vancomycin

vancomycin
IUPAC name	(1S,2R,18R,19R,22S,25R,28R,40S)-48-{[(2S,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-22-(carbamoylmethyl)-5,15-dichloro-2,18,32,35,37-pentahydroxy-19-[(2R)-4-methyl-2-(methylamino)pentanamido]-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-3,5,8,10,12(48),14,16,29(45),30,32,34,36,38,46,49-pentadecaene-40-carboxylic acid
Width	200
CAS number	1404-90-6
DrugBank	DB00512
ATC prefix	J01
ATC suffix	XA01
PubChem	14969
ChemSpiderID	14255

vancomycin. It is a glycopeptide antibiotic discovered from the soil bacterium Amycolatopsis orientalis (originally classified as Streptomyces orientalis). Primarily used to treat serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile, it is often reserved as a drug of last resort. Its complex chemical structure and mechanism of action, which involves binding to bacterial cell wall precursors, make it a critical agent in modern antimicrobial chemotherapy.

History

The discovery of this antibiotic was reported in 1956 by Edmund Kornfeld working at the Eli Lilly and Company laboratories. It was isolated from a soil sample collected from the interior of Borneo, with the producing organism initially named Streptomyces orientalis. Its early clinical use in the late 1950s was tempered by the emergence of less toxic alternatives like methicillin. However, with the global rise of beta-lactam resistance, particularly the spread of MRSA in the 1970s and 1980s, its importance was dramatically revived. The landmark development of the Hospira-marketed intravenous formulation solidified its role in hospital formularies worldwide.

Medical uses

It is a first-line treatment for severe infections due to methicillin-resistant Staphylococcus aureus (MRSA), including bacteremia, endocarditis, meningitis, and osteomyelitis. It is also the primary therapy for severe, recurrent Clostridium difficile colitis, typically administered orally for this indication. Furthermore, it is used for infections caused by other resistant Gram-positive organisms such as Enterococcus faecalis and Enterococcus faecium, and is a key component of prophylaxis and treatment in patients with penicillin allergy undergoing procedures like cardiac surgery. Its use is guided by monitoring serum levels to ensure efficacy and minimize toxicity.

Mechanism of action

It exerts its bactericidal effect by inhibiting the synthesis of the bacterial cell wall. It binds with high affinity to the D-alanyl-D-alanine terminus of cell wall precursor units, specifically to the peptidoglycan monomers containing N-acetylmuramic acid and N-acetylglucosamine. This binding sterically hinders the action of transglycosylase and transpeptidase enzymes, preventing the polymerization and cross-linking of the peptidoglycan strands. This disruption leads to weakening of the cell wall, ultimately causing osmotic lysis and death of the bacterium, a process particularly effective against dividing cells.

Administration and pharmacokinetics

For systemic infections, it is administered intravenously due to poor oral absorption; for Clostridium difficile infections, it is given orally where it acts locally within the gastrointestinal tract. It exhibits primarily renal excretion, with a half-life of approximately 6 hours in patients with normal kidney function, necessitating dosage adjustment in renal impairment. Therapeutic drug monitoring, measuring trough levels, is standard practice to optimize dosing, especially in serious infections like MRSA bacteremia. Its volume of distribution is relatively low, as it does not penetrate well into the cerebrospinal fluid unless the meninges are inflamed.

Adverse effects and resistance

Significant adverse effects include nephrotoxicity and ototoxicity, risks that are heightened when co-administered with other agents like aminoglycosides. A characteristic reaction known as Red man syndrome, an infusion-related histamine release causing pruritus and erythema, can occur with rapid administration. Regarding resistance, the most concerning mechanism involves the alteration of the bacterial target from D-alanyl-D-alanine to D-alanyl-D-lactate, a modification encoded by the vanA gene cluster found in organisms like vancomycin-resistant Enterococcus (VRE). Other forms of resistance, including intermediate susceptibility in Staphylococcus aureus (VISA), involve thickening of the bacterial cell wall.

Chemical properties and structure

It is a complex glycosylated non-ribosomal peptide, or glycopeptide, with a molecular weight of approximately 1449 g/mol. The core structure is a heptapeptide backbone consisting of seven amino acids, including unusual residues like β-hydroxytyrosine and 4-hydroxyphenylglycine. This backbone is cross-linked to form a rigid, cup-shaped structure that is essential for binding its target. The molecule also contains a disaccharide moiety composed of vancosamine and glucose, which influences its solubility and pharmacokinetic properties. Its stability in solution is pH-dependent, and it is formulated as a hydrochloride salt for clinical use.

Category:World Health Organization essential medicines Category:Antibiotics Category:Eli Lilly and Company