An outbreak of vancomycin-resistant Enterococcus faecium in liver transplant recipients

Vancomycin-resistant Enterococcus faecium (VREF) has become a significant nosocomial pathogen for immunosuppressed patients. During a 5-month period in 1993, 8 cases of invasive infection with VREF (7 with bacteremia) were identified in liver transplant recipients, half of whom were adults. Epidemiology and microbiology studies were designed to identify the source and to determine the risk factors for this infection. Overall mortality was 50% (3 adults and 1 child). Mortality in bacteremic patients was 57%. A case-control study showed that cases were more likely to have been treated with a third-generation cephalosporin or vancomycin and to have undergone more than four biliary tract procedures. Environmental surveillance cultures yielded only one VREF isolate from a rectal temperature probe, but this device was used in only 2 of the cases. Cultures from all surgery and radiology suites were negative. All VREF isolates were genotyped by contour-clamped homogenous electric field electrophoresis of chromosomal DNA restriction fragments. These studies showed that a single clone was responsible for the outbreak, although other clones could be detected in the hospital. After implementing strict contact isolation on the liver transplant unit, only 1 additional patient with VREF was identified during this outbreak. In conclusion, it was found that antibiotic use and biliary tract manipulation were risk factors for developing invasive infections with VREF after liver transplantation. Optimal treatment is still unclear but most likely includes a combination of two or more antibiotics. Prompt institution of infection control measures can preclude rapid spread of this nosocomial pathogen.     

Effect of a vancomycin restriction policy on ordering practices during an outbreak of vancomycin-resistant Enterococcus faecium

A miniaturized pivot bearing-supported centrifugal blood pump (Gyro PI) has been developed as a long-term biventricular assist system (BiVAS). In this study we determined the anatomical configuration of this system using a bovine model. Under general anesthesia, a left lateral thoracotomy was performed to open the chest. Two Gyro PI-601 pumps for left and right assists were placed in the preperitoneal pocket by a subcostal abdominal incision. The left pump could be placed along the dome of the diaphragm just beneath the apex of the left ventricle. The right pump could be placed next to the left pump. The inlet and outlet ports of both pumps penetrated the diaphragm. The inlet port of the left pump, with a length of 55 mm, was inserted directly into the apex of the left ventricle. A woven Dacron graft (150 mm long, 11 mm inner diameter) was placed between the outlet port of the left pump and the descending aorta. As for the right pump, a 100 mm long and 120 degree angled inflow conduit was placed between the inlet port and the right ventricular infundibulum. The outlet port of the right pump was connected to the main trunk of the pulmonary artery using a 90 mm long, 11 mm inner diameter Dacron graft. We could perform biventricular assistance to confirm the anatomical feasibility of the Gyro implantable centrifugal BiVAS.     

Treatment of vancomycin-resistant Enterococcus faecium infections

OBJECTIVE: To define the clinical characteristics of patients infected with vancomycin-resistant enterococci (VRE) and the outcome of the infections without the availability of effective antimicrobial therapy. METHODS: Charts of 28 patients with VRE infections were reviewed for demographics, clinical findings at the time of isolation of VRE, underlying medical problems, surgical procedures, invasive devices, treatment with antimicrobial agents, microbiological data, and patients' responses and outcomes. RESULTS: The infections included 6 cases of bacteremia, 9 surgical site infections (SSIs), 4 cases of peritonitis, 2 pelvic abscesses, 7 urinary tract infections (UTIs), and 2 soft tissue infections (STIs). Four of the 6 bacteremia cases were central-line related and resolved with line removal alone; 1 was treated with a combination product of quinupristin and dalfopristin (Synercid) and 1 had persistent bacteremia in the presence of a ventriculoperitoneal shunt. Seven of 9 SSIs resolved with surgical debridement and 2 of the 9 patients received antibiotics for organisms other than VRE. Similarly, 2 patients with STIs were treated with local debridement and antibiotics directed at organisms other than VRE and 2 patients with pelvic abscesses were treated with drainage and surgical debridement with antibiotics directed at other organisms; the infections resolved completely. Patients with peritonitis were treated with removal of their Tenckhoff catheters, drainage, and irrigation and 1 patient was treated with quinupristin-dalfopristin; 3 of 4 patients were cured. Two of 7 patients with UTIs were treated with nitrofurantoin and their urine cultures showed no growth after treatment; however, most patients with UTIs experienced resolution despite a lack of specific antimicrobial therapy. CONCLUSIONS: Although no antimicrobial agents are currently available for VRE infections, VRE line-related bacteremias could be treated by line removal alone. Surgical site infections, STIs, and abscesses could be managed by surgical debridement and drainage without specific antimicrobial agents against VRE and UTIs could be resolved with nitrofurantoin or removal of Foley catheters. Removal of foreign devices, debridement, and surgical drainage seemed to be important in the resolution of VRE infections.     

Activity of disinfectants against vancomycin-resistant Enterococcus faecium

Myospherulosis is a chronic inflammatory reaction to the mixture of red blood cells and petroleum based ointments. A literature review does not reveal any cases involving ophthalmic manifestations. We present the first reported case of a patient experiencing recurrent eyelid inflammation from myospherulosis after endoscopic sinus surgery. The pathophysiology and management of myospherulosis are discussed.     

Emergence and dissemination of a highly vancomycin-resistant vanA strain of Enterococcus faecium at a large teaching hospital

We prospectively identified patients at the Massachusetts General Hospital from whom vancomycin-resistant enterococci (VRE) were isolated from a clinical specimen from 1 January 1991 through 31 December 1995. VRE strains were available from 139 (82%) of the 169 patients with clinical cases. Of these, 39 (28%) were identical or closely related by pulsed-field gel electrophoresis (i.e., VRE type A strain), including 38 (43%) of 89 VRE strains in 1995. By multivariate analysis, acquisition of the VRE type A strain was associated with receipt of clindamycin (odds ratio [OR] = 10.5), 15 or more days of hospitalization before the first isolation of VRE (OR = 2.9), and residence on one of the general medical floors (OR = 7.8). The VRE type A strain was a vanA strain of Enterococcus faecium and was highly resistant to all antimicrobial agents tested except chloramphenicol. These findings document the rapid dissemination of a highly resistant strain of E. faecium among patients and among other extant VRE strains at the Massachusetts General Hospital in 1995.     

Treatment options for chronic prostatitis due to vancomycin-resistant Enterococcus faecium

Prostatitis due to vancomycin-resistant enterococci has not been previously described. Reported here is a case of chronic prostatitis due to Enterococcus faecium, resistant to vancomycin, ampicillin, ciprofloxacin and doxycycline, in a 42-year-old liver transplant recipient. Treatment with a combination of rifampin and nitrofurantoin for 6 weeks resulted in long-lasting cure. Other antimicrobial agents active in vitro against vancomycin-resistant enterococci, such as quinupristin/ dalfopristin and chloramphenicol, are unlikely to achieve sufficient prostatic tissue levels to be successfully utilized for treatment of this condition.     

Successful treatment of persistent bacteremia due to vancomycin-resistant, ampicillin-resistant Enterococcus faecium

Emergence of vancomycin-resistant enterococci has become an increasing problem in many medical centers. We report a liver transplant recipient with vancomycin-resistant Enterococcus faecium bacteremia who was successfully treated using very high dose continuous infusion ampicillin/sulbactam, plus gentamicin after he remained bacteremic on high dose ampicillin and gentamicin. At our institution, 83% of E. faecium isolates from 1994 were inhibited by ampicillin/sulbactam compared to 66% for ampicillin at an MIC < or = 64 micrograms/ml. None of these strains produced beta-lactamase, suggesting sulbactam may have an unexplained beneficial effect against some enterococci. Although an MIC of < or = 8 micrograms/ml is required for ampicillin to be considered active against enterococci, much higher levels of ampicillin or ampicillin/sulbactam are safely achievable. The response of our patient and the reported in vivo data have implications for future treatment of this pathogen, and may necessitate a reevaluation of susceptibility interpretation guidelines by clinical laboratories, and therapeutic drug dosing by clinicians.     

Epidemiological study of hospital-acquired infection with vancomycin-resistant Enterococcus faecium: possible transmission by an electronic ear-probe thermometer

Clonal spread of vancomycin-resistant Enterococcus faecium among seven patients on one ward of a community teaching hospital was identified by contour-clamped homogeneous electric-field gel electrophoresis. Environmental cultures isolated the same strain from the handle of a shared electronic ear-probe thermometer. Cross-contamination of the clonal strain between two geographically separate units on this ward, sharing equipment but not personnel, suggests the possibility of an environmental source.     

Treatment of vancomycin-resistant Enterococcus faecium infections with an investigational streptogramin antibiotic (quinupristin/dalfopristin): a report of fifteen cases

OBJECTIVE: Previous studies of surgical treatment for acromegaly have used varied criteria for 'cure', but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer-term outcome for patients not offered further treatment when post-operative levels of GH < 5 mU/l were achieved. DESIGN: We studied a retrospective group of patients who underwent transsphenoidal surgery for acromegaly at St Bartholomew's Hospital between 1985 and 1993. PATIENTS: One hundred consecutive patients (53 male, mean age 46 years, range 18-68 years) undergoing transsphenoidal surgery for acromegaly were assessed. The patients were followed for a mean of 3.8 years (range 0.5-8 years) after operation. MEASUREMENTS: GH levels are represented as a mean value from a four-point day curve taken at 0830, 1300, 1700 and 1900 h. ACTH reserve was assessed basally and, if this was normal, with the insulin tolerance or glucagon tests. TSH, T4, PRL, LH, FSH, testosterone or oestradiol and plasma and urine osmolality were also measured. RESULTS: Post-operatively, 42% of patients achieved a mean GH level of < 5 mU/l. The success of surgery was related to the preoperative GH level; 65% of the patients with preoperative GH levels < 20 mU/l but only 18% of the patients with GH levels > 100 mU/l achieved post-operative GH values < 5 mU/l. In addition, tumour size influenced the outcome of surgery with 61% of patients with a microadenoma but only 23% of patients with a macroadenoma achieving post-operative GH levels of < 5 mU/l. Of the 42 patients considered in remission post-operatively (mean GH < 5 mU/l), 32 were available for long-term follow-up and were not offered any further treatment: only one of these has shown evidence of mild biochemical recurrence after a mean follow-up of 3.8 years (range 0.5-8). There were no peri-operative deaths. Two patients required surgical repair for CSF leaks and there were eight documented cases of meningitis. Permanent diabetes insipidus was noted in eight patients post-operatively. New anterior pituitary deficiency occurred in 21% of patients following surgery; 73% had unaltered pituitary function and in 6% recovery of partial hypopituitarism was noted. CONCLUSIONS: The stated outcome of surgery depends on the criteria adopted. Safe GH levels (mean levels < 5 mU/l) can be achieved in 42% of an unselected series of patients with acromegaly and if the tumour is a microadenoma this figure rises to 61%. Based on the current evidence it is safe not to offer further treatment to those patients in whom post-operative GH < 5 mU/l are achieved.     

Vancomycin-resistant Enterococcus faecium colonization in children

This paper describes the genomic structure of the human Prostaglandin F receptor gene (FP) with its exon-intron borders and 5' flanking sequences. Furthermore, the location of the gene has been localized to a very small region on 1p31.1 using FISH and radiation hybrids analysis. The PGF receptor (FP) is highly expressed in mouse tissues especially in the corpora lutea in ovaries and in the kidney. Recently, it has been shown that homozygous knockout-mice lacking the gene for this receptor are unable to deliver normal fetuses at term. It might be speculated that the lack of the FP gene has the same effect in human as in mouse. Mutation analysis in families with difficulties in parturition would therefore be of high interest. The results presented here provides data necessary for further investigations of the FP gene.     

Avoparcin used as a growth promoter is associated with the occurrence of vancomycin-resistant Enterococcus faecium on Danish poultry and pig farms

We determined the association between the use of the glycopeptide antibiotic avoparcin as a growth promoter and the occurrence of Enterococcus faecium (VREF) with high-level resistance to vancomycin (MIC > or = 64 micrograms ml-1) on poultry and pig farms. The investigations were conducted as retrospective cohort studies, where groups of farms exposed or not exposed to avoparcin between September 1994 and April 1995 were compared. In poultry, the association between the use of avoparcin and the occurrence of VREF was confounded by the use of broad-spectrum antibiotics, and the adjusted relative risk was 2.9 (1.4-5.9). In pigs, the association had a similar magnitude with a non-adjusted relative risk of 3.3 (0.9-12.3). The similar findings in the two studies provide evidence in favour of a causal association between the use of avoparcin and the occurrence of VREF on farms, and suggest that food animals constitute a potential reservoir of infection for VREF in humans.     

Screening of stool samples for identification of vancomycin-resistant Enterococcus isolates should include the methyl-alpha-D-glucopyranoside test to differentiate nonmotile Enterococcus gallinarum from E. faecium

The methyl-alpha-D-glucopyranoside (MDG) test has been shown to be superior to motility testing in differentiating Enterococcus faecium from E. gallinarum. In the present study, 33 vancomycin-resistant enterococcus (VRE) isolates collected as part of a stool surveillance study were compared by using motility and MDG. Motility testing identified all 33 isolates as E. faecium, whereas MDG identified 11 of the 33 isolates as nonmotile E. gallinarum. The MDG results were confirmed by sequencing the 16S rDNA V6-to-V8 region. We conclude that the MDG test is a necessary component of routine VRE screening.     

Pharmacodynamic analysis of the activity of quinupristin-dalfopristin against vancomycin-resistant Enterococcus faecium with differing MBCs via time-kill-curve and postantibiotic effect methods

Quinupristin-dalfopristin (Q-D) is a new water-soluble, semisynthetic antibiotic that is derived from natural streptogramins and that is combined in a 30:70 ratio. A number of studies have described the pharmacodynamic properties of this drug, but most have investigated only staphylococci or streptococci. We evaluated the relationship between Q-D, quinupristin (Q), and/or dalfopristin (D) susceptibility parameters and antibacterial activities against 22 clinical isolates of vancomycin-resistant Enterococcus faecium (VREF) by using the concentration-time-kill-curve method and by measuring postantibiotic effects. Q-D, Q, and D MICs and minimum bactericidal concentrations (MBCs) ranged from 0.125 to 1 and 0.25 to 64, 8 to 512 and >512, and 2 to 8 and 8 to 512 microgram/ml, respectively. There were no significant relationships between susceptibilities to the individual components and the susceptibilities to the Q-D combination product. In the time-kill-curves studies, Q-D at a concentration of 6 microgram/ml was at least bacteriostatic against all VREF tested. There was increased activity against more susceptible isolates when the isolates were grouped either by Q-D MBCs or by Q MICs. By multivariate regression analyses, the percent change in the inoculum from that at the baseline was significantly correlated with the Q MIC (R = 0.74; P = 0.008) and the Q-D concentration-to-MBC ratio (R = 0.58; P = 0.02) and was inversely correlated with the Q-D MBC-to-MIC ratio (R = 0.68; P = 0.003). A strong correlation existed between the killing rate and the Q-D concentration-to-MBC ratio (R = 0.99; P < 0.0001). Time to 99.9% killing was best correlated with the Q-D MBC (R = 0.96; P < 0.0001). The postantibiotic effect ranged from 0.2 to 3.2 h and was highly correlated with the Q-D concentration-to-MBC ratio (R = 0.96; P < 0.0001) and was less highly correlated with the Q MIC (R = 0.42; P = 0.04). Further study of these relationships with in vitro or in vivo infection models that simulate Q-D pharmacokinetics should further define the utility of these pharmacodynamic parameters in the prediction of Q-D activity for the treatment of VREF infections in humans.     

Heat tolerance of vancomycin resistant Enterococcus faecium

The heat tolerance of 27 Enterococcus faecium isolates in water was studied. Stationary phase cultures including vancomycin resistant and sensitive clinical and food isolates were exposed to heat at 60 degrees, 65 degrees, 71 degrees, and 80 degrees C for one, three, 10, and 30 minutes and the log10 reductions in bacterial counts were determined. Exposure at 71 degrees and 80 degrees C resulted in > 6 log10 reduction in viable counts for all isolates. Seven (24%) isolates survived (< 5 log10 reduction) heat at 65 degrees C for 10 minutes. The E faecium isolates were more resistant to heat than the two E faecalis reference strains. No differences in heat tolerance were observed between vancomycin sensitive and resistant strains or between isolates of human or food origin.     

Genetic linkage and cotransfer of a novel, vanB-containing transposon (Tn5382) and a low-affinity penicillin-binding protein 5 gene in a clinical vancomycin-resistant Enterococcus faecium isolate

Mechanisms for the intercellular transfer of VanB-type vancomycin resistance determinants and for the almost universal association of these determinants with those for high-level ampicillin resistance remain poorly defined. We report the discovery of Tn5382, a ca. 27-kb putative transposon encoding VanB-type glycopeptide resistance in Enterococcus faecium. Open reading frames internal to the right end of Tn5382 and downstream of the vanXB dipeptidase gene exhibit significant homology to genes encoding the excisase and integrase of conjugative transposon Tn916. The ends of Tn5382 are also homologous to the ends of Tn916, especially in regions bound by the integrase enzyme. PCR amplification experiments indicate that Tn5382 excises to form a circular intermediate in E. faecium. Integration of Tn5382 in the chromosome of E. faecium C68 has occurred 113 bp downstream of the stop codon for the pbp5 gene, which encodes high-level ampicillin resistance in this clinical isolate. Transfer of vancomycin, ampicillin, and tetracycline resistance from C68 to an E. faecium recipient strain occurs at low frequency in vitro and is associated with acquisition of a 130- to 160-kb segment of DNA that contains Tn5382, the pbp5 gene, and its putative repressor gene, psr. The interenterococcal transfer of this large chromosomal element appears to be the primary mechanism for vanB operon spread in northeast Ohio. These results expand the known family of Tn916-related transposons, suggest a mechanism for vanB operon entry into and dissemination among enterococci, and provide an explanation for the nearly universal association of vancomycin and high-level ampicillin resistance in clinical E. faecium strains.