基質特異性拡張型βラクタマーゼ（ESBL）産生腸内細菌科細菌に対し、標的治療としてセファマイシン系抗菌薬のセフメタゾール（CMZ）の使用が期待されている。しかしながら、ESBL産生腸内細菌科細菌感染症患者におけるCMZの母集団薬物動態（PPK）解析や薬物動態学/薬力学（PK/PD）関係の報告は非常に少なく、遊離形濃度と治療効果及び安全性の関係性も明らかになっていない。そこで本研究では、CMZでの治療患者のPPKを明らかにし、遊離形濃度を用いたPK/PD解析する事で有効性、安全性が確保された腎機能及びアルブミン（ALB）濃度毎に最適な投与方法を構築する。
2021年8月〜2022年3月の間に東京ベイ・浦安市川医療センター（当院）でCMZ患者のカルテ情報を収集し、HPLCを用いて血清中濃度及び遊離形濃度を測定した。また、ESBL産生腸内細菌科細菌のMICを微量液体希釈法により測定した。本研究は当院及び慶應義塾大学薬学部の研究倫理委員会（承認番号: 697、210709-3）の承認を得ている。
対象の37症例において年齢は73（62-82）歳、CLcrは66.3 (37.5-82.8) mL/min、シスタチンCによるeGFRは57.7 (34.1-74.2) mL/min/m2であった。 CMZのトラフ濃度（n=51）は血清中濃度0.6-39.1 μg/mL、遊離形濃度0.1-11.7 μg/mLであり、蛋白結合率は40.4-94.2 %であった。CMZは腎排泄型薬物であり腎障害による腎クリアランス低下に伴い、遊離形濃度及び血清中濃度の上昇を認めた。CMZは高蛋白結合薬剤（83.6-84.8 %）であり、ALB濃度の低下に伴う蛋白結合率の低下により、ALB濃度とCMZの蛋白結合率は有意な相関関係を示した（r=0.559、p<0.001）。ESBL産生腸内細菌科細菌（n=114）のMIC50は2 μg/mL、MIC90は4 μg/mLであった。
今後、ESBL産生腸内細菌科細菌に対するCMZの最適なPK/PDパラメータであるfT>MIC≧69.6%、遊離形濃度及びMIC分布を用いた腎機能及びALB濃度毎に最適な投与方法の構築を行う予定である。
Cefmetazole (CMZ), a cephamycin, is expected to be the definitive therapy against extended spectrum β lactamase (ESBL)-producing Enterobacteriaceae bacteremia. However, there are very few reports on pharmacokinetics/pharmacodynamics (PK/PD) and population pharmacokinetic (PPK) analysis of CMZ for patients with ESBL-producing Enterobacteriaceae bacteremia. Furthermore, the relationship between free CMZ concentration and therapeutic effect and safety is unclear. Therefore, the purpose of this study is to establish the optimal dosing regimen according to renal function and albumin concentration, which ensures efficacy and safety, by PPK and PK/PD analysis based on free CMZ concentration for patients undergoing treatment.
Between August 2021 and March 2022, data were collected from medical records of patients who received CMZ at Tokyo Bay Urayasu Ichikawa Medical Center (our hospital). Serum and free drug concentration of CMZ were determined using HPLC. Minimum inhibitory concentration (MIC) against ESBL-producing Enterobacteriaceae bacteremia was also determined by broth microdilution method. This study was approved by the Ethics Committee of our hospital and the Keio University Faculty of Pharmacy (Approval No. 697, No. 210709-3).
In the 37 patients included, the mean age was 73 (62–82) years, creatinine clearance (CLcr) was 66.3 (37.5–82.8) mL/min, and estimated glomerular filtration rate (eGFR) as calculated using cystatin C was 57.7 (34.1–74.2) mL/min/m2. The serum and free CMZ trough concentrations (n=51) ranged from 0.6 to 39.1 μg/mL and 0.1 to 11.7 μg/mL, respectively. As CMZ is renally excreted, the free and serum drug concentrations increased with decreasing renal clearance due to renal impairment. CMZ is highly protein bound (83.6–84.8 %), and the decrease in protein binding with the decrease in ALB concentration showed a significant correlation between ALB concentration and protein binding rate of CMZ (r = 0.559, p<0.001). MIC50 and 90 were 2 and 4 μg/mL against ESBL-producing Enterobacteriaceae bacteremia, respectively.
In the future, we will establish the optimal dosing regimen of CMZ against ESBL-producing Enterobacteriaceae bacteremia according to the renal function and ALB using optimal PK/PD parameter of CMZ, fT>MIC≧69.6%, free drug concentration and MIC distribution.