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Surveillance for vancomycin-resistant enterococci: type, rates, costs, and implications.

OBJECTIVE: To evaluate 2 active surveillance strategies for detection of enteric vancomycin-resistant enterococci (VRE) in an intensive care unit (ICU). DESIGN: Thirty-month prospective observational study. SETTING: ICU at a university-affiliated referral center. PATIENTS: All patients with an ICU stay of 24 hours or more were eligible for the study. INTERVENTION: Clinical active surveillance (CAS), involving culture of a rectal swab specimen for detection of VRE, was performed on admission, weekly while the patient was in the ICU, and at discharge. Laboratory-based active surveillance (LAS), involving culture of a stool specimen for detection of VRE, was performed on stool samples submitted for Clostridium difficile toxin detection. RESULTS: Enteric colonization with VRE was detected in 309 (17%) of 1,872 patients. The CAS method initially detected 280 (91%) of the 309 patients colonized with VRE, compared with 25 patients (8%) detected by LAS; colonization in 4 patients (1%) was initially detected by analysis of other clinical specimens. Most patients with colonization (76%) would have gone undetected by LAS alone, whereas use of the CAS method exclusively would have missed only 3 patients (1%) who were colonized. CAS cost Dollars 1,913 per month, or Dollars 57,395 for the 30-month study period. Cost savings of CAS from preventing cases of VRE colonization and bacteremia were estimated to range from Dollars 56,258 to Dollars 303,334 per month. CONCLUSIONS: A patient-based CAS strategy for detection of enteric colonization with VRE was superior to LAS. In this high-risk setting, CAS appeared to be the most efficient and cost-effective surveillance method. The modest costs of CAS were offset by the averted costs associated with the prevention of VRE colonization and bacteremia.

Cost-Benefit Analysis↗

Molecular characterization of vancomycin-resistant enterococci from clinical and surveillance specimens.

OBJECTIVE: To compare the molecular characteristics of infection-derived (ID) isolates and intestinal colonization-derived (ICD) isolates of vancomycin-resistant enterococci (VRE) recovered from hospitalized patients. DESIGN: A 12-month prospective cohort study. SETTING: A 1,000-bed teaching facility. METHODS: From January through December 2004, a total of 30 pairs of vanA-containing enterococcal isolates were collected from patients admitted to a teaching hospital in South Korea. Each pair comprised an ID and an ICD VRE isolate from the same patient. All VRE isolates were investigated on the basis of SmaI-restricted pulsed-field gel electrophoresis (PFGE) pattern, Tn1546 type, and presence of the esp gene, including A and C repeat number variation. RESULTS: Members of 19 pairs (63%) of VRE isolates were genetically indistinguishable from each other. The 11 patients for whom the molecular characteristics of the ID isolates differed from those of the ICD isolates had longer durations of hospitalization and intensive care unit (ICU) stay, compared with the other 19 patients. CONCLUSIONS: These findings suggest the longer durations of hospitalization and ICU stay may be possible risk factors for colonization with multiple clones of VRE.

Carrier State↗

Improving the assessment of vancomycin-resistant enterococci by routine screening.

BACKGROUND: As infection with vancomycin-resistant enterococci (VRE) increases in hospitals, knowledge about VRE reservoirs and improved accuracy of epidemiologic measures are needed. Many assessments underestimate incidence by including prevalent carriers in at-risk populations. Routine surveillance cultures can substantially improve prevalence and incidence estimates, and assessing the range of improvement across diverse units is important. METHODS: We performed a retrospective cohort study using accurate at-risk populations to evaluate the range of benefit of admission and weekly surveillance cultures in detecting unrecognized VRE in 14 patient-care units. RESULTS: We assessed 165 unit-months. The admission prevalence of VRE was 2.2%-27.2%, with admission surveillance providing 2.2-17-fold increased detection. Medical units were significantly more likely to admit VRE carriers than were surgical units. Monthly incidence was 0.8%-9.7%, with weekly surveillance providing 3.3-15.4-fold increased detection. The common practice of reporting incidence using the total number of patients, rather than patients at risk, underestimated incidence by one-third. Overall, routine surveillance prevented the misclassification of 43.0% (unit range, 0%-85.7%) of "incident" carriers on the basis of clinical cultures alone and increased VRE precaution days by 2.4-fold (unit range, 2.0-2.6-fold). CONCLUSIONS: Routine surveillance markedly increases the detection of VRE, despite variability across patient-care units. Correct denominators prevent the substantial underestimation of incidence.

Academic Medical Centers↗

Resistance of enterococci to ampicillin and glycopeptide antibiotics in Italy. The Italian Surveillance Group for Antimicrobial Resistance.

We report the results of the monitoring of resistance to ampicillin, vancomycin, and teicoplanin in enterococci by an Italian network of clinical microbiology laboratories. A total of 16,226 strains were analyzed; 9,169 of these strains were Enterococcus faecalis, 913 were Enterococcus faecium, and 6,144 were Enterococcus species. The average rate of resistance to ampicillin was 1.9% (range, 0-6.5%) for E. faecalis and 70% (range, 33.3%-98.7%) for E. faecium; the average rate of resistance to vancomycin was 1.1% (range, 0.1%-2%) for E. faecalis and 8.5% (range, 0-36.1%) for E. faecium; and the average rate of resistance to teicoplanin was 0.8% (range, 0-2.4%) for E. faecalis and 8.7% (range, 0-36.1%) for E. faecium.

Ampicillin Resistance↗

Clostridium difficile infection is a risk factor for bacteremia due to vancomycin-resistant enterococci (VRE) in VRE-colonized patients with acute leukemia.

A cohort study was conducted in a cancer center to identify risk factors for bacteremia with vancomycin-resistant enterococci (VRE) in neutropenic cancer patients colonized with VRE. There were 10 patients with VRE bacteremia among 56 colonized with VRE, of whose charts 51 were available for review. One hundred percent of patients with VRE bacteremia (10 of 10) vs. 56% of patients without VRE bacteremia (23 of 41) had acute leukemia (P = .01, Fisher's exact test). Four of the 10 patients with VRE bacteremia had a positive Clostridium difficile toxin assay within 6 days of their first positive VRE blood culture. Both C. difficile infection and antimicrobial (vancomycin and ciprofloxacin) use during VRE colonization were significant risk factors for VRE bacteremia in univariate analysis. When a Cox proportional hazards model was used to account for differences in follow-up time, C. difficile infection was the only statistically significant risk factor (risk ratio, 8.2; P = .007) for VRE bacteremia in VRE-colonized patients with acute leukemia.

Acute Disease↗

Prevalence of vancomycin-resistant enterococci among children with end-stage renal failure. Mid-European Pediatric Peritoneal Dialysis Study Group.

To evaluate the prevalence of colonization with vancomycin-resistant enterococcus (VRE) in end-stage renal failure (ESRF), we screened the intestinal flora from 338 pediatric ESRF patients treated in 13 pediatric nephrology units in mid-Europe. Eighty-one patients were undergoing hemodialysis, 66 were undergoing chronic peritoneal dialysis, and 191 were transplant recipients. A total of 363 enterococcal strains were recovered from 232 patients. Twenty-seven enterococcal strains from 24 patients (7.1%) had reduced susceptibility to vancomycin (minimal inhibitory concentration [MIC], >4 microg/mL). Although two patients (0.6%) carried enterococci with high-level resistance to vancomycin (MIC, >32 microg/mL; i.e., VRE), strains of enterococcus with reduced susceptibility to vancomycin (ERSV) were recovered from the other 22 subjects. Past use of vancomycin (P = .05) and tacrolimus therapy (P = .011) were independent risk factors for ERSV or VRE carriage. Enterococcal infections occurred with a similar frequency among enterococcal carriers and noncarriers; no infections with VRE or ERSV were reported. In conclusion, the prevalence of ERSV carriage and the rate of VRE colonization among mid-European children and adolescents with ESRF currently are moderate and low, respectively.

Adolescent↗

A polyclonal outbreak of predominantly VanB vancomycin-resistant enterococci in northeast Ohio. Northeast Ohio Vancomycin-Resistant Enterococcus Surveillance Program.

We studied the molecular epidemiology of vancomycin-resistant enterococci (VRE) isolated in northeast Ohio during 1996 and examined the association between isolation of VRE from samples other than stool and antimicrobial purchases for five Cleveland hospitals. Susceptibility testing and pulsed-field gel electrophoresis were used to analyze 363 isolates from individual patients from 13 hospitals. Susceptibility testing indicated that 287 strains (79%) expressed the VanB phenotype and 76 (21%) expressed the VanA phenotype. The outbreak was polyclonal, with 30 total genotypes. Both VanA and VanB VRE demonstrated multiple genotypes. One genotype was present in all hospitals, suggesting spread between hospitals. For five teaching hospitals, rates of isolation from non-stool sources and from blood correlated positively with purchases of ticarcillin/clavulanic acid (P = .005). In summary, this outbreak demonstrates transmission of VRE between several hospitals in a geographic region and suggests that use of certain beta-lactam antibiotics may be associated with an increased prevalence of VRE.

Disease Outbreaks↗

Prescribing pattern of vancomycin in a community teaching hospital with low prevalence of vancomycin-resistant enterococci.

A 1-month prospective survey of all inpatients given vancomycin was performed in a community teaching hospital with a low prevalence of vancomycin-resistant enterococci. Only 20 of the 97 vancomycin orders written from August 1 to September 1, 1996, were consistent with Hospital Infection Control Practices Advisory Committee (HICPAC) guidelines. Surgical prophylaxis accounted for 37 of the 77 orders inconsistent with HICPAC guidelines.

Drug Resistance, Microbial↗

Susceptibility of vancomycin-resistant enterococci to environmental disinfectants.

OBJECTIVE: To determine the susceptibilities of vancomycin-resistant and -sensitive enterococci (VRE and VSE) to various concentrations of commonly used, commercial, hospital-grade disinfectants. DESIGN: A microbial suspension test using inocula of 10(8) cells per mL in a disinfectant test dilution was used to determine inactivation kinetics of the test strains. In each test, 1-mL aliquots were removed from the cell-disinfectant mixtures at 15 and 30 seconds and then at 1-minute intervals for 5 minutes and neutralized. Appropriate serial dilutions were plated on agar medium for enumeration of survivors. RESULTS: VRE and VSE challenge inocula (in the absence of any additional protein or serum challenge) were below the limit of detection (5 colony-forming units/mL) after 15 seconds' exposure to the manufacturers' suggested use-dilutions of quaternary ammonium, phenolic, or iodophor germicidal detergents. In subsequent tests, when the disinfectants were diluted far beyond-the recommended use-dilutions (extended dilution), no differences were demonstrated between the susceptibilities of VRE and VSE. CONCLUSIONS: VRE and VSE are sensitive to a spectrum of commonly used environmental disinfectants and have parallel inactivation rates when challenged with extended dilutions of these products. Our findings did not demonstrate a relationship between antibiotic and germicide resistance. Routine disinfection and housekeeping protocols presently used in hospitals need not be altered due to concerns about the potential for environmentally mediated transmission of antibiotic-resistant microorganisms.

Anti-Bacterial Agents↗

Vancomycin-resistant enterococci in stool specimens submitted for Clostridium difficile cytotoxin assay.

The prevalence of, and clinical risk factors associated with, vancomycin-resistant enterococcal colonization were investigated in patients suspected of having Clostridium difficile infection. Stools submitted for C difficile cytotoxin testing were screened for vancomycin-resistant enterococci (VRE). Isolates were speciated and characterized further by antibiotic susceptibility testing, DNA fingerprinting, and DNA:DNA hybridization for detection of specific vancomycin resistance genes. Of the 79 evaluable patients identified during a 3-month period, 16.5% were VRE-positive. The VRE isolates were genetically heterogeneous, although all carried the vanA gene. DNA fingerprinting data suggest that patient-to-patient transmission occurred, implicating colonized patients as potential reservoirs for VRE transmission. A positive C difficile cytotoxin assay and diabetes mellitus were the only identifiable risk factors associated with VRE colonization. Patients at risk for C difficile infection therefore may serve as reservoirs for VRE.

Anti-Bacterial Agents↗

Absence of rectal colonization with vancomycin-resistant enterococci among high-risk pediatric patients.

We prospectively surveyed for rectal colonization with vancomycin-resistant Enterococcus among 93 high-risk pediatric patients who were hospitalized at least 5 (median, 20) days. Fifty-two patients (56%) had enterococcal colonization; none had active infection with Enterococcus. All enterococci were vancomycin-susceptible (minimum inhibitory concentration < or =4 microg/mL). Associated exposures included recent antibiotics (50, 96%), surgical procedures (26, 58%), and immunosuppression (15, 29%).

Anti-Bacterial Agents↗

Environmental contamination with vancomycin-resistant enterococci in an outpatient setting.

Eleven cancer patients colonized with vancomycin-resistant enterococci (VRE) were followed as outpatients. Environmental cultures were obtained from clinic rooms before and after patients care. Environmental contamination occurred in 29% of encounters. Superficial disinfection did not eradicate contamination, although more thorough cleaning did. We conclude that environmental VRE contamination occurs in the outpatient setting. Infection control practices, similar to those used in the inpatient setting, may be necessary for outpatient clinics.

Adolescent↗

Spread of vancomycin-resistant enterococci: differences between the United States and Europe.

There are major differences in the epidemiology of vancomycin-resistant enterococci (VRE) between the United States and Europe. In contrast with Europe, VRE in the United States are resistant to many antibiotics, and there appears to be less genetic variability among these isolates. European VRE of human origin are usually susceptible to many other antibiotics and are highly polyclonal. These clinical isolates have the same susceptibility profiles as VRE isolated from animals. The differences in the spread of VRE between the United States and Europe might be explained by the overconsumption of glycopeptides and other antibiotics in hospitals in the United States and the use of avoparcin as a growth promotor in Europe.

Animals↗

Molecular analysis of vanA enterococci isolated from humans and animals in northeastern Italy.

A total of 53 vancomycin-resistant vanA-positive enterococci isolates from poultry farms (17 Enterococcus faecium; 8 Enterococcus durans) and from different hospitals (23 E. faecium; 5 Enterococcus faecalis) in northeastern Italy were compared on the basis of their antibiotic susceptibilities, their SmaI pulsed-field gel electrophoresis (PFGE) patterns, and the organization of their Tn1546-related elements. Ampicillin resistance was similar in both groups of isolates (52 and 60.7%, respectively), whereas human strains were more resistant to high-level gentamicin and streptomycin. A total of 52% of animal strains and 60% of human strains were resistant to tetracycline, and 56% and 46.4% to quinupristin/dalfopristin, respectively. In E. faecium and E. durans animal isolates, nine and six distinct PFGE patterns, respectively, were found: in two instances indistinguishable isolates were found from different farms. In E. faecium and E. faecalis human isolates, nine and six distinct PFGE patterns, respectively, were found; among E. faecium strains, 12 were identical or closely related and were isolates from the same hospital. Elements mediating vanA-glycopeptide resistance were characterized by PCR with primers that amplified 10 overlapping fragments of Tn1546. A total of 84.6% of animal strains and 64.2% of human strains contained elements indistinguishable from the prototype Tn1546. In addition, nine different types were identified, but none was common to animal and human strains.

Animals↗

In vitro activity of 19 antimicrobial agents against enterococci from healthy subjects and hospitalized patients and use of an ace gene probe from Enterococcus faecalis for species identification.

We tested 165 enterococcal isolates, biased toward vancomycin resistant (VR) isolates, collected during recent years from fecal samples of healthy subjects and clinical specimens of hospitalized patients (mostly from United States and some from Europe) for susceptibility to 19 antimicrobials. Nosocomial isolates, whether VR or not, were more often highly resistant to aminoglycosides and clindamycin than fecal isolates from healthy community volunteers and more often resistant to erythromycin, chloramphenicol, trimethoprim, levofloxacin and, for E. faecium, ampicillin (93 vs. 0%). Resistance rates were similar between nosocomial and community-fecal isolates for minocycline, rifampin and quinupristin-dalfopristin (Q-D). None of the 165 enterococci tested hybridized with aph(2'')-Ic and aph(2'')-Id probes for recently described gentamicin resistance genes and 37 of the 39 isolates with high level resistance (HLR) to gentamicin hybridized with an intragenic aac(6')-aph(2'') probe. Of the two newer drugs tested, daptomycin MIC90s were 0.25 microg/mL for E. faecalis and 1 microg/mL for E. faecium, regardless of their vancomycin resistance level or source. For Q-D, none of 28 E. faecium from community based healthy subjects in the USA and 7 of 66 E. faecium from hospitalized patients in the United States were resistant. Among these 7 Q-Dr United States isolates and 7 Q-Dr isolates from Europe (MICs of Q-D of 4-8 microg/mL), none hybridized with vat(D) (formerly satA) and vat(E) (formerly satG) DNA probes, indicating the involvement of other mechanism/s of resistance in these isolates. We also demonstrated that an intragenic probe of the gene ace from E. faecalis showed specific hybridizations to all E. faecalis isolates, suggesting the usefulness of this gene for identification of this species.

Adhesins, Bacterial↗

Persistence of vancomycin-resistant enterococci (VRE) in broiler houses after the avoparcin ban.

The glycopeptide growth promoter avoparcin was banned from animal production in the EU in 1997 due to concern for the spread of vancomycin-resistant enterococci (VRE) from food animals to humans. In recent Norwegian and Danish studies, extensive occurrence of VRE on broiler farms and in broiler flocks after the avoparcin ban has been reported. The present study was undertaken to investigate the epidemiology of VRE on broiler farms in the absence of the selective pressure exerted by avoparcin. Environmental samples were obtained from five broiler houses after depopulation, cleaning, and disinfection of the houses between rotations, and two consecutive broiler flocks from each house were sampled by taking cloacal swabs from the broilers at the time of slaughter. A total of 69 vancomycin-resistant Enterococcus faecium isolates obtained from broiler flocks and broiler houses were subjected to molecular typing by pulsed-field gel electrophoresis (PFGE). Forty-one PFGE-profiles were observed. VRE with indistinguishable or highly similar PFGE profiles were isolated from consecutive broiler flocks and from environmental samples from the houses in which the flocks were reared, whereas VRE-isolates from different broiler houses and from flocks reared in different houses appeared to be genetically unrelated. These findings indicated that VRE was transmitted between consecutive broiler flocks by clones of resistant bacteria surviving in the broiler houses despite cleaning and disinfection between rotations. Thus, the extensive occurrence of VRE in broiler flocks after the avoparcin ban may be explained by persistence of VRE in the broiler house environment.

Animal Feed↗

Vancomycin-resistant enterococci (VRE) in broiler flocks 5 years after the avoparcin ban.

The glycopeptide growth promoter avoparcin was banned from animal production in Denmark in 1995. In this study, we investigated the occurrence of vancomycin-resistant enterococci (VRE) in broiler flocks in the absence of the selective pressure exerted by the use of avoparcin. One hundred sixty-two broiler flocks from rearing systems with different histories of avoparcin exposure were investigated for the presence of VRE. Using a direct selective plating procedure, VRE were isolated from 104 of 140 (74.3%) broiler flocks reared in broiler houses previously exposed to avoparcin on conventional and extensive indoor broiler farms. In contrast, only 2 of 22 (9.1%) organic broiler flocks reared on free-range farms with no history of previous exposure to avoparcin were VRE-positive. Furthermore, the occurrence of VRE over time in flocks reared in broiler houses previously exposed to avoparcin was investigated. Results obtained by direct selective plating showed no significant decrease in the proportion of VRE-positive flocks during the study period (1998-2001). This study demonstrated the extensive occurrence of VRE in broiler flocks more than 5 years after the avoparcin ban in Denmark, and indicates that VRE may persist in the absence of the selective pressure exerted by avoparcin. The results differ markedly from previously published Danish surveillance data on VRE in broilers. This may reflect differences in isolation procedures.

Aging↗

Stability, persistence, and evolution of plasmid-encoded VanA glycopeptide resistance in enterococci in the absence of antibiotic selection in vitro and in gnotobiotic mice.

Long-term persistence of VanA glycopeptide-resistant enterococci (GRE) has been observed in the absence of antibiotic selection. In the present study, we examined fitness parameters of a glycopeptide-susceptible Enterococcus faecium parent strain and its plasmid-mediated, VanA-resistant derivative before and after 1,000 generations in serial transfer broth cultures with or without antibiotic selection. With the exception of the vanA-containing plasmid, the strains were otherwise isogenic. The stability of the plasmid-encoded vanA resistance determinant was also investigated in vitro and in gnotobiotic mice. Competition experiments revealed that GRE with newly acquired VanA resistance had a 4% reduction in fitness relative to their susceptible parental counterpart. The relative difference in competitive fitness between resistant and susceptible strains was not significantly changed after 1,000 generations. Environmental adaptation was observed in all strains and exceeded the biological cost of resistance. Thus, the evolved VanA-resistant E. faecium populations out-numbered their unevolved ancestral susceptible E. faecium strain in mixed cultures, but remained less competitive than the evolved parent. The glycopeptide resistance determinant was similarly stably maintained during long-term colonization in gnotobiotic mice without antibiotic selection. In vivo vanA plasmid transfer was observed. The results suggest that environmental adaptation, in vivo gene transfer, and plasmid maintenance system(s) favor long-term VanA GRE persistence without antibiotic selection and compensate for the biological costs of possessing the resistance genes.

Animals↗