Pharmacokinetics of flomoxef in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue of patients undergoing lower gastrointestinal surgery: Dosing considerations based on site-specific pharmacodynamic target attainment

Hirano, Toshinori; Ohge, Hiroki; Ikawa, Kazuro; Uegami, Shinnosuke; Watadani, Yusuke; Shigemoto, Norifumi; Yoshimura, Kosuke; Kitagawa, Hirohisa; Kaiki, Yuki; Morikawa, Norifumi; Takahashi, Shinya

doi:10.1016/j.jiac.2022.10.017

Cited by 2 publications

(5 citation statements)

References 31 publications

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“…In this study, we attempted to establish canine-specific nonclinical PK-PD cutoff values by using MCS analysis. Our data showed that nonclinical PK-PD cutoff values in dogs increase with shorter dosing intervals, irrespective of dose, as previously reported in humans [20]. In addition, the nonclinical PK-PD cutoff values of 40 mg/kg are higher than the MIC90 of ESBL-K. pneumoniae and -P. mirabilis (1 µg/mL each) and that of ESBL-Escherichia coli (4 µg/mL) [13,14] when administered at q8h and q6h, respectively.…”

Section: Discussionsupporting

confidence: 89%

“…In addition, the CFR simulated in this study suggests that the q6h and q8h regimens of FMX are appropriate for the treatment of ESBL-Escherichia coli, -K. pneumoniae, and -P. mirabilis infections in dogs. The similar dosing intervals were proposed to achieve bactericidal concentrations against ESBL-E infections as found in human patients based on PK-PD simulations [20]. These findings in our study indicate that FMX administration at shorter dose intervals can be an alternative treatment for ESBL-Escherichia coli, -K. pneumoniae, and -P. mirabilis infections in dogs.…”

Section: Discussionsupporting

confidence: 77%

“…We could not include too many dogs because our university's Animal Use Committee placed importance on reducing experimental animals. Second, the PK parameters of FMX are also different among body tissues [20], underlining the need to investigate the parameters in sites other than blood in dogs. Third, the correlation between drug concentration and antibacterial effect was not assessed because only the MIC was used as the PD parameter in this study.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetic and Pharmacodynamic Analysis of the Oxacephem Antibiotic Flomoxef against Extended-Spectrum β-Lactamase-Producing Enterobacterales from Dogs

Kusumoto,

Jitsuiki,

Motegi

et al. 2024

IJMS

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Flomoxef (FMX) may be a potential alternative to carbapenems for dogs infected with Enterobacterales-producing extended-spectrum β-lactamase (ESBL-E). However, the appropriate dosage of FMX in dogs with ESBL-E infections has yet to be established. This study was carried out to establish appropriate treatment regimens for FMX against ESBL-E infections in dogs using a pharmacokinetics–pharmacodynamics (PK–PD) approach. Five dogs were intravenously administered at a bolus dose of FMX (40 mg/kg body weight). Serum concentrations of FMX were calculated with high-performance liquid chromatography-tandem mass spectrometry, and then applied to determine PK indices based on a non-compartmental model. The cumulative fraction of response (CFR) was estimated based on the dissemination of minimum inhibitory concentrations among wild-type ESBL-E from companion animals. From the results, the dosage regimens of 40 mg/kg every 6 and 8 h were estimated to attain a CFR of >90% for wild-type isolates of ESBL-producing Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis for dogs. By contrast, all regimens had a CFR of <80% for ESBL-producing Enterobacter cloacae. Our results indicated that dosage regimens of 40 mg/kg FMX every 6 and 8 h can be a non-carbapenem treatment for canine infections of ESBL-producing Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, but not for those of ESBL-producing Enterobacter cloacae.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetic and Pharmacodynamic Analysis of the Oxacephem Antibiotic Flomoxef against Extended-Spectrum β-Lactamase-Producing Enterobacterales from Dogs

Kusumoto,

Jitsuiki,

Motegi

et al. 2024

IJMS

View full text Add to dashboard Cite

show abstract

“…In this study, we attempted to establish canine-specific nonclinical PK-PD cutoff values by using MCS analysis. Our data showed that nonclinical PK-PD cutoff values for FMX increase with shorter dosing intervals, as previously reported in humans [23]. In addition, these nonclinical PK-PD cutoff values are higher than the MIC90 of ESBL-K. pneumoniae and -P. mirabilis (1 µg/mL each) and that of ESBL-Escherichia coli (4 µg/mL) [12,13] when administered at q8h and q6h, respectively.…”

Section: Discussionsupporting

confidence: 86%

“…In addition, the CFR simulated in this study suggests that the q6h and q8h regimens of FMX are appropriate for treatment of ESBL-Escherichia coli, -K. pneumoniae and -P. mirabilis infections in dogs. The similar dosing intervals were proposed to achieve bactericidal concentrations against ESBL-E infections as found in human patients based on PK-PD simulation [23]. These findings in our study indicate that FMX administration at shorter dose intervals can be an alternative treatment for ESBL-Escherichia coli, -K. pneumoniae and -P. mirabilis infections in dogs.…”

Section: Discussionsupporting

confidence: 76%

Pharmacokinetic and Pharmacodynamic Analysis Using Monte Carlo Simulation of the Oxacephem Antibiotic Flomoxef against Extended-Spectrum β-Lactamase-Producing Enterobacterales from Dogs

Kusumoto,

Jitsuiki,

Motegi

et al. 2023

Preprint

View full text Add to dashboard Cite

Flomoxef (FMX) may be a potential alternative to carbapenems for dogs infected with Enterobacterales producing extended-spectrum β-lactamase (ESBL-E). However, the appropriate dosage of FMX in dogs with ESBL-E infections has yet to be established. This study was carried out to establish appropriate treatment regimens for FMX against ESBL-E infections in dogs by a pharmacokinetics–pharmacodynamics (PK–PD) approach. Five dogs received an intravenous bolus dose of FMX (40 mg/kg). Serum FMX concentrations were evaluated using high-performance liquid chromatography-tandem mass spectrometry, and PK indices were determined based on non-compartmental model. The cumulative fraction of response (CFR) was calculated based on the distribution of minimum inhibitory concentrations among wild-type ESBL-E from companion animals. As the results, the dosage regimens of 40 mg/kg q8h and q6h were estimated to achieve a CFR of &gt;90% for wild-type isolates of ESBL-producing Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis for dogs. In contrast, all regimens exhibited a CFR of &lt;80% for ESBL-producing Enterobacter cloacae. Our results indicated that dosage regimens of 40 mg/kg FMX q8h and q6h can be a non-carbapenem treatment for dogs infected with ESBL-producing isolates of Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, but not for those infected with ESBL-producing Enterobacter cloacae.

show abstract

Pharmacokinetics of flomoxef in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue of patients undergoing lower gastrointestinal surgery: Dosing considerations based on site-specific pharmacodynamic target attainment

Cited by 2 publications

References 31 publications

Pharmacokinetic and Pharmacodynamic Analysis of the Oxacephem Antibiotic Flomoxef against Extended-Spectrum β-Lactamase-Producing Enterobacterales from Dogs

Pharmacokinetic and Pharmacodynamic Analysis of the Oxacephem Antibiotic Flomoxef against Extended-Spectrum β-Lactamase-Producing Enterobacterales from Dogs

Pharmacokinetic and Pharmacodynamic Analysis Using Monte Carlo Simulation of the Oxacephem Antibiotic Flomoxef against Extended-Spectrum β-Lactamase-Producing Enterobacterales from Dogs

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