Incidence and outcome of vancomycin-resistant enterococcal bacteremia following autologous peripheral blood stem cell transplantation

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1 (2000) 25, Macmillan Publishers Ltd All rights reserved /00 $ Incidence and outcome of vancomycin-resistant enterococcal bacteremia following autologous peripheral blood stem cell transplantation D Kapur, D Dorsky, JM Feingold, RD Bona, RL Edwards, J Aslanzadeh, PJ Tutschka and S Bilgrami Bone Marrow Transplant Program, University of Connecticut Health Center, Farmington, CT, USA Summary: A retrospective evaluation of 321 consecutive recipients of high-dose chemotherapy (HDC) and autologous peripheral blood stem cell transplantation (PBSCT) was conducted to ascertain the incidence and outcome of vancomycin-resistant enterococcal (VRE) bacteremia. Ten patients developed VRE bacteremia at a median of 6 days following PBSCT. Nine isolates were Enterococcus faecium and one was E. faecalis. The median duration of bacteremia was 5 days. The central venous catheter was removed in seven individuals. Nine patients were treated with a variety of antimicrobial agents including quinupristin-dalfopristin, chloramphenicol, doxycycline, oral bacitracin, co-trimoxazole, and nitrofurantoin. Bacteremia resolved without adverse sequelae in seven patients. Two individuals who died of other causes had persistent or relapsed bacteremia at the time of death. An additional patient suffered multiple relapses of VRE bacteremia and died as a result of VRE endocarditis 605 days following PBSCT. Mortality as a direct result of VRE bacteremia was 10% in this series. The optimal type and duration of treatment of VRE bacteremia has not been clearly defined. Therefore, we perform weekly stool surveillance cultures for VRE in our hospitalized transplant population and apply strict barrier precautions in those individuals in whom stool colonization has been identified. Furthermore, the empiric use of vancomycin has been restricted. (2000) 25, Keywords: vancomycin-resistant enterococcus; autologous stem cell transplant Gram-positive bacterial infections are a major cause of significant morbidity following bone marrow transplantation, and high-dose chemotherapy with autologous peripheral blood stem cell transplantation (HDC/PBSCT). 1 3 Several factors seem to contribute to the increasing incidence of infection by gram-positive organisms including the exten- Correspondence: Dr S Bilgrami, MC-1315, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA Received 20 May 1999; accepted 5 September 1999 sive use of central venous catheters, selective gut decontamination which is directed towards the prevention of gram-negative bacterial infections, and empiric use of broad-spectrum antibiotic therapy. Enterococci are important pathogens and have emerged as the second most common cause of nosocomial infections in the USA. 4 6 The emergence of strains of enterococci which are resistant to conventional antibiotic therapy is of particular concern. Infection with vancomycin-resistant enterococcus (VRE) species in severely immuno-compromised individuals, such as those who have recently undergone HDC followed by allogeneic or autologous transplantation, has the potential for significant morbidity and mortality. A substantial period of immunologic dysfunction follows HDC/PBSCT 7 in addition to nearly 1 week of profound neutropenia immediately following autologous stem cell infusion. The aim of the current study was to ascertain the incidence and outcome of VRE bacteremia following HDC/PBSCT. Patients and methods Three hundred and twenty one consecutive patients who underwent HDC/PBSCT between March 1993 and August 1998 at the University of Connecticut Health Center, Farmington, CT, USA, were eligible for this retrospective evaluation. Clinical data were obtained from comprehensive chart reviews (Table 1). Underlying malignancies included carcinoma of the Table 1 Patient characteristics All patients Patients with VRE Number of patients Median age in years (range) 44 (1 66) 45 (20 56) Male:Female 94:227 3:7 Solid tumor:hematologic 185:136 7:3 malignancy BUCAT:other conditioning 198:123 4:6 regimens Median duration of neutropenia in 7 (3 12) 7 (5 9) days (range) Median day of engraftment (range) +9 (+7 to +13) +9 (+8 to +11) VRE = vanomycin-resistant enterococcus; BUCAT = busulfan, carboplatin, thiotepa.

2 148 breast (n = 155), non-hodgkin s lymphoma and Hodgkin s disease (n = 98) multiple myeloma (n = 24), acute leukemia (n = 14), ovarian cancer (n = 9), and miscellaneous solid tumors (n = 21). The HDC regimen consisted of busulfan 16 mg/kg body weight orally, carboplatin mg/m 2 i.v., and thiotepa mg/m 2 i.v. (BUCAT) (n = 198); busulfan 16 mg/kg body weight orally, cyclophosphamide 90 mg/kg i.v., and etoposide 60 mg/kg i.v. (BUCET) (n = 105); and other regimens (n = 18). A Hickman-type double- or triple-lumen central venous catheter was inserted prior to HDC/PBSCT. Specialists in oral diagnosis evaluated all patients, and any corrective dental surgery was performed at least 2 or 3 months prior to PBSCT. During the transplant admission, the oral cavitycare protocol consisted of liquid nystatin units swish and expectorate twice daily, and half-strength hydrogen peroxide swish and expectorate four times daily. Antibiotic prophylaxis against gram-negative organisms consisted of ciprofloxacin 500 mg orally twice daily from the beginning of conditioning chemotherapy (day 7 to day 10) until engraftment (absolute neutrophil count (ANC) /l) or initiation of parenteral antibiotics for fever. Children under 16 years of age received co-trimoxazole (5 mg/kg of trimethoprim) orally twice daily instead of ciprofloxacin. Additionally, 123 patients were given ampicillin 250 mg orally four times daily and 77 patients received clarithromycin 250 mg orally twice daily as prophylaxis against gram-positive organisms from day +2 until engraftment or initiation of parenteral antibiotics. Compliance with prophylactic oral antibiotic therapy was not an issue because all patients remained hospitalized from day 7 or 10 until engraftment. Cotrimoxazole (800 mg/160 mg) orally twice daily every Monday and Thursday was initiated following engraftment for prophylaxis against Pneumocystis carinii. Acyclovir 250 mg/m 2 i.v. three times daily was utilized prophylactically from the initiation of conditioning chemotherapy until engraftment and was then continued orally at a dose of 400 mg orally twice daily until day +50 in all individuals who were sero-positive for Herpes simplex. Blood cultures were obtained for any febrile episode (fever 38 C) and subsequently as indicated clinically. Blood was collected in culture bottles (BACTEC NR-660, Becton Dickinson, Towson, MD, USA) and incubated at 35 C. Once a positive reading was obtained, an aliquot from each positive bottle was gram-stained and inoculated on the appropriate agar media. Following overnight growth the isolates were speciated utilizing the API Identification System (BioMerieux, Hazelwood, MO, USA). Susceptibility testing was performed by means of the Sensititre Microbroth Dilution System (Trek Diagnostic Systems, Westlake, OH, USA) and interpreted according to the guidelines of the National Committee for Clinical and Laboratory Standards (NCCLS). 8,9 Vancomycin resistance was defined as MIC 16 g/ml. Gentamicin-resistance was defined as MIC 500 g/ml. During aplasia, all febrile episodes were treated initially with empiric ceftazidime 1 g i.v. every 8 h with or without vancomycin 1 g i.v. every 12 h. The antibiotic regimen was altered in accordance with the susceptibility of any organisms that were identified subsequently. Vancomycin-resistant enterococcus bacteremia was defined as at least one positive blood culture during the first 2 weeks following PBSCT. Transplant-related mortality was defined as death during the first 100 days following stem cell infusion from causes other than relapse of the underlying malignancy. Any individual undergoing HDC/PBSCT was admitted to a hepa-filtered room with an attached bathroom which was not shared with other patients. Strict protective isolation was enforced. Hospital personnel and visitors were required to wash their hands with a disinfectant soap prior to entering any room. Additionally, gloves, gown and mask had to be worn if the patient s ANC was /l. Patients were allowed to ambulate within the confines of the bone marrow transplant unit but were instructed to wear gloves, gown and mask if their ANC was /l. Each nurse was entrusted with the care of more than one patient simultaneously. In April 1998, rectal swabs or stool cultures were submitted weekly for culture starting on the day of admission. Any individual colonized by VRE was placed under significant organism-associated precautions in addition to the universal precautions already described. Hospital personnel and visitors were required to wear gloves, gown and shoe-covers, as well as a mask if the patient was neutropenic, before entering the room of a VRE-positive patient. All gloves and disposable apparel had to be discarded in a receptacle within the patient s room, and hands had to be washed with antiseptic soap immediately after emerging from the room. Thermometers, stethoscopes, sphygmomanometers, i.v. poles and wheel-chairs were dedicated to the rooms of VRE-positive patients. Daily and terminal cleaning of rooms followed previously approved hospital guidelines. Results Incidence Ten patients (3.1%) developed VRE bacteremia at a median of 6 days following PBSCT. Species of VRE included E. faecium (n = 9) and E. faecalis (n = 1). Only three patients developed VRE bacteremia following engraftment (two patients, 1 day following engraftment; one patient, 3 days following engraftment). Five of 123 patients receiving ciprofloxacin and ampicillin prophylactically and five of 77 patients receiving ciprofloxacin and clarithromycin developed VRE bacteremia. A comparison of clinical characteristics seen in the entire group of patients (n = 321) and those with VRE bacteremia is presented in Table 1. Underlying diagnoses and time of onset of VRE bacteremia in relation to PBSCT in patients who developed VRE bacteremia are outlined in Table 2. Surveillance cultures for VRE were instituted in April A total of 29 patients underwent HDC/PBSCT between April 1998, and August Fifteen of these individuals were found to be colonized by VRE, and four of these 15 patients went on to develop VRE bacteremia (patients 7, 8, 9 and 10). Patients 1 and 2 developed bacteremia in August 1995 and May 1996, respectively. Patients 3, 4 and 5 were clustered between April and June However each patient was admitted to a separate room. Similarly, patients 6 10 were

3 Table 2 Clinical features and outcome Diagnosis Days post Empiric antibiotic therapy Treatment Result PBSCT Multiple myeloma 10 Vancomycin, Ceftazidime LD, GEN, C, VRE persistent, died of CHL, SYN enterococcal endocarditis, nearly 2 years post PBSCT 2 Metastatic bladder 12 Vancomycin, Ceftazidime, Tobramycin, LD, BACIT, C VRE persistent, died of other carcinoma Metroindazole causes 3 Recurrent medulloblastoma 4 Vancomycin, Ceftazidime, Tobramycin LD, DOX, RIF, VRE resolved GEN, BACIT 4 Recurrent ovarian CA 6 Vancomycin, Ceftazidime RIF VRE resolved 5 Non-Hodgkin s lymphoma 7 Vancomycin, Ceftazidime, Tobramycin LD VRE resolved 6 Metastatic breast cancer 5 Vancomycin, Ceftazidime, LD, GEN VRE resolved 7 Metastatic breast cancer 10 Vancomycin, Ceftazidime LD, DOX, CHL, VRE resolved SYN 8 Metastatic breast cancer 6 Vancomycin, Ceftazidime LD, CHL VRE resolved 9 Recurrent Ewing s sarcoma 5 Vancomycin, Ceftazidime, NIT VRE resolved 10 Non-Hodgkin s lymphoma 6 Vancomycin, Ceftazidime, CHL VRE persistent, died of other causes LD = lines discontinued; CHL = chloramphenicol; RIF = rifampin; GEN = gentamicin; VANC = vancomycin; NIT = nitrofurantoin; BACIT = Bacitracin; C = Co-trimoxazole; DOX = doxycycline; SYN = Synercid. clustered between March and May 1997, and were also each admitted to separate, non-overlapping rooms. Clinical features, treatment and outcome Fever was the presenting feature in all 10 patients. Clinical features and outcomes of VRE bacteremia are outlined in Table 3. The organism was isolated from the blood stream on more than one occasion ( 1 day) in six individuals. In vitro antibiotic susceptibility test results are outlined in Table 4. All strains of VRE were multiply drug resistant. The following antibiotics were utilized in the management of VRE bacteremia: chloramphenicol 12.5 mg/kg i.v. every 6 h for 1 week in four patients; doxycycline 100 mg orally twice daily for 1 week in two patients; bacitracin units orally four times daily for 2 weeks in two patients; quinupristin/dalfopristin 7.5 mg/kg i.v. every 8 h for 6 weeks in two patients; rifampin 300 mg orally or i.v. twice daily for 4 weeks in two patients; co-trimoxazole 5 mg/kg (of trimethoprim) every 6 h for 1 week in two patients; and nitrofurantoin 100 mg orally every 6 h for 10 days in one patient. Four patients received more than one antimicrobial agent. The central venous catheter was removed in seven patients but was retained in three other individuals without complications. The catheter tip was submitted for culture in these seven patients. However, VRE could not be iso- Table 3 Clinical features and outcome summary Number of patients with VRE bacteremia 10 Enteroccoccus faecium:e. Faecalis 9:1 Median day after transplant when VRE was isolated 6 (4 12) Median interval from first to last positive blood 5 (1 605) cultures in days Resolution of bacteremia 9 Relapse of bacteremia following resolution 2 Presence of bacteremia at the time of death 3 Mortality from VRE 1 VRE = vancomycin-resistant enterococcus. lated from culture of any of these specimens despite coexistent bacteremia. Vancomycin-resistant enterococcal bacteremia resolved in one patient following removal of the central venous catheter without the need for antibiotic therapy. Bacteremia resolved completely without adverse sequelae in seven individuals. Two patients with persistent or relapsed VRE bacteremia died of other causes (anthracycline cardiomyopathy and cytomegalovirus pneumonitis, respectively). One patient, who failed a full course of treatment with quinupristin/dalfopristin, developed numerous relapses of VRE bacteremia and died of VRE endocarditis 605 days following PBSCT. Discussion Enterococci are facultative anaerobic, gram-positive cocci seen microscopically either singly or in pairs and chains. They exist in humans as normal commensals of the gastrointestinal and vaginal tracts, and the oral cavity. Normally, E. faecalis and E. faecium constitute 80 90% and 10 15%, respectively, of all enterococcal species isolated from culture. 10 However, the incidence of E. faecium, especially of drug resistant strains, is increased markedly in immunocompromised patients such as organ transplant recipients and individuals with acute leukemia and neutropenia All 10 individuals reported in the current study developed VRE bacteremia within 2 weeks of autologous PBSCT. Ninety percent of isolates were E. faecium. The myeloablative regimens utilized in our study were particularly toxic to the gut. All 10 patients who developed VRE bacteremia also developed severe stomatitis and diarrhea. It is possible that VRE species were translocated from the gut into the blood stream after the development of severe mucositis within the gastro-intestinal tract. Once within the circulation, VRE organisms may have colonized the indwelling catheter of an occasional patient. Enterococci are responsible for at least 12% of all nosocomial infections and 8% of all nosocomial bacteremias. 4

4 150 Table 4 In vitro antibiotic suceptibility Drug MIC ( g/ml) Patient number Vancomycin 64(R) 64(R) 64(R) 64(R) 64(R) 16(R) 16(R) 16(R) 16(R) 16(R) Ampicillin 16(R) 16(R) 32(R) 16(R) 16(R) 8(R) 8(R) 8(R) 8(R) Gentamicin 500(R) 500(R) 500(R) 500(R) 500(R) 500(R) Tobramycin 16(R) Ciprofloxacin 4(R) 4(R) 4(R) 4(R) 4(R) 2(R) 2(R) 2(R) 2(R) Cefazolin 128(R) 16(R) 16(R) 16(R) Chloramph 4(S) 8(S) 4(S) 4(S) 4(S) 4(S) Tetracycline 0.25(S) 0.25(S) Nitrofurantoin 32(S) 64(I) 32(S) 64(I) Rifampin 1(S) 0.5(S) Synercid S S Teichoplanin 0.12(S) R = resistant; S = susceptible; I = intermediate; Chloramph = chloramphenicol. The emergence of drug resistant strains has limited treatment options. Resistance to vancomycin is generally associated with resistance to aminoglycosides and ampicillin making these organisms virtually untreatable with commonly utilized antimicrobial chemotherapy. 15,16 At present, VRE is a common intestinal colonizer among hospitalized individuals. 5 Vancomycin-resistant E. faecium has been isolated increasingly among patients in intensive care units. 11,12 Furthermore, VRE faecium has also been associated with an increased incidence of bacteremia 17,18 and mortality. 19 Enterococci readily acquire antibiotic resistant genes and elaborate substances which promote adherence to host tissues, induce tissue damage, and produce inflammatory reactions. 10 Risk factors predicting the acquisition of VRE include the presence of a central venous catheter, neutropenia, 20 intestinal colonization, 5,17 recent or current administration of vancomycin, third generation cephalosporins, metronidazole, clindamycin or imipenem, 5,17,21 severity of underlying disease, 5 7 or more days of hospitalization especially in a surgical ICU, 21 more than 7 days of vancomycin use, 21 and transfer between floors. 21 Most of the patients in the current study were neutropenic and all were severely immuno-compromised. Numerous antibiotics, including vancomycin, had been initiated empirically prior to the isolation VRE bacteremia. Every individual had already been hospitalized for 7 days in a bone marrow transplant unit. Moreover, every individual had an indwelling central venous catheter and was suffering from a potentially lethal malignancy. The treatment of VRE bacteremia poses a unique set of challenges. Indwelling central venous catheters should be removed as soon as possible. Surprisingly, VRE could only be cultured from the catheter tip of one out of seven of our patients in whom the central line was removed. However, clinical signs and symptoms did improve to some extent in the majority of these seven patients following the removal of their central catheters, and bacteremia resolved in one patient without the need for anti-microbial therapy. Chloramphenicol mg i.v. every 6 h has been utilized with moderate success and without any significant and irreversible adverse hematologic sequelae. 22 Other agents such as doxycycline, 23 nitrofurantoin, 24 co-trimoxazole and oral bacitracin 25 have also been used to treat VRE infection. Oral bacitracin was utilized in the treatment of two of our patients with persistent bacteremia as an adjunct to other anti-microbial agents. The rationale was based on previous reports suggesting reduction or elimination of fecal carriage of VRE following the administration of oral bacitracin. 25,26 Since it is our assumption that the primary source of VRE was the gastro-intestinal tract in our patients, oral bacitracin was utilized in an effort to decrease the VRE bacterial load in the gut. It must be stated that oral bacitracin, an agent that is not absorbed from the gut, was not used to treat the actual VRE bacteremia. Similarly, nitrofurantoin has been utilized previously to treat urinary tract infections due to VRE. 27 However, there does not appear to be any basis for its use in the treatment of VRE bacteremia. More recently, quinupristin/dalfopristin (Synercid; Rhone-Poulenc-Rorer Pharmaceuticals, Collegeville, PA, USA) has been a valuable addition to the armamentarium. 28 However, there is no definite strategy outlining the optimal type and duration of treatment. Unfortunately, mortality from VRE bacteremia and infection is still considerable despite appropriate management. 19,29 In a recent study, 20 of 56 patients colonized by VRE developed bacteremia. 30 Unlike our patients, the majority of these patients had undergone allogeneic transplantation (n = 43). Seventeen of these 20 patients with VRE bacteremia died, 16 as a result of non-relapse mortality. The authors concluded that VRE infection and bacteremia was associated with a high mortality rate and may be associated with an increased risk for graft failure. Therefore, it is surprising that the mortality from VRE bacteremia in our group of patients was only 10% and transplantrelated mortality was only 20% in these 10 individuals. Enterococci are likely spread by hospital personnel. 31,32 These organisms have been identified on doors, bedrails, linen, electronic thermometers, electrocardiography monitors and sphygmomanometer cuffs Various strategies have been employed to reduce nosocomial spread of VRE. These include strict hand washing by hospital employees with antiseptic soaps, restriction of empiric vancomycin usage, and performance of weekly stool surveillance culture for VRE among hospitalized patients. All individuals colonized with VRE should be cared for with strict barrier

5 precautions, including the use of gloves and gowns. 36 Unfortunately, one large study failed to demonstrate any reduction in the rate of VRE colonization despite the institution of these precautions. 5 The current study is the first to ascertain the incidence and outcome of VRE bacteremia following HDC/PBSCT. Bacteremia resolved without relapse in 70% of patients. Numerous antimicrobial agents were utilized singly or in combination but their role in resolving VRE bacteremia is unclear. Furthermore, the optimal antimicrobial agent and duration of therapy have not been defined in patients undergoing HDC/PBSCT. Surprisingly, three patients cleared their bloodstream of enterococci without removal of their central venous catheter. Most instances of VRE bacteremia resolved following recovery of the ANC. However, because effective antimicrobial agents against VRE are lacking, successful preventive strategies need to be developed. 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