The Changing Epidemiology of Vancomycin-Resistant Enterococcus (VRE) Bacteremia in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients

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1 The Changing Epidemiology of Vancomycin-Resistant Enterococcus (VRE) Bacteremia in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients Mini Kamboj, 1 Dick Chung, 1 Susan K. Seo, 1 Eric G. Pamer, 1 Kent A. Sepkowitz, 1 Ann A. Jakubowski, 2, * Genovefa Papanicolaou 1, * The impact of the rising prevalence of vancomycin-resistant Enterococcus (VRE) prior to hematopoietic stem cell transplantation (HSCT) and changes in transplant techniques on risk of VREB (VRE bacteremia) early after HSCT is not known. This is a retrospective study of 247 adult patients who underwent allogeneic HSCT in the years 2008 and 2009 at the Memorial Sloan-Kettering Cancer Center. Sixty-eight of 247 (27.5%) patients were VRE colonized on pretransplant screening. VRE was the leading cause of bacteremia in the first 30 days after HSCT; 23 of 43 (53.5%) patients with positive blood cultures had VRE. Only 13 (57%) of the 23 patients with early VREB were colonized with VRE on pre-hsct screening cultures. Mortality was directly attributable to VRE infection in 9% of patients with early VREB. VRE is emerging as the most common cause of preengraftment bacteremia in patients undergoing allogeneic HSCT, and is associated with substantial mortality. Pre-HSCT screening for VRE with stool cultures will not identify all patients who are at risk for VREB. The use of alternate agents with activity against Gram-positive bacteria for fever and neutropenia early after HSCT should be evaluated further in prospective studies. Biol Blood Marrow Transplant 16: (2010) Ó 2010 American Society for Blood and Marrow Transplantation KEY WORDS: VRE, Preengraftment bacteremia, Allogeneic transplant INTRODUCTION From the 1 Infectious Disease, Department of Medicine, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York; and 2 Adult Bone Marrow Transplantation Services, Department of Medicine, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York. Financial disclosure: See Acknowledgments on page * Both authors contributed equally to this article. Correspondence and reprint requests: Mini Kamboj, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY ( Kambojm@mskcc.org). Received March 8, 2010; accepted May 14, 2010 Ó 2010 American Society for Blood and Marrow Transplantation /$36.00 doi: /j.bbmt Vancomycin-resistant Enterococcus (VRE) is a common problem among patients receiving hematopoietic stem cell transplant (HSCT). Studies over the last 15 years, since the emergence of the pathogen, have described rates of early VRE bacteremia (VREB) after HSCT from 3.6% to 22%, with mortality ranging from 0.04% to 85% [1-6]. In the years since the emergence of VRE, numerous changes have occurred in the prevention and management of this infection; 4 new drugs with activity against VRE are now available, and screening and decolonizing strategies have been proposed. In addition, allogeneic transplant approaches have fundamentally changed, with the introduction of cord blood grafts and nonmyeloablative conditioning regimens, resulting in an ever-widening group of patients, including those older than 60 years, who receive HSCT. To better define the frequency and timing of VRE infection after HSCT, we reviewed our recent experience with this organism among adult allogeneic HSCT recipients. This information will facilitate the development of an optimal approach for screening and other preventive strategies for VRE. PATIENTS AND METHODS The Memorial Sloan-Kettering Cancer Center (MSKCC) institutional review board (IRB) reviewed the study and granted a HIPPA waiver of authorization. At the time of this study, the MSKCC was a 432-bed tertiary care facility in New York City with 19,000 annual admissions and 140,000 patient days. The allogeneic HSCT database was used to identify all adult patients admitted for an allogeneic HSCT from January 1, 2008, to December 31, Electronic medical records, HSCT, and infection control databases were used to retrieve demographic, clinical, and laboratory information. The adult bone marrow transplant (BMT) unit at MSKCC is comprised of 1576

2 Biol Blood Marrow Transplant 16: , 2010 Preengraftment bacteremia with VRE 1577 a 29-bed unit. All allogeneic HSCT patients are admitted to private rooms and routinely placed under protective isolation (mask and gloves). All VRE colonized and/or infected persons are placed under barrier precautions. Since August 2004, all patients admitted for allogeneic transplant routinely undergo screening for VRE colonization at admission and weekly. Rectal swabs for VRE surveillance were collected by patients for the most part of the study period (January 2008 to June 2009) and by nurses for the last 6 months (July 2009 to December 2009). BBL Campy CVA Agar is used to detect VRE from stool. If Gram-positive cocci in pairs and chains are detected on the Gram stain, further identification with catalase, PYR, vancomycin disk susceptibility, and a Microscan Positive ID 2 Panel is performed. Since June 2006, all patients found to be VRE colonized on pre-hsct screening receive linezolid (instead of vancomycin) as empiric therapy for fever and neutropenia (until blood cultures are negative for 48 hours). Other antibacterial prophylaxis includes intravenous (i.v.) vancomycin (beginning day 22 for myeloablative (MA) regimens and first fever for others), and fluoroquinolone from day 22 to engraftment or alternate antibiotic regimen. Engraftment is defined by first day of 3 consecutive days with an absolute neutrophil count (ANC).500 cells/ml. Statistical Analysis Univariate analyses were performed by using chisquare tests of independence for sex, primary disease, transplant source, MA conditioning regimen, allograft T cell depletion, and pretransplant VRE colonization. Median age at time of transplant of infected and noninfected patients was analyzed using the Wilcoxon Mann-Whitney test. Variables with a univariate P value \.25 were incorporated into a multivariate model. Transplant source was also included in the model. A logit regression was used to predict VRE bloodstream infection using primary disease, transplant source, T cell depletion, VRE colonization, and age at time of transplant. Primary disease was collapsed into 3 categories: leukemia, lymphoma, and other disorder category. All statistical analyses were performed using SAS 9.1 (SAS, Cary, NC). RESULTS During the study period (January 1, 2008, to December 31, 2009), 307 patients underwent allogeneic HSCT, including 247 adults and 60 pediatric patients (\18 years of age). No early VREB occurred in a patient younger than 18 years and only 1 pediatric HSCT recipient developed VREB after 30 days. Among the adult patients, the median age was 50.8 years (range: years) and 133 (61%) were males. The demographic and transplant characteristics of the adult HSCT population are shown in Table 1. Sixty-eight of 247 (27.5%) patients were VRE colonized on pretransplant screening. Twenty-seven (11%) patients developed VREB in the posttransplant period. In 23 of 27 (85%) patients, infection occurred early, within the first 10 days after HSCT. VREB Early after HSCT (First 30 Days) VRE was the leading cause of first episode of bacteremia in the first 30 days after HSCT, accounting for 53.5% of all bacteremias followed by enteric Gramnegative rods accounting for 30% of all bacteremias. There were no secondary bacteremias because of VRE. Among the 23 patients with VREB, VRE was the first and only organism isolated from blood cultures in the preengraftment period. Over 80% of patients had VRE isolated from peripheral and central venous catheter blood cultures, suggesting that the gut may have been the source of VRE bacteremia. Only 2 patients had VRE isolated only from central venous catheter blood culture. All patients had prompt catheter removal. There was no catheter exchange over the wire. Catheter tips were not routinely cultured. Five catheter tips were cultured and were positive for VRE. Transplant Characteristics All VREB in the early post-hsct period occurred within the first 3 to 10 days, with most infections occurring around day 7 (39%) (Figure 1). The median time to engraftment (ANC.500 cells/ml) was 11 days (range: 1-37 days). Five of 40 (12.5%) cord blood recipients and 17 of 194 (8.8%) PBSC recipients developed VREB (P 5.55). Risk Factors Associated with VREB In univariate analyses, age, primary disease, VRE colonization, and T cell depletion were associated with VRE bacteremia (Table 1). In multivariate analyses, out of all predictors, only pretransplant colonization with VRE and T cell depletion were significant predictors of VRE bloodstream infections, although the 95% confidence intervals were notably very wide. Patients colonized with VRE had 3.88 times higher odds of eventual bloodstream infection than patients who were not colonized prior to transplant (VRE colonization 95% confidence interval [CI] ; p and T cell depletion odds ratio [OR] , 95% CI ; P 5.028). Clinical Characteristics Thirteen (57%) of the 23 patients with early VREB were colonized with VRE on pre-hsct screening cultures. Six patients with negative initial screening cultures were found to be colonized with VRE on

3 1578 M. Kamboj et al. Biol Blood Marrow Transplant 16: , 2010 Table 1. Demographic and Transplant Characteristics of Adult HSCT Recipients Showing a Comparison between Patients with No and Early VREB No VRE Bloodstream Infection (%) Early VRE Bloodstream Infection (%) P-Value Patients n 5 220* n 5 23 Median age (range) 50.8 ( ) 58.2 ( ) Male 133 (60.55) 14 (60.9%) Primary disease Acute lymphoblastic leukemia 17 (7.7%) 5 (21.7%) Acute myelogenous leukemia 79 (35.9%) 12 (52.2%) Chronic lymphocytic leukemia 11 (5.0%) 0 (0%) Chronic myelogenous leukemia 2 (0.9%) 0 (0%) Hodgkin Lymphoma 10 (4.5%) 0 (0%) Myelodysplastic syndrome 21 (9.5%) 3 (13.0%) Multiple myeloma 11 (5.0%) 0 (0%) Non-Hodgkin lymphoma 52 (23.6%) 1 (4.3%) Others 17 (7.7%) 2 (8.7%) Transplant characteristics Myeloablative conditioning regimen 106 (48.2%) 11 (47.8%) Allograft T cell depletion 101 (45.9%) 17 (73.9%).01 Peripheral blood stem cell allograft 175 (79.5%) 17 (73.9%) Bone marrow allograft 12 (5.5%) 1 (4.3%) Cord blood allograft 33 (15.0%) 5 (21.7%) HLA- matched sibling donor 74 (33.6%) 6 (26.1%) Median follow-up for survivors (days) (35-756) 357 (35-742) Median days to ANC 500 engraftment (range) 11 (1-37) 11 (9-43) VRE colonized pretransplant 55 (25.0%) 13 (56.5%).001 VRE indicates vancomycin-resistant Enterococcus; ANC, absolute neutrophil count. *Excludes 4 patients who developed VREB 90 days after HSCT. a subsequent culture, done after transplant but prior to onset of bacteremia. The median duration of bacteremia was 2 days (range: 1-18 days). Mortality was directly attributable to VRE infection in 2 of 23 patients with early VREB. The 30-day all cause mortality for patients without early bacteremia was 2% compared to 4.4% in patients with VRE bacteremia and 15% in patient with non-vre bacteremia. Four patients required ICU admission within 72 hours after the onset of VREB. One ICU admission was because of narcotic overdose and the patient quickly recovered. The remaining 3 patients developed a similar syndrome that included fever, dyspnea, confusion, and mental status changes. All 3 had progressive declines in mental status, were intubated, and required prolonged ICU care. No infection, other than VREB, or other ascertainable cause of clinical decline could be identified. Table 2 details the clinical course of the 3 patients with this early VREB syndrome. Patient #3 eventually recovered but required tracheostomy. The other 2 patients died after prolonged ICU stay; neither underwent autopsy. DISCUSSION VRE emerged in the late 1980s and now is among the most common causes of bacteremia in critically ill and neutropenic patients with cancer [7]. Initially, antibiotic choices for treatment of VRE infections were limited and VREB was associated with a high mortality [2,5,8,9]. Since then, 4 antibiotics (quinupristindalfopristin, linezolid, daptomycin, and tigecycline) with activity against VRE have been approved by the FDA, and numerous prevention strategies have been developed. In addition, conditioning regimens for HSCT have changed. The impact of these basic changes in the medical care of transplant patients on VRE epidemiology and outcome has not been described. Previous studies from larger centers have reported highly variable VRE colonization rates in HSCT recipients ranging from 5% to 27%, although the rates of VRE bacteremia among colonized patients was similar: approximately 30% across all studies [5,10,11]. A previous study from MSKCC (between August 2004 and February 2006) showed a colonization rate of 29%; 27 among 92 HSCT recipients screened prior to transplant were VRE colonized, and 34% of all colonized persons developed VREB early (within first 35 days) after HSCT [4]. Because of the high occurrence of VREB among colonized persons in that study at MSKCC, linezolid is used preemptively for fever early after HSCT in VRE colonized patients only (Figure 2). In a previous study from MSKCC by Almyroudis et al. [1] ( ), Streptococcus viridans and Enterobacteriacae followed by Enterococcus faecium were the most common bacterial pathogens causing blood stream infection (BSI) in the preengraftment period. VREB occurred in 4.7% of all HSCT recipients in the preengraftment period. Another study by Avery et al. [2] at the Cleveland Clinic during the same time period ( ) described VREB incidence of 3.6% among 281 allogeneic HSCT recipients in the preengraftment period.

4 Biol Blood Marrow Transplant 16: , 2010 Preengraftment bacteremia with VRE 1579 Table 2. Clinical Characteristics of Three Severe Cases of VREB in the Early Post-HSCT Period Treatment for VRE* Outcome Duration of Bacteremia Hospital Course Copathogens Clinical Presentation Onset of VREB Transplant Type Donor Underlying Disease Age/ sex died day + 21 None Daptomycin, gentamicin tigecycline 18 days progressive decline in mental status, bibasilar lung consolidation, VDRF, persistent bacteremia 1. 57/F ALL Cord MM day +4 fever, delirium, hypoxia diarrhea None Linezolid died day day and 3 days progressive decline in mental status, bilateral GG infiltrates, VDRF, renal failure, recurrent bacteremia 2. 68/F AML TCDPBSCT MUD day +6 fever, confusion, hypoxia, diarrhea None Linezolid Alive, late graft failure 3 days progressive decline in mental status, interstitial lung infiltrates, VDRF, tracheostomy 3. 65/F MDS TCDPBSCT MM day +6 fever, change in mental status, hypoxia and bloody diarrhea TCDPBSCT indicates T cell-depleted peripheral blood stem cell transplant; MM, mismatched; MUD, matched unrelated donor; VDRF, ventilator dependent respiratory failure; GG, ground glass; HSCT, hematopoietic stem cell transplantation; VREB, vancomycin-resistant Enterococcus bacteremia. *All patients underwent prompt catheter removal. For linezolid resistant VRE, Daptomycin dose 4-6 mg/kg every 24 hours, Gentamicin 1 mg/kg every 12 hours (renally adjusted dose). Since the MSKCC study by Almyroudis et al. [1], we have used vancomycin prophylaxis (beginning late 2005) in the peritransplant period for prevention of S. viridans in myeloablative HSCTs [12] and fluoroquinolone prophylaxis (since 2006) is routinely used in HSCT recipients (Figure 2) [13]. Our current study has several important findings; we have reported a high pre-hsct prevalence of VRE colonization in a much larger cohort of patients undergoing HSCT at MSKCC than previously described [4]. In addition, we have observed a shift in the spectrum of bacteria causing BSIs in the preengraftment period. VRE now accounts for the majority of the infections (53.5%), and the rate of VREB early after HSCT has almost doubled (from 5% in previous study to 9.3% in the current study); Streptococcus viridans BSI rates in the preengraftment period have declined from 8.1% ( ) to 1.3% (current study). We believe the cause of change in epidemiology of preengraftment BSI s is multifactorial; first, antibacterials that disrupt commensal Gram-negative bacteria (such as ciprofloxacin) promote high-grade VRE colonization by disrupting innate immune defense mechanisms in the gut [14], and vancomycin use, which has been previously identified as a risk factor for VRE [15], has increased significantly in our transplant population. We believe the increased use of these 2 drugs for prophylaxis in HSCT recipients has played a role in the emergence of VRE as a predominant pathogen early after HSCT. Second, the prevalence of gastrointestinal colonization of VRE has probably increased since the previous report by Almyroudis et al. [1]. In the current series, all cases of early VREB occurred within the first 10 days after transplant, and mostly periengraftment. Although severe cases of VREB early after HSCT have been reported previously [9], the risk period for infection is not well defined. The current study and previous reports from our institution [1,4] identify the highest risk for VREB during the first 2 weeks after HSCT, particularly periengraftment, which may in part relate to the period when the presence of mucositis is greatest and barriers against VRE in the gastrointestinal tract are the lowest. Currently, the ASBMT guidelines do not make recommendations regarding routine screening and prophylaxis for VRE [16]. However, the high prevalence of VRE among leukemia and HSCT patients has been commonly described [3,6,8,9,17-20]. In the current study, pre-hsct screening alone identified 13 of 23 (56.5%) patients who subsequently developed VREB, and an additional 6 patients were found to be colonized on a follow-up culture after initial negative screen. Five percent of noncolonized (on pre-hsct screen) developed VREB, much lower than the incidence (13 of %) in VRE carriers, but concerning nevertheless. Pre-HSCT screening and weekly surveillance identified approximately 80% of patients

5 1580 M. Kamboj et al. Biol Blood Marrow Transplant 16: , 2010 Figure 1. Frequency of VREB by days posttransplant (until day 130). at risk. Although nosocomial acquisition of VRE is certainly a possibility in the 4 patients who developed VREB with negative stool screening for VRE, variability in sample collection technique and poor sensitivity of culture-based methods for detection of VRE is well recognized [21]. Our findings suggest that pre-hsct screening alone will miss a proportion of patients at risk for VREB, and prophylactic strategies should not be guided entirely by pre HSCT stool screening results. Few studies have evaluated the utility of polymerase chain reaction (PCR)-based approaches for detection of VRE in this setting [5]. Therapy with an agent active against VRE in all patients with fever (regardless of VRE colonization) in the most vulnerable period after HSCT merits clinical investigation. The current choices include linezolid, quinupristin-dalfopristin, daptomycin, and tigecycline. Of these, only linezolid and quinupristindalfopristin are FDA approved for treatment of VRE. Linezolid, in particular, appears to be safe when used in HSCT patients [22]; resistance among VRE to linezolid occurs rarely, and has been reported after prolonged use [23-25]. However, the effect of early use of linezolid in HSCTs on VREB and mortality from VRE infections should be evaluated further in prospective studies. Last, we have reported 3 cases of severe VREB early after HSCT. Although we cannot attribute all the clinical findings to VRE infection because of a lack of autopsy information, the similarity in clinical presentation among all 3 patients is striking, and demonstrates that acute decompensation can occur with this bacteria. This supports an aggressive approach in devising preventive strategies for VRE in HSCT recipients. This study has several limitations: (1) its retrospective design, (2) BSI rates per transplant days for early VREB were not determined, (3) the impact of preemptive linezolid use in prevention of VRE infection and mortality was not assessed, (4) the technique for collection of rectal swabs changed during the study period: samples for VRE surveillance were collected by patients before June 2009 and by nurses in the last 6 months of the study period. Last, the antibiotic regimen for empiric treatment of fever and neutropenia needs to be tailored for individual transplant centers in the context of their patient population and hospital epidemiology. Figure 2. Incidence and attributable mortality from VREB in the preengraftment period from 3 studies done at MSKCC, with VRE colonization rates and changes in prophylactic antibacterial regimens during the study years.

6 Biol Blood Marrow Transplant 16: , 2010 Preengraftment bacteremia with VRE 1581 In conclusion, we have reported a change in the spectrum of bacteria causing BSIs early after HSCT, with emergence of VRE as a dominant pathogen in the preengraftment period. VRE colonization is predictive of infection, but more sensitive and accurate screening methods are needed. The empiric use of Gram-positive agents with activity against VRE in all patients with fever in the preengraftment period needs formal investigation. Studies in the prevention of VRE colonization and bacteremia during HSCT need to target infectious disease management of patients during treatment of their primary malignancy. ACKNOWLEDGMENTS Ms. Crystal Son completed the statistical analysis. Financial disclosure: G.A.P. has received research grants from Pfizer. The remaining authors have nothing to disclose. REFERENCES 1. Almyroudis NG, Fuller A, Jakubowski A, et al. 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