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173（ 73 ）〈Original Article〉

Influence of meropenem treatment on hepatic andrenal function in Japanese patients withcreatinine clearance rates of 10 to 50 mL/min:
A single-center retrospective study
Ichiro Nakakura1, Seigo Iwakawa2, Kota Sakakura1,
Kaori Imanishi1, Rumi Sako1 and Kunio Yamazaki1
1

Department of Pharmacy,
National Hospital Organization Osaka National Hospital
2
Kobe Pharmaceutical University(Received for publication March 22, 2019)

Background: Meropenem is used as empirical therapy for severe sepsis andvarious infections. It is important to understand the tolerability of meropenem toadminister it at a sufﬁciently high dose (e.g. 1 g or 2 g every 8 or 12 hours) and ensure
adequate time above the minimum inhibitory concentration. However, the dosetolerability and risk factors for hepatic and renal dysfunction in meropenem-treatedpatients with baseline renal dysfunction remain unclear.
Objectives: To conﬁrm the dose tolerability of meropenem and to identify thefactors affecting hepatic and renal dysfunction after meropenem treatment inJapanese patients with creatinine clearance rates of 10 to 50 mL/min.
Methods: This was a retrospective, single-center study, where 142 subjects withcreatinine clearance rates ranging from 10 to 50 mL/min were administered meropenem
between April 1, 2012 and October 31, 2015. Safety was evaluated using the Common
Terminology Criteria for Adverse Events (CTCAE) v4.0. Abnormal hepatic function
was evaluated based on alanine aminotransferase (ALT) and alkaline phosphatase(ALP) levels, and abnormal renal function was evaluated using serum creatinine(SCr) levels. Adverse events were considered as worsening if the grade of each item
increased from baseline values.
Results: Worsening of ALT, ALP, and SCr grades was observed in 17.9%, 18.3%,
and 4.2% of patients, respectively. Dose of 2 g/day or more, treatment duration, or
the degree of patientʼs renal function had no effect on hepatic and renal dysfunction.
Corresponding author: Ichiro Nakakura, Tel: ＋81–6–6942–1331, E-mail: nakakura.ichiro.ur@mail.hosp.go.jp

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Thus, the risk factors for hepatic and renal dysfunction were not related to meropenem.
Conclusion: Meropenem dose and treatment duration are not risk factors forhepatic and renal dysfunction in Japanese patients with creatinine clearance rates of
10 to 50 mL/min.

Introduction
Meropenem is a carbapenem antibiotic used against gram-positive, gram-negative (including extended-spectrum β-lactamase-producing bacteria and AmpC β-lactamase-producing bacteria), and anaerobic bacteria1). Meropenem has proven tolerability, as reported in a comparative investigation of
cephems2). It is used as empirical therapy for severe sepsis and severe infections such as pneumonia,
febrile neutropenia, and bacterial meningitis1). Following intravenous administration of meropenem, asmall amount is metabolized, while most of it is excreted unaltered via urine1). The elimination halflife of meropenem in patients with normal kidney function is 1 h. For patients with impaired renal
function, such as those with creatinine clearance rates less than 50 mL/min, the dose or interval of meropenem administration requires adjustment1). Importantly, the minimum inhibitory concentration andthe mutant prevention concentration (an index for preventing resistant bacteria) are different depending on the bacterial species3). Therefore, when meropenem is used for empirical treatment, it should be
administered at the highest tolerable dose to ensure adequate time above the minimum inhibitory concentration of most bacteria. However, administration of meropenem at a high-dose of 2 g/day or more
has been shown to cause hepatic dysfunction4〜6). In a questionnaire survey targeting physicians, many
physicians had safety concerns regarding high dose of 2 g/day or more administration of meropenem7),
suggesting that administration of meropenem at high doses should be avoided7).
We previously reported the tolerable meropenem dose in Japanese patients with creatinine
clearance rates of 50 mL/min or more8). We also showed that the frequency of side effects such as
hepatic and renal dysfunction was not dependent on meropenem dosage8). Regarding the safety ofmeropenem in Japanese patients with baseline renal dysfunction, although the rate of adverse
event occurrence has been reported, the details have not been provided9). Furthermore, the dosetolerability and risk factors for hepatic and renal dysfunction in meropenem-treated patients withbaseline renal dysfunction remain unclear. In this study, we report meropenem dose tolerability
and the factors affecting organ dysfunction during meropenem treatment in Japanese patientswith creatinine clearance rates ≥10 to ＜50 mL/min.

Patients and Methods
Study design, setting, and subjects
This retrospective study was conducted in an acute care hospital in Osaka, Japan. In total,

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175（ 75 ）Figure 1. Flowchart of study patient selection

2,121 patients were treated with brand-name meropenem (Meropen®, Sumitomo Dainippon Pharma
Co. Ltd, Osaka, Japan) between April 1, 2012 and March 31, 2016 at the Osaka National Hospitalin Osaka, Japan. Of these patients, 1,979 were excluded from the study because their creatinine
clearance was ≥50 or ＜10 mL/min, their body weight was ＜50 kg, their age was ＜18 years, they
had received renal replacement therapy, their meropenem treatment duration was ＜5 days, clinicallaboratory values were not conﬁrmed, or termination of meropenem administration due to death(Figure 1). The reason for excluding patients with creatinine clearance levels ＜10 mL/min is thatthe dose interval for meropenem administration is once every 24 h (Meropen® interview form, July
2018 revision, 15th edition), and therefore the dose would not be 2 g/day or more. The reason for
excluding patients with aged ＜18 years is that creatinine clearance rates were calculated using the
Cockcroft–Gault formula10). The reason for excluding patients with body weight ＜50 kg is that to
avoid including the study patients with overexposure of meropenem due to low body weight. The
reason for excluding patients with meropenem treatment duration ＜5 days is that drug-induced
liver injury is generally occurs between 5 and 90 days after drug ingestion11). Subsequently, 142 patients with creatinine clearance rates ≥10 to ＜50 mL/min were included in the study.
Data collection
We collected data from patientʼs medical records, including background information (bodyweight, age, sex, underlying disease, and intensive care unit admission), infectious disease diagnosis,

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June 2019clinical laboratory data [alanine aminotransferase (ALT), alkaline phosphatase (ALP), and serum
creatinine (SCr) levels], concomitant medication use, and meropenem administration duration.
Deﬁnitions
Creatinine clearance rates were calculated using the Cockcroft–Gault formula10).
Safety was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE)
12)v4.0 published by the National Cancer Institute.
Abnormalities in hepatic function were evaluated using ALT and ALP levels, and abnormalities in renal function were evaluated using SCr levels. Adverse events were considered as worsening if the grade of each laboratory data at completion of administration of meropenem increased from the baseline grade (i.e., start of drug administration).
Endpoints
The primary endpoint was worsening hepatic and renal function in meropenem-treated patients with creatinine clearance rates ≥10 to ＜50 mL/min. The secondary endpoints included (1)differences in hepatic and renal function due to dosage (patients were grouped by meropenem
dose: ＜2 g/day vs. ≥2 g/day); (2) differences in hepatic and renal function due to baseline renal
function (patients were grouped by creatinine clearance rates: ≥10 to ＜25 mL/min vs. ≥25 to ＜50 mL/min); and (3) evaluation of risk factors for hepatic and renal dysfunction during meropenem treatment.
Statistical analysis
Continuous variables are presented as medians (interquartile range), and differences between
groups were assessed using the Studentʼs t-test. Categorical variable differences between groups
were assessed using the chi-square test or Fisherʼs exact test. Risk factors for hepatic and renal
dysfunction were evaluated using univariate and multivariate logistic regression. However, multivariate logistic regression was performed when multiple factors were present in univariate logistic regression. A p-value ≤0.05 indicated statistical signiﬁcance. All statistical analyses were performed using JMP® 9.0.2 (SAS Institute Inc., Cary, NC, USA).
EthicsThis study was conducted in compliance with the standards of the Declaration of Helsinki
and the current ethical guidelines. Approval from the ethics committee board of the Osaka National Hospital, reference number 16028, was obtained. To protect patient privacy, identifying
data were encrypted in an electronic database. Written informed consent was exempted because
no intervention was involved and patient-identifying data were not included in the study.

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177（ 77 ）Results
Patient baseline characteristics are presented in Table 1. Worsening of ALT, ALP, and SCrlevels was observed in 17.9%, 18.3%, and 4.2% of patients, respectively.
Patient characteristics in the ＜2 g/day and ≥2 g/day groups are presented in Table 2. In the＜2 g/day group, the percentage of patients with creatinine clearance ＜25 mL/min at the start ofmeropenem administration was higher and elderly patients. In contrast, in the ≥2 g/day group, thenumber of days of administration of meropenem was longer than that in the ＜2 g/day group. Although a difference in patient background was observed between the two groups, no difference
was observed in worsening of ALT (17.6% vs. 18.0%, P＝0.96), ALP (18.4% vs. 18.2%, P＝0.98), and SCr (5.8% vs. 2.2%, P＝0.19) levels between the ＜2 g/day and ≥2 g/day groups.
The characteristics of patients with creatinine clearance rates ≥10 to ＜25 mL/min and thosewith creatinine clearance rates ≥25 to ＜50 mL/min are presented in Table 3. In patients with creatinine clearance rates ≥10 to ＜25 mL/min, the daily dose of meropenem was lower than that inpatients with creatinine clearance rates ≥25 to ＜50 mL/min group, and it was elderly. However,there was no difference in worsening of ALT (4.2% vs. 20.7%, P＝0.076), ALP (15.8% vs.
18.8%, P＝1.00), and SCr (4.0% vs. 4.3%, P＝1.00) levels between patients with creatinine clearance rates ≥10 to ＜25 mL/min and those with creatinine clearance rates ≥25 to ＜50 mL/min.
Meropenem dose and treatment duration were not risk factors for hepatic or renal dysfunction in univariate logistic regression. The risk factors for hepatic dysfunction included concomitantly administered drugs (Tables 4 and 5). The risk factors for elevated ALT levels included administration of parenteral nutrition solutions and heparin sodium (Table 4). The only risk factor
for elevated ALP was the use of parenteral nutrition solutions (Table 5). On the other hand, norisk factors for renal dysfunction were identiﬁed (Table 6).

Discussion
This study was the ﬁrst to describe dose tolerability and risk factors associated with administering meropenem to Japanese patients with creatinine clearance rates between 10 and 50 mL/
min. We report two useful ﬁndings. First, the incidence of worsening hepatic and renal function
in meropenem-treated patients with creatinine clearance rates between 10 and 50 mL/min was
similar to that in patients with creatinine clearance rates of 50 mL/min or more. Second, no factors directly related to meropenem administration, such as daily dose or administration period,
were identiﬁed as risk factors for hepatic or renal function deterioration.
In previous reports, worsening of hepatic and renal function was observed in 3.4 to 45%2,4〜6,13)
and 0.1 to 4.2%2,4,5) of meropenem-treated patients, respectively. Furthermore, hepatic dysfunction was reportedly higher with high dose meropenem administration (2 or 3 g/day or more)5,6). In178（ 78 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Table 1. Patient characteristics and hepatic or renal dysfunction incidence during meropenem
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179（ 79 ）Table 2. Comparison of patient characteristics and hepatic and renal function between
different meropenem dosing groups

Table 3. Comparison of patient characteristics and hepatic and renal function between
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Table 4. Univariate and multivariate logistic regression analyses to identify risk factors
associated with worsening ALT levels in meropenem-treated patientsthe present study, meropenem administration resulted in increased ALT, ALP, and SCr levels in
17.9%, 18.3%, and 4.2% of patients, respectively. These results did not differ from those of previous studies using CTCAE criteria for the evaluation of hepatic and renal function4,8). In our previous study, worsening of ALT, ALP, and SCr levels was observed in 18.8% (45/240 patients),
18.5% (44/238), and 2.5% (6/240) of patients with creatinine clearance rates of 50 mL/min or
more, respectively8). These results conﬁrmed reproducibility in the incidence of meropenem-associated hepatic and renal function deterioration.
We also evaluated the effects of baseline renal function and daily meropenem dose; they
showed no signiﬁcant effects on worsening of hepatic or renal function. Therefore, we consideredthat baseline renal function and daily meropenem dose did not inﬂuence hepatic or renal function
deterioration. Risk factor analysis for worsening hepatic or renal function did not reveal any risk
factors related to meropenem administration, i.e., daily meropenem dose or treatment duration inpatients with creatinine clearance ≥10 and ＜50 mL/min. Accordingly, meropenem daily dose andrenal function at baseline were not related to worsening hepatic or renal function. Similar conclusions were obtained in our previous study8).
In contrast, the use of concomitant medication affected hepatic dysfunction. Speciﬁcally,

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181（ 81 ）Table 5. Univariate logistic regression analysis to identify risk factors associated withworsening ALP levels in meropenem-treated patients

parenteral nutrition was a risk factor for increased ALT and ALP levels, and use of heparin sodium was a risk factor for increased ALT. Hepatobiliary complications due to parenteral nutrition
solutions14〜18) and elevated hepatic enzymes (such as transaminase) due to heparin administration19〜22) are common. Therefore, when using these medications in combination with meropenem, hepatic function should be monitored.
The mechanism underlying hepatic function deterioration following meropenem treatment is
unknown. In general, hepatic dysfunction caused by β-lactam antibiotics, such as cephalosporins,
occurs via an immunological mechanism23,24).
According to the present study, the daily dosage and duration of meropenem treatment were
not risk factors for worsening of hepatic or renal function in patients with creatinine clearance
rates ≥10 and ＜50 mL/min. We concluded that patients infected with multi-drug resistant pathogens or with infections in organs with poor antibiotic penetration could be given empirical therapy with high-dose (2 g/day or more) meropenem at dosing intervals determined by renal function, without affecting hepatic or renal function.
This study has a few limitations. First, it was a single-center retrospective study. Second, thenumber of cases was limited. Therefore, there could be other factors causing hepatic and renal
dysfunction that we did not identify in this study.
In conclusion, meropenem is well tolerated in patients with baseline renal impairment, and182（ 82 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Table 6. Univariate logistic regression analysis to identify risk factors associated with worsening
SCr in meropenem-treated patients

its dose and duration are not risk factors for hepatic and renal function deterioration.
Acknowledgments
We would like to thank Editage (www.editage.jp) for English language editing.
Conﬂicts of interest
The authors have no conﬂicts of interest directly relevant to the content of this article.

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