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

Published:November 01, 2022DOI:



      Flomoxef is generally used to treat abdominal infections and as antibiotic prophylaxis during lower gastrointestinal surgery. It is reportedly effective against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and an increasingly valuable alternative to carbapenems. However, its abdominal pharmacokinetics remain unclear. Herein, pharmacokinetic analysis of flomoxef in the abdominal tissue was conducted to simulate dosing regimens for pharmacodynamic target attainment in abdominal sites.


      Flomoxef (1 g) was administered intravenously to a patient 30 min before commencing elective lower gastrointestinal surgery. Samples of plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue were collected during surgery. The flomoxef tissue concentrations were measured. Accordingly, non-compartmental and compartmental pharmacokinetic parameters were calculated, and simulations were conducted to evaluate site-specific pharmacodynamic target values.


      Overall, 41 plasma samples, 34 peritoneal fluid samples, 38 peritoneum samples, and 41 subcutaneous adipose samples from 10 patients were collected. The mean peritoneal fluid-to-plasma ratio in the areas under the drug concentration-time curve was 0.68, the mean peritoneum-to-plasma ratio was 0.40, and the mean subcutaneous adipose tissue-to-plasma was 0.16. The simulation based on these results showed the dosing regimens (q8h [3 g/day] and q6h [4 g/day]) achieved the bactericidal effect (% T > minimum inhibitory concentration [MIC] = 40%) in all tissues at an MIC of 1 mg/L.


      We elucidated the pharmacokinetics of flomoxef and simulated pharmacodynamics target attainment in the abdominal tissue. This study provides evidence concerning the use of optimal dosing regimens for treating abdominal infection caused by strains like ESBL-producing bacteria.



      AUC (area under the drug concentration-time curve), ESBL (extended-spectrum beta-lactamase), HPLC (high-performance liquid chromatography), MIC (minimum inhibitory concentration), PK/PD (pharmacokinetic/pharmacodynamic), SD (standard deviation), SSI (surgical site infection)
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        • Chong Y.
        • Shimoda S.
        • Shimono N.
        Current epidemiology, genetic evolution and clinical impact of extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
        Infect Genet Evol. 2018; 61: 185-188
        • Bevan E.R.
        • Jones A.M.
        • Hawkey P.M.
        Global epidemiology of CTX-M β-lactamases: temporal and geographical shifts in genotype.
        J Antimicrob Chemother. 2017; 72: 2145-2155
        • Dubinsky-Pertzov B.
        • Temkin E.
        • Harbarth S.
        • Fankhauser-Rodriguez C.
        • Carevic B.
        • Radovanovic I.
        • et al.
        Carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae and the risk of surgical site infection after colorectal surgery: a prospective cohort study.
        Clin Infect Dis. 2019; 68: 1699-1704
        • Rodríguez-Baño J.
        • Gutiérrez-Gutiérrez B.
        • Machuca I.
        • Pascual A.
        Treatment of Infections caused by extended-spectrum-beta-lactamase-, ampc-, and carbapenemase-producing Enterobacteriaceae.
        Clin Microbiol Rev. 2018; 31 (e00079–17)
        • van Duin D.
        • Doi Y.
        The global epidemiology of carbapenemase-producing Enterobacteriaceae.
        Virulence. 2017; 8: 460-469
        • Tsuji T.
        • Satoh H.
        • Narisada M.
        • Hamashima Y.
        • Yoshida T.
        Synthesis and antibacterial activity of 6315-S, a new member of the oxacephem antibiotic.
        J Antibiot. 1985; 38: 466-476
        • Ito M.
        • Ishigami T.
        The meaning of the development of flomoxef and clinical experience in Japan.
        Infection. 1991; 19: S253-S257
        • Darlow C.A.
        • da Costa R.M.A.
        • Ellis S.
        • Franceschi F.
        • Sharland M.
        • Piddock L.
        • et al.
        Potential antibiotics for the treatment of neonatal sepsis caused by multidrug-resistant bacteria.
        Paediatr Drugs. 2021; 23: 465-484
        • Kobayashi M.
        • Takesue Y.
        • Kitagawa Y.
        • Kusunoki M.
        • Sumiyama Y.
        Antimicrobial prophylaxis and colon preparation for colorectal surgery: results of a questionnaire survey of 721 certified institutions in Japan.
        Surg Today. 2011; 41: 1363-1369
        • Partina I.
        • Kalinogorskaya O.
        • Kojima S.
        • Gostev V.
        • Volkova M.
        • Ageevets V.
        • et al.
        Surveillance of antimicrobial susceptibility of Enterobacteriaceae pathogens isolated from intensive care units and surgical units in Russia.
        Jpn J Antibiot. 2016; 69: 41-51
        • Santanirand S.
        • Kojima T.
        • Yamaguchi K.
        • Wongnak S.
        • Thokaew S.
        • Chiaranaicharoen S.
        Antimicrobial activity of flomoxef against Enterobacteriaceae including extended spectrum beta-lactamases-producing strains isolated at Ramathibodi Hospital: a 1000-bed tertiary care hospital in Bangkok, Thailand.
        J Infect Dis Ther. 2018; 6: 378
        • Ito A.
        • Tatsumi Y.M.
        • Wajima T.
        • Nakamura R.
        • Tsuji M.
        Evaluation of antibacterial activities of flomoxef against ESBL producing Enterobacteriaceae analyzed by Monte Carlo simulation.
        Jpn J Antibiot. 2013; 66: 71-86
        • Jung Y.
        • Lee S.S.
        • Song W.
        • Kim H.S.
        • Uh Y.
        In vitro activity of flomoxef against extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae in Korea.
        Diagn Microbiol Infect Dis. 2019; 94: 88-92
        • Matsumura Y.
        • Yamamoto M.
        • Nagao M.
        • Komori T.
        • Fujita N.
        • Hayashi A.
        • et al.
        Multicenter retrospective study of cefmetazole and flomoxef for treatment of extended-spectrum-β-lactamase-producing Escherichia coli bacteremia.
        Antimicrob Agents Chemother. 2015; 59: 5107-5113
        • Lee C.H.
        • Chen I.L.
        • Li C.C.
        • Chien C.C.
        Clinical benefit of ertapenem compared to flomoxef for the treatment of cefotaxime-resistant Enterobacteriaceae bacteremia.
        Infect Drug Resist. 2018; 11: 257-266
        • Lee C.H.
        • Su L.H.
        • Chen F.J.
        • Tang Y.F.
        • Li C.C.
        • Chien C.C.
        • et al.
        Comparative effectiveness of flomoxef versus carbapenems in the treatment of bacteraemia due to extended-spectrum β-lactamase-producing Escherichia coli or Klebsiella pneumoniae with emphasis on minimum inhibitory concentration of flomoxef: a retrospective study.
        Int J Antimicrob Agents. 2015; 46: 610-615
        • Ikawa K.
        • Morikawa N.
        • Ikeda K.
        • Ohge H.
        • Sueda T.
        Development of breakpoints of cephems for intraabdominal infections based on pharmacokinetics and pharmacodynamics in the peritoneal fluid of patients.
        J Infect Chemother. 2008; 14: 141-146
        • Nakamura K.
        • Ikawa K.
        • Nishikawa G.
        • Kobayashi I.
        • Tobiume M.
        • Sugie M.
        • et al.
        Clinical pharmacokinetics of flomoxef in prostate tissue and dosing considerations for prostatitis based on site-specific pharmacodynamic target attainment.
        J Infect Chemother. 2020; 26: 236-241
        • Murao N.
        • Ohge H.
        • Ikawa K.
        • Watadani Y.
        • Uegami S.
        • Shigemoto N.
        • et al.
        Pharmacokinetics of piperacillin-tazobactam in plasma, peritoneal fluid and peritoneum of surgery patients, and dosing considerations based on site-specific pharmacodynamic target attainment.
        Int J Antimicrob Agents. 2017; 50: 393-398
        • Takayama Y.
        • Komatsu T.
        • Nakamura K.
        • Tomoda Y.
        • Toda M.
        • Miura H.
        • et al.
        Association of serum and fat tissue antibiotic concentrations with surgical site infections in lower gastrointestinal surgery.
        Surgery. 2022; 171: 1000-1005
        • Bratzler D.W.
        • Dellinger E.P.
        • Olsen K.M.
        • Perl T.M.
        • Auwaerter P.G.
        • Bolon M.K.
        • et al.
        American society of health-system pharmacists; infectious disease society of America; surgical infection society; society for healthcare epidemiology of America. Clinical practice guidelines for antimicrobial prophylaxis in surgery.
        Am J Health Syst Pharm. 2013; 70: 195-283
        • Konaka R.
        • Hashimoto H.
        • Nishimura R.
        • Kuruma K.
        • Hirauchi K.
        Assays of 6315-S (flomoxef) and its metabolites in body fluids by high-performance liquid chromatography.
        Jpn J Chemother. 1987; 35: 137-144
        • Yamaoka K.
        • Tanigawara Y.
        • Nakagawa T.
        • Uno T.
        A pharmacokinetic analysis program (multi) for microcomputer.
        J Pharmacobio-Dyn. 1981; 4: 879-885
        • Barbour A.M.
        • Schmidt S.
        • Zhuang L.
        • Rand K.
        • Derendorf H.
        Application of pharmacokinetic/pharmacodynamic modelling and simulation for the prediction of target attainment of ceftobiprole against meticillin-resistant Staphylococcus aureus using minimum inhibitory concentration and time-kill curve-based approaches.
        Int J Antimicrob Agents. 2014; 43: 60-67
        • Kobayashi I.
        • Ikawa K.
        • Nakamura K.
        • Nishikawa G.
        • Kajikawa K.
        • Yoshizawa T.
        • et al.
        Penetration of piperacillin-tazobactam into human prostate tissue and dosing considerations for prostatitis based on site-specific pharmacokinetics and pharmacodynamics.
        J Infect Chemother. 2015; 21: 575-580
        • Ikawa K.
        • Morikawa N.
        • Hayato S.
        • Ikeda K.
        • Ohge H.
        • Sueda T.
        Pharmacokinetic and pharmacodynamic profiling of cefepime in plasma and peritoneal fluid of abdominal surgery patients.
        Int J Antimicrob Agents. 2007; (270–3)
        • Ikawa K.
        • Morikawa N.
        • Matsuda S.
        • Ikeda K.
        • Ohge H.
        • Takesue Y.
        • et al.
        Peritoneal penetration and pharmacodynamic exposure of intravenous cefozopran in abdominal surgery patients.
        Int J Antimicrob Agents. 2007; 30: 352-355
        • Yasunaga K.
        • Okamoto Y.
        • Maehara K.
        • Mase K.
        • Iida Y.
        • Yoshioka S.
        • et al.
        Phase-1 clinical study on 6315-S (Flomoxef).
        Chemotherapy. 1987; 35: 494-517
        • Tashiro S.
        • Hayashi M.
        • Takemura W.
        • Igarashi Y.
        • Liu X.
        • Mizukami Y.
        • et al.
        Pharmacokinetics/pharmacodynamics evaluation of flomoxef against extended-spectrum beta-lactamase-producing Escherichia coli in vitro and in vivo in a murine thigh infection model.
        Pharm Res (N Y). 2021; 38: 27-35
        • Darlow C.A.
        • Hope W.
        Flomoxef for neonates: extending options for treatment of neonatal sepsis caused by ESBL-producing Enterobacterales.
        J Antimicrob Chemother. 2022; 77: 711-718
        • Ambrose P.G.
        • Bhavnani S.M.
        • Rubino C.M.
        • Louie A.
        • Gumbo T.
        • Forrest A.
        • et al.
        Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it's not just for mice anymore.
        Clin Infect Dis. 2007; 44: 79-86
        • Ueda T.
        • Takesue Y.
        • Matsumoto T.
        • Tateda K.
        • Kusachi S.
        • Mikamo H.
        • et al.
        Change in antimicrobial susceptibility of pathogens isolated from surgical site infections over the past decade in Japanese nation-wide surveillance study.
        J Infect Chemother. 2021; 27: 931-939
        • Yamaguchi K.
        • Ishii Y.
        • Tateda K.
        • Iwata M.
        • Watanabe N.
        • Shinagawa M.
        • et al.
        [Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2012].
        Jpn J Antibiot. 2014; 67: 73-107
        • Shinagawa N.
        • Taniguchi M.
        • Hirata K.
        • Furuhata T.
        • Mizuguchi T.
        • Osanai H.
        • et al.
        [Bacteria isolated from surgical infections and its susceptibilities to antimicrobial agents - special references to bacteria isolated between April 2011 and March 2012].
        Jpn J Antibiot. 2014; 67: 339-383
        • Alobaid A.S.
        • Hites M.
        • Lipman J.
        • Taccone F.S.
        • Roberts J.A.
        Effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients: a structured review.
        Int J Antimicrob Agents. 2016; 47: 259-268
        • Chen X.
        • Brathwaite C.E.M.
        • Barkan A.
        • Hall K.
        • Chu G.
        • Cherasard P.
        • et al.
        Optimal cefazolin prophylactic dosing for bariatric surgery: no need for higher doses or intraoperative redosing.
        Obes Surg. 2017; 27: 626-629
        • Lillico R.
        • Sayre C.L.
        • Sitar D.S.
        • Davies N.M.
        • Baron C.M.
        • Lakowski T.M.
        Quantification of cefazolin in serum and adipose tissue by ultra high performance liquid chromatography-Tandem mass spectrometry (UHPLC-MS/MS): application to a pilot study of obese women undergoing cesarean delivery.
        J Chromatogr, B: Anal Technol Biomed Life Sci. 2016; 1031: 94-98
        • Hoshi S.
        • Kuwahara M.
        • Orikasa S.
        • Nakano S.
        • Onuma T.
        • Chiba R.
        • et al.
        Diffusion into human prostate and clinical evaluation of 6315-S (flomoxef) in urinary tract infection.
        Jpn J Chemother. 1987; 35: 968-978
        • Imaizumi M.
        • Watanabe H.
        • Ojika T.
        • Fujita K.
        • Sakakibara M.
        • Kondo D.
        • et al.
        A clinical study on pulmonary tissue uptake of flomoxef.
        Jpn J Antibiot. 1991; 44: 22-34
        • Komatsu T.
        • Tsumuraya S.
        • Takayama Y.
        • Kaizu T.
        • Okamoto M.
        • Tajima H.
        • et al.
        Population pharmacokinetic-pharmacodynamic target attainment analysis of flomoxef in the serum and liver tissue of patients undergoing hepatic resection.
        Antimicrob Agents Chemother. 2022; 66e0230321