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.

- 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 for vancomycin.

^{1}Situations in which the use of vancomycin should be discouraged:- 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

- 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%.

^{19}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.

^{20}Patients with multiple risk factors are particularly at risk for vancomycin induced 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 125 is necessary (some researchers recommend a ratio of 400 or more for problem bugs).Vancomycin Outcome vs 24h-AUC/MIC ratio **24h-AUC/MIC ratio****Satisfactory****Unsatisfactory**< 125 4 ( **50%**)4 > 125 71 ( **97%**)2 - Tissue penetration
Vancomycin concentrations in body tissues

following multiple-dose IV administration**Body tissue****Tissue/serum ratio**Abscess 0.94 Aorta 6.4 Heart 1.32 Kidney

normal renal fxn45.8 Kidney

renal failure0.47 Liver 3.77 Lung 2.45 - Pharmacokinetic parameters
When given by IV infusion over 60 minutes, vancomycin follows a 2-compartment pharmacokinetic model; α (distribution) and β (elimination). The α (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 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 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."^{26}Obese patients present another conundrum, some clinicians recommend lean body weight, others prefer total body weight or an adjusted body weight.**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.

Regardless of the pk model used to assess the serum concentration time profiles, the terminal elimination half-life of vancomycin is prolonged and the total body clearance is reduced in patients with impaired renal function:

- Prospective 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.

Zokufa et al. examined five methods (Matzke, Moellering, Nielsen, Lake—Peterson, and the manufacturer’s) for dosing vancomycin and achieving desired peak and trough serum concentrations. In their study of 37 patients, the simulated concentrations from the methods were accurate only within 10% of the actual measured concentration 3—16% of the time.

^{24}Murphy, et al published an evaluation of the accuracy of seven popular vancomycin dosing methods.

^{25}The methods were ranked by least bias or greatest precision.The Burton method using an adjusted body weight (ABW) was ranked number one:

- CL
_{vanco}(mL/min/kg) = ([CrCl × 0.0075] + 0.04) - Vd = 0.47 L/kg

Vd was estimated using an adjusted body weight (ABW).

Matzke's method using actual (total) body weight (TBW) was ranked second:

- CL
_{vanco}(mL/min) = (CrCl× 0.689) + 3.66

CrCl was estimated using the Cockcroft and Gault method and the patient’s actual (total) body weight (TBW). - Vd = 0.72 L/kg if CrCl is >60 mL/min
- Vd = 0.89 L/kg if CrCl is 10 to 60 mL/min
- Vd = 0.9 L/kg if CrCl is less than 10 mL/min

Vd was estimated using the patient’s actual (total) body weight (TBW).

Regardless, the authors of the Murphy study 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."^{25} - CL
- Retrospective dosing methods
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 is the one-compartment open model. Because vancomycin exhibits a multi-compartment pharmacokinetic profile, the clinical application of the one-compartment model requires post-distribution serum samples which may be difficult to accurately obtain. Compared with the one-compartment model, the two-compartment model may produce better results in some patient populations.

- The following patient parameters should be monitored
during vancomycin therapy:
- Vancomycin peak and trough levels

Obtain at steady-state (approximately four half lifes) and then 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.

- Vancomycin peak and trough levels
- Therapeutic serum concentrations
Considerable controversy exists concerning

**peak**levels. Less controversial are recommendations for**trough**levels. Because of the pharmacodynamics of vancomycin, trough levels must remain above the MIC for continual anti-bacterial activity.- 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.

- Risk factors for vancomycin nephrotoxicity include:
- Obesity
- High dose/trough
- Long duration
- Concomitant nephrotoxins
- ICU stay
- Vasopressors
- High APACHE II score

- 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 common 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 could lead to significant errors in analysis, therefore it is important to 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, the computerized algorithms outlined below can only assist in the decision-making process and should never become a substitute for rational thought or informed judgement.

- Vancomycin accumulation
Recent data have shown that prolonged treatment with vancomycin (>10 days) may result in a decline in the drugs 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.

^{18} - PK variability
Vancomycin pharmacokinetics are highly variable, it is a difficult drug to model empirically, look at the divergent methods in the literature. In short, vancomycin is not a drug to hang your "pk hat" on.

Before calculating an initial dose or analyzing serum level data, enter the target trough level and the standard length of infusion.

**Initial dosing**

The program calculates an ideal dose and interval, the user enters a practical dose and interval. The program then displays estimated steady-state peak and trough serum levels.**Dosage adjustment based on serum levels**

Enter the current dosage regimen, date and time of sample infusion and date and time of serum level(s). The program calculates an ideal maintenance dose and the user enters a practical maintenance dose and interval. The program then displays estimated steady-state peak and trough serum levels.The program supports five different serum level analysis methods for the one-compartment model:

The Kinetics© program adds optional two compartment analysis which requires one or two serum levels. In general the more data input into the model, the more accurate the calculation.

**Drug models**

The vancomycin models are not hard-coded into the program. The parameters are
found in the drug model database and are fully user-editable. You can tailor each
drug model to fit your patient population, or you can create your own models. See the
Edit drug models section of the help file for further
information.

**Initial one compartment dosing**

An initial dose, prior to serum level measurement, is based solely on the population model As stated above, the pk models supplied with the program may be edited, also multiple models of the same drug may be added to reflect different patient populations. In fact, two one compartment models are included in the program, the CL model is based on Winter's method, the Kel model is based on Matzke's data.- Determine elimination rate (Kel) and Volume of Distribution (Vd)

**Kel method**

Kel = CrCl x 0.0008

Vd = 0.7 L/kg**CL method**

CL = CrCl x 0.06

Vd = 0.7 L/kg - Determine ideal dosing interval (tau)

tau = tinf + (-1 /Kel) x ln (Cp_{tmax}/Cp_{tmin})

where- Cp
_{tmin}= Target trough

- Cp
_{tmax}= Target peak

- Cp
- Determine ideal maintenance dose (IMD)

IMD = Kel x Vd x Cp_{tmax}x (1 - e^{-Kel x tau}/ 1 - e^{-Kel x tinf}) - User selects practical dosage and interval
- Calculate expected peak & trough levels

Peak = (MD / t_{inf }x Vd x Kel ) x (1 - e^{-Kel x tinf}/1 - e^{-Kel x tau})

Trough = Peak * e^{-Kel x (tau - tinf)}

where tinf = length of infusion

- Determine elimination rate (Kel) and Volume of Distribution (Vd)
**Initial two compartment dosing**

Two compartment modeling is available in the**Kinetics© program only**.- Calculate Clearance

CL = 0.17 + (CrCl x 0.06) - Determine ideal dosing interval (tau)

Tau = 6 x (72 / [(10 * CL) + 1.9]) - Determine ideal maintenance dose (k
_{0})

The target trough level drives the dose.

k_{0}= 1/{[(k_{12}-α) (1 - e^{α x tinf}) e^{α x t})] / [V_{p}x α (α-k_{el}) (1 - e^{α x tau})] +

[(β-k_{21}) (1 - e^{β x tinf}) e^{β x t})] / [V_{p}x β (α-k_{el}) (1 - e^{β x tau})]} / 1/CP_{target}

where- k
_{0}= infusion rate (mg/hour) - tau = dosing interval (hours)
- t
_{inf}= infusion time (hours) - t = time at which to predict serum concentration
- k
_{12}= rate constant for distribution from central to peripheral compartment (1.12 hr^{ -1}) - k
_{21}= rate constant for distribution from peripheral to central compartment (0.48 hr^{ -1}) - V
_{p}= Volume of peripheral compartment (0.74 L/kg) - α (hybrid distribution rate constant) = (k
_{21}x k_{10})/k_{el}

where- k
_{10}= CL/Vc - k
_{el}= CL/Vp

- k
- β (hybrid elimination rate constant) = (k
_{21}x k_{el}) / α

- CP
_{target}= Target trough level

- k
- User selects practical dosage and interval

- Calculate expected peak & trough levels

CPss = [k_{0}(k_{12}-k_{d}) (1 - e^{kd x tinf}) e^{kd x t})] / [V_{p}x k_{d}(k_{d}-k_{el}) (1 - e^{kd x tau})] +

[k_{0}(k_{el}-k_{21}) (1 - e^{kel x tinf}) e^{kel x t})] / [V_{p}x k_{el}(k_{d}-k_{el}) (1 - e^{kel x tau})]

- Calculate Clearance
**Adjust dose using 1-compartment model**

Patient specific pharmacokinetic parameters are calculated from peak and trough serum levels using the Sawchuk and Zaske method as described in the aminoglycoside section of the manual. If a single trough level is analyzed the Bayesian method is used (see below).There is one important caveat when using a 1-compartment vancomycin model. Because of the long distribution phase of vancomycin, peak sampling time is an important consideration. 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.

**Adjust dose using 2-compartment model**- Minimize Bayesian function

The Bayesian method uses population-derived pharmacokinetic parameters (1-cpt: Vd, CL ; 2-cpt: Vp, Vc and CL) as a starting point and then adjusts those parameters based on the serum level results, taking into consideration the variability of the population-derived parameters and the variability of the drug assay procedure. To achieve that end, the least squares method based on the Bayesian algorithm estimates the parameters which minimize the following function: - Determine ideal dosing interval (tau)

Clearance is used to approximate the ideal tau. - Calculate ideal dose

Same equation as initial dosing. - User selects practical dosage and interval
- Calculate expected peak & trough levels

Same equation as initial dosing.

- Minimize Bayesian function

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