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PubMed1991

High incidence of vancomycin-associated leucopenia and neutropenia in a cardiothoracic surgical unit.

A retrospective case record review was undertaken to determine the incidence of vancomycin-associated leucopenia in a cardiothoracic surgical unit. Forty-nine patients received 50 courses of vancomycin therapy. Nine patients (18%) developed reversible leucopenia (white cell count less than 4000 x 10(6)/l) or neutropenia (polymorphonuclear leucocyte count less than 1500 x 10(6)/l). Four patients (8%) had severe neutropenia (less than 1000 x 10(6)/l). The median total dosage associated with leucopenia and neutropenia was 30 g, range 22-56 g. The median duration of treatment in leucopenic and neutropenic patients was 22 days, range 6-28 days. The median recovery time to a normal white cell count was 4 days, range 1-11 days. Patients who developed leucopenia on vancomycin therapy did not differ from those who did not with respect to age, total vancomycin dose, length of therapy, underlying illness, incidence of cardiac surgery or use of concomitant medications. Vancomycin-associated leucopenia and neutropenia is common in patients with cardiothoracic infections, many of whom are on several other medications. White cell counts should be estimated regularly in such patients.

Adult↗

PubMed2002

Gastrointestinal transit survival of an Enterococcus faecium probiotic strain administered with or without vancomycin.

The primary aim of this study was to evaluate if an ingested probiotic, containing viable Enterococcus faecium could survive gastrointestinal transit and if so, correlate the amount of the recovered probiotic strain with the host's own enterococci. The second aim was to investigate if simultaneous vancomycin intake influenced the survival and persistence of the probiotic strain and the stability of endogenous enterococci strains. Twenty healthy volunteers were given the probiotic product once daily for 10 days. Half of the subjects were simultaneously given vancomycin. Isolates of E. faecium strains were genotypically or phenotypically analysed with pulsed-field gel electrophoresis (PFGE) and the PhenePlate system, respectively. In eight of the ten volunteers given only the probiotic, the ingested E. faecium could be detected on day 10, while in none on day 31. From subjects given both probiotic and vancomycin no ingested E. faecium could be detected on day 10 or day 31. The estimated amount of ingested E. faecium recovered from faeces on day 10 ranged from 1.2 x 10(3) to 4.2 x 10(6) colony forming units per gram faeces, which in several cases were a substantial part of the total amount of E. faecium. The E. faecium isolated before probiotic plus vancomycin administration showed no close relationship to the ones isolated 3 weeks after ceased intake in any subjects. In conclusion, the ingested E. faecium strain can survive gastrointestinal transit. After intake, the E. faecium probiotic strain might become a large part of the total E. faecium population. The occurrence of the probiotic strain in the human gut seems to be transient after intake stop. Re-colonization of E. faecium after simultaneous probiotic plus vancomycin intake occurs mainly with strains without close genetic relationship to the strains harboured before treatment or to the ingested E. faecium strain.

Anti-Bacterial Agents↗

PubMed1988

Efficacy of coumermycin, ofloxacin and vancomycin against methicillin-resistant Staphylococcus aureus in vitro and in experimental infections of mice.

In vitro, coumermycin (a bis-hydroxicoumarin gyrase inhibitor) proved significantly more active than ofloxacin and vancomycin against 100 strains of methicillin-resistant Staphylococcus aureus (MRSA). The MIC90 was 0.5 microgram/ml, whereas the corresponding figures for the other antimicrobials were 2.0 and 4.0 micrograms/ml. In vivo, an otherwise lethal septicemia, induced by intraperitoneal administration of a MRSA in mice, was "successfully treated" in 50% of the animals (ED50) with the following dosages (microgram/g b. wt.): coumermycin 0.9, ofloxacin 10.8, vancomycin 22.4. The ED50 of coumermycin was significantly (2 p less than 0.01) different from those of the other drugs. Renal infection as produced in mice by transcutaneous inoculation of the same MRSA was treated with either of the antimicrobials at different dosages (single doses of 0.0 or 1.6 or 6.3 or 25.0 micrograms/g b. wt., twice daily) during 6 days. The largest reductions of viable counts in the kidneys at each dosage as compared to the bacterial counts of untreated animals were achieved with coumermycin (3.4 or 5.5 or 7.7 log10). These reductions are significantly (2 p less than 0.01) different from those achieved with the comparable dosages of ofloxacin and vancomycin which were 0.1 or 1.8 or 2.8 and 0.4 or 1.4 or 3.0 log10 respectively. After a single subcutaneous injection of 250 micrograms mean concentrations in serum of mice for coumermycin were 6.2-5.0 micrograms/ml for 8 h, for ofloxacin 2.0-0.5 micrograms/ml for 2 h, and for vancomycin 14.7-2.5 micrograms/ml for 2 h. Coumermycin and ofloxacin could be alternatives to vancomycin in the therapy of human infections due to MRSA.

Aminocoumarins↗

PubMed1992

Vancomycin elimination during high-flux hemodialysis: kinetic model and comparison of four membranes.

Vancomycin clearance was measured in five patients during dialysis with cuprophane (CU), polysulfone (PS), cellulose triacetate (CT), and polyacrylonitrile (PAN) dialyzers. Vancomycin was significantly cleared during routine high-flux (HF) hemodialysis (HD) with the latter three membranes, but not by CU. Postdialytic rebound of serum vancomycin concentrations was noted following HF dialysis, necessitating use of a two-compartment pharmacokinetic model. Measurement of serum vancomycin concentration immediately postdialysis significantly overestimates intradialytic removal, possibly resulting in inappropriate dose adjustment. Vancomycin infusion during HF HD results in significant drug removal during its administration to the patient, complicating the calculation of an adequate dose.

Acrylic Resins↗

PubMed1997

Preoperative vancomycin prophylaxis decreases incidence of postoperative hemodialysis vascular access infections.

The role of vancomycin in the treatment of infected arteriovenous chronic dialysis access is well established. However, the role of preoperative vancomycin administration in preventing infection in newly placed, revised, or surgically thrombectomized grafts has not been determined. We performed a prospective randomized study to examine whether vancomycin prophylaxis can decrease the incidence of postoperative graft infections. Over a 5-year period, 206 patients undergoing 408 permanent vascular access procedures were randomized into two groups. Group 1 (206 procedures) received a single intravenous dose of 750 mg of vancomycin approximately 6 to 12 hours before vascular access placement procedures, while group 2 (202 procedures) did not. Patients were evaluated for access infection within the following 30 days and before use of the access for chronic dialysis. Access infection developed in two patients (1%) in group 1 and in 12 patients (6%) in group 2 (P = 0.006). All 14 infections occurred in upper extremity polytetrafluoroethylene grafts. We conclude that the use of preoperative single-dose intravenous vancomycin prophylaxis for hemodialysis vascular graft procedures reduces the risk of postoperative access infection.

Adolescent↗

PubMed2003

Inactivation of mprF affects vancomycin susceptibility in Staphylococcus aureus.

A chemically generated mutant of Staphylococcus aureus RN4220, GC6668, was isolated that had a fourfold increase in resistance to vancomycin. This phenotype reverted back to susceptibility by insertional mutagenesis with Tn917. In a selected set of revertants, Tn917 insertion was mapped to a unique chromosomal region upstream of mprF, a recently described gene that determines staphylococcal resistance to several host defense peptides. The genetic linkage between the vancomycin susceptibility and Tn917 insertion was then confirmed by transduction backcrosses into both GC6668 and GISA isolates, MER-S12 and HT2002 0127. Northern blot analysis, insertional inactivation and complementation experiments showed that mprF mediates vancomycin susceptibility in S. aureus. The inactivation of mprF by Tn917 insertion in HT2002 0127 caused a significant increase in the binding of vancomycin to the cell membranes. This observation serves as a likely mechanism of the increased vancomycin susceptibility associated with mprF inactivation.

Aminoacyltransferases↗

PubMed2001

[The comparative costs of vancomycin treatment versus teicoplanin in osteoarticular infection caused by methicillin-resistant staphylococci].

This clinical and economical study compared two glycopeptides regimen i.e., vancomycin and teicoplanin in the treatment of osteoarticular infection involving methicillin-resistant staphylococcus. After randomization, 15 patients (group 1) received vancomycin (23 F per gram) in continuous infusion through a central venous catheter and 15 others (group 2) intramuscular teicoplanin (311-357 F a 400 mg vial). The clinical study focused on treatment tolerance in an in-patient setting as well as in a non in-patient one. The cost analysis focused on total expenses including those of antibiotics, those of medical devices for antibiotic administration and those of the complications caused by the antibiotics use. Total expenses per patient averaged 8744 F with vancomycin and 8555 F with teicoplanin (NS). The apparent money saving by using a cheap antibiotic (i.e. vancomycin) was illusionary as one took in account the expenses for medical devices e.g., central venous catheters required to administer vancomycin and the complications due to the use of these devices.

Acute Disease↗

PubMed1999

Controlled release of vancomycin from poloxamer 407 gels.

The purpose of this study was to investigate Poloxamer 407 25% (w/w) formulations aimed at prolonging the residence time of vancomycin, a time-dependent antibiotic, in a body site with a high infectious risk. Reversible thermal gelation of the formulations permitted their local injection in liquid form and in situ gelation as they warmed to body temperature. Neither the rheological properties of the Poloxamer matrices nor the antibacterial activity of vancomycin was altered by their combination. In vitro, the dispersed form exhibited prolonged release, with a lower diffusion coefficient of vancomycin compared to the solubilized form (4.7x10(-8) vs 2. 1x10(-7) cm(2) s(-1)131 mg l(-1) for the solubilized form), followed by lower but effective antibacterial levels for at least 8 days. Controlled-release profiles, good preservation of vancomycin activity, good tolerability in rats, and ease of administration suggest that Poloxamer 407 may be useful as a vancomycin delivery vehicle for local prophylaxis of infections, especially in prosthetic surgery.

Animals↗

PubMed1998

A modified HPLC method for the determination of vancomycin in plasma and tissues and comparison to FPIA (TDX).

A modified high performance liquid chromatography (HPLC) method for the quantification of vancomycin levels in plasma and tissues is described. The method uses solid phase extraction (SPE) of vancomycin from the samples and reversed phase HPLC with UV detection. The method was fully validated in terms of recovery, linearity, selectivity and various stability conditions. Vancomycin was determined in plasma samples obtained from 15 patients undergoing cardiopulmonary bypass, before and repeatedly during 12 h after drug administration. The vancomycin levels in plasma were measured by HPLC and by fluorescence polarization immunoassay (FPIA) (TDX). The following correlation was found: TDX = 0.84 HPLC + 1.04. The mean vancomycin levels in skin, fat, atrium, pericardium and sternum, before and after bypass, are reported.

Bone and Bones↗

PubMed1998

In vitro activity of RPR 106972 alone and in combination with vancomycin, ampicillin, and gentamicin against multidrug-resistant enterococci.

This investigation used checkerboard and time-kill assays to evaluate the in vitro activity of RPR 106972 (45% pristinamycin IB and 55% pristinamycin IIB) alone and in combination with vancomycin or ampicillin +/- gentamicin against multidrug-resistant enterococci. The checkerboard procedure resulted in synergistic or additive effects in 91% of the isolates with the combination of RPR 106972 plus vancomycin versus 68% with RPR 106972 plus ampicillin. The addition of gentamicin to either combination resulted in synergistic or additive results in 100% of the isolates. Inhibitory activity was observed with the time-kill assay with mean change in log10 CFU/mL at 24 h of -0.31 for RPR 106972, 3.3 for vancomycin, -0.46 for RPR 106972 plus vancomycin, and -0.35 for RPR 106972 plus vancomycin and gentamicin. No antagonism was noted with any of the combinations. RPR 106972 demonstrates good inhibitory activity against Enterococcus faecium and may prove useful in the treatment of enterococcal infections.

Ampicillin↗

PubMed2000

Gram positive infection in trauma patients: new strategies to decrease emerging Gram-positive resistance and vancomycin toxicity.

Bacterial resistance to antibiotics has become a serious problem in medicine. Particularly worrisome is the increasing incidence of multi-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Not surprisingly, in view of the high incidence of life-threatening infections and heavy antibiotic use, resistance has become very frequent and problematic in intensive care units. The standard approach for the treatment of MRSA is vancomycin or teicoplanin. Long-term therapeutic and unrestricted prophylactic use of vancomycin has given rise to VRE which in turn may lead to the emergence of vancomycin-resistant S. aureus (VRSA) through plasmid mediated transmission. In order to reduce the incidence of VRE and to avoid the emergence of VRSA, vancomycin use should be restricted and alternative antibiotic strategies should be developed. Using those antibiotics to which MRSA are still generally sensitive, perhaps in combination with new ones, such as, quinupristin/dalfopristin, should be entertained. We performed a retrospective review of the Gram-positive infections in our Level 1 Trauma Center Intensive Care Unit, and an analysis of the resistance patterns of the NMSA infections showed that additional resistance rarely develops within less than 5 days. We then designed a new strategy for the treatment of MRSA infections. This strategy consists of the sequential use of a range of antibiotics with activity against MRSA in short 5-7 day pulses until the full clinical course is completed. Studies validating the benefit of this approach are currently in preparation.

Anti-Bacterial Agents↗

PubMed2001

Vancomycin levels in human aqueous humour after intravenous and subconjunctival administration.

The purpose of the present study was to evaluate the level of vancomycin in human aqueous humour after intravenous (i.v.) and subconjunctival administration. One hundred patients scheduled to undergo cataract extraction participated in the study. Fifty-three of them received 20 mg vancomycin subconjunctivally and 47 received two doses of vancomycin i.v. (1 g b.i.d.). Specimens of aqueous humour from the first group were collected 1, 2, 2.5, 3, 3.5, 5, 6, 7, and 8 h after the subconjunctival injection. In the second group, specimens of blood and aqueous humour were collected 1, 2, 4, 6, 8, 10, and 12 h after the end of infusion of the second dose of the antibiotic. The levels of vancomycin were determined by fluorescent polarization immunoassay. In the first group peak levels of 24.82+/-3.55 microg/ml were achieved in aqueous humour at 5 h, whereas in the second group peak levels of 1.42+/-0.47 microg/ml were detected at 6 h. The latter levels, although higher than the MICs of most of the Gram-positive pathogens causing eye infections, are inadequate for the treatment of infections in vivo. These results support the need for subconjunctival instead of i.v. administration of vancomycin in order to achieve therapeutic levels of the drug in human aqueous humour or for prophylactic use whenever indicated.

Administration, Topical↗

PubMed2001

Lactoferrin-induced reduction of vanB vancomycin resistance in enterococci.

The mucosal protein lactoferrin (LF) reduces the MIC of vancomycin for staphylococcal isolates sensitive to this glycopeptide. The purpose of this research was to investigate the effect of LF on the MIC of vancomycin for vanB resistant isolates of Enterococcus faecalis (Efs1) and E. faecium (Efm1). At a concentration of 2048 microg/ml, LF reduced the MIC of vancomycin 16-fold for Efs1 and eight-fold for Efm1. The cell wall precursors of Efs1 were examined following growth in media supplemented with LF, D-alanine or D-lactate. The precursors were extracted from harvested cells by ether and ion exchange chromatography and the amino acid and lactate composition was determined. Compared with that of unsupplemented media, D-alanine or LF supplementation caused an increase in the D-alanine content of the precursors. Concomitantly, the D-lactate content was reduced. Exogenous D-lactate did not affect the composition of the precursors. This suggests that LF caused an increase in the pool of pentapeptide cell wall precursors. The LF-induced reduction in the vancomycin resistance of enterococci at in vivo concentrations suggests a potential use for this protein as an adjunctive agent to vancomycin.

Cell Wall↗

PubMed1999

Influence of adjunctive interferon-gamma on treatment of gentamicin- and vancomycin-resistant Enterococcus faecalis infection in mice.

Increasing antibiotic resistance and the development of multidrug-resistance in the enterococci has complicated the treatment of serious enterococcal infections. It has been demonstrated in vitro that interferon-gamma (IFN-gamma) significantly augments the activities of gentamicin and vancomycin against Enterococcus faecalis resistant to these antibiotics. The present study was aimed at determining whether this beneficial effect of IFN-gamma on antienterococcal antibiotic activity can be validated in vivo. Following intraperitoneal inoculation in mice with a gentamicin- and vancomycin-resistant E. faecalis clinical isolate, the animals received IFN-gamma, antibiotic or a combination of both agents, subcutaneously, at determined dosing regimens. Treatment with IFN-gamma alone significantly improved survival of infected animals in a dose-dependent manner. High dose IFN-gamma was not beneficial and the level of enterococcal infectious burden influenced the effectiveness of the cytokine. The addition of IFN-gamma to therapy with gentamicin or vancomycin, or a combination of both antibiotics was associated with a marked increase in survival of infected non-neutropenic mice compared to treatments with the agents alone. However, the same treatments made in infected neutropenic mice did not show an enhancement effect by IFN-gamma after a combination therapy with antibiotics. In a study to examine pharmacokinetic interactions, concurrent administration with IFN-gamma significantly modified the disposition of gentamicin but not that of vancomycin. The results of this study suggest that the use of IFN-gamma in combination with vancomycin or gentamicin is a new treatment option that might improve the outcome of therapy of multidrug-resistant E. faecalis infections.

Animals↗

PubMed2000

Binding interactions of vancomycin tracers with a bacterial cell wall peptidoglycan analogue.

Binding interactions between several vancomycin tracers and (N,N'-diacetyl)KDADA in solution were evaluated in a competition format using a surface plasmon resonance instrument. Tracers derivatized from the carboxy terminus or the N-vancosaminyl sugar moiety of vancomycin bind the peptide with an affinity similar to that of underivatized vancomycin. In contrast, N-methylleucyl derivatized vancomycin tracers bind the peptide with a reduced affinity relative to vancomycin.

Anti-Bacterial Agents↗

PubMed1996

Crystal structure of vancomycin.

BACKGROUND: Vancomycin and other related glycopeptide antibiotics are clinically very important because they often represent the last line of defence against bacteria that have developed resistance to antibiotics. Vancomycin is believed to act by binding nascent cell wall mucopeptides terminating in the sequence D-Ala-D-Ala, weakening the resulting cell wall. Extensive NMR and other studies have shown that the formation of asymmetric antibiotic dimers is important in peptide binding. Despite intensive efforts the crystal structure of vancomycin has been extremely difficult to obtain, partly because high-resolution data were unavailable, and partly because the structure was too large to be solved by conventional "direct methods'. RESULTS: Using low-temperature synchrotron X-ray data combined with new ab initio techniques for solving the crystallographic phase problem, we have succeeded in determining the crystal structure of vancomycin at atomic resolution. The structure provides much detailed information that should prove invaluable in modelling and mechanistic studies. CONCLUSIONS: Our structure confirms that vancomycin exists as an asymmetric dimer. The dimer conformation allows the docking of two D-Ala-D-Ala peptides in opposite directions; these presumably would be attached to different glycopeptide strands. In the crystal, one of the binding pockets is occupied by an acetate ion that mimics the C terminus of the nascent cell wall peptide; the other is closed by the asparagine sidechain, which occupies the place of a ligand. The occupied binding pocket exhibits high flexibility but the closed binding pocket is relatively rigid. We propose that the asparagine sidechain may hold the binding pocket in a suitable conformation for peptide docking, swinging out of the way when the peptide enters the binding pocket.

Anti-Bacterial Agents↗

PubMed2001

Direct interaction of a vancomycin derivative with bacterial enzymes involved in cell wall biosynthesis.

BACKGROUND: The glycopeptide antibiotic vancomycin complexes DAla-DAla termini of bacterial cell walls and peptidoglycan precursors and interferes with enzymes involved in murein biosynthesis. Semisynthetic vancomycins incorporating hydrophobic sugar substituents exhibit efficacy against DAla-DLac-containing vancomycin-resistant enterococci, albeit by an undetermined mechanism. Contrasting models that invoke either cooperative dimerization and membrane anchoring or direct inhibition of bacterial transglycosylases have been proposed to explain the bioactivity of these glycopeptides. RESULTS: Affinity chromatography has revealed direct interactions between a semisynthetic hydrophobic vancomycin (DCB-PV), and select Escherichia coli membrane proteins, including at least six enzymes involved in peptidoglycan assembly. The N(4)-vancosamine substituent is critical for protein binding. DCB-PV inhibits transglycosylation in permeabilized E. coli, consistent with the observed binding of the PBP-1B transglycosylase-transpeptidase. CONCLUSIONS: Hydrophobic vancomycins interact directly with a select subset of bacterial membrane proteins, suggesting the existence of discrete protein targets. Transglycosylase inhibition may play a role in the enhanced bioactivity of semisynthetic glycopeptides.

Anti-Bacterial Agents↗

PubMed2004

A successful challenge in a patient with vancomycin-induced linear IgA dermatosis.

BACKGROUND: Linear IgA bullous dermatosis (LABD), a subepidermal, blistering skin disease, is generally believed to be idiopathic. It has been reported in association with multiple medications, including vancomycin. In each case, complete clearance of the skin lesions occurred with discontinued use of the drug. A subsequent rechallenge reproduced the eruption within hours to days. OBJECTIVE: To present a patient with vancomycin-associated LABD who underwent a successful challenge with the antibiotic 4 years after the initial reaction. METHODS: The patient developed blistering lesions over her trunk and extremities 10 days after the initiation of vancomycin for sepsis. A biopsy specimen of a skin eruption was consistent with linear IgA dermatosis. Following discontinued use of the drug, her skin lesions resolved. Four years later, she required vancomycin for osteomyelitis. RESULTS: The patient underwent a vancomycin-graded challenge of 5 doses over 5 days. On day 1, she received 10 mg, and this was increased in a semilog fashion to 1,000 mg on day 5. She had no recurrence of her skin lesions. CONCLUSIONS: This is the first case, to our knowledge, to show a successful rechallenge in a patient with drug-associated LABD. Since the patient did not have a reaction to the challenge, it is possible that the IgA antibodies responsible for drug-induced LABD are only present transiently and diminish over time.

Autoimmune Diseases↗