医薬品相互作用研究

Vol.39, No. 3（2016）17（145）

医薬品相互作用研究
一
般論
文
39（3） 17-28 （2016）

Consideration of dosage regimen for meropenem in mixed
infusions containing L-cysteine and/or SBS
Noriyuki SHINO1,2), Yasuo NOMURA2)，Miyako YOSHIDA1) and Takahiro UCHIDA1)*
1)

Mukogawa Womenʼs University, Department of Clinical Pharmaceutics
2)
Pharmacy of Saiseikai Chuwa Hospital（Received October 14, 2015; Accepted January 5, 2016）

The purpose of this study was to simulate the concentration‒time profile, C max and area under the curve (AUC)of serum meropenem (MEPM) when administered in mixed infusions containing L-cysteine and/or SBS, and to
determine the percentage of time that free drug concentrations remain above the minimum inhibitory
concentration (MIC) of an unspecified pathogen (%TAM), with a target attainment (TA) of 40%TAM. The mixed
infusions were administered over a period of 0.5 or 2 hr. after being kept for 0, 1 or 2 hr. at 4ºC or 25ºC after
mixing. Dosage regimens tested were 500 mg quaque 24hr. (q24hr.), 1000 mg q12hr. or q8hr.. When MEPM
was mixed with AMINOFLUID Injection (AM-F) or AMIGRAND Injection (AM-G), both of which containL-cysteine and SBS, to obtain a MIC of <0.5 mg/L, 40%TAM was achieved under nearly all conditions. With MIC
2 mg/L, TA% >80% was achieved under nearly all conditions when the mixture was stored for 0 or 1 hr. andinfused over 0.5 hr.. However, TA% declined markedly when the mixed infusion was administered over 2 hr.,even if administered immediately after mixing. In infusions of MEPM mixed with AM-F or AM-G, MEPM levels
were all lower than when MEPM was administered in normal saline. When MEPM was mixed with Fructlact
Injection (Fru), which contains SBS but not L-cysteine, no differences in TA% were found in comparison with
MEPM in normal saline. When MEPM was mixed with Fru TA% >80% could be achieved by extending theduration of the infusion. However, when mixed with AM-F or AM-G, MEPM must be administered over a 0.5-hr.
period immediately after mixing to achieve TA% >80%.
Key Words: : meropenem, %TAM, PK-PD parameters, MIC, stability

administration to maximize this parameter 3‒5).

Introduction
Meropenem (MEPM) is a carbapenem

It has been reported that the stability ofantibacterial agent with broad-spectrum activity

carbapenems declines markedly when they areagainst Gram-negative, Gram-positive andadministered in mixed infusions which include

anaerobic bacteria1).

L-cysteine and/or so dium bisulfite (SBS)6-8).

Carbapenems are

particularly important for the treatment of severe

Recently, Takasu. reported on the stability of

infections caused by multi-resistant

MEPM when administered together with. The maincommercially available mixed infusions 6) . In theirpharmacokinetic‒pharmacodynamic (PK-PD)

article, the concentration of MEPM declined

parameter that correlates best with theaccording to first-order kinetics but the rate oftherapeutic efficacy of carbapenems is thedecline varied considerably when the antibiotic

percentage of Time that free drug concentrations

was administered with different mixed infusions.

Gram-negative bacteria

2 )remain Above the Minimum inhibitory

MEPM is generally administered as an infusion

concentration (MIC) of the pathogen (%TAM), andin normal saline. Although MEPM is rarely mixed

extended infusion is the preferred route of

w ith parenteral nutrit ion fluids, MEPM may be

Mukogawa Womenʼs University, Department of Clinical Pharmaceutics 11-68 Koshien 9-Bancho, Nishinomiya 663-8179, Japan
Pharmacy of Saiseikai Chuwa Hospital 232 Abe sakurai-shi, Nara 633-0054, Japan*連絡著者：Takahiro Uchida (E-mail: takahiro@mukogawa-u.ac.jp)1）2）

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医薬品相互作用研究

Vol.39, No. 3（2016）

mixed in the infusion management of highly

Injection (Fru), AMINOFLUID® Injection (AM-F) orinvasive patient, such as sepsis. There have been

AMIGRAND® Injection (AM-G) for periods of 0, 1

no reports on the serum concentration of MEPM

o r 2 h r. a n d a t 4 ℃ o r 2 5 ℃ . F r u c o n t a i n s S B S ,when administered after mixing with such

while AM-F and AM-G contain both L-cysteine andinfusions, so it was decided to investigate the rate

SBS.

of decline of MEPM concentrations in these

Methods

situations.
In the present study, we aimed to predict the

1. Mixed injections and infusion conditions

serum MEPM concentrat ion‒t ime profile, C m a x ,Using information from the package insert andarea under the curve (AUC) and obtained target

actual clinical practice, we selected 0.5 and 2 hr.

attainment ( TA) of 40%TAM based on different

as infusion times and 0, 1 and 2 hr. after mixing as

MICs (0.5, 1, 2 and 4 mg/L) of infectious

storage times. Mixtures of MEPM with Fru

organisms using a Monte Carlo simulation. The(500mL), AM-F (500mL) or AM-G (500mL) wereeffects of storage condit ions (temperature andexamined, as shown in Table 1. The storage

time after mixing) were also investigated. MEPM

temperature was fixed at either 4℃ or 25℃. MEPM

was administered as either a 0.5-hr. or 2-hr.

injection preparations contained either 500 mg orinfusion after storage of mixtures with Fructlact1000 mg MEPM.

Table 1 Mixed injections and infusion conditions

Storage
MEPM dose

Infusion time (hr.)

500 mg0.5 or 2

1000 mg

0.5 or 2

Mixed with

L-Cysteine (g/L) SBS (g/L)

Fructlact Injection-

AMINOFLUID® Injection

0.3

AMIGRAND® Injection

0.3

Fructlact Injection-

AMINOFLUID® Injection

0.3

AMIGRAND® Injection

0.3

0.2
0.2
0.02
0.2
0.2
0.02

Temp ( C)Time (hr.)

4 or 25

0, 1 or 2

4 or 25

0, 1 or 2

SBS: sodium bisulfite
Temperature: Temp

2. Stability prediction of MEPM in mixed infusions

volume for MEPM were estimated from population

In the article of Takasu et al., MEPM was shown

parameters of Japanese adult patients, as reported

to decrease according to first-order degradation
6)

previously 9).

kinetics in mixtures with AM-F, AM-G and Fru . In

CL=0.0905×CCR+2.03; Q=4.02

the present study, therefore, first-order

V 1=0.199×WT; V 2=4.55

degradation kinetics (ka in the following equation)

where CL = total body clearance (L/hr), CCR =were used to simulate the decline of MEPM levels

creatinine clearance (mL/min),during infusion.

inter-compartmental (central‒peripheral)dX 1/dt=-ka・X 1

Q =clearance, V 1 and V 2 = the distribution volumes ofEquation 1

where X1 is the amount of MEPM in thecompound compartment (mg) and ka is its-1

the central and peripheral compartments (L),respectively, and WT = bodyweight (kg)degradation rate constant (h ). At 25 °C, ka values

The input rate of MEPM followed the reductionof AM-F, AM-G and Fru were 0.695, 0.828 andin concentration (equation 1) was incorporated

0.0060, respectively, while at 4℃, ka values were

into

6)

0.329, 0.453 and 0.0008, respectively .

simulation using population

pharmacokinetic parameter of Japaneseconsidering mo del based on dosage frequency,

3. Pharmacokinetic analysis
As PK parameters, clearance and distribution

quaque 8hr.(q8hr.), q12hr. or q24hr..
The dosage and frequency of dosing required to医薬品相互作用研究

Vol.39, No. 3（2016）19（147）maintain serum MEPM concentrations, in view ofacross a range of MICs, chosen on the basis of

the degradation rate described in equation 1, was

MEPM susceptibilities determined in a surveillance

incorporated into a Monte Carlo simulation model

study. Typical MICs (0.5, 1, 2 and 4 mg/L) wereusing pharmacokinetic parameters from theused in the simulations 11).

Japanese population. A thousand simulated serum

A p r o t e i n - b i n d i n g f r a c t i o n d e r i ve d f r o m t h e

c o n c e n t r a t i o n c u r ve s w e r e p r o d u c e d f o r e a c hpackage inserts of MEPM (2.4%), was applied to

dosage regimen (500 mg q24hr., 1000 mg q12hr.

correct for the plasma protein-binding fraction inand 1000 mg q8hr.), assuming a normal

the simulation.

distribution. The range of possible values was

Results

restricted to the 95% confidence interval in order
to discard marginal variable values in the randomWe

simulated

the

serum

MEPM

process. The simulation was performed using

concentration‒time profile, C max , AUC and obtained

Microsoft Excel 2007.

t a r g e t a t t a i n m e n t o f 4 0 % TA M b y M o n t e C a r l o

The drug dosages and dosage frequencies ofsimulation after different dosage regimens of

MEPM were based on the following Sanford Guide

MEPM were mixed with infusions (AM-G, AM-F orregimens: CCR<10, 500 mg q24hr.; 10≤CCR≤50,

Fru) containing L-cysteine and/or SBS, stored for 0,1000 mg q12hr.; CCR>50, 1000 mg q8hr. 10).

1 or 2 hr. at 4℃ or 25℃, and infused over a 0.5-hr.

The serum concentration‒time profiles of MEPM

or 2-hr. period. Our aim was to propose thewere described using the corresponding system of

optimum dosage regimen for mixtures of MEPM

differential equations.

with infusions containing L-cysteine and/or SBS at
different MICs (0.5, 1, 2 and 4 mg/L, depending on
the organism causing the infectious disease).
MEPM reconstituted in normal saline was used ascontrol, and MEPM plasm concentration-time

For model outputs, serum concentration = X 2/V 1.

profile in vivo were simulated w ith or w ithout

The differential equations give the rate of change

considering the drug degradation rate.

of the amount of MEPM (mg) in the serum
compartment (equation 2) and the peripheralcompartment (equation 3), whereis the1. MEPM 0.5-hr. infusion after mixture with
AM-F or AM-G

piece-wise input function for MEPM intravenous

Figure 1 (a, b and c) shows simulated serum

administration, CL represents clearances (L/hr),

MEPM concentration‒time profiles, with dosages

and V 1 and V 2 are the volume terms for the plasmaand duration of infusion determined by three CCR

compartments.

g rades (CCR<10, 10≤CCR≤50, CCR>50) on the

We u s e d M i c r o s o f t E x c e l 2 0 0 7 t o s o l ve t h ebasis of the Sanford Guide when MEPM is mixed

system of ordinary differential equations usingwith AM-F or AM-G and injected over 0.5 hr. under

Laplace transformation. As the criterion of efficacy,various conditions.

%TAM was calculated according to the following
5)equation :%TAM = ln [Dose/( Vd × MIC)) × ( T 1 / 2 /ln2) ×(100/DI)
Where T 1 / 2 = half-life (hr), DI = dosing interval(hr), Vd = volume of distribution.

The figure shows that the serum concentration of
MEPM is dramatically decreased compared with
control when MEPM is administered in a mixed
infusion with AM-F or AM-G and injected over 0.5hr..
T h e s i m u l a t e d C m a x , AU C a n d t h e p e r c e n t a g e

As reported previously, a TAM of over 40% isreaching 40%TAM as a function of MIC isessential for bactericidal action of MEPM 5 ) . The

summarized in Table 2. With a 0.5-hr. infusion,

target %TAM was therefore fixed at >40% in thisboth Cmax and AUC decreased compared withstudy, and the probability of target attainment forcontrol when MEPM was administered as a mixedeach antibiotic regimen was then calculated as theinfusion. For example, with CCR<10, 500 mg

fract ion of 1000 subjects achieving >40% TAM

q24hr., both C m a x and AUC decreased (C m a x , 18.4

20（148）

医薬品相互作用研究

Vol.39, No. 3（2016）a) CCR<10, MEPM 500 mg q24hr.
Mixture with AM-F

Mixture with AM-G

50 0hr. storage0
1hr.
-2 storage at 25°C
2hr. storage at 25°C

Concentration (mg/L)

Concentration (mg/L)

MEPM (control)

1hr. storage at 4°C
2hr. storage at 4°C
Time (hr.)

Time (hr.)

Concentration (mg/L)

Concentration (mg/L)b) 10 CCR 50, MEPM 1000 mg q12hr.

Time (hr.)

Time (hr.)

Concentration (mg/L)

Concentration (mg/L)c) 50<CCR, MEPM 1000 mg q8hr.

Time (hr.)

Time (hr.)

Fig. 1 Simulated serum MEPM concentration-time proﬁle when infused over 0.5 hr. after mixture with AM-F or AM-G
Median of simulated serum MEPM concentrations for three typical MEPM dosage regimens (a) CCR<10, 500 mg q24hr. (b) 10≤CCR≤50, 1000 mg
q12hr. and (c) CCR>50, 1000 mg q8hr., incorporating degradation as well as pharmacokinetic variability in 1000 simulations. It was assumed
that MEPM, mixed with AM-F or AM-G, was administered by a 0.5-hr. infusion. KEY: Control (filled triangles), 0 hr. storage after mixing(X-marks), 1 hr. storage at 4˚C (open squares) or 25˚C (filled squares) after mixing, and 2 hr. storage at 4˚C (open diamonds) or 25˚C (filled
diamonds) after mixing.

医薬品相互作用研究

Vol.39, No. 3（2016）21（149）

Table 2 TA% for MEPM when mixed with AM-F or AM-G and infused over 0.5 hr. after storage for 0, 1 or 2 hr. at 4 or 25˚C
Storage
Figure part

Dosage regimen

MixtureMEPM (control)

MEPM+AM-F
Figure 1(a)CCR<10500 mg q24hr.
MEPM+AM-GMEPM (control)

MEPM+AM-F
Figure 1(b)10 CCR 50
1000 mg q12hr.
MEPM+AM-GMEPM (control)

MEPM+AM-F
Figure 1(c)CCR ! 501000 mg q8hr.
MEPM+AM-G

Temp (°C)
4
4
25
25
4
4
25
25
4
4
25
25
4
4
25
25
4
4
25
25
4
4
25
25

TA (%)
Time (hr.)
0
1
2
1
2
0
1
2
1
2
0
1
2
1
2
0
1
2
1
2
0
1
2
1
2
0
1
2
1
2

Cmax (mg/L)
25.7
18.4
14.2
11.6
11.9
8.2
17.3
13.0
9.9
10.4
6.7
47.8
34.4
26.5
21.7
22.3
15.4
32.2
24.1
18.6
19.5
12.6
45.2
32.2
24.6
20.4
20.9
14.2
30.2
22.6
17.4
18.2
11.9

AUC (mg h/L)
120.7
85.8
65.9
54.0
55.6
38.2
80.4
60.2
46.1
48.3
31.5
110.1
78.3
60.3
49.5
50.8
34.9
73.5
55.0
42.3
44.2
28.8
70.3
50.6
39.0
32.0
32.8
22.5
47.5
35.6
24.5
28.5
18.6

MIC=0.5
100
100
100
100
100
100
100
100
100
100
99.8
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100

MIC=1
100
100
100
99.5
99.7
89.5
100
100
99.5
98.6
47.0
100
100
100
100
100
99.9
100
100
100
100
98.6
100
100
100
100
100
99.2
100
100
100
100
98.6

MIC=2
99.8
96.4
73.7
18.3
27.0
0
93.7
73.7
18.3
4.4
0
100
100
99.4
97.0
97.0
52.0
100
99.4
97.0
91.1
4.4
100
99.9
98.6
87.6
92.5
41.9
99.8
98.6
87.6
80.2
6.2

MIC=4
41.9
0.4
0
0
0
0
0
0
0
0
0
97.9
77.2
22.5
0.7
0.7
0
61.5
22.5
0.7
0
0
97.5
56.9
6.2
0
0
0
41.9
6.2
0
0
0

TA: target attainment
CCR: creatinine clearance rate (mL/min)
Temperature: Temp

mg/L; AUC 85.8 mg･h/L), compared with control

52.0%, 1000 mg q8hr.: 92.5% to 41.9%) and at 4°C(C max , 25.7 mg/L, AUC 120.7 mg･h/L) when MEPM

(500 mg q24hr.: 73.7% to 18.3%, 1000 mg q12hr.:

was administered as a mixed infusion with AM-F

99.4% to 97.0%, 1000 mg q8hr.: 98.6% to 87.6%).

immediately after mixing, as shown in Table 2(upper part) and Figure 1a. The decrease of C m a x

2. MEPM 2-hr. infusion after mixing with AM-F

and AUC when MEPM was administered as a mixed

or AM-G

infusion with AM-F were very similar. When kept

Figure 3 (a, b and c) shows simulated serumat 4℃ or 25℃ after mixing, the C m a x and AUC of

MEPM concentration‒time profiles, with dosages

MEPM administered as a mixed infusion decreased

and duration of infusion determined by three CCR

more rapidly when the storage time was extended

g rades (CCR<10, 10≤CCR≤50, CCR>50) on thefrom 1 to 2 hr..

basis of the Sanford Guide, when MEPM is mixed

The TA% based on different MICs (0.5, 1, 2 and4 mg/L) is also shown in Table 2 and the evolutionof TA% is described in Figure 2 (a, b and c).

with AM-F or AM-G and injected over 2 hr. undervarious storage conditions.
S i m u l a t e d C m a x , AU C a n d TA % c a l c u l a t e d a s aWith an MIC of 0.5 mg/L, TA% in all regimens

function of MIC are summarized in Table 3 and thewas maintained at nearly 100% as shown in Table

evolution of the TA% is represented in Figure 4 (a,2. With an MIC of 2 mg/L, all reg imens w ith ab and c). With a 2-hr. infusion, the AUC and C m a x

0.5-hr. infusion maintained TA% >80% when mixed

decreased dramat ically compared w ith control

infusion were stored for 0 hr. after mixing. TA%

under all storage condit ions and for all dosage

decreased when storage time was extended from 1

regimens when MEPM was administered as a

to 2 hr. after mixing with AM-F both at 25 °C (500

mixed infusion with both AM-F and AM-G ( Table

mg q24hr.: 27.0% to 0%, 1000 mg q12hr.: 97.0% to3).

22（150）

医薬品相互作用研究

Vol.39, No. 3（2016）

With an MIC of 0.5 mg/L, nearly all regimens

immediately after mixing, under all storage

maintained TA%>80% ( Table 3). With an MIC of 2

condit ions. The TA% dropped to 0‒14.6% whenm g / L a n d a 2 - h r . i n f u s i o n , TA % c o u l d n o t b e

mixed infusions were stored for 1 or 2 hr. at 4℃ or

maintained>80% when MEPM was administered

25℃ after mixing.

a) CCR<10, MEPM 500 mg q24hr.

MEPM (control)
Mixture with AM-G

Target attainment (%)

Target attainment (%)

Mixture with AM-F

MIC (mg/L)

50 0hr. storage0
1hr.
-2 storage at 25°C
2hr. storage at 25°C
1hr. storage at 4°C
2hr. storage at 4°C

MIC (mg/L)

Target attainment (%)

Target attainment (%)b) 10 CCR 50, MEPM 1000 mg q12hr.

MIC (mg/L)

MIC (mg/L)

Target attainment (%)

Target attainment (%)c) 50<CCR, MEPM 1000 mg q8hr.

MIC (mg/L)

MIC (mg/L)

Fig. 2 Calculated attainment rate of 40%TAM as a function of MIC after mixture with AM-F or AM-G
The attainment rate of 40%TAM as a function of MIC was calculated for three typical MEPM dosage regimens (a) CCR<10, 500 mg q24hr., (b) 10≤CCR≤50, 1000 mg q12hr. and (c) CCR>50, 1000 mg q8hr.. MEPM mixed with AM-F or AM-G was administered as a 0.5-hr. infusion. KEY:
Control (filled triangles), 0 hr. storage after mixture (X-marks), 1 hr. storage after mixture at 4˚C (open squares) or 25˚C (filled squares), and 2 hr.
storage after mixture at 4˚C (open diamonds) or 25˚C (filled diamonds).

医薬品相互作用研究

Vol.39, No. 3（2016）23（151）a) CCR<10, MEPM 500 mg q24hr.
Mixture with AM-G

Mixture with AM-F

50 0hr. storage0
1hr.
-2 storage at 25°C
2hr. storage at 25°C

Concentration (mg/L)

Concentration (mg/L)

MEPM (control)

1hr. storage at 4°C
2hr. storage at 4°C
Time (hr.)

Time (hr.)

Concentration (mg/L)

Concentration (mg/L)b) 10 CCR 50, MEPM 1000 mg q12hr.

Time (hr.)

Time (hr.)

Concentration (mg/L)

Concentration (mg/L)c) 50<CCR, MEPM 1000 mg q8hr.

Time (hr.)

Time (hr.)

Fig. 3 Simulated serum MEPM concentration‒time proﬁle after administration as a 2-hr. infusion regimen when mixed with AM-F or AM-G
Medians of simulated serum MEPM concentrations for three typical MEPM dosage regimens (a) CCR<10, 500 mg q24hr., (b) 10≤CCR≤50, 1000
mg q12hr. and (c) CCR>50, 1000 mg q8hr., incorporating degradation as well as pharmacokinetic variability in an average of 1000 simulations.
MEPM mixed with AM-F or AM-G was administered as a 2-hr. infusion. KEY: Control (filled triangles), 0 hr. storage after mixture (X-marks), 1 hr.
storage after mixture at 4˚C (open squares) or 25˚C (filled squares), and 2 hr. storage after mixture at 4˚C (open diamonds) or 25˚C (filled
diamonds).

24（152）

医薬品相互作用研究

Vol.39, No. 3（2016）a) CCR<10, MEPM 500 mg q24hr.

MEPM (control)
Mixture with AM-G

Target attainment (%)

Target attainment (%)

Mixture with AM-F

MIC (mg/L)

50 0hr. storage0
1hr.
-2 storage at 25°C
2hr. storage at 25°C
1hr. storage at 4°C
2hr. storage at 4°C

MIC (mg/L)

Target attainment (%)

Target attainment (%)b) 10 CCR 50, MEPM 1000 mg q12hr.

MIC (mg/L)

MIC (mg/L)

Target attainment (%)

Target attainment (%)c) 50<CCR, MEPM 1000 mg q8hr.

MIC (mg/L)

MIC (mg/L)

Fig. 4 Calculated rate of attainment of 40%TAM as a function of MIC after mixture with AM-F or AM-G
The rate of attainment of 40%TAM as a function of MIC was calculated for three typical MEPM dosage regimens (a) CCR<10, 500 mg q24hr., (b)10<CCR<50, 1000 mg q12hr. and (c) CCR>50, 1000 mg q8hr., assuming administration of MEPM mixed with AM-F or AM-G by 2-hr. infusion.
KEY: Control (filled triangles), 0 hr. storage after mixture (X-marks), 1 hr. storage after mixture at 4˚C (open squares) or 25˚C (filled squares), and
2 hr. storage after mixture at 4˚C (open diamonds) or 25˚C (filled diamonds).

医薬品相互作用研究

Vol.39, No. 3（2016）25（153）

Table 3 TA% for MEPM when mixed with AM-F or AM-G and infused over 2 hr. after storage for 0, 1 or 2 hr. at 4 or 25˚C
Storage
Figure part

Dosage regimen

MixtureMEPM (control)

MEPM+AM-F
Figure 3(a)CCR<10500 mg q24hr.
MEPM+AM-GMEPM (control)

MEPM+AM-F
Figure 3(b)10 CCR 50
1000 mg q12hr.
MEPM+AM-GMEPM (control)

MEPM+AM-F
Figure 3(c)CCR! 501000 mg q8hr.
MEPM+AM-G

Temp (°C)
4
4
25
25
4
4
25
25
4
4
25
25
4
4
25
25
4
4
25
25
4
4
25
25

TA (%)
Time (hr.)
0
1
2
1
2
0
1
2
1
2
0
1
2
1
2
0
1
2
1
2
0
1
2
1
2
0
1
2
1
2

Cmax (mg/L)
19.9
6.0
4.4
3.6
3.9
2.7
5.3
3.9
3.0
3.1
2.1
31.1
10.4
7.6
6.3
6.8
4.6
9.2
7.0
5.3
5.5
3.6
25.6
8.5
6.9
5.6
5.2
3.4
8.2
6.2
4.8
8.2
3.3

AUC (mg h/L)
120.7
34.1
23.1
18.9
22.1
15.2
27.1
20.3
15.6
16.3
10.6
110.1
34.7
23.9
19.6
22.5
15.4
28.3
21.2
16.3
17.0
11.1
70.3
20.9
16.9
6.9
12.8
8.4
20.0
15.0
11.5
12.0
7.8

MIC=0.5
100
100
98.8
83.0
97.5
41.9
99.7
98.8
83.0
52.0
0.1
100
100
100
100
100
99.6
100
100
100
99.9
91.1
100
100
100
100
100
99.9
100
100
100
99.9
92.5

MIC=1
100
77.2
3.0
0
1.2
0
22.4
3.0
0
0
0
100
98.6
93.7
77.2
95.6
41.9
98.6
93.7
77.2
52
0.1
100
99.6
97.5
80.2
97.5
70.0
98.6
97.5
80.2
70.0
6.2

MIC=2
100
0
0
0
0
0
0
0
0
0
0
100
61.5
0.7
0
0.7
0
8.5
0.7
0
0
0
100
41.9
14.6
0.4
0.1
0
27.0
14.6
0.4
0
0

MIC=4
83.0
0
0
0
0
0
0
0
0
0
0
99.9
0
0
0
0
0
0
0
0
0
0
99.9
0
0
0
0
0
0
0
0
0
0

TA target attainment
CCR:creatinine clearance rate (mL/min)
Temperature: Temp

3. MEPM mixed with Fru

method of mixture-administration, it is possible

Serum MEPM concentration‒time profiles werethat serum MEPM concentrations may fall below

simulated, with dosages and duration of infusion

the MIC for the pathogen concerned. Therefore, it

determined by three CCR grades (CCR<10, 10≤CCR

was considered important to evaluate whether or≤50, CCR>50) on the basis of the Sanford Guide,

not such mixture-administration would increase

after mixing MEPM with Fru and subjecting thethe risk of a significant decline in serum

mixture to various storage conditions. The

concentrations of MEPM.

simulated serum MEPM concentration‒time profile

In the present study, we performed simulations

after mixture with Fru was almost the same as thatwhich included not only populationof the control MEPM solution. The calculated TA%

pharmacokinetics for MEPM and but also

as a function of MIC is summarized in Table 4. No

degradation rates after mixing with an infusion

differences in TA% in comparison w ith control

containing L-cysteine and/or SBS. Commonly usedwere found when the infusion was stored for 0, 1

dosage regimens and storage conditions wereor 2 hr. after mixing.

tested and efficacy was evaluated as %TAM,
considering a range of MICs from 0.5 to 4 mg/L. A

Discussion

simulation study was conducted to evaluate theAccording to the drug package insert, MEPM isdecrease of %TA for different dosage regimes whenusually administered as an infusion in normal

the infusions are stored for 0, 1 or 2 hr. and at 4℃

s a l i n e . H o w e ve r, i n c l i n i c a l p r a c t i c e , M E P M i s

or 25℃ after mixing with Fru, AM-F or AM-G.

occasionally administered in mixed with infusions

When MEPM was mixed with Fru, which contains

containing L-cysteine and/or SBS. By adopting this

only SBS, the simulations indicate that >80% TAM

26（154）

医薬品相互作用研究

Vol.39, No. 3（2016）

Table 4 TA% obtained with diﬀerent infusion regimens of MEPM when mixed with Fru and stored for 0, 1 or 2 hr. at 4°
C or 25°
C

Storage
Dosage regimen
CCR<10500 mg q24hr.
0.5-hr. infusion

CCR<10500 mg q24hr.
2-hr. infusion

10 CCR 50
1000 mg q12hr.
0.5-hr. infusion

Temp ( C)-Time (hr.)-

MIC=0.5
100

MIC=1
100

MIC=2
99.8

MIC=4
47.0

-

0

100

100

99.8

47.0

MEPM+Fru

4 or 25

1

100

100

99.7

47.0

4 or 25

2

100

100

99.7

47.0

MEPM (control)

-

-

100

100

100

77.2

MixtureMEPM (control)

-

0

100

100

100

77.2

MEPM+Fru

4 or 25

1

100

100

100

77.2

MEPM (control)

4 or 25
-

2
-

100
100

100
100

100
100

77.2
97.9

-

0

100

100

100

97.9

4 or 25

1

100

100

100

97.9

4 or 25

2

100

100

100

97.9

-

-

100

100

100

99.6

MEPM+Fru
MEPM (control)

10 CCR 50
1000 mg q12hr.
2-hr. infusion
CCR! 501000 mg q8hr.
0.5-hr. infusion
CCR>501000 mg q8hr.
2-hr. infusion

TA (%)

-

0

100

100

100

99.6

MEPM+Fru

4 or 25

1

100

100

100

99.6

4 or 25

2

100

100

100

99.6

MEPM (control)

-

0

100
100

100
100

99.2
99.2

97.5
97.5

MEPM+Fru

4 or 25

1

100

100

99.2

97.5

MEPM (control)

4 or 25
-

2
-

100
100

100
100

99.2
100

97.5
100

-

0

100

100

100

100

4 or 25

1

100

100

100

100

4 or 25

2

100

100

100

100

MEPM+Fru

TA: target attainment
CCR: creatinine clearance rate (mL/min)
Temperature: Temp

is likely to be attained in all dosage regimes,

it may just be necessary to extend the infusion

similar to the performance of MEPM in normal

time to 2 hr. 2) . Fru could always be administeredsaline, regardless of extending the storage time

separately if MEPM needed to be administered as afrom 1 to 2 hr.. In previous studies, MEPM

2-hr. infusion.

concentrations in normal saline have been

The present study also showed that, in mixedr e p o r t e d t o r e d u c e b y 1 . 6 6 % a f t e r 2 h r. a f t e r

infusion with AM-F or AM-G, %TA decreases whenstorage at room temperature

12, 13). The degradation

either the length of the infusion is increased (fromrate constant of MEPM mixed with Fru was also

0.5 to 2 hr.) or the storage time after mixing (fromvery small, and similar to that obtained with

1 to 2 hr.). When considering bacteria with MIC

normal saline solution.

0.5 mg/L, nearly all regimens, except 500 mg

This result suggests that the concentration of

q24hr. (2-hr. infusion), maintained 40%TAM. This

SBS contained in Fru (0.2 g/L according to theresult suggests that, under all storage conditions

package insert), has extremely small influence ontested, infusion of MEPM in normal saline or in%TA in storage time or infusion time under study

combination with AM-F or AM-G would be equallycondition. To maintain serum drug concentrations

effective against

above the MIC for intermediate or resistantan organism that causes a significant proportion of

microorganisms (MIC >2 mg/L) such as

all Gram-negative infections in the urinary tract 14) .

11)

For an MIC of 2 mg/L, the simulations indicate that

spp. and,(MIC<0.06‒0.25),

医薬品相互作用研究

Vol.39, No. 3（2016）27（155）nearly all MEPM 0.5-hr. infusion regimens with nol e n g t h o f t h e i n f u s i o n t o m a i n t a i n TA % > 8 0 % .

storage after mixture maintained 40%TAM. For

MEPM have to be administered as an infusion inintermediate or resistant microorganisms (MIC >2

normal saline, but not in parenteral nutrition fluidsmg/L) like

spp. andc o n t a i n i n g S B S o r L- c y s t e i n e s u c h a s A M - F o r, however, the results suggest that

AM-G. But in the infusion management of highly

40%TAM cannot be maintained due to degradation

invasive patient, such as sepsis, parenteralcaused by contact with the amino acid solutions.

nutrition fluids is administrated mixed with MEPM.

Treatments for infections caused by the

Infusions of MEPM mixed with AM-F or AM-G,

abovementioned organisms are limited, however,which contain L-cysteine and SBS, must be

and carbapenems may be the only option. Our

administered as a 0.5-hr. infusion immediately

results suggest that, in this situation, MEPM

after mixing to maintain TA% >80%.

11)

should be administered as a 0.5-hr. infusion

References

immediately after mixing with AM-F or AM-G, so as
to minimize the decrease in concentration of
MEPM.

１）Wiseman LR、Wagstaff AJ、Brogden RN、etal:Meropenem:a review of its antibacterial

In many clinical situations, MEPM is also

activity、pharmacokinetic properties andadministered through a Y-site, together with amino

clinical efficacy、Drugs、50、73‒101、1995.

acid injection preparations containing L-cysteineand SBS. In this case, MEPM is generally２）Nicolau DP: Pharmacokinetic andpharmacodynamic properties of meropenem、

administered via a 0.5-hr. infusion, keeping the

Clin. Infect. Dis、47 Suppl1、S32‒40、2008.

contact time with amino acids short. It was３）Craig WA: Pharmacokinetic/pharmacodynamic

previously thought that the extent of degradation

parameters: rationale for anti-bacterial dosingof MEPM when administered via a Y-site would beof mice and men.、Clin. Infect. Dis、26(1)、1‒10、

lower than if it were to be mixed directly with the

1998.

15)

amino acid preparations . However, when dealing

４）Drusano GL: Antimicrobial pharmacodynamics:

with intermediate or resistant microorganisms,

critical interactions of ʻbug and drugʼ.、Nat.

MEPM administration must be extended, which can

Rev. Microbiol、2(4)、289‒300、2004.

increase the potential contact time, thereby５）Turnidge JD: The pharmacodynamics of βleading to an increased risk of MEPM degradation.
Yoshioka. reported that the effectiveness of-lactams.、Clin. Infect. Dis、27(1)、10‒22、1998.
６）Takasu Y、Yoshida M、Tange M、Asahara K、

doripenem in the resolution of fever was decreased

Uchida T: Prediction of the Stability of(75.1%) by a Y-site administration with an amino

Meropenem in Intravenous Mixtures.、Chem.

acid infusion line

16)

. The effectiveness of a 0.5 hr.

Pharm. Bull、63、248‒254、2015.

MEPM infusion may therefore be decreased even in７）Zaccardelli DS、Krcmarik CS、Wolk R、Khalidi

Y-site administration. This will need to be

N:Stability of imipenem and cilastatin sodium

confirmed in future studies.

in total parenteral nutrient solution.、JPEN J.

This interaction between carbapenems andParenter. Enteral Nutr、14、306‒9、1990.

amino acid infusions, will need to be considered in８）Itagaki F、Kudo C、Katagiri S、Oshitari T、order to maximize the effectiveness of the

Takahashi H、Natsugari H、Watanabe

antibiotics.

M:Incompatibility between Meropenem

In conclusion, using a Monte Carlo simulation,

Injection and Amino Acid Infusions caused byour study showed that co-administration of MEPM

L-Cysteine.、Jpn J. Pharm. Health Care Sci、39、

and an amino acid solution does not allow the521‒527、2013.

same exposure to be achieved as an infusion of９）Ikawa K、Morikawa N、Ohge H、et

MEPM in normal saline. For microorganisms

al:Pharmacokinetic‒pharmacodynamic target

susceptible to MEPM (MIC ≥2 mg/L),

attainment analysis of meropenem in Japaneseco-administration with Fru, which contains SBS,

adult patients.、J. Infect. Chemother、16、

can be made safe and effective by extending the25‒32、2010.

28（156）

医薬品相互作用研究

10）Gilbert DN、Moellering Jr RC、Eliopoulos GM、etal:The Sanford Guide to Antimicrobial
Therapy、40th ed.、Sperryville、VA、
Antimicrobial Therapy、2010.
11）Niki Y、Matsumoto T、Kohno S、et al:Nationwide
surveillance of bacterial respiratory pathogens
conducted by the Japanese Society of
Chemotherapy in 2007.、J. Infect. Chemother、
15(3)、156‒67、2009.
12）Jaruratanasirikul S、Sriwiriyajan S:Stability ofmeropenem in normal saline solution after
storage at room temperature.、Southeast Asian
J. Trop. Med、34、627‒629、2003.
13）Patel PR、Cook SE:Stability of meropenem inintravenous solutions.、Am. J. Health Syst.
Pharm、54、412‒21、1997.
14）Ishikawa K、Matsumoto T、Yasuda M、Uehara S、
Muratani T、Yagisawa M:The nationwide studyof bacterial pathogens associated with urinary
tract infections conducted by the JapaneseSociety of Chemotherapy.、J. Infect.
Chemother、17(1)、126‒138、2011.
15）Aygin BE、Kutay D: Clinical nutrition and druginteractions、Ulusal Cer Derg、29、177‒186、2013.
16）Yoshioka M、Takenaka M、Shin Y、Orita T、Shundo K、Watari M:Effects of amino acidinfusions on doripenem injection at the Y-site.、
Jpn J. Chemother、56、1‒6、2008.

Vol.39, No. 3（2016）