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PEDIATRICS Vol. 110 No. 4 October 2002, pp. 707-711

The Effect of Antibiotic Rotation on Colonization With Antibiotic-Resistant Bacilli in a Neonatal Intensive Care Unit

Philip Toltzis, MD, Michael J. Dul, PhD, Claudia Hoyen, MD, Ann Salvator, MS, Michele Walsh, MD, Laura Zetts, RN and Hasida Toltzis, MS

From the Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children’s Hospital of the University Hospitals of Cleveland, Cleveland, Ohio

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   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. This study was designed to test whether rotation of antibiotics can reduce colonization with resistant Gram-negative bacilli in a neonatal intensive care unit (NICU).

Methods. A monthly rotation of gentamicin, piperacillin-tazobactam, and ceftazidime was compared with unrestricted antibiotic use in side-by-side NICU populations (rotation team vs control team). Pharyngeal and rectal samples were obtained 3 times a week and tested for Gram-negative bacilli resistant to each of the rotation antibiotics. Pulsed-field gel electrophoresis analysis determined the numbers of genetically discordant resistant organisms on each team. The association between colonization with a resistant bacillus (the primary outcome) and team assignment was tested.

Results. A total of 1062 infants were studied during a 1-year period. A total of 10.7% infants on the rotation team versus 7.7% on the control team were colonized with a resistant bacillus. No interteam differences were distinguishable when the numbers of genetically discordant resistant organisms were normalized to the total number of team admissions. The incidence of nosocomial infection and mortality also were similar across teams.

Conclusion. These data indicate that rotation of parenteral antibiotics according to the applied protocol has no detectable effect in decreasing the reservoir of resistant Gram-negative bacilli in a tertiary-care NICU.

Key Words: antibiotic resistance • Gram-negative bacilli • neonatal intensive care • antibiotic utilization • colonization • pulsed-field gel electrophoresis

Abbreviations: NICU, neonatal intensive care unit • PFGE, pulsed-field gel electrophoresis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The past 2 decades have witnessed a dramatic increase in infections with Gram-negative organisms resistant to 1 or more classes of broad-spectrum parenteral antibiotics, particularly among severely ill patients hospitalized in intensive care units.1–3 Strategies that recommend manipulating in-hospital antibiotic use have been suggested to reduce the likelihood of emergence of resistance in the critically ill patient. One such strategy is to schedule a rotation of antibiotics.4–7 This strategy entails a regimented preference for a specified antibiotic in a given environment over a fixed period, after which preference is switched to an alternative agent with a similar spectrum of activity. The assumption underlying this strategy is that the exposure to each antibiotic in the schedule is sufficiently short to preclude the emergence of significant populations of organisms resistant to any 1 of them. Applying this strategy to a tertiary-care neonatal intensive care unit (NICU), we tested the hypothesis that antibiotic rotation can reduce the size of the reservoir of antibiotic-resistant Gram-negative bacilli colonizing infants who are admitted to this setting.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Setting and Antibiotic Schedule
The study was conducted in a 38-bed tertiary care NICU serving approximately 1200 patients per year. The NICU has 6 main rooms that house 3 to 6 infants each, a seventh 6-bed transitional unit, and 2 single-bed isolation rooms. Care in the NICU is divided between 2 geographically separated teams composed each of an attending physician, fellow, nurse practitioners, and residents, although infants in the transitional room and the 2 isolation rooms are assigned to either team. Infants are admitted to a given team on the basis of bed availability.

Beginning in November 1998, antibiotics for proven or suspected Gram-negative infections were administered on 1 of the teams (the rotation team) on a rotating schedule that changed monthly: gentamicin followed by piperacillin-tazobactam followed by ceftazidime. Antibiotic courses that spanned the first of the month were continued unchanged into the next month until the course was completed. Antibiotics primarily chosen for coverage of Gram-positive infection, usually vancomycin or ampicillin, were unregulated and ordered at the discretion of the attending physician. On the second team (the control team), physicians chose antibiotics according to their individual preference. This usually included ampicillin and gentamicin for infection suspected at birth, vancomycin and gentamicin for hospital-acquired infection, ampicillin and cefotaxime for meningitis, and piperacillin-tazobactam for necrotizing enterocolitis. Surgical patients in the NICU were assigned to 1 of the 2 pediatric teams and had the same antibiotic guidelines applied as nonsurgical patients.

Breaks in protocol on the rotation team were allowed for the following conditions: 1) group B streptococcal infection (addition of gentamicin permitted), 2) meningitis (a third-generation cephalosporin permitted), 3) necrotizing enterocolitis (piperacillin-tazobactam recommended), 4) persistent coagulase-negative staphylococcal infection (addition of gentamicin permitted), 5) infection by an organism that was not fully susceptible to the assigned protocol antibiotic, and 6) clinical failure of the protocol antibiotic in the absence of a positive culture as judged by the attending physician. The attending neonatologist made the final decision for all antibiotic choices. The incidence of nosocomial infection, as defined according to criteria used by the National Nosocomial Infection Surveillance system,8 and the organisms implicated in these infections during the course of the study were derived from the records of the Infection Control program and the clinical microbiology laboratory at the study site. The study was approved by the Institutional Review Board at University Hospitals of Cleveland and was reviewed and approved by the Divisions of Neonatology and Infectious Disease at Rainbow Babies and Children’s Hospital before commencement. The requirement for individual informed consent was waived, but a description of the study was posted in the NICU.

Microbiologic Data
The incidence of colonization with resistant bacilli was determined as previously described.9 For the purpose of this study, an "antibiotic-resistant Gram-negative organism" was defined as any Gram-negative bacillus resistant to gentamicin, piperacillin-tazobactam, or ceftazidime. Pharyngeal and rectal swab specimens were obtained on all infants every Monday, Wednesday, and Friday. Samples were screened for antibiotic resistance by inoculating on MacConkey agar adjusted to either gentamicin (8 µg/mL), piperacillin-tazobactam (128 µg/mL piperacillin and 4 µg/mL tazobactam), or ceftazidime (32 µg/mL). Organisms that grew after overnight culture on the screening plates were identified using an automated system (Microscan, Sacramento, CA), which uses 24 biochemical tests to yield an 8-digit "octal code." Susceptibility testing was achieved by microdilution using the same system.

Pulsed-Field Gel Electrophoresis
Pulsed-field gel electrophoresis (PFGE) was performed to ensure an accurate measure of the number of genetically distinct resistant organisms isolated on each team. All resistant organisms were analyzed by PFGE at least once, unless the species was isolated on only a single occasion during the course of the entire study. For patients who had an organism of the same species cultured repeatedly, the following criteria were used to select organisms for PFGE: 1) for Enterobacteriaceae that had identical octal codes and for non-Enterobacteriaceae that differed by <=1 digit in their octal code, isolates were selected every seventh day of NICU admission; 2) for organisms that differed biochemically from the first isolate (ie, Enterobacteriaceae that differed by >=1 digit in their octal code or non-Enterobacteriaceae that differed by >=2 digits in their octal code), PFGE was performed regardless of when the organism was first cultured; 3) for organisms that became resistant to any of the 3 rotation antibiotics over time compared with the original isolate, PFGE analysis was performed regardless of when it was first cultured.

PFGE was achieved using standard techniques.10 Isolated bacterial genomic DNA was digested with an endonuclease restriction enzyme predicted to yield between 10 and 25 bands when separated by electrophoresis. The enzymes used were as follows: XbaI for Klebsiella, Citrobacter, and Stenotrophomonas; SpeI for Pseudomonas and Serratia; NotI for Escherichia coli; and SmaI for Acinetobacter. For other genera, the DNA was digested with both XbaI and SpeI. Restriction fragments were separated on 1% agarose gels according to preset programs recommended by the manufacturer of the apparatus (CHEF Genepath System, Biorad, Hercules, CA). Organisms were judged to be concordant when visual inspection of the endonuclease restriction pattern differed by <=3 bands and to be discordant otherwise, as suggested by Tenover et al.10 All assignments of concordance or discordance were established independently by 2 of the investigators (P.T. and C.H.) while blinded to the identity of the patients from whom the organisms were derived. Assignment was confirmed by converting each gel to a digitized image and correlating banding patterns by the Dice coefficient, using a commercially available program (Molecular Analysis Fingerprinting Plus Software, Biorad).

Analysis
The effectiveness of antibiotic rotation was assessed by testing the differences of selected microbiologic outcomes between teams. Comparisons of discontinuous variables were achieved by {chi}2. Differences in continuous variables were tested by t test for parametrically distributed data and Wilcoxon rank sum for nonparametrically distributed data. Significance was assigned at P < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
During a 12-month period (December 1, 1998, through November 30, 1999), 1062 consecutive infants were enrolled prospectively. Ninety-three percent of infants were admitted to the NICU by the third day of life. A total of 514 infants were admitted on the rotation team, and 548 were admitted on the control team. Baseline characteristics of the infants on the 2 teams were similar with regard to gestational age (mean: 35.5 weeks [standard deviation: 4.67 weeks] on the rotation team versus 35.4 weeks [4.65 weeks] on the control team), birth weight (2510 g [998 g] on the rotation team versus 2536 g [1005 g] on the control team), and length of stay (12.0 days [21.8 days] on the rotation team versus 10.6 days [17.7 days] on the control team; all comparisons not significant).

Adherence to the antibiotic rotation protocol was assessed by monthly calculations of the number of antibiotic-days administered for each of the 3 test antibiotics (Fig 1). Marked differences in antibiotic utilization patterns were noted between the 2 teams, with a sawtooth pattern apparent on the rotation team, as driven by the protocol, and a predominant use of gentamicin on the control team, as anticipated by previous NICU practice (Fig 1). On the rotation team, the 3 protocol antibiotics were administered according to the mandated schedule on 84.3% of all antibiotic-days using a rotation antibiotic. Total antibiotic use did not differ between teams. The mean number of antibiotic-days administered, considering just the 3 rotation antibiotics, was 5.31 days (8.31 days) per admission on the control team versus 5.67 days (9.54 days) per admission on the rotation team (P < .9). In addition, considering days of vancomycin and ampicillin use, the principal antibiotics used outside those included in the rotation, antibiotic exposure still was equivalent (10.36 antibiotic-days [14.18 antibiotic-days] on the control team versus 10.86 antibiotic-days [15.23 antibiotic-days] on the rotation team; P < .9)



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  		Fig 1. Antibiotic utilization during the study period. A, Utilization on the rotation team. B, Utilization on the control team. The x axis denotes each month of the study period; the second row under the x axis in A represents the preferred antibiotic assigned for that month on the rotation team. G, gentamicin; P, piperacillin-tazobactam; C, ceftazidime. The y axis in each panel represents total antibiotic-days, with each antibiotic-day indicating at least 1 dose of the designated antibiotic given per patient per day.

 
No differences in the incidence of colonization with resistant organisms between the 2 study teams were detectable. A total of 97 (9.1%) of the 1062 infants were colonized with at least 1 antibiotic-resistant Gram-negative bacillus during the course of the 12-month study period, with 10.7% of infants colonized on the rotation team versus 7.7% of infants on the control team (P < .09; Table 1).


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  		TABLE 1. Effects of Antibiotic Rotation on Resistant Bacillary Colonization

 
PFGE was used to define the total numbers of genetically discordant organisms isolated on each team, to elucidate further the effect of antibiotic rotation on the size of the reservoir of colonizing resistant bacilli. The technique could not be performed on 8.6% of selected isolates as a result of autodigestion of DNA during preparation or failure to grow from frozen stocks. Excluding these samples, a total of 215 organisms discordant by PFGE were isolated during the course of the study—139 on the rotation team and 111 on the control team. Multiple comparisons were made to test the association between team assignment and resistant colonization, but in no instance could an advantage be demonstrated by admission to the rotation team. First, the mean numbers of resistant organisms isolated per culture-positive patient were compared according to team assignment. Nearly identical means were measured (Table 1). The effect of antibiotic rotation was assessed further by comparing the total number of genetically discordant resistant colonizing bacteria normalized to the total number of patients admitted to that team during the course of the trial. Again, no effect of antibiotic rotation could be detected (Table 1). The organisms were subdivided further according to resistance phenotype, considering resistance to each of the 3 rotation antibiotics separately. In no instance was a difference between teams detectable (Table 1).

More than 30 different species were isolated during the course of the study. The majority of the resistant organisms could be grouped into 8 genera. The distribution of these genera identified on each team was similar (Table 2). The proportion of organisms that expressed co-resistance to >1 of the rotation antibiotics also was similar on both teams. Specifically, on the rotation team, 37.4% of organisms discordant by PFGE analysis expressed resistance to 2 of the 3 rotation antibiotics and 10.8% expressed resistance to all 3, whereas these proportions were 45.9% and 9.0%, respectively, on the control team (P < .2).


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  		TABLE 2. Genera Among Resistant Isolates*

 
It was possible that the effectiveness of antibiotic rotation was confounded by a high incidence of horizontal transmission of resistant organisms. Taking both teams together, however, horizontal transmission occurred among only approximately 12% of genetically discordant isolates, as previously reported.9 Horizontal transmission across teams was unusual, with only 10 of the 215 genetically discordant organisms crossing from 1 team to the other.

The incidence of the principal nosocomial infections experienced by infants on each team during the study period was compared (Table 3). No differences were apparent. A total of 131 organisms were identified as the putative cause of these nosocomial events among infants from both teams. Among these, 34 (26.0%) were Gram-negative bacilli. In all but 3 of these Gram-negative isolates, susceptibility data for all 3 of the rotation antibiotics were retrieved. The marked majority of the Gram-negative organisms implicated in these infections were susceptible to all 3 of the rotation-schedule antibiotics. One patient on the rotation team had an E coli isolated from the blood that was resistant to piperacillin-tazobactam. One infant on the control team had pneumonia attributed to Stenotrophomonas maltophilia resistant to both ceftazidime and piperacillin-tazobactam. Among the remainder of pathogens implicated as causes of nosocomial infections, 83 (63.4%) were Gram-positive cocci. These Gram-positive species were evenly distributed over both teams (41 on the control team and 42 on the rotation team). The majority of the Gram-positive species were coagulase-negative staphylococci; of these, 27 of 34 on the control team and 21 of 30 on the rotation team were resistant to gentamicin (P < .4). Mortality from all causes was similar on both teams during the course of the study (3.2% on the rotation team vs 2.3% on the control team; P < .18).


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  		TABLE 3. Nosocomial Infections During Study Period*

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although antibiotic rotation has been recommended as a strategy to decrease resistance in a given unit or hospital,4–7 many aspects regarding the ideal rotation strategy have not been defined. Indeed, few previous reports have tested the practice of antibiotic rotation among hospitalized patients even outside the NICU.11–13 The number of antibiotics required, the duration of exposure to each of the separate agents, and the ideal antibiotics to include in the schedule are uncertain. It also is possible that the strategy will be effective in some settings but not in others. In the absence of previous studies recommending specific schedules, the current study chose a 3-drug monthly rotation including 2 broad-spectrum ß-lactams and an aminoglycoside. Recognizing that it tested only a single schedule, the current study demonstrated no evidence that antibiotic rotation is useful in decreasing the size of the reservoir of resistant Gram-negative bacilli in a tertiary care nursery.

Several factors may be postulated to account for the failure of antibiotic rotation in our study. First, the NICU population may possess intrinsic characteristics that render them unsuitable for an antibiotic rotation study. However, it can be argued that the flora of the initially sterile gastrointestinal tract of the NICU patient should be particularly sensitive to the selective pressures imposed by local antibiotic practice,9,14,15 rendering the lack of effect in the current study all the more striking. Second, it may be posited that colonization by resistant bacilli extended beyond 2 months; consequently, the rotation was too rapid to relieve the unit of antibiotic pressure imposed by any of the component agents. Our previous study in this unit, however, indicated that colonization by resistant bacilli among NICU admission is very short term and fluid.9 In that study, the majority of resistant bacilli on both teams were detected on only a single occasion.

A third consideration is that the inclusion of a third-generation cephalosporin in the rotation may have undermined beneficial effects of the strategy. The third-generation cephalosporins are potent selectors for organisms that express autologous resistance in several clinical settings,16–18 including the NICU.19 It should be noted that we were limited regarding the antibiotics available to us for our rotation study in this newborn population. Two alternative families of antibiotics with broad activity against Gram-negative bacilli, namely, the quinolones and the carbapenems, were precluded, the former because of concerns of arthropathy in very young patients, as has been seen in experimental animals,20 the latter out of concern that overuse would ultimately undermine their benefit in infections caused by organisms resistant to everything else, an issue that has been raised by others.18,21 It is noteworthy that in a recent study supporting antibiotic rotation in an adult surgical ICU,13 ciprofloxacin and a carbapenem were used, both of which are associated with a low frequency of spontaneous, high resistance-rendering mutations among a given population of Gram-negative organisms.22,23 One may question whether the inclusion of these antibiotics in the adult trial was more important in reducing resistance than rotation of these agents per se.

It must be considered further whether the use of ampicillin on both teams presented sufficient selective pressure on the indigenous flora to dilute any potential effects by the rotation schedule. Ampicillin exposure among healthy outpatients has not selected resistance to aminoglycosides or newer generation ß-lactams in stool flora.24,25 It may be argued, however, that in an environment that harbors large numbers of organisms that express broad-spectrum ß-lactamases, as would be expected in a tertiary care NICU, exposure even to early penicillins may be sufficient to sustain the presence of these resistant organisms. If rotation requires cessation of the use of early-generation penicillins to be successful, however, it is unlikely that the strategy would ever be acceptable in the NICU setting.

Finally, it is possible that the concept of antibiotic rotation is intrinsically faulty. Transferable bacterial elements are known to acquire new resistance determinants sequentially.26,27 As a consequence, co-resistance to many agents is common in hospital-acquired pathogens, as was seen in the isolates in the current study, and changing from 1 broad-spectrum agent to another may not relieve antibiotic pressure. In addition, some resistance determinants are linked to other factors that confer survival advantage, such as those that improve adherence to epithelial surfaces or result in resistance to disinfectants,28,29 properties that will not be easily surrendered in the face of antibiotic rotation. Indeed, Bonhoeffer et al30 mathematically modeled 3 patterns of multiple antibiotic use to evaluate their relative propensity to delay or reverse antibiotic resistance: combination use in all patients, equal use of each antibiotic in equal numbers of patients, and cycling. In almost all of the scenarios evaluated, cycling was inferior to the other strategies. In light of these considerations, the current empiric trial, although testing only a single rotation schedule, offers little support for the routine application of antibiotic rotation in the NICU to reduce the numbers of resistant bacilli.


   ACKNOWLEDGMENTS
 
This work was supported by grant HD 31323-05 from the National Institutes of Health for the Pediatric Pharmacology Research Unit.


   FOOTNOTES
 
Received for publication Mar 4, 2002; Accepted May 15, 2002.

Reprint requests to (P.T.) Division of Pharmacology and Critical Care, Rainbow Babies and Children’s Hospital, 11100 Euclid Ave, Cleveland, OH 44106. E-mail: pxt2{at}po.cwru.edu

This work was presented in part at the annual meeting of the Society for Pediatric Research; May 2000; Boston, MA.


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 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics



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