**Vancomycin dosing**

**I. 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 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 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 is relatively infrequent. In the medical literature from 1956 to 1984, there are approximately 20 case reports of nephrotoxicity. Many of these cases are complicated by concomitant aminoglycoside therapy and pre-existing renal problems. There is little data that correlates vancomycin serum levels with nephrotoxicity. It appears to be concentration-related, with an increased risk at trough concentrations greater than 30 mcg/ml.

- 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 - 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 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. Obese patients present another conundrum, some clinicians recommend LBW, others prefer TBW.**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.

- 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.

^{9}In their evaluation, 71% of peak concentrations were within the range of 20 to 30 mcg/ml, and 81% of trough levels were within the range of 5 to 10 mcg/ml.^{10}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.

^{8}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.

**II. Monitoring parameters**

- 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, especially concerning peak levels.

Only one recommendation is certain, because of the pharmacodynamics of vancomycin, trough levels must remain above the MIC for continual anti-bacterial activity.- Trough level (30 minutes prior to dose) = 15 mcg/ml (some advocate up to 20 mcg/ml)

**III. 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, have everyone 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 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.

^{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.

**IV. Program procedure**

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.

**V. Vancomycin dosing flow chart**

**VI. Pharmacokinetic formulas**

**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 = 0.009 + (CrCl x 0.0022)

Vd = 0.5 L/kg**CL method**

CL = CrCl x 0.065

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

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

where Cp_{tmin}= Target trough

Cp_{tmax}= Target peak - 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**. The two compartment model is based on published data used to develop the Lake and Peterson nomogram for empiric dosing of Vancomycin.^{3}- 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}-k_{d}) (1 - e^{kd x tinf}) e^{kd x t})] / [V_{c}x k_{d}(k_{d}-k_{el}) (1 - e^{kd x tau})] +

[(k_{el}-k_{21}) (1 - e^{kel x tinf}) e^{kel x t})] / [V_{c}x k_{el}(k_{d}-k_{el}) (1 - e^{kel 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 (.42 hr^{ -1}) - V
_{c}= Volume of central compartment (.205 L/kg) - k
_{d}(hybrid distribution rate constant) = (k_{21}x k_{10})/k_{el}

where- k
_{10}= CL/Vc

- k
- k
_{el}(hybrid elimination rate constant) = CL/Vd

where- CL= .17 + (.06 x CrCl)
- Vd = .65 L/kg

- 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_{c}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_{c}x k_{el}(k_{d}-k_{el}) (1 - e^{kel x tau})]

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 (.42 hr^{-1}) - V
_{c}= Volume of central compartment (.205 L/kg) - k
_{d}(hybrid distribution rate constant) = (k_{21}x k_{10})/k_{el}

where- k
_{10}= CL/Vc

- k
- k
_{el}(hybrid elimination rate constant) = CL/Vd

where- CL= .17 + (.06 x CrCl)
- Vd = .65 L/kg

- k

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

Patient specific pharmacokinetic parameters are calculated from serum levels using the Sawchuk and Zaske method as described in the aminoglycoside section of the manual.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 (ie., Vd 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

**VII. Bibliography**

- Recommendations for Prevention and Spread of Vancomycin Resistance MMWR 44(RR12);1-13, September 22, 1995.
- Rybak MJ, Boike SC. Monitoring vancomycin therapy. Drug Intell Clin Pharm. 1986;20:757-761.
- Matzke GR, Zhanel GG, Guay DRP. Clinical pharmacokinetics of vancomycin. Clin Pharmacokinet 1986 Jul-Aug;11(4):257-82. [ PubMed ]
- Cheung RP, DiPiro JT. Vancomycin: An Update. Pharmacotherapy 1986 Jul-Aug;6(4):153-69. [ PubMed ]
- Rodvold KA, et al. Routine monitoring of serum vancomycin concentrations: can waiting be justified? Clin Pharm 1987;6:655-658.
- Healy DP, Sahai JV, Fuller SH, Polk RE. Vancomycin-induced histamine release and 'red man syndrome' comparison of 1- and 2-hour infusions. Antimicrobial Agents and Chemo 34; 550-554, 1990. [ PubMed ]
- Sheiner LB, Beal S. Bayesian individualization of pharmacokinetics: simple implementation and comparison with non-Bayesian methods. J Pharm Sci 1982 71:1344-1348. [ PubMed ]
- Matzke GR, Kovarik JM, et al. Evaluation of the vancomycin-clearance: creatinine-clearance relationship for predicting vancomycin dosage. Clin Pharm 1985;4:311-315.
- Lake KS, Peterson CD. A simplified dosing method for initiating vancomycin therapy. Pharmacotherapy 1985; 5:340-344. [ PubMed ]
- Musa DM, Pauly DJ. Evaluation of a new vancomycin dosing method. Pharmacotherapy 1987;7:69-72. [ PubMed ]
- Rybak MJ, Boike SC. Individualized adjustment of vancomycin dosage: comparison with two dosage nomograms. Drug Intell Clin Pharm. 1986;20:64-68.
- Garrelts JC, Godley PJ, et al. Accuracy of Bayesian, Sawchuk-Zaske, and nomogram dosing methods for vancomycin. Clin Pharm 1987;6:795-799.
- Pryka RD, Rodvold KA, Garrison M, Rotschafer JC. Individualizing vancomycin dosage regimens: one- versus two-compartment Bayesian models. Ther Drug Mon 1989 11:45-454. [ PubMed ]
- Ackerman, Bruce H. Evaluation of three methods for determining initial vancomycin doses. Drug Intell Clin Pharm. 1989;23:123-7. [ PubMed ]
- Ito MK, Duren LL, Simonian JS, Dreyfus-Vigil SD, Cookson TL. Computer program for the initiation of vancomycin therapy. Clin Pharm 1993 12:126-30. [ PubMed ]
- Pryka RD, Rovold KA, Erdman SM. An updated comparison of drug dosing methods part IV: Vancomycin. Clin Pharmacokinet. 1991 Jun;20(6):463-76. [ PubMed ]
- Leader WG, Chandler MH, and Castiglia M. Pharmacokinetic optimisation of Vancomycin therapy.Clin Pharmacokinet 28(4);327-42 1995. [ PubMed ]
- Pou L, Rosell M, et al. Changes in vancomycin pharmacokinetics during treatment. Ther Drug Mon 1996 18:149-153. [ PubMed ]

**VIII. Recommended Reading**

- Bauer, Larry A. Applied Clinical Pharmacokinetics. McGraw-Hill. 2001.
- Evans W, Schentag J, Jusko J (eds): Applied Pharmacokinetics 3rd edition. San Francisco, CA. Applied Therapeutics, 1992.

**IX. Additional WWW Resouces**

- A First Course in Pharmacokinetics and Biopharmaceutics
- RxKinetics Pharmacokinetics tutorial
- A PK/PD Approach to Antibiotic Therapy

©Copyright 1984 - 2011, RxKinetics. All rights reserved