Post-Transplant Events

Early vancomycin-resistant enterococcus (VRE) bacteremia after allogeneic bone marrow transplantation is associated with a rapidly deteriorating clinical course

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Summary:

Vancomycin-resistant enterococcal (VRE) infection is a growing threat. We studied the incidence, risk factors, and clinical course of early-onset VRE bacteremia in allogeneic hematopoietic stem cell transplant recipients. We carried out a chart review of 281 allogeneic hematopoietic stem cell transplant recipients from 1997–2003, including preparative regimen, diagnosis, status of disease, graft-versus-host disease prophylaxis, antimicrobial therapy, and survival. VRE bacteremia developed in 12/281 (4.3%) recipients; 10 (3.6%) were within 21 days of transplant. Diagnoses were acute leukemia (7), NHL (2), and MDS (1). In all, 70% had refractory/relapsed disease; 30% were in remission. In total, 50% had circulating blasts. Nine of 10 had matched unrelated donors (7/9 with CD8+ T-cell depletion). The average time to positive VRE cultures was 15 days; average WBC was 0.05, and 80% had concomitant infections. Despite treatment, all patients died within 73 days of VRE bacteremia. Intra-abdominal complications were common. Causes of death included bacterial or fungal infection, multiorgan failure, VOD, ARDS, and relapse. A total of 60% of patients engrafted neutrophils, but none engrafted platelets. Early VRE bacteremia after allogeneic bone marrow transplant is associated with a rapidly deteriorating clinical course, although not always directly due to VRE. Early VRE may be a marker for the critical condition of these high-risk patients at the time of transplant.

Main

In recent years, the prevailing microbiologic isolates from blood cultures and other invasive infections in leukemic and bone marrow transplant (BMT) patients have undergone a shift. Gram-positive bacteremias, including those due to staphylococci, streptococci, and enterococci, are now more numerous than Gram-negative infections.1 Reasons cited for this include increased use of indwelling central venous catheters, antimicrobial prophylaxis with quinolones, and chemotherapy-induced mucositis.1 There has been a concomitant trend toward antimicrobial resistance in both Gram-positive and Gram-negative bacteria.1,2,3

The development of vancomycin resistance in enterococci has been a difficult challenge for both the clinician and the infection control practitioner.4 In one outbreak involving leukemic patients, the mortality rate was 73%.5 Risk factors for vancomycin-resistant enterococcus (VRE) colonization and infection include prior antimicrobial therapy, including vancomycin, and severity of underlying illness.4

Given the above, it might be expected that VRE infection would be associated with severe illness in hematopoietic stem cell transplant recipients. Kapur et al6 studied 321 autologous peripheral blood stem cell transplant recipients, and found that 10/321 developed VRE bacteremia at a median of 6 days following transplant. Of these 10 patients, seven were successfully treated, but one died of VRE endocarditis and two had persistent bacteremia but died of other causes.6 Isolated case reports of VRE infection in BMT patients have appeared as early as 1991.7 Koc et al8 reported VRE in two MUD allo-BMT patients, including a case of VRE meningitis. An outbreak of vancomycin-dependent Enterococcus faecium infection in five patients on a BMT unit has been described.9 However, little is known about the incidence of infection in allogeneic BMT patients, or outcome in larger series.

Methods

The study population consisted of 281 consecutive allogeneic bone marrow or peripheral blood stem cell transplant recipients from 1997 to 2003 at a tertiary medical center. Of these, 178 (63%) had related donors and 103 (37%) had matched unrelated donors. From this group of 281 patients, 12 were identified who had blood cultures positive for VRE, and 10 of these 12 were identified as early-onset VRE (within 21 days of transplantation). These 10 patients are the focus of the current study. The median age of these 10 patients was 45 years and all were male. Underlying diseases were AML (n=5), ALL (n=2), NHL (n=2), and MDS (n=1). Preparative regimens were busulfan (14 mg/kg)/cyclophosphamide (60 mg/kg)/VP-16 (50 mg/kg) (n=7), photopheresis/total body irradiation (1200 cGy)/cyclophosphamide (60 mg/kg) (n=2), and total body irradiation (1320 cGy)/VP-16 (60 mg/kg × 2 days) (n=1). Nine of 10 patients had matched unrelated donor transplants, and seven of these underwent selective CD8+ T-cell depletion. Graft-versus-host disease prophylaxis was with tacrolimus (0.03 mg/kg) plus methotrexate (5 mg/m2 on days 1, 3, 6, and 11) for seven recipients, and cyclosporine plus methotrexate for three recipients. All patients had trilumen-tunneled catheters placed prior to transplant.

Antimicrobial prophylaxis

All patients received trimethoprim-sulfamethoxazole unless allergic, and acyclovir prophylaxis. With the first neutropenic fever, a regimen of vancomycin, piperacillin-tazobactam, and gentamicin was started (modified for allergies or for positive cultures). Amphotericin B was started at a dose of 0.2 mg/kg/day on day +1 and increased to 0.5 mg/kg/day or higher for persistent fever or suspected fungal infection.

Results

In all, 10 patients (3.6%) developed early-onset VRE bacteremia at a median of 15 days post transplant (range, 8–21 days). Two other patients developed VRE bacteremia on day 157 and day 355, respectively. The current analysis is limited to the 10 early-onset VRE patients. Screening for asymptomatic VRE colonization is not routinely performed at this center. One patient was a known VRE carrier prior to transplant and had had a prior VRE perirectal abscess; no other patients had had VRE infections diagnosed prior to transplantation. The hospital's infection control committee did not identify any clusters or outbreaks among these patients. Four isolates that appeared to be clustered in time were subjected to ribotyping at the University of Iowa Laboratory and were found to be unrelated strains. All isolates speciated were E. faecium. All were resistant to ampicillin, with negative synergy assays for gentamicin and streptomycin. All isolates tested for MIC to chloramphenicol, quinupristin-dalfopristin, and linezolid were sensitive to these agents (this includes all isolates from 2002 onward, and those performed by request prior to that time.) Of these 10 patients, 70% had refractory or relapsed disease at the time of transplant and 30% were in remission. A total of 50% of patients had circulating blasts at the time of transplant. By contrast, in the overall group of 281 allogeneic BMT recipients, 49% had refractory or relapsed disease and 51% were in remission. Of those with refractory/relapsed disease, 40% had circulating blasts at the time of transplant.

The mean WBC count at the time of development of VRE bacteremia was 0.05 (range, 0.01–0.14). Ultimately 60% of patients engrafted neutrophils, but none significantly engrafted platelets before death.

The median duration of VRE bacteremia was 3 days (range, 1–26 days). All but one patient cleared blood cultures of VRE prior to death. All patients with early-onset VRE died, at a median of 18 days after VRE bacteremia was first documented (range, 7–73). Causes of death included bacterial infection (n=4), multisystem organ failure (n=1), aspergillosis (n=1), VOD (n=1), ARDS (n=1), and relapse (n=1). Only one patient was thought to have died as a direct result of VRE infection; however, VRE may have contributed to some of these other complications.

Concomitant infections (defined as simultaneous positive blood cultures, or other defined infections within several days of the VRE bacteremia) were common, and included coagulase-negative staphylococcal bacteremias (n=3), Gram-negative bacteremias (n=4, including Pseudomonas, Enterobacter, Klebsiella), CMV viremia (n=2), viridans streptococcal bacteremia (n=1), Lactobacillus bacteremia (n=1), and disseminated aspergillosis (n=1). Some patients had more than one concomitant infection. Only two patients had no other identified concomitant infections.

Treatment included linezolid in five, quinupristin/dalfopristin (Synercid) in five, and chloramphenicol in two patients. Some patients received more than one agent sequentially. The Hickman catheter was removed in seven of 10. Intra-abdominal complications on the same admission as the VRE bacteremia included GI-GvHD in two patients, typhlitis in one patient, upper GI bleeding in one patient, and acalculous cholecystitis in one patient.

Discussion

VRE bacteremia can be associated with high mortality in the immunocompromised patient, but death in these patients may be due to their underlying disease or other complications. In this study, VRE bacteremia occurred almost exclusively in the higher-risk, matched unrelated donor group. Although approximately one-third of patients overall in this series had unrelated donors, nine of 10 patients with early VRE bacteremia had unrelated donors. Prior antibiotic use, including vancomycin, was universal in these patients, but also in many of the other 269 BMT recipients who did not develop VRE infection. At this center, vancomycin is included in the initial treatment regimen for neutropenic fever in BMT recipients due to a high incidence of MRSE bacteremia, but where possible vancomycin is omitted later. Whether or not reduction in vancomycin utilization could have reduced the incidence of VRE in this population cannot be determined from the information in the present study.

Therapy for VRE infection in this patient population is difficult. Linezolid, which has been successful in the treatment of VRE in immunocompromised patients,10,11 is associated with cytopenias and a potential concern for delayed engraftment. In addition, Hachem et al12 reported two cases of serotonin syndrome and myelosuppression in BMT recipients treated with linezolid and concomitant selective serotonin reuptake inhibitors. Synercid (quinupristin-dalfopristin) has been successfully utilized,13 but may be associated with debilitating painful myalgias and liver function test elevations. Tetracycline-based combinations have been utilized;14 chloramphenicol carries the risk of cytopenias. As yet, there is no effective treatment to eradicate VRE colonization, but the investigational agent ramoplanin holds promise in that regard.15

All of the patients in this series were treated with therapy directed at VRE (summarized above), and 70% had central venous catheters removed. Concomitant intra-abdominal complications occurred in 50% of patients, including GI-GVHD, upper GI bleed, acalculous cholecystitis, and typhlitis.

Although mortality in this series was 100%, in only one case was the patient's death thought to be directly a result of VRE bacteremia. However, VRE may have contributed to the development of organ failure, ARDS and other complications noted. Early VRE infection appears to be a marker for a high-risk group of patients, most of whom are already very ill at the time of transplant. Vigorous infection control measures and more aggressive limitation of vancomycin use are measures that may protect these high-risk patients; decolonization with agents such as ramoplanin may play a role in the future.

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Acknowledgements

We would like to acknowledge with gratitude the kind assistance of Geraldine Hall, PhD.

Author information

Correspondence to B Bolwell.

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Avery, R., Kalaycio, M., Pohlman, B. et al. Early vancomycin-resistant enterococcus (VRE) bacteremia after allogeneic bone marrow transplantation is associated with a rapidly deteriorating clinical course. Bone Marrow Transplant 35, 497–499 (2005) doi:10.1038/sj.bmt.1704821

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Keywords

  • vancomycin-resistant enterococcal infection
  • allogeneic bone marrow transplant
  • toxicity

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