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PubMed2001

Use of vancomycin in the culture of Mycobacterium tuberculosis from gastric lavage.

BACKGROUND & OBJECTIVES: Earlier studies from the Tuberculosis Research Centre, Chennai, on culture of Mycobacterium tuberculosis from gastric lavage (GL) specimens in selective Kirchner's medium (SK) resulted in a loss of 60 per cent culture results due to contamination with aerobic spore bearers (ASB). Addition of vancomycin to SK (SKV) effectively reduced the contamination rate to 20 per cent. The objective of the present study was to further reduce the contamination by collecting the specimens in bottles containing vancomycin, thus providing continuous exposure of the sample to the drug, which is bactericidal to ASB. METHODS: One thousand GL specimens collected from children in vancomycin containing bottles were decontaminated and cultured in SK medium, with and without vancomycin, subcultured on Lowenstein Jensen (LJ) medium and the culture results compared. RESULTS: The contamination of cultures in SK and SKV was 15 and 4 per cent respectively when the specimens were collected in bottles containing vancomycin compared to 60 and 20 per cent contamination reported in the earlier studies. INTERPRETATION & CONCLUSION: The reduced contamination in SK and SKV is most likely due to the collection of samples in vancomycin containing bottles. Although a concurrent comparison of samples processed in vancomycin free conditions would have been ideal, it could not be done due to practical difficulties. The study thus confirms the value of vancomycin as a major deterrent for contamination due to aerobic spores and better results can be obtained if vancomycin is used in sample collection bottles, transport media and liquid culture media used in mycobacteriology laboratories particularly in humid and tropical environment.

Culture Media↗

PubMed2005

High active local levels of vancomycin without nephrotoxicity released from impacted bone allografts in 20 revision hip arthroplasties.

BACKGROUND: Cancellous bone can act as a delivery vehicle for vancomycin without impairment of graft incorporation. However, local and systemic antibiotic levels, biological activity of vancomycin, interaction with antibiotic-loaded cement, and also nephrotoxicity of these composites have not yet been studied clinically. MATERIAL AND METHODS: Blood, drainage and urine samples of 20 consecutive patients undergoing revision total hip arthroplasties with impaction grafting technique utilizing 1 g of vancomycin per femoral head were studied. Plain PMMA cement was used in 10 cases, while PMMA with gentamycin was used in 5 cases and tobramycin was used in the remaining 5 cases. Biological activity of vancomycin was studied using kinetic killing curves in three ATCC organisms (methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosas). Quantification was done with fluorescent polarized immunoassay. Renal function was evaluated with preoperative and postoperative urea and creatinine. RESULTS: Local active bactericidal levels of vancomycin reached 1400 microg/mL (average 5-point level = 367 microg/mL) without nephrotoxicity. Vancomycin was present in urine until the fifteenth day. Both aminoglycosides in the cement had activity against Pseudomonas aeruginosas. INTERPRETATION: Local levels of vancomycin were 35 times greater than the highest levels reported with vancomycin-loaded PMMA. A synergistic effect was observed between vancomycin released from impacted allografts and aminoglycoside-loaded PMMA.

Adult↗

PubMed1991

Mechanism of vancomycin transport in the kidney: studies in rabbit renal brush border and basolateral membrane vesicles.

The effect of vancomycin, a putatively nephrotoxic amine glycopeptide antibiotic, on the transport of organic cations was examined in rabbit renal basolateral and brush border membrane vesicles. The studies were conducted using a rapid filtration technique and the prototypic organic cation tetraethylammonium. In basolateral membrane vesicles, vancomycin cis-inhibited the electrogenic transport of tetraethylammonium with an IC50 value of 260 microM. In contrast, gentamicin, an aminoglycoside, was without effect. Inhibition by mepiperphenidol, a classical organic cation transport inhibitor, was observed with an IC50 value of 24 microM. Countertransport, that is, trans-stimulation experiments, were initiated in order to determine whether or not vancomycin was capable of traversing the plasma membrane. Vancomycin caused trans-stimulation of tetraethylammonium uptake. The specificity of inhibition was assessed by determining the effect of vancomycin on the transport of p-aminohippurate, an organic anion. Vancomycin did not inhibit transport, whereas probenecid, a classical organic anion inhibitor, did. In the brush border membrane, vancomycin had no effect on the transport of tetraethylammonium. These data are consistent with mediated transport for vancomycin across the basolateral membrane, but not across the brush border membrane. This implies that the nephrotoxicity of vancomycin may be due to entry through the basolateral membrane and the absence of mediated egress at the brush border membrane.

Animals↗

PubMed2006

Clearance of vancomycin during high-efficiency hemodialysis.

BACKGROUND: Vancomycin is commonly used for the treatment of MRSA infections in critically ill patients with renal diseases. Vancomycin is mainly eliminated through the kidney. Its excretion is therefore substantially reduced in severe renal impaired patients. Although several studies have demonstrated that significant amounts of vancomycin are removed during High-Flux/High-Efficiency Hemo Dialysis (HF/HEHD), more data are required to optimize clinical applications. OBJECTIVE: Predict the appropriate vancomycin intradialytic dosage and dosing interval among patients receiving HEHD. MATERIAL AND METHOD: Twenty patients who were receiving HEHD with cellulose triacetate dialyzer were included to determine the vancomycin intradialytic clearance. Two patients were included twice and one patient was included three times due to reinfections. This gave rise to 24 patient-times. The study was carried out at Songklanagarind Hospital between January 2003 and March 2004. RESULTS: In a prospective opened label design, each patient received 1g vancomycin, 1 hour infusion, immediately after completion of HEHD. Six scheduled blood samples were drawn as follows: (1) 60 minutes following completion of vancomycin infusion (Cmax); (2) immediately before starting the second HEHD; (3) 2 hours after starting the second HEHD; (4) immediately after completion of the second HEHD; (5) immediately before starting the third HEHD; and (6) immediately after the third HEHD ended (Cmin). The authors measured vancomycin serum levels using HPLC technique. The serum concentrations were used to calculate all relevant pharmacokinetic parameters. The pharmacokinetic parameters (mean +/- SD) were: intradialytic clearance (CLHD) 93.4 +/- 37.1 mL/min; intradialytic elimination rate constant (k) 1.1 +/- 0.5 hr(-1); overall elimination half-life (t(1/2)) 77.1 +/- 37.8 hr; volume of distribution (Vd) 82.1 +/- 40.3 L; Cmax 25.8 +/- 8.12 mg/L (range 12.04-48.80); Cmin 6.2 +/- 3.1 mg/L; and % removal during the second HEHD 37.9 +/- 12.9. Subtherapeutic levels were found in 66.7% (16/24) and 91.6% (22/24) of patients after the second and the third HEHD, respectively. CONCLUSION: HEHD with cellulose triacetate dialyzer removes significant amount of vancomycin. Based on the authors' findings, a loading dose of 1 g, and 500 mg after every subsequent HEHD is recommended.

Adult↗

PubMed1991

Pharmacokinetics of vancomycin in patients undergoing hemodialysis with polyacrylonitrile.

The pharmacokinetics of vancomycin in patients undergoing dialysis with cuprophane membranes are well known, however little has been reported of the use of polyacrylonitrile membranes in dialysis. We studied, in a crossover design, eight dialysis patients (7 men, 1 woman) aged 30 to 66 years who prospectively received 1 gram of vancomycin i.v. before first dialysis and were subsequently hemodialyzed with cuprophane every second day for a total of three times. A month later trial was repeated using polyacrylonitrile. A mono-compartment model was used to calculated pharmacokinetic parameters. Mean +/- standard deviation of vancomycin clearance varied from 5.2 +/- 2.1 ml/min in the interdialysis period to 9.7 +/- 2.7 ml/min during dialysis with cuprophane and to 58.4 +/- 15.6 ml/min during dialysis with polyacrylonitrile (p less than 0.001). Vancomycin half-life varied from 71.5 +/- 23.0 to 35.9 +/- 9.8 and to 6.1 +/- 1.4 hours, respectively (p less than 0.001). Fractional removal of vancomycin increased from 4% using the cuprophane dialyzer to 34% using the polyacrylonitrile dialyzer (p less than 0.001). Serum vancomycin levels at 100 and 168 hours were higher with cuprophane than with polyacrylonitrile (7.0 +/- 2.2 vs 3.9 +/- 1.2 micrograms/ml) (p less than 0.001). Moreover, the mean levels at 100 hours were suboptimal on polyacrylonitrile. Approximately 208 +/- 53 mg of vancomycin were removed during one polyacrylonitrile dialysis. Thus, those patients who undergo dialysis with polyacrylonitrile and are treated with vancomycin may need supplementary doses post dialysis or to lessen dosage intervals than those traditionally used for dialysis patients since clearance of the drug is significantly higher than with cuprophane dialyzers. Continuous monitoring of vancomycin levels is also recommended.

Acrylic Resins↗

PubMed1985

Intravenous vancomycin as initial treatment for gram-positive peritonitis in patients on chronic peritoneal dialysis.

Fourteen episodes of peritonitis complicating chronic peritoneal dialysis were treated with intravenous injections of 1 gm of vancomycin weekly for 4 successive weeks. Peak (one hour after completion of injection) and trough (immediately before the next injection) serum and dialysate vancomycin levels were measured. Vancomycin treatment resulted in a cure in 12 episodes (85.7%). Serum vancomycin levels were always above therapeutic range, but did not rise, with subsequent injections, to toxic range. Dialysate vancomycin levels were therapeutic for more than 85% of the measurements. One patient, who failed to respond to vancomycin plus cephalosporins, was cured with intraperitoneal streptokinase plus the same antibiotics. In another patient, a relapse was cured with vancomycin plus oral rifampin. Dialysate vancomycin levels were therapeutic in the last two patients. Peritoneal catheters were not removed. No significant side effects of vancomycin treatment were observed.

Adult↗

PubMed1994

[Penetration of vancomycin in cardiac and mediastinal tissues in humans].

Vancomycin penetration into heart tissues (valves, myocardium, auricles and pericardium) and mediastinal tissues (fat and sternal bone) after two regimens of administration was evaluated in a prospective, randomized study. Twenty adult patients undergoing mitral or aortic valve replacement were included in the study and divided into two groups of ten patients each: Group 1 patients were administered a 15 mg/kg intravenous dose of vancomycin over 90 min upon anesthesia. Group 2 patients received the same dose followed by a second 7.5 mg/kg intravenous dose of vancomycin over 30 min at time of initiation of the cardiopulmonary bypass. In both groups further vancomycin administrations (10 mg/kg) were performed on hour 8, 16 and 24. Plasma and tissue vancomycin concentrations were assayed by fluorescence polarization immunoassay. At different times of the surgical procedures (thorax opening and closure, period of cardiopulmonary bypass) 67 to 100% of the patients in group 1 had vancomycin concentrations in the studied tissues above the MIC 90 for Staphylococcus aureus (1 microgram/g) and Staphylococcus epidermidis (2 micrograms/g). In group 2, for the same periods and the same tissues, 72 to 100% of patients had adequate vancomycin concentrations. In group 1 patients, mean ratios of vancomycin tissue concentrations/MIC 90 were 6 +/- 2 to 20 +/- 4 for Staphylococcus aureus (MIC 90: 1 microgram/g) and 3 +/- 1 to 10 +/- 4 for Staphylococcus epidermidis (MIC 90: 2 micrograms/g). In group 2 patients, mean ratios were 8 +/- 3 to 20 +/- 4 for Staphylococcus aureus and 4 +/- 1 to 10 +/- 3 for Staphylococcus epidermidis. The use of a second dose of vancomycin in group 2 significantly increased plasma concentrations (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Antibiotic impregnated bone cement in total hip arthroplasty. An in vivo comparison of the elution properties of tobramycin and vancomycin.

A prospective in vivo quantification was performed to measure the elution of tobramycin and vancomycin antibiotics from two commonly used bone cements. Forty patients were divided into four groups: Group I, tobramycin-Simplex; Group II, tobramycin-Palacos-R; Group III, vancomycin-Simplex; and Group IV, vancomycin-Palacos-R. Antibiotic levels were measured from hemovac wound drainage, urine, and serum and compared with control groups who received either intravenous tobramycin or vancomycin. There were no significant differences in daily mean tobramycin levels in hemovac samples between Groups I and II. Tobramycin hemovac levels from Groups I and II were significantly higher than the tobramycin control group. Similarly, no differences were seen in daily mean vancomycin levels of the hemovac samples between Group III and IV; however, the intravenous vancomycin control group had significantly higher levels in the hemovac fluid than Groups III or IV. Tobramycin in the hemovac fluid from Groups I and II was highly bioactive against the control organism. Vancomycin in the hemovac fluid from Groups III and IV had variable bioactivity against the control organism. In 30% of the cases, no vancomycin was detected in the hemovac fluid, and in these cases, the hemovac fluid had no effect on the control organism. Tobramycin elutes to give adequate local tissue levels and releases antibiotic effects when used in an antibiotic bone cement combination. Vancomycin has variable elution properties and is not a predictable additive for the bone cements tested.

Bone Cements↗

PubMed1999

A comparison of polymerase chain reaction and phenotyping for rapid speciation of enterococci and detection of vancomycin resistance.

This study aimed to ascertain the ability of the microbiology laboratory to detect and identify catalase-negative Gram-positive cocci with particular reference to vancomycin-resistant enterococci (VRE). Twenty-seven reference strains and 42 prospectively collected catalase-negative Gram-positive cocci were screened by agar dilution breakpoint susceptibility and linked biochemical methods in routine use. Ability to speciate organisms was then compared using: (i) a multiplex polymerase chain reaction, designed to detect gene sequences specific to Enterococcus faecalis and E. faecium, and vancomycin resistance (van) genes; (ii) a commercial "API 20 strep" (iii) an algorithm using individual tests from a commercial API 20 strep strip; and (iv) the same algorithm utilising traditional phenotyping methods. All vancomycin resistant catalase-negative Gram-positive cocci were detected by an agar dilution screening plate containing 4 micrograms/ml of vancomycin. Polymerase chain reaction (PCR) detected all enterococci with van genes, speciated all vancomycin-sensitive E. faecalis and E. faecium isolates and excluded non-enterococcal vancomycin-resistant catalase-negative Gram-positive cocci. Algorithm-based methods speciated 41 of the 42 study isolates (98%). The API 20 strep correctly identified only 25 (60%) of these organisms, 38 of which were vancomycin-sensitive E. faecalis. VRE are detected by current screening methods for vancomycin-resistant catalase-negative Gram-positive cocci in this laboratory. API 20 strep, currently used to speciate catalase-negative Gram-positive cocci, is less reliable and should be replaced. Algorithm-based phenotyping by either method tested is more reliable for speciation than API 20 strep in its recommended form. Compared to the other methods tested, PCR is a rapid, accurate and inexpensive method of detecting and speciating vancomycin-resistant enterococci and it provides important extra information impacting on clinical therapy and infection control.

Algorithms↗

PubMed2005

Rapid decrease of free vancomycin in dense staphylococcal cultures.

Bacterial numbers in broth cultures were determined by bioluminescence assay of intracellular bacterial ATP. Broth MICs for strains of Staphylococcus epidermidis (ATCC 14990 and 35984) and Staphylococcus aureus (ATCC 25923, 29213 and 6538) were determined for cultures with different inocula (10(5)-10(8) bacteria/ml) after 24 h of incubation in supplemented Mueller-Hinton broth containing vancomycin. All of the tested strains except one were susceptible to methicillin, and all of the strains were susceptible to vancomycin. Free vancomycin concentrations in the broth cultures of all strains were determined with an agar well bioassay after 24 h of incubation. Free vancomycin concentrations and bacterial numbers of ATCC 35984 and ATCC 29213 were also determined after 0.5, 2, 4, and 8 h. In a low inoculum (10(5) bacteria/ml), the broth MICs were 1-4 microg/ml. In a high inoculum (approximately 10(8) bacteria/ml), the broth MICs increased two- to fourfold to 4-8 microg/ml. In dense inocula ( approximately 10(9)-10(10) bacteria/ml), the concentrations of free vancomycin in the broth were reduced, in most cases below the detection limit of the bioassay (</=0.5 microg/ml). This reduction of free vancomycin was fast, occurring in initially dense inocula in less than 30 min. No emergence of resistance was seen. These results show a rapid reduction of free vancomycin in the broth and a simultaneous increase in broth MICs in high inocula, without development of resistance. This indicates that the dosing regimen of vancomycin is of particular importance in staphylococcal infections with dense inocula, e.g. infective endocarditis.

Adenosine Triphosphate↗

PubMed2001

Clinical isolates of Streptococcus pneumoniae that exhibit tolerance of vancomycin.

The ability of Streptococcus pneumoniae to escape lysis and killing by vancomycin, a property termed "tolerance," has recently been noted in a laboratory strain of the species. Vancomycin tolerance in clinical isolates represents a potential new health risk. We determined the prevalence of vancomycin and penicillin tolerance among 116 clinical isolates of pneumococci by monitoring lysis and viability after exposure to the respective antibiotic for 4 hours. Eight percent of the strains were tolerant to penicillin and 3% were tolerant to vancomycin. The 3 vancomycin-tolerant isolates also had a high ratio of minimum bactericidal concentration to minimum inhibitory concentration, in contrast to nontolerant strains. They were of serotype 9V and had reduced susceptibility to penicillin. Only 1 was also tolerant to penicillin. Growth rate and ability to divide were not affected in the 3 vancomycin-tolerant strains, and they all lysed with deoxycholate, which indicates autolysin production. Vancomycin tolerance among clinical isolates of pneumococci will necessitate tracking to determine the magnitude of the evolving health risk, since tolerance may contribute to treatment failure (in particular, cases of meningitis, in which bactericidal activity is critical for eradication) and since it may also be a favored background for acquisition of resistance of vancomycin.

Amino Acid Sequence↗

PubMed2006

Prevalence and clinical implications of Staphylococcus aureus with a vancomycin MIC of 4 microg/ml in Korea.

In addition to vancomycin-intermediate Staphylococcus aureus (VISA), S. aureus with a vancomycin MIC of 4 microg/ml has been reported to be the cause of therapeutic failure. This study was designed to determine the prevalence of methicillin-resistant S. aureus (MRSA) with a vancomycin MIC of 4 microg/ml and to clarify the clinical characteristics of infections caused by these isolates. During the 8-week period from April to May, 2001, 27 hospitals participated in a nationwide surveillance program for VISA and vancomycin-resistant S. aureus (VRSA) in Korea. After screening on brain-heart infusion agar containing 4 microg/ml of vancomycin as previously described, 100 isolates with confluent growth were tested. The medical records of the patients involved were reviewed. Even though VISA or VRSA was not detected among 3,756 MRSA isolates, 18 (0.5%) had a vancomycin MIC of 4 microg/ml. The infections in 12 of these patients, excluding 5 that were colonized, were 8 chronic osteomyelitis, 1 surgical site infection, 1 pneumonia, 1 intra-abdominal infection, and 1 catheter-related infection. Although 11 cases were exposed to glycopeptides for a long time (median 56 days), the site of infection became culture-negative in only 1 case. Two patients died of their S. aureus infections. MRSA with a vancomycin MIC of 4 microg/ml was rare. Chronic osteomyelitis was the most common type of infection, and prolonged exposure to glycopeptides was associated with reduced susceptibility to vancomycin.

Anti-Bacterial Agents↗

PubMed2003

Transcriptional induction of the penicillin-binding protein 2 gene in Staphylococcus aureus by cell wall-active antibiotics oxacillin and vancomycin.

We found an increased abundance of pbpB-specific transcripts in vancomycin intermediate-resistant Staphylococcus aureus (VISA) isolates compared with that found in paired, genetically identical, susceptible isolates. This difference in expression cannot be explained by differences in the pbpB promoter sequence. Since the factors controlling pbpB gene expression have remained largely unexplored, various conditions that might affect pbpB transcript abundance were examined. In both vancomycin-susceptible and VISA strains, pbpB expression varied with the growth phase, with the highest abundance of pbpB-specific transcripts detected during mid-log phase. Interestingly, both vancomycin and oxacillin were able to induce pbpB transcription above a constitutive level. When vancomycin was absent, one of the three pbpB-specific transcripts that were usually faintly detected in non-VISA strains was more readily detected in VISA strains during mid-log but not stationary phase. This transcript was enhanced in non-VISA strains by vancomycin induction. Gel shift assays indicated that an increased amount of the putative transcription factor that binds to both P1 and P1' promoter regions is present in the cytosol of vancomycin-induced cells. Neither the SigB sigma factor nor the quorum-sensing agr locus was required for growth phase-variable pbpB expression or transcriptional induction of pbpB by vancomycin or oxacillin. Also, MecI, MecR1, BlaI, and BlaR1, regulatory proteins that mediate beta-lactam-inducible expression of mecA and beta-lactamase, were not required for antibiotic induction of pbpB transcription. These data support the idea that pbpB expression is modulated by a trans-acting factor in response to the presence of the cell wall-active antibiotics vancomycin and oxacillin.

Anti-Bacterial Agents↗

PubMed2006

Combating vancomycin resistance in bacteria: targeting the D-ala-D-ala dipeptidase VanX.

In the past 20 years, vancomycin and other glycopeptide antibiotics have been administered to patients with Streptococcal and Staphylococcal infections that were resistant to all other antibiotics or to patients who were allergic to penicillins and cephalosporins. After extensive use of vancomycin and other glycopeptide antibiotics in humans, several strains of Enterococcus have developed high-level vancomycin resistance (collectively called VRE, vancomycin-resistant Enterococcus), and this resistance phenotype has spread to other organisms. The spread of vancomycin resistance to other pathogens and, potentially, to bacterial strains on the CDC's bioterrorism watch list is a major biomedical concern. Bacteria most often become resistant to vancomycin by acquiring a transposon containing genes that encode for a number of proteins, five of which are essential for the high-level resistance phenotype. The five essential gene products are called VanR, VanS, VanH, VanA, and VanX. Previous studies have shown that the inactivation of VanX results in an organism that is sensitive to vancomycin and that VanX is an excellent inhibitor target. In this review the known inhibitors and structural and mechanistic properties of VanX will be discussed. These data will be used to offer suggestions for novel, rationally-designed or -redesigned inhibitors, which could potentially be used in combination with existing glycopeptide antibiotics as a treatment for vancomycin-resistant bacterial infections.

Anti-Bacterial Agents↗

PubMed2005

The first pediatric case of Staphylococcus aureus with heterogenous resistant to vancomycin endocarditis in Thailand.

Staphylococcus aureus with reduced susceptibility to vancomycin has been reports worldwide. Here we report the first pediatric case of heterogeneous vancomycin intermediate resistance Staphylacoccus aureus (hVISA) causing endocarditis in Thailand. A 4 months old girl with truncus arteriosus type IV and ventricular septal defect developed methicillin-resistant S. aureus (MRSA) bacteremia and endocarditis after total repair operation. The patient did not respond to combination antimicrobial treatment including vancomycin. The strain was susceptible to trimethoprim-sulfamethoxazole and vancomycin by conventional antimicrobial susceptibily test. The vancomycin minimal inhibitory concentration by E-test was 2 microg/ml. The strain was judged to be possible heteroresistant when screening was done by one-point population analysis. The subsequent population analysis and testing for the emergence of mutants with reduced susceptible to vancomycin confirmed that this strain was hVISA. Despite the treatment with vancomycin, amikacin, rifampicin and cotrimoxazole, the patient died. hVISA should be suspected in MRSA infections that were refractory to vancomycin therapy could be due to. The emergence hVISA underscored the importance of the prudent use of antibiotics, the laboratory capacity to identify MRSA and hVISA and proper communication with treating clinicians, and the meticulous infection-control measures to prevent transmission.

Anti-Bacterial Agents↗

PubMed2000

Effect of conformation on the rate of deamidation of vancomycin in aqueous solutions.

The instability of vancomycin, a glycopeptide antibiotic, limits its shelf-life because the deamidation of its asparagine residue results in the formation of a zwitterion with limited aqueous solubility. Analysis of the pH-rate profile for vancomycin indicates that the deamidation reaction is notably sensitive to the ionic state of the molecule. This observation results in a hypothesis in which the ionic state of vancomycin may influence the conformation of the molecule and therefore affect its reactivity. Two-dimensional nuclear magnetic resonance (NMR), homonuclear Hartmann-Hahn (HOHAHA) and rotating frame Overhauser enhancement spectroscopy (ROESY) information combined with molecular dynamic simulations were used to estimate the apparent conformation of vancomycin in aqueous solution at pH 4 and pH 9 where the molecule exists primarily as a monocation and monoanion, respectively. The apparent conformation for vancomycin at pH 4 is compact, and the proximity of the backbone amide nitrogen to the side chain carbonyl carbon of asparagine is favorable for the rapid formation of the cyclic imide intermediate, thus increasing its reactivity. The apparent conformation for vancomycin at pH 9, however, is expanded in comparison with the conformation at pH 4, and the increase in distance between the reacting atoms leads to slower cyclic imide formation and thus decreased intrinsic reactivity. That cyclic imide formation was rate limiting at both pH values was confirmed by cyclic imide isolation and stability estimation. It becomes apparent from the analysis of the pH-rate and conformational profiles of vancomycin that the deamidation rate of vancomycin is largely influenced by the ionization state of the N-methyl leucine nitrogen.

Amides↗

PubMed2006

Vancomycin as chiral selector for enantioselective separation of selected profen nonsteroidal anti-inflammatory drugs in capillary liquid chromatography.

The chiral selector vancomycin was used either as mobile phase additive or bound as a chiral stationary phase (CSP) for the stereoselective separation of seven racemic nonsteroidal anti-inflammatory drugs (NSAIDs), fenoprofen, carprofen, flurbiprofen, indoprofen, flobufen, ketoprofen, and suprofen, by capillary liquid chromatography. The effect of the type of stationary phase, the chiral column Chirobiotic V or the achiral stationary phases Nucleosil 100 C8 HD and Nucleosil 100 C18 HD, and the concentration of vancomycin in the mobile phase on separation of the drug enantiomers were evaluated. All the drugs, except flobufen, were successfully enantioseparated on Nucleosil 100 C8 HD with 4 mM vancomycin present in the mobile phase (composed of methanol and buffer) in the reversed phase mode. On the vancomycin-bonded chiral stationary phase, it was difficult to get enantioseparations of the profen NSAIDs. However, flobufen gave better enantioseparation on the vancomycin CSP. The better enantioresolution of the majority of profen derivatives on the achiral columns with vancomycin added to the mobile phase can be attributed in particular to the higher separation efficiency of this capillary chromatographic system. In addition, vancomycin dimers, formed in the mobile phase, seem to offer a better steric arrangement for stereoselective interaction to these analytes than the vancomycin bonded on the CSP. These substantial differences in the CS structure significantly influence the chiral discrimination mechanism.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Identification of the up- and down-regulated genes in vancomycin-resistant Staphylococcus aureus strains Mu3 and Mu50 by cDNA differential hybridization method.

We previously reported the first vancomycin-resistant Staphylococcus aureus (VRSA) clinical strain, Mu50, whose cell wall is remarkably thickened resulting from the activation of cell-wall synthesis. To explore the genetic basis for the vancomycin resistance, cDNA differential hybridization was performed using RNAs extracted from a set of closely related S. aureus strains with various levels of vancomycin susceptibilities. The strains were Mu3 (MIC = 2 microg/ml), Mu50 (MIC = 8 microg/ml), and a susceptible revertant of Mu50, Mu50omega (MIC = 0.5 microg/ml). In this study, we report identification of a novel response regulator, designated vraR (standing for vancomycin-resistance associated gene R) whose transcription was remarkably up-regulated in Mu3 and Mu50 as compared to Mu50omega. Experimental over-expression of VraR in vancomycin-susceptible strain N315P raised vancomycin resistance of the strain. Also, the genes coding for fructose utilization, fatty acid metabolism, and two putative ATP-binding cassette (ABC) transporter genes were found to be up-regulated in Mu3 and Mu50. On the other hand, Protein A expression was suppressed in Mu50, as compared with Mu3 and Mu50omega. We consider that the response regulator vraR is one of the key regulators modulating the level of vancomycin-resistance in S. aureus. Presumed increased uptake of fructose and altered fatty acid metabolism may also contribute to vancomycin resistance by supplying more precursor metabolites for cell-wall synthesis.

Anti-Bacterial Agents↗