
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 betalactams or has a methicillin resistant staphylococcal
infection, the patient might be better served using a betalactam
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
Concentrationtoxicity 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 histaminemediated 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 concentrationrelated, 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 higherdose vancomycin
regimens are associated with a higher likelihood of vancomycinrelated 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 vancomycininduced 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.
Concentrationefficacy relationships
The pharmacodynamic properties of vancomycin are:
 Timedependent killing
 Moderate postantibiotic effect
The ideal dosing regimen for vancomycin maximizes the amount of drug received.
Therefore, the 24hAUC/MIC ratio is the parameter that correlates with efficacy.
For vancomycin, a 24hAUC/MIC ratio of at least 125 is necessary (some researchers
recommend a ratio of 400 or more for problem bugs).
Vancomycin Outcome vs 24hAUC/MIC ratio
24hAUC/MIC ratio

Satisfactory

Unsatisfactory

< 125

4 (50%)

4

> 125

71 (97%)

2

Hyatt et al, 1995
Tissue penetration
Vancomycin concentrations in body tissues following multipledose IV administration
Body tissue

Tissue/serum ratio

Abscess

0.94

Aorta

6.4

Heart

1.32

Kidney normal renal fxn

45.8

Kidney renal failure

0.47

Liver

3.77

Lung

2.45

Torres et al, 1979
Pharmacokinetic parameters
When given by IV infusion over 60 minutes, vancomycin follows a 2compartment
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 interpatient 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 yintercept
(nonrenal 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 nonrenal 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 halflife 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}
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 patientspecific
information (i.e., serum level data) in predicting dosage requirements.
The pharmacokinetic model most widely used by clinicians is the onecompartment open model.
Because vancomycin exhibits a multicompartment pharmacokinetic profile, the clinical
application of the onecompartment model requires postdistribution serum samples which may be
difficult to accurately obtain. Compared with the onecompartment model, the twocompartment
model may produce better results in some patient populations.
II. Monitoring parameters
 The following patient parameters should be monitored
during vancomycin therapy:
 Vancomycin trough levels
Obtain at steadystate (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 24hr AUC/MIC ratio.
The target vancomycin trough level of 1520 mg/liter was chosen in the 2009 vancomycin TDM guidelines to maximize the
likelihood of achieving a 24hr 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, vancomycinassociated 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).
 Risk factors for vancomycin nephrotoxicity include:
 Obesity
 High dose/trough
 Long duration
 Concomitant nephrotoxins
 ICU stay
 Vasopressors
 High APACHE II score
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 12 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 drugdosage
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 decisionmaking
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.
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
steadystate 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 steadystate peak and
trough serum levels.
The program supports five different serum level analysis methods for the
onecompartment 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.
VI. Pharmacokinetic formulas
Drug models
The vancomycin models are not hardcoded into the program. The parameters are
found in the drug model database and are fully usereditable. 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
 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
 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 (αk_{el}) (1  e^{α x tau})] +
[(βk_{21}) (1  e^{β x tinf}) e^{β x t})] / [V_{p} x β (αk_{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
 β (hybrid elimination rate constant) = (k_{21} x k_{el}) / α
 CP_{target} = Target trough level
 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})]
 Adjust dose using 1compartment 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 1compartment 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 2compartment model
 Minimize Bayesian function
The Bayesian method uses populationderived pharmacokinetic
parameters (1cpt: Vd, CL ; 2cpt: 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 populationderived
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.
VII. Bibliography

Recommendations for Prevention and Spread of Vancomycin Resistance
MMWR 44(RR12);113, September 22, 1995.
 Rybak MJ, Boike SC.
Monitoring vancomycin therapy.
Drug Intell Clin Pharm. 1986;20:757761.
 Matzke GR, Zhanel GG, Guay DRP.
Clinical pharmacokinetics of vancomycin.
Clin Pharmacokinet 1986 JulAug;11(4):25782.
[ PubMed ]
 Cheung RP, DiPiro JT.
Vancomycin: An Update.
Pharmacotherapy 1986 JulAug;6(4):15369.
[ PubMed ]
 Rodvold KA, et al.
Routine monitoring of serum vancomycin concentrations: can waiting be justified?
Clin Pharm 1987;6:655658.
 Healy DP, Sahai JV, Fuller SH, Polk RE.
Vancomycininduced histamine release and 'red man syndrome' comparison of 1 and 2hour infusions.
Antimicrobial Agents and Chemo 34; 550554, 1990.
[ PubMed ]
 Sheiner LB, Beal S.
Bayesian individualization of pharmacokinetics: simple implementation and comparison with nonBayesian methods.
J Pharm Sci 1982 71:13441348.
[ PubMed ]
 Matzke GR, Kovarik JM, et al.
Evaluation of the vancomycinclearance: creatinineclearance relationship for predicting vancomycin dosage.
Clin Pharm 1985;4:311315.
 Lake KS, Peterson CD.
A simplified dosing method for initiating vancomycin therapy.
Pharmacotherapy 1985; 5:340344.
[ PubMed ]
 Musa DM, Pauly DJ.
Evaluation of a new vancomycin dosing method.
Pharmacotherapy 1987;7:6972.
[ PubMed ]
 Rybak MJ, Boike SC.
Individualized adjustment of vancomycin dosage: comparison with two dosage nomograms.
Drug Intell Clin Pharm. 1986;20:6468.
 Garrelts JC, Godley PJ, et al.
Accuracy of Bayesian, SawchukZaske, and nomogram dosing methods for vancomycin.
Clin Pharm 1987;6:795799.
 Pryka RD, Rodvold KA, Garrison M, Rotschafer JC.
Individualizing vancomycin dosage regimens: one versus twocompartment Bayesian models.
Ther Drug Mon 1989 11:45454.
[ PubMed ]
 Ackerman, Bruce H.
Evaluation of three methods for determining initial vancomycin doses.
Drug Intell Clin Pharm. 1989;23:1237.
[ PubMed ]
 Ito MK, Duren LL, Simonian JS, DreyfusVigil SD, Cookson TL.
Computer program for the initiation of vancomycin therapy.
Clin Pharm 1993 12:12630.
[ PubMed ]
 Pryka RD, Rovold KA, Erdman SM.
An updated comparison of drug dosing methods part IV: Vancomycin.
Clin Pharmacokinet. 1991 Jun;20(6):46376.
[ PubMed ]
 Leader WG, Chandler MH, and Castiglia M.
Pharmacokinetic optimisation of Vancomycin therapy.
Clin Pharmacokinet 28(4);32742 1995.
[ PubMed ]
 Pou L, Rosell M, et al.
Changes in vancomycin pharmacokinetics during treatment.
Ther Drug Mon 1996 18:149153.
[ PubMed ]
 Lodise TP, Lomaestro B, Graves J, Drusano GL.
Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity.
Antimicrob Agents Chemother. 2008 Apr;52(4):13306. Epub 2008 Jan 28.
[ PubMed ]
 Vandecasteele SJ and De Vriese AS.
Recent changes in vancomycin use in renal failure. Kidney International 77, 760764 (May 2010).
[ PubMed ]
 John E. Murphy; David E. Gillespie; Carol V. Bateman.
Predictability of Vancomycin Trough Concentrations Using Seven Approaches for Estimating
Pharmacokinetic Parameters.
Am J HealthSyst Pharm. 2006;63(23):23652370.
[ Medscape ]
 Hyatt JM1, McKinnon PS, Zimmer GS, Schentag JJ.
The importance of pharmacokinetic/pharmacodynamic surrogate markers to outcome. Focus on antibacterial agents.
Clin Pharmacokinet. 1995 Feb;28(2):14360.
[ PubMed ]
 Torres JR; Sanders CV; Lewis AC.
Vancomycin serum concentrations in human tissues; preliminary report.
Journal of Antimicrobial Chemotherapy. 5: 475477, 1979.
 Zokufa HZ, Rodvold KA, Blum RA et al.
Simulation of vancomycin peak and trough concentrations using five dosing methods in 37 patients.
Pharmacotherapy. 1989; 9:10—6.
 John E. Murphy; David E. Gillespie; Carol V. Bateman.
Predictability of Vancomycin Trough Concentrations Using Seven Approaches for Estimating
Pharmacokinetic Parameters.
Am J HealthSyst Pharm. 2006;63(23):23652370.
[ Medscape ]
 Edwards, D. J.
Therapeutic drug monitoring of aminoglycosides and vancomycin: guidelines and controversies.
J. Pharm. Prac. 1991; 4:211–224.
VIII. Recommended Reading
 Bauer, Larry A.
Applied Clinical Pharmacokinetics, 3rd edition. McGrawHill. 2014.
 Burton M, Shaw L, Schentag J, Evans W (eds):
Applied Pharmacokinetics and Pharmacodynamics, 4th edition.
San Francisco, CA. Applied Therapeutics, 2005.
IX. Additional WWW Resouces
