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Although numerous publications in the past several years have described the pharmacokinetics of vancomycin in various patient populations, disparity still exists regarding the most appropriate methods of monitoring, including therapeutic range, timing of peak determinations, and methods for adjusting doses.
1. Antimicrobial spectrum
Vancomycin is primarily effective against gram-positive cocci. Staphylococcus aureus and Staphylococcus epidermidis, including both methicillin-susceptible (MSSA & MSSE) or resistant-species (MRSA & MRSE), are usually sensitive to vancomycin with minimum inhibiting concentrations (MIC) less than 1.5 mg/L. Most strains of streptococcus are sensitive to vancomycin. Vancomycin is considered bactericidal (MBC/MIC < 4) except with enterococci and some tolerant (MBC/MIC > 32) staphylococci. When staphylococcal tolerance has been demonstrated, most clinicians add a second antibiotic such as an aminoglycoside to the regimen. Enterococcal infections should be treated with vancomycin combined with gentamicin. Vancomycin is also effective against the anaerobes, diphtheroids and clostridium species, including C. Difficile.
Significant controversy has arisen in recent years regarding the efficiency by which vancomycin kills gram positive bacteria and the potential misuse of the drug. Several studies have shown that with both staphylococci and enterococci vancomycin does not kill the bacteria as quickly or sterilize the blood as rapidly as nafcillin or ampicillin. For this reason many authors suggest that unless the patient has an allergy to beta-lactams or has a methicillin resistant staphylococcal infection, the patient might be better served using a beta-lactam agent over vancomycin.
Concern over the ever increasing problems with vancomycin resistant enterococci (VRE) prompted the Center for Disease Control to issue a statement suggesting appropriate prescribing criteria vancomycin (MMWR 44:No RR-12, September 22, 1994). Vancomycin is not recommended for:
2. Concentration-toxicity relationships
Ototoxicity is an infrequent event occurring in fewer than 2% of patients receiving vancomycin. It is unclear whether elevated trough or peak levels are responsible for ototoxicity. Data in the literature suggest that trough levels of 13 to 32mcg/ml and peak levels of 21 to 62mg/ml are associated with this adverse effect. Such a wide range makes determination of the precise correlation of vancomycin serum levels with ototoxicity difficult.
A histamine-mediated reaction, often called 'red man syndrome', involves a rash over the upper body, possibly accompanied by hypotension. The syndrome is thought to be related to peak serum concentration. Healy (1990) reported that none of 11 volunteers receiving vancomycin 500mg every 6 hours demonstrated evidence of this reaction, while 9 of the same 11 showed symptoms consistent with 'red man syndrome' when receiving vancomycin 1000mg every 12 hours.
Vancomycin nephrotoxicity appears to be concentration-related, with an increased risk at trough concentrations greater than 15 mcg/ml.
Higher vancomycin doses carry a substantial risk for nephrotoxicity. Recent studies have shown that higher-dose vancomycin regimens are associated with a higher likelihood of vancomycin-related nephrotoxicity. A significant difference in nephrotoxicity between patients receiving >= 4 g vancomycin/day vs those receiving <4 g vancomycin/day was noted: 34.6% vs 10.9%.
Critically ill patients, patients receiving concomitant nephrotoxic agents, and patients with already compromised renal function are particularly at risk for vancomycin-induced nephrotoxicity. This risk is incremental with higher trough levels and longer duration of vancomycin use.
Risk factors for vancomycin nephrotoxicity include:
3. Concentration-efficacy relationships
The pharmacodynamic properties of vancomycin are:
The ideal dosing regimen for vancomycin maximizes the amount of drug received. Therefore, the 24h-AUC/MIC ratio is the parameter that correlates with efficacy. For vancomycin, a 24h-AUC/MIC ratio of at least 125 is necessary (some researchers recommend a ratio of 400 or more for problem bugs).
Vancomycin Outcome vs 24h-AUC/MIC ratio
Hyatt et al, Clin Pharmacokinet 28: 143, 1995
4. Pharmacokinetic parameters
When given by IV infusion over 60 minutes, vancomycin follows a 2-compartment pharmacokinetic model; alpha (distribution) and ß (elimination). The alpha (distribution) phase is relatively long, averaging two hours. This has important implications for peak serum level sampling. If the peak level is drawn during the distribution phase, it cannot be used for analysis of the one compartment model.
Volume of distribution
Compared with aminoglycosides, the variability in the distribution volume of vancomycin is much larger. Published inter-patient variability has been reported as 0.26 to 1.30 L/kg, 0.21 to 1.51 L/kg, 0.2 to 1.3 L/kg, and 0.37 to 1.40 L/kg in a series of studies. The average Vd also varies widely in the literature, with early reports suggesting a value of 0.9 L/kg and more recent studies indicating a smaller Vd of 0.5 L/kg. There does not appear to be any readily identifiable clinical characteristic to explain this variability. Unlike the aminoglycosides where one can often predict a larger or smaller than average Vd based on fluid status, variability in vancomycin Vd appears to be completely unpredictable. Obese patients present another conundrum, however most clinicians recommend TBW.
Like the aminoglycosides, vancomycin is primarily cleared by glomerular filtration. Correlation of vancomycin clearance to creatinine clearance typically gives values for slope of between 0.5 and 0.8 and y-intercept (non-renal clearance) of up to 15 ml/min. All studies have demonstrated a strong correlation between vancomycin clearance and creatinine clearance, however, there is significant variability in the non-renal clearance component. This unpredictability is particularly evident in patients with impaired renal function who are more dependent on nonrenal clearance. Therefore, extra caution is required when estimating clearance in patients with markedly decreased renal function.
Given the variability of Vd and clearance seen with vancomycin, standard doses are likely to be associated with a significant degree of variability in serum concentrations.
5. Dosing methods
An evaluation of the accuracy of seven popular vancomycin dosing methods has recently been published. John Murphy and colleagues concluded "The seven methods studied for estimating vancomycin pharmacokinetic parameters varied widely in predicting vancomycin trough concentrations compared with measured serum concentrations and were not sufficiently reliable to replace therapeutic monitoring of vancomycin serum concentrations."
These following adult dosing recommendations are based on a consensus statement of the American Society of Health-System Pharmacists, the IDSA, and The Society of Infectious Diseases Pharmacists on guidelines for vancomycin dosing.
Modification of vancomycin dosing is a major concern in the patient with renal insufficiency. For patients with creatinine clearances less than 15ml/min, the method of Matzke may be the best choice. Vancomycin is not removed appreciably by hemodialysis and thus is administered only every 7 to 10 days in dialysis patients. Clearance during peritoneal dialysis is more controversial. Originally thought not to be removed by peritoneal dialysis, recent reports have shown that vancomycin is cleared by this route. Dosing of vancomycin in peritoneal dialysis patients remains controversial.
For evaluation of serum level data, methods incorporating Bayesian principles appear to give the best overall predictive performance compared with traditional methods of vancomycin dosage adjustment. The Bayesian approach combines both population and patient-specific information (i.e., serum level data) in predicting dosage requirements.
The pharmacokinetic model most widely used by clinicians has been one-compartment. Because vancomycin exhibits a multi-compartment pharmacokinetic profile, the clinical application of the one-compartment model requires post-distribution serum samples which are often difficult to accurately obtain. Compared with the 1-compartment model, the 2-compartment model results in a significant improvement in both bias and precision in predicting vancomycin peak and trough concentrations.
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