Effect of Antibiotic Therapy on the Density of Vancomycin-Resistant Enterococci in the Stool of Colonized Patients
Curtis J. Donskey, M.D., Tanvir K. Chowdhry, M.D., Michelle T. Hecker, M.D., Claudia K. Hoyen, M.D., Jennifer A. Hanrahan, D.O., Andrea M. Hujer, B.S., Rebecca A. Hutton-Thomas, B.S., Christopher C. Whalen, M.D., Robert A. Bonomo, M.D., and Louis B. Rice, M.D.
Background Colonization and infection with vancomycin-resistantenterococci have been associated with exposure to antibioticsthat are active against anaerobes. In mice that have intestinalcolonization with vancomycin-resistant enterococci, these agentspromote high-density colonization, whereas antibiotics withminimal antianaerobic activity do not.
Methods We conducted a seven-month prospective study of 51 patientswho were colonized with vancomycin-resistant enterococci, asevidenced by the presence of the bacteria in stool. We examinedthe density of vancomycin-resistant enterococci in stool duringand after therapy with antibiotic regimens and compared theeffect on this density of antianaerobic agents and agents withminimal antianaerobic activity. In a subgroup of 10 patients,cultures of environmental specimens (e.g., from bedding andclothing) were obtained.
Results During treatment with 40 of 42 antianaerobic-antibioticregimens (95 percent), high-density colonization with vancomycin-resistantenterococci was maintained (mean [±SD] number of organisms,7.8± 1.5 log per gram of stool). The density of colonizationdecreased after these regimens were discontinued. Among patientswho had not received antianaerobic antibiotics for at leastone week, 10 of 13 patients who began such regimens had an increasein the number of organisms of more than 1.0 log per gram (meanincrease, 2.2 log per gram), whereas among 10 patients who beganregimens of antibiotics with minimal antianaerobic activity,there was a mean decrease in the number of enterococci of 0.6log per gram (P= 0.006 for the difference between groups). Whenthe density of vancomycin-resistant enterococci in stool wasat least 4 log per gram, 10 of 12 sets of cultures of environmentalspecimens had at least one positive sample, as compared with1 of 9 sets from patients with a mean number of organisms instool of less than 4 log per gram (P=0.002).
Conclusions For patients with vancomycin-resistant enterococciin stool, treatment with antianaerobic antibiotics promoteshigh-density colonization. Limiting the use of such agents inthese patients may help decrease the spread of vancomycin-resistantenterococci.
In case–control studies, colonization and infection withvancomycin-resistant enterococci have been associated with exposureto vancomycin,1,2,3,4,5,6 third-generation cephalosporins,3,4,5,6antibiotics that are active against anaerobes,3,6,7,8 ciprofloxacin,1and aminoglycosides.4 The microbiologic basis for these associationsis not well defined. If some antibiotics promote colonizationand infection more than others that are equally effective, limitingthe use of these agents may limit the spread of vancomycin-resistantenterococci.
We previously examined the effect of various antibiotics onintestinal colonization with vancomycin-resistant enterococciin mice.9 In mice with established colonization, as evidencedby the high density of vancomycin-resistant enterococci in stool,the administration of antibiotics with potent activity againstanaerobes maintained this level of colonization, whereas theadministration of antibiotics with less potent antianaerobicactivity did not.9 We prospectively tested the hypothesis thatantianaerobic antibiotics promote high-density colonizationwith vancomycin-resistant enterococci, whereas antibiotics withminimal antianaerobic activity do not. In a subgroup of patients,we tested the hypothesis that high-density colonization wouldresult in increased shedding of the bacteria, increasing thelikelihood of contamination of the environment.
Methods
Study Design
We performed a seven-month prospective study of all inpatientsat the Louis Stokes Cleveland Veterans Affairs Medical Centerwho had documented or newly diagnosed intestinal colonizationwith vancomycin-resistant enterococci. This institution includesan acute care facility and a nursing home facility that housespatients with colonization.
Stool samples were collected weekly from all patients with documentedcolonization to determine whether colonization was still present.The samples were refrigerated at 4°C and processed withinone week. Patients who were colonized with Enterococcus gallinarumor E. casseliflavus, species that are intrinsically resistantto low concentrations of vancomycin, were excluded from thestudy. Information regarding the demographic characteristicsof the patients, coexisting illnesses, and the use of antibiotictherapy was obtained through standardized chart review. Writteninformed consent was obtained from patients for whom environmentalspecimens (e.g., from bed linen, bedrails, clothes, and bedsidetables) were obtained for culture. The hospital's institutionalreview board approved the study protocol.
We analyzed the density of vancomycin-resistant enterococciin stool during and after therapy with all antianaerobic antibioticsand assessed the effect of initiating therapy with antianaerobicantibiotics as compared with antibiotics with minimal antianaerobicactivity.
Assessment of the Density of Vancomycin-Resistant Enterococci in Stool
Antianaerobic antibiotics in the antimicrobial formulary includedpiperacillin–tazobactam, ampicillin–sulbactam, amoxicillin–clavulanate,cefoxitin, cefotetan, imipenem–cilastatin, meropenem,metronidazole, clindamycin, alatrofloxacin, vancomycin, andceftriaxone.10,11 Vancomycin has potent in vitro activity onlyagainst gram-positive anaerobes, but oral administration ofvancomycin results in marked inhibition of bacteroides speciesin humans.12 Ceftriaxone has less potent antianaerobic activitythan cefoxitin or cefotetan, but it is excreted in bile andmarkedly decreases the levels of anaerobic flora in the stoolin humans.13,14 Antibiotic regimens that included more thanone antibiotic were classified as antianaerobic if they containedat least one antianaerobic antibiotic. Antibiotics with minimalantianaerobic activity on the formulary include ciprofloxacin,levofloxacin, dicloxacillin, nafcillin, cephalexin, cefepime,aztreonam, gentamicin, and trimethoprim–sulfamethoxazole.10
We assessed the density of vancomycin-resistant enterococciin stool during and after therapy with antianaerobic antibiotics.We compared oral and intravenous regimens, individual monotherapyregimens (when sufficient data were available), monotherapyregimens with regimens containing two or more antibiotics, andmonotherapy with clindamycin or metronidazole with regimenswith a broader spectrum of activity (i.e., activity againstanaerobes and Enterobacteriaceae or vancomycin-susceptible enterococci).
Comparison of Antianaerobic-Antibiotic Regimens and Regimens of Antibiotics with Minimal Antianaerobic Activity
We compared the effect of initiating therapy with antianaerobicantibiotics and antibiotics with minimal antianaerobic activityon the density of vancomycin-resistant enterococci in stool.Patients were included in the analysis if the results of a base-linedetermination of density were available within two weeks beforethe initiation of the regimen, if an antianaerobic antibiotichad not been administered within seven days before the regimenwas initiated, and if density was reassessed at least two daysafter the initiation of the regimen but no more than seven daysafter the completion of the antibiotic course. If multiple measurementshad been made during the course of antibiotic therapy, the mean(±SD) was determined and used for analysis. Measurementsof enterococci were analyzed on a logarithmic scale (base 10).
Environmental Cultures
One to three sets of environmental specimens were obtained fromthe gowns, linen, bedrails, and bedside tables of 10 patientswith fecal incontinence. The density of vancomycin-resistantenterococci was quantified for a stool sample obtained withinone week before the environmental specimens were obtained. Patientswith diarrhea were excluded because diarrhea has previouslybeen associated with environmental contamination.15 The specimenswere obtained by swabbing 6 cm2 of each designated area witha premoistened swab. The swabs were placed in Todd–Hewittbroth, incubated overnight at 37°C, and inoculated ontoagar plates (Enterococcosel, Becton Dickinson, Sparks, Md.),which contained 6 µg of vancomycin per milliliter. Theplates were incubated for 48 hours at 37°C before beingread.
Microbiologic Analysis and Molecular Typing
Species were identified according to standard methods. Selectedisolates were inoculated onto plates of brain–heart infusionagar that contained 100 µg of ampicillin per milliliter,10 or 100 µg of ciprofloxacin per milliliter, and 10 or100 µg of levofloxacin per milliliter. The density oforganisms per gram of stool in stool samples of approximately75 mg was determined as previously described.9 If no vancomycin-resistantenterococci were detected, the lower limit of detection wasassigned (approximately 2.8 log per gram). There was no significantdifference in the results when four portions of a single stoolspecimen were analyzed or when four samples were analyzed aftertwo weeks of refrigeration. Selected samples were plated onMacConkey agar to identify the number of aerobic and facultativegram-negative bacilli. In the case of six patients, pulsed-fieldgel electrophoresis was performed on stool and environmentalisolates with the use of a commercial kit (CHEF genomic bacterialDNA plug kit, BioRad, Hercules, Calif.). The method used wasa modification of the technique of Hoyen et al.16 The plugswere digested with SmaI for 16 hours (Promega, Madison, Wis.).
Statistical Analysis
Student's unpaired t-test was used to compare continuous variablesbetween groups. Student's paired t-test was used to comparein individual patients the changes in density associated withtreatment with antianaerobic-antibiotic regimens with the changesassociated with regimens of antibiotics with minimal antianaerobicactivity. All reported P values are two-sided. Analysis of variancewas performed to compare the densities associated with therapywith different antianaerobic antibiotics. Fisher's exact testwas used to evaluate the association between high-density colonization(defined as 4 log per gram) and positive cultures of environmentalspecimens and to compare the number of regimens that containedtwo or more antibiotics in the antianaerobic-antibiotic groupand in the group of antibiotics with minimal antianaerobic activity.Computations were performed with the use of Stata software (version6.0, Stata, College Station, Tex.). Unless otherwise stated,mean values are given as means ±SD.
Results
Characteristics of the Patients
A total of 61 inpatients had intestinal colonization with vancomycin-resistantenterococci during the study. Ten of these patients were excludedfrom the analysis for the following reasons: stool samples fromsix patients were unavailable, two patients were colonized withE. casseliflavus, and information about antimicrobial therapywas unavailable for two patients.
The base-line characteristics of the 51 patients and eventsthat occurred during the study are shown in Table 1. Twenty-nineof 51 patients (57 percent) had at least three measurementsof the density of vancomycin-resistant enterococci in stool;there was a total of 227 measurements. Eleven patients had pairedstool samples collected one to three days apart, either whenthey were not receiving antibiotics or when they were receivingstable regimens of antibiotics. The mean difference in the numberof organisms between these paired specimens was 0.4 log pergram of stool (range, 0.1 log to 0.7 log per gram). The eightpatients from whom vancomycin-resistant enterococci was isolatedfrom cultures of blood, urine, or a sacral wound had large numbersof organisms (6 log per gram) in stool specimens obtained concurrently.
Table 1. Base-Line Characteristics of the 51 Patients and Events during the Study.
Density of Vancomycin-Resistant Enterococci during and after Therapy with Antianaerobic Antibiotics
Thirty-three patients received a total of 42 regimens of antianaerobicantibiotics. During 40 of these 42 regimens (95 percent), thedensity of colonization remained high (mean number of organisms,7.8±1.5 log per gram). Among the 78 measurements of stoolsamples obtained during antianaerobic-antibiotic therapy, thedensity exceeded 6 log per gram in 68 (87 percent). There wereno significant differences in the mean number of organisms instool samples between oral regimens and intravenous regimens(8.3±1.5 log and 7.7±1.5 log per gram, P=0.26),between regimens containing one antibiotic and those containingtwo or more antibiotics (7.8±1.6 log and 7.7 ±1.4log per gram, P=0.88), between clindamycin or metronidazolemonotherapy and regimens that had a broader spectrum of activity(8.2±1.9 log and 7.8 ±1.5 log per gram, P=0.54),or between individual monotherapy regimens, including vancomycin,piperacillin–tazobactam, amoxicillin–clavulanate,metronidazole, and clindamycin (P=0.6 for all comparisons).Figure 1 shows the increase in the density of vancomycin-resistantenterococci and aerobic and facultative gram-negative bacilliin stool that was associated with oral exposure to clindamycinin one patient.
Figure 1. The Effect of Antibiotic Therapy on the Numbers of Vancomycin-Resistant Enterococci and the Total Number of Aerobic and Facultative Gram-Negative Bacilli in Stool Samples from a 57-Year-Old Man with Cirrhosis Resulting from Hepatitis C.
Six weeks before entering the study, the patient received a course of oral clindamycin; two weeks before entering the study, he received a course of oral ciprofloxacin. Five weeks after the study began, he received two days of oral clindamycin prophylactically before having teeth extracted at a time when he was doing well in the nursing home unit.
Orally administered antianaerobic antibiotics included metronidazole,amoxicillin–clavulanate, clindamycin, and vancomycin.Intravenously administered antianaerobic antibiotics includedvancomycin, piperacillin–tazobactam, ampicillin–sulbactam,meropenem, imipenem–cilastatin, cefoxitin, ceftriaxone,alatrofloxacin, clindamycin, and metronidazole. The two patientsin whom high-density colonization was not maintained duringtherapy with antianaerobic antibiotics were receiving piperacillin–tazobactam;isolates from these patients had a high level of resistanceto piperacillin (minimal inhibitory concentration, 1056 µgper milliliter). In a previous report, piperacillin concentrationsin stool ranged from undetectable to 276 mg per kilogram duringtherapy with intravenous piperacillin–tazobactam.17
When regimens of antianaerobic antibiotics were discontinued,the density of vancomycin-resistant enterococci in stool decreasedin all 19 patients who had samples collected four or more weekslater. Nine patients were followed until one or more measurementsshowed that levels were undetectable (lower limit of detection,approximately 2.8 log per gram). The mean interval between thediscontinuation of antibiotics and the finding of undetectablelevels of vancomycin-resistant enterococci in stool was 17.4weeks (range, 6 to 20).
Effect of Antianaerobic-Antibiotic Regimens and Regimens of Antibiotics without Antianaerobic Activity
The effects of antianaerobic-antibiotic regimens and regimensof antibiotics with minimal antianaerobic activity on the densityof vancomycin-resistant enterococci in stool are shown in Figure 2.Ten of 13 patients who received antianaerobic-antibioticregimens had an increase in the number of organisms of morethan 1.0 log per gram (mean increase, 2.2 log per gram), ascompared with 0 of 10 patients who received regimens of antibioticswith minimal antianaerobic activity (P=0.006). The mean changein stool samples from these 10 patients was a decrease of 0.6log per gram. Three patients received both types of regimensat different times; an increase in the number of organisms instool of at least 1.0 log per gram occurred in all three duringthe antianaerobic-antibiotic regimens, but in none of the threeduring the other type of regimen (P=0.1). Figure 3 shows thechanges in the density of vancomycin-resistant enterococci instool associated with exposure to various antibiotic regimensin one patient.
Figure 2. Effect on the Density of Vancomycin-Resistant Enterococci in Stool of Therapy with Antianaerobic-Antibiotic Regimens in 13 Patients and Regimens of Antibiotics with Minimal Antianaerobic Activity in 10 Patients.
A selected isolate from each study patient demonstrated a high level of resistance to vancomycin (minimal inhibitory concentration, >60 µg per milliliter) and ampicillin (minimal inhibitory concentration, >256 µg per milliliter). Isolates from patients who received ciprofloxacin or levofloxacin as part of a regimen of antibiotics with minimal antianaerobic activity had a high level of resistance to ciprofloxacin in vitro (minimal inhibitory concentration, >100 µg per milliliter) but not to levofloxacin (minimal inhibitory concentration, >10 µg but <100 µg per milliliter). Isolates from the two patients who received trimethoprim–sulfamethoxazole were resistant to this agent in vitro. All antibiotics were given intravenously unless the route is designated as oral.
Figure 3. Effect of Therapy with Antianaerobic-Antibiotic Regimens and Regimens of Antibiotics with Minimal Antianaerobic Activity on the Density of Vancomycin-Resistant Enterococci in Stool Samples from a 69-Year-Old Male Nursing Home Resident with a History of Cerebrovascular Accidents.
The patient initially received an antianaerobic-antibiotic regimen consisting of intravenous meropenem and vancomycin for 17 days, beginning in week 1. He then received a regimen of antibiotics with minimal antianaerobic activity: oral trimethoprim–sulfamethoxazole (TMP-SMX) for five days, beginning in week 10, followed by oral levofloxacin (Levo) for three days. The third regimen consisted of a combination of the two types of antibiotics: intravenous piperacillin–tazobactam (P-T) and cefepime (C) was given for 8 days, followed by oral ciprofloxacin (Cipro) for 10 days. The fourth regimen consisted of intravenous vancomycin — an antianaerobic antibiotic — for 14 days. Cultures of environmental specimens obtained from the patient's bedside table and bed linen were positive during week 20, whereas cultures of specimens from the patient's gown and bedrail were negative. Cultures of all four types of environmental specimens obtained during week 24 and week 27 were negative. The patterns on pulsed-field gel electrophoresis of three isolates obtained from stool cultures and an isolate obtained from the culture of an environmental specimen were identical. Vancomycin-resistant enterococci were detectable in all samples.
When the antianaerobic-antibiotic regimens were compared withthe regimens of antibiotics with minimal antianaerobic activity,there were no significant differences in the duration of therapybefore density was measured in stool samples (mean ±SE,8.3±1.8 and 10.2±2.3 days; P=0.44), the totalnumber of antibiotics received before the regimen being analyzed(mean ±SE, 4.0±0.49 and 3.8±0.53; P=0.8),or the patients' Karnofsky performance scores (mean ±SD,34.0±3.4 and 28.6±3.4; P=0.29). The changes indensity associated with the two types of regimens did not differsignificantly between the acute care facility and the nursinghome facility (data not shown). The antianaerobic-antibioticregimens were more likely to include at least two antibioticsthan were the regimens of antibiotics with minimal antianaerobicactivity (9 of 13 vs. 2 of 10 regimens, P=0.04). There was nosignificant difference, however, in the change in density betweenthe use of a single antianaerobic antibiotic and the use ofa regimen that included two or more such antibiotics (mean increasein the number of organisms, 2.7±2.0 log and 2.1±2.6log per gram, respectively; P=0.64). A comparison of the 4 regimensthat consisted of one antianaerobic antibiotic with the 10 regimensof antibiotics with minimal antianaerobic activity also revealeda significant difference in density between the groups (P=0.01).
Results of Environmental Cultures
Twenty-one sets of cultures of environmental specimens wereobtained from 10 patients with fecal incontinence. Ten of 12sets of cultures (83 percent) obtained from patients with aconcurrent stool density of at least 4 log per gram had oneor more positive samples, as compared with 1 of 9 sets (11 percent)obtained from patients with less than 4 log per gram (P=0.002).Three patients had positive cultures of environmental specimenswhen the density of vancomycin-resistant enterococci in stoolwas at least 4 log per gram, and negative cultures when thedensity was less than 4 log per gram. Isolates of vancomycin-resistantenterococci from stool samples from 6 of the 10 patients hadfive distinct patterns on pulsed-field gel electrophoresis.An isolate from cultures of environmental specimens from eachof these six patients was clonally related to a correspondingisolate obtained from a stool sample.
Discussion
In this prospective study of patients who were colonized withvancomycin-resistant enterococci, we found that the use of antianaerobic-antibioticregimens perpetuated high-density intestinal colonization, whereasthe use of antibiotics with minimal antianaerobic activity thatwe studied did not. In a subgroup of patients with fecal incontinence,those with high-density colonization were more likely to havepositive cultures of environmental specimens than those withlow-density colonization. These results suggest that limitingthe use of antianaerobic antibiotics in patients colonized withvancomycin-resistant enterococci will minimize the level andduration of colonization and may reduce the rate of transmissionof these organisms.
Several factors must be considered in evaluating the effectof antibiotics on intestinal vancomycin-resistant enterococci,including the spectrum of antimicrobial activity and the levelof active antibiotic in the intestinal tract.18 An antibioticmay directly inhibit vancomycin-resistant enterococci if itis active against the colonizing strain, or it may inhibit bacteriathat compete for nutrients or space and thus promote the overgrowthof vancomycin-resistant enterococci. The amount of active antibioticin the intestinal tract depends on the extent of biliary orintestinal secretion and the degree of inactivation of the antibiotic.18For example, imipenem–cilastatin has broad-spectrum antibacterialactivity, but its level of excretion in bile is minimal, andin some studies, it produced only minor changes in intestinalflora.19 Therefore, our results should be considered in thecontext of other studies that have examined the effect of antibioticson the intestinal flora of humans.
Our data are compatible with the hypothesis that antibioticspromote the overgrowth of vancomycin-resistant enterococci inthe intestinal tract primarily through the inhibition of intestinalanaerobes. Antibiotic regimens with potent antianaerobic activitybut minimal activity against other components of the intestinalflora (e.g., metronidazole and clindamycin) promoted high-densitycolonization. In contrast, antibiotic regimens with minimalantianaerobic activity but with activity against susceptiblemembers of Enterobacteriaceae (e.g., ciprofloxacin, trimethoprim–sulfamethoxazole,and cephalexin) did not promote overgrowth. Several studieshave demonstrated that these types of antibiotics may have similareffects on the density of vancomycin-susceptible enterococciin the stool of humans20,21,22,23,24 (Table 2). Clinical studieshave also demonstrated an association between the use of antianaerobicantibiotics and colonization or infection with vancomycin-susceptibleenterococci.26,27,28,29,30,31
Table 2. Studies of the Effect of Antibiotics on the Stool Flora of Healthy Subjects and Patients.
A direct inhibitory effect on vancomycin-resistant enterococciin the intestinal tract by the quinolone antibiotics with minimalantianaerobic activity cannot be excluded. For patients whoreceived quinolones as part of regimens of antibiotics withminimal antianaerobic activity, selected isolates demonstrateda high level of resistance to ciprofloxacin but not to levofloxacin(Figure 2). Quinolone antibiotics are present in high concentrationsin stool (21 to 94 mg per kilogram of stool in the case of orallyadministered levofloxacin24 and 185 to 2200 mg per kilogramof stool in the case of orally administered ciprofloxacin32),but the activity of these antibiotics may be markedly reducedas a result of reversible binding to fecal matter.24,33 In humans,ciprofloxacin or levofloxacin minimally affects the anaerobicflora and either may decrease or have no effect on the densityof enterococci.22,24 The fact that a high density of vancomycin-resistantenterococci (6.4 log colony-forming units per gram) was maintainedin the stool of nine patients who received levofloxacin or ciprofloxacinas one component of an antianaerobic-antibiotic regimen suggeststhat any inhibitory effect of these antibiotics was outweighedby the effect of the other antibiotics (data not shown).
Data regarding the effect of other antibiotics with minimalantianaerobic activity on the density of vancomycin-resistantenterococci in stool are needed. In an earlier study, we demonstratedthat subcutaneous cefepime or aztreonam did not promote theovergrowth of vancomycin-resistant enterococci in mice.9 Cefepimeis an extended-spectrum cephalosporin that has relatively littleantianaerobic activity, is excreted primarily by the kidneys,and causes minimal changes in the intestinal flora of humans.25We have hypothesized that cephalosporin antibiotics promotethe overgrowth of vancomycin-resistant enterococci to varyingdegrees, given the wide variation in their antianaerobic activityand degree of biliary excretion.9 Aztreonam is a monobactamantibiotic whose activity is limited to gram-negative aerobes.34In humans, the administration of aztreonam has been associatedwith the overgrowth of stool enterococci in some studies,35,36but not in others.34,37 Louie34 demonstrated that treatmentof febrile patients with neutropenia with a combination of moxalactam(a potent antianaerobic antibiotic) and tobramycin, but notwith a combination of aztreonam and tobramycin, resulted insuppression of fecal anaerobes, overgrowth of enterococci, andan increased frequency of fungal colonization.
The fact that the regimens of antibiotics with minimal antianaerobicactivity included only orally administered single agents whereasthe regimens of antianaerobic antibiotics were mostly givenintravenously and included two or more agents is a potentialconfounding variable. Patients who required therapy with intravenousregimens that included multiple antibiotics might have beensicker than those who received oral therapy with a single antibiotic.An increased severity of illness has been associated with anincreased likelihood of colonization or infection with vancomycin-resistantenterococci.38 Several findings argue against the possibilitythat these factors introduced statistically significant bias,however. The Karnofsky performance scores of patients who receivedantibiotics with minimal antianaerobic activity did not differsignificantly from those of patients who received antianaerobicantibiotics; oral and single-drug regimens of antianaerobicantibiotics promoted high-density colonization as much as didintravenous and multiple-drug regimens; and in one patient whodid not meet the criteria for analysis, low-density colonizationwas maintained during therapy with intravenous levofloxacin.
Our findings have important implications for the care of patientswho are colonized with vancomycin-resistant enterococci. Theuse of antianaerobic antibiotics should be avoided in this groupof patients. In clinical practice, antianaerobic antibioticsare often prescribed when their spectrum of activity is notrequired. The primary benefit of limiting the use of antianaerobicantibiotics in the population of patients we studied may bea reduction in the duration of colonization and, therefore,a reduction in the cost and inconvenience of the infection-controlmeasures implemented. Since high-density colonization was morelikely to be associated with positive cultures of environmentalspecimens, this measure may also reduce the rate of transmissionof vancomycin-resistant enterococci. Since the use of antianaerobicantibiotics has been associated with bacteremia from vancomycin-resistantenterococci in patients with cancer,7,8 limiting the use ofthese antibiotics in higher-risk patients may reduce morbidityand mortality.
Supported by a Career Development Award grant (to Dr. Donskey);by the Office of Research and Development, the Department ofVeterans Affairs; and in part by a training grant from the NationalInstitutes of Health (AI 07024, to Drs. Donskey and Hoyen).
We are indebted to Lisa Parino, Kathy Willis, and members ofthe nursing and microbiology staffs at the Louis Stokes ClevelandVeterans Affairs Medical Center for their assistance; and toRachel Meyers and Anna Gazos for assistance in the preparationof the manuscript.
Source Information
From the Infectious Diseases Section (C.J.D., A.M.H., R.A.H.-T., R.A.B.) and the Medical Service (L.B.R.), Louis Stokes Cleveland Veterans Affairs Medical Center; the Division of Infectious Diseases (T.K.C.) and the Department of Epidemiology (C.C.W.), Case Western Reserve University; the Division of Infectious Diseases, MetroHealth Medical Center (M.T.H., J.A.H.); and the Division of Pediatric Infectious Diseases, Rainbow Babies and Children's Hospital (C.K.H.) — all in Cleveland.
Address reprint requests to Dr. Donskey at the Louis Stokes Cleveland Veterans Affairs Medical Center, Infectious Diseases Section 1110 (W), 10701 East Blvd., Cleveland, OH 44106, or at curtisd123{at}yahoo.com.
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4 log per gram) and positive cultures of environmental specimens and to compare the number of regimens that contained two or more antibiotics in the antianaerobic-antibiotic group and in the group of antibiotics with minimal antianaerobic activity. Computations were performed with the use of Stata software (version 6.0, Stata, College Station, Tex.). Unless otherwise stated, mean values are given as means ±SD. 
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