Vancomycin

Background

• A glycopeptide antibiotic

Mechanism of Action

• Inhibits cross-linking of peptidoglycans in the cell wall

Mechanisms of Resistance

• Alterations in peptidoglycans conferred by chromosomal or plasmid-mediated vanA, vanB, or vanC

Spectrum of Activity

• Broadly active against Gram-positive bacteria, including anaerobes
• Not active against Gram-negative bacteria
• Notable resistance occurs in:
  • Clostridium innocuum
  • Enterococcus gallinarum, Enterococcus casseliflavus, and Enterococcus flavus (chromosomal vanC)
  • Erysipelothrix rhusiopathiae
  • Lactobacillus, except Lactobacillus acidophilus and Lacobacillus delbrueckii
  • Leuconostoc
  • Pediococcus
  • Weissella

Pharmacokinetics and Pharmacodynamics

• Bactericidal
• Concentration-independent with post-antibiotic effect
• Efficacy predicted by AUC₂₄:MIC

Clinical Breakpoints

Species	Breakpoints (μg/mL)
	S	I	R
Staphylococcus aureus	≤2	4-8	≥16
Staphylococcus species other than S. aureus	≤4	8-16	≥32
Enterococcus species	≤4	8-16	≥32
Streptococcus pneumoniae	≤1	—	—
β-hemolytic streptococci	≤1	—	—

Dosing

• Common dose
  • Loading dose of 25-30 mg/kg given once for serious infections
  • 15 mg/kg/dose with timing based on renal function (q12h if normal)
  • Titrate based on monitoring parameters (below)
  • Adjustments assume linear pharmacokinetics, so a doubling of the daily dose, for example, should double the trough or AUC:MIC

Renal Dosing

• CrCl >100 mL/min: 15-20 mg/kg q8-12h
• CrCCl 50 to 100: 15-20 mg/kg q12h
• CrCl 20-49: 15-20 mg/kg q24h
• CrCl <20: 15-20 mg/kg q48h
• Hemodialysis: target pre-dialysis levels of 15 to 20
  • If next HD in 1 day, give 15 mg/kg
  • If next HD in 2 days, give 25 mg/kg
  • If next HD in 3 days, give 35 mg/kg
  • Give at rate of 15 mg/min over the last 120 minutes of HD to coincide with the end of dialysis
• CAPD: 7.5 mg/kg q48-96h
• CRRT: 10-15 mg/kg q24-48h

Obesity

• Dosing should use actual body weight, with a maximum loading dose of 3 g

Monitoring

• Based on PK/PD modelling, the trough level was previously used to dose vancomycin
  • Serum trough drawn within hour before fourth dose
  • 10-15 for low-risk infections
  • 15-20 for high-risk Staphylococcus aureus infections such as osteomyelitis, meningitis, and bacteremia
• Current guidelines recommend AUC:MIC monitoring using Bayesian calculators1
  • Use peak 60 min after infusion and trough 1 to 60 minutes before next dose, and record times accurately
  • Target AUC/MIC_BMD ratio of 400 to 600 for serious Staphylococcus aureus infections

Adverse Reactions

• Primarily include renal failure and red person syndrome

Renal Failures

• Risk factors
  • Prolonged courses >21 days
  • Higher trough
  • Concomitant nephrotoxic medication
  • Older age
  • CKD/AKI
  • Liver disease
  • Peritonitis
  • Neutropenia
  • Male sex
• Mechanism of injury: oxidative stress in the proximal tubular cells

Red Person Syndrome

• Rash, pruritis, and hypotension, with onset of vancomycin, resolves on stopping
• Very high incidence previously
• Histamine-mediated
• Can decrease dose or prolong infusion, prophylactic antihistamines