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Pharmacokinetics of vancomycin when administered during high flux hemodialysis.

This study was undertaken to evaluate the pharmacokinetics of relatively high-dose vancomycin when administered during high-flux hemodialysis using a polysulfone membrane (F-80, Fresenius). Five noninfected, anuric patients received a single dose of 25 mg/kg of vancomycin infused during hemodialysis at a rate of one gram per hour and timed such that the end of the infusion coincided with the end of dialysis. Blood samples were drawn during the infusion, up to six hours after the end of dialysis and then prior to the next three dialysis treatments. Spent dialysate was collected during the infusion. Samples were analyzed using the EMIT assay. The percent of vancomycin lost during the first dialysis session ranged from 39.1 to 55.1% (mean, 45.7+/-6.4). The concentration of vancomycin at 6 hours after hemodialysis ranged from 18.2 to 45.1 mg/L (mean, 29.6+/-10.0 mg/l). Dialysis clearance ranged from 96.1 to 158.1 ml/min (mean, 130.7 +/-30.0 ml/min). One week after dosing, serum concentrations ranged from 8.14 mg/l to 10.1 mg/l (mean, 9.0+/-1.0 mg/l). This study suggests than an initial dose of 25 mg/kg of vancomycin, given during high-flux dialysis, may provide adequate serum concentrations in anuric hemodialysis patients for up to seven days. This dosing scheme reduces inconvenience to the patient and staff, and potentially can reduce nursing costs associated with post-dialysis administration; its cost is minimal. At this point, subsequent dosing is best determined by therapeutic drug monitoring.

Adult↗

[A novel method of detecting Staphylococcus aureus heterogeneously resistant to vancomycin (hetero-VRSA)].

We have developed a new method of detecting clinical S. aureus strains possessing heterogeneous resistance to vancomycin (hetero-VRSA). The method exploits characteristic antagonism between vancomycin and beta-lactam antibiotics against the strain Mu3, a representative hetero-VRSA. The method comprises of the following procedures: 1) overnight culture of bacteria is streaked on brain heart infusion agar containing 4 micrograms/ml of vancomycin, 2) paper discs impregnated with any one of beta-lactam antibiotics are placed onto the plate, and 3) the plate is incubated at 37 degrees C and the cell growth was observed after 24 h and 48 h of incubation. The Mu3 cells were grown only around the beta-lactam discs due to the antagonism between vancomycin and beta-lactam against Mu3 cells. A total of 321 MRSA clinical strains isolated in 1995 and 1996 from 12 medical facilities in Japan were tested with this method. A total of 39 strains (12.1%; 24 h) and 67 strains (20.96%; 48 h) grew around the beta-lactam discs. All the 10 strains (representing 10 facilities), tested with the analysis of resistant subpopulations to vancomycin, showed similar heterogeneous patterns as observed with Mu3. The method was considered as a convenient and rapid substitute for the population analysis, the authentic method for the detection of hetero-VRSA strains.

Anti-Bacterial Agents↗

Analysis of molecular epidemiological characteristics and antimicrobial susceptibility of vancomycin-resistant and linezolid-resistant Enterococcus in China.

BACKGROUND: This study investigates the distribution and characteristics of linezolid and vancomycin susceptibilities among Enterococcus faecalis (E. faecalis) and Enterococcus faecium (E. faecium) and explores the underlying resistance mechanisms. METHODS: A total of 2842 Enterococcus clinical isolates from patients were retrospectively collected, and their clinical data were further analyzed. The minimum inhibitory concentrations (MICs) of vancomycin and linezolid were validated by broth dilution method. The resistance genes optrA, cfr, vanA, vanB and vanM were investigated using polymerase chain reaction (PCR). Housekeeping genes and resistance genes were obtianed through whole-genome sequencing (WGS). RESULTS: Of the 2842 Enterococcus isolates, 88.5% (2516) originated from urine, with E. faecium accounted for 60.1% of these. The vanA gene was identified in 27/28 vancomycin resistant Enterococcus (VRE) isolates, 4 of which carried both vanA and vanM genes. The remaining strain was vanM positive. The optrA gene was identified in all E. faecalis isolates among linezolid resistant Enterococcus (LRE). E. faecium showed a higher multiple antibiotic resistance index (MAR index) compared to E. faecalis. The multi-locus sequence typing (MLST) showed the sequence type of E. faecium mainly belongs to clonal complex (CC) 17, nearly E. faecalis isolates analyzed were differentiated into 7 characteristics of sequence types (STs), among which ST16 of CC16 were the major lineage. CONCLUSION: Urine was the primary source of VRE and LRE isolates in this study. E. faecium showed higher levels of resistance compared to E. faecalis. OptrA gene was detected in 91.6% of LRE, which could explain linezolid resistance, and van genes were detected in all vancomycin resistant Enterococcus strains, while vanA was a key resistance mechanism in VRE identified in this study.

Linezolid↗

Study of the pharmacokinetics of vancomycin in patients with impaired liver function.

Infections caused by methicillin-resistant Staphylococcus aureus pose a serious problem postoperatively. Patients with hepatic dysfunction can be considered to be more susceptible to infection. Since little is known about the effects of the severity of hepatic dysfunction on the pharmacokinetics of vancomycin, we studied the pharmacokinetics of vancomycin in preoperative patients with hepatic dysfunction, after the intravenous infusion of 500 mg. In patients with liver disease and normal renal function, an enhancement of renal clearance caused by a reduction in percent protein binding was canceled out by a reduction in non-renal clearance caused by liver dysfunction, resulting in liver disease having no effect on the total clearance of the drug. In patients with impaired liver and renal functions and/or obstructive jaundice, the unbound fraction of vancomycin increased, whereas the renal excretion of vancomycin was delayed. It should be noted that an excessive increase in blood vancomycin concentration may be brought about even with a conventional dose in patients with hepatic dysfunction.

Journal Article↗

A survey of metronidazole and vancomycin resistance in strains of Clostridium difficile isolated in Warsaw, Poland.

The drug of choice used to treat Clostridium difficile-associated diarroea (CDAD) are metronidazole and vancomycin. Information about emergence of antimicrobial resistance among C. difficile strains to metronidazole and intermediate resistance to vancomycin in some countries are alarming. This study was performed to determine the susceptibility to metronidazole and vancomycin of 193 C. difficile strains isolated in our diagnostic laboratory between year 1998 and 2003 from patients adults and children suffering from CDAD. Among these strains, 142 produced toxin A and B (TcdA(+)TcdB(+)), 43 only B (TcdA(-)TcdB(+)) and 8 were nontoxigenic. We have not observed any differences in susceptibility to metronidazole and vancomycin between all C. difficile strains under investigation (toxinogenic and non-toxinogenic). Resistance to metronidazole and vancomycin was not observed.

Journal Article↗

D-Ala-D-Ala ligases from glycopeptide antibiotic-producing organisms are highly homologous to the enterococcal vancomycin-resistance ligases VanA and VanB.

The crisis in antibiotic resistance has resulted in an increasing fear of the emergence of untreatable organisms. Resistance to the glycopeptide antibiotic vancomycin in the enterococci, and the spread of these pathogens throughout the environment, has shown that this scenario is a matter of fact rather than fiction. The basis for vancomycin resistance is the manufacture of the depsipeptide D-Ala-D-lactate, which is incorporated into the peptidoglycan cell wall in place of the vancomycin target D-Ala-D-Ala. Pivotal to the resistance mechanism is the production of a D-Ala-D-Ala ligase capable of ester formation. Two highly efficient depsipeptide ligases have been cloned from vancomycin-resistant enterococci: VanA and VanB. These ligases show high amino acid sequence similarity to each other ( approximately 75%), but less so to other D-Ala-D-X ligases (<30%). We have cloned ddls from two glycopeptide-producing organisms, the vancomycin producer Amycolatopsis orientalis and the A47934 producer Streptomyces toyocaensis. These ligases show strong predicted amino acid homology to VanA and VanB (>60%) but not to other D-Ala-D-X ligases (<35%). The D-Ala-D-Ala ligase from S. toyocaensis shows D-Ala-D-lactate synthase activity in cell-free extracts of S. lividans transformed with the ddl gene and confirms the predicted enzymatic activity. These results imply a close evolutionary relationship between resistance mechanisms in the clinics and in drug-producing bacteria.

Actinobacteria↗

Comparison of vancomycin-resistant enterococci isolates from human, poultry and pigs in Korea.

Vancomycin-resistant enterococci (VRE) have emerged as an important nosocomial pathogen. Since 1989, a rapid increase in the incidence of enterococcal bacteremia and endocarditis by VRE has been reported. The use of avoparcin in animal husbandry is reportedly associated with the appearance of VRE. In this study, a multiplex polymerase chain reaction (PCR) method was established to detect and differentiate resistant types of enterococci, which specifically amplify the four van genes that encode vancomycin resistance elements. Using this method, we investigated the incidence rates and types of VRE from two types of farms: those that had used avoparcin and those that had not used avoparcin. A total of 1091 animal fecal samples were collected from 70 pig farms and 32 poultry farms. A total of 425 enterococci were isolated from the fecal samples. Among the 425 isolates, six showed a pattern of high-level vancomycin resistance (Minimal Inhibitory Concentration, MIC: 64-256 microg/ml). Out of six high-level VRE, three were isolated from poultry farms that had used avoparcin and three were not. The six high-level VRE harbored the vanA gene. Sixty-seven of 425 isolates that showed a pattern of low-level vancomycin resistance (MIC: 4-8 microg/ml) were associated with the presence of vanC-1 or vanC-2/3 gene. We also performed a repetitive extragenic palindromic PCR (rep-PCR) method to compare the genetic relatedness between the high-level VRE of six animal isolates and 31 human isolates. None of the animal isolates had a similar rep-PCR pattern as the human isolates but similarities between human VRE isolates were observed.

Animals↗

Prevalence of vancomycin-resistant Enterococcus faecium (VREF) in pig faeces from slaughterhouses in Spain.

A study to estimate the prevalence of vancomycin-resistant Enterococcus faecium in faecal samples from pigs at slaughterhouses in Spain was carried out between November 1998 and January 1999 with 900 samples taken from four abattoirs representing 9.7% of all pig slaughtered in 1998. Using a selective enrichment broth with vancomycin (8microg/ml), 64 samples (7.1%; 95% CI: 5.5, 9.0%) had E. faecium vancomycin-resistant strains that showed minimal inhibitory concentrations of 256microg/ml (62 strains) and 512microg/ml (two strains). Results by farm showed that 43 of the 240 pig farms represented in the sampling had at least one faecal sample with vancomycin-resistant E. faecium.

Abattoirs↗

Occurrence of the vancomycin-resistant genes vanA, vanB, vanCl, vanC2 and vanC3 in Enterococcus strains isolated from poultry and pork.

It is suspected that the use of avoparcin as a feeding antibiotic for the fat stock contributes to development of cross-resistance against vancomycin and teicoplanin. After isolating enterococci strains from poultry and pork meat by cultivation on citrate azide Tween carbonate agar (CATC) and screening the vancomycin resistance on Columbia colistin nalidixic acid agar (CNA, supplemented with 5% sheepblood and 5 mg vancomycin/l) the polymerase chain reaction (PCR) was used for the detection of the vancomycin resistance genes vanA ('high level'), vanB ('moderate high level'), vanC1, vanC2 and vanC3 ('low level'). Out of 1643 E.-isolates from 115 poultry and 50 pork samples, 420 isolates could be identified as vancomycin resistant, 202 isolates of which carry the vanA, one isolate both the vanA and the vanC1, 38 isolates the vanC1, 14 isolates the vanC2, nine isolates both the vanC1 and the vanC3 gene and 156 isolates carry no gene. The vanB gene was not found in these isolates. Comparing vanA-positive food isolates with those from different human sources by means of the pulsed field gel electrophoresis (PFGE) it could clearly be demonstrated that they do not show homological fingerprints according to the source of origin. It is therefore unlikely that there is a close genetic relationship between isolates from animal foodstuff and humans.

Animals↗

A nationwide, multicenter, case-control study comparing risk factors, treatment, and outcome for vancomycin-resistant and -susceptible enterococcal bacteremia.

National Nosocomial Resistance Surveillance Group participants from 22 hospitals across the United States reviewed medical records for hospitalized patients with vancomycin-resistant enterococcal (VRE) or vancomycin-susceptible enterococcal (VSE) bacteremia to identify risk factors associated with the acquisition of VRE bacteremia, describe genetic traits of VRE strains, and identify factors predictive of clinical outcome. VRE cases were matched to VSE controls within each institution. Multiple logistic regression (LR) and classification and regression tree (CART) analysis were used to probe for factors associated with VRE bacteremia and clinical outcome. A total of 150 matched-pairs of VRE cases and VSE controls were collected from 1995 to 1997. Using LR, the following were found to be highly associated with VRE bacteremia: history of AIDS, positive HIV status, or drug abuse (OR 9.58); prior exposure with parenteral vancomycin (OR 8.37); and liver transplant history (OR 6. 75). CART analysis revealed that isolation of Enterococcus faecium, prior vancomycin exposure, and serum creatinine values > or = 1.1 mg/dl were predictors of VRE bacteremia. Greater proportions of clinical failure (60% versus 40%, P < 0.001) and all-cause mortality (52% versus 27%, P < 0.001) were seen in patients with VRE versus VSE bacteremia. Results from both LR and CART indicated that patients with persisting enterococcal bacteremia, intubation at baseline, higher APACHE II scores, and VRE bacteremia were at greater risk for poor outcome.

APACHE↗

Bacteremia due to Staphylococcus aureus with reduced susceptibility to vancomycin.

Four cases of bacteremia caused by Staphylococcus aureus with heteroresistance to vancomycin (hetero-VRSA) were described. In at least two of these four mortalities, the cause of death was temporally related to the hetero-VRSA bacteremia. The vancomycin and teicoplanin MICs of the resistant subpopulations of these four hetero-VRSA were 8 and 24 microg/ml, respectively. All isolates were producers of beta-lactamase, produced penicillin-binding protein PBP2a, and possessed the mecA gene accounting for methicillin resistance. Thickening of the peptidoglycan cell wall was observed by electron microscopy. When ampicillin was combined with vancomycin, in vitro synergism was detected using the checkerboard titration method (epsilonFIC = 0.13). The use of vancomycin plus ampicillin-sulbactam could be a viable option in treating severe hetero-VRSA infection in view of the higher affinity of ampicillin toward PBP2a.

Aged↗

Impact on human intestinal microflora of an Enterococcus faecium probiotic and vancomycin.

The aims of this study were to evaluate the impact of a fermented milk product containing viable Enterococcus faecium on human intestinal microflora and to evaluate any risk of development of vancomycin-resistant enterococci (VRE). Twenty Danish and 20 Swedish healthy volunteers were given 150 ml of the fermented milk product once daily, equivalent to a daily dose of 4.5 x 10(9) to 7.5 x 10(9) CFU E. faecium, for 10 d. Half of the volunteers also received 125 mg vancomycin orally q.i.d. for 10 d. Faecal samples were collected on day 0 before intake, on day 10 directly after end of intake and on day 31, 3 weeks after the end of the experiment. There was a significant increase in the total number of enterococci on day 10 (p < 0.01) in the group receiving only the E. faecium supplement, but 3 weeks later the level was as before intake. In the vancomycin group, the total number of enterococci was reduced on day 10 (p < 0.01) but had increased on day 31 (p < 0.01) in relation to day 0. In none of the Swedish and 4 of the Danish volunteers, VRE were sporadically detected, but without relation to intake of the probiotic or vancomycin. In healthy young Danish individuals the VRE carrier rate tended to be higher than previously found.

Adult↗

Cost of hospitalization for and risk factors associated with vancomycin-resistant Enterococcus faecium infection and colonization.

The increase in costs of hospitalization for patients with drug-resistant infection may be associated with drug resistance itself or with the severity of the underlying illness that predisposes patients to acquire the drug-resistant infection. To address this issue, risk factors and cost of hospitalization were compared for patients infected or colonized with vancomycin-susceptible Enterococcus faecium (VSEF) or vancomycin-resistant E. faecium (VREF) in a large tertiary-care hospital in New York City. From January 1995 through December 1996, 157 patients with VSEF and 262 patients with VREF were identified. CMI (case-mix index) was assigned to each patient as a measure of severity of illness, with a CMI of 1 considered to represent illness of average severity. For all patients who were assigned a CMI of <3, the cost per day of hospitalization for patients with VREF was significantly greater than that for patients with VSEF. However, for patients with a CMI of >3, there was no difference between cost of hospitalization for patients with VREF and that for patients with VSEF. These observations indicate that, although vancomycin resistance is associated with an increased cost of hospitalization for less severely ill patients with VREF, patients with severe underlying illness, regardless of vancomycin resistance, incur similar hospitalization costs.

Adolescent↗

Staphylococcus aureus with reduced susceptibility to vancomycin.

Infections with Staphylococcus aureus with reduced susceptibility to vancomycin continue to be reported, including 2 cases caused by S. aureus isolates with full resistance to vancomycin. This review first outlines the definitions of vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) and risk factors for infection. Next, we describe the mechanisms of resistance and methods of laboratory detection of the organisms. Finally, we address infection control and management issues associated with isolation of VISA and VRSA.

Animals↗

Vancomycin use in pediatric hematology-oncology patients.

Across-sectional study was performed of pediatric hematology-oncology patients who received vancomycin; use was compared to the Centers for Disease Control and Prevention (CDC) recommendations for vancomycin use. Thirty-seven patients received 308 doses of vancomycin. AR patients initially received vancomycin as empirical therapy; 100% of this use was not consistent with the CDC recommendations.

Adolescent↗

Enterococci with reduced susceptibility to vancomycin in New Zealand.

This study was conducted to determine the prevalence of vancomycin-resistant enterococci (VRE) in the stools of hospitalized patients with possible antibiotic-associated diarrhoea. From 176 faecal samples collected during 1997 and 1998, 66 strains of enterococci were recovered using vancomycin enrichment techniques. Only six of these displayed reduced susceptibility to vancomycin (MIC 8-12 mg/L). All VRE were positive for the presence of the vanC gene. Based on motility, pigment production and automated Gram-positive identification (GPI Vitek card), four of these six VRE isolates were identified as Enterococcus gallinarum. The remaining two isolates were non-motile and therefore were considered to be Enterococcus faecium. However, 16S rDNA sequence analysis and positive methyl-alpha-D-glucopyranoside tests indicated that they were non-motile species of E. gallinarum. This is consistent with the intrinsic, low-level vanC-1-mediated resistance associated with this species. Pulsed-field gel electrophoresis analysis comparisons between the VRE indicated genetic relatedness between some strains. This work confirms that vancomycin-resistant E. faecium and Enterococcus faecalis are rare in New Zealand.

Anti-Bacterial Agents↗

Molecular and clinical epidemiology of vancomycin-resistant Enterococcus faecalis.

OBJECTIVES: With the recent emergence of vancomycin-resistant (VR) Staphylococcus aureus, subsequent to the suggested transfer of the vanA resistance gene from Enterococcus faecalis, we sought to determine risk factors for acquisition of VR E. faecalis and to evaluate the molecular epidemiology of this less-prevalent and less-studied species of VR enterococcus. METHODS: We compared clinical isolates of VR E. faecalis from 71 patients, collected over 12 years in a large community teaching hospital, with isolates from 126 patients with vancomycin-susceptible E. faecalis. RESULTS: Risk factors for VR E. faecalis acquisition by multivariate analysis were nursing home residence (P = 0.0005), haemodialysis (P = 0.009), decubitus ulcers (P = 0.03) and receipt of parenteral vancomycin (P = 0.0002). Twenty-one percent of VR E. faecalis demonstrated vanA and 79% vanB resistance. The number of VanA isolates increased over time. Molecular analysis showed vanA or vanB in multiple PFGE groups. CONCLUSIONS: The results of this study suggest gene dissemination among some isolates and intra-hospital spread of other isolates. The risk factors identified clearly suggest that VR E. faecalis is a nosocomial pathogen and should be considered in infection control practices. Further surveillance of VR E. faecalis is warranted, due to the potential spread of vancomycin resistance among enterococci and staphylococci.

Confidence Intervals↗

Development of systemic bacteraemia after oral inoculation of vancomycin-resistant enterococci in mice.

Bacteraemia caused by vancomycin-resistant enterococci (VRE) is an important clinical problem because there are only a few potent antimicrobial agents against such bacteria. Therefore, understanding the pathogenic mechanisms of VRE bacteraemia is important for prophylaxis. This study shows that treatment of mice with cyclophosphamide and a combination of metronidazole, kanamycin and vancomycin reduced normal intestinal flora and induced systemic VRE bacteraemia. Translocation of VRE and the normal intestinal flora to the mesenteric lymph nodes, liver, spleen and blood, and mortality rate were dependent on treatment with cyclophosphamide and each of the three antimicrobial drugs. Among the different strains studied, C57BL/6 mice were the most susceptible to VRE. The virulence of vancomycin-resistant Enterococcus faecalis was greater than that of vancomycin-resistant Ent. faecium. On the day after inoculation of VRE, Escherichia coli was also detected in many VRE-positive specimens including blood, liver and the mesenteric lymph nodes. Moreover, both VRE and E. coli were detected simultaneously in almost all blood samples obtained from dead and dying mice, and VRE organisms outnumbered E. coli in those samples by 100:1 or more. These results indicate that changes in normal intestinal flora by administration of antimicrobial drugs and severity of neutropenia induced by cyclophosphamide are important factors that contribute to the development of systemic VRE bacteraemia. E. coli may be intimately associated with the establishment of VRE translocation.

Administration, Oral↗