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PubMed1994

Binding studies of vancomycin to the cytoplasmic peptidoglycan precursors by affinity capillary electrophoresis.

The ability of vancomycin to bind three cytoplasmic peptidoglycan precursors in bacterial species was studied using affinity capillary electrophoresis (ACE). The ACE binding assay was established with the normal precursor, UDP-N-acetylmuramyl-L-Ala-D-Glu-L-Lys-D-Ala-D-Ala, from Staphylococcus aureus 209P under conditions where vancomycin served as substrate ligand included in the buffer system. This precursor was found to bind to vancomycin with a binding constant of 1.6 x 10(-5) M-1 (or a dissociation constant of 62.5 microM) obtained from Scatchard plots. No migration shifting was observed under the same conditions for the other two precursors from Leuconostoc mesenteroides VR1 and Lactobacillus casei 7469, suggesting structural modifications at the stem peptide terminus. The reduction of their affinity to vancomycin is consistent with proposed structures, UDP-N-acetylmuramyl-L-Ala-D-Glu-L-Lys-(L-Ala)-D-Ala-D-lactate and UDP-N-acetylmuramyl-L-Ala-D-Glu-L-Lys-D-Ala-D-lactate, from L. mesenteroides VR1 and L. casei 7469, respectively, based on mass spectrometry. This rapid technique provides additional evidence in the understanding of one mechanism of bacterial resistance.

Amino Acid Sequence↗

PubMed2004

A mechanistic study of enantiomeric separation with vancomycin and balhimycin as chiral selectors by capillary electrophoresis. Dimerization and enantioselectivity.

The role of the sugar moiety of glycopeptide antibiotics in chiral recognition was investigated with capillary electrophoresis. Two glycopeptide antibiotics, vancomycin and balhimycin, were employed as models since they possess the same aglycon and almost identical sugar moieties, however, with different attachment sites to the aglycon. The observed enantioselectivity of balhimycin for dansylated alpha-amino acids is 2.6 times higher than that of vancomycin. Blocking of the sugar amino group of balhimycin by N-carbamoylation reaction with KOCN led to a significantly decreased enantioselectivity compared to vancomycin, which remained almost the same upon carbamoylation. These results suggest a major role of the amino sugar together with its site of attachment to the aglycon. A dimerization-based mechanism is proposed to explain this phenomenon due to the fact that the dimerization properties of glycopeptides are similarly related to their glycosylation patterns; e.g., the dimerization constant of balhimycin is 78 times higher than that of vancomycin. Furthermore, the dimerization of glycopeptides promotes their affinity to carboxyl-containing ligands via cooperativity effects between the dimerization and the formation of glycopeptide-ligand complexes. The higher dimer stability probably leads to a more favorable conformation for chiral recognition. Thus, it is concluded that a weakened dimerization of N-carbamoylated balhimycin results in a decreased enantioselectivity.

Amino Acids↗

PubMed1993

Purification and characterization of VanR and the cytosolic domain of VanS: a two-component regulatory system required for vancomycin resistance in Enterococcus faecium BM4147.

Resistance to the glycopeptide antibiotic vancomycin requires five genes. Two of these, vanR and vanS, have sequence homology to cytoplasmic response regulatory (VanR) and transmembrane sensory (VanS) proteins of two-component regulatory systems used to sense and transduce environmental signals. We report the overproduction and purification to homogeneity of VanR (27 kDa) and of a fusion protein of VanS (residues 95-374, the cytosolic domain) to the maltose binding protein (MBP), yielding a MBP-VanS protein of 76 kDa. The MBP-VanS fusion protein displayed an ATP-dependent autophosphorylation on a histidine residue with a rate of 0.17 min-1 and a phosphorylation stoichiometry of 10-15%. 32P-PhosphoMBP-VanS transferred the phosphoryl group to VanR. 32P-Phospho VanR showed chemical stability anticipated for an aspartyl phosphate and was relatively stable to hydrolysis (t1/2 = 10-12 h). Thus, the vancomycin resistance operon appears to have collected and specifically tailored the His kinase and Asp phosphoryl receptor of two-component signal transduction logic for sensing extracellular vancomycin and turning on structural genes, vanA and vanH, to make altered peptidoglycan structures such that vancomycin does not bind.

ATP-Binding Cassette Transporters↗

PubMed1990

Structure of vancomycin and a vancomycin/D-Ala-D-Ala complex in solution.

Restrained molecular dynamics simulations were used to study the interactions between the glycopeptide antibiotic vancomycin and the dipeptide Ac-D-Ala-D-Ala. Restraints were obtained from a combination of homonuclear and heteronuclear two-dimensional NMR experiments (NOESY, ROESY, 1H-15N inverse correlation). The comparison between the structures obtained for vancomycin alone and for the complex suggests a new hypothesis on the binding mode of this system. The numerical simulations were not straightforward because vancomycin is made of building blocks for which standard force-fields are not available. The representation of unusual chemical environments is also mandatory. We believe that our extension of the force-field parameters to our system could be of more general interest. Furthermore, we consider vancomycin and its complex a good example for exploring the more general problem of molecular recognition, a challenge that has been widely approached in the past few years but for which no unique and general methodology has, so far, been recognized.

Alanine↗

PubMed1975

Initial membrane reaction in the biosynthesis of peptidoglycan. Spin-labeled intermediates as receptors for vancomycin and ristocetin.

Phospho-N-acetylmuramyl-pentapeptide translocase (UDP-MurNAc-Ala-DGlu-Lys-DAla-DAla:undecaprenyl phosphate, phospho-MurNAc-pentapeptide transferase) catalyzes the initial membrane reaction in the biosynthesis of peptidoglycan. The spin-labeled nucleotide, UDP-MurNAc-Ala-DGlu-Lys (Nepsilon-2,2,5,5-tetramethyl-N-oxyl-pyrroline-3-carbonyl)-DAla-DAla, was used as a substrate by this enzyme for the synthesis of membrane-associated undecaprenyl-diphosphate-MurNAc-Ala-DGlu-Lys(Nepsilon-Tempyo)-DAla-DAla. The spin-labeled substrate and product complex with the antibiotics vancomycin and ristocetin. The association constants for the spin-labeled nucleotide are 6.2 times 10(5) and 6.2 times 10(4) M-1 for vancomycin and ristocetin, respectively. The association constants for the spin-labeled lipid intermediate are 3.0 times 10(4) and 2.1 times 10(4) M-1 for vancomycin and ristocetin, respectively. These results indicate that the acyl-DAla termini of membranes-associated spin-labeled undecaprenyl-diphosphate-MurNAc-pentapeptide are accessible to vancomycin and ristocetin and that the association constants are smaller than those determined for the corresponding antibiotic spin-labeled UDP-MurNAc-pentapeptide complexes.

Binding Sites↗

PubMed2002

Atropselective macrocyclization of diaryl ether ring systems: application to the synthesis of vancomycin model systems.

Vancomycin is the last line of defense available in the clinic for treating multidrug-resistant bacterial infections. Vancomycin contains two 16-membered diaryl ether macrocycles, each of which contains a stereogenic axis across the diaryl ether linkage. Since an effective total synthesis of vancomycin requires that these stereogenic axes be formed in a stereoselective manner, we have developed an atropselective variation of the triazene mediated diaryl ether forming reaction. This variation introduced an energetic penalty into the transition state of the undesired atropisomer. This reaction is used to synthesize the C-O-D diaryl ether macrocycle found in vancomycin with high diastereoselectivity (de > 90%), providing the naturally occurring atropisomeric configuration.

Anti-Bacterial Agents↗

PubMed2003

Poly(ethylene glycol) transport forms of vancomycin: a long-lived continuous release delivery system.

The facile reaction of vancomycin with various PEG linkers, at the V(3) position, has been selectively accomplished by using an excess of base in DMF. Using rPEG as a blocking group for V(3) provides crystalline derivatives that can be further PEGylated to give pure V(3)-X(1) latentiated species (transport forms). V(3) tetrameric species were also prepared in order to increase the loading of drug on PEG. All PEG-vancomycin transport forms show significant antibacterial activity that is on the same order of native vancomycin. Significant increases in the AUC were observed for all PEG-vancomycin conjugates thus making them potential single dose therapies.

Animals↗

PubMed2003

Low prevalence of colonization with vancomycin-resistant Enterococcus in patients awaiting liver transplantation.

The orthotopic liver transplant (OLT) population has been particularly affected by the increase in vancomycin-resistant enterococcus (VRE) infections in recent years. Pre-transplant colonization prevalence, the role of spontaneous bacterial peritonitis (SBP) antimicrobial prophylaxis as a risk factor, and the risk of post-OLT infection in colonized patients are all unknowns. We prospectively evaluated OLT candidates at our center with the aim of answering these questions. Vancomycin-resistant enterococcus colonization status was determined by rectal culture. Data collected included illness severity, antibiotic use (including SBP prophylaxis), waiting time, previous hospitalizations, and invasive procedures. Eighty-eight patients (31 female, 57 male, median age 52 years) were enrolled. The most common diagnoses were hepatitis C (49%), primary sclerosing cholangitis (13.6%), and alcoholic liver disease. Median MELD score was 11.5 (range 7-24), and median waiting time was 551 days (range 1-2224). Vancomycin-resistant enterococcus risk factors were common in our patients: recent hospitalization in 16%, recent antibiotic exposure in 39%, and renal insufficiency in 7%. Seventeen percent were receiving SBP prophylaxis. Despite the presence of established risk factors, VRE colonization prevalence was 3.4%. Preliminary limited data showed poor correlation between screening rectal cultures and operative/peri-operative cultures. Vancomycin-resistant enterococcus colonization prevalence in an OLT candidate population with mid-level MELD scores was low, and SBP prophylaxis was not a significant risk factor.

Adult↗

PubMed1986

Vancomycin elimination in patients with burn injury.

Patients with burns clinically appear to require considerably larger doses of vancomycin than normal to attain therapeutic serum concentrations. It has been presumed that this phenomenon is a result of increased renal elimination of this drug consequent to increased glomerular filtration rates in such patients, as has been documented with aminoglycoside antibiotics. We measured the serum clearance of vancomycin in 10 patients with burns and found this parameter to correlate closely with creatinine clearance (serum clearance = 12.5 + 0.695 creatinine clearance; r = 0.932; P less than 0.001). The slope of this relationship was similar to that reported by other investigators in patients not suffering from thermal injury. We conclude that at all levels of renal function, patients with burns clear vancomycin in a manner similar to that of other patients. Consequently, renal function can be used to select a dosing regimen for vancomycin in such patients.

Adult↗

PubMed1988

Altered vancomycin dose vs. serum concentration relationship in burn patients.

Drug elimination in patients sustaining serious thermal injury may be altered, resulting in an increased clearance and shortened half-life. Nine burn and eight medical/surgical patients with normal renal function were studied prospectively. Doses were adjusted to achieve peak and trough vancomycin serum concentrations within a narrow range. No significant difference between the groups was noted in terms of demographic characteristics, creatinine clearance, or vancomycin serum concentrations. However, the difference in daily dose needed to maintain the specified serum concentrations was significantly greater for burn patients (p less than 0.02). Burn patients also had to be dosed significantly more often than medical/surgical patients to achieve peak and trough vancomycin serum concentrations within the desired range (p less than 0.02). The elimination half-life in burn patients was significantly shorter than that in control patients (p less than 0.001). Because of the unusually high dosage requirements in burn patients, along with their poor predictability, individualization of therapy with vancomycin serum concentrations is recommended to ensure a successful therapeutic outcome.

Adolescent↗

PubMed1998

Analysis of the value of empiric vancomycin administration in febrile neutropenia occurring after autologous peripheral blood stem cell transplants.

We conducted a retrospective review of 125 patients undergoing high-dose therapy and stem cell rescue in order to evaluate the incidence of documented infection and the utility of the administration of vancomycin empirically. All patients received prophylactic oral quinolone therapy. Because neutropenia in this setting is relatively brief, 21 patients never manifested fever, and no patient died of infection. Of the remaining 104 patients, positive blood cultures were obtained in only 10, nine with a gram stain positive and one with a gram stain negative organism. Sixty-two patients without any evidence of gram positive infection received vancomycin according to the existing algorithm for care of neutropenic fevers. In this population of patients, empiric administration of vancomycin for neutropenic fevers without culture documentation appears to be unnecessary, could be discontinued safely and at substantial cost savings, and might slow the appearance of vancomycin-resistant organisms.

Adult↗

PubMed2002

Competitive immunoassay for vancomycin using capillary electrophoresis with laser-induced fluorescence detection.

A competitive immunoassay using capillary electrophoresis with laser-induced fluorescence was developed for vancomycin. Capillary electrophoresis using a Tris-glycine running buffer provided adequate separation of the antibody-bound from the unbound fluorescent probe (tracer) in less than 4 min. Laser-induced fluorescence polarization (LIFP) provided high sensitivity detection and simultaneous monitoring of fluorescence intensity and polarization. A fluorescence polarization value of 0.30 confirmed the formation of the antibody-tracer complex. Calibration curves showed a working linear range of 2-3 orders of magnitude with a minimum detectable concentration of 0.98 ng mL(-1) (or 1.1 fg vancomycin). Clinical samples obtained from patients undergoing vancomycin treatment were analyzed for vancomycin and the results correlated well with a standard immunoassay based on latex particle detection that was routinely used by a hospital laboratory. Only 1/10 of the reagents were needed as compared with the standard immunoassay.

Anti-Bacterial Agents↗

PubMed1970

Iodinated vancomycin and mucopeptide biosynthesis by cell-free preparations from Micrococcus lysodeikticus.

A particulate preparation from Micrococcus lysodeikticus was used to synthesize cell-wall mucopeptide. Radioactive iodinated vancomycin became attached to the preparation simultaneously with a complete inhibition of mucopeptide synthesis. After mucopeptide synthesis had occurred in the absence of antibiotic, the preparation took up more vancomycin, suggesting that new binding sites terminating in acyl-d-alanyl-d-alanine had been produced. The mucopeptide product was divided into a soluble and an insoluble portion, both sensitive to lysozyme. The soluble portion did not combine with vancomycin and hence had presumably lost its terminal d-alanine residues, either by transpeptidation or because of carboxy-peptidase action. The synthesis of both portions was unaffected by the presence of penicillin, but the insoluble part showed increased affinity for vancomycin, thus indicating that penicillin had caused conservation of d-alanyl-d-alanine termini.

Binding Sites↗

PubMed1971

Modifications of the acyl-D-alanyl-D-alanine terminus affecting complex-formation with vancomycin.

Vancomycin forms complexes with peptides terminating in d-alanyl-d-alanine that are analogous to the biosynthetic precursors of bacterial mucopeptides. The specificity of complex-formation has been studied by means of many synthetic peptides, prepared by both solid-phase and conventional methods. The following conclusions can be drawn: (a) three amide linkages are required to form a stable complex; (b) the terminal carboxyl group must be free; (c) the carboxyl terminal and subterminal residues must be either glycine or of the d-configuration; (d) the size of the side chain in these residues greatly influences the affinity for vancomycin, a methyl group being the optimum in each case; (e) the nature of the side chain in the third and fourth residues has a smaller effect on complex-formation, but an l-configuration was somewhat better than a d-configuration in the third position. In addition to acyl-d-alanyl-d-alanine, other peptides that occur in bacterial cell walls will combine with vancomycin, although less strongly, e.g. acyl-d-alanyl-d-alpha-amino acid (where the terminal d-residue may form the cross-link in mucopeptide structure) and acyl-l-alanyl-d-glutamylglycine (a sequence found in the mucopeptide of Micrococcus lysodeikticus and related organisms). These results throw some light on the specificity of the uptake of vancomycin by living bacteria.

Alanine↗

PubMed1999

Gene vanXYC encodes D,D -dipeptidase (VanX) and D,D-carboxypeptidase (VanY) activities in vancomycin-resistant Enterococcus gallinarum BM4174.

VanX and VanY have strict D,D-dipeptidase and D,D-carboxypeptidase activity, respectively, that eliminates production of peptidoglycan precursors ending in D-alanyl-D-alanine (D-Ala-D-Ala) in glycopeptide-resistant enterococci in which the C-terminal D-Ala residue has been replaced by D-lactate. Enterococcus gallinarum BM4174 synthesizes peptidoglycan precursors ending in D-Ala-D-serine (D-Ala-D-Ser) essential for VanC-type vancomycin resistance. Insertional inactivation of the vanC-1 gene encoding the ligase that catalyses synthesis of D-Ala-D-Ser has a polar effect on both D, D-dipeptidase and D,D-carboxypeptidase activities. The open reading frame downstream from vanC-1 encoded a soluble protein designated VanXYC (Mr 22 318), which had both of these activities. It had 39% identity and 74% similarity to VanY in an overlap of 158 amino acids, and contained consensus sequences for binding zinc, stabilizing the binding of substrate and catalysing hydrolysis that are present in both VanX- and VanY-type enzymes. It had very low dipeptidase activity against D-Ala-D-Ser, unlike VanX, and no activity against UDP-MurNAc-pentapeptide[D-Ser], unlike VanY. The introduction of plasmid pAT708(vanC-1,XYC) or pAT717(vanXYC) into vancomycin-susceptible Enterococcus faecalis JH2-2 conferred low-level vancomycin resistance only when D-Ser was present in the growth medium. The peptidoglycan precursor profiles of E. faecalis JH2-2 and JH2-2(pAT708) and JH2-2(pAT717) indicated that the function of VanXYC was hydrolysis of D-Ala-D-Ala and removal of D-Ala from UDP-MurNAc-pentapeptide[D-Ala]. VanC-1 and VanXYC were essential, but not sufficient, for vancomycin resistance.

Anti-Bacterial Agents↗

PubMed1997

Thrombocytopenia induced by vancomycin-dependent platelet antibody.

BACKGROUND AND OBJECTIVES: Many drugs are associated with thrombocytopenic purpura through immune-mediated platelet destruction. The case of a woman who suffered life-threatening thrombocytopenia during vancomycin treatment for Staphylococcus aureus septicemia is reported. MATERIALS AND METHODS: Conventional clinical and laboratory methods, including flow cytometry. RESULTS: After treatment of septicemia with vancomycin, severe thrombocytopenia and bleeding occurred, without detection of drug-dependent platelet antibodies (DDPA). This was followed by vegetative endocarditis, whereupon antibiotics were withdrawn so as to isolate the organism. The thrombocytopenia was corrected. On day 34, antibiotics including vancomycin were reinstituted, and three days later thrombocytopenia recurred. With a change in antibiotics, the platelet count corrected itself within four days. CONCLUSIONS: Vancomycin may induce potentially severe immunological thrombocytopenia.

Aged↗

PubMed2001

Initial treatment of peritoneal dialysis peritonitis without vancomycin with a once-daily cefazolin-based regimen.

To reduce the use of vancomycin, the current recommendations of the International Society of Peritoneal Dialysis (PD) for the initial treatment of peritonitis complicating PD are to administer intraperitoneal (IP) cefazolin or cephalothin in every PD fluid bag, together with once-daily gentamicin. In view of the inherent impracticalities of this regimen, we studied the efficacy of once-daily cefazolin (1.5 g) IP with gentamicin IP as initial treatment for primary (nonrecurrent) PD peritonitis. This regimen has been used in all episodes of peritonitis not associated with tunnel or exit-site infections or fluid leaks. Sixty-nine episodes in 61 patients were analyzed (44 patients, continuous ambulatory PD; 22 patients, automated PD; and 3 patients, hospital-based intermittent PD), of which 38 episodes (55%) were gram-positive infections, 6 episodes (9%) were gram-negative infections, and 18 episodes (26%) had negative culture results. Four patients died within 4 weeks of infection (none considered attributable to inadequate treatment of their peritonitis). Ten catheters (14.5%) required removal to clear the infection; 7 catheters were in patients with gram-negative infections. The relapse rate within 4 weeks of ceasing antibiotic therapy was 8.9%. Compared with the results of 40 episodes of peritonitis treated initially with our previous IP vancomycin and gentamicin regimen, successful treatment (no death, catheter removal, or recurrence) was achieved in 52 of 69 episodes in the cefazolin group (75.4%) versus 23 of 40 episodes in the vancomycin group (57.5%; P: = 0.058). In conclusion, once-daily IP cefazolin and gentamicin for the initial treatment of PD peritonitis is at least as effective as a vancomycin-based regimen and is well tolerated.

Adult↗

PubMed2000

Knowledge of Centers for Disease Control and Prevention guidelines for the use of vancomycin at a large tertiary care children's hospital.

OBJECTIVE: In 1994, the Centers for Disease Control and Prevention (CDC) published guidelines to encourage prudent use of vancomycin. We sought to determine whether physicians could demonstrate knowledge consistent with the guidelines. DESIGN: Survey consisting of 18 clinical vignettes based on the CDC guidelines. PARTICIPANTS: All residents, fellows, and attending physicians involved in pediatric inpatient services. SETTING: Tertiary care children's hospital providing service to an inner-city population and community referral base. MAIN OUTCOME MEASURES: Comparison of survey scores and individual responses among respondents. RESULTS: Survey scores did not vary with level of training or whether the respondent was a pediatrician or non-pediatrician. Average scores of attending physicians, fellows, and residents were 74.1% (SD = 13.1), 77.2% (SD = 11.5), and 73.4% (SD = 10.5), respectively, and did not differ significantly. Questions incorrectly answered by more than 30% of respondents concerned the use of vancomycin as: (1) first-line treatment of Clostridium difficile colitis, (2) a topical solution for wound infection, (3) initial, empiric treatment of patients with fever and neutropenia, (4) peri-operative prophylaxis, (5) a preferred agent over beta-lactam antimicrobial agents. CONCLUSION: Deficits in knowledge regarding appropriate vancomycin use can be localized to certain clinical settings. This observation lends optimism to the notion that targeted educational intervention may improve the appropriate use of vancomycin.

Adolescent↗