Vancomycin is an antibiotic used in the prophylaxis and treament of infections caused by Gram-positive bacteria. It is a branched tricyclic glycosylated nonribosomal peptide produced by the fermentation of the actinomycete bacteria Amycolatopsis orientalis (formerly Nocardia orientalis).
It is often reserved as the "drug of last resort", used only after treatment with other antibiotics had failed. With the increasing prevalence of antibiotic resistant-bacteria, vancomycin has increasingly become a first line therapy when faced with Staphylococcus aureus infections in a patient where antibiotic resistance can reasonably be anticipated.
Vancomycin hydrochloride has been developed and marketed by Eli Lilly under the trade name Vancocin®. Their patent expired in the early 1980s and generic versions of the drug are now available internationally under various trade names.
Mechanism of action
Vancomycin acts by inhibiting proper cell wall synthesis in Gram-positive bacteria. The mechanism inhibited, and various factors related to entering the outer membrane of Gram-negative organisms mean that vancomycin is not active against Gram-negative bacteria.
Specifically, vancomycin prevents incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits from being incorporated into the peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls.
The large hydrophilic molecule is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Normally this is a five-point interaction. This binding of vancomycin to the D-Ala-D-Ala prevents the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix.
Therapeutic considerations
Owing to its renal excretion and nephrotoxic potential, vancomycin must be used cautiously in patients with poor renal function, or when given in conjunction with other nephrotoxic drugs. This dose and/or dosing interval are reduced in patients with renal impairment. Vancomycin may also potentially cause ototoxicity. These risk of nephrotoxic and ototoxic effects are increased with concomitant administration of aminoglycoside antibiotics.
It is unnecessary to monitor serum concentrations of vancomycin in most patients. However there are circumstances which warrant therapeutic drug monitoring (TDM) such as patients receiving concomitant aminoglycoside therapy, patients with (potentially) altered pharmacokinetic parameters, patients on haemodialysis, during high dose or prolonged treatment, and patients with impaired renal function. (Rossi, 2004)
Vancomycin needs to be given intravenously (IV) for systemic therapy since it does not cross through the intestinal lining. It is a large hydrophilic molecule which partitions poorly across the gastrointestinal mucosa. Vancomycin must be administered in a dilute solution slowly, over at least 60 minutes, due to the high incidence of pain and thrombophlebitis.
The only indication for oral vancomycin therapy is in the treatment of pseudomembranous colitis, where it must be given orally to get to reach the site of infection in the colon.
Clinical indications
Vancomycin is indicated for the treatment of serious, life-threatening infections by Gram-positive bacteria which is unresponsive to other less toxic antibiotics.
The increasing emergence of vancomycin-resistant enterococci has resulted in the develop of guidelines for use by the Centers for Disease Control (CDC) Hospital Infection Control Practices Advisory Committee. These guidelines restrict use of vancomycin to the following indications:
- treatment of serious infections caused by susceptible organisms resistant to penicillins (MRSA and multi-resistant Staphylococcus epidermidis (MRSE)) or in people with serious allergy to penicillins
- pseudomembranous colitis (relapse or unresponsive to metronidazole treatment)
- antibacterial prophylaxis for endocarditis following certain procedures in penicillin-hypersensitive people at high risk
- surgical prophylaxis for major procedures involving implantation of prostheses in institutions with a high rate of MRSA or MRSE
(Rossi, 2004)
Resistance
As of July 2002, there were reports of a woman in the city of Detroit, United States, having been infected by a strain of Staphylococcus aureus resistant to vancomycin. She was kept in isolation to prevent the infection from being spread to others.
Resistance to vancomycin, such as in the above case, appears to be a growing problem for healthcare sector. With vancomycin being the last-line antibiotic for serious Gram-positive infections there is a fear that resistance to even this will result in a return to the days when fatal bacterial infections were common.
There is some suspicion that agricultural use of avoparcin , another similar glycopeptide antibiotic, has contributed to the emergence of vancomycin-resistant organisms.
The mechanism of resistance appears to be alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits, normally D-alanyl-D-alanine, which vancomycin binds to. Variations such as D-alanyl-D-lactate and D-alanyl-D-serine result in only a 4-point hydrogen bonding interaction being possible between vancomycin and the peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity.
In Enterococci this modification appears to be due to the expression of an enzyme which alters the terminal residue. Three main resistance variants have been characterised to date among resistant Enterococcus faecium and E. faecalis populations.
- VanA - resistance to vancomycin and teicoplanin, inducible on exposure to these agents
- VanB - lower level resistance, inducible by vancomycin but strains may remain susceptible to teicoplanin
- VanC - least clinically important, resistance only to vancomycin, constitutive resistance
The development of novel antibiotics such as linezolid is expected to delay, but not halt, the emergence of bacteria resistant to all available antibiotics.
See also:
External links:
References
- Rossi S (Ed.) (2004). Australian Medicines Handbook 2004 (AMH). Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2.
Last updated: 09-12-2005 02:39:13
