GUI DELI NE

Practice guidelines for therapeutic drug monitoring

of vancomycin: a consensus review of the Japanese Society
of Chemotherapy and the Japanese Society of Therapeutic Drug
Monitoring
Kazuaki Matsumoto

Yoshio Takesue

Norio Ohmagari

Takahiro Mochizuki

Hiroshige Mikamo

Masafumi Seki

Shunji Takakura

Issei Tokimatsu

Yoshiko Takahashi

Kei Kasahara

Kenji Okada

Masahiro Igarashi

Masahiro Kobayashi

Yukihiro Hamada

Masao Kimura

Yoshifumi Nishi

Yusuke Tanigawara

Toshimi Kimura
Received: 22 January 2013 / Accepted: 1 April 2013
Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2013
Keywords Guideline Vancomycin Therapeutic drug
monitoring MRSA
Introduction
Vancomycin (VCM) is a glycopeptide antibiotic that was
introduced in Japan in November 1991. VCM is widely
used for the treatment of invasive multi-resistant gram-
positive bacterial infections, particularly those involving
methicillin-resistant Staphylococcus aureus (MRSA) [15].
VCM use is associated with adverse events, including red
man syndrome [6], nephrotoxicity [79], and ototoxicity
[10, 11]. Compared with other antimicrobial agents, the
therapeutic range is narrow in VCM, and therapeutic drug
monitoring (TDM) is required for maximizing efcacy
while minimizing the onset of these toxicities [1214].
Extensive pharmacokinetics studies in a variety of
patient populations have allowed physicians and pharma-
cists to target serum VCM concentrations precisely in a
relatively narrow range. Consensus review of the TDM of
K. Matsumoto Y. Takesue (&) N. Ohmagari H. Mikamo
M. Seki S. Takakura I. Tokimatsu Y. Takahashi
K. Kasahara
Committee of Practice Guidelines for TDM of Antimicrobial
Agents, Japanese Society of Chemotherapy, Nichinai Kaikan B1,
3-28-8 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
e-mail: karyo@jc4.so-net.ne.jp
T. Mochizuki K. Okada M. Igarashi M. Kobayashi
Y. Hamada M. Kimura Y. Nishi Y. Tanigawara
T. Kimura
Sectional Committee of Practice Guidelines for TDM,
Antimicrobial Agents, The Japanese Society of Therapeutic
Drug Monitoring, Niigata, Japan
K. Matsumoto
Department of Clinical Pharmacy and Pharmacology, Graduate
School of Medical and Dental Sciences, Kagoshima University,
Kagoshima, Japan
Y. Takesue
Department of Infection Control and Prevention, Hyogo Medical
College Hospital, Hyogo, Japan
N. Ohmagari
Disease Control and Prevention Center National Center for
Global Health and Medicine Hospital, Tokyo, Japan
T. Mochizuki
Department of Pharmacy, Shizuoka Cancer Center, Shizuoka,
Japan
H. Mikamo Y. Hamada
Department of Infection Control and Prevention, Aichi Medical
University Graduate School of Medicine, Aichi, Japan
M. Seki
Division of Infection Control and Prevention, Osaka University
Medical Hospital, Osaka, Japan
S. Takakura
Department of Infection Control and Prevention, Kyoto
University Hospital, Kyoto, Japan
I. Tokimatsu
Internal Medicine II, Oita University Faculty of Medicine, Oita,
Japan
Y. Takahashi
Department of Pharmacy, Hyogo Medical College Hospital,
Hyogo, Japan
K. Kasahara
Center for Infectious Diseases, Nara Medical University, Nara,
Japan
1 3
J Infect Chemother
DOI 10.1007/s10156-013-0599-4
VCM by the American Society of Health-System Phar-
macists, the Infectious Disease Society of America (IDSA),
and the Society of Infectious Disease Pharmacists was
published in 2009 [14], and recommendations for VCM
dosing and monitoring were described in clinical practice
guidelines by the IDSA for the treatment of MRSA
infections in adults and children [15]. Despite the presence
of these currently published guidelines, the Japanese
Society of Chemotherapy (JSC) and the Japanese Society
of Therapeutic Drug Monitoring (JSTDM) decided to
develop a novel clinical practice guideline for TDM of
VCM for the following reasons.
First, denitive recommendations for TDMand the dosing
of VCM were not stated in these guidelines for patients with
deterioration of renal function and those undergoing he-
modialysis or continuous renal replacement therapy (CRRT).
Second, because recent publishedguidelines advocatedVCM
intensive dosing to achieve a higher trough concentration for
complicated MRSA infections, the committee considered
that safety-conscious administration planning should be
addressed to prevent the occurrence of VCM-associated renal
failure. Third, as the practice of routine monitoring and initial
dosing of VCMwere inconsistent among institutions in Japan
[16] where administration planning with simulation software
is in widespread use, a consensus in regard to TDMand VCM
dosing was required.
This guideline evaluated the scientic data associated
with serum VCM monitoring and provided recommenda-
tions based on the available evidence. Potential limitations
of this guideline, however, include the ndings that few
prospective or randomized trials of TDM VCM in the
treatment of MRSA infections are available and that most
of the published literature describes observational studies.
Methods
Clinical practice guidelines for TDM of VCM were
reviewed by a practice guideline committee that con-
sisted of 18 experts in TDM convened from the JSC and
the JSTDM. The committee completed a review of
papers published since 2000 and also analyzed the data
before 1999 if necessary. In evaluating the evidence
regarding TDM, the committee followed the Canadian
Task Force [17], including a systematic weighting of the
quality of the evidence and recommended grade of
recommendation by the Minds classication (Table 1).
The committee discussed in person on 7 occasions and
533 times by e-mail via mailing lists. Draft guidelines
of the executive summary were uploaded to the home
page of JSC and JSTDM. Feedback from external public
comments was obtained between April 9, 2012 and May
8, 2012. The guidelines in the Japanese version were
approved by the JSC and JSTDM Board of Directors
and were published in the Japanese Journal of Chemo-
therapy in June 2012.
All members of the clinical practice guideline commit-
tee complied with the JSC policy on conict of interest,
which requires disclosure of any nancial or other interest
that might be construed as constituting an actual, potential,
or apparent conict. Potential conicts of interest are listed
in the Acknowledgments section. At 3-year intervals, the
committee will determine the need for revisions to the
guidelines.
Indications of TDM
Executive summary
1. TDM should be performed in patients who are likely to
receive courses of VCM therapy of more than 3 days
(B-II).
2. TDM should be planned from the start of VCM
therapy in patients receiving intensive dosing of VCM,
at high risk of nephrotoxicity, with serious infections,
unstable (deteriorating or improving) renal function,
hemodialysis, obesity, low body weight, and special
conditions that cause uctuating volumes of distribu-
tion (C1-III).
Literature review
A consensus review for TDM of VCM published in the
United States showed that TDM was recommended for
patients receiving courses of VCM therapy exceeding
35 days [14]. Pritchard et al. [18] reported that the
K. Okada T. Kimura
Department of Pharmacy, Tokyo Womens Medical University
Hospital, Tokyo, Japan
M. Igarashi
Department of Pharmacy, Toranomon Hospital, Tokyo, Japan
M. Kobayashi
Department of Pharmacy, Kitasato University Hospital,
Kanagawa, Japan
M. Kimura
Department of Pharmacy, Aichi Medical University Hospital,
Aichi, Japan
Y. Nishi
Department of Pharmacy, Kyorin University School of
Medicine, Tokyo, Japan
Y. Tanigawara
Department of Clinical Pharmacokinetics and
Pharmacodynamics, Keio University School of Medicine,
Tokyo, Japan
J Infect Chemother
1 3
average onset of nephrotoxicity occurred 5.6 days after
VCM therapy. As VCM was changed to b-lactams if
causative organisms proved to be methicillin-sensitive
with the susceptibility test result, which is usually
obtained after 3 days of isolation, it is considered to be a
practical approach that TDM is indicated for patients
receiving VCM for more than 3 days. Patients with heart
failure tend to show higher actual measurement concen-
trations than predicted values [19]. It is difcult to pre-
dict the blood concentration in obese patients and those
with unstable renal function [20]. TDM is suitable for
specic populations in which it is difcult to predict the
blood concentration [14, 1823] and for patients receiv-
ing aggressive treatments with high-dose VCM, which
causes a high incidence of adverse effects.
Pharmacokineticspharmacodynamics (PKPD)
Executive summary
1. Although it is considered that an AUC/MIC ratio
C400 is the PK-PD parameter associated with a
clinical and bacteriological response to VCM ther-
apy, routine AUC assessment is not recommended in
clinical practice (C2-III). To calculate AUCfor any other
purpose, blood collection from at least two points is
required.
2. In clinical practice, trough concentrations are used as a
surrogate of AUC (B-II). Trough concentration, how-
ever, is not an appropriate indicator to achieve an
AUC/MIC ratio C400 in patients who are administered
VCM every 8 h or at even shorter intervals, those with
impaired renal function, and children.
3. Trough concentrations are used to monitor for neph-
rotoxicity (B-II).
4. There is no consensus that monitoring for ototoxicity
is able to prevent the occurrence of adverse events
(C2-III). Monitoring is considered for patients receiv-
ing additional use of ototoxic agents, such as amino-
glycosides (C1-III).
Literature review
In patients with lower respiratory tract infections caused by
MRSA, the targeted AUC/MIC ratio was showed to be
C400 for a successful microbiological outcome [24].
Patients with VCM AUC/MIC ratio \421 were found to
have signicantly higher rates of failure than patients with
AUC/MIC ratio C421 in the treatment of MRSA bactere-
mia, and independent predictors of VCM treatment failure
were AUC/MIC ratio \421, nosocomial-acquired infec-
tion, initial VCM trough \15 lg/ml, and VCM MIC
[1 lg/ml [25]. Routine AUC assessment is not recom-
mended in clinical practice. Information available from
AUC is generally interchangeable in trough concentrations.
Many authors have shown an incremental risk of neph-
rotoxicity associated with higher VCM doses, ranging from
12 to 42.7 % of patients [8, 9, 21, 24, 25]. The risk increases
with higher VCM maximum trough levels, longer duration
of VCM use, concomitant use of other nephrotoxic agents,
and in patients who are critically ill or have previously
compromised renal function [21]. Saunders [26] investi-
gated post-dose increases in serum peak concentrations in
routine clinical practice. The results suggested that so long
as trough concentrations did not exceed 15 lg/ml, peak
levels did not exceed normally accepted safe concentrations,
and the conclusion was that routine monitoring of peak
levels was not required from a safety standpoint in VCM.
For ototoxicity, however, there was no signicant dif-
ference in the highest VCM trough concentrations between
Table 1 Grading system for ranking recommendations and evidence level adopted in the guideline
Category,
grade
Denition
Strength of recommendation
A Good evidence to support a recommendation for use
B Moderate evidence to support a recommendation for use
C1 Recommendation for use regardless of poor evidence
C2 Poor evidence to support a recommendation for use
D Good-to-moderate evidence to support a recommendation against use
Quality of evidence
I Evidence from C1 properly randomized, controlled trial
II Evidence from C1 well-designed clinical trial, without randomization from cohort or case-controlled analytcal studies, multiple
time-series, or dramatic results from uncontrolled experiments
III Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert
committees
J Infect Chemother
1 3
patients with and without worsening audiograms [27].
Incidence of hearing impairment detected by audiogram
was 0 % in patients \53 years old and 19 % in those
C53 years old. Age was a signicant factor in the occur-
rence of ototoxicity regardless of the blood concentrations
of VCM [27].
Methods of TDM
Executive summary
1. In TDM of VCM, trough concentrations should be
measured (B-II). Routine measurement of peak con-
centrations is not recommended (C2-III).
2. Trough concentrations should be assessed at steady
state. In patients with normal renal function who are
administered VCM twice daily, a trough sample is
obtained before the fourth or fth dose (on day 3)
(B-II). In patients with deteriorated renal function,
trough concentrations on day 3 do not reach steady
state because of extended half-life, and underestima-
tion should be considered in such patients (C1-III).
3. Weekly monitoring is recommended after initial TDM.
More frequent follow-up trough monitoring is required
in patients with hemodynamic instability, high-dose
VCM administration, unstable renal function (i.e.
deteriorating or improving), and those at high risk
for nephrotoxicity (C1-III).
4. A trough sample is obtained within 30 min before
administration. Peak concentration should be assessed
after the completionof tissue distribution, anda sample is
obtained 12 h after the end of infusion (C1-III).
Literature review
The time required for a drug concentration to reach steady
state is determined by the drugs half-life. It takes four
half-lives to reach 93.8 % of the steady state, and in most
clinical situations, the attainment of steady state can be
assumed after three to ve half-lives [28, 29]. As the half-
life of VCM is 612 h in patients with normal renal
function, steady-state concentration is achieved before the
fourth to fth dose (on day 3) [14]. As a consequence of the
prolonged half-life in patients with impaired renal function,
trough concentrations measured on day 3 do not reach
steady state [30, 31]. Takahashi et al. [32] demonstrated
that there was a signicant difference in relative increase of
follow-up minimal concentration (C
min
) between TDM
conducted on days 3 and 4 in patients whose creatinine
clearance (C
cr
) was\80 ml/min (34.5 vs. 16.6 %). If initial
TDM is performed on day 3 in patients with impaired renal
function, the subsequent VCM dosage should be adjusted
in anticipation of a further increase of C
min
.
As a proportional relationship is observed between the
given dose and blood concentration under steady-state
conditions, the prediction of the subsequent trough con-
centration is relatively accurate in patients in whom the
dosage regimen is altered based on the initial trough level.
Pharmacokinetics modeling software is a potential tool to
improve the timeliness of achieving adequate dosing by
allowing concentrations to be determined before the steady
state [20].
Maximal concentration (C
max
), which is a term used in
pharmacokinetics, refers to the maximal concentration that
a drug achieves immediately after the completion of drug
administration. Different from C
max
, peak concentration
(C
peak
) should be assessed after completion of distribution
equilibrium between the drug in tissues and in plasma. The
initial decay half-life (at
1/2
) results primarily from drug
distribution in the tissue volume of distribution. Because
the at
1/2
of VCM is 0.40.5 h, the time to reach distribution
equilibrium is 12 h after the end of 1-h infusion [31, 33].
Target of serum concentrations in TDM
Executive summary
1. Trough concentrations of 1020 lg/ml are recom-
mended (B-II).
2. Trough concentration should be maintained at C10 lg/
ml to improve the clinical outcome of MRSA infec-
tions and to avoid the development of resistance (B).
3. Trough concentrations [20 lg/ml are not recom-
mended because of the risk of nephrotoxicity (D-II).
4. To improve the outcome of serious infections, such as
bacteremia, infective endocarditis, osteomyelitis, men-
ingitis, and hospital-acquired and healthcare-associated
pneumonia caused by MRSA, VCM trough concentra-
tions of 1520 lg/ml are recommended (B-II).
Literature review
Patel et al. [33] reported that when trough concentrations
were 1520 lg/ml, the observed probability of achieving
an AUC/MIC ratio C400 was 100 % at MIC values of 0.5
and 1 lg/ml. When the analysis was restricted to patients
with trough concentrations between 10 and 15 lg/ml, the
observed probability of target attainment was 100 % at an
MIC value of 0.5 lg/ml and variable according to a sim-
ulated regimen at 1 lg/ml. Trough concentration between
10 and 15 mg/L did not consistently result in AUC/MIC
ratios C400 when the MIC was 1 lg/ml.
J Infect Chemother
1 3
In Japan, VCM MIC
50
and MIC
90
for MRSA are 1.0 and
2.0 lg/ml, respectively [34]. Considering that MIC of the
main isolates is 1 lg/ml, trough concentrations of
1520 lg/ml are required to assure the achievement of the
targeted AUC/MIC C400 in all patients. Mohr and Murray
[35] also reported similar ndings. Kullar et al. [25] reported
that initial VCM trough \15 lg/ml was an independent
predictor of VCM failure in patients with MRSA bactere-
mia. A consensus review of TDM of VCM [14] and clinical
practice guidelines for the treatment of MRSA infections
[15] recommended a VCM target trough concentration of
1520 lg/ml for serious infections, such as bacteremia,
infective endocarditis, osteomyelitis, meningitis, pneumo-
nia, and severe skin and soft tissue infections caused by
MRSA. Australian Therapeutic Guidelines recommended a
target trough range of 1218 lg/ml from 2010 [36]. It is
reported that the emergence of hetero-VCM intermediate S.
aureus was detected in patients with a history of VCM use
and trough concentrations of \10 lg/ml [3739].
Although the denition of VCM-induced nephrotoxicity
has varied, a reasonable composite from the literature
denes this adverse effect as an increase of[0.5 mg/dl or a
50 % increase in serum creatinine over the baseline in
consecutively obtained daily serum creatinine values. An
exposureresponse relationship was observed between the
initial VCM trough concentrations and the occurrence of
nephrotoxicity [40]. The occurrence of nephrotoxicity
signicantly increased as the initial trough concentration
increased. The incidence rates of nephrotoxicity for trough
concentrations of B10, 1015, 1520 and[20 lg/ml were
5, 21, 20 and 33 %, respectively. Several reports have
shown that trough concentrations of [20 lg/ml had a
signicantly higher incidence of nephrotoxicity than those
of \20 lg/ml [25, 41, 42].
Initial administration plan
Executive summary
1. Doses of 1520 mg/kg (as actual body weight) given
every 12 h are recommended in patients with normal
renal function. Doses [1.5 g should be administered
with care, and should not exceed 2 g per dose (C1-III).
2. Continuous infusion regimens are not recommended
(D-II).
3. To avoid red man syndrome, VCM doses of 1 g should
be administered intravenously over an infusion period
of 1 h. For higher doses, the duration of infusion
should be extended by more than 30 min per 500 mg
(B-II).
4. Unexpectedly high trough concentrations can occur
with the use of a normal dosage in patients with heart
failure, dehydration and deteriorating general condi-
tion. Changes in the patients clinical status should be
observed carefully during therapy (C1-III).
5. There are limited data to support the safety of
sustained trough concentrations of 1520 lg/ml. Initial
therapy should be conducted at the normal dosage or
target trough concentrations of 1015 lg/ml. Dosage
can be adjusted to achieve trough concentrations of
1520 lg/ml after the acquisition of initial trough
concentrations according to observed concentrations,
clinical course, change in images of infectious lesions,
and the MIC value of isolated MRSA (C1-III).
6. In some instances, the dosage may be designed to
achieve a trough concentration of 1520 lg/ml at the
start of therapy in patients with serious conditions or
complicated infections, as already mentioned. In such
cases, the initial dosage should be determined in
consideration of the balance between clinical efcacy
and risks of nephrotoxicity (C1-III).
7. A loading dose of 2530 mg/kg at initial administra-
tion can be used to facilitate rapid attainment of the
target trough concentration in patients with serious or
complicated infections (C1-III).
8. For isolates with VCM MIC 2 lg/ml, an alternative to
VCM may be considered (C1-III).
9. For isolates with VCM MIC 4 lg/ml [VCM-interme-
diate S. aureus (VISA)], an alternative to VCM should
be used. Teicoplanin might not be an appropriate
alternative because of cross-resistance with VCM.
Further studies are required in regard to the clinical
efcacy of daptomycin in the treatment of VISA.
Literature review
There are limited data on VCM dosing in obese patients.
There was no signicant difference in the daily dose (in
milligrams per kilogram per day) evaluated from the actual
body weight required to produce a steady-state concentra-
tion of 15 lg/ml between the normal weight group and
morbidly obese group (23.4 1.5 vs. 24.0 3.4 mg/kg/
day) [43]. In addition, strong correlations were found
between total body weight and either the volume of dis-
tribution or total body clearance (correlation coefcient
0.981). These results implied that actual body weight
should be used to calculate VCM doses even for morbidly
obese patients. As it is difcult to predict blood concen-
trations [20] and the increased risk for nephrotoxicity in
obese patients [22, 44], the dosage should be adjusted on
the basis of VCM concentrations obtained from initial
TDM to maintain an adequate therapeutic range.
Clinical practice guideline by IDSA recommended a
VCM dose of 1520 mg/kg given every 812 h for adult
J Infect Chemother
1 3
patients with normal renal function, and 15 mg/kg every
6 h in children [15]. VCM 15 mg/kg or 1 g every 12 h is
the standard adopted regimen in many clinical studies [41,
4547]. Leu et al. [48] developed a VCM nomogram for
achieving a trough of 1520 lg/ml, and 1 g VCM was
administered every 8 h to patients whose body weight was
\80 kg, and C
cr
was 70 ml/min or more. Although
microbiological eradication was higher than with conven-
tional dosing, the incidence of a trough level [20 lg/ml
was 23.5 %, and nephrotoxicity occurred in 28.6 % of
patients.
To avoid excess use of the administration three times
per day of a standard single dose in general clinical prac-
tice, we recommended doses of 1520 mg/kg given every
12 h for adult patients with normal renal function. In
addition, the recommendation for young patients was
15 mg/kg every 6 h for infants and school children, and
15 mg/kg every 8 h for adolescents as mentioned later in
Chapter 6. TDM in patients under particular clinical
conditions and pediatric consideration.
A common error in VCM monitoring is using trough
concentration target ranges without accounting for the
dosing frequency. Although trough concentrations are used
as a surrogate of AUC in clinical practice, trough con-
centrations of 1520 lg/ml are not appropriate indicators
to achieve the AUC/MIC ratio of C400 in patients who are
administered VCM every 68 h. The same AUC and pre-
sumably the same efcacy will be achieved whether the
total daily dose is given at 8- or 12-h dosing intervals.
Trough concentrations, however, will be different for the
same total daily dose when different dosing intervals are
used, despite the same total VCM exposure and AUC. For
these reasons, splitting a particular total daily dose into
more than two equal portions to achieve higher trough
concentrations (i.e. 800 mg per 8 h instead of 1,200 mg per
12 h) is not recommended for the initial administration plan
in adult patients.
There was a doseresponse relationship between
increasing the daily dose of VCM administered, and the
risk of nephrotoxicity, and likelihood was highest among
intensive care unit (ICU) patients [33]. The incidence of
nephrotoxicity was 9 % for a dose of 1.5 g and 14 % for
2.0 g given every 12 h not in the ICU, and 25 and 34 % for
these dosages in the ICU, respectively. Doses [2.0 g
should be avoided, especially in patients who have any risk
for VCM-induced nephrotoxicity. If a maximum dose of
2 g given every 12 h cannot achieve the target trough
concentration after adjusting on the basis of TDM results,
administration three times a day or an alternative to VCM
should be considered.
In a retrospective cohort study of patients receiving
VCM by continuous infusion, 15.7 % of patients devel-
oped nephrotoxicity [49]. Independent risk factors for
nephrotoxicity were a VCM steady-state concentration of
[28 lg/ml (relative risk 21.1), arterial hypertension, and
the concurrent use of aminoglycosides or loop diuretics.
Ingram et al. [50] compared VCM continuous infusion with
intermittent administration. Although the ultimate preva-
lence of nephrotoxicity was identical, continuous infusion
was associated with a slower onset of nephrotoxicity. In a
study of ICU patients after elective open-heart surgery,
nephrotoxicity was observed in 27.7 % with continuous
infusion, and 36.7 % with intermittent administration [51].
Although there was no signicant difference in C
cr
before
VCM therapy, the minimum C
cr
during VCM therapy was
22 ml/min in the intermittent administration group and
36 ml/min in the continuous infusion group (P = 0.015).
It was shown by meta-analysis that the continuous
infusion group was associated with a signicantly lower
risk of nephrotoxicity than the VCM intermittent infusion
group [52]; however, a study of high trough concentration
targeted at 2025 lg/ml to treat osteomyelitis [53] had a
considerable effect on the result of this meta-analysis. The
use of VCM continuous infusion is based on the assump-
tion that the time above the MIC is the PKPD parameter
predicting VCM activity. This assumption, however,
turned out to be inaccurate with the AUC/MIC being the
key PKPD parameter for VCM. In spite of some reports
already described, there is no apparent evidence that con-
tinuous infusion has clinical superiority to intermittent
infusion, and VCM continuous administration was dis-
couraged in this guideline.
VCM-induced red man syndrome is mediated in part
by histamine release and manifests as tingling and ushing
of the face, neck, and upper torso [6]. It is most likely to
occur when larger dosages are infused rapidly. VCM is
generally administered intravenously over an infusion
period of 1 h to avoid red man syndrome. Healy et al. [54],
however, compared the occurrence of red man syndrome
between 1 and 2-h infusion by a randomized, double-blind
study in patients receiving 1 g doses. Of 10 subjects, 8
showed evidence of the syndrome during 1-h infusion,
whereas only 3 of the 10 subjects showed development (all
mild) during 2-h infusion. The 1-h infusion was associated
with a signicantly greater peak concentration of histamine
in plasma. In another report, the syndrome occurred in 9 of
11 volunteers who received 1 g doses and in none of those
who received 0.5 g doses [55]. As their incidence rates of
red man syndrome were extremely high as compared with
the rates in clinical practice, we recommended in this
guideline that a VCM dose of 1 g should be administered
intravenously over an infusion period of 1 h. For higher
dosages, a consensus review of TDM of VCM in the
United States showed that when individual doses exceed
1 g (i.e., 1.5 and 2 g), the infusion period should be
extended to 1.52 h [2].
J Infect Chemother
1 3
Recent guidelines recommend more intensive VCM
dosing schedules to maintain VCM troughs between 15 and
20 lg/ml to improve outcomes. The widespread use of
these intensive regimens, however, has been associated
with an increase in VCM-associated nephrotoxicity. van
Hal et al. [56] performed a meta-analysis, and higher
troughs (C15 mg/L) were associated with an increased
odds ratio of nephrotoxicity (2.67). Although nephrotoxi-
city was reversible in the majority of cases, short-term
dialysis was required in 3 % of episodes.
Lodise et al. [44] reported a signicant difference in the
occurrence of nephrotoxicity between patients receiving a
larger daily dose (C4 g) and the standard dose (34.6 vs.
10.9 %). Initial trough levels were 18.4 and 9.1 lg/ml,
respectively. There are limited data to support the safety of
an intensive regimen aiming at trough levels of 1520 lg/
ml at the start of therapy. In addition to high trough con-
centrations, signicant risk factors for VCM-associated
nephrotoxicity are the concomitant administration of
nephrotoxic agents (aminoglycosides, amphotericin B,
furosemide, non-steroidal anti-inammatory drugs and
radiopaque dye) [21, 22, 49], prolonged duration of VCM
therapy [21, 42], use of a vasopressor [42], patients with
renal impairment [21, 42, 57], or dehydration [42, 57] and
critically ill patients [21]. As ICU patients tend to have the
risk factors just mentioned, they are likely to develop
nephrotoxicity during VCM therapy [40]. An ICU stay was
selected as a factor independently associated with the
occurrence of nephrotoxicity in multivariate logistic
regression analysis (odds ratio 3.25). The threshold of the
initial VCM trough causing the predicted probability of
nephrotoxicity of [20 % was [10 lg/ml in ICU patients
and [20 lg/ml in non-ICU patients.
Hidayat et al. [58] reported that 10 of 11 patients with
VCM-induced renal impairment had also received amino-
glycosides or amphotericin B. The risk of nephrotoxicity
increased incrementally as therapy continued in patients
who attained trough concentrations of 1520 lg/ml; 6 %
for B7 days, 21 % for 814 days and 30 % for [14 days.
Wong-Beringer et al. [22] reported that high-dose VCM
therapy targeting a trough concentration of 1520 lg/ml
was safe in patients who did not have any signicant risk
factors for nephrotoxicity (i.e. vasopressors, concomitant
nephrotoxin), those with a limited duration of VCM ther-
apy (B14 days), and obese patients who were dosed using
their ideal body weight.
Clinical practice guidelines by IDSA for the treatment of
MRSA [15] showed that a loading dose of 2530 mg/kg
can be used to facilitate rapid attainment of the target
trough concentration in seriously ill patients. In a small
study of critically ill patients with serious S. aureus
infections, a loading dose of 25 mg/kg infused at a rate of
500 mg/h was found to be safe without producing toxic
peak concentrations [59]. Li et al. [60] administered a
loading dose C25 mg/kg in 26 % of patients treated with
VCM, and target AUC/MIC C400 was achieved in 32.3 %.
Truong et al. [61] reported the effect of introducing a
loading dose in VCM therapy. In the pre-intervention
period, a loading dose was not administered to any patients
treated with VCM. With intervention, 63.9 % of patients
were administered 2 g as the loading dose, and the mean
initial trough concentration was 15.7 lg/ml in loaded
patients, which was signicantly higher than 9.8 lg/ml in
the pre-intervention period. Recent nomograms adopted a
loading dose even in patients with decreased renal function
[21, 62]. Although the loading dose of initial VCM
administration without alteration of the standard mainte-
nance dose is a simple approach to reach the target trough
level recommended in recent guidelines, further studies are
considered to be required to standardize this intensive
administration.
Recent data suggested that VCM was less effective
against MRSA infections with MIC values at the higher
end of the susceptibility range [6368]. Soriano et al. [63]
demonstrated that independent predictors of mortality in
multivariate analysis in patients with MRSA bacteremia
included the receipt of empirical VCM and having isolates
with a VCM MIC of 2 lg/ml (odds ratio 6.39). Takesue
et al. [64] described that isolates with VCM 2 lg/ml, ICU
stay, and liver cirrhosis were independent risk factors for
death in patients with MRSA bacteremia, and initial
appropriate therapy lowered the risk in multivariate anal-
ysis. A systemic review and meta-analysis indicated that
VCM MIC was signicantly associated with mortality from
MRSA infections irrespective of the source of infection or
MIC methodology (odds ratio 1.64) [65]. This mortality
association was predominantly driven by bloodstream
infections and isolates with VCM 2 lg/ml by Etest (odds
ratio 1.72). In addition, VCM MIC was signicantly
associated with treatment failure (odds ratio 2.69).
The incidence of strains with VCM MIC 2 lg/ml varied
considerably among several studies [6972]. As reasons for
this inconsistency, the increase of these strains could be
caused by either extensive use of VCM or the dissemina-
tion of clones with less sensitivity to VCM. In addition,
Etest and other methods had a tendency to show MIC
results that were higher than those reported by reference
broth microdilution [7375]. MIC creep may be a
technical artifact that depends on the test method used. For
this reason, IDSA guidelines for the treatment of MRSA
infections recommended that for isolates susceptible to
VCM according to the Clinical and Laboratory Standards
Institute (CLSI) break point including MIC 2 lg/ml, the
patients clinical response should determine the continued
use of VCM, independent of the MIC [15]. It was also
reported that a low success rate of VCM and poor
J Infect Chemother
1 3
prognosis was not apparent in 2 lg/ml MIC strains isolated
from MRSA infections other than bacteremia [64]. In
addition, data are needed to determine whether other agents
can remedy the outcomes observed with VCM for MRSA
infections with elevated VCM MIC values.
Although no apparent consensus was not attained in regard
to the clinical evaluation of isolates with MICs of 2 lg/ml, as
already mentioned, the committee suggested that for isolates
with VCM MIC 2 lg/ml, an alternative to VCM may be
considered, especially in patients with serious MRSA infec-
tions suchas bacteremia inwhich treatment delay causes poor
prognosis. As for VISA, on the other hand, a growing amount
of microbiological and clinical data has indicated that isolates
of MRSA were less likely to respond to VCM therapy when
the VCM MICs were 4 lg/ml [76, 77].
Considering the current problems with VCM treatment,
it is necessary to clarify whether new anti-staphylococcal
agents, such as linezolid, daptomycin, or tigecycline, are
superior to VCM when the strain has VCM MIC[1 lg/ml.
Cui et al. [78] demonstrated a strong positive correlation
between reduced daptomycin susceptibility and VCM
resistance in VISA. Kelley et al. [79] reported that the
percentage of daptomycin non-susceptible isolates was
62 % by Etest and 38 % by broth microdilution for VISA.
Although there were conicting data for MRSA with MICs
of 2 lg/ml [80, 81], clinicians should show caution when
using daptomycin in situations where serious VISA infec-
tion is a possibility.
TDM in patients under particular clinical conditions
and pediatric considerations
Executive summary
Patients with impaired renal function
1. Standard or reduced single doses are givenevery 24 h or at
even longer intervals according to renal function (C1-III).
2. To facilitate rapid attainment of the target trough
concentration, experts recommend an initial loading
dose regardless of renal function (C1-III).
3. As no nomogram predicts VCM concentrations pre-
cisely especially in patients with impaired renal
function, dosage should be adjusted individually based
on measured VCM concentrations (B-III).
Patients receiving hemodialysis
1. Initial dose of 1525 mg/kg (as actual body weight) is
recommended. As an initial dose of 15 mg/kg may
not be adequate to achieve recommended trough
concentrations, experts recommend that a loading dose
of 2025 mg/kg should be administered (C1-III).
2. As a greater amount of VCM is removed during
hemodialysis (HD), doses of 500 mg (7.510 mg/kg)
after each dialysis treatment are given as maintenance
doses (C1-III). Weekly VCM dosing results in sub-
therapeutic serum levels and should be abandoned in a
high-ux setting (D-III).
3. Achievement of a steady-state concentration is delayed in
patients onHD. Althoughthere is noevidence concerning
the timing of TDM in patients undergoing HD, the
committee recommended that TDM is performed within
1 week after the start of VCM therapy (C1-III).
4. There is no consensus concerning the necessity of
follow-up TDM in patients with HD in whom the
dosage regimen was not altered (unresolved issue).
5. Blood samples for TDM should be drawn before dialysis
treatment. Because of the rebound phenomenon, trough
levels immediately after the completion of hemodialysis do
not reect the exact drugconcentrations of patients (C1-III).
6. Although the maintenance of trough concentrations of
\20 lg/ml is desirable, there is no consensus con-
cerning the concentrations causing adverse events in
patients undergoing HD (unresolved issue).
Patients receiving continuous renal replacement therapy
1. An initial dose of 1520 mg/kg (as actual body
weight) is generally administered. Some experts rec-
ommend that a higher loading dose is required to
achieve target trough concentrations (C1-III).
2. As a great amount of VCM is removed during
continuous venovenous hemodialtration (CVVHDF),
doses of 500 mg (7.510 mg/kg) are given every 24 h
as maintenance doses. It is recommended to adjust the
doses according to the result of TDM (C1-III).
3. In patients with residual renal function in whom the
main purpose of CVVHDF is removal of several
mediators that cause detrimental effects during sepsis,
increased VCM dosing may be required according to
the results of TDM (C1-III).
Patients receiving continuous ambulatory peritoneal
dialysis (CAPD)
1. Intraperitoneal VCM is well absorbed and therapeutic
concentration in serum can be achieved over 1 week
with a single intraperitoneal administration (i.e.,
30 mg/kg) (B-II).
2. To treat CAPD-related peritonitis, doses of 1530 mg/
kg are given intraperitoneally every 57 days in anuric
J Infect Chemother
1 3
patients. For patients with residual renal function, the
doses are increased by 25 % (B-II).
Pediatric considerations
1. First trough concentration can be obtained before
the fourth dose (on day 2 if administered every 6-h)
(C1-III).
2. VCM 15 mg/kg every 6 h is recommended for infants
and children, and doses should be adjusted according
to the result of TDM. Although few data are available
to guide the dosing regimen in adolescent patients of
C12 years old, doses of 15 mg/kg may be given every
8 h (C1-III).
3. To date, there are limited data to support the efcacy
and safety of targeting trough concentrations of
1520 lg/ml in children, and additional study is
required (unresolved issue).
Literature review
Patients with impaired renal function
Patients with impaired renal function are at increased risk
of developing acute renal injury and needing subsequent
renal replacement therapy. It is unknown if the current
higher target trough levels (i.e. 1520 lg/ml) recom-
mended by guidelines [14, 15] are appropriate for the
population with impaired renal function. Attaining high
trough levels is challenging in these patients because of the
higher risk of developing nephrotoxic serum levels of
VCM. An alternative to VCM (i.e. teicoplanin, daptomy-
cin, or linezolid) should be considered for patients with
severely impaired renal function who have not yet been
treated with dialysis.
Declining renal function has been associated with a
marked reduction in the elimination of VCM; therefore,
dosage adjustments should be performed to avoid the
accumulation of this drug. Adjustments in the dosage
regimen are characterized by reducing the maintenance
dose, prolonging the dosing interval, and a hybrid of these
adjustments in patients with impaired renal function.
Marked variability exists in the dosage schedules proposed
for VCM. Substantial pharmacokinetics studies and clinical
verication are required to develop an optimal nomogram
in these patients.
Moellering et al. [82] developed a nomogram with daily
dosage adjustments in patients with various degrees of
impaired renal function. This nomogram requires from
several days to a few weeks to achieve steady-state con-
centrations. In general, standard or reduced maintenance
doses have been given every 24 h or at even longer inter-
vals in patients with renal dysfunction. Matzke et al. [83]
developed a nomogram with a dosing interval (s) adjust-
ment. An initial dose of 25 mg/kg followed by 19 mg/kg
every s (determined from the nomogram) achieved serum
peak concentrations of 30 lg/mL and trough concentra-
tions of 7.5 lg/mL. However, there are limited data to
support the clinical efcacy of VCM use over marked
prolonged intervals (i.e. more than 4872 h).
The time required to reach a steady state by the
administration of a maintenance dose at a constant dosing
interval was shown to be approximately ve half-lives [28,
29]. VCM has a markedly prolonged plasma half-life in
patients with renal dysfunction. Therefore, the adminis-
tration of a loading dose is required to facilitate the rapid
attainment of trough concentrations within the therapeutic
window [21, 62] (Table 2).
Established nomograms aim for target concentrations
that are generally lower than those currently recommended.
Recently, Kullar et al. [84] developed a VCM dosing
nomogram to attain recommended trough serum concen-
trations. The median initial trough concentration was
17.5 lg/ml, with 58 % of patients achieving the initial
target trough of 1520 lg/ml. Leu et al. [48] developed
two VCM nomograms with trough targets at 515 and
1520 lg/ml. With these nomograms, patients frequently
have trough concentrations within the target range and also
a slightly better outcome than that with conventional
Table 2 VCM dosing according to renal function (nomogram targeted comparatively high trough concentration)
Initial dose Maintenance dose
Vandecasteele
et al. [92]
2530 mg/kg Estimated glomerular ltration rate (ml/min/1.73 m
2
) (chronic kidney disease stage)
]90 (0) 6089 (2) 4559 (3A) 3044 (3B) 1529 (4) \15 (5)
1520 mg/
kg q 12 h
2030 mg/kg q
24 h
1520 mg/
kg q 24 h
1015 mg/
kg q 24 h
710 mg/kg
q 24 h
10 mg/kg
q 48 h
Thomson et al.
[62]
\60 kg: 1 g 6090 kg:
1.5 g [90 kg: 2.0 g
Creatinine clearance (ml/min)
[110 90110 7589 5574 4054 3039 2029 \20
1.5 g q 12 h 1.25 g
q12 h
1.0 g q
12 h
0.75 g q
12 h
0.5 g q
12 h
0.75 g
q 24 h
0.5 g q
24 h
0.5 g q
48 h
J Infect Chemother
1 3
dosing. As no published nomogram can precisely predict
serum VCM concentrations in patients with impaired renal
function, dosages should be assessed and altered if neces-
sary based on measured serum concentrations.
Patients receiving hemodialysis
Because of redistribution after hemodialysis (HD), trough
concentrations of blood samples drawn immediately fol-
lowing dialysis do not reect the exact concentration of
patients [8588]. Pollard et al. [85] described that VCM
levels increased gradually after dialysis treatment in all
patients. Although serum VCM levels decreased 33 %
during HD, the post-rebound values after HD reached 87 %
of the pre-dialysis concentrations. To prevent underesti-
mation of VCM concentrations, blood samples for trough
concentration should be drawn before dialysis.
Because of the prolonged half-life of VCMin patients with
HD, the time to reach the steady state will also be delayed;
therefore, a loading dose is required for prompt achievement
of target trough levels. It was reported that pre-HD serum
concentrations on day 3 were 20.2 3.6 lg/ml in patients
administered VCMat 20 mg/kg as the initial dose [89]. Barth
and DeVincenzo [90] demonstrated that pre-HD serum con-
centrations 48 h after administration of 15, 20, and 25 mg/kg
of the initial dose were 12.6, 16.3, and 20.1 lg/ml, respec-
tively. Similarly, Brown et al. [91] described that pre-HD
serum concentrations approximately 24 h after administra-
tion of the same doses as in Barth et al. [90] were 19.0, 23.2,
and 27.3 lg/ml. Vandecasteele et al. [92] suggested that the
period to the next dialysis should be taken into account for
calculation of the loading dose leading to trough concentra-
tions of 1520 lg/ml, with a loading dose of 15 mg/kg for a
1-day interval, 25 mg/kg for a 2-day interval, and 35 mg/kg
for a 3-day interval to the next dialysis session. A xed
loading dose of 20 mg/kg led to sub-therapeutic trough levels
in one-half of patients.
Previously, VCM was often administered to HD patients
with a long interval (i.e. once a week). Many authors,
however, demonstrated that VCM was signicantly
removed by high-ux hemodialysis and the weekly regimen
has been abandoned. Crawford et al. [93] indicated that
trough levels with a single dose of VCM 35 mg/kg
administered during HD did not retain the therapeutic serum
concentration on day 8. Alternatively, a revised regimen
with a loading dose followed by maintenance doses after
each dialysis was recommended recently. Barth and De-
Vincenzo [90] demonstrated that with a 20 mg/kg initial
dose of VCM followed by 500 mg doses after each dialysis
treatment, the pre-dialysis level was 15.9 5.7 lg/ml, and
only 13 % were\10 lg/ml and 5 % were[25 lg/ml in HD
patients. By contrast, in patients treated weekly, 77 % of
levels were \10 lg/ml by 5 days after administration.
Data on VCM maintenance doses are equivocal. Van-
decasteele et al. [92] developed a VCM dose calculator and
conrmed that it enabled accurate VCM dosing in patients
undergoing HD. Maintenance dose was 8.1 mg/kg and was
accurate in 77.9 % of patients. A weight-based loading
dose of 2025 mg/kg should be used in dialysis patients,
although most xed-dose maintenance regimens fail to
reach target levels in the majority of HD patients, and clear
evidence on optimal maintenance dosing is lacking.
Although the threshold of concentration that causes
adverse events in patients on HD is not clear, the com-
mittee recommended that an initial dose of 2025 mg/kg
followed by 500 mg (7.510.0 mg/kg) after each HD
treatment should be administered to maintain trough con-
centrations of 1520 lg/ml in patients undergoing HD.
After achieving trough concentrations, adjustment of the
maintenance dosage is required.
Patients receiving continuous renal replacement therpay
(CRRT)
CRRT is now commonly used as a mean of support for
critically ill patients with renal failure. CRRT is better
tolerated by hemodynamically unstable patients. Solute
removal with CRRT is particularly relevant to antimicro-
bial therapy, because many critically ill patients with acute
renal failure have serious infections and require treatment
with antimicrobials. Several methods of CRRT exist.
During continuous venovenous hemoltration, solute
elimination is through convection, whereas continuous
venovenous hemodialysis utilizes gradients through coun-
tercurrent dialysate ow, and drug removal depends on
dialysate and blood ow rates. CVVHDF utilizes both
diffusive and convective solute transports. In Japan,
CVVHDF is widely used for CRRT.
Mechanical factors affect drug clearance. Increasing the
blood or dialysate ow rate can increase drug clearance. In
general, the blood ow rate in Japan is lower than the
setting in USA, UK, and Australia (80 vs. 150, 150200,
200 ml/min) [9496]. The dialysate concentration may also
affect drug removal in hemoltration. Last, the membrane
pore size is directly proportional to the degree of drug
removal. Characteristics of antimicrobials also affect drug
elimination. Antibiotics with high molecular size, high
protein capacity, and a large volume of distribution reduce
antibiotic removal during CRRT. Although VCM is a mid-
molecular weight antibiotic, CVVHDF effectively remove
VCM [97, 98].
A VCM loading dose of 1520 mg/kg is warranted in
patients undergoing CVVHDF for the same reason as
patients with HD. A higher loading dose may be desirable
to reach recent recommended target trough levels of
1520 lg/ml. Maintenance doses are administered mainly
J Infect Chemother
1 3
every 24 h in patients receiving CVVHDF. Recommended
maintenance doses, however, vary among several studies.
The Sanford Guide 2011 recommended 500 mg every
2448 h. Trotman et al. [97] recommended 1 g every 24 h
in patients with CVVHDF. To achieve the higher steady-
state trough concentration recommended by recent guide-
lines, a 12 h dosing regimen was reported in CRRT.
Chaijamorn et al. [99] described that the maintenance dose
of VCM, calculated from parameters of patients, would be
500750 mg every 12 h to provide a steady-state trough
concentration of 1520 lg/ml. DelDot et al. [100] dem-
onstrated that the maintenance dose required to achieve a
target trough level of 15 lg/ml was 450 mg every 12 h.
Considering the relatively low ow setting of CVVHDF in
Japan, lower maintenance doses may be desirable.
Yamamoto et al. [101] proposed a pharmacokinetically
optimized dosage regimen of VCM in patients receiving
CVVHDF using a criterion of AUC
024h
/MIC of 400.
When the MIC of MRSA strains is 1 lg/ml, initial dose of
20 mg/kg followed by maintenance dose of 7.6 mg/kg
every 24 h is calculated to achieve a trough concentration
of 11.7 lg/ml. From these reasons, the committee recom-
mended administering maintenance doses of 7.510 mg/kg
every 24 h.
The pharmacokinetics of drug removal in critically ill
patients receiving CRRT is very complex, with multiple
variables affecting clearance. These variables make gen-
eralized dosing recommendations in CVVHDF difcult
compared with HD. Monitoring the plasma VCM concen-
trations and subsequent dose adjustments are crucial to
achieve the desired trough concentrations in patients
receiving CVVHDF. In Japan, CVVHDF is also performed
to remove several inammatory mediators that have det-
rimental effects in septic shock [102]. In such patients with
residual renal function, adjustment of the VCM dose
should be considered according to the results of TDM.
Patients receiving continuous ambulatory peritoneal
dialysis
Morse et al. [103] compared VCM PK after a 15 mg/kg
intravenous dose with 30 mg/kg intraperitoneal dose (to
compensate for 50 % intraperitoneal absorption) during
CAPD. In patients with intravenous administration, the
mean peak concentration in serum was 57.1 lg/ml, which
decreased to 19.8 lg/ml at 24 h and 8.6 lg/ml at 168 h
(after 1 week). In patients with intraperitoneal adminis-
tration, VCM appeared slowly in serum (8.8 lg/ml at 6 h),
and peak concentration (30.4 lg/ml) was obtained by the
end of the second dwell-period. A similar delayed decline
of serum levels as intravenous administration was observed
(21.0 lg/ml at 24 h, 7.0 lg/ml at 168 h). Both methods
of administrating VCM maintained therapeutic serum
concentration over 1 week. With gradual absorption,
however, intraperitoneal administration avoids the abrupt
increase of serum level seen after intravenous dosing, thus
potentially reducing the risk of adverse reaction.
Bacterial peritonitis predominantly caused by MRSA
remains a major complication of CAPD. The Cochrane
Library showed that intraperitoneal administration of anti-
biotics was superior to intravenous dosing for treating peri-
toneal dialysis peritonitis [104]. Intraperitoneal
administration can maintain concentrations greater than MIC
for many hours in the peritoneal cavity. Montanes et al. [105]
reported that the mean plasma concentrations 24, 48 and
168 h after intraperitoneal VCM administration were 24.6,
18.7 and 8.6 lg/ml, and the mean peritoneal concentrations
were 16.6, 11.8 and 4.7 lg/ml, respectively. Li et al. [106]
recommended intraperitoneal antibiotic dosing in patients
with CAPD-related peritonitis. Doses of 1530 mg/kg every
57 days are recommended for anuric patients, and for
patients with residual renal function dened as[100 ml/day
urine output, the doses are increased by 25 %.
Intraperitoneal antibiotics can be given in each
exchange (i.e., continuous dosing) or intermittent dosing
(i.e., once daily). In the continuous regimen, a loading dose
of 1000 mg followed by 25 mg in each exchange is rec-
ommended [106]. A model with once-a-day dosing pre-
dicted that a loading dose of 30 mg/kg followed by 7 mg/
kg would achieve steady-state plasma concentrations of
1114.8 lg/ml in patients treated with intraperitoneal
administration [107]. Manley et al. [108] reported that
35 mg/kg intraperitoneally on day 1, then 15 mg/kg
thereafter (i.e., once daily) was required to provide ade-
quate concentrations over a 24-h period in automated
peritoneal dialysis patients. In intermittent dosing, the
antibiotic-containing dialysis solution must be allowed to
dwell for at least 6 h to achieve adequate absorption of the
antibiotic by the systemic circulation. Although intraperi-
toneally administered VCM is absorbed at about 50 % in
the absence of peritonitis, absorption rate increase up to
90 % in the presence of peritonitis, which permits sub-
sequent reentry into the peritoneal cavity during ensuing
exchanges of fresh dialysis solution.
Pediatric considerations
Trough concentrations should be assessed at a steady state.
The time required to reach a steady state by the adminis-
tration of a maintenance dose at a constant dosing interval
was shown to be approximately three to ve half-lives [28,
29]. Half-life is calculated from volume of distribution and
clearance. Clearance, if normalized for body weight, is
depressed in the neonate, but increases rapidly such that, by
1 year, half-life is about one half the adult value [29].
During childhood and adolescence, the half-life becomes
J Infect Chemother
1 3
longer because clearance, a function of surface area,
increases more slowly with growth than does volume of
distribution, a function of body weight. Half-life, however,
still remains considerably shorter than adult value
throughout childhood and adolescence. These changes in
clearance and weight with age explain why the mainte-
nance dose per kilogram of body weight is higher in chil-
dren than in adult patients. In addition, steady state is
achieved earlier than in adults because of the abbreviated
half-life in pediatric patients, and in general, rst trough
concentration can be obtained within 30 min of the fourth
dose (on day 2 if administered every 6 h).
Several pediatric studies have determined that the tra-
ditional dose of 4045 mg/kg/day was not sufcient to
obtain the desired trough concentration [109, 110]. Recent
guidelines recommended 60 mg/kg/day (15 mg/kg/dose
every 6 h) for children with serious or invasive disease
[15]. Even with the use of the recommended higher dosage,
it was difcult to achieve desirable concentrations. Eiland
et al. [111] demonstrated that only 40 % of trough con-
centrations were therapeutic levels (1020 lg/ml) in
patients to whom the average dose of 59 mg/kg/day was
administered. Frymoyer et al. [112] also reported that
\14 % of pediatric patients achieved a trough level in the
range of 1520 lg/ml in the high-dose group (60 mg/kg/
day). Glover et al. [113] mentioned that the mean trough
concentration was 7.8 lg/ml in patients with a nal pre-
scribed total daily dose of 60.6 mg/kg.
Although there is no supporting clinical evidence, sev-
eral authors have proposed an aggressive dosing regimen to
achieve target trough concentrations. Eiland et al. [111]
reported that their equation predicted that 85 mg/kg/day
would be required to achieve a trough of 15 lg/ml. McC-
abe et al. [114] predicted a VCM dosage stratied by age:
95, 88, and 75 mg/kg/day for patients aged 1 month
2 years, 212 years, and 1218 years, respectively. How-
ever, it is not known in children how well the AUC
24
/MIC
correlates with trough VCM concentrations, and the adult
target trough concentrations recommended by recent
guidelines apply equally to children. Several authors have
questioned the relationship between efcacy and safety and
the currently recommended trough level in children
because of the lack of studies indicating the effect [111,
112, 115, 116]. Escalating VCM doses may be associated
with a higher likelihood of VCM-related nephrotoxicity.
Taken together, the committee did not recommend a fur-
ther aggressive dosing regimen for children to achieve the
target trough concentrations suggested in adults.
In the study by Gordon et al. [115], children younger
than 6 years had lower repeatedly adjusted serum trough
levels than children older than 6 years, independent of the
total daily dose and dosing frequency, suggesting that the
clearance of VCM is higher in young children. Eiland et al.
[111] described that children \6 years of age had shorter
dosing intervals than children 6 years and older. Broome
and So [109] noted that the mean age of the patient pop-
ulation was around 56 years old, falling into the shortest
half-life group for VCM, in almost all pediatric studies
assessing VCM dosing and subsequent serum concentra-
tions, and they started dosing VCM at 15 mg/kg every 6 h
for children, and 20 mg/kg every 8 h for adolescents.
Owing to the small sample size of adolescents in each
study, no conclusion can be drawn regarding initial VCM
dosing. As many adolescents are the size of adults and
weight-based dosing may exceed adult population dosages
to a considerable degree, the committee determined not to
recommend the dosage regimen indicated in infants and
children for adolescent patients.
Drugdrug interaction
Executive summary
There is no report of drugdrug interaction in VCM.
Measuring method of blood concentration
Executive summary
There is no report concerning factors that affect the results
of measurement (FPIA, PETINIA, EMIT, CLIA, and latex-
enhanced turbidimetric immunoassay methods).
Conict of interest Yoshio Takesue has received a speakers
honorarium from Pzer Japan Inc., Astellas Pharma, Shionogi & Co.,
Ltd., MSD KK, Taisho Toyama Pharmaceutical Co., Ltd., and Dai-
nippon Sumitomo Pharma. Yoshio Takesue has received Grant sup-
port from Pzer Japan Inc., Astellas Pharma, Shionogi & Co., Ltd.,
MSD KK, Taisho Toyama Pharmaceutical Co., Ltd., Takeda Phar-
maceutical Company Limited, and Dainippon Sumitomo Pharma.
Norio Ohmagari has received speakers honorarium from Pzer Japan
Inc., Shionogi & Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd.
Masafumi Seki has received a speakers honorarium from Pham.
Corporations as follows: Astellas Inc., MSD Inc., Pzer Japan Inc.,
Shionogi Inc., and Taisho Toyama Inc. Shunji Takakura has received
speakers honorarium from Pzer Japan Inc., Astellas Pharma Inc.
Yusuke Tanigawara is a consultant to Meiji Seika Pharma Co., Ltd.
Toshimi Kimura has received a speakers honorarium from Meiji
Seika Pharma.
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