Section 2 - Vancomycin

Section 2 - Applied Pharmacokinetics

Vancomycin

Introduction

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 determining doses.

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 mcg/ml. 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:

Routine surgical prophylaxis
Treatment of a single positive blood culture for coagulase negative staphylococci
Empiric therapy of a febrile neutropenic patient where no evidence of gram positive infection exists
Continued empiric therapy
Selective gut decontamination
MRSA colonization
Primary therapy for pseudomembraneous colitis
Topical application or irrigation
Treatment of MSSA or other susceptible gram positive infections in dialysis patients
Prophylaxis in CAPD patients
Prophylaxis in low birth weight infants
Systemic or local prophylaxis for indwelling central or local catheters

Pharmacokinetics

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 serum level sampling.

If the one compartment model is used, the peak level must be drawn after the distribution phase, which is at least one hour after the end of the infusion.

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 32 mcg/ml and peak levels of 21 to 62 mcg/ml are associated with this adverse effect. Such a wide range makes determination of the precise correlation of vancomycin serum levels with otoxicity 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.

Patients with multiple risk factors are particularly at risk for vancomycin induced nephrotoxicity.

Risk factors for vancomycin nephrotoxicity

Concentration-efficacy relationships

The pharmacodynamic properties of vancomycin are:

Time-dependent killing
Moderate post-antibiotic effect

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 400 is necessary for MRSA.

Vancomycin Outcome vs 24h-AUC/MIC ratio

24h-AUC/MIC ratio	Satisfactory	Unsatisfactory
< 125	4 (50%)	4
> 125	71 (97%)	2

Hyatt et al, Clin Pharmacokinet 28: 143, 1995

Since this paper was published there has been an explosion of research regarding the optimal AUC ratio for Vancomycin. Most experts now agree that a 24h-AUC/MIC ratio of at least 400 is necessary for efficacy.

Dosing methods

The relatively unpredictable relationship between dose and resultant serum levels of vancomycin has prompted the development of a wide variety of dosing methods. For patients with creatinine clearances of 15ml/min or greater, the method of Lake and Peterson appears to be the least biased and most precise predictor of vancomycin dosage. In their evaluation, 71% of peak concentrations were within the range of 20 to 30 mcg/l, and 81% of trough levels were within the range of 5 to 10 mcg/ml.

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.

Population model parameters

Volume of distribution
Compared with aminoglycosides, the variability in the Vd of vancomycin is extreme. 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 Vd closer to 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.

Clearance
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.

Monitoring parameters
Careful observation for signs of drug toxicity is imperative.

The following patient parameters should be monitored during vancomycin therapy:

Vancomycin trough levels
Obtain at steady-state (approximately four half lifes) after initiation and after dose changes. Then at least weekly during therapy.
BUN and serum creatinine
Measure every two days, or every day in unstable renal function.
Weight
Weigh patient every two to seven days.
Urine output
Measure and monitor urine output daily.
Baseline and weekly audiograms.
Check for signs of phlebitis daily.

Therapeutic trough concentrations

For serious infections, such as bacteremia, infective endocarditis, osteomyelitis, meningitis, pneumonia, and severe SSTI (eg, necrotizing fasciitis) due to MRSA, vancomycin trough concentrations of 15 to 20 mcg/ml are recommended.
For less serious infections such as skin and soft tissue infections, trough concentrations of 10 to 15 mcg/ml are recommended.

Targeted AUC dosing

The trough is but a surrogate marker for the true pharmacodynamic parameter for Vancomcyin, the 24-hr AUC/MIC ratio. The target vancomycin trough level of 15-20 mg/liter was chosen in the 2009 vancomycin TDM guidelines to maximize the likelihood of achieving a 24-hr AUC/MIC ratio of >400 mg·h/liter.
Targeting the trough level has been criticized as trough concentrations underestimate the true AUC by 25% on average. Recent pharmacokinetic data suggest that the majority of patients can achieve AUC values of >400 with trough concentrations less than 15.
Although controversy remains regarding whether vancomycin has a direct toxic effect, vancomycin-associated nephrotoxicity has been linked to troughs greater than 15. Monitoring vancomycin by AUC would be expected to reduce unnecessarily high vancomycin exposure and thus reduce nephrotoxicity.
Although clinical data suggest that targeting the daily vancomycin AUC above 400 will ensure efficacy, the AUC range associated with nephrotoxicity has not been clearly defined. Based on current data, it appears prudent to maintain the AUC below 600 (and trough below 20).

Precautions

Proper timing of serum sampling is critical.
The trough sample should be obtained just prior to the dose. The timing of peak levels continues to be an area of controversy. Most experts now agree that peak samples are most appropriately obtained 15 to 30 minutes after infusion rather than 1-2 hours after, because peaks drawn later substantially underestimate the true peak levels achieved immediately after infusion.

Drawing at exactly the right time is not as important as having the lab note the exact times that the samples were drawn. Also, have the nurse note the exact times that the sample infusion was started and when it ended. Please be aware of the widespread policy of nursing personnel to record a dose as having been given exactly as ordered if it is given within 30 minutes of the recorded time. This will lead to significant errors in analysis, please ensure that all those involved record the exact times.

This issue cannot be stressed enough. Inaccurate recording of drug administration times and lab draw times are the greatest source of calculation error, having a greater effect than pharmacy preparation error or lab assay error.

Outliers
In general the Bayesian approach to the determination of individual drug-dosage requirements performs better than other approaches. However, outlying patients in a population (ie, those patients whose pharmacokinetic parameters lie outside of the 95th percentile of the population) may be put at risk. As is always the case, computerized algorithms can only assist in the decision-making process and should never become a substitute for informed clinical judgement.

Vancomycin accumulation
Recent data have shown that prolonged treatment with vancomycin (>10 days) may result in a decline in the drug’s clearance despite stable renal function. Given this risk of decreased elimination, close monitoring of serum levels is advisable even in patients with normal and stable renal function.

Inter-patient variability
Vancomycin pharmacokinetics are highly variable, it is a difficult drug to model empirically. For example, look at the divergent dosing methods in the literature. In short, vancomycin is not a drug to hang your "pk hat" on.

Section 2 - Applied Pharmacokinetics