International Journal of
HEMATOLOGY
Intensified Strategies to Control Vancomycin-Resistant Enterococci in Immunocompromised Patients M. Schmidt-Hieber,a I. W. Blau,a S. Schwartz,a L. Uharek,a K. Weist,b T. Eckmanns,b D. Jonas,c H. Rüden,b E. Thiel,a C. Brandtb a Department of Hematology, Oncology and Transfusion Medicine, Universitätsmedizin Berlin, Charité – Campus Benjamin Franklin, Berlin, Germany; bInstitute of Hygiene and Environmental Medicine, Universitätsmedizin Berlin, Charité – Campus Benjamin Franklin, Berlin, Germany; cInstitute of Environmental Medicine and Hospital Hygiene, Freiburg, Germany
Received September 20, 2006; received in revised form March 20, 2007; accepted May 9, 2007
Abstract Increasing colonization and infection with vancomycin-resistant enterococci (VRE) in immunocompromised patients are associated with increased mortality. Despite contact precautions for VRE control, rapid limitation of its spread is often impossible. We report on a VRE outbreak in a hematologic/oncologic unit including 33 patients. Although 28 of the patients had only VRE colonization, VRE-related infection was probable in 4 patients, and VRE infection of the bloodstream occurred in 1 case. Two patients were identified by VRE screening on admission, 20 were identified by weekly routine VRE screening, and 6 were identified from specimens taken to clarify infections (eg, urine, bronchoalveolar lavage). Five individuals acquired VRE colonization as inpatients (contact patients). Multiple-locus variable-number tandem repeat analysis (MLVA) proved that the outbreak was caused by VanA gene–positive Enterococcus faecium belonging to MLVA genogroup C1 (MLVA types 1, 7, 12). The outbreak strains exhibited the potential virulence factor esp (enterococcus surface protein). The outbreak was terminated within 2 months by intensified infection-control measures, including quarantine and the cohorting of patients who tested positive for VRE; however, VRE spread recurred after the measures were discontinued but was again limited by resuming the measures. We conclude that intensive infection-control strategies enable the timely termination of VRE outbreaks, even those involving VRE strains with high epidemic potential on “high-risk wards” (eg, hematologic/oncologic units). Premature discontinuation of infection-control measures may cause recurrence of the VRE spread. Int J Hematol. 2007;86:158-162. doi: 10.1532/IJH97.E0632 © 2007 The Japanese Society of Hematology Key words: Vancomycin-resistant enterococci (VRE); Outbreak; Hematologic/oncologic units; MLVA genogroup C1; Infection control
1. Introduction
increased in intensive care unit (ICU) settings from 0.4% to 25.0% over a 10-year period [4-6]. In Europe, vancomycin resistance was prevalent in the 1990s and then disappeared almost completely. In 2004, VRE reappeared in Germany (EARSS reports; see http://www.earss.rivm.nl). The increased use of antibiotics and the emergence of multiresistant enterococci with high epidemic potential are factors that probably contribute to the increasing frequency of VRE isolates [7,8].A recently published meta-analysis demonstrated that the mortality rate for bloodstream infections (BSI) due to VRE was approximately twice as high as those caused by vancomycin-susceptible enterococci [2]. Several risk factors recently identified for VRE BSI include the following: prior VRE colonization, duration of hospital stay, ethnicity, prior and current antibiotic treatment,
Vancomycin-resistant enterococci (VRE) causing infection or colonization are increasingly detected in high-risk patients, including immunocompromised patients receiving antineoplastic treatment [1-4]. The spread of VRE particularly involves several European countries and the United States, where vancomycin resistance rates among enterococci have
Correspondence and reprint requests: Martin Schmidt-Hieber, MD, Medizinische Klinik III (Hämatologie, Onkologie and Transfusionsmedizin), Charité – Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany; 49-30-8445-2310; fax: 49-30-8445-4468 (e-mail:
[email protected]).
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use of a central venous catheter, and immunosuppression (eg, neutropenia or immunosuppressive drug therapy) [1,9]. Despite measures to ensure early detection of VRE colonization and efforts to eradicate VRE and prevent its spread, outbreaks tend to last and spread extensively on high-risk wards [10-12]. Because therapeutic options for VRE infections are very limited [13,14], effective strategies to prevent and control VRE spread are urgently needed. We report on a VRE outbreak caused by a multiresistant VanA gene-positive Enterococcus faecium strain in a hematologic/oncologic department between April and December 2005.
2. Patients and Methods 2.1. Screening Methods and Definitions VRE screening periods are depicted in Figure 1. At week 27, screening of ward patients was implemented and conducted weekly until the end of the observation period. Screening included 70 patients housed on 4 hematologic/oncologic wards with an ICU in a university hospital. In addition, VRE screening on admission with quarantine and segregation was implemented at week 29.This screening system was established temporarily and terminated at week 36. VRE screening on admission and weekly surveillances were carried out with rectal swab or fecal cultures. The VRE status was defined as follows: 1. Patients testing positive for VRE. These patients had at least 1 positively testing rectal swab or fecal specimen (VRE colonization) or a positive culture from normally sterile sites, such as blood or urine (VRE infection). VRE detection in specimens from organ systems normally not colonized by
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enterococci (eg, bronchoalveolar lavage) was also assessed as VRE colonization. VRE BSI was documented in patients who demonstrated VRE growth in at least one blood culture and signs of infection without detection of any other causative organism. 2. Patients with a negative VRE status. These patients had at least 1 negatively testing rectal swab on admission or at least 3 negative swabs after previous VRE colonization. 3. Patients with an unknown VRE status. These patients had an unknown VRE status on admission. Roommates of patients who tested positive for VRE were also considered to be potentially positive until results from swabs or fecal specimens became available. To elucidate the modes of VRE transmission, we regularly took specimens for VRE screening from the hands of staff and noncritical devices (stethoscopes, thermometers, sphygmomanometers).
2.2. Infection-Control Measures and Interventions The following intensified infection-control measures were implemented 10 weeks after the first detection of VRE (the index case) in April 2005 (Figure 1): 1. Hand disinfection with alcohol-based solutions and the use of disposable gloves and gowns (single use per patient) became mandatory for all staff members before and after entering a patient’s room. 2. Patient cohorting was implemented. Patients were housed on separate hematologic wards according to their VRE status. Those with an unknown VRE status were housed on a separate ward and then grouped according to the VRE-screening results. Each patient cohort was attended by a separate nursing staff. The bone marrow
Figure 1. Time course of the vancomycin-resistant enterococci (VRE) outbreak and interventions. A indicates VanA gene–positive Enterococcus faecium; B, VanB gene–positive E faecium; black squares, patients with VRE infection (including blood stream infection); gray squares, patients with VRE colonization only; superscript, multiple-locus variable-number tandem repeat analysis type (nd, not done); incidence, cases of newly detected VRE colonization/infection per week.
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3. Results 3.1. Course of the Outbreak and Typing Experiments
Figure 2.
Mutiple-locus variable-number tandem repeat (VNTR) analysis (MLVA) typing of 7 VanA gene–positive vancomycin-resistant enterococci (VRE) isolates during the outbreak. The typing scheme [17] uses 6 VNTR loci: 1, 2, 7, 8, 9, and 10. Each VNTR locus has a specific repeat length (in bp), and the number of repeats may vary between VRE strains. An MLVA profile is created from the number of repeats for each of the VNTR loci, and VRE isolates with identical MLVA profiles produce the same MLVA type. The results shown are for VNTR loci 7, 8, 9, and 10. For example, the framed polymerase chain reaction band of isolate no. 1 for VNTR locus 10 is sized at 354 bp and consists of 2 repeats. Isolate nos. 1 and 3 to 7 share the same MLVA profile and belong to MLVA type 7; isolate no. 2 belongs to MLVA type 12 (see Figure 1).
transplantation unit was excluded from segregation, because these patients were housed in single rooms for protective isolation. 3. Regular training with detailed instructions accompanied the implementation of infection-control measures for all staff members and patients.
2.3. Laboratory Methods After incubation for 24 hours in tryptic soy broth, rectal or stool swabs were plated onto Enterococcosel agar plates containing 8 μg/mL of vancomycin (BD Medical Systems, Heidelberg, Germany) to screen for VRE. If growth was obtained in 6.5% sodium chloride, 3 to 5 colonies were separately classified by 6 biochemical reactions (L-arabinose, pyruvate, sorbitol, raffinose, pigment, motility) as E faecium, E faecalis, or E casseliflavus. Enterococci growing on Enterococcosel agar were tested for vancomycin susceptibility by Etest (Inverness Medical Deutschland, Cologne, Germany) according to Clinical Laboratory Standard Institute guidelines [15]. Phenotypically resistant VRE isolates (vancomycin ≥32 μg/mL) were tested for the VanA and VanB genes by a modified multiplex polymerase chain reaction (PCR) analysis [16]. VRE isolates were genotyped by multiple-locus variablenumber tandem repeat analysis (MLVA) as previously reported [17] and allocated to distinct MLVA genotypes [16]. Selected isolates were tested for the presence of the enterococcus surface protein (esp)-encoding esp gene. If positive, an A-repeat profile of that particular gene was determined, as previously reported [18].
The outbreak was divided into 2 phases and affected 33 patients who tested positive for VRE (Figure 1).The index patient with bacterial cystitis was identified in April 2005 (week 17). The recognition of the outbreak in July (week 27) led to the implementation of systematic VRE screening and patient cohorting. The first termination of this outbreak was achieved in mid-August (week 33), and the intensified measures (eg, VRE screening on admission, segregation system) were discontinued 3 weeks later. Recurrence of the outbreak in September 2005 (week 37) led to reimplementation of the intensified infection-control measures. New VRE transmissions were again reduced. The outbreak was limited to the hematologic/oncologic department. Three patients required treatment in the ICU, where swabs were taken from contact patients. Of the 14 contact patients in the medical ICU, only 1 patient was colonized by VRE, and this event happened during week 27, when the isolation precautions had not yet been initiated. All 33 isolates were identified as vancomycin-resistant E faecium, with 30 isolates (91%) carrying the VanA gene and 3 (9%) carrying the VanB gene (Figure 1). All isolates showed in vitro susceptibility to linezolid, tetracycline, rifampicin, fosfomycin, and streptomycin. Twenty-seven of the VanA gene–positive isolates were genotyped. MLVA type 7 was detected in 19 patients (70.5%), type 1 was detected in 6 patients (22.0%), and type 12 was detected in 2 patients (7.5%) (Figure 2). Thus, the majority of genotyped isolates belonged to the MLVA C1 complex according to the Homan criteria (MLVA types 1, 7, and 12). These MLVA types belong to the clonal complex CC17 according to multilocus sequence typing analysis. VanB isolates were characterized as MLVA type 159 in 2 cases and as type 12 in 1 case (Figure 1). Exemplary genotyping showed that all tested isolates harbored the esp gene. Esp gene–repeat profiling of 4 isolates disclosed 3 esp A repeats in 3 of these isolates, all of which belonged to the VanA gene–positive group. One VanB gene–positive isolate showed 4 esp A repeats.
3.2. Patient Characteristics and Risk Factors Fifteen (45%) of 33 affected patients were female and 18 (55%) were male. Twenty-eight patients (85%) had only VRE colonization, and the respiratory tract (growth of VRE in bronchoalveolar lavage) was included in 2 patients. Four patients (12%) had infections that were probably VRE related, including 2 patients with urinary tract infection, 1 with local skin infection at the central venous catheter insertion site, and 1 with intra-abdominal infection. VRE BSI was found in only 1 patient (3%). The underlying diseases of these patients were leukemia or non-Hodgkin’s lymphoma in 24 cases (73%), solid tumor in 5 cases (15%), and another disease in 4 patients (12%) (renal failure in 3 cases and sickle cell anemia in 1 case). At the first VRE-detection phase, 13 patients (39%) had neutropenia (leukocytes ≤1.0 × 109/L or an
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absolute neutrophil count ≤0.5 × 109/L) as a risk factor for VRE colonization/infection. The majority of patients with VRE colonization/infection had received intravenous drug therapy by a central venous catheter and previous antibiotic therapy. Twenty-eight (85%) of the 33 patients were discharged to our outpatient department, and 4 patients (12%) died of causes unrelated to VRE infection. The patient with VRE BSI probably died of VRE-related septicemia, even though antibiotic therapy had immediately been initiated with linezolid after in vitro susceptibility testing.
3.3. Screening Results and Transmission Modes There were 160 VRE admission screenings, as well as 852 weekly screenings of ward patients (including those with known VRE colonization or infection). Two of 33 patients with VRE colonization/infection were detected by VRE screening at admission, 20 patients were detected by weekly ward screening for VRE, and 6 patients were identified by specimens taken according to the clinical indication (eg, urine, bronchoalveolar lavage). Five patients acquired VRE colonization as roommates of VRE-colonized patients (contact patients). An analysis of the duration of VRE colonization included patients with at least 5 serial weekly swabs after the first detection of VRE. Fourteen (70%) of 20 evaluable patients were VRE negative at the last follow-up, but 6 patients (30%) were still colonized. VRE was found in only 1 swab specimen (from a bathroom facility) taken from the hospital environment (including patients’ beds and lavatories) and staff hands (10 physicians and 13 nurses).
4. Discussion We report on a VRE outbreak involving 33 patients on 4 hematologic/oncologic wards with a medical ICU in a university hospital. Our examination of isolates revealed E faecium that was VanA gene positive in 30 patients and VanB gene positive in 3 patients. We assume the transmission was nosocomial in the cases of VanA gene–positive E faecium colonization and sporadic or community acquired in the 3 cases of VanB gene–positive E faecium colonization. The hypothesis of nosocomial rather than community-acquired transmission in the former is based on the following observations: (1) Implementation and discontinuation of intensified infection control measures correlated strongly with the termination of the first phase of the outbreak and the recurrence of VRE spread, respectively. (2) Exemplary PCR analyses revealed esp expression in all isolates tested. This virulence factor, which contributes to urinary tract colonization and biofilm formation, is typical of VRE strains found in outbreaks and not in community-acquired cases [18-20]. (3) Exemplary assessment of the A-repeat profile disclosed 3 A repeats in all 3 isolates investigated. Recently, the number of A repeats has been shown to vary between 0 and 6; however, despite marked polymorphism in the repeat region of the esp gene, strains from a single outbreak typically show identical repeat regions [18,21].
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VRE was probably transmitted mainly by the hands of personnel and by patient-to-patient contact; transmission possibly also occurred via the inanimate environment. These transmission modes were identified in previous VRE outbreaks [8,22]. However, we used hand swabs to evaluate transmission by the staff. This method is less sensitive than the bag-broth method [23], and our use of the swab method may be the reason why VRE transmission by the staff was not demonstrated in our study. Intensified infection-control measures, including quarantine and cohorting, required approximately 2 months to terminate the first VRE spread. The subsequent discontinuation of these measures led to recurrence of the spread 3 weeks after the first part of the outbreak had terminated. Our observations are in contrast to a number of reports that have described long-lasting VRE outbreaks, particularly among immunocompromised patients and involving VRE strains with high epidemic potential [10,11,12,24]. Most recently, a hematologic/oncologic ward had to be closed because of the uncontrolled spread of VRE strains with high epidemic potential (personal communication, M. Dettenkofer and F. D. Daschner, Institute of Environmental Medicine and Hospital Hygiene, Freiburg, Germany). Noteworthy is the fact that this outbreak was restricted to the hematologic/oncologic department. The use of disposable gloves and gowns was evaluated as a standard procedure in various VRE outbreaks and has frequently proved to be ineffective in the control of outbreak spread. We therefore think that patient cohorting according to the VRE status was a major factor contributing to the first termination of VRE spread in our series. Strict segregation of the nursing staff may also have played an important role. Because early discontinuation of these measures led to recurrence of the spread of the VRE outbreak, one may assume that these measures should be maintained for at least several months. Interestingly, we found only 1 case of VRE BSI, despite the fact that the majority of VRE-colonized patients had additional risk factors for BSI, including neutropenia, prior and current antibiotic treatment, and hematologic/oncologic malignancies. In this connection, our data may confirm previous reports indicating that active surveillance may also lower VRE bacteremia [11,24-26]. This result may partly be because VRE-colonized patients can be identified more frequently by a systematic surveillance system than by sporadic VRE detection (“dilution effect”). Analysis of serial perianal swab samples revealed long persistence of VRE colonization in the majority of our patients, an observation that others have previously reported [7]. Transient absence of VRE detection in a large number of documented patients seems to reflect low detection sensitivity more often than de novo VRE colonization. We therefore assume that patient segregation must be maintained until serial VRE swab samples remain negative during a prolonged observation period. All VanA gene–positive VRE isolates found in this outbreak belonged to the C1 lineage, with 3 distinguishable strains characterized by MLVA types 1, 7, and 12. Transmission involved mainly MLVA type 7 in July and August and MLVA type 1 in September and October. What remains unresolved, however, is whether the present polyclonal
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outbreak originated from VanA gene plasmid transfer of MLVA type 7 E faecium or whether an index patient harbored this strain primarily. Outbreaks caused by this VRE lineage have been reported in the United States, Australia, the United Kingdom, and some other European countries [15,18,27,28]. However, this lineage was rarely detected in Germany until recently, when it started causing outbreaks in hospitals in southwest Germany (EARSS reports, http://www.earss.rivm.nl). We conclude that intensified infection-control measures may enable the timely termination of VRE spread, even in high-risk patients, and that the premature discontinuation of such measures might lead to recurrence of the spread.
Acknowledgments We thank Mrs. K. Bunte-Schönberger (Institut für Hygiene und Umweltmedizin, Universitätsmedizin Berlin, Charité – Campus Benjamin Franklin) for thorough data documentation. We also thank Dr. J. Weirowski for her valuable grammatical and stylistic proofreading of the manuscript.
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