Vanco 2

ASHP REPORT
Therapeutic monitoring of vancomycin for serious

methicillin-resistant Staphylococcus aureus infections:
A revised consensus guideline and review by the American
Society of Health-System Pharmacists, the Infectious Diseases
Society of America, the Pediatric Infectious Diseases Society,
Downloaded from https://academic.oup.com/ajhp/advance-article-abstract/doi/10.1093/ajhp/zxaa036/5810200 by guest on 19 March 2020

and the Society of Infectious Diseases Pharmacists
Supplementary material is
available with the full text of this
T he first consensus guideline for ther-
apeutic monitoring of vancomycin
in adult patients was published in 2009.
Staphylococcus aureus (MRSA) infec-
tions. It should be noted, however, that
when the recommendations were orig-
article at AJHP online.
A committee representing 3 organiza- inally published, there were important
Am J Health-Syst Pharm. 2020; XX:XX-XX tions (the American Society for Health- issues not addressed and gaps in know-
Michael J. Rybak, PharmD, MPH, PhD, FCCP,
System Pharmacists [ASHP], Infectious ledge that could not be covered ade-
FIDP, FIDSA, Anti-Infective Research Laboratory, Diseases Society of America [IDSA], quately because of insufficient data.
Department of Pharmacy Practice, Eugene
Applebaum College of Pharmacy & Health Sciences, and Society for Infectious Diseases In fact, adequate data were not avail-
Wayne State University, Detroit, MI, School of
Medicine, Wayne State University, Detroit, MI, and Pharmacists [SIDP]) searched and re- able to make recommendations in the
Detroit Receiving Hospital, Detroit, MI viewed all relevant peer-reviewed data original guideline for specific dosing
Jennifer Le, PharmD, MAS, FIDSA, FCCP,
FCSHP, BCPS-AQ ID, Skaggs School of Pharmacy on vancomycin as it related to in vitro and monitoring for pediatric patients
and Pharmaceutical Sciences, University of and in vivo pharmacokinetic and phar- outside of the neonatal age group; spe-
California San Diego, La Jolla, CA
Thomas P. Lodise, PharmD, PhD, Albany College macodynamic (PK/PD) characteristics, cific recommendations for vancomycin
of Pharmacy and Health Sciences, Albany, NY, and including information on clinical effi- dosage adjustment and monitoring
Albany Medical Center Hospital, Albany, NY
Donald P. Levine, MD, FACP, FIDSA, School of cacy, toxicity, and vancomycin resistance in the morbidly obese patient popu-
Medicine, Wayne State University, Detroit, MI, and in relation to serum drug concentration lation and patients with renal failure,
Detroit Receiving Hospital, Detroit, MI
John S. Bradley, MD, JSB, FIDSA, FAAP, and monitoring. The data were summar- including specific dialysis dosage ad-
FPIDS, Department of Pediatrics, Division of ized, and specific dosing and monitoring justments; recommendations for the
Infectious Diseases, University of California at San
Diego, La Jolla, CA, and Rady Children’s Hospital recommendations were made. The pri- use of prolonged or continuous in-
San Diego, San Diego, CA
Catherine Liu, MD, FIDSA, Division of Allergy and
mary recommendations consisted of fusion (CI) vancomycin therapy; and
Infectious Diseases, University of Washington, Seattle, eliminating routine monitoring of serum safety data on the use of dosages that
WA, and Vaccine and Infectious Disease Division, Fred
Hutchinson Cancer Research Center, Seattle, WA peak concentrations, emphasizing a ratio exceed 3 g per day. In addition, there
Bruce A. Mueller, PharmD, FCCP, FASN, FNKF, of area under the curve over 24 hours were minimal to no data on the safety
University of Michigan College of Pharmacy, Ann
Arbor, MI to minimum inhibitory concentration and efficacy of targeted trough concen-
Manjunath P. Pai, PharmD, FCCP, University of (AUC/MIC) of ≥400 as the primary PK/ trations of 15 to 20 mg/L.
Michigan College of Pharmacy, Ann Arbor, MI
Annie Wong-Beringer, PharmD, FCCP, FIDSA,
PD predictor of vancomycin activity, and This consensus revision evaluates
University of Southern California School of promoting serum trough concentrations the current scientific data and contro-
Pharmacy, Los Angeles, CA
John C. Rotschafer, PharmD, FCCP, University
of 15 to 20 mg/L as a surrogate marker versies associated with vancomycin
of Minnesota College of Pharmacy, Minneapolis, MN for the optimal vancomycin AUC/MIC dosing and serum concentration moni-
Keith A. Rodvold, PharmD, FCCP, FIDSA,
University of Illinois College of Pharmacy, Chicago, IL
if the MIC was ≤1 mg/L in patients with toring for serious MRSA infections (in-
Holly D. Maples, PharmD, University of Arkansas normal renal function. The guideline also cluding but not limited to bacteremia,
for Medical Sciences College of Pharmacy &
Arkansas Children’s Hospital, Little Rock, AR
recommended, albeit with limited data sepsis, infective endocarditis, pneu-
Benjamin M. Lomaestro, PharmD, Albany support, that actual body weight be used monia, osteomyelitis, and meningitis)
Medical Center Hospital, Albany, NY
to determine the vancomycin dosage and and provides new recommendations
Address correspondence to Dr. Rybak loading doses for severe infections in pa- based on recent available evidence.
([email protected]).
tients who were seriously ill.1 Due to a lack of data to guide appro-
Keywords: nephrotoxicity,
pharmacokinetics and pharmacodynamics, Since those recommendations were priate targets, the development of this
target attainment, vancomycin, vancomycin generated, a number of publications guideline excluded evaluation of van-
consensus guideline
have evaluated the impact of the 2009 comycin for methicillin-susceptible
© American Society of Health-System guidelines on clinical efficacy and tox- S. aureus (MSSA) strains, coagulase-
Pharmacists 2020. All rights reserved.
For permissions, please e-mail: journals. icity in patients receiving vancomycin negative staphylococci, and other
[email protected]. for the treatment of methicillin-resistant pathogens; thus, the extrapolation of
DOI 10.1093/ajhp/zxaa036
AM J HEALTH-SYST PHARM | VOLUME XX | NUMBER XX | XXXX XX, 2020 1

ASHP REPORT GUIDELINE ON VANCOMYCIN MONITORING
guideline recommendations to these

Table 1. Grading System for Recommendations Based on Quality of
pathogens should be viewed with ex-
Evidencea
treme caution. Furthermore, serious
invasive MRSA infections exclude Category and Grade Definition
nonbacteremic skin and skin structure
Strength of
and urinary tract infections. Since this
recommendation
guideline focuses on optimization of

vancomycin dosing and monitoring, A Good evidence to support a recommendation for or
against use
recommendations on the appropriate-
ness of vancomycin use, combination B Moderate evidence to support a recommendation for
or against use
or alternative antibiotic therapy, and
multiple medical interventions that C Poor evidence to support a recommendation
may be necessary for successful treat- Quality of evidence
ment of invasive MRSA infections are
I Evidence from 1 or more properly randomized con-
beyond the scope of this guideline and trolled trials
will not be presented.
II Evidence from 1 or more well-designed clinical trials,
without randomization; from cohort or case-
controlled analytic studies (preferably from more
Methods
than 1 center); from multiple time-series; or from
These are the consensus state- dramatic results from uncontrolled experiments
ments and guideline of ASHP, IDSA, the III Evidence from opinions of respected authorities,
Pediatric Infectious Diseases Society based on clinical experience, descriptive studies, or
(PIDS), and SIDP. Guideline panel com- reports of expert committees
position consisted of physicians, phar- Adapted from the Canadian Task Force on the Periodic Health Examination.2
a
macists, and a clinical pharmacologist

with expertise in clinical practice and/or
research with vancomycin. Committee Potential limitations of this review MICBMD ratio approximates or exceeds
members were assigned key topics re- included the fact that there are few 400. Furthermore, in vitro data sug-
garding vancomycin dosing and moni- published randomized clinical trials gest that an AUC of <400 potentiates
toring. A draft document addressing of vancomycin dosing and monitoring the emergence of MRSA resistance and
these specific areas was reviewed by all available in the literature. Most pub- vancomycin-intermediate S. aureus
committee members and made avail- lished studies evaluating vancomycin strains.8,9 There are also mounting clin-
able for public comments for 30 days dosing, dosage adjustment, and moni- ical data, albeit mostly retrospective in
through ASHP, IDSA, PIDS, and SIDP. toring were retrospective PK or PD nature, in support of this PK/PD target
The committee then met to review and clinical assessments or retrospective for vancomycin.10-18 A summary of these
revise the document based on the sub- observational studies in patients with investigations and their findings can be
mitted comments, suggestions, and MRSA infections. found in eTable 1.10-17,19-23
recommendations. After careful discus- PK/PD efficacy targets. To
sion and consideration, the document optimize the dosing of any antimicro- Clinical PK/PD Data: Adults
was revised and circulated among the bial agent, a firm understanding of the While an AUC/MICBMD ratio of ≥400
committee and supporting organiza- drug’s exposure-effect and exposure- is currently considered the optimal
tions prior to final approval and publi- toxicity links are required. While a va- PK/PD “efficacy” target, it is important
cation. A search of PubMed and Embase riety of PD indices for vancomycin have to recognize that this target has been
was conducted using the following been suggested, an AUC/MIC ratio of largely derived from retrospective,
search terms: vancomycin, pharmacoki- ≥400 (with the MIC determined by broth single-center, observational studies of
netics, pharmacodynamics, efficacy, re- microdilution [BMD]) is the current ac- patients with MRSA bloodstream infec-
sistance, toxicity, obesity, and pediatrics. cepted critical PK/PD index in light tions.11-17 It is also important to recog-
All relevant and available peer-reviewed of our limited experience and studies nize that most of the landmark clinical
studies in the English-language litera- evaluating AUC/MIC values of <400.1,3-7 studies that established the contem-
ture published from 1958 through 2019 In vitro and in vivo assessments of PK/ porary PK/PD efficacy target relied on
were considered. Studies were rated by PD models applicable to human MRSA simple vancomycin clearance (CL) for-
their quality of evidence, and the subse- infection have found that bactericidal mulas based on daily vancomycin dose
quent recommendations were graded activity (ie, a 1- to 2-log reduction in bac- and estimated renal function to deter-
using the classification schemata de- terial inoculum in the animal model) is mine AUC values.10,11,13 Current evalu-
scribed in Table 1. achieved when the vancomycin AUC/ ation of these data demonstrates that
2 AM J HEALTH-SYST PHARM | VOLUME XX | NUMBER XX | XXXX XX, 2020

GUIDELINE ON VANCOMYCIN MONITORING ASHP REPORT
these CL formulas provide imprecise (bioMérieux USA, Hazelwood, MO) data for a MIC of 2 mg/L are limited, sug-
estimates of the AUC.24-26 This finding method, to arrive at an AUC/MICEtest gesting the need for more studies to ascer-
is not surprising, as there is consid- value.12,14,15 The MICEtest value tends to tain the optimal AUC/MIC target for this
erable interpatient variability in van- be 1.5- to 2-fold higher than the MICBMD MIC value or consideration for the use of
comycin exposure profiles in clinical value; therefore, it is likely that the alternative antibiotics. The currently avail-
practice, and it is not possible to gen- AUC threshold needed for response able data also highlight the critical need
erate valid estimates of exposure vari- from these 3 studies,12,14,15 if calculated for large-scale, multicenter, randomized,

ables in a given individual based on CL using the MICBMD, would align with the vancomycin dose–optimized clinical out-
formulas that are derived from glomer- studies by Lodise et al16 and Casapao comes trials. As data from future prospec-
ular filtration rate estimation equations et al.17 tive, multicenter clinical studies emerge, it
alone.10,11,13 In most cases, the formula- In an effort to surmount the is important that clinicians recognize that
based approach will overestimate van- limitationsassociated with previous our current understanding of the PK/PD
comycin CL by approximately 40% to single-center, retrospective vancomy target associated with maximal effect and
50%.16 cinexposure-response clinical ana- toxicity is subject to change, and this may
While it has been cumbersome to lyses, a multicenter, observational ultimately alter the current way we dose
estimate AUC in the clinical setting prospective study was performed to vancomycin to optimize effect and mini-
in the past, Neely and colleagues24 re- evaluate the relationship between the mize toxicity.
cently demonstrated that Bayesian soft- prespecified day 2 AUC/MIC ratios (ie,
ware programs (refer to Therapeutic AUC/MICEtest of ≥320 and AUC/MICBMD Toxicodynamics: AKI
Monitoring section) can be used to gen- of ≥650) and outcomes in adult pa- A major concern with vancomycin
erate accurate and reliable estimates of tients (n = 265) with MRSA bacteremia. use is the occurrence of AKI. While
the daily AUC values with trough-only In the multivariate analyses, treatment multiple definitions of vancomycin-
PK sampling. However, the accuracy failure rates were not significantly dif- associated AKI have been employed in
of AUC estimation is higher with peak ferent between the prespecified day 2 the literature, most studies defined it
and trough measurements compared AUC/MIC groups. Post hoc global out- as an increase in the serum creatinine
to trough-only PK sampling.24 Using comes analyses suggested that patients (SCr) level of ≥0.5 mg/dL, or a 50% in-
this validated Bayesian method to es- in the 2 lowest AUC exposure quintiles crease from baseline in consecutive
timate the daily AUC in a single-center, (ie, those with an AUC of ≤515 mg·h/L) daily readings, or a decrease in calcu-
retrospective study of patients with experienced the best global outcome lated creatinine CL (CLcr) of 50% from
MRSA bloodstream infections, Lodise (defined as absence of both treatment baseline on 2 consecutive days in the
and colleagues16 found that outcomes failure and acute kidney injury [AKI]). absence of an alternative explanation.1
were maximized when day 1 and day While global outcomes were similar Recently, it has been proposed that a
2 AUC/MICBMD ratios exceeded 521 in the 2 lowest AUC-exposure quin- more sensitive threshold (ie, an increase
and 650, respectively. Employing the tiles, only 20% of the study population in SCr of ≥0.3 mg/dL over a 48-hour pe-
same Bayesian approach to estimate (n = 54) had an AUC of ≤400 mg·h/L, riod) may be considered as an indicator
daily AUC values, Casapao and col- and it is unclear if efficacy outcomes of vancomycin-associated AKI. This
leagues17 also noted that the risk of are maintained at an AUC less than threshold was adopted from the Acute
vancomycin treatment failure among this threshold of 400 mg·h/L.23 Notably, Kidney Injury Network (AKIN) and
patients with MRSA infective endo- the higher AUC value cited above (515 the Kidney Disease: Improving Global
carditis was greatest among those mg·h/L) provides a new index that in- Outcomes (KDIGO) criteria.27-29 The
with an AUC/MICBMD ratio of ≤600 and corporates both efficacy and AKI that incidence of vancomycin-associated
that this exposure-failure relationship is still within the recommended AUC AKI has varied across published
persisted after adjusting for factors range of 400 to 600 mg·h/L (assuming a studies. In a meta-analysis by van Hal
such as intensive care unit (ICU) ad- MIC of 1 mg/L). and colleagues,29 the prevalence of
mission, presence of heteroresistant Collectively, recent studies highlight vancomycin-associated AKI varied
vancomycin-intermediate S. aureus, the importance of generating valid esti- from 5% to 43%. Similarly, a recent
and other comorbidities. In contrast to mates of the AUC values through Bayesian meta-analysis of 13 studies by Sinha
the studies by Lodise et al and Casapao modeling techniques when conducting Ray et al30 reported that the relative
et al, several small-scale, retrospec- vancomycin exposure-outcomes analyses risk of AKI with vancomycin was 2.45
tive clinical evaluations of vancomycin in patients. Current vancomycin exposure- (95% confidence interval, 1.69-3.55),
exposure-response reported lower effectiveness data originated largely from with an attributable risk of 59%. Most
Bayesian-derived thresholds for AUC/ studies of MRSA bacteremia, with some episodes of AKI developed between 4
MIC since the AUC was measured at studies for pneumonia and infective en- and 17 days after initiation of therapy.
steady-state conditions and indexed docarditis and none for osteomyelitis Many patients, especially those who are
to the MIC, as determined by the Etest and meningitis. Furthermore, outcomes critically ill, do not fully recover renal

function after AKI,31 and even mild AKI increased along the day 2 AUC con- (i.v.) contrast dye, and vasopressors
can significantly decrease long-term tinuum in a stepwise manner and that has been shown to increase the risk of
survival rates, increase morbidity, pro- patients with day 2 AUC values of ≥793 nephrotoxicity. Recently, piperacillin/
long hospitalizations, and escalate mg·h/L were at the greatest risk for AKI.23 tazobactam and flucloxacillin have
healthcare costs.22,32 Given the understanding about po- been reported to increase the risk
With any drug, an understanding of tential toxic concentrations, there are for AKI in patients receiving vanco-
its toxicodynamic profile is required for also data to suggest that AUC-guided mycin.39-44 It is unclear if the threshold

optimal dosing. Several studies, largely vancomycin dosing may reduce the oc- for vancomycin-induced AKI varies
retrospective in nature, have attempted currence of vancomycin-associated AKI. according to these covariates, but clin-
to quantify the relationship between In a retrospective, quasi-experimental icians should be mindful of the poten-
vancomycin exposure and probability study of 1,280 hospitalized patients, tial for additional risk when prescribing
of AKI.33,34 Although data are limited, Finch et al20 compared the incidence of vancomycin to patients when these
the collective literature suggests that nephrotoxicity in patients monitored by conditions are present.34,40-50
the risk of AKI increases as a function individualized AUC vs trough concen- Based on the current best avail-
of the trough concentration, espe- tration. AUC-guided dosing was found able evidence, daily vancomycin AUC
cially when maintained above 15 to to be independently associated with a values (assuming a MIC of 1 mg/L)
20 mg/L.29 Similarly, there are recent significant decrease in AKI (odds ratio should be maintained between 400 and
data to suggest that the risk of AKI in- [OR], 0.52; 95% CI, 0.34-0.80; P = 0.003).20 600 mg·h/L to minimize the likelihood
creases along the vancomycin AUC Median Bayesian-estimated AUC was of nephrotoxicity and maximize effi-
continuum, especially when the daily significantly lower with AUC-guided cacy for suspected or definitive serious
AUC exceeds 650 to 1,300 mg·h/L.24,33-35 dosing vs trough monitoring (474 [SD, invasive MRSA infections. Once culture
Furthermore, animal studies corrob- 360-611] mg·h/L vs. 705 [SD, 540-883] results or the clinical presentation rule
orate the finding that increased AUC mg·h/L; P < 0.001). In the prospective out invasive MRSA infection, the em-
rather than trough concentration is a study by Neely et al,22 252 patients were piric use of vancomycin at guideline-
strong predictor of AKI.36,37 monitored via troughs of 10 to 20 mg/L recommended exposures should be
Suzuki et al33 evaluated the mean in year 1 vs Bayesian-estimated AUC de-escalated, either by a decrease in
vancomycin AUC in relation to AKI. values of ≥400 mg·h/L in years 2 and 3 vancomycin exposure or initiation of
Most patients who developed AKI of the investigation. Nephrotoxicity oc- alternative antibiotics. Extrapolation
had AUC values between 600 and 800 curred in 8% of subjects in year 1 and of guideline recommendations to non-
mg·h/L, compared with 400 to 600 in 0% and 2% of subjects in years 2 and invasive MRSA and other pathogens
mg·h/L in those without AKI (P = 0.014). 3, respectively (P = 0.01). The median should be viewed with extreme caution.
Furthermore, Lodise and colleagues34 trough concentration and AUC values
showed that the probability of AKI in- associated with AKI were 15.7 mg/L and Therapeutic Monitoring
creased 2.5-fold among patients with 625 mg·h/L, as compared with values Therapeutic monitoring has cen-
AUC values above 1,300 mg·h/L com- of 8.7 mg/L and 423 mg·h/L in subjects tered on maintaining trough con-
pared with patients with lower values without AKI (P = 0.02).22 centrations between 15 and 20 mg/L
(30.8% vs 13.1%, P = 0.02). Although AUC Collectively, the published clinical for serious infections due to MRSA.
values above 1,300 mg·h/L were associ- exposure-response analyses suggest Previous expert guidelines recom-
ated with a substantial increase in AKI, that a daily AUC of ≥400 is the driver mended monitoring trough concen-
an AUC exposure-response relationship of effectiveness and that the risk of AKI trations as a surrogate marker for the
appeared to exist, and the probability of is related to AUC and trough values. AUC/MIC ratio based on the historical
a nephrotoxic event increased as a func- More importantly, these data provide difficulty in estimating the AUC in clin-
tion of the daily AUC and patient’s body the foundation for the current under- ical practice.1,5 In the past, calculation
weight.38 A study by Zasowski et al21 also standing of the therapeutic window of AUC in clinical practice involved col-
reported a similar relationship between for vancomycin. When evaluating the lection of multiple vancomycin serum
Bayesian-estimated vancomycin AUC toxicodynamics of vancomycin, it is im- concentrations during the same dosing
thresholds and AKI in 323 patients; AUC portant to recognize other factors that interval, with subsequent use of PK
values of ≥1,218 mg·h/L for 0 to 48 hours, may complicate or exacerbate the risk software that was not readily available
≥677 for 0 to 24 hours, and ≥683 for 24 of AKI. Host-related factors associated at all institutions. As such, the guide-
to 48 hours or troughs of ≥18.2 mg/L with nephrotoxicity include increased line viewed trough-directed dosing as a
were associated with a 3- to 4-fold in- weight, pre-existing renal dysfunc- more practical alternative to AUC/MIC-
creased risk of nephrotoxicity. Similarly, tion, and critical illness. Concurrent guided dosing in clinical practice.
the aforementioned multicenter, pro- administration of nephrotoxic agents Although the recommendation
spective study of patients with MRSA such as aminoglycosides, loop di to maintain trough values between
bloodstream infections found that AKI uretics, amphotericin B, intravenous 15 and 20 mg/L for serious infections

due to MRSA has been well integrated First, the range of vancomycin MIC based on the way the drug behaved
into practice, the clinical benefits values among contemporary MRSA in a population of prior patients
of maintaining higher vancomycin isolates is narrow, and the BMD MIC90 (the Bayesian prior) and the revised
trough values have not been well docu- in most institutions is 1 mg/L or less.58-62 probability distribution of a specific
mented.38,51-55 From a PK/PD perspec- Second, measurement of MIC values is patient’s PK parameter values using
tive, it is not surprising that there are imprecise, with dilution of ±1 log2 and exact dosing and drug concentration
limited clinical data to support the variation of 10% to 20% considered ac- data (the Bayesian conditional poste-

range of 15 to 20 mg/L. Recent studies ceptable; therefore, the variability of rior). In short, Bayesian dose optimi-
have demonstrated that trough values reported MIC values encountered in zation software uses a well-developed
may not be an optimal surrogate for routine clinical practice is likely to re- vancomycin population PK model as
AUC values.26,56,57 While trough attain- flect measurement error.63 Third, there the Bayesian prior, together with the
ment ensures achievement of a min- is a high degree of variability between individual patient’s observed drug
imum cumulative exposure, a wide commercially available MIC testing concentrations in the data file, to cal-
range of concentration-time profiles methods relative to the BMD method culate a Bayesian posterior parameter
can result in an identical trough value. (see Vancomycin Susceptibility Testing value distribution for that patient.
Patel et al26 reported a wide range of section). Last, MIC results are typically The dose optimization software then
AUC values from several different not available within the first 72 hours calculates the optimal dosing reg-
dosing regimens yielding similar trough of index culture collection, yet cur- imen based on the specific patient’s
values. The therapeutic discordance rent data indicate that the vancomycin profile.65-67
between trough and AUC values is not AUC/MIC ratio needs to be optimized An advantage of the Bayesian ap-
surprising, as the AUC is the integrated early in the course of infection. proach is that vancomycin concentra-
quantity of cumulative drug exposure Daily AUC values (assuming a tions can be collected within the first 24
(ie, the serum drug concentration–time MICBMD of 1 mg/L) should be main- to 48 hours rather than at steady-state
curve over a defined interval). In con- tained between 400 and 600 mg·h/L conditions (after the third or fourth
trast, the trough represents a single ex- to maximize efficacy and minimize dose), and this information can be used
posure point at the end of the dosing the likelihood of AKI. In the past, AUC to inform subsequent dosing (adap-
interval. In clinical practice, monitoring monitoring required the collection of tive feedback control). As part of their
of trough concentrations will translate multiple concentrations over the same output, Bayesian dosing programs pro-
into achievement of one specific min- dosing interval. With these data, a clini- vide innovative treatment schemes,
imum daily AUC value, whereas the cian would calculate the AUC using the such as front-loading doses with subse-
24-hour AUC (AUC24) largely represents linear-trapezoid rule. This approach quent transition to a lower maintenance
the average concentration during that required precise collection of vanco- dosing regimen, to rapidly achieve
time period [AUC24 (mg·h/L) = average mycin concentrations, making it largely target concentrations within the first 24
concentration (mg/L) x 24 (hours)]. For impractical outside of a research set- to 48 hours among critically ill patients.
troughs of 15 to 20 mg/L, this typically ting. However, this is no longer the case. The Bayesian approach also provides
equates to a daily AUC in excess of 400 It is now possible to accurately estimate the ability to integrate covariates, such
mg·h/L. However, there is considerable the AUC with limited PK sampling. as CLcr, in the structural PK models (the
variability in the upper range of AUC One such approach involves the use Bayesian prior density file) that account
values associated with a given trough of Bayesian software programs to esti- for the pathophysiological changes that
value. Although trough-only moni- mate the vancomycin AUC value with readily occur in critically ill patients.
toring is practical, the potential limita- minimal PK sampling (ie, 1 or 2 van- Incorporation of covariates that account
tions surrounding the practice suggest comycin concentrations) and provide for these “dynamic” changes serves
that trough monitoring may be insuffi- AUC-guided dosing recommendations as a way to identify dosing schemes
cient to guide vancomycin dosing in all in real time. An alternative approach that optimize effect and predict future
patients. involves use of 2 concentrations (peak dosing in a patient who has an evolving
Although the AUC/MIC ratio is con- and trough) and simple analytic PK PK profile.67
sidered the PK/PD driver of efficacy for equations to estimate AUC values.57,64 Bayesian dose-optimizing software
vancomycin, clinicians trying to opti- Bayesian-derived AUC moni- programs are now readily available and
mize vancomycin treatment for patients toring. Bayesian-guided dosing is can be used in real time to identify the
with serious MRSA infections may be based in part on Bayes’ Theorem, as it optimal vancomycin dosage that readily
best advised to use AUC-guided dosing quantifies the sequential relationship achieves the AUC target (assuming
and assume a MICBMD of 1 mg/L (unless between the estimated probability a MICBMD of 1 mg/L).66,68 Bayesian
it is known, through BMD, to be greater distribution of an individual patient’s programs offer numerous advantages
or less than 1 mg/L). The MIC value is PK parameter values (eg, volume [Vd] over the traditional first-order equa-
of less importance for several reasons. or CL) prior to administering the drug tion software programs. Using richly

sampled vancomycin PK data from proportional changes in observed the dosing interval (ie, 12 vs 24 hours)
3 studies comprising 47 adults with AUC24.6,71-73 The major limitation of this than steady-state conditions. Given
varying renal function, Neely and col- approach is that it is not adaptive like the importance of early, appropriate
leagues24 demonstrated that Bayesian the Bayesian approach, as it can only therapy,74 targeted AUC exposures
software programs, embedded with a provide a snapshot of the AUC for the should be achieved early during the
PK model based on richly sampled van- sampling period. As such, this AUC cal- course of therapy, preferably within
comycin data as the Bayesian prior, can culation will not be correct if a physio- the first 24 to 48 hours. If monitoring

be used to generate accurate and reli- logic change such as renal dysfunction is initiated after the first dose, the con-
able estimates of the daily AUC values occurs during or after the sampling tribution of the loading dose to the
with trough-only PK sampling. Of note, period. Furthermore, it is extremely dif- actual AUC may vary depending on
there was limited inclusion of special ficult to estimate the vancomycin AUC24 the magnitude of the loading dose vs
populations in this study, and it is un- with the equation-based method in pa- maintenance doses. The decision to
clear if this trough-only Bayesian AUC tients who receive multiple dosing re- delay therapeutic monitoring beyond
estimation approach can be applied gimens within a 24-hour period. If the 48 hours should be based on severity of
to obese patients, critically ill patients, vancomycin dosing interval is more infection and clinical judgment.
pediatric patients, and patients with frequent than once a day, the AUC24 will
unstable renal function. A random- be a function of the number of identical Summary and
ized controlled study of 65 subjects by doses administered during that interval recommendations:
Al-Sulaiti et al69 showed that estimating (eg, AUC must be multiplied by 2 for a
AUC using both peak and trough con- 12-hour dosing interval to calculate the 1. In patients with suspected or definitive
centrations (vs trough-only estimates) true AUC24). It is also highly preferred serious MRSA infections, an individu-
may improve vancomycin-associated that concentrations are collected near alized target of the AUC/MICBMD ratio
therapeutic cure. Until more data are steady-state conditions. of 400 to 600 (assuming a vancomycin
available, it is preferred to estimate the Despite its drawbacks, this es- MICBMD of 1 mg/L) should be advo-
Bayesian AUC using 2 vancomycin con- timate of AUC is a clear step above cated to achieve clinical efficacy while
centrations (peak and trough). trough-only or peak-only concentra- improving patient safety (A-II). Doses
First-order PK analytic equation interpretation and is familiar to of 15 to 20 mg/kg (based on actual
tions. Alternatively, the AUC can be most clinicians. Several large medical body weight) administered every 8 to
accurately estimated based on the col- centers within the United States have 12 hours as an intermittent infusion
lection of 2 timed steady-state serum already adopted this approach of ac- are recommended for most patients
vancomycin concentrations and the quiring 2 postdose serum concentra- with normal renal function when as-
use of first-order PK equations.57 The tion estimates of the AUC to perform suming a MICBMD of 1 mg/L (A-II). In
equations used to compute AUC from 2 routine vancomycin dosing and moni- patients with normal renal function,
samples are based in part on an original toring and have demonstrated a con- these doses may not achieve the thera-
approach proposed by Begg, Barclay, siderable improvement in safety over peutic AUC/MIC target when the MIC
and Duffull70 for aminoglycosides the current trough-only concentration is 2 mg/L.
and modified by Pai and Rodvold.57 It monitoring method.37,64 2. Given the narrow vancomycin AUC
is preferred that a near steady-state, PK sampling time. Timing of range for therapeutic effect and
postdistributional peak (1 to 2 hours achievement of targeted AUC values minimal AKI risk, the most accurate
after end of infusion) and trough con- (assuming a MICBMD of 1 mg/L) re- and optimal way to manage van-
centrations within the same dosing mains unclear. The early AUC/MIC comycin dosing should be through
interval (if possible) are used when target ratios derived in animal models AUC-guided dosing and monitoring
estimating the AUC with the equation- were based on the AUC value from 0 to (A-II). We recommend to accomplish
based methods. 24 hours.3,4 More recent clinical assess- this in one of two ways.
The major advantage of this ap- ments that identified a link between a. One approach relies on the collec-
proach is that it is simpler and re- AUC/MIC ratio and outcomes also as- tion of 2 concentrations (obtained
lies on fewer assumptions than the sessed the AUC values achieved early near steady-state, postdistributional
Bayesian approach. The first-order PK in the course of therapy.1,3,5-7,10,13,20-22 The peak concentration [Cmax] at 1 to
equations used to estimate the AUC 2009 vancomycin guideline stated that 2 hours after infusion and trough
are also familiar to most clinicians, the trough should be assessed prior concentration [Cmin] at the end of
facilitating ease of use in practice. to steady-state conditions (ie, prior to the dosing interval), preferably but
Once the AUC24 is estimated, the clini- the fourth dose).1,5 In fact, steady-state not required during the same dosing
cian simply revises the total daily dose conditions are difficult to determine interval (if possible) and utilizing
to achieve the desired AUC24, as alter- in clinical practice, and the timing of first-order PK equations to estimate
ations of total daily dose will provide the fourth dose is more dependent on the AUC (A-II).

b. The preferred approach to monitor MICBMD of 1 mg/L unless it is known variability in MIC results between the
AUC involves the use of Bayesian to be greater or less than 1 mg/L susceptibility testing methods.
software programs, embedded with by BMD). Independent of MRSA The challenge is that, according
a PK model based on richly sampled infection, vancomycin monitoring to the Clinical Laboratory Standards
vancomycin data as the Bayesian is also recommended for all pa- Institute (CLSI), acceptable variability
prior, to optimize the delivery of tients at high risk for nephrotoxicity for MIC measurement methods is within
vancomycin based on the collection (eg, critically ill patients receiving ±1 doubling dilution (essential agree-

of 1 or 2 vancomycin concentrations, concurrent nephrotoxins), patients ment), such that current susceptibility
with at least 1 trough. It is preferred with unstable (ie, deteriorating or testing methods are unable, with high
to obtain 2 PK samples (ie, at 1 to 2 significantly improving) renal func- reproducibility, to distinguish MICs
hours post infusion and at end of the tion, and those receiving prolonged of 1 mg/L from MICs of 0.5 mg/L or
dosing interval) to estimate the AUC courses of therapy (more than 3 to 2 mg/L. Most institutions routinely
with the Bayesian approach (A-II). 5 days). We suggest the frequency perform MIC testing using automa
A trough concentration alone may of monitoring be based on clinical ted systems: BD Phoenix (BD, Franklin
be sufficient to estimate the AUC judgment; frequent or daily moni- Lakes, NJ), MicroScan WalkAway
with the Bayesian approach in some toring may be prudent for hemo- (Beckman Coulter, Brea, CA), or Vitek
patients, but more data are needed dynamically unstable patients (eg, 2 (bioMérieux), and in some cases the
across different patient populations those with end-stage renal disease), Etest methodology (bioMérieux). In a
to confirm the viability of using with once-weekly monitoring for study of 161 MRSA blood isolates, when
trough-only data (B-II). hemodynamically stable patients using the essential agreement defini-
3. When transitioning to AUC/MIC (B-II). tion of ±1 log2 dilution error, Vitek 2 and
monitoring, clinicians should con- MicroScan WalkAway demonstrated a
servatively target AUC values for 96.3% agreement with BMD, whereas
patients with suspected or docu- Vancomycin Susceptibility BD Phoenix demonstrated an 88.8%
mented serious infections due to Testing agreement.77 The Etest method had the
MRSA assuming a vancomycin With the MIC being a component lowest agreement with BMD, at 76.4%
MICBMD of 1 mg/L or less at most of the vancomycin AUC/MIC targeted (results were consistently higher by 1
institutions. Given the importance of surrogate for efficacy, it is important to 2 dilutions). The Etest will likely pro-
early, appropriate therapy, vanco- to be aware of local and national van- duce a higher value (0.5 to 2 dilutions
mycin targeted exposure should be comycin susceptibility patterns for higher) than BMD. In another study,
achieved early during the course of MRSA. Although in some centers there 92% of the strains were demonstrated
therapy, preferably within the first 24 has been a steady increase in the av- to have a vancomycin MIC of 1 mg/L by
to 48 hours (A-II). As such, the use of erage vancomycin MIC over several BMD; corresponding figures were 70%
Bayesian-derived AUC monitoring decades, recent national and inter- for MicroScan WalkAway and Etest and
may be prudent in these cases since it national studies that have evaluated 41% for Vitek 1.78
does not require steady-state serum MRSA susceptibility to glycopeptides, Rybak et al79 compared MicroScan
vancomycin concentrations to allow lipopeptides, and beta-lactams have WalkAway, Vitek 2, BD Phoenix, and
for early assessment of AUC target demonstrated that vancomycin MICs Etest to BMD methods among 200
attainment. have remained constant over time, with MRSA strains. In contrast to previous
4. Trough-only monitoring, with a a MIC of ≤1 mg/L demonstrated for studies, these investigators used an
target of 15 to 20 mg/L, is no longer more than 90% of isolates.58-62 A meta- absolute agreement definition of ±0
recommended based on efficacy analysis of 29,234 MRSA strains from log2 dilution error to better charac-
and nephrotoxicity data in patients 55 studies revealed that the MIC deter- terize the precision. Using this def-
with serious infections due to MRSA minations performed by BMD, Etest, inition, results with BD Phoenix
(A-II). There is insufficient evidence and automated systems were predomi- and MicroScan WalkAway had the
to provide recommendations on nately 1 mg/L and that there was no ev- highest agreement with BMD (66.2%
whether trough-only or AUC-guided idence of a MIC creep phenomenon.75 and 61.8%, respectively), followed
vancomycin monitoring should be Furthermore, a global surveillance pro- by Vitek 2 (54.3%). As noted above,
used among patients with noninva- gram reported that 95% of 57,319 MRSA Etest tended to produce results that
sive MRSA or other infections. isolates had MICs of 1 mg/L, with no were 1 to 2 dilutions higher (agree-
5. Vancomycin monitoring is re- signs of MIC creep over 20 years.76 ment with BMD was 36.7%). However,
commended for patients receiving While there does not seem to be a large when compared to BMD, Etest identi-
vancomycin for serious MRSA number of organisms with a vanco- fied a MIC of 2 mg/L 80% of the time.
infections to achieve sustained mycin MIC of ≥2 mg/L when reference When compared to BMD, Micro
targeted AUC values (assuming a methods are used, there is considerable Scan WalkAway (prompt method)

overcalled MIC values of 1 mg/L by the lack of precision and variability vancomycin CI (n = 61) and II (n = 58)
74.1%, and BD Phoenix and Vitek 2 in MIC results depending on method in 119 patients. Most patients had
undercalled MIC values of 2 mg/L by used (B-II). pneumonia or bacteremia, mostly due
76% and 20%, respectively. to MRSA. Mean serum steady-state and
The high variability of MIC results trough concentrations attained were
among the 4 systems compared to Continuous Infusion vs 24 mg/L and 15 mg/L, respectively,
BMD clearly poses a challenge to the Intermittent Infusion for both the CI and II groups. AUC24

clinician making treatment decisions Administration of vancomycin by values were comparable between the
based on MIC and poses questions as continuous infusion (CI) has been CI and II groups, with significantly less
to the most relevant MIC method.79 evaluated as an alternative to intermit- variability in the CI group (P = 0.026).
This variability between MIC values tent infusion (II) with potential advan- Clinical failure rates were similar in
and testing methods routinely per- tages of earlier target attainment, less the CI and II groups on day 10 (21% vs
formed at most institutions further variability in serum concentrations, 26%) and at end of treatment (21% vs
supports the use of AUC (assuming ease of drug level monitoring (less de- 19%), although the mean AUC24 was
a MICBMD of 1 mg/L) to guide vanco- pendence on sampling time or multiple shown to be lower in the CI group than
mycin empiric dosing. For nonserious concentrations to calculate AUC), and in the II group (596 [SD, 159] mg·h/L
infections, this variability may be in- lower the potential risk of AKI. vs 685 [SD, 260] mg·h/L, P < 0.05).
consequential. In a critically ill patient Comparative studies. Published Nephrotoxicity occurred in 18% of pa-
infected by MRSA, who may require studies that compared intermittent to tients overall, with similar rates in the
prompt achievement of the target continuous administration primarily CI and II groups (16% vs 19%). However,
AUC/MIC, it is imperative to verify focused on 2 distinct populations, adult dialysis was required more often in
the MIC by a standardized method critically ill patients in the ICU with sus- those who received CI vs II (6 of 10 pa-
(preferably BMD, as Etest may result pected or documented infections and tients vs 3 of 11 patients). Risk factors
in a higher MIC than BMD) as soon those receiving outpatient antimicro- for nephrotoxicity such as diabetes and
as possible to avoid a delay in effec- bial therapy (OPAT) for bone and joint concomitant diuretic, aminoglycoside,
tive therapy. An AUC/MICBMD of 400 infections.80-89 Most studies compared and iodine use were similar between
to 600 is approximately equivalent CI to II for the risk of AKI and attain- groups. It is notable that the study only
to an AUC/MICEtest of 200 to 400, re- ment of target serum concentrations; had 23% power to detect a difference in
flecting values that are 1 to 2 dilutions only 4 studies included other outcome clinical outcomes between groups.1
higher than those yielded by Etest. endpoints such as treatment failure and Another study compared mor-
Furthermore, there are no data to sup- mortality.80,84,87,89 Measures of vanco- tality among critically ill burn patients
port decreasing the dose to achieve mycin drug exposure reported in clin- receiving CI (n = 90) or II (n = 81).84
the targeted AUC/MIC of 400 to 600 if ical trials include trough and average Mortality rates in the hospital and on
the MIC is less than 1 mg/L. steady-state concentrations and AUC24. days 14 and 28 were numerically higher
One challenge when comparing clin- for those receiving CI, but the differ-
Summary and ical outcomes between CI and II is the ences did not reach statistical signifi-
recommendations: lack of consistent reporting of exposure cance (10% vs 6.2%, 18.9% vs 11%, and
parameters between groups treated 32% vs 21%, respectively). However,
6. Based on current national vancomycin using the 2 dosing strategies. For CI, when mortality was compared by treat-
susceptibility surveillance data, the most commonly reported drug ex- ment indications, those who received
under most circumstances of empiric posure parameter was the steady-state CI for non–gram-positive sepsis had
dosing, the vancomycin MIC should concentration, while for II it was the significantly higher mortality (70% vs
be assumed to be 1 mg/L. When the trough concentration. For future inves- 16.7%, P = 0.001); nearly half of this sub-
MICBMD is >1 mg/L, the probability of tigations it would be beneficial to report group had gram-negative bacteremia or
achieving an AUC/MIC target of ≥400 AUC and/or average steady-state con- candidemia. It is possible that the dif-
is low with conventional dosing; centration for both CI and II groups to ference in outcome may be attributed to
higher doses may risk unnecessary enable direct comparison of drug expo- differences in the management of those
toxicity, and the decision to change sure between groups and correlate with infections and not directly related to van-
therapy should be based on clinical efficacy and safety endpoints. comycin administration. Nephrotoxicity
judgment. In addition, when the Critically ill patients. A total of occurred numerically less frequently in
MICBMD is <1 mg/L, we do not recom- 7 studies compared CI vs II of vanco- the CI group than in the II group (per-
mend decreasing the dose to achieve mycin in critically ill patients.81-87 Only centage of patients with increase in Scr
the AUC/MIC target. It is important to one study, by Wysocki et al,80 evalu- of 0.5 mg/dL at end of therapy, 6.7% vs
note the limitations in automated sus- ated both efficacy and safety in a pro- 14.8%). While higher mean vancomycin
ceptibility testing methods, including spective randomized trial comparing concentrations were noted in the CI

group relative to the II group (20 [SD, 3.8] 1-mg/L increase in serum concentra- of 80 patients, a trend towards less fre-
mg/L vs 14.8 [SD, 4.4] mg/L, P < 0.001), tion was associated with an 11% increase quent occurrence of nephrotoxicity was
which would be expected when com- in the risk of nephrotoxicity, with lower observed in the CI group vs the II group
paring steady-state and trough concen- odds in those receiving II. However, lo- (10% vs 25%, P = 0.139), and when neph-
trations, AUC24 was not reported, thereby gistic regression analysis indicated the rotoxicity did occur it had a later onset
precluding comparison of drug exposure contrary in that II was associated with in the CI group (P = 0.036).88 Patients
between the CI and II groups. an 8-fold higher odds of nephrotoxicity were matched by age, comorbid condi-

Five other studies compared serum (95% confidence interval, 2.87-23.41). tions, gender, baseline Scr, and receipt
drug concentrations achieved and the The lack of information provided on of concurrent nephrotoxins; those who
risk of nephrotoxicity between CI and confounding variables such as receipt of had an Scr of ≥1.5 mg/dL at baseline,
II in critically ill patients.81-83,85,86 As ex- concomitant nephrotoxins and relative developed nephrotoxicity as inpatients
pected, the ranges of measured vanco- AUCs between treatment groups pre- prior to OPAT, or experienced hypo-
mycin concentrations from the studies clude drawing a definitive conclusion tension resulting in renal dysfunction
were significantly higher in the CI groups regarding the safety of CI, especially in were excluded. In another retrospective
than in the II groups (steady-state con- light of the disparate results of bivariate study,90 the same investigators identified
centrations of 20-25 mg/L vs troughs and logistic regression analyses. a steady-state average concentration of
of 10-15 mg/L, respectively). Another Patients receiving OPAT. To date 28 mg/L as the threshold breakpoint for
study showed that a higher percentage there have been 2 studies comparing the development of nephrotoxicity using
of patients attained a vancomycin con- the efficacy of vancomycin adminis- CART (classification and regression
centration of >20 mg/L at least once tration by CI vs II in patients whose tree) analysis: Nephrotoxicity occurred
during the treatment course with CI therapy was initiated in the hospital and in 71.4% (5 of 7) and 11.6% (11 of 95) pa-
vs II administration (63.2% vs 44.9%, continued as OPAT. Duration of therapy tients with steady-state concentrations
P = 0.065).82 One study reported lower ranged from 30 days to 14 weeks.87,89 of ≥28 mg/L and <28 mg/L, respectively.
mean AUC24 with CI vs II (529 [SD, 98] Most patients were treated for bone and In one prospective study of an elderly
mg·h/L vs 612 [SD, 213] mg·h/L, P value joint and skin structure–related infec- cohort (mean age, 70 years) receiving
not stated), and increased steady-state tions. In a small prospective study, rates high-dose vancomycin therapy by CI,
concentration compared with trough of osteomyelitis cure, defined as re- with targeting of a steady-state concen-
(25 ± 4 vs 17 ± 4.7 mg/L, respectively, maining asymptomatic 12 months after tration of 30 to 40 mg/L for a median
P = 0.42) with CI vs. II.83 The discordance completion of therapy, did not differ duration of 6 weeks, nephrotoxicity oc-
observed in the relationship of trough significantly between groups (94% vs curred in 32% of patients. Additionally,
concentration and AUC24 underscores 78%, P = 0.3), but only 27 patients were 4 patients in that study developed
the importance of measuring AUC24 to evaluable.87 Another study retrospec- leukopenia.91
compare relative drug exposure with CI tively evaluated the efficacy of vanco- Dosing and other consider-
vs II in future studies. mycin in patients with MRSA infections; ations for use of CI. Most published
In general, the rate of nephrotoxicity most had bone and joint and skin struc- studies of critically ill patients receiving
was reported to be similar or numeri- ture–related infections, while 10% had vancomycin CI employed a loading
cally lower with CI vs II administration bloodstream infections or endocar- dose of 15 to 20 mg/kg followed by daily
(range, 4%-16% vs 11%-19%); the same ditis.89 Rates of clinical failure were sim- maintenance infusions at doses of 30 to
trend but higher rates were reported in ilar in the CI and II groups (19% [25 of 40 mg/kg (up to 60 mg/kg) to achieve
studies that applied the AKIN criteria for 133 patients] vs 25% [9 of 36], P = 0.41) a target steady-state concentration of
nephrotoxicity (26%-28% vs 35%-37%).81- after excluding 29% of study patients 20 to 25 mg/L. By simply multiplying
83,85,86
In addition, Saugel et al85 noted who had subtherapeutic serum van- the steady-state concentration by 24, a
significantly less frequent need for renal comycin concentrations for more than target steady-state concentration of 20
replacement therapy (RRT) during van- 1 week. However, it is not clear how to 25 mg/L would equate to an AUC24/
comycin treatment for patients in the CI frequent serum concentrations were MIC of 480 to 600 (assuming a MIC of
group than for those in the II group (7% monitored, if in-hospital treatment du- 1 mg/L). Of note, the PK/PD target for
[7 of 94 patients] vs 23% [12 of 52 pa- ration before OPAT differed between CI has not been validated. All of the PK/
tients] required RRT; P = 0.007). Of in- groups, and whether treatment success PD data supporting an AUC24/MIC ratio
terest, in the largest retrospective study rates differed by type of infection. of >400 as the best correlate for clinical
comparing CI and II, conducted in 1,430 In studies that evaluated the safety of outcomes were derived from patients
ICU patients, Hanrahan et al86 reported a CI vancomycin as OPAT, treatment dura- who received II vancomycin dosing.
higher rate of nephrotoxicity in those re- tion ranged from 4 to 14 weeks, with a re- Rapid attainment of target serum
ceiving CI vs II (25% [161 of 653 patients] ported average mean steady-state serum concentrations has been cited as a po-
vs 20% [77 of 390 patients]; P = 0.001); concentration of 13 to 30 mg/L.87,88 In tential advantage of CI over II when
bivariate analysis indicated that every a retrospective matched cohort study treating acute infections, particularly

in ICU patients early during the course 25 mg/L throughout the entire dosing events. An infusion rate of 10 mg/min
of infection. In 2 comparative studies, interval) by a factor of 24. Attaining or less is associated with fewer infusion-
target steady-state concentrations of 20 the desired drug exposure may be related events. Loading doses of 25 to
to 25 mg/L were achieved more rapidly more readily accomplished given the 35 mg/kg will require infusion times of
with use of CI vs II: in a mean time of ease of sampling time and dosage at least 2 to 3 hours.99 After administra-
36 (SD, 31) hours vs 51 (SD, 39) hours adjustment by changing the rate of tion of the loading dose, the initiation of
(P = 0.03) in one study and 16 (SD, infusion, which is a highly desirable the maintenance dose should occur at

8) hours vs 50 (SD, 21) hours (P < 0.001) feature in critically ill patients (B-II). the next dosing interval (eg, an interval
in the other.81,83 Importantly, less var- 8. The risk of developing nephrotoxicity of every 6 hours indicates initiating the
iability in the steady-state concentra- with CI appears to be similar or lower maintenance dose 6 hours after the start
tion and fewer blood samples (a single than that with intermittent dosing of the loading dose).
steady-state concentration vs both when targeting a steady-state concen- In most studies that have employed
peak and trough concentrations) are tration of 15 to 25 mg/L and a trough loading doses, vancomycin dosing was
required to calculate AUC24 among pa- concentration of 10 to 20 mg/L (B-II). based on actual body weight. While
tients receiving CI vs II. Timing of blood Definitive studies are needed to com- this practice is commonplace, dosing
sampling for trough determinations pare drug exposure based on meas- by actual body weight assumes there
is critical during II, whereas steady- ured AUC24 and factors that predispose is a linear relationship between key
state concentration can be measured to development of nephrotoxicity, such population PK parameters (ie, Vd and
any time after steady state has been as receipt of concomitant nephro- clearance) and the body size descriptor
reached during CI. In addition, vanco- toxins, diuretics, and/or vasopressor employed. While a wide variety of ac-
mycin administration by CI in patients therapy in patients receiving CI vs II of tual weight–based estimates of Vd (for
receiving OPAT has the theoretical ad- vancomycin. example, 0.4 to 1 L/kg) have been re-
vantage of a need for less frequent ac- 9. Incompatibility of vancomycin ported in the literature,6 mounting
cess to the i.v. catheter and thus less with other drugs commonly data suggest that it is not entirely ac-
complications resulting from thrombus coadministered in the ICU requires curate to describe vancomycin Vd as
formation or infections. On the other the use of independent lines or mul- being proportional to body weight,
hand, incompatibility of vancomycin tiple catheters when vancomycin is particularly among obese patients
with certain drugs (particularly at high being considered for CI (A-III). (refer to Dosing in Obesity section).
concentrations), that are commonly As noted in several recent articles dis-
administered in the critical care setting cussing vancomycin PK in obesity, as
is a notable challenge of vancomycin Loading Doses weight increases the coefficient used
CI.92,93 The use of proper concentration, Loading doses of vancomycin have to calculate Vd decreases.48,110,111 At this
alternative agents, independent lines, been evaluated in several studies during point, dosing should be based on ac-
or multiple catheters may be warranted the past decade.94-109 Providing loading tual body weight, with doses capped
if vancomycin is to be administered by doses of 20 to 35 mg/kg based on ac- at 3,000 mg (refer to Dosing in Obesity
CI. tual body weight rapidly achieves tar- section.112 More intensive therapeutic
geted ranges of serum vancomycin monitoring should also be performed
Summary and concentrations and decreases the risk of in obese patients.
recommendations: subtherapeutic concentrations during
the first days of therapy. Loading doses are Summary and
7. The pharmacokinetics of CI suggest recommended in patients who are criti- recommendations:
that such regimens may be a reason- cally ill or in the ICU,95-102 require dialysis
able alternative to conventional II or renal replacement therapy,102-106 or are 10. In order to achieve rapid attain-
dosing when the AUC target cannot receiving vancomycin CI therapy.94-98,105,108 ment of targeted concentrations in
be achieved (B-II). Based on cur- While this approach is not currently sup- critically ill patients with suspected
rently available data, a loading dose ported by evidence from large random- or documented serious MRSA in-
of 15 to 20 mg/kg, followed by daily ized clinical trials, vancomycin loading fections, a loading dose of 20 to
maintenance CI of 30 to 40 mg/kg doses can be considered in the treatment 35 mg/kg can be considered for
(up to 60 mg/kg) to achieve a target of serious MRSA infections. Vancomycin intermittent-infusion administration
steady-state concentration of 20 to should be administered in a dilute solu- of vancomycin (B-II).1
25 mg/L may be considered for crit- tion (eg, concentrations of no more than 11. Loading doses should be based on
ically ill patients (B-II). AUC24 can 5 mg/mL) and infused over a period of actual body weight and not exceed
be simply calculated by multiplying not less than 60 minutes or at a rate of 3,000 mg (refer to Dosing in Obesity
the steady-state concentration (ie, 10 to 15 mg/min (≥1 hour per 1,000 mg) section). More intensive and early
the desired therapeutic range of 20 to to minimize infusion-related adverse therapeutic monitoring should

also be performed in obese patients tendency estimates approaching 75 L approaches to estimating vancomycin
(B-II). are observed in obese adults.112,120,121 CL, such as that defined by Rodvold
The nonlinear relationship between and colleagues,125 can be used to esti-
vancomycin Vd and body weight can be mate the total daily maintenance dose.
Dosing in Obesity resolved with piecewise functions of al- The population model–estimated van-
The original vancomycin dosing ternate weight descriptors, allometric comycin CL multiplied by the target
strategies predate our current defin- scaling, use of lower mg/kg doses with AUC estimates the initial daily main-

itions of obesity and understanding increasing body size, or capping the tenance dose.112,120,122 For example,
of drug pharmacokinetics in obesity. dose at a threshold.118,122 The underlying studies report an average vancomycin
Obesity is defined as a body mass index rationale for a loading dose is rapid at- CL of approximately 6 L/h in obese
(BMI) of ≥30 kg/m2 and is currently tainment of therapeutic concentra- patients that equates to achieving an
divided into 3 tiers: class I obesity tions. Therefore, using actual body AUC of approximately 500 mg·h/L with
(30.0-34.9 kg/m2), class II obesity (35.0- weight–based loading doses of 20 to a daily dose of 3,000 mg. Empiric van-
39.9 kg/m2), and class III, or morbid, 25 mg/kg (doses lower than previously comycin maintenance dosages above
obesity (≥40 kg/m2).113 The prevalence recommended), with consideration of 4,500 mg/day are not expected in obese
of obesity increased from approxi- capping doses at 3,000 mg, is the most adults, because vancomycin CL rarely
mately 10% in the 1950s to 39.8% in practical strategy in obese patients exceeds 9 L/h.112,120,121
2015-2016, and the average US adult with serious infections.112 For example, Population PK models of vanco-
weighs approximately 83 kg, compared this strategy would result in calculated mycin cannot account for more than
to the historical standard of 70 kg.114,115 loading doses of 1,500 to 2,500 mg in 50% of the interindividual variabili
This shift in the distribution of body patients weighing 80 to 99 kg, 2,000 ty, which supports therapeutic drug

size is relevant to the calculation of to 3,000 mg in those weighing 100 to monitoring (TDM) in this popula-
vancomycin doses based on patient 119 kg, and 2,500 to 3,000 mg in pa- tion.117,118,120,122 A reliable estimate of
body weight. Obesity may be associated tients with a weight of ≥120 kg (doses vancomycin Vd is necessary for AUC
with an increased risk of vancomycin- rounded to the nearest 250 mg). The estimation when AUC is based solely
induced nephrotoxicity, in part due to decision of whether or not to employ a on a trough concentration measure-
supratherapeutic exposure resulting loading dose, as well as the magnitude ment.24,121,126,127 This bias is addressed
from maintenance doses calculated of this dose, should be driven by the and precision is improved by meas-
using actual body weight.45,116 severity of infection and the urgency urement of both a peak (collected
The selection of vancomycin to achieve a therapeutic concentration at least 1 hour after the end of infu-
loading dose is dependent on the es- rather than by body size alone. sion) and a trough concentration to
timated Vd. Pharmacokinetic studies Empiric maintenance dosing of estimate AUC accurately in obese
have repeatedly demonstrated that the vancomycin is reliant on estimated CL. patients.126 Once a reliable PK es-
vancomycin Vd increases with actual Vancomycin CL is predicted by kidney timate of vancomycin elimination
body weight; however, this PK param- function, which is most commonly is determined by using these 2 con-
eter does not increase with actual body estimated as CLcr with the Cockcroft- centration measurements, subsequent
weight in a proportionate manner and Gault equation using patient age, sex, vancomycin AUC estimation is achiev-
is not reliably predictable in obese indi- Scr, and body size.123 There is considerable with trough-only measurements
viduals.111,117-121 Blouin and colleagues111 able controversy regarding the optimal by Bayesian methods in physiologically
demonstrated a statistically significant body size metric for this calculation in stable patients.57 For critically ill obese
difference in weight-indexed Vd be- obese patients.124 The Cockcroft-Gault patients with unstable physiology, ad-
tween obese and nonobese patients. equation predates the global standard- ditional work to design adaptive feed-
Similarly, using data from 704 patients, ization of Scr measurement traceable back models to tailor doses is needed.
Ducharme and colleagues118 found that to isotopic-dilution mass spectrometry
mean weight-indexed vancomycin Vd (IDMS) standards advocated to reduce Summary and
decreased with increasing body size. intralaboratory and interlaboratory recommendations:
The average weight-indexed Vd in a measurement variability.124 A recent
study by Bauer and colleagues119 was population PK study by Crass and col- 12. A vancomycin loading dose of 20
much lower in 24 morbidly obese pa- leagues112 of obese patients (n = 346) to 25 mg/kg using actual body
tients (0.32 L/kg) than in 24 patients of with BMI values of 30.1 to 85.7 kg/m2 weight, with a maximum dose of
normal weight (0.68 L/kg, P < 0.001). and body weights of 70 to 294 kg pro- 3,000 mg, may be considered in
Recent studies in obese adults corrob- vided an equation to estimate vanco- obese adult patients with serious
orate these findings and suggest that mycin CL based on age, sex, Scr (IDMS infections (B-II). Initial mainte-
lower Vd estimates of approximately traceable), and allometrically scaled nance doses of vancomycin can be
0.5 L/kg or weight-independent central body weight. This model or similar computed using a population PK

estimate of vancomycin clearance these patients. These considerations and published a wide variety of vanco-
and the target AUC in obese patients. include the amount of time between mycin dosing protocols in an attempt to
Empiric maintenance doses for most vancomycin dose administration and compensate for the increase in vanco-
obese patients usually do not exceed the scheduled time of the next dialysis mycin dialytic CL caused by increases
4,500 mg/day, depending on their session,104 whether the dose is given in dialyzer permeability.
renal function (B-II). Early and fre- during dialysis or after hemodialysis An added complication of appro-
quent monitoring of AUC exposure is has ended, and the dialyzer’s per- priate vancomycin dosing in patients

recommended for dose adjustment, meability if the dose is administered receiving hemodialysis is the prevailing
especially when empiric doses exceed intradialytically.131 Dialysis frequency practice of administering the drug during
4,000 mg/day (A-II). Measurement also plays a role in dosing decisions. the final hours of the hemodialysis pro-
of peak and trough concentrations is For non–critically ill patients receiving cess, thus resulting in some of the infused
recommended to improve the accu- hemodialysis, 2 or 3 days is the most drug being removed immediately by the
racy of vancomycin AUC estimation common interdialytic period. Some hemodialyzer. This practice started back
and maintenance dose optimi- critically ill patients with severe catab- when low-permeability dialyzers were
zation in obese patients, aligning olism and AKI may require more than used and little vancomycin was elimin-
with recommendations 2 and 5 for thrice-weekly hemodialysis for optimal ated by hemodialysis. The practice has
nonobese adults. metabolic control, and their main- persisted at most dialysis units because
tenance vancomycin doses should most dialysis units treat 3 shifts of patients
be based on serum concentration per day, and holding a dialysis chair for
Renal Disease and Renal monitoring.132 60 to 90 additional minutes while vanco-
Replacement Therapies Vancomycin dosing in patients mycin infuses into a patient is not cost-ef-
Intermittent hemodialysis. with acute or chronic kidney failure fective. Indeed, it is more cost-effective
Despite the common use of vanco- has transformed over time due to to infuse “extra” vancomycin during the
mycin in patients receiving hemodial- the changes in dialysis technology hemodialysis session to compensate for
ysis, there are few published outcome and techniques.133 Older (pre-1990s) intradialytic loss than it is to keep a dial-
studies that provide guidance on the hemodialyzers were not very perme- ysis unit open later to allow vancomycin
optimal PK/PD targets in this popula- able to large molecules. Vancomycin infusions. Intradialytically infused vanco-
tion. Previously published drug dosing (with a molecular weight of 1,450 Da) mycin results in reduced delivery of drug
recommendations generally targeted a was not considered “dialyzable” be- to the patient, similar to a first-pass phe-
predialysis serum concentration, even cause it poorly crossed the hemodi- nomenon. The extent of intradialytic drug
though other PD targets may be more alysis membranes of the era. Indeed, removal is variable and depends on pa-
appropriate. Predialysis vancomycin even today’s vancomycin package in- tient and dialysis system factors, the most
concentration to MRSA MIC ratios of sert, based on PK studies conducted important of which is dialyzer membrane
>18.6 have been associated with im- in the 1980s, states that “vancomycin permeability.135,137-139 Approximately 20%
proved bacteremic patient outcomes, is poorly removed by dialysis.” 134 As to 40% of an intradialytically adminis-
suggesting that serum concentration hemodialysis membrane technology tered vancomycin dose is removed by
monitoring is essential throughout the has improved, dialyzers have become the simultaneous hemodialysis, with the
course of therapy.128 Dosing to achieve far more permeable. Vancomycin is highly permeable dialyzers tending to the
predialysis vancomycin concentrations cleared substantially by contemporary higher end of this range.137,140,141
of 10 to 20 mg/L, as has been done clin- high-permeability hemodialyzers135,136; Maintenance dosing strategies that
ically,129 results in mean AUC24 values consequently, vancomycin dosing do not provide a dose with every he-
ranging from 250 to 450 mg·h/L, with strategies have changed substantially modialysis session (eg, a maintenance
some values below the AUC/MIC goals as well. For example, in spite of the dose is given with every second or
recommended in other populations.130 package insert statement “In anuria, third hemodialysis session) have been
Outcome studies validating the AUC24h a dose of 1000 mg every 7 to 10 days studied,102,142,143 but none have been
goal of 400 to 600 mg·h/L used in other has been recommended” and the found to meet vancomycin exposure
patient populations have not been con- statement that “vancomycin is poorly goals in the last day of the dosing in-
ducted in the hemodialysis population. removed by dialysis,” 134 far more fre- terval without giving massive doses
Nonetheless, the maintenance doses quent doses are needed to maintain that result in very high peak concen-
recommended in this section aim to therapeutic serum concentrations in trations. Consequently, maintenance
reach this AUC24 target (ie, 400-600 patients receiving hemodialysis. The vancomycin doses are recommended
mg·h/L), as recommended throughout extent of vancomycin removal by dial- to be administered with each hemo-
this document. ysis is dependent on the permeability dialysis session to ensure therapeutic
Many dialysis-related factors affect of the hemodialyzer used131; conse- serum concentrations throughout
the degree of vancomycin exposure in quently, investigators have developed the dosing interval. In the typical

thrice-weekly hemodialysis schedule, other patient populations have not been

Timing and Dialyzer Vancomycin
25% larger doses are needed for the conducted in the hemodialysis popula-
Permeability Dose, mg/kga
3-day interdialytic period (eg, Friday to tion. While determination of AUC/MIC
Monday) to maintain sufficient vanco- attainment is recommended, limited Intradialytic
mycin exposure on the third day.130,144 serum concentration monitoring is pos-
Low permeability Loading: 30
Dosing that is weight based ap- sible in patients receiving hemodialysis Maint.: 7.5-10b
pears to be superior to standard dosing in the outpatient setting for 2 reasons. The

High permeability Loading: 35
schemes that do not account for patient first reason is that frequent phlebotomy Maint.: 10-15b
size. Further, doses should be based on must be avoided in order to preserve
actual body weight rather than a calcu- future hemodialysis vascular access
a
From references 104, 129, 130, 137, 138, 140,
and 147.
lated body weight (see Dosing in Obesity needs; the second is that it is imprac- b
Thrice-weekly dose administration.
section for considerations on how to tical to obtain blood samples aside from
dose morbidly obese patients). Because the predialysis sample that is obtained 14. Since efficacy data are unavailable
vancomycin is water soluble, vanco- from the blood catheter inserted for use for AUC values of <400 mg·h/L,
mycin dosing in fluid overloaded patients in the dialysis process. Patients leave the monitoring based on predialysis
should also be based on actual body dialysis unit after hemodialysis and do serum concentrations and extrapo-
weight at the time of dosing rather than not return until the next dialysis session lating these values to estimate AUC
on some calculated adjusted weight.102-105 days later. Consequently, since data are is most practical. Maintaining
Serum concentration monitoring unavailable for an optimal AUC target in predialysis concentrations be-
is a valuable tool to guide vancomycin these patients, and no data are available tween 15 and 20 mg/L is likely
dosing in patients receiving dialysis, to demonstrate efficacy below an AUC to achieve the AUC of 400 to 600
provided that serum concentrations are threshold value of 400, the goal should mg·h/L in the previous 24 hours
obtained and interpreted correctly. For be to attain the AUC target of 400 to 600 (C-III). Predialysis serum con-
example, blood sampling for assess- mg·h/L used in other patient popula- centration monitoring should be
ment of vancomycin concentrations tions. It is most practical to continue performed not less than weekly and
should not occur during or for at least monitoring based on predialysis con- should drive subsequent dosing, as
2 hours after a hemodialysis treatment. centrations and extrapolate these values opposed to a strict weight-based
These samples will not be reflective of to estimate AUC. Maintaining predialysis recommendation, although these
the true vancomycin body load because concentrations between 15 and 20 mg/L recommended doses provide a
of the dialytic removal of vancomycin. is likely to attain the AUC target of 400 useful starting point until serum
Vancomycin serum concentrations will to 600 mg·h/L in the previous 24 hours, concentrations have been deter-
be low immediately following a dialysis with higher AUC/MIC values occurring mined (B-II).
treatment but will rebound substan- on days prior.
tially as drug redistributes from the tis- Hybrid hemodialysis ther-
sues back to the blood over the next few apies. Contemporary renal replace-
Summary and
hours.131,142,145 Dosing decisions based ment therapies used to treat kidney
recommendations:
on serum concentrations obtained disease have expanded well beyond
during or soon after hemodialysis will thrice-weekly, 3- to 4-hour hemodial-
13. The following tabulation outlines ysis sessions. In the outpatient setting,
be inherently incorrect and could re-
recommended vancomycin loading shorter, more frequent home hemodi-
sult in administration of doses higher
and maintenance doses for pa- alysis treatments are used in a growing
than necessary.145 Serum concentration
tients receiving hemodialysis, with number of patients. In the inpatient set-
monitoring performed with blood sam-
accounting for permeability of the ting, various types of “hybrid” hemodi-
ples obtained prior to the hemodialysis
dialyzer and whether the dose is ad- alysis therapies are employed. These
treatment is recommended to guide
ministered intradialytically or after hybrid treatments go by many names,
dosing, although other serum concen-
dialysis ends (B-II). including prolonged intermittent renal
tration monitoring techniques have
been suggested.146 replacement therapy (PIRRT) and
Dosing to achieve predialysis vanco- Timing and Dialyzer Vancomycin slow-low efficiency dialysis (SLED).
mycin concentrations of 10 to 20 mg/L, Permeability Dose, mg/kga Essentially these hybrid therapies use
as has been conducted clinically,129 re- standard hemodialysis machines that
After dialysis ends
sults in mean AUC24 values ranging from run at slower blood and dialysate flow
250 to 450 mg·h/L, often below the AUC/ Low permeability Loading: 25 rates and for longer durations (usually
Maint.: 7.5b 6 to 12 hours per day). Even hemodi-
MIC goals recommended in other popu-
lations.130 Outcome studies validating the High permeability Loading: 25 alysis itself differs in the inpatient and
AUC target of 400 to 600 mg·h/L used in Maint.: 10b outpatient settings, as patients with AKI

are often hemodynamically unstable recognizing that these hybrid dialysis to 10 mg/kg every 12 hours (B-II).
and lack sufficient vascular access for therapies efficiently remove vanco- Maintenance dose and dosing in-
robust blood flow through the dialysis mycin (B-III). Initial doses should not terval should be based on serum con-
vascular access. All these hybrid dial- be delayed to wait for a dialysis treat- centration monitoring, which should
ysis therapies clear vancomycin to a ment to end. Maintenance doses of be conducted within the first 24
different extent than standard intermit- 15 mg/kg should be given after hybrid hours to ensure AUC/MIC targets are
tent hemodialysis.148,149 The timing of hemodialysis ends or during the final met.154 In fluid overloaded patients,

the vancomycin dose in relation to the 60 to 90 minutes of dialysis, as is done doses may be reduced as patients
hybrid hemodialysis session is essen- with standard hemodialysis (B-III).130 become euvolemic and drug Vd de-
tial in determining a dosing regimen. Concentration monitoring should creases. The use of CI of vancomycin
If hybrid hemodialysis is started soon guide further maintenance doses. in patients receiving CRRT appears
after the dose is administered, much of to be growing,84,105 and this method
the dose will be removed, whereas the Continuous renal replacement could be used in place of intermittent
same vancomycin dose given after the therapies. The use of continuous vancomycin dosing, especially when
dialysis session ends will yield a much renal replacement therapy (CRRT) mo- high CRRT ultrafiltrate/dialysate
larger AUC24 and much higher average dalities like continuous venovenous flow rates are employed (B-II).
serum concentrations. As is the case hemofiltration (CVVH), continuous
with any hemodialysis therapy, serum venovenous hemodialysis (CVVHD), and
concentrations obtained during or continuous venovenous hemodiafiltration Pediatric Patients
within 2 hours from the end of hemo- (CVVHDF) has grown in popularity in In 2011, prior to the availability of
dialysis will be artificially low because critically ill patients with AKI because of alternative agents for MRSA in pediat-
dialysis will have efficiently removed their superior ability to provide fluid and rics, vancomycin was recommended
vancomycin from the blood, and van- solute balance. Provided these therapies as the drug of choice for invasive MRSA
comycin located in the tissues will not operate in an uninterrupted fashion, infections in children.5 Although there
have had time to redistribute back into vancomycin CL is relatively constant are limited prospective, comparative
the bloodstream. Calculation of main- over the dosing interval, although CL data on the value of vancomycin thera-
tenance doses based on an intra- or may decline as the hemodiafilter clogs peutic monitoring in adults with respect
postdialytic vancomycin serum con- over time.151 Vancomycin is removed to improving outcomes and decreasing
centration may result in doses that are by CRRT and its CL is related closely to toxicity, virtually no prospectively col-
too high. Caution is recommended in the rate of ultrafiltrate/dialysate flow,105 lected data on outcomes of MRSA infec-
basing any maintenance dosing on with hemodiafilter type being of lesser tion in newborns, infants and children
these serum concentration values. importance, because contemporary exist. Further, for newborns (particu-
Little has been published on the hemodiafilters are all very permeable to larly premature infants) compared with
patient outcomes achieved when van- the drug. older infants, immature renal elimina-
comycin is used in patients receiving In patients on CRRT, serum concen- tion mechanisms and a relative increase
hybrid dialysis. Authors of one small tration attainment goals often are not met in Vd by body weight further complicate
case series of 27 courses of vancomycin with conventional dosing.84,152 Although dosing guidelines during the first sev-
given to patients receiving a hybrid he- outcomes studies specific to patients re- eral weeks of life. Additional complexity
modialysis therapy reported that pre- ceiving CRRT have not been conducted, for dosing strategies during early child-
scribers have tried a wide variety of it seems prudent to apply the same van- hood is based on a continual maturation
dosing schemes.150 By these authors’ comycin AUC/MIC target (ie, 400-600) of glomerular filtration, which is directly
criteria, 89% of the prescribed vanco- in these critically ill patients as is recom- related to vancomycin CL. The glomer-
mycin doses in their institution were mended throughout this document. ular filtration rate increases through the
too low. Given the absence of outcome first years of life to rates in school-aged
data in patients receiving these ther- Summary and children that are greater than those in
apies, it seems prudent to use the same recommendations: adults, with subsequent decline during
vancomycin AUC goal recommended the teen years to adult normal rates.
throughout this document (400 to 600 16. Loading doses of 20 to 25 mg/kg by Such a diversity of PK parameter values
mg·h/L assuming a MIC of 1 mg/L). actual body weight should be used based on developmental pharmacology
in patients receiving CRRT at con- from neonates to adolescents pro-
Summary and ventional, KDIGO-recommended vides a challenge to develop general-
recommendations: effluent rates of 20 to 25 mL/kg/h ized vancomycin dosing. However, this
(B-II).153 Initial maintenance has improved with the application of
15. Loading doses of 20 to 25 mg/kg dosing for CRRT with effluent rates population-based PK models using al-
actual body weight should be used, of 20 to 25 mL/kg/h should be 7.5 lometric scaling and renal maturation

covariates. In a population-based PK and outcomes data to support the of 1 mg/L or less, p resumably as a re-
study by Colin and colleagues155 that higher end of the AUC target range in sult of greater vancomycin CL than is
evaluated vancomycin PK throughout pediatrics, it is prudent to aim for an seen in adults.1,161-164 For children in-
the entire age continuum from infancy AUC/MIC of 400 in pediatrics to limit fected by MRSA pathogens with a MIC
to geriatric years using pooled data from the development of exposure-related of >1 mg/L, it is unlikely that the target
14 studies, age, weight, and kidney func- AKI. Furthermore, in pediatrics, an exposure can be reliably achieved with
tion were important factors in estimating AUC/MIC target of 400 is more readily previously investigated dosages of van-

clearance. Careful monitoring in the achievable than it is in adults and cor- comycin in children.
pediatric population is prudent, espe- relates to trough concentrations of 7 Le and colleagues164 utilized
cially with the evident dynamic changes to 10 mg/L rather than concentrations population-based PK modeling to an-
in renal function in this population. As of 15 to 20 mg/L as are reported in alyze 1,660 vancomycin serum con-
with adults, comorbidities and concur- adults. This wide variability in trough centrations obtained at 2 institutions
rent medications can influence vanco- concentrations between these popula- from 2003 to 2011 among 702 children
mycin tissue distribution, elimination, tions with regard to achieving an AUC/ older than 3 months of age with varying
and toxicity. MIC of 400 corroborates the need for comorbidities. They demonstrated that
Limitation of outcomes data. an AUC-guided approach to dosing 4 important factors (age, weight, renal
Recent retrospective studies on bac- and monitoring. It is possible that in function as assessed by SCr, and MIC)
teremic S. aureus infections (both otherwise healthy children with fewer contributed to vancomycin exposure.
MRSA and MSSA strains) in children comorbidities than are typically seen Monte Carlo simulations were created
treated with vancomycin suggest that in adults, a lower target may yield out- using population-based PK modeling
trough concentrations of >15 mg/L comes equivalent to an AUC of 400 to with Bayesian estimation and MICs of
were not associated with improved 600 mg·hr/L. The decision to retain or clinical isolates as determined by Etest,
outcomes, yet an increase in AKI increase AUC target exposure should with 85% of clinical isolates demon-
was observed.156-158 Furthermore, an- be based on clinical judgment in the strated to have a MICEtest of 1 mg/L or
other retrospective pediatric study management of these patients. less. To achieve an AUC/MICEtest of ≥400
evaluating outcomes of MRSA bac- With use of currently recommended in 90% of subjects, a dosage of 80 mg/kg/
teremia as a function of an AUC/ vancomycin dosages of 45 to 60 mg/ day was necessary, particularly in those
MICBMD of ≥400 did not show im- kg/day, widespread treatment failures less than 12 years of age with normal
proved outcomes.159 Similarly, van- in children have not been reported in renal function. At a dosage of 80 mg/
comycin trough concentrations of the literature, which may be reflective kg/day, the median AUC and median
<10 mg/L, as compared with concen- of a younger host with a more robust trough concentration were 675 mg·h/L
trations of >10 mg/L, were not associ- systemic and immunologic response and 16 mg/L, respectively. As expected,
ated with increased 30-day mortality to infection, a different management subjects 12 years of age or older achieved
and recurrent bacteremia in chil- approach (surgical and antibiotic) to similar exposure at lower dosages of 60
dren, although the lower concentra- invasive MRSA infection, lack of associ- to 70 mg/kg/day. At a dosage of 60 to
tions were associated with prolonged ated comorbidities, or publication bias. 70 mg/kg/day (divided doses admin-
bacteremia.160 Prospective comparative clinical trials istered every 6 hours), an AUC of 400
In the absence of prospective, com- involving children with documented mg·h/L correlated to a mean trough of 8
parative outcomes data in children re- infections treated with different vanco- to 9 mg/L.164 The clinical applicability of
garding unique AUC/MIC exposures mycin dosages or exposures have not this PK model for vancomyin CL estima-
necessary for clinical and microbio- been published. tion to determine AUC exposure was val-
logic success in treating serious MRSA Empiric maintenance regimen. idated in a small study by Ploessl et al.165
infections in different neonatal and Published retrospective PK/PD data Other studies corroborated Le and
pediatric populations to validate the in children suggest that current van- colleagues’ findings regarding the need
observations reported in adults (see comycin dosing of 45 to 60 mg/kg/day to use higher dosages, ranging from 60
Clinical PK/PD Data: Adults section), (in divided doses administered every to 80 mg/kg/day, depending on age and
dosing in children should be designed 6 to 8 hours) may be insufficient to renal function.162,164,166,167 Using the liter-
to achieve an AUC of 400 mg·h/L and achieve currently recommended tar- ature for vancomyin CL published in or
potentially up to 600 mg·h/L (assuming gets for adults of an AUC of 400 to 600 before 2000 and Bayesian estimation
a MIC of 1 mg/L). This PD target range, mg·h/L (assuming a MIC of 1 mg/L).1 for one 25-kg base subject, Frymoyer
specifically a range closer to an AUC/ In fact, higher dosages, ranging from et al163 evaluated the relationship be-
MIC of 400 rather than 600, has been 60 to 80 mg/kg/day and given in di- tween AUC and trough concentrations,
widely used by investigators to model vided doses every 6 hours, may be showing that a dosage of 60 mg/kg/day
pediatric dosing and therapeutic moni- needed to achieve these targets for achieved trough concentrations of 7 to
toring. With inadequate PK studies MRSA strains with a vancomycin MIC 10 mg/L and an AUC/MIC of ≥400 in

90% of children for MRSA pathogens every 8 hours) in renally impaired chil- greater than 15 to 20 mg/L and AKI in
with a MIC of 1 mg/L. However, their dren achieved AUC exposure similar to pediatric patients. In addition, they
finding may not be extrapolatable to the that achieved with a dosage of 60 mg/kg/ showed that children who received con-
entire pediatric population given the day in children with normal renal func- current nephrotoxic drugs (particularly
variable ages and renal function. In a tion. Notably, they showed that in 87% furosemide) and stayed in the pediatric
second study, these investigators dem- of children with initial renal impairment, ICU were also more likely to experi-
onstrated that a dosage of 60 mg/kg/day vancomycin CL improved (with a lag in ence AKI. Four studies published later

achieved AUC/MICBMD values between the recovery of renal function as assessed corroborated these findings, indicating
386 and 583 (assuming a MICBMD of by SCr) within the first 5 days of therapy, that the interplay of multiple factors
1 mg/L) in children 2 to 12 years of age, indicating some degree of renal function in addition to vancomycin exposure
indicating that some younger children recovery, a finding that provides support contributed to AKI.173-176 Interestingly,
may require higher doses to achieve for ongoing vancomycin TDM. In ad- Sinclair et al174 reported that a 5-mg/kg
target AUC/MICBMD.162 The probability dition, vancomycin CL does not always dose augmentation or each additional
of target attainment was not provided, correlate well with renal function (as as- day of vancomycin use increased the
and dosages above 60 mg/kg/day were sessed by creatinine CL) in children, par- risk of AKI. Knoderer and colleagues173
not evaluated in this study. ticularly in those who are acutely ill in the evaluated late-onset AKI (defined as
Two retrospective studies that util- ICU setting and have varying degrees of occurring after 7 days of vancomycin
ized non-Bayesian methods evaluated renal dysfunction. Rapid return of renal therapy) and observed that young age
trough concentration targets of 10 to function may occur over the first few days (<1 year) was independently associated
20 mg/L (a higher range than that used after ICU admission. As such, therapeutic with late AKI.
by Le et al164 and Frymoyer et al163, who monitoring of both serum concentrations One pediatric study evaluated the
also assessed AUC) in children 1 month and renal function should be conducted relationship of AKI with vancomycin
to 18 years of age. An interesting finding during vancomycin therapy.170,171 AUC and trough concentrations, both
of the study of Madigan et al166 was that Loading doses. Loading doses derived by Bayesian estimation. Le
a dosage of 60 mg/kg/day achieved the of 25 to 30 mg/kg for critically ill adults and colleagues19 conducted a large
target trough concentration in only 17% have been suggested to achieve steady- population-based PK analysis using
of preschool-aged children 2 to 5 years state concentrations more quickly, but 1,576 serum concentrations collected
old, which was the lowest attainment preliminary data on pediatric patients from 680 pediatric subjects. A contin-
for any pediatric age group. Eiland and suggest that the benefit of a loading uous exposure-response relationship
colleagues161 showed that dosages of dose of 30 mg/kg is quickly lost if the was observed, with 10%, 33%, and 57%
70 to 80 mg/kg/day were necessary to maintenance dose is insufficient to of patients who respectively achieved
achieve trough concentrations of 10 to provide adequate ongoing exposure.167 AUC values of ≥400, 800, and 1,000
20 mg/L. Another study, by Abdel et al,168 However, the concept of a loading dose mg·h/L experiencing AKI. Even after
demonstrated that dosages higher than accompanied by a daily maintenance adjusting for ICU stay and concomi-
60 mg/kg/day were necessary to achieve dose sufficient to achieve the target tant use of nephrotoxic drugs, an AUC
an AUC/MIC of ≥400 in children with exposure and initiated at a specified of ≥800 mg·h/L and trough concentra-
cancer. The mean age in this study co- time after the loading dose should be tions of ≥15 mg/L were independently
hort was 6 (SD, 2.5) years; it is possible investigated. associated with a greater than 2.5-fold
that young age with greater CL may have Minimizing AKI risk. Similar to increased risk of AKI. The linkage of
been a contributing factor for the need the literature on adults, the literature AUC to AKI, along with the strong cor-
for an increased dose, an observation in pediatrics suggests, in aggregate, relation between AUC and trough con-
uncovered in studies by Le et al164 and that the risk of AKI increases as a func- centrations (Spearman’s coefficient,
Madigan et al.166 tion of vancomycin exposure, espe- 0.963; P < 0.001), reinforces AUC as a
As a drug that demonstrates renal cially when the trough concentration plausible PK/PD parameter for thera-
elimination, vancomycin requires dosage exceeds 15 to 20 mg/L. In fact, Fiorito peutic monitoring that encompasses
adjustment in children with acute or and colleagues158 reported in a recent both therapeutic and toxic responses.
chronic renal insufficiency. Le and col- meta-analysis of 10 pediatric studies Vancomycin exposure should be main-
leagues169 conducted a population-based that troughs of ≥15 mg/L increased the tained at an AUC of <800 mg·h/L to
PK analysis with Bayesian methods that OR for AKI by 2.7-fold (95% confidence minimize AKI risk. As such, vanco-
evaluated 63 case-control pairs (matched interval, 1.82-4.05) and that AKI was mycin dosages of ≥100 mg/kg/day
by age and weight) with 319 vancomycin further correlated with a stay in the pe- should be avoided given that the pro-
serum concentrations. The mean age of diatric ICU. McKamy and colleagues172 jected median AUC and trough values
this study cohort was 13 (SD, 6) years. The published results of the first study that are 843 mg·h/L and 21 mg/L, respec-
investigators reported that a vancomycin uncovered the association between tively, at a dosage of 100 mg/kg/day.164
dosage of 45 mg/kg/day (ie, 15 mg/kg vancomycin trough concentrations However, enhanced renal clearance of

vancomycin may transiently occur in in the various pediatric age groups, and concentrations to achieve the AUC/MIC
specific situations in children, in which the differences in tissue site-of-infection target. Early monitoring of observed
case the dose of vancomycin may need drug exposure (eg, common occurrence concentrations is recommended when
to be higher than is usually prescribed of multifocal complicated osteomyelitis doses exceed 2,000 to 3,000 mg/day (A-
to achieve an AUC of 400 mg·h/L, in children requiring therapeutic bone III). Furthermore, close monitoring of
highlighting the need for therapeutic concentrations, with rare occurrence observed concentrations and renal func-
monitoring. of MRSA endocarditis) suggest that fur- tion is prudent in patients with poor or

Therapeutic monitoring. Recent ther studies in children that incorporate augmented renal clearance, as resolu-
literature on vancomycin in pediatrics prospective assessment of clinical out- tion of their renal function abnormal-
has focused primarily on PK analysis comes and large sample size are needed ities may occur within the first 5 days of
to support optimal dosing. Le and col- to identify the optimal dosing strat- therapy.
leagues177 conducted a population- egies for MRSA infections in pediatrics.
based PK analysis in 138 pediatric Until additional data are available, the 18. AUC-guided therapeutic moni-
subjects who were more than 3 months AUC target used in adults (ie, from 400 toring for vancomycin, preferably
of age, evaluating 712 serum vanco- up to 600 mg·h/L [assuming a MIC of with Bayesian estimation, is sug-
mycin concentrations (collected mostly 1 mg/L]) appears to be the most appro- gested for all pediatric age groups,
after the third or fourth dose). They priate initial target for vancomycin ex- based on developmental changes
showed that both accuracy and preci- posures in all pediatric age groups. For of vancomycin CL documented
sion for estimating AUC24 (calculated most children across the pediatric age from the newborn to the adolescent.
by total daily dose over vancomycin CL, groups, assuming a vancomycin MIC Based on current available data,
with the integration of Bayesian estima- of 1 mg/L, published data suggest that the suggestion for AUC-guided
tion) were improved using 2 concentra- a dosage of 60 to 80 mg/kg/day (given in monitoring in pediatrics aligns with
tions (peak and trough), compared with divided doses every 6 hours) is required the approach for adults, including
trough-only monitoring. Furthermore, to achieve an AUC target of 400 to 600 the application of Bayesian esti-
the 2-concentration approach im- mg·h/L. mation for 1 trough concentration
proved the prediction of future AUC or first-order PK equations with 2
exposure in patients.177 Another study, Summary and concentrations (B-II). The Bayesian
by Stockmann et al,178 evaluated AUC‐ recommendations: AUC-guided dosing strategy may be
based vancomycin monitoring in 23 an optimal approach to individu-
pediatric patients with cystic fibrosis. 17. Based on an AUC target of 400 alize vancomycin therapy in pediat-
The researchers demonstrated that mg·h/L (but potentially up to 600 rics since it can incorporate varying
2 concentrations calculated using a mg·hr/L, assuming a vancomycin ages, weights, and renal function.
standard PK equation and a trough MIC of ≤1 mg/L for MRSA) from Both serum concentrations of van-
concentration calculated using a adult data, the initial recommended comycin and renal function should
Bayesian population-based PK model vancomycin dosage for children with be monitored since vancomycin CL
produced similar AUC estimations. normal renal function and suspected and CLcr are not always well correl-
Despite the availability of limited serious MRSA infections (including ated in pediatrics. Furthermore, ag-
studies on vancomycin monitoring in pneumonia, pyomyositis, multifocal gressive dosing to maintain target
pediatrics, the findings appear con- osteomyelitis, complicated bacte- AUC exposure and decrease the
gruent with adult data supporting remia, and necrotizing fasciitis) is: risk of potential AKI in treatment
AUC-guided therapeutic moni- of MRSA infection necessitates drug
toring that incorporates the Bayesian 60 to 80 mg/kg/day, in divided
• monitoring.
method, especially if only a single doses given every 6 hours, for chil- 19. Therapeutic monitoring may begin
trough concentration is available. dren ages 3 months to less than within 24 to 48 hours of vancomycin
Furthermore, this AUC-guided moni- 12 years or therapy for serious MRSA infections
toring approach also appears prudent 60 to 70 mg/kg/day, in divided
• in children, as in adults (B-III). Any
in order to predict toxicity in light of doses given every 6 to 8 hours, for delay in therapeutic monitoring
AKI data in pediatrics. those ≥12 years old (A-II). should be based on severity of infec-
Overall, there are limited pediatric tion and clinical judgment. Dosing
outcomes data to support the AUC The maximum empiric daily dose is adjustment should be made for those
target correlated with drug effectiveness usually 3,600 mg in children with ad- with renal insufficiency, those with
in adults. Some of the differences found equate renal function (C-III). Most obesity (see Pediatric Obesity), and
between adults and children treated for children generally should not require those receiving concurrent nephro-
MRSA infections with vancomycin in- more than 3,000 mg/day, and doses toxic drug therapy. Following the
clude the complexity of vancomycin CL should be adjusted based on observed initial dose, dosing adjustment is

important for those with acute renal studies by Heble et al181 and Miller the use of a 20-mg/kg loading dose
insufficiency, but subsequent adjust- et al182 documented higher vancomycin based on total body weight in obese
ment (particularly within the first trough concentrations in overweight children increased achievement of an
5 days of therapy) may be necessary and obese children, as compared to AUC/MIC of ≥400, especially within the
for those experiencing recovery of normal-weight children, with dosing first 12 hours of therapy. In addition, 1
renal function. Sustained or subse- based on total body weight. No increase of every 5 obese children had an AUC
quent decreases in dosage may be in AKI was noted in the overweight of ≥ 800 mg·h/L, indicating that routine

needed, particularly for those with children.182 therapeutic and safety monitoring is
chronic renal insufficiency and those Collectively, non-Bayesian studies prudent.188
receiving concurrent nephrotoxic of obese children have evaluated main-
drug therapy (B-III). tenance regimens ranging from 40 to Summary and
20. Vancomycin exposure may be op- 80 mg/kg/day (calculated using total recommendations:
timally maintained below the thresh- body weight), with some instituting
olds for AUC of 800 mg·h/L and for maximum doses of 1 to 2 g over 1 to 2 22. Data suggest that obese children are
trough concentrations of 15 mg/L to hours.180,181,183,184 As an alternative to likely to have vancomycin exposures
minimize AKI (B-II). The safety of total body weight, one study recom- that may be statistically greater than
vancomycin dosages above 80 mg/ mended the use of body surface area to those in normal-weight children when
kg/day has not been prospectively dose vancomycin, which necessitates doses are calculated on a mg/kg basis,
evaluated. Avoiding vancomycin establishing a different dosing regimen but these differences are not known
dosages of ≥100 mg/kg/day is sug- and obtaining height measurements to be of sufficient clinical importance
gested since they are likely to surpass that may not always be readily avail- to suggest different mg/kg empiric
these thresholds (B-III). able in clinical practice.185 Body sur- vancomycin dosages in obese children
21. Insufficient data exist on which face area is not typically used for dosing at this time. Similar to nonobese chil-
to base a recommendation for a medications in children, except for dren, obese children < 12 years old,
loading dose among the nonobese chemotherapeutic agents.186 compared with those ≥ 12 years, may
pediatric population. Loading Using a Bayesian population-based require a higher mg/kg dose (B-II).
doses from adult studies may be PK analysis of 389 vancomycin serum 23. Therapeutic monitoring is likely to be
considered, but further studies are concentrations collected from 87 of particular value in obese children,
needed to elucidate the appropriate pairs of obese and nonobese children both for therapeutic response and
dose for the various pediatric popu- (matched by age and baseline SCr), Le the risk of AKI. The specific recom-
lations from the neonate to adoles- and colleagues187 showed that the Vd mendations for therapeutic moni-
cent (C-III). was strongly correlated with actual or toring in nonobese children may also
total body weight and that CL correl- apply for obese children (B-II).
Pediatric obesity. Vancomycin ated with allometric weight (ie, weight x 24. A loading dose of 20 mg/kg by total
is a large glycopeptide molecule that 0.75) and body surface area. Using this body weight is recommended in
is hydrophilic, suggesting that distri- PK model, Nguyen and colleagues164,166 obese children (A-III).
bution into tissues with high lipid con- concluded, using Monte Carlo simu-
centrations, such as adipose tissue, is lations with Bayesian estimation, that Neonates. Vancomycin ther-
decreased, as noted above for adults vancomycin 60 mg/kg/day dosed by apeutic monitoring is important in
(see Dosing in Obesity section). When total body weight, as compared with neonates, based on developmental
vancomycin dosing is based on total other weight measures, resulted in the considerations of prominent increasing
body weight (mg/kg) for both obese highest rate of achievement of the target renal function that occurs over the
and nonobese children, serum con- AUC/MIC of ≥400 in obese children (ie, first several weeks of life.189 Models to
centrations have been documented to the target was achieved in 76% when predict vancomycin dosing have var-
be higher in obese children, assuming vancomycin was given by total body iously incorporated weight-based
that renal CL is similar between the 2 weight, in 66% when given by adjusted dosing, chronologic age–based dosing,
populations.179 Moffett retrospectively body weight, and in 31% when given postmenstrual age–based dosing, SCr-
compared vancomycin pharmacoki- by allometric weight). Furthermore, based dosing (except for the first week of
netics in 24 obese children who were when given dosages of vancomycin life, when transplacental maternal cre-
matched with 24 nonobese control of 60 mg/kg/day by total body weight, atinine in the neonatal circulation ren-
children.180 Vancomycin dose admin- fewer obese children of <12 vs ≥12 years ders neonatal SCr values inaccurate in
istration per child was slightly higher of age achieved an AUC/MIC of ≥400 estimating renal function), or combin-
in the obese children, which resulted (70% and 84%, respectively), an age- ations of these strategies. Regardless of
in increased trough concentrations. based observation also identified in which model is used, therapeutic moni-
Similarly, 2 retrospective non-Bayesian nonobese children.164,166 Interestingly, toring in the neonate is essential due to

the rapid maturation of renal function PK analysis was conducted to create not be evaluated rigorously in this study
over the first weeks of life. a model for vancomycin CL that was due to the small sample size. Overall,
Mehrotra et al190 compared 4 models based on weight, postmenstrual age, the clinical utility of CI in neonates re-
for predicting vancomycin serum con- and SCr (measured by a modified ki- quires further evaluation, as the most
centrations, based on their population netic Jaffé reaction). Monte Carlo common pathogen causing late-onset
PK model, using a standard weight- simulations with Bayesian estimation sepsis requiring vancomycin therapy is
based dose, a postmenstrual age–based demonstrated that trough concentra- Staphylococcus epidermidis, with limited

dose, a postmenstrual and postnatal tions ranging from 7 to 11 mg/L were cases of S. aureus sepsis. While the op-
age–based dose, and a SCr-based dose. highly predictive of an AUC24 of >400 timal AUC/MIC target for S. epidermidis
Serum creatinine–based dosing pre- mg·h/L in at least 90% of neonates. is not well studied, a lower target may be
dicted trough concentrations with the Dosages to achieve this PK/PD target reasonable, but further data to support
smallest variability in both term and pre- ranged from 15 to 20 mg/kg every 8 to 12 this recommendation are needed.
term neonates. However, for those who hours, depending on postmenstrual age The incidence of vancomycin-
wish to achieve a target exposure based and SCr.194 Stockmann et al196 later sup- associated AKI reported in neonates
on high trough concentrations within a ported the predictive performance and has been low, ranging from 1% to
narrow range of 15 to 20 mg/L, it should generalizability of this model in their 9%.200 Nonetheless, a positive correla-
be noted that only 13% to 21% of neo- study of 243 neonates with 734 vanco- tion between increasing vancomycin
nates were within this range across the mycin concentrations. While a trough trough concentrations and AKI has
4 dosing regimens. Marqués-Miñana concentration of 11 mg/L predicted the been reported by Bhargava et al.201
et al191 also developed a population PK attainment of an AUC of ≥400 mg·h/L Furthermore, in a large, retrospec-
model and proposed dosing based on in 93% of neonates, Stockmann and tive, multicenter, propensity score–
postmenstrual age. SCr-based rather colleagues noted that a trough concen- matched cohort study of 533 neonates
than postmenstrual or postconceptional tration alone did not precisely predict receiving vancomycin and gentamicin
age–based dosing has been supported AUC and concluded that Bayesian ap- and 533 receiving gentamicin alone,
by Irikura et al192 and Capparelli et al.193 proaches to support vancomycin dosing Constance et al202 concluded that AKI
However, when evaluating published decisions for neonates in the clinical was not associated with vancomycin
neonatal PK models, no consensus on setting are needed.196 Furthermore, Cies alone but may occur in the presence
an optimal dosing regimen was achieved et al197 reported differences in vanco- of other recognized risk factors, in-
by experts on neonatal vancomycin, mycin pharmacokinetics, in particular cluding patent ductus arteriosus,
Zhao et al reported.194 After evaluating rapid vancomycin CL, in neonates with concomitant nonsteroidal anti-in-
the predictive performance of 6 models, extracorporeal oxygenation life sup- flammatory drug use, 1 or more pos-
Zhao et al concluded the importance of port, reiterating the need for Bayesian- itive blood cultures, low birth weight,
evaluating analytical techniques for SCr derived dosing decision support in this and higher scores for severity of ill-
and vancomycin concentrations best vulnerable population. Lastly, Leroux ness and risk of mortality.
explained the variability of predictions et al198 demonstrated the success of the
between the models. Zhao et al found clinical integration of a model-based Summary and
that the Jaffé method overestimated SCr vancomycin dosing calculator, devel- recommendations:
concentrations when compared to the oped from a population PK study, that
enzymatic method and that for vanco- was successful in improving the rate of 25. Doses recommended to achieve an
mycin concentrations, the fluorescence attainment of a serum concentration of AUC of 400 mg·h/L (assuming a MIC
polarization immunoassay method 15 to 25 mg/L from 41% to 72% without of 1 mg/L) in neonates and infants
and enzyme-multiplied immunoassay any cases of AKI. up to 3 months old range from 10
method assays showed different predic- As an alternative to intermittent ad- to 20 mg/kg every 8 to 48 hours,
tive performances as well.194 ministration, CI of vancomycin has been depending on postmenstrual age,
With the knowledge that AUC, as evaluated in infants. In a multicenter, weight, and SCr (A-II). AUC-guided
compared with trough concentrations, randomized controlled trial involving therapeutic dosing and monitoring,
is a more achievable target in pediat- 111 infants less than 90 days of age, Gwee preferably with Bayesian estimation,
rics, Frymoyer and colleagues195 evalu- et al199 showed that the use of CI resulted can best achieve the target vanco-
ated the association between AUC and in fewer dose adjustments and a lower mycin exposure likely to be required
trough concentrations in neonates. mean daily dose than intermittent ad- for a successful outcome of treat-
Using 1,702 vancomycin concentrations ministration. The target trough concen- ment for a MRSA infection for all
(measured by the homogenous particle- trations were 10 to 20 mg/L for II, and the neonates, regardless of gestational
enhanced turbidimetric inhibition steady-state concentrations were 15 to and chronologic age. The specific
immunoassay) collected from 249 neo- 25 mg/L for CI. The AUC and clinical out- recommendations for AUC-guided
nates up to 3 months of age, population comes, including nephrotoxicity, could therapeutic monitoring in children

20
Table 2. Primary Recommendations for Vancomycin Dosing and Therapeutic Drug Monitoring
A. ADULTS AND PEDIATRIC PATIENTS
1. In patients with suspected or definitive serious MRSA infections, an individualized target AUC/MICBMD ratio of 400 to 600 (assuming a vancomycin MICBMD of 1 mg/L) should be
advocated to achieve clinical efficacy while improving patient safety (A-II).
2. When transitioning to AUC/MIC monitoring, clinicians should conservatively target AUCs for patients with suspected or documented serious infections due to MRSA, assuming
a vancomycin MICBMD of 1 mg/L or less at most institutions. Given the importance of early, appropriate therapy, vancomycin targeted exposure should be achieved early during
ASHP REPORT
the course of therapy, preferably within the first 24 to 48 hours (A-II). As such, the use of Bayesian-derived AUC monitoring may be prudent in these cases since it does not re-
quire steady-state serum vancomycin concentrations to allow for early assessment of AUC target attainment.
3. Trough-only monitoring, with a target of 15 to 20 mg/L, is no longer recommended, based on efficacy and nephrotoxicity data in patients with serious infections due to MRSA
AM J HEALTH-SYST PHARM
(A-II). There is insufficient evidence to provide recommendations on whether trough-only or AUC-guided vancomycin monitoring should be used among patients with noninva-
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sive MRSA or other infections.
4. Vancomycin monitoring is recommended for patients receiving vancomycin for serious MRSA infections to achieve a sustained targeted AUC (assuming a MICBMD of 1 mg/L
unless it is known to be greater or less than 1 mg/L by BMD). Independent of MRSA infection, vancomycin monitoring is also recommended for all patients at high risk for
nephrotoxicity (eg, critically ill patients receiving concurrent nephrotoxins), patients with unstable (ie, deteriorating or significantly improving) renal function, and those receiving
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prolonged courses of therapy (more than 3 to 5 days). We suggest the frequency of monitoring be based on clinical judgment; frequent or daily monitoring may be prudent for
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hemodynamically unstable patients (eg, those with end-stage renal disease), with once-weekly monitoring for hemodynamically stable patients (B-II).
5. Based on current national vancomycin susceptibility surveillance data, under most circumstances for empiric dosing, the vancomycin MIC should be assumed to be 1 mg/L.
When the MICBMD is greater than 1 mg/L, the probability of achieving an AUC/MIC target of ≥400 is low with conventional dosing; higher doses may risk unnecessary tox-
icity, and the decision to change therapy should be based on clinical judgment. In addition, when the MICBMD is less than 1 mg/L, we do not recommend decreasing the dose
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to achieve the AUC/MIC target. It is important to note the limitations in automated susceptibility testing methods, including the lack of precision and variability in MIC results
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depending on the method used (B-II).
6. The pharmacokinetics of continuous infusion suggest that such regimens may be a reasonable alternative to conventional intermittent infusion dosing when the AUC target
cannot be achieved (B-II).
7. Incompatibility of vancomycin with other drugs commonly coadministered in the ICU requires the use of independent lines or multiple catheters when vancomycin is being con-
XXXX XX, 2020

sidered for continuous infusion (A-III).
B. ADULTS
8. Given the narrow vancomycin AUC range for therapeutic effect and minimal associated risk of acute kidney injury (AKI), the most accurate and optimal way to manage vanco-
mycin dosing should be through AUC-guided dosing and monitoring (A-II). We recommend to accomplish this in one of two ways:
a. One approach relies on the collection of 2 concentrations (obtained near the steady-state, post-distributional peak concentration at 1 to 2 hours after infusion and trough at end
of dosing interval), preferably but not required during the same dosing interval (if possible) and utilizing first-order pharmacokinetic (PK) equations to estimate the AUC (A-II).
b. The preferred approach to monitor AUC involves the use of Bayesian software programs, embedded with a PK model based on richly sampled vancomycin data as the
Bayesian prior, to optimize the delivery of vancomycin based on the collection of 1 or 2 vancomycin concentrations, with at least 1 trough. It is preferred to obtain 2 PK samples
(ie, 1 to 2 hours post infusion and at the end of the dosing interval) to estimate the AUC with the Bayesian approach (A-II). A trough concentration alone may be sufficient to
estimate the AUC with the Bayesian approach in some patients, but more data across different patient populations are needed to confirm the viability of using trough-only data
(B-II).
9. Doses of 15 to 20 mg/kg (based on actual body weight) administered every 8 to 12 hours as an intermittent infusion are recommended for most patients with normal renal func-
tion when assuming a MICBMD of 1 mg/L (A-II). In patients with normal renal function, these doses may not achieve therapeutic AUC/MIC targets when the MIC is 2 mg/L.
Continued on next page

GUIDELINE ON VANCOMYCIN MONITORING

Continued from previous page
B. ADULTS
10. Continuous Infusion: Based on current available data, a loading dose of 15 to 20 mg/kg, followed by daily maintenance CI of 30 to 40 mg/kg (up to 60 mg/kg), to achieve a
target steady-state concentration of 20 to 25 mg/L may be considered for critically ill patients (B-II). AUC24 can be simply calculated when multiplying the steady-state concen-
tration (ie, desired therapeutic range of 20 to 25 mg/L throughout the entire dosing interval) by a factor of 24 (B-II). Attaining the desired drug exposure may be more readily
accomplished, given the ease of sampling time and dosage adjustment, by changing the rate of infusion, which is a highly desirable feature in critically ill patients (B-II).
11. The risk of developing nephrotoxicity with CI appears to be similar or lower compared to intermittent dosing when targeting a steady-state concentration of 15 to 25 mg/L and
a trough concentration of 10 to 20 mg/L, respectively (B-II). Definitive studies are needed to compare drug exposure based on measured AUC24 and factors that predispose to
development of nephrotoxicity, such as receipt of concomitant nephrotoxins, diuretics, and/or vasopressor therapy in patients receiving continuous vs intermittent infusion of
vancomycin.
12. In order to achieve rapid attainment of targeted concentrations in critically ill patients with suspected or documented serious MRSA infections, a loading dose of 20 to 35 mg/
kg can be considered for intermittent administration of vancomycin (B-II). Loading doses should be based on actual body weight and not exceed 3,000 mg. More intensive
and early therapeutic monitoring should also be performed in obese patients (B-II).
13. Adult Obesity: A vancomycin loading dose of 20 to 25 mg/kg using actual body weight, with a maximum of 3,000 mg, may be considered in obese adult patients with serious
infections (B-II). Empiric maintenance doses for most obese patients usually do not exceed 4,500 mg/day, depending on their renal function (B-II). Early and frequent moni-
toring of AUC exposure is recommended for dose adjustment, especially when empiric doses exceed 4,000 mg/day (A-II).
14. Intermittent Hemodialysis: Since efficacy data are unavailable for an AUC of <400 mg · h/L, monitoring based on predialysis serum concentrations and extrapolating these
values to estimate AUC is most practical. Maintaining predialysis concentrations between 15 and 20 mg/L is likely to achieve the AUC of 400 to 600 mg · h/L in the previous
24 hours (C-III). Predialysis serum concentration monitoring should be performed not less than weekly and should drive subsequent dosing rather than a strict weight-based
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recommendation, although these recommended doses provide a useful starting point until serum concentrations have been determined (B-II).
15. Hybrid Dialysis Therapies (eg, Slow-Low Efficiency Dialysis [SLED]): Loading doses of 20 to 25 mg/kg actual body weight should be used, recognizing that these hybrid dialysis
therapies efficiently remove vancomycin (B-III). Initial doses should not be delayed to wait for a dialysis treatment to end. Maintenance doses of 15 mg/kg should be given
after hybrid hemodialysis ends or during the final 60 to 90 minutes of dialysis, as is done with standard hemodialysis (B-III). Concentration monitoring should guide further
VOLUME XX
maintenance doses.
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16.
Continuous Renal Replacement Therapy (CRRT): Loading doses of 20 to 25 mg/kg by actual body weight should be used in patients receiving CRRT at conventional, KDIGO-
recommended effluent rates of 20 to 25 mL/kg/h (B-II). Initial maintenance dosing for CRRT with effluent rates of 20 to 25 mL/kg/h should be 7.5 to 10 mg/kg every 12 hours (B-
II). Maintenance dose and dosing interval should be based on serum concentration monitoring, which should be conducted within the first 24 hours to ensure AUC/MIC targets
are met. In fluid overloaded patients, doses may be reduced as patients become euvolemic and drug Vd decreases. The use of CI vancomycin in patients receiving CRRT ap-
NUMBER XX
pears to be growing, and this method could be used in place of intermittent vancomycin dosing, especially when high CRRT ultrafiltrate/dialysate flow rates are employed (B-II).
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C. PEDIATRIC PATIENTS
17. Based on an AUC target of 400 mg · h/L (but potentially up to 600 mg · hr/L assuming a MIC of ≤1 mg/L) from adult data, the initial recommended vancomycin dosage for chil-
dren with normal renal function and suspected serious MRSA infections is 60 to 80 mg/kg/day, divided every 6 to 8 hours, for children ages 3 months and older (A-II).

ASHP REPORT
XXXX XX, 2020 21

22
C. PEDIATRIC PATIENTS
ASHP REPORT
18. The maximum empiric daily dose is usually 3,600 mg/day in children with adequate renal function (C-III). Most children generally should not require more than 3,000 mg/day,
and doses should be adjusted based on observed concentrations to achieve the AUC/MIC target. Early monitoring of observed concentrations is recommended when doses
exceed 2,000 to 3,000 mg/day (A-III). Furthermore, close monitoring of observed concentrations and renal function is prudent in patients with poor or augmented renal clear-
ance as resolution of their renal function may occur within the first 5 days of therapy.
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19. AUC-guided therapeutic monitoring for vancomycin, preferably with Bayesian estimation, is suggested for all pediatric age groups, based on developmental changes of vanco-
mycin CL documented from the newborn to the adolescent. Based on current available data, the suggestion for AUC-guided monitoring in pediatrics aligns with the approach
for adults, including the application of Bayesian estimation for 1 trough concentration, or first-order PK equations with 2 concentrations (B-II). The Bayesian AUC-guided
dosing strategy may be an optimal approach to individualize vancomycin therapy in pediatrics since it can incorporate varying ages, weights, and renal function. Both serum
VOLUME XX
concentrations of vancomycin and renal function should be monitored since vancomycin CL and creatinine CL are not always well correlated in pediatrics. Furthermore, ag-
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gressive dosing to maintain target AUC exposure and decrease the risk of potential AKI in treatment of MRSA infection necessitates drug monitoring.
20. Therapeutic monitoring may begin within 24 to 48 hours of vancomycin therapy for serious MRSA infections in children, as in adults (B-III). Any delay in therapeutic monitoring
should be based on severity of infection and clinical judgment. Dosing adjustment should be made for those with renal insufficiency, or those with obesity, or for those re-
ceiving concurrent nephrotoxic drug therapy. Following the initial dose, dosing adjustment is important for those with acute renal insufficiency, but subsequent adjustment (par-
NUMBER XX
ticularly within the first 5 days of therapy) may be necessary for those experiencing recovery of renal function. Sustained or subsequent decreases in dosage may be needed,
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particularly for those with chronic renal insufficiency and those receiving concurrent nephrotoxic drug therapy (B-III).
21. Vancomycin exposure may be optimally maintained below the thresholds for AUC of 800 mg · h/L and for trough concentrations of 15 mg/L to minimize AKI (B-II). The safety
of vancomycin above 80 mg/kg/day has not been prospectively evaluated. Avoiding vancomycin dosages of ≥100 mg/kg/day is suggested since they are likely to surpass
these thresholds (B-III).
XXXX XX, 2020

22. Insufficient data exist on which to base a recommendation for a loading dose among the nonobese pediatric population. Loading doses from adult studies may be considered,
but further studies are needed to elucidate the appropriate dose for the various pediatric populations, from neonates to adolescents (C-III).
23. Pediatric Obesity: Data suggest that obese children are likely to have vancomycin exposures that may be statistically greater than in normal-weight children when doses are
calculated on a mg/kg basis, but these differences are not known to be of sufficient clinical importance to suggest different mg/kg empiric vancomycin dosages in obese chil-
dren at this time. Similar to nonobese children, obese children < 12 years old, compared with those ≥ 12 years, may require higher mg/kg doses (B-II).
24. Pediatric Obesity: Therapeutic monitoring is likely to be of particular value in obese children, both for therapeutic response and to minimize the risk of AKI. The specific re-
commendations for therapeutic monitoring in nonobese children may also apply for obese children (B-II). A loading dose of 20 mg/kg by total body weight is recommended in
obese children (A-III).
25. Neonates: Dosages recommended to achieve an AUC of 400 mg · hr/L (assuming a MIC of 1 mg/L) in neonates and infants up to 3 months old range from 10 to 20 mg/kg
every 8 to 48 hours depending on postmenstrual age, weight, and SCr (A-II).
Abbreviations (not defined in body of table): AUC, area under the curve; BMD, broth micodilution; CL, clearance; ICU, intensive care unit; KDIGO, Kidney Disease: Improving Global Outcomes; MIC,
minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; SCr, serum creatinine; Vd, volume of distribution.

should also apply for neonates (see Disclosures was a speaker at the American Society for
recommendation 18, A-III). Dr. Wong-Beringer received a grant from Microbiology and European Society for
Merck & Co. and consulted for Rempex Clinical Microbiology and Infectious Diseases
Pharmaceuticals, INSMED, Merck & Co., ASM/ESCMID conference; served on the 2015–
Conclusion Nabriva Therapeutics, GlaxoSmithKline, 2019 Program Committee and was 2016–2018
Paratek Pharmaceuticals, Achaogen, Inc., Program Co-Chairperson for the American
To optimize vancomycin use for the
Bayer HealthCare, and SIGA Technologies. Microbiology Society; and was a member
treatment of serious infections caused of the 2017–2019 Antimicrobial Resistance
Dr. Bradley served on a planning committee

by MRSA, we recommend targeting an for the US Food and Drug Administration Committee for IDSA. Dr. Rybak received re-
AUC/MICBMD ratio of 400 to 600 (as- and European Medicines Agency at the search grants from Bayer Pharmaceuticals, the
suming an MICBMD of 1 mg/L) for em- American College of Clinical Pharmacy’s NIH Research Project Grant (RO1) Program,
annual meeting; participated in the design Merck, Allergan, the Michigan Department
piric dosing in both adult and pediatric
of a a pediatric clinical trial; served on an of Health and Human Services, Accelerate
patients to maximize clinical efficacy Diagnostics, Inc., NIH, Contrafect, Motif
executive committee for the United States
and minimize AKI risk. Furthermore, Committee on Antimicrobial Susceptibility Biosciences, and the Michigan Translational
the AUC should be therapeutically Testing; and consulted for Achaogen, Research and Commercialization Program;
monitored using 1 or 2 postdose con- Allergan, ContraFect, GlaxoSmithKline, and served as a grant review panel member
Janssen, Melinta, Merck, Nabrive, Pfizer, for NIH. The other authors have declared no
centrations (ie, a peak concentration
Theravance, and Zavante. Dr. Liu received a potential conflicts of interest.
measured after the early vancomycin
research grant from Nohla Therapeutics and
tissue distribution phase and a trough was a member of an Independent Efficacy References
level measured prior to the next dose), Adjudication Committee with Theravance. 1. Rybak MJ, Lomaestro BM,
preferably integrating the Bayesian ap- Dr. Le received research awards from the Rotschafer JC, et al. Therapeutic moni-
proach. The primary recommendations Sternfels Prize for Drug Safety Innovation, toring of vancomycin in adult patients:
are summarized in Table 2. The suc- Duke University, the National Institutes of a consensus review of the American
Health (NIH) and National Institute of Child Society of Health-System Pharmacists,
cessful use of these guideline recom- Health and Human Development, and JMI the Infectious Diseases Society of
mendations to positively impact patient Laboratories; was an invited advisory board America, and the Society of Infectious
outcomes may require multifaceted member for FDA, the Asian Pacific Health Diseases Pharmacists. Am J Health-Syst
interventions, including educational Foundation, and Infectious Diseases and Pharm. 2009; 66(1):82-98.
meetings, guideline implementation, Therapy journal. Dr. Levine served on the data 2. The periodic health examination.
safety monitoring board for Contrafect and Canadian Task Force on the Periodic
and dissemination of educational ma- served on an adjudication panel for Novartis. Health Examination. Can Med Assoc J.
terial on vancomycin dosing, moni- Dr. Lodise received grants from the Antibiotic 1979; 121(9):1193-1254.
toring, and nephrotoxicity.203,204 While Resistance Leadership Group (ARLG), Merck 3. Craig WA. Basic pharmacodynamics
valuable literature pertaining to adults, & Co, and Motif Bio PLC; served as a health of antibacterials with clinical appli-
children, and neonates has emerged outcomes project consultant for Paratek cations to the use of beta-lactams,
Pharmaceuticals, Allergan, Merck & Co., glycopeptides, and linezolid.
since the last vancomycin guideline, and Melinta Therapeutics; served on advi- Infect Dis Clin North Am. 2003;
future studies in all patient popula- sory boards for Paratek Pharmaceuticals, 17(3):479-501.
tions are necessary to address existing Motif Bio PLC, Achaogen, Nabriva, and 4. Drusano GL. Antimicrobial pharma-
gaps, including (1) efficacy data to sup- Tetraphase; served as a consultant to Paratek codynamics: critical interactions of
port vancomycin use in specific pa- Pharmaceuticals, ARLG, Allergan, Merck & ‘bug and drug’. Nat Rev Microbiol. 2004;
Co., Melinta Therapeutics, Motif Bio PLC, 2(4):289-300.
tient populations (including neonates Achaogen, Nabriva, and Tetraphase; and 5. Liu C, Bayer A, Cosgrove SE, Daum RS
and pediatric patients and patients was a speaker for Melinta Therapeutics, et al. Clinical practice guidelines by The
with renal disease and obesity) and for Tetraphase, and Sunovion. Dr. Maples served Infectious Diseases Society of America
other types of infections, (2) efficacy as an international working group member for the treatment of methicillin-
data for specific pathogens, including for the European Cystic Fibrosis Society and resistant Staphylococcus aureus
North American Cystic Fibrosis Society, infections in adults and children: execu-
coagulase-negative staphylococcus served on an advisory panel for the Centers tive summary. Clin Infect Dis. 2011;
and Streptococcus species; (3) robust for Disease Control and Prevention and Pew 52(3):285-292.
pediatric efficacy data for MRSA and Charitable Trust, and was on a committee for 6. Rybak MJ. The pharmacokinetic and
other gram-positive pathogens causing the Arkansas Health Department. Dr. Mueller pharmacodynamic properties of van-
different types of serious infections; received research grants from Merck & Co. comycin. Clin Infect Dis. 2006; 42(Suppl
and Hope Pharmaceutical and served on an 1):S35-S39.
(4) optimal loading and maintenance advisory board for NxStage and Baxter. Dr. 7. Kullar R, Leonard SN, Davis SL et al.
dosing regimens for patients with obe- Pai received a grant from Merck, Inc., served Validation of the effectiveness of a van-
sity and renal insufficiency; (5) efficacy on an advisory board for Shinogi and Paratek comycin nomogram in achieving target
benefit and the need for a dosing al- Pharmaceuticals, and served on the meet the trough concentrations of 15-20 mg/L
gorithm (specifically incorporating a professor program for Merck. Dr. Rodvold re- suggested by the vancomycin con-
ceived a grant from Theravance Biopharm, sensus guidelines. Pharmacotherapy.
loading dose followed by maintenance NIH, ARLG, and Allergan; consulted for BLC, 2011; 31(5):441-448.
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eTable 1. Summary of Adult and Pediatric Studies With Outcome Assessment
30
Method to
Population, Design, Method to Determine AUC/MIC
Authors(Year Published) Infection Type(s) Determine AUC24 MIC Breakpoint/ Target Outcome(s) Measured Reference
Moise-Broder et al (2004) Adults; retrospective; S. aureus Dose24h/clearance BMD ≥350BMD Bacterial eradication 10
lower respiratory infections
ASHP REPORT
(n = 107)
Kullar et al (2011) Adults; retrospective; Dose24h/clearance BMD/Etest ≥421BMD Composite failure (based on 30-day 11
MRSA bacteremia mortality and persistent signs &
(n = 320) symptoms of infection, >7 days of
|
bacteremia)
Holmes et al (2013) Adults; retrospective; MRSA bac- Dose24h/clearance BMD/Etest >373BMD/271.5Etest 30-day all-cause mortality 13
teremia
(n = 182)
VOLUME XX
|
Jung et al (2014) Adults; retrospective; Dose24h/clearance BMD/Etest <430BMD/ 398.5Etest 30-day all-cause mortality 15
MRSA bacteremia
(n = 76)
Brown et al (2012) Adults; retrospective; Bayesian Etest ≥211 Attributable mortality 12
NUMBER XX
MRSA bacteremia (n = 50)
|
Gawronoski et al (2013) Adults; retrospective; Bayesian Etest >292 Time to bacterial clearance 14
MRSA bacteremia & osteomyelitis
(n = 59)
Lodise et al (2014) Adults; retrospective; MRSA bac- Bayesian BMD/Etest 521BMD/303Etest Composite failure (based on 30-day 16
XXXX XX, 2020

teremia mortality, >7 days of bacteremia,
(n = 123) recurrence of bacteremia within
60 days of discontinuation of therapy)
Casapao et al (2015) Adults; retrospective; Bayesian BMD >600 Composite failure (based on >7 days of 17
MRSA bacteremia & endocarditis bacteremia and/or 30-day
(n = 139) attributable mortality)
Le et al (2015) Pediatric patients; retrospective; all Bayesian NA ≥800 Nephrotoxicity 19
pediatric infection types
(n = 680)
Finch et al (2017) Adults; retrospective, quasi-study AUC derived from NA <400 Nephrotoxicity 20
design; all infection types except multiple samples
UTI, SSSI, meningitis; surgical
prophylaxis
(n = 1,300)


eTable 1. Summary of Adult and Pediatric Studies With Outcome Assessment
Method to
Population, Design, Method to Determine AUC/MIC
Authors(Year Published) Infection Type(s) Determine AUC24 MIC Breakpoint/ Target Outcome(s) Measured Reference
Zasowski et al (2017) Adults; retrospective; pneumonia or Bayesian NA >700 Nephrotoxicity 21

bloodstream infection
(n = 323)
Neely et al (2018) Adults; prospective; all infection Bayesian NA ≥400 Nephrotoxicity, resolution or improve- 22
types ment in signs & symptoms, relapse,
(n = 252) and mortality
Lodise et al (2019) Adults; multicenter, observational, Bayesian BMD/Etest No threshold identi- Composite failure (based on >7 days of 23
prospective; MRSA bacteremia fied, but only 20% bacteremia and/or 30-day mortality)
of study population
had AUC/MICBMD
ratio of <420
Abbreviations: AUC, area under the curve; BMD, broth microdilution; MRSA, methicillin-resistant Staphylococcus aureus; NA, not applicable; SSSI, skin and skin structure infection; UTI, urinary tract infection.
|
VOLUME XX
|
NUMBER XX
|
ASHP REPORT
XXXX XX, 2020 31


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ASHP REPORT

Therapeutic monitoring of vancomycin for serious

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guideline recommendations to these

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macists, and a clinical pharmacologist

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thrice-weekly hemodialysis schedule, other patient populations have not been

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