Vancomycin

Nine things you didn’t know you wanted to know about Vancomycin….

1. Vancomycin, like 80% of all antibiotics, is produced by Streptomyces bacteria (Amycolatopsis orientalis, previously called Streptomyces orientalis).  Streptomyces are gram positive bacteria present in large numbers in the soil.  Streptomyces are interesting because they produce many compounds, not just antibiotics.  For example, they also produce Geosmin, the reason for soils ‘earthy’ odour. 
2. The 1950s were the golden age of antibiotic discovery, but the search for new antibiotics was essentially a low yield screening process, searching through soil samples for bacteria producing them.  Vancomycin was discovered in this way in 1952, from a soil sample sent from Borneo to Dr. Edmund Kornfeld, a chemist working for Eli Lilly. Early techniques to purify the compound required an explosive chemicall, but the alternative was not ideal either; the purity achieved was only 82% and the resulting solution had the look of muddy water (for this reason it was known as Mississippi mud).  Despite this, the solution was deemed to be suitable for use and was administered to a patient with a resistant foot infection facing amputation.  The foot was saved, and the infection successfully treated, just as stocks of Vancomycin ran out.  Further cases of successful use followed and only five years after first use the FDA gave approval.  Soon after this approval however, use of Vancomycin declined due to the emergence of newer drugs with fewer side effects and the ability to be given orally.  Vancomycin returned to popularity in the 1980s with the emergence of C. Difficile colitis, and latterly, with the unfortunate rise in antimicrobial resistance. 
3. Originally known as compound 05865, The name ‘Vancomycin’ comes from ‘vanquish’, the idea being that Vancomycin would vanquish all Staphylococcal infection.
4. Vancomycin is ineffective against gram negative organisms because of its molecular size, being too large to penetrate the cell membrane. Vancomycin acts by inhibiting cell wall synthesis by binding to terminal peptide residues on the glycopeptide chain (D-alanyl-D-alanine).  The large Vancomycin molecule then ‘gets in the way’, blocking cross linking and resulting in a fragile cell wall. 
5. Vancomycin resistant Enterococci (VRE) produce an enzyme that changes the D-alanyl-D-alanine terminal peptide residue to either D-alanyl-D-lactate or D-alanyl-D-serine, greatly reducing the affinity for Vancomycin.  It is thought that Enterococci resistance may have been promoted by the widespread use of enteral Vancomycin in the treatment of C. Difficile.
6. Resistant Staphylococci are thankfully not as common as VRE.  Vancomycin Intermediate Staph Aureus (VISA) populations demonstrate partial resistance to Vancomycin by producing an excess of free D-alanyl-D-alanine, which ‘mops up’ some of the Vancomycin molecules.  VISA is rare, but so called heteroresistant VISA (hVISA) populations are becoming more common.  hVISA populations contain small subpopulations of VISA (one VISA per 10⁵-10⁶ bacteria) but have a measured MIC in the usual range.  hVISA can be a cause of treatment failure (giving yet another acronym – SA-RVS, Staph Aureus with reduced Vancomycin susceptibility), and the observed rise in hVISA is seen as a worrying precursor to more VISA infections.  Although very rare, cases of Resistant Staph Aureus (VRSA) have also unfortunately been reported.  The mechanism of VRSA is transfer of resistance genes from VRE.
7. Vancomycin should be dosed according to actual body weight, and as it is excreted unchanged in the urine a dose adjustment is required in renal failure.
8. The nephrotoxicity attributed to Vancomycin may not be as common as suspected.  The evidence base isn’t strong, and patients receiving Vancomycin often have many cofounders for renal injury.  The reputation for nephrotoxicity was also established in historic preparations of the drug.
9. Red man syndrome is a histamine mediated anaphylactoid reaction to rapid infusion of Vancomycin (rates>1g/hr).  It is unclear whether the reaction is mediated by increased histamine release or reduced metabolism.  The treatment of red man syndrome is to stop the infusion, give antihistamines and supportive measures, and to restart the infusion at a slower rate. 

Further Reading

• Procópio REL, Silva IR, Martins MK,  Azevedo JL et al. Antibiotics produced by Streptomyces. The Brazilian Journal of Infectious Diseases. 2012;16(5):466-471.

• Levine DP. Vancomycin: A History. Clinical Infectious Diseases. 2006;42:S5-12