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 Staphylococcus aureus	≤4	8-16	≥32
Enterococcus	≤4	8-16	≥32
Streptococcus pneumoniae	≤1	—	—
β-hemolytic streptococci	≤1	—	—

Dosing

Intermittent Infusion

• 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
  • Alternatively:
    • < 70 kg: 1000mg IV x 1, then 500mg post-dialysis
    • 70 –100kg: 1250mg IV x 1, then 750mg post-dialysis
    • >100 kg: 1500mg IV x 1, then 1000mg post-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

Continuous Infusion

• Particularly useful in the following patients:
  • Total daily doses of 4 g or higher, since it will lower the total dose and therefore associated toxicitynephro
  • Home antibiotic therapy, to simplify drug monitoring
• At least as safe and effective as intermittent infusion
• Limited by pump availability and IV access
• Consider loading dose in patients who are not already on intermittent infusion and who are hemodynamically unstable
• Initial dose based on creatinine clearance and weight

TBW (kg)	CrCl (mL/min)	Load (mg)	Maintenance (mg/24h)
<100	≥90	1000	2000
100-119		1500	2500
≥120		2000	3000
Obesity and Renal Failure
100-115	70-89	1000	1750
	50-69	1000	1250
	40-49	1000	1000
	30-39	1000	750
	20-29	1000	500
116-139	70-89	1250	2000
	50-69	1250	1500
	40-49	1250	1250
	30-39	1250	1000
	20-29	1250	750
140-159	70-89	1500	2500
	50-69	1500	1750
	40-49	1500	1500
	30-39	1500	1250
	20-29	1500	750
160-179	70-89	1500	2750
	50-69	1500	2000
	40-49	1500	1500
	30-39	1500	1250
	20-29	1500	1000
180-199	70-89	1750	3000
	50-69	1750	2500
	40-49	1750	2000
	30-39	1750	1500
	20-29	1750	1000

Monitoring

• Random vancomycin levels
  • First level is 24 hours after starting
  • Monitor weekly, any time the patient is unstable, and 24 hours after any dose adjustments
  • Target levels are typically 15 to 20
• Serum creatinine should be measured twice weekly
• CBC monitored weekly

Adverse Reactions

• Primarily include renal failure and red person syndrome

Renal Failures

• Dose-dependent risk, with significant increase with trough over 15
• Lower risk with AUC-based dosing, which promotes lower dosing, and with continuous infusion
• Risk factors: prolonged courses >21 days, higher troughs, concomitant nephrotoxic medication, older age, CKD/AKI, liver disease, peritonitis, neutropenia, and male sex
• Mechanism of injury: either AIN or ATN from oxidative stress in the proximal tubular cells
  • May be able to detect it early with serum Kim-1 elevation, or NGAL elevation (though less specific)

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