Vancomycin is a glycopeptide antibiotic which has been clinically used to treat a large number of species of gram-positive bacteria. Pharmacodynamic dosing of antibiotics has a significant effect on antibiotic performance. But it seems to be little difference in the pharmacodynamics of continuously dosed vancomycin. Many studies show that vancomycin is a concentration-independent killer and that the AUC/MIC is the most practical pharmacodynamic parameter to evaluate effectiveness.
Key words (AUC; area under the curve. MIC; minimum inhibitory concentration. MRSA; methcillin-resistant strains).
Vancomycin is a glycopeptide antibiotic which has been clinically used to treat a large number of species of gram-positive bacteria such as Staphylococcus aureus (including methicillin-resistant (MRSA) strains), Staphylococcus epidermidis (including resistant strains), Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Strreptococcus bovis, Streptococcus mutans, viridans streptococci, enterococci, Clostridium species, diphtheroids, Listeria monocytogenes, and Lactobacillus species. There has been no increase in resistance to vancomycin during the past three decades. (3)
Figure 1. Structural formula of vancomycin. (2)
Vancomycin is available as an asymmetric dimer. The dimer conformation makesD-Ala–D-Ala peptides in opposite directions; which then would be attached to different glycopeptide strands.(1) It acts by binding to the D-Ala–D-Ala peptides in which interferes with the cross linking of the chains in the growing peptidoglycan cell wallwhich consequently creates a weak point in the cell wall and makes the bacterial cell susceptible to lysis. (4)
Figure 2. (Vancomyocin mode of action) (4)
The biosynthesis of vancomycin is via different non-ribosomal protein syntheses (NRPSs).Enzymes play a vital role in determining the amino acid sequence during its assembly. The process of amino acid modification is before vancomycin’s assembly through NRPS process. L-tyrosine is modified to become the ?-hydroxychlorotyrosine (?-hTyr) and 4-hydroxyphenylglycine (HPG) residues. Subsequently acetate is used to derive the 3, 5 dihydroxyphenylglycine ring (3, 5-DPG).(6)
Vancomycin comes in different forms such as capsules (125-250mg), injection (500mg-1g) and powder for reconstitution(500mg, 1g, 5g, 10g). It is poorly absorbed from GI tract, widely distributed with Vd 0.4-1L/kg; CSF levels 7-30% of serum levels with meningeal inflammation; lung tissue 5-41% of serum levels, ?-distribution phase 30min; ?-elimination half-life 6-12h 90% excreted by glomerular filtration. Vancomycin has some adverse effects such as nephrotoxicity and ototoxicity, for example red man or “red neck” syndrome, phlebitis, rash, chills and fever.(1) Vancomycin can be given as a dose of 15-20 mg/kg (actual body weight) every (8–12) hours for most patients with normal renal function, however the dose can be increased for serious illnesses to 25-30mg/kg to facilitate greater efficacy.(1)
Pharmacokinetic and pharmacodynamic properties of vancomycin
There are many studies been carried out to overview vancomycin pharmacokinetic and pharmacodynamic properties in which they found out that serum concentration–time profile of vancomyocin is very complex and has been characterized as one, two and three compartment pharmacokinetic models. Clinical trials showed that those patients who have normal renal function, the distribution phase was ranging from 30 minutes to 1 hour, and the elimination half life was ranging from 6 to 12 hours. The volume of distribution was 0.4–1 L/kg. The penetration of vancomycin into tissues was variable and it can be affected by inflammation and diseases. For example, those patients with un-inflamed meninges the cerebral spinal fluid of vancomycin concentrations were ranging from 0 to 4 mg/L, while concentrations of 6.4–11.1 mg/L were seen in those patients with inflammation.Penetration into skin tissue was lower for patients with diabetes (0.01–0.45 mg/L) compared with non-diabetic patients which were (0.46–0.94mg/L).Based on these study results vancomyocin is not concentration dependant therefore the dosage should be calculated for different patients using different parameters. Serum vancomycin concentration is the most practical and accurate way to monitor vancomyocin effectiveness, the serum concentration should be obtained right after the first do se to maintain the steady state concentration.(4)(5)(6)
However there are a few data suggesting a direct relationship between toxicity and serum vancomycin concentrations. Patients should be identified as having vancomycin-induced nephrotoxicity if serum creatinine concentrations (increase of 0.5 mg/dL or ?50% increase from baseline, whichever is greater) after several days of using vancomycin therapy.(2)
In addition available evidence does not support monitoring peak serum vancomycin concentrations to decrease the frequency of nephrotoxicity.
Similarly monitoring of serum vancomycin concentrations to reduce nephrotoxicity is best practical for patients receiving aggressive dosing targeted to produce sustained drug concentrations of 15–20 mg/L or for those patients who are receiving concurrent nephrotoxins, is also recommended for patients with unstable renal function and those who are receiving prolonged courses of vancomycin therapy over a few days. (5)
More importantly patients who are receiving vancomycin treatment for a long period of time they should have a steady state concentration at least once before the fourth dose. Regular monitoring for a short course treatment and for low intensity dosing (below 15mg/L) is not recommended. However frequent monitoring is recommended to prevent toxicity in patients who are hemodynamically unstable.
In general, pharmacodynamic dosing of antibiotics has a significant effect on antibiotic performance. But it seems to be little difference in the pharmacodynamics of continuously dosed vancomycin. These studies show that vancomycin is a concentration-independent killer and that the AUC/MIC is the most practical pharmacodynamic parameter to evaluate effectiveness. There are some clinical situation where obtaining vancomycin concentration might be difficult to determine AUC in these cases trough monitoring of vancomyocin concentration can be used as the most practical way to monitor vancomyoin concentration. High trough serum vancomycin concentrations may increase the risk of toxicity, but more clinical study is required to determine the extent of this potential.
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