Aug. 2012

THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

221（ 1 ）Evaluation of arbekacin anti-MRSA agents for
adult in Japan
YUKIHIRO HAMADA*1, KAZUYOSHI TAMURA2, IKUMI KOYAMA2,MEGUMI SEKI2, KAZUO YAGO2,3, KEISUKE SUNAKAWA4 and
MASAKAZU KUROYAMA1,3
1

Department of Pharmacy, Kitasato University East Hospital2
Department of Pharmacy, Kitasato University Hospital
3
Kitasato University School of Pharmaceutical Science
4
Kitasato University of Kitasato Institute for Life Sciences(Received for publication March 23, 2012)

There are a limited number of reports that compare the clinical ef¿cacy of antiMRSA agents such as arbekacin (ABK), vancomycin (VCM), teicoplanin (TEIC)
and linezolid (LZD). There is a tendency for these four agents to show variation in
the inÀammatory response parameters, in C-reactive protein (CRP) and in whiteblood cell count (WBC), depending on the administration period. There was no
signi¿cant difference among the agents in analysis of variance (ANOVA) in thegroup of days 1–3 (p＝0.0536) but there was some signi¿cant difference in thegroup of days 4–7, as well as days 8–14 (p＜0.001, p＜0.01) in relative variation
rate of CRP. Furthermore, we compared in more detail the groups of LZD, VCM and
ABK, with a signi¿cant decrease of CRP, each of which showed more decrease incomparison with the group of TEIC in the period days 4–7 (p＜0.01). We took 1-hr
serum level after days 3–4, with the ABK treatment as the peak concentration(Cpeak). Having made nonlinear logistic regression analysis of CRP and Cpeak/MIC,
we concluded that the decrease rate estimable by early inÀammatory effect could bedecreased to some 40%, assuming that Cpeak/MIC shows the high value within 4days after ABK treatment.

Introduction
The anti-MRSA agents currently available in Japan are: arbekacin (ABK) of the antibacterial
agent aminoglycoside, and both vancomycin (VCM) and teicoplanin (TEIC) of the agent
glycopeptide. Also, linezolid (LZD) of the agent oxazolidinone was considered appropriate to add
as one of the anti-MRSA agents. Recently, daptomycin (DAP) is a newly-approved antibacterial

222（ 2 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

Aug. 2012

agent, the ¿rst lipopeptide agent to be released onto the market in Japan. The antibacterial power
against MRSA using ABK, VCM, TEIC and LZD, showed an equivalent value of MIC901–3). The
quick sterilizing ef¿cacy using these 4 drugs against MRSA, in vitro, resulted in ABK signi¿cantly reducing bacterial count, VCM less signi¿cantly, LZD less than VCM, and TEIC less than
VCM1). It is important to clinically decrease patientsʼ inÀammatory parameters quickly, in orderto support their QOL and treatment fees. There have been limited reports on this point, and analysis is dif¿cult until various inÀuencing factors have been excluded. We previously calculated therelative variation rate of reduction of CRP related to the drug administration period, using a commonly available simple measuring method. We also evaluated the clinical ef¿cacy of these four
drugs as well as the medical economic problem4). This time we extended the examination period
and added WBC in the examination items prior to evaluation. Examination of the details indicated that the results of using the anti-MRSA agents varied, depending on the part infected and inwhich department of the hospital the patient belonged. Therefore, in order to avoid distortion, we
examined the following points by grouping the clinical effects of each administration period:
calculation of the relative variation rate of CRP and WBC in the anti-MRSA drug administration
period and evaluation of the cases with ABK, using pharmacokinetic-pharmacodynamic (PK-PD)
parameters. The early CRP reduction rate was evaluated by nonlinear logistic regression analysis.

Materials and Methods
We examined all patients who had received ABK, LZD, TEIC and VCM of the injectableanti-MRSA agents at Kitasato University Hospital from April 2006 to August 2007. Patientstreated with TEIC were included in the survey only when they had received a loading dose of thesame drug.

(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)

Evaluation on relative variation rate of CRP and WBC
Patients matching any of the following criteria were excluded from the objects of this study:
pediatric patientspatients taking anticancer drugs within one month after the dose of the anti-MRSA agentspatients taking steroids within one month after the dose of the anti-MRSA drugs
patients taking anti-fungal agents during dosage of the anti-MRSA treatment
patients not undergoing a hematological test within 3 days before or after the dose of theanti-MRSA drugs
patients with hemorrhagic shock or DIC
patients with a hematogenic tissue tumor
patients taking the anti-MRSA drugs for less than 3 days
patients whose decrease rate of CRP value after taking the anti-MRSA drugs was under 30%

Aug. 2012

THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

223（ 3 ）Calculation of the relative change in CRP and WBC
The starting day of anti-MRSA treatment was regarded as day 0. The day of the laboratory
test was regarded as day 0, provided it was performed after the initiation of treatment and within
48 hours. The following days were counted as days 1 and 2.
Relative change in CRP on day N was calculated using equation 1 shown below.
&53 GD\ 1 − &53 GD\ (Equation 1)
5HODWLYH FKDQJH LQ &53  ＝× 
&53 GD\ 
The dosing period was divided into three periods: days 1–3, days 4–7 and days 8–14. For eachperiod, the mean relative change in CRP in response to each anti-MRSA agent was calculated. In
addition, homogeneity of the data for each of the three groups relative to the data for the entire
population studied was evaluated by ANOVA. If this analysis revealed signi¿cant inter-group differences, pairwise comparison and statistical tests were performed. WBC was also analyzed in
the same way. In the days 1–3 group, the percentage of reduction in CRP relative to its baseline
value was calculated against each agent.
PK-PD analysis through nonlinear logistic regression analysis of ABK
The drug concentration within an hour after a dose of ABK was considered peak concentration (Cpeak) and PK-PD was analyzed by examining the values of primary MIC and CRP. For
safety evaluation purposes, the drug concentration immediately prior to the dose was regarded
as Ctrough. Ccr was calculated using blood urea nitrogen (BUN), serum creatinine (Scr) and
COCKCROFT-GAULT equation analysis5). These three indicate renal function. When Scr was below
0.4 ȝg/mL, which is the detectable limit of ABK, the drug concentration was regarded as 0.4 ȝg/
mL.
Criteria for judgment of infection
Such cases were deemed to be infectious when bacteria were isolated from the aseptic parts,
e.g., blood, and when bacteria at a level over 106 CFU/mL were isolated from the non-aseptic
parts, e.g., sputum.
Identi¿cation of bacteria and assessment of bacteria sensitivity to drugs
Assessment during the settled period was based on the microdilution method approved by
The Clinical and Laboratory Standards Institute (CLSI)6). MIC was measured to determine sensitivity to drugs using the microwell panel PC6.1J; MicroScan Walk-Away-96® (Dade BehringInc., Deer¿eld, IL). MIC of the clinically isolated strain at the beginning of dosage of the antiMRSA agents was considered to be the primary MIC.

224（ 4 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

Aug. 2012

Blood sampling and measurement of ABK serum concentration
The attending physician took patientsʼ blood samples of ABK serum concentration after day
3 or 4: the measured value within one hour after the dose of the drug was considered Cpeak, andthe measured value immediately prior to the dose was considered Ctrough, safety was measured byevaluation on a randomly selected day. This laboratory sample testing was carried out with theinformed consent of patients or their families. Serum concentration was measured with TDxArbekacin Kit® (Abbott Japan) and by Àuorescence polarization immunoassay (the FPIA
method).
Calculation method of PK-PD parameters of ABKWith PK parameters, we evaluated the early ef¿cacy of the ABK and regarded the bloodlevel after day 3 or 4 with the ABK treatment as Cpeak. We carefully evaluated the Ctrough, emphasizing clinical safety of the sampling data. As for PD parameters, we used the primary MIC aswell as CRP of the day, or within 24 hours after the dose of the drug, for evaluating ef¿cacy. The
nonlinear logistic regression analysis was made after examining the primary analysis of thecovariant in each item of these parameters. On the basis of the above analysis, the predicted value
yƍ was calculated with Cpeak/MIC as x, and CRP improvement percentage as y, the objective variate (Equation 2).
Nonlinear logistic regression analysis was carried out using the nonlinear least squares
method. (algorithm: Dan-Ping Gauss-Newton method).

\′ ＝ γ  ＋α × H[S −β [ (Equation 2)

Safety was evaluated through the analysis of BUN, Scr and Ccr. The total concentration was analyzed because the protein-binding rate is known to be low: 3–12%7).
Statistical analysis
The computer program JMP®7 (SAS Institute Inc.) was used for the statistical analysis ofdata. As for evaluation of variation rate in CRP and WBC relative to the administration period,
during which patientsʼ body temperature was taken on the ¿rst day, fourth day and the last day ofthe dosage, homogeneity of the entire group was tested by ANOVA. The Tukey-Kramer HSD test
was carried out when this analysis revealed signi¿cant differences. The both-side-risk-rate lessthan 5% (p＜0.05) was regarded to be statistically signi¿cant. The study was designed as an observation study using existing data derived from clinical practice. It was carried out in accordancewith the Ethical Guidelines on epidemiological studies (Ministry of Education, Culture, Sports,
Science and Technology, and Ministry of Health, Labour and Welfare of Japan) and the law onprotection of individual information, as well as the Ethical Guidelines for Clinical studies of our
hospital.

Aug. 2012

THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

225（ 5 ）Results
There were 660 cases dosed with anti-MRSA agents in our hospital from April 2006 to August, 2007. Of these, 110 cases were with ABK, 82 cases with LZD, 170 cases with TEIC, and298 cases with VCM. A total of 314 strains of MRSA were isolated. The data of primary MIC areshown on Fig. 1.
Ef¿cacy of relative variation rate in CRP and WBC
The analytic objects were 14 cases with dosage of ABK, 26 of LZD, 29 of TEIC and 80 of
VCM. The excluded patients with less than 30% CRP included 16 cases with dosage of ABK, 6 of
LZD, 26 of TEIC and 42 of VCM. There were signi¿cant differences among these groups within
the administration period (p＜0.05). Comparison revealed a signi¿cantly shorter administration
period in the ABK and the VCM treatment groups, than in the TEIC treatment group. The statistical analysis according to patientsʼ body temperature taken on the ¿rst day, fourth day and the last
day after the dosage, revealed a signi¿cant difference with ABK and VCM on the ¿rst and the lastdays (p＜0.05, Table 1). Patients were divided into three groups according to the administration
period: days 1–3, days 4–7 and days 8–14. The relative variation rate in CRP of the anti-MRSA
agents showed no signi¿cant difference in any pairwise comparison of the group of days 1–3 (p＝0.0536, ANOVA, Fig. 2-1).
Fig. 1. Distribution of primary MIC against clinically isolated MRSA strains.

226（ 6 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

Aug. 2012

Table 1. Patient characteristics.

* Statistically significant by Studentʼs t-test (p＜0.05)** Tukey-Kramer HSD test (p＜0.05)
ABK: arbekacin, LZD: linezolid, TEIC: teicoplanin, VCM: vancomycina
Cpeak: the serum arbekacin concentration 1 hour after administrationb
Ctrough: the serum arbekacin (teicoplanin) concentration immediately before administration

In the group of days 4–7, there were signi¿cant differences among the drugs concerning therelative variation rate in CRP (p＜0.001, ANOVA). There was a signi¿cant reduction of CRP in
the VCM, LZD and ABK treatment groups, compared to the TEIC treatment group (p＜0.01, Fig.
2-1).
In the group of days 8–14, there were also signi¿cant differences among the drugs concerning the relative variation rate in CRP (p＜0.01, ANOVA). Here there was a signi¿cant reductionof CRP in the LZD (p＜0.05, Fig. 2-1), VCM and ABK treatment groups, compared to the TEIC
treatment group (p＜0.01, Fig. 2-1).
The relative variation rate in WBC was analyzed in the same way as CRP, dividing the patients according to the drug administration period: days 1–3, days 4–7 and days 8–14. The relative
variation rate of decrease of WBC varied signi¿cantly (ANOVA) in the days 4–7 group. Comparison revealed a signi¿cant decrease of WBC in the LZD treatment group relative to the TEIC
group (p＜0.05, Fig. 2-2).
Pharmacokinetic and pharmacodynamic analyses of ABK
Mainly ABK was analyzed because the administration period of this agent was the shortest
among that of other anti-MRSA agents. In the group of days 4–7 and days 8–14, ABK was signi¿cantly showed improvement among the drugs concerning the relative variation rate in CRP.
Data at 6 points in the cases were included in the ef¿cacy evaluation. The median Cpeak for the 6
points was 7.8 ȝg/mL (range: 4.1–26.2) (Table 2). When the percent CRP improvement was plotted against the Cpeak of ABK, the variance was large and no correlation was noted (Fig. 3-1). The

THE JAPANESE JOURNAL OF ANTIBIOTICS
65—4

The dosing period was divided into three periods: days 1–3, days 4–7 and days 8–14.
For each period, the mean relative change in CRP in response to each anti-MRSA agent was calculated.
If ANOVA revealed significant inter-group differences, pairwise comparison and statistical tests were performed.
Tukey–Kramer HSD test, * p＜0.05, ** p＜0.01

Fig. 2. Relative change in CRP and WBC in relation to the administration period (day 1–3, 4–7, 8–14).

Aug. 2012
227（ 7 ）228（ 8 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

Aug. 2012

Table 2. Characteristic of arbekacin using for PK-PD analysis.

Cpeak: the serum arbekacin concentration 1 hour after administration,
Ctrough: the serum arbekacin concentration immediately before administration,
MIC of ABK: minimal inhibitory concentration of arbekacin,
AST: aspartate aminotransferase,
ALT: alanine aminotransferase,
BUN: blood urea nitrogen.

MIC of ABK in the 6 points was 1 or 2 ȝg/mL. In the analysis of CRP reduction relating to Cpeak,a signi¿cant regression curve was obtained for Cpeak/MIC and CRP reduction. The percentage of
the CRP reduction rate was suf¿ciently high at the level close to 10 ȝg/mL (Fig. 3-2). The equation for prediction (yƍ) was obtained by the nonlinear least squares method (Equation 3).

yc＝ 39.29/(1＋ 5.46 × exp(− 0.34 × x))
x: Cpeak /MIC

(Equation 3)

Data on Ctrough at 25 points in 24 patients were included in the safety evaluation. Data on
patients with disease associated with compromised renal function, or disease involving the risk
for such a function, are shown in Table 2, including overlapped cases. Ctrough was often high inpatients with compromised renal function (Fig. 4-1, 4-2). Very strict management was enforced
for these cases.

Discussion
MRSA is currently one of the most drug-resistant bacteria extant, causing in-hospital infections and being comparable to Pseudomonas aeruginosa. If susceptible hosts are infected withMRSA, the infection will be intractable, often leading to such severe conditions as pneumonia
and sepsis. Fig. 1 summarizes the MIC of various drugs against MRSA at the start of treatment
with the drugs. ABK is expected to play a signi¿cant role, in view of the several reports published, concerning vancomycin-intermediate resistant Staphylococcus aureus (VISA)8) orAug. 2012

THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

229（ 9 ）Fig. 3-1. Pharmacokinetic and pharmacodynamic analyses of ABK plotting CRP against
Cpeak.

As for PK and PD parameters, Cpeak and CRP on day 3–4 served as anindicator of early efficacy.
Cpeak: the serum arbekacin concentration 1 hour after administration,
CRP: C-reactive protein

Fig. 3-2. Pharmacokinetic and pharmacodynamic analyses of ABK (nonlinear logistic
regression curve, plotting CRP against Cpeak/MIC).

As for PK and PD parameters, Cpeak and CRP on day 3–4 served as anindicator of early efficacy, and primary MIC served as indicators of efficacy.
The MIC of ABK is all sensitive.
Cpeak: the serum arbekacin concentration 1 hour after administration,
MIC: minimal inhibitory concentration,
CRP: C-reactive protein

230（ 10 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

Fig. 4-1. ABK plotting Ctrough against Ccr (other and CRF patients).

Ctrough: the drug concentration immediately before the next dose was deemed as the troughconcentration, Ccr: creatinine clearance, CRF: chronic renal failure, Others: others low renal
function disease.

Fig. 4-2. Ccr plotting against renal function in each disease group.

Ccr: creatinine clearance, DM: diabetes mellitus, CRF: chronic renal failure, Others: others low
renal function disease, Normal: normal renal function.

Aug. 2012

Aug. 2012

THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

231（ 11 ）ȕ-lactam antibiotic-induced vancomycin-resistant Staphylococcus aureus (BIVR)9,10). Four drugs(ABK, LZD, TEIC and VCM that DAP is excluded) are approved as anti-MRSA agents in Japanand MIC90 in each agent differs little1–3). However, the administration period for the same disease
tends to vary among these drugs11) and the percent reduction of inÀammatory reactions tends todiffer depending on the administration period. We have previously evaluated early inÀammatory
parameters and reported that CRP showed a signi¿cant decrease with the group of ABK in comparison with the group of VCM and TEIC in the period of days 1–34). According to another report, the clinical ef¿cacy of ABK was superior to that of VCM and TEIC12). With such a background, we extended the survey period of our study and analyzed early inÀammatory reactions in
response to treatment with anti-MRSA agents at the different dosing periods, using the relative
variation rate of CRP and WBC as indicators. Furthermore, using PK and PD parameters of ABK,
analysis of new concepts with a nonlinear logistic model was carried out, which evaluated theef¿cacy in a more clinically feasible way by predicting the ef¿cacy on early inÀammatory reactions and by adopting the PK-PD parameters published previously13–16).
The relative variation rate of CRP did not differ signi¿cantly among the four anti-MRSA
agents in the group of days 1–3. However, the CRP decrease during days 1–3 tended to be greaterwith ABK than with the other three drugs (Fig. 2-1). KURAZONO, et al., compared the acute bactericidal activity in terms of MIC of ABK, LZD, TEIC and VCM, and indicated that ABK exercised the most potent activity1). There was no signi¿cant difference in the outcome in ABK or any
other drugs in the group of days 1–3. One possible reason for this result is that there were fewercases with ABK in the present study, compared to the cases with other drugs previously studied.
As for the effects of TEIC on CRP, this antibiotic was signi¿cantly inferior to the other threedrugs in the period of days 4–7 and 8–14 (Fig. 2-1). As for the effects on early inÀammatory parameters, this antibiotic was lower than the other three in the period of days 1–3, although the difference was not statistically signi¿cant. Usefulness of ABK has been endorsed since its oncedaily administration was approved in Japan in March 200817). During this present survey, thisdrug was administered once daily to 76 of the 110 cases and twice daily to the remaining 34
cases. ABK is known to exert a concentration-dependent bactericidal activity, and is expected toyield excellent results when administrated once daily13,14,17,18). The present survey did not involve
evaluation of the clinical ef¿cacy of single-dose ABK. If single-dose analysis is performed, it isexpected that ef¿cacy in alleviating early inÀammatory reactions will be marked. In view of thewell-known characteristics of TEIC (large distribution volume and low clearance)19), this drug is
expected to exert higher clinical ef¿cacy when the initial loading dose level is increased. In previous studies of high-dose TEIC therapy reported by several investigators20–22), excellent clinical ef¿cacy was noted and no serious adverse reaction was observed, verifying this expectation. An initial trough concentration of TEIC is low in this survey. Therefore, this survey is thought that
TEIC loading dose is a few. Treatment with LZD resulted in a signi¿cant decrease of CRP in the232（ 12 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

Aug. 2012group of days 1–3 and 4–7, compared to treatment with TEIC (p＜0.05, p＜0.01) (Fig. 2-1). LZD
is known to show its effective transfer to tissues, and can suppress the formation of cytokines aswell23). These features of LZD probably explain the data obtained in the present study regardinginÀammatory parameters. Regarding the change of WBC, the ef¿cacy of LZD was signi¿cantly
different from that of TEIC only in the group of days 4–7 (Fig. 2-2). Although care is required regarding bone marrow suppression, which is a serious adverse effect of LZD, the present study
revealed no signi¿cant difference in such suppression among the drugs, suggesting the reliabilityof the LZD data obtained in the present study. As for the relative variation rate in CRP, VCM
reduced CRP more signi¿cantly than TEIC in the group of days 4–7 and 8–14 (p＜0.01). In thegroup of days 1–3, the effect of TEIC on inÀammatory parameters was the second highest next to
ABK. The data shown in Fig. 2 also indicate a stable level of CRP reduction during the treatment
with VCM, and is therefore expected to consistently exert stable ef¿cacy. There was no case with
low CRP value this time, but it is necessary to be aware that we must be very careful when CRP
does show low value under conditions of severe infection.
PK-PD analylsis of ABK was carried out using the data on serum ABK concentration measured during the ¿rst 3 or 4 days of treatment. The CRP response rate was plotted against Cpeak as
a preliminary analysis, but the variance was too large (Fig. 3-1). When we corrected the MIC for
Cpeak, the variation became smaller, and then a useful nonlinear logistic regression curve for Cpeak/
MIC and CRP response rate was yielded (Fig. 3-2). It is indicated that the predicted CRP
response rate of early inÀammatory parameters will decrease about 40% if Cpeak/MIC is high during the ¿rst 4 days of ABK treatment. However, we must add that this decrease rate of approximately 40% was the maximum rate among those cases with good analytical results. It will be necessary to increase the number of cases in order to improve reliability24). There were no cases withsepsis this time, nor any serious cases with low CRP value.
Regarding the relation of body temperature to the predicted WBC improvement curve following treatment with AGs against infections caused by Gram-negative bacterium (GNB),KASHUBA et al., reported that the improvement rate tends to rise as the Cpeak/MIC during the initial
treatment period becomes higher25). In the future, it will be important to conduct this sort of study
in a larger subject population, involving calculation of AUC on the basis of PK, and evaluation of
AUC/MIC26,27).
In the case of ABK, it has been reported that Ctrough is associated with its adverse effects andthat the incidence of nephropathy rises as Ctrough becomes higher14). In the present study, Ctrough was
higher in patients with impaired renal function (Fig. 4-1). Ccr tended to be lower in the group of
DM, CRF and other groups compared to the disease-free normal group (Fig. 4-2). Some patients
who were under hemodialysis were included in the group of CRF, and the Ctrough immediately prior
to hemodialysis was adopted in this group, which resulted an apparent high Ctrough (Fig. 4-1).
These patients continued to receive TDM management and showed no serious adverse reactions.

Aug. 2012

THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

233（ 13 ）The present study was carried out in a clinical setting and the treatment plan was tailored to
TDM in the individual cases. Particularly strict management was enforced as to renal dysfunction. As a result, no serious adverse reaction was noted in any cases. We retrospectively evaluatedthe clinical ef¿cacy of the above four agents in a clear-cut manner with CRP and WBC during theadministration period. It needs to analyze with DAP in the future. Henceforth, it will be necessary
to make an incorporative investigation with the bacteriological evaluation, the analysis against
each disease, the analysis of pediatric patients, the analysis of breast X-ray images in this study.
The de¿nite statement we can issue at the present time is that the use of TDM allows predictionof early response of inÀammatory parameters in patients, except those who may have risk factors(e.g., impaired renal function and auditory disorder)28,29), or those who may have a high primary
MIC. We can also state that ABK, which is expected to be effective also against GNB30), is apromising ¿rst-line anti-MRSA agent.

References
1） KURAZONO, M.; K. YAMADA, Y. HIRAI, et al.: Epidemiological survey of drug resistance of methicillin-resistant Staphylococcus aureus isolated in Japan in 2000. Jpn. J. Chemother. 50: 494〜499,
20022） MIKUNIYA, T.; Y. KATO, Y. MUTO-KOBAYASHI, et al.: Prevalence of drug resistant gene and changes
in susceptibility of methicillin-resistant Staphylococcus aureus strains isolated from 1990 to 2006
in Japan to antimicrobial agents. Jpn. J. Chemother. 57: 37〜40, 2009
3） FUJIMURA, T.; I. YOSHIDA, Y. ITOH, et al.: Antimicrobial susceptibility of clinical isolates of aerobic
Gram-positive cocci and anaerobic bacteria in 2004. Jpn. J. Chemother. 56: 543〜561, 2008
4） HAMADA, Y.; K. TAMURA, K. OTORI, et al.: In improving inÀammatory response early after the startof treatment that relative rate changes in CRP levels in anti-MRSA agents. Antibiotics & Chemother. 24: 102〜108, 2008
5） COCKCROFT, D. W. & M. H. GAULT: Prediction of creatinine clearance from serum creatinin. Nephron. 16: 31〜41, 1976
6） BAUER, A. W.; W. M. KIRBY, J. C. SHERRIS, et al.: Antibiotic susceptibility testing by a standardized
single disk method. Am. J. Clin. Phathol. 45: 493〜496, 1966
7） MITOMI, N.; T. MATSUMOTO, M. FUJIGAKI, et al.: Absorption, distribution, and excretion of arbekacin
after intravenous and intramuscular administration in rats. Jpn. J. Antibiotic. 40: 357 〜364, 1987
8） HANAKI, H.; Y. HOSOSAKA, C. YANAGISAWA, et al.: Occurrence of vancomycin-intermediate-resistant Staphylococcus aureus. J. Infect. Chemother. 13: 118〜121, 2007
9） HOSOSAKA, Y.; H. HANAKI, C. YANAGISAWA, et al.: Nosocomial infection of ȕ-lactam antibiotic-induced vancomycin-resistant Staphylococcus aureus (BIVR). J. Infect. Chemother. 12: 181〜184,
200610） MAEBASHI, K.; M. TABATA, M. TANI, et al.: In vitro activity of antibacterial agents against ȕ-lactam
antibiotic-induced vancomycin resistant MRSA. Jpn. J. Chemother. 53: 5〜10, 200511） HAMADA, Y.; H. NAITOH, S. MIYAMOTO, et al.: Methicillin-resistant Staphylococcus aureus (MRSA)
medication with head and neck tumor. Pract. Otol. 100: 303〜307, 200712） SHIMIZU, K.; N. AIKAWA, Y. TANIGAWARA, et al.: Actual use of anti-MRSA drugs in Japan with thefocus on arbekacin. Jpn. J. Chemother. 51: 717〜730, 2003

234（ 14 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

65—4

Aug. 201213） KOBAYASHI, M.; A. SAIKYO, K. SOMA, et al.: Pharmacokinetic and pharmacodynamic (PK/PD)
analysis to determine the optimal method of arbekacin administration. Jpn. J. Chemother. 54:
18〜24, 2006
14） SATO, R.; Y. TANIGAWARA, M. KAKU, et al.: Pharmacokinetic-pharmacodynamic relationship of arbekacin for treatment of patients infected with methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 50: 3763〜3769, 2006
15） TANIKAZE, N.; M. KOMATSU, K. SHIMAKAWA, et al.: Study of clinical signi¿cance of PK/PD (pharmacokinetic/pharmacodynamic) parameters after administering arbekacin to patients with pulmonary methicillin-resistant Staphylococcus aureus infection. Jpn. J. Chemother. 52: 469〜473, 200416） HASHIMOTO, M.; M. KIYOSUKE, F. SAITA, et al.: Evaluation of arbekacin sulfate used in elderly patients in terms of therapeutic drug monitoring (TDM) and pharmacokinetics/pharmacodynamics(PK/PD). J. Jpn. Soc. Hosp. Pharm. 43: 1403〜1405, 200717） AIKAWA, N.; S. KOHNO, M. KAKU, et al.: An open clinical study of arbekacin 200 mg q.d. inpatients infected with methicillin-resistant Staphylococcus aureus (MRSA)—A clinical pharmacology study—. Jpn. J. Chemother. 56: 299〜312, 200818） KIMURA, T.; K. SUNAKAWA, K. TOTSUKA, et al.: Dose ¿nding study on arbekacin sulfate for appropriate peak levels. Jpn. J. Chemother. 59: 597〜604, 201119） BUNIVA, G.; A. DEL FAVERO, A. BERNAREGGI, et al.: Pharmacokinetics of 14C-teicoplanin in healthy
volunteers. J. Antimicrob. Chemother. 21 (Suppl. A): 23〜28, 1988
20） UEDA, Y.; S. NOGUCHI, M. MAKI, et al.: Clinical ef¿cacy of high dose treatment with teicoplanin(TEIC) against MRSA infections and trough concentration of TEIC. Jpn. J. Chemother. 55: 8〜16,200721） NOGUCHI, S.; Y. UEDA, M. SHIBUYA, et al.: Effectiveness of treatment strategy using high-doseteicoplanin(TEIC) in emergency and critical care medicine. Jpn. J. Pharm. Health Care Sci. 34:
662〜670, 200822） SUGAWARA, M.; Y. YAMASAWA, K. SAITO, et al.: The assessment of MRSA infection remedy basedon therapeutic monitoring of teicoplanin. Jpn. J. TDM 25: 28〜36, 200823） PILAR, G. R.; M. R. JAVIER, S. S. ARACELI, et al.: Linezolid diminishes inÀammatory cytokine production from human peripheral blood mononuclear cells. Arch. Med. Res. 37: 31〜35, 200624） DUTTA, S.; Y. MATSUMOTO & W. F. EBLING: Is it possible to estimate the parameters of the sigmoid
Emax model with truncated data typical of clinical studies? J. Pharm. Sci. 85: 232〜239, 1996
25） KUSHUBA, A. D.; A. N. NAFZIGER, G. L. DRUSANO, et al.: Optimizing aminoglycoside therapy fornosocomial pneumonia caused by Gram-negative bacteria. Antimicrob. Agents Chemother. 43:
623〜629, 1999
26） KIMURA, T.; K. SUNAKAWA, N. MATSUURA, et al.: Population pharmacokinetics of arbekacin, vancomycin, and panipenem in neonates. Antimicrob. Agents Chemother. 48: 1159〜1167, 2004
27） TANIGAWARA, Y.; R. SATO, K. MORITA, et al.: Population pharmacokinetics of arbekacin in patients
infected with methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 50:
3754〜3762, 200628） PREZANT, T. R.; J. V. AGAPIAN, M. C. BOHLMAN, et al.: Mitochondrial ribosomal RNA mutation associated with both antibiotic- induced and non-syndromic deafness. Nat. Genet. 4: 289〜294, 199329） HAMASAKI, K. & R. R. RANDO: Speci¿c binding of aminoglycosides to a human rRNA constructbased on a DNA polymorphism which causes aminoglycoside-induced deafness. Biochemis. 36:
12323〜12328, 199730） HAMADA, Y.; K. TAMURA, I. KOYAMA, et al.: Clinical ef¿cacy of arbekacin for Gram-negative bacteria. J. Infect. Chemother. 17: 876〜879, 2011