Risk Factors for Vancomycin‐Resistant Enterococcus (VRE) Infection in Colonized PatientsWith Cancer  • Author(s): Rola Husni , MD; Ray Hachem , MD; Hend Hanna , MD, MPH; Issam Raad , MD, FACPSource: Infection Control and Hospital Epidemiology, Vol. 23, No. 2 (February 2002), pp. 102-103Published by: The University of Chicago Press on behalf of The Society for Healthcare Epidemiologyof AmericaStable URL: http://www.jstor.org/stable/10.1086/502016 .

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102 INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY February 2002

Risk Factors for Vancomycin-ResistantEnterococcus (VRE) Infection inColonized Patients With Cancer

Rola Husni, MD; Ray Hachem, MD; Hend Hanna,MD, MPH; Issam Raad, MD

ABSTRACTTo determine the risk factors for vancomycin-resistant

Enterococcus (VRE) infection in colonized patients with cancer, weconducted a case–control study. According to multivariate analy-sis, the only significant factors were neutropenia (< 500 cells/mm3)for more than 1 week and the use of oral vancomycin. Therefore,colonized neutropenic patients with cancer who have previouslyused oral vancomycin are most prone to VRE infection (InfectControl Hosp Epidemiol 2002;23:102-103).

Vancomycin-resistant Enterococcus (VRE) infectionsare among the most serious nosocomial infections world-wide, constituting a major public health problem.1

Mounting evidence has now established VRE as the causeof significant morbidity and mortality, mostly among criti-cally ill patients and especially among immunocompro-mised patients with cancer.2 Colonization and infection withVRE have frequently been reported among patients withcancer. One prior study evaluated the risk of infection withVRE after colonization in patients with underlying malig-nancy.3 In an attempt to further evaluate the risk factors forVRE infection among patients with cancer colonized withthis organism, we conducted a case–control study at M.D.Anderson Cancer Center comparing patients infected withVRE with patients who were only colonized with VRE.

METHODS

We reviewed the medical records of all patients withVRE isolated from any site in the year 1997. Data extractedincluded gender, age, type of cancer, underlying diseases,chemotherapy, length of stay in the intensive care unit, gas-trointestinal problems, Acute Physiology and Chronic HealthEvaluation (APACHE II) score, neutropenia, previous use ofantibiotics, and outcome. Colonization was defined as having1 or more stool cultures with positive results for VRE withoutclinical or microbiological evidence of infection. Infection wasdocumented when VRE was isolated from a sterile site withclinical evidence of infection. Neutropenia was defined as hav-ing an absolute neutrophil count of 500 cells/mm3 or fewer.

Analyses were performed using the StatisticalPackage for the Social Sciences (SPSS for Windows, ver-sion 8.0; SPSS Inc., Chicago, IL). Predictors of risk factorswere sought by univariate analysis. The chi-square test andFisher exact test were used as appropriate to compare ratesand proportions. Multivariate logistic regression analysiswas performed to identify independent risk factors.

RESULTS

A total of 82 patients had 1 or more cultures with posi-tive results for VRE from 1 or more sites during the studyperiod in 1997. Forty-three patients were infected and 39patients were only colonized. The distribution of VRE infec-

tions included 77% with bacteremia, 9% with urinary tractinfections, 9% with pneumonia, and 5% with surgical woundinfections. The colonized and the infected groups were com-pared according to age, gender, underlying cancer (eg,leukemia, lymphoma, or solid tumor), having had a bonemarrow transplant during the year preceding the time of theculture with a positive result for VRE, prior use of intra-venous or oral vancomycin, gastrointestinal complications(eg, diarrhea, bleeding, mucositis, or colitis), and neutrope-nia and its duration (Table). The risk factors for VRE infec-tion identified as significant by univariate analysis were dura-tion of hospitalization, APACHE II score, prior use of oralvancomycin, prior use of metronidazole, and more than 1

TABLECHARACTERISTICS OF PATIENTS WITH CANCER COLONIZED OR

INFECTED WITH VANCOMYCIN-RESISTANT ENTEROCOCCUS (VRE)

Characteristic Infected Colonized P

No. 43 39Mean age, y (range) 52 (6–86) 59 (25–82) .06Gender .79

Male 23 (53%) 22 (56%)Female 20 (47%) 17 (44%)

Underlying disease .69Leukemia 27 (63%) 27 (69%)Lymphoma 8 (19%) 5 (13%)Solid tumors 5 (12%) 6 (15%)

Mean hospital 37 (4–102) 22 (2–83) .006duration, d (range)

BMT in year preceding 8 (19%) 2 (5%) .09VRE culture

Mean APACHE II score 17 (5) 15 (4) .03(SD)

Clostridium difficile 4 (9%) 1 (3%) .4infection

GI complications* 24 (56%) 22 (56%) .96History of neutropenia† 31 (72%) 20 (51%) .05

(> 1 week prior to VRE culture)

Previous antibiotic use 38 (88%) 36 (92%) .72Mean duration of anti- 22.5 (15) 18 (14) .16

biotic use before VRE culture (SD)

Prior use of intravenous 33 (77%) 25 (64%) .21vancomycin

Prior use of oral 8 (19%) 0 .006vancomycin† 30 days before VRE culture

Prior use of ceftazidime 18 (42%) 16 (41%) .94Prior use of imipenem 22 (51%) 16 (41%) .36Prior use of metronidazole 9 (21%) 1 (3%) .016

BMT = bone marrow transplant; APACHE II = Acute Physiology and Chronic HealthEvaluation; SD = standard deviation; GI = gastrointestinal.*GI complications included diarrhea, mucositis, GI bleeding, and C. difficile colitis.†According to multivariate logistic regression analysis, history of neutropenia and prior use oforal vancomycin were statistically significant, independent variables (P = .014 and P = .002,respectively).

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Vol. 23 No. 2 CONCISE COMMUNICATIONS 103

week of neutropenia prior to VRE culture (Table); havinghad a bone marrow transplant approached significance(Table). According to multivariate regression analysis, onlyneutropenia for more than 1 week (P = .014) and the use oforal vancomycin (P = .0002) were significant. Oral van-comycin was given as a therapeutic agent for 2 to 12 (mean,6.3) days. There was no statistical difference in the durationof prior use of intravenous vancomycin between the 2 groups(P = .7).

DISCUSSION

Reports of colonization and infection with VRE arerapidly increasing among hospitalized patients. In addition,it has been well established that patients with cancer are atincreased risk for VRE infection. The main risk factors forVRE colonization and infection include severity of illness,the use of vancomycin or other antibiotics, and duration ofintravenous vancomycin use (more than 7 days).4-6

Limited data are available regarding the risk of VREinfection in colonized patients with cancer. Kuehnert et al.3reported that the severity of mucositis was independentlyassociated with an increased risk of VRE bloodstreaminfections. In the same study, neutropenia was not found tobe a risk factor, but the median absolute neutrophil countin both groups was zero, thus limiting the ability to detecta difference in the immunosuppressive state in the twostudy arms. In contrast, our study shows that a history ofneutropenia for more than 1 week before the occurrence ofVRE infection is a definite risk factor.

The use of oral vancomycin was another risk factor forVRE infection in colonized patients with cancer. The presenceof vancomycin-dependent enterococci reported in the litera-ture might explain why oral vancomycin promotes the growthof VRE in the gastrointestinal tract, leading to infection.7,8

However, a more likely explanation is that oral vancomycingives VRE organisms colonizing the gastrointestinal tract aselective growth advantage by suppressing competitive bacte-rial flora. Subsequently, VRE overgrowth results in invasion ofthe bloodstream in the setting of neutropenia.

Duration of vancomycin use was not significantly differ-ent between the two groups. Recently, Donskey et al. showedthat treatment with anti-anaerobic antibiotics in patients colo-nized with VRE promotes high-density colonization.9

Although prior infection with Clostridium difficile wasnot significantly associated with VRE infection, its likelihoodof occurrence was threefold higher in the group infectedwith VRE (9% vs 3%). Roghmann et al. found in a prospectivestudy that C. difficile infection is an independent risk factorfor VRE bacteremia in patients with leukemia colonized withVRE.10 Given the retrospective nature of our study and thefact that oral vancomycin and metronidazole were givenempirically for the treatment of C. difficile infections in ourpatients with diarrhea, the frequency of this infection in thisstudy could have been underestimated.

Therefore, we conclude that VRE colonization inpatients with cancer predisposes to infection following pro-longed neutropenia and use of oral vancomycin. Becausethere are a limited number of available drugs effective against

VRE infection, prevention is still the best option. Therefore,oral vancomycin should be used judiciously for this group ofpatients. In addition, VRE should be suspected as a pathogenin neutropenic, febrile, colonized patients with cancer, espe-cially if oral vancomycin has been used. Empirical treatmentfor VRE should be considered in this setting.

The authors are from The University of Texas M.D. AndersonCancer Center, Department of Infectious Diseases, Infection Control andEmployee Health, Houston, Texas.

Address reprint requests to Issam Raad, MD, Professor ofMedicine, The University of Texas M.D. Anderson Cancer Center, 1515Holcombe Blvd., Box 402, Houston, TX 77030.

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10. Roghmann M-C, McCarter RJ, Brewrink J, Cross AS, Morris JG.Clostridium difficile infection is a risk factor for bacteremia due to van-comycin-resistant enterococci (VRE) in VRE-colonized patients withacute leukemia. Clin Infect Dis 1997;25:1056-1059.

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