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Vancomycin

Vancomycin is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. Vancomycin was first isolated in 1953 at Eli Lilly, from a soil sample collected from the interior jungles of Borneo by a missionary. It is a naturally occurring antibiotic made by the soil bacterium Actinobacteria species Amycolatopsis orientalis (formerly designated Nocardia orientalis). It is a complex chemical compound and an example of a comparatively rare haloorganic natural compound, containing two covalently bonded chlorine atoms.

The original indication for vancomycin was for the treatment of penicillin-resistant Staphylococcus aureus, a use kept alive for many years by the fact that compound had to be given intravenously and thus provided bacteria fewer opportunities to evolve resistance, and the fact that organisms were relatively slow to evolve to adapt to it, even in experiments.

Vancomycin never became the first-line treatment for Staphylococcus aureus for several reasons:
1) It possesses poor oral bioavailability; it must be given intravenously for most infections.
2) β-Lactamase-resistant semi-synthetic penicillins such as methicillin (and its successors, nafcillin and cloxacillin) were subsequently developed, which have better activity against non-MRSA staphylococci.
3) Early trials used early impure forms of vancomycin ("Mississippi mud"), which were found to be toxic to the ears and to the kidneys;[1] these findings led to vancomycin's being relegated to the position of a drug of last resort.[2]

This antibiotic is widely used for the treatment of infections caused by staphylococci that are resistant to methicillin (MRSA) and other b-lactam antibiotics, and for serious infections with Gram-positive organisms in patients who are allergic to penicillin. It is poorly absorbed when given by mouth and must be administered by injection. Oral administration is indicated in the treatment of antibiotic-associated diarrhoea caused by toxigenic strains of Clostridium difficile. Early preparations of vancomycin contained impurities that gave the drug a reputation for toxicity. The purified formulations now available are much safer, but renal and ototoxicity still occur, particularly with high dosage. The drug is given by slow intravenous infusion to avoid red man syndrome.

Therapeutic use

 

Dosage and Administration

 

Toxicology

The oral LD50 in mice is 5000 mg/kg. The median lethal intravenous dose is 319 mg/kg in rats and 400 mg/kg in mice.

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
infant TDLo intravenous 30mg/kg/20M-C (30mg/kg) LUNGS, THORAX, OR RESPIRATION: CYANOSIS
CARDIAC: OTHER CHANGES
Archives of Disease in Childhood. Vol. 73, Pg. F123, 1995.
infant TDLo intravenous 119mg/kg (119mg/kg) LUNGS, THORAX, OR RESPIRATION: CYANOSIS
VASCULAR: BP LOWERING NOT CHARACTERIZED IN AUTONOMIC SECTION
CARDIAC: PULSE RATE INCREASE WITHOUT FALL IN BP
Journal of Toxicology, Clinical Toxicology. Vol. 34, Pg. 83, 1996.
infant TDLo intravenous 295mg/kg/3D-I (295mg/kg) KIDNEY, URETER, AND BLADDER: INTERSTITIAL NEPHRITIS Journal of Toxicology, Clinical Toxicology. Vol. 30, Pg. 285, 1992.
man TDLo intravenous 15mg/kg/2H-C (15mg/kg)   Annals of Pharmacotherpy. Vol. 33, Pg. 1043, 1999.
man TDLo intravenous 15mg/kg/2H-C (15mg/kg) VASCULAR: BP ELEVATION NOT CHARACTERIZED IN AUTONOMIC SECTION
LUNGS, THORAX, OR RESPIRATION: DYSPNEA
Annals of Pharmacotherpy. Vol. 33, Pg. 1043, 1999.
mouse LD50 intraperitoneal 1734mg/kg (1734mg/kg)   "Index of Antibiotics from Actinomycetes," Umezawa, H. et al., eds., Tokyo, Univ. of Tokyo Press, 1967Vol. -, Pg. 675, 1967.
mouse LD50 intravenous 430mg/kg (430mg/kg)   Journal of Antibiotics. Vol. 43, Pg. 913, 1990.
mouse LD50 subcutaneous 5gm/kg (5000mg/kg)   "CRC Handbook of Antibiotic Compounds," Vols.1- , Berdy, J., Boca Raton, FL, CRC Press, 1980Vol. 1, Pg. 315, 1980.
women TDLo intravenous 15mg/kg/90M-C (15mg/kg) SKIN AND APPENDAGES (SKIN): "DERMATITIS, ALLERGIC: AFTER SYSTEMIC EXPOSURE" New England Journal of Medicine. Vol. 313, Pg. 756, 1985.
women TDLo intravenous 170mg/kg/19D- (170mg/kg) BLOOD: AGRANULOCYTOSIS Canadian Medical Association Journal. Vol. 132, Pg. 39, 1985.
women TDLo multiple routes 30mg/kg/2D-I (30mg/kg) SKIN AND APPENDAGES (SKIN): "DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE" Annals of Internal Medicine. Vol. 115, Pg. 410, 1991.

 

Pharmacokinetic

Bioavailability Negligible (oral)
Protein binding 30-60%

May be decreased to 1929% in those with hypoalbuminemia (e.g., burn patients, those with end-stage renal disease).

Metabolism excreted unchanged
Half-life 4-11 hrs
Cmax (mg/ml)  
tmax (hrs)  
Distribution volume Vd (l)  
Clearance 0.06 L/kg/h
Excretion renal

 

Absorption

Not appreciably absorbed from GI tract in most patients; must be given parenterally for treatment of systemic infections. Oral bioavailability usually <5% [3]; bioavailability increased in C. difficile-associated diarrhea and colitis and/or in severe renal impairment [3-5]. Clinically important serum vancomycin concentrations may occur following multiple enteral or oral doses in some patients being treated for active C. difficile-associated diarrhea and colitis, particularly those with renal impairment [4-5].  

Distribution

Widely distributed into body tissues and diffuses following IV administration, including pericardial, pleural, ascitic, and synovial fluids. Small amounts are distributed into bile [6].

Does not readily distribute into CSF in the absence of inflammation unless serum concentrations are exceedingly high [7]. Low concentrations may be attained in CSF if meninges are inflamed, but negligible amounts detected in CSF in most patients with uninflamed meninges [7]. The relationship between CSF concentrations and clinical efficacy of vancomycin in the treatment of meningitis is unclear.
Crosses the placenta and is distributed into cord blood. Distributed into milk following IV administration; not known whether distributed into milk following oral administration.

Excretion

Following oral administration, excreted mainly in feces. Following IV administration, 7590% of a dose eliminated unchanged in urine by glomerular filtration; only small amounts are excreted in bile.

Metabolism

Does not appear to be metabolized.

Mechanism of Action

Vancomycin acts by inhibiting proper cell wall synthesis in Gram-positive bacteria. Due to the different mechanism by which Gram-negative bacteria produce their cell walls and the various factors related to entering the outer membrane of Gram-negative organisms, vancomycin is not active against Gram-negative bacteria (except some non-gonococcal species of Neisseria).
The large hydrophilic molecule is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Under normal circumstances, this is a five-point interaction. This binding of vancomycin to the D-Ala-D-Ala prevents cell wall synthesis in two ways. It prevents the synthesis of the long polymers of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) that form the backbone strands of the bacterial cell wall, and it prevents the backbone polymers that do manage to form from cross-linking with each other. The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics.


 

Medicinal Chemistry

 

CAS number: 1404-93-9   EINECS: 215-772-6
 

Molecular Formula: C66H75Cl2N9O24

Average mass: 1449.25354 Da

Monoisotopic mass: 1447.430176 Da

 

Systematic name: (1S,2R,18R,19R,22S,25R,28R,40S)-22-(2-Amino-2-oxoethyl)-48-{[2-O-(3-amino-2,3,6-trideoxy-3-methyl-α-L-lyxo-hexopyranosyl)-β-D-glucopyranosyl]oxy}-5,15-dichloro-2,18,32,35,37-pentahydroxy-19-[(N -methyl-D-leucyl)amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta-3,5,8(48),9,11,14,16,29(45),30,32,34,3 6,38,46,49-pentadecaene-40-carboxylic acid

SMILES: C[C@H]1[C@H]([C@@](C[C@@H](O1)O[C@@H]2[C@H]([C@@H]([C@H](O[C@H]2Oc3c4cc5cc3Oc6ccc(cc6Cl)[C@H]([C@H](C(=O)N[C@H](C(=O)N[C@H]5C(=O)N[C@@H]7c8ccc(c(c8)-c9c(cc(cc9O)O)[C@H](NC(=O)[C@H]([C@@H](c1ccc(c(c1)Cl)O4)O)NC7=O)C(=O)O)O)CC(=O)N)NC(=O)[C@@H](CC(C)C)NC)O)CO)O)O)(C)N)O

Std. InChI: 1S/C66H75Cl2N9O24/c1-23(2)12-34(71-5)58(88)76-49-51(83)26-7-10-38(32(67)14-26)97-40-16-28-17-41(55(40)101-65-56(54(86)53(85)42(22-78)99-65)100-44-21-66(4,70)57(87)24(3)96-44)98-39-11-8-27(15-33(39)68)52(84)50-63(93)75-48(64(94)95)31-18-29(79)19-37(81)45(31)30-13-25(6-9-36(30)80)46(60(90)77-50)74-61(91)47(28)73-59(89)35(20-43(69)82)72-62(49)92/h6-11,13-19,23-24,34-35,42,44,46-54,56-57,65,71,78-81,83-87H,12,20-22,70H2,1-5H3,(H2,69,82)(H,72,92)(H,73,89)(H,74,91)(H,75,93)(H,76,88)(H,77,90)(H,94,95)/t24-,34+,35-,42+,44-,46+,47+,48-,49+,50-,51+,52+,53+,54-,56+,57+,65-,

ACD/LogP: -1.409 # of Rule of 5 Violations: 3
ACD/LogD (pH 5.5): -4.90 ACD/LogD (pH 7.4): -4.49
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 33 #H bond donors: 21
#Freely Rotating Bonds: 23 Polar Surface Area: 530.49 Å2
Index of Refraction: 1.735 Molar Refractivity: 350.837 cm3
Molar Volume: 874.685 cm3 Polarizability: 139.083 10-24cm3
Surface Tension: 105.146003723145 dyne/cm Density: 1.657 g/cm3
Flash Point: C Enthalpy of Vaporization: kJ/mol
Boiling Point: C at 760 mmHg Vapour Pressure: mmHg at 25C

Stability

Powder for Infusion

1530C.

Following reconstitution with sterile water for injection, solutions prepared in single-use vials are stable for 2 weeks at room temperature; the manufacturers state reconstituted solutions may be stored for 96 hours at 28C without substantial loss of potency.

After further dilution to a concentration of 5 mg/mL in 530% dextrose injection, solutions are stable when stored in plastic syringes for 24 hours at 4C and then subsequently for 2 hours at room temperature [8].

When reconstituted as directed using 5% dextrose injection or 0.9% sodium chloride injection, solutions prepared from ADD-Vantage vials are stable for 24 hours at room temperature or 14 days in a refrigerator.

 


1. Griffith RS. "Introduction to vancomycin". Rev Infect Dis 1981, 3: S200S204.

2. Moellering, RC Jr. "Vancomycin: a 50-year reassessment". Clin Infect Dis. 2006, 42 Suppl 1: S34.

3. Frye RF, Capitano B, Matzke GR. Vancomycin (AHFS 8:12.28). In: Murphy JE. Clinical pharmacokinetics pocket reference. Bethesda, MD: American Society of Health-system Pharmacists; 2005, 349-64.

4. Spitzer PG, Eliopoulos GM. Systemic absorption of enteral vancomycin in a patient with pseudomembranous colitis. Ann Intern Med. 1984; 100:533-4.

5.  Dudley MN, Quintiliani R, Nightingale CH et al. Absorption of vancomycin. Ann Intern Med. 1984; 101:144.

6.  Geraci JE. Vancomycin. Mayo Clin Proc. 1977; 52:631-4.

7. Ahmed A. A critical evaluation of vancomycin for treatment of bacteria meningitis. Pediatr Infect Dis J. 1997; 16:895-903.

8. Matzke GR, OConnell MB, Collins AJ et al. Disposition of vancomycin during hemofiltration. Clin Pharmacol Ther. 1986; 40:425-30.

 

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