 y of single antibiotic rotation (carbapenem to cefepime to ciprofloxacin to piper-tazo) [3 mo.] • 792/369/695

≥72%

• In comparison with dual antibiotic rotation, single rotation was associated with an increased incidence of ICUacquired infections due to resistant GNB and an increased prevalence of resistance in GNB to cephalosporins, pipertazo and more than one drug class • Before-and-after study. Only one tandem of cycling (either dual or single rotation). During the single rotation period patients were sicker and acquired more infections, which determined an increase in the number of antibiotic courses and, by unclear reasons, a longer duration of them. Hence, antibiotic pressure was probably higher during single rotation, and this could have worsen resistance regardless of the rotation schedule by itself

17 (3)

• Surgical ICU. • Empiric treatment of GNB infections • Patients staying >24 h • Acquisition of GNB (assessed by weekly respiratory and rectal cultures) resistant to the drug of choice during the cycle

• Levofloxacin to cefpirome to levofloxacin to piper-tazo [4 mo.] • 89/106/96/59 (admissions)

96%

• Prevalence of resistance to levofloxacin increased during the period of predominant use and decreased in the cefpirome but not in the piper-tazo period. Prevalence of resistance to both β-lactams increased during the periods of exposure and decreased during levofloxacin periods. Acquisition of levofloxacin-resistant and piper-tazo-resistant GNB peak during levofloxacin and piper-tazo periods, respectively. Acquisition of cefpirome-resistant GNB was similar in all periods • Sequential design. No comparison with other strategies. For unclear reasons, global use of antibiotics increased during the last cycle and this could have influenced the pattern of resistance during that period

Ref.

Adhesion to the scheduled regimen

30

* Figures in parentheses refer to studies selected for description in the text.

Outcome/Weaknesses of the study

ANTIBIOTIQUES, 2006 ; 8 : 25-33 © 2007. ELSEVIER MASSON SAS. TOUS DROITS RÉSERVÉS

Therapeutics

Table 1 Clinical trials of antibiotic cycling. Études cliniques utilisant la rotation d’antibiotiques.

Setting/Indication /Inclusion criteria /Primary outcome measurement

Cycle description [cycle duration] /no. of patients included per period

18 (5)

• General ICU with 3 separate subunits • Empirical therapy of common infections • Patients staying >48 h • Susceptibility among infecting isolates and those retrieved from twice-weekly cultures of oropharynx, respiratory secretions and urine

• Ceftazidime or cefepime, β-lactamase-inhibitors combinations, quinolones (Latin square design for the 3 subunits) [8 mo.] • 546 (total)

Estimated ≈ 37%-88%

• No change over time in global resistance or rates of infection. Higher resistance in P. aeruginosa to quinolones and imipenem during preferential quinolone usage and to quinolones during preferential β-lactamase-inhibitors usage; higher resistance to piper-tazo in Enterobacteriaceae during β-lactamase-inhibitors usage; higher resistance to cefotaxime in AmpC-Enterobacteriaceae during cephalosporin periods • Only one cycling period per subunit. No comparison with other strategies. Susceptibility data are presented by periods of time and periods of preferential use of each one of the antibiotics, but the effect of rotation in each subunit is not described. Stability in the rates of resistance over time could have been due to preferential use of a different antibiotic class in each one of the subunits at the same time rather than to rotation

19

• Two medical ICUs • P. aeruginosa coverage deemed necessary • Patients staying ≥48 h • Acquisition of GNB resistant to the antibiotics under intervention

• 4 months of intended mixing vs. 4 month of intended cycling [1 mo.] • 179/167

Estimated ≈ 45%

• During mixing a higher proportion of patients acquired a strain of P. aeruginosa resistant to cefepime and there was a trend towards a higher acquisition of resistance to ceftazidime and carbapenems. No differences in the acquisition of other GNB, MRSA or incidence of nosocomial infections. • Sequential and pseudo-cross-over design. Short-term study comparing only one period of mixing and cycling. Neither mixing nor cycling were perfectly accomplished. Low power to detect significant differences in the incidence of infections or other medical outcomes.

20 (6)

• General ICU • Treatment of VAP • Patients staying more than 48 h • Incidence of colonization/infection as assessed by culture of clinical samples with targeted organisms, and susceptibility patterns

• 10 months of individualized therapy, then 1 y cycling period (prioritization) of carbapenems to cephalosporins to piper-tazo, then 1 y of 4-month restriction cycles (no piper-tazo, no cephalosporins, no carbapenems), then 10 months of mixing [4 mo. for prioritization and restriction] • 777/614/556/674

Estimated as 59%-69%

• An outbreak of a carbapenem-resistant A. baumannii strain occurred during the prioritization period (apparently originated during the cycle of preferential carbapenem usage) that extended to the restriction period. During prioritization there was an increase in ESBL-producing Enterobacteriaceae (apparently originated during the cycle of preferential cephalosporin use). No changes in the incidence of resistant P. aeruginosa. Incidence of E. faecalis increased during prioritization and restriction periods. No changes in the incidence of MRSA. • Sequential design. An infection control program for the management of CVC was introduced during the restriction period. Patient-specific and mixing periods were associated with a lower use of antipseudomonal cephalosporins than of other antipseudomonal β-lactams

Ref.

Adhesion to the scheduled regimen

Outcome/Weaknesses of the study

* Figures in parentheses refer to studies selected for description in the text.

multi-drug resistance in P. aeruginosa strains through selection of mutants over-expressing efflux pumps [31]. In addition, it is difficult to ascertain why a given antibiotic did not produce the same resistance outcome in all studies: differences in the actual prevalence of use of the involved antibiotics or the predominantly administered agent within a class (levofloxacin vs. ciprofloxacin, for instance) may, in part, explain some of the discrepant results. LONG-TERM EFFECT OF CYCLING ON RESISTANCE

In regards to the ability of cycling in maintaining the average prevalence of resis-

tance unchanged over time, the short duration of most studies preclude a definitive answer. However, those studies in which the intervention was sustained for at least one year with one or more re-introductions of the same agents (the “true” strictly speaking “cycling studies”) did not show any definitive trend towards an increased acquisition of antibiotic-resistant bacteria [8, 12-15]. In fact, the longest clinical experience, in which antibiotics were rotated every month during five years [14], showed that the prevalence of resistance in non-fermentative Gram-negative bacilli remained stable or improved steadily. Although the scheduled antibiotics were changed monthly in three of these studies [8, 13, 14], they were rotated

every 3 months in the remaining two [12, 15]. These results did not support the suggestion that rotation may not be effective in the long run due to the eventual development over time of multipledrug resistance [16-18]. COMPARISON OF CYCLING WITH OTHER STRATEGIES

The last question concerning the impact of cycling on resistance is whether this strategy may actually be better than other approaches. In this regard, the results of clinical trials are also heterogeneous, a circumstance that may depend in part on the kind of antibiotic use against which cycling is compared. The most striking

31

Advantages and drawbacks of antibiotic cycling in the critical care setting

32

beneficial effect of rotation proceed from ICU studies in which cycling at 1 month intervals substituted for a systematic use of ceftazidime plus ciprofloxacin [8, 14] or a dual quarterly cycling strategy substituted for a rather mixed spontaneous utilization of the same antibiotics classes [10]. In the former studies [8, 14], a sustained increase in susceptibility of P. aeruginosa and other non-fermenters to some of the antibiotics under intervention and a decreased incidence of MRSA was observed in patients with VAP. In the latter one [10], dual cycling (meaning that in each quarter different antibiotics were given depending on the type of infection, hence some mixing of two drugs was guaranteed within the periods) was associated with a reduction in the incidence of antibiotic-resistant Gram-positive and Gram-negative infections. Interestingly, the same investigators later reported that in comparison with dual cycling, a quarterly single-drug rotation (a single antibiotic used predominantly for all infections within the scheduled period) was associated with an increased incidence of ICU-acquired infection due to resistant Gram-negative bacilli and a higher prevalence of multidrug resistance [16]. MIXING STRATEGIES VERSUS CYCLING

Other studies in which single-antibiotic rotation (with cycle duration of 34 months) was compared with baseline periods or a parallel cohort in settings where some unintended mixing was already done [13, 15] have essentially showed neither beneficial nor untoward effects of single-antibiotic cycling on acquisition of resistant bacteria. Two recent studies have more specifically addressed the issue of comparing cycling with mixing [19, 20] in the ICU setting. In one of them [19], a 4-month period of monthly rotation of antipseudomonal ß-lactams and ciprofloxacin was associated with a lower acquisition rate of P. aeruginosa resistant to cefepime (and a trend towards a lower acquisition of strains resistant to ceftazidime, carbapenems and any ß-lactam) when compared with a 4-month mixing period. However, adherence to cycling was relatively poor, with no more than 45% of patients receiving the scheduled antibiotic within a given cycle. This means

that there was a good deal of mixing during the intended cycling, a situation which may be reminiscent of the dualantibiotic rotation study discussed above [10]. In the second work [20], several strategies producing different “rates” of mixing and cycling (4-month duration) were compared. The rotation period was associated with an outbreak of a carbapenem-resistant A. baumanii, an increase in ESBL-producing Enterobacteriaceae and a higher incidence of E. faecalis infections. The occurrence of an outbreak of a multi-resistant A. baumanii renders difficult the interpretation of results. It is of note that the incidence of resistant P. aeruginosa and MRSA did not significantly change among the different antibiotic strategies. Although the lessons gathered from this variegate information might be subjected to personal interpretation, the following suggestions may be appropriate: 1. Rotation strategies with very short cycle duration (1 month) can maintain the prevalence of resistance stable over long periods of time (up to 5 years). 2. Rotation strategies with cycle duration of 3 months or longer may not prevent the emergence of multi-drug resistance. 3. The beneficial effect of cycling on resistance seems to be noticeable in settings where rotation substituted for the systematic use of a single drug or drug combination. This traditional approach should probably be definitely abandoned. 4. As predicted by mathematical models, mixing or some kind of mixing-cycling (such as dual-antibiotic rotation) may be more effective than single-drug rotation, at least when cycles of 3-month duration or longer are used. However, the relative merits of mixing versus cycling need to be clarified in well-designed future clinical trials. OTHER OUTCOMES AND ISSUES

In some studies, all from the critical care setting, a scheduled change of antibiotic or the implementation of a full cycling strategy have been associated with a decrease in the incidence of VAP [6, 8], a reduction in the administration of inadequate therapy for Gram-negative infection, lower mortality of patients with APACHE II score ≥15 [7], and a decrease in the rate of mortality associated with infection [10]. These favorable outcomes are not entirely unexpected for any stra-

J.A. Martínez

tegy that effectively reduces the pool of antibiotic-resistant bacteria in a given setting. On the contrary, lower rates of resistance will result in more adequate initial treatments, a major determinant of prognosis and probably in a higher prophylactic activity of antibiotics against microorganisms commonly involved in nosocomial infections. Implementation of any strategy of use of antibiotics that alters current prescription habits is not an easy task. A good deal of education for attending physicians and full cooperation of unit directors and pharmacy services are necessary [32]. As experience has demonstrated, these barriers are not insurmountable and cycling policies can even be extended to the entire hospital. Some rotation programs have been associated with an increase in the total amount of antibiotics given and cost [33], which are not specific drawbacks of cycling by itself. They may indicate a more appropriate use at the individual level of available drugs. In any case, it has to be remembered that neither cycling nor any other policy of antibiotic use is a safeguard allowing relaxation in current good practices of antibiotic prescription. CONCLUSIONS

Due to methodological drawbacks found in cycling studies, it is difficult to give a definitive answer about the efficacy of this strategy for preventing resistance or improving other clinical outcomes in the ICU setting. Homogeneous use of an antibiotic during a 3-month period or longer carries a substantial risk of increasing the prevalence of resistance to the prioritized agent up to clinically worrisome levels, with potential development of resistance to other antibiotic classes. Under these conditions of antibiotic use, the expected decrease in resistance after withdrawal of exposure may proceed at a slower pace than predicted by theoretical models. However, no increase in resistance over time has been observed in studies which changed antibiotics on a monthly basis. Hence, homogeneous use of a given antibiotic as part of a cycling strategy should probably not be prolonged beyond two months. Despite methodological drawbacks, there is suggestive evidence that when there is a background of preferential use

ANTIBIOTIQUES, 2006 ; 8 : 25-33 © 2007. ELSEVIER MASSON SAS. TOUS DROITS RÉSERVÉS

of a single drug or a mixed spontaneous utilization of different antibiotics or an intended mixing protocol, the implementation of a scheduled change of antibiotics or a full cycling strategy (with or without other interventions) may be associated with favorable outcomes. Beneficial effects may include lower rates of resistance in GNB (particularly nonfermenters), lower incidence of infections and of ventilator-associated pneumonia or even a decrease in mortality. These outcomes may depend on a high prevalence of resistance to the baseline antibiotic with low rates of cross-resistance to alternative agents, periods of homogenous antibiotic use not longer than one month, and heterogeneity in the use of antibiotics at any given time. When comparing two strategies, it would be preferable to assign patients to simultaneous separate cohorts within the same unit, in order to get rid of possible timedependent confounders. This may be difficult to accomplish given the small size of most ICUs. Different ICUs may be involved, provided that the case-mix of patients, basal prevalence of resistance in relevant organisms and uniform care criteria are applied. Estimation of some epidemiological variables such as the rate of transmission of key organisms is desirable to assure that no substantial changes have occurred which may influence the prevalence of resistance. The heterogeneity of antibiotic use may be the key factor in determining resistance. The real effect of cycling strategy can only be fully assessed if the antibiotics under intervention are introduced and withdrawn at least three times during the study period.

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