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Pharmacokinetics and Pharmacodynamics of Temocillin

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Abstract

Temocillin, a 6-α-methoxy derivative of ticarcillin, is a forgotten antibiotic that has recently been rediscovered, and issues about clinical breakpoints and optimal therapeutic regimens are still ongoing. Temocillin spectrum is almost restricted to Enterobacteriaceae. The addition of the α-methoxy moiety on ticarcillin confers resistance to hydrolysis by Ambler classes A and C β-lactamases (extended spectrum β-lactamases, Klebsiella pneumoniae carbapenemase and AmpC hyperproduced enzymes). Temocillin is bactericidal, and the effect of inoculum size on its activity is relatively mild. The proportion of spontaneous resistant mutants in vitro to temocillin is low, as found in vivo. After intravenous infusion, temocillin showed a prolonged elimination half-life of approximately 5 h. The percentage of protein binding of temocillin is high (approximately 80%), and is concentration-dependent. Temocillin clearance is mainly renal, and urinary recovery is high, ranging from 72 to 82% after 24 h. Furthermore, the penetration of temocillin into bile and peritoneal fluid is high, but poor into cerebrospinal fluid. The cumulative percentage of a 24-h period during which the free drug concentration exceeds the minimum inhibitory concentration (fT > MIC) at steady-state pharmacokinetic conditions seems to be the best pharmacokinetic/pharmacodynamic (PK/PD) index correlating with temocillin efficacy. An fT > MIC of 40–50% is associated with antibacterial effect and survival in vivo. Monte Carlo simulations performed in critically ill patients showed that the 2 g every 12 h and 2 g every 8 h regimens provide a 95% probability of target attainment of 40% fT > MIC up to an MIC of 8 mg/L. In less severely ill patients or in specific foci of infection, such as urinary tract infection, a 4 g daily regimen should be adequate for strains with temocillin MIC up to 16 mg/L. Data regarding actual wild-type MIC distribution, clinical efficacy, PK profiling in volunteers or patients, and PD targets are scarce, and further studies are required to support appropriate dosing recommendations and determination of clinical breakpoints.

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Fig. 1

Adapted from PubChem

Fig. 2

Reproduced from De Jongh et al. [35], with permission

Fig. 3

Reproduced from Laterre et al. [55], with permission

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References

  1. Miranda Bastos AC, Vandecasteele SJ, Tulkens PM, Spinewine A, Van Bambeke F. Development and validation of a high performance liquid chromatography assay for the determination of temocillin in serum of haemodialysis patients. J Pharm Biomed Anal. 2014;90:192–7.

    Article  CAS  PubMed  Google Scholar 

  2. Livermore DM, Tulkens PM. Temocillin revived. J Antimicrob Chemother. 2008;63:243–5.

    Article  PubMed  Google Scholar 

  3. SPILF. Diagnostic et antibiothérapie des infections urinaires bactériennes communautaires de l’adulte. 2015. Available at: http://www.infectiologie.com/UserFiles/File/spilf/recos/infections-urinaires-spilf-argumentaire.pdf.

  4. Labia R, Baron P, Masson JM, Hill G, Cole M. Affinity of temocillin for Escherichia coli K-12 penicillin-binding proteins. Antimicrob Agents Chemother. 1984;26:335–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bush K, Smith SA, Ohringer S, Tanaka SK, Bonner DP. Improved sensitivity in assays for binding of novel beta-lactam antibiotics to penicillin-binding proteins of Escherichia coli. Antimicrob Agents Chemother. 1987;31:1271–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jules K, Neu HC. Antibacterial activity and beta-lactamase stability of temocillin. Antimicrob Agents Chemother. 1982;22:453–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Slocombe B, Basker MJ, Bentley PH, Clayton JP, Cole M, Comber KR, et al. BRL 17421, a novel beta-lactam antibiotic, highly resistant to beta-lactamases, giving high and prolonged serum levels in humans. Antimicrob Agents Chemother. 1981;20:38–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Malottke R, Potel J. Antibacterial activity of temocillin. Drugs. 1985;29(Suppl 5):67–73.

    Article  CAS  PubMed  Google Scholar 

  9. Martinez-Beltran J, Loza E, Gomez-Alferez A, Romero-Vivas J, Bouza E. Temocillin. In vitro activity compared with other antibiotics. Drugs. 1985;29(Suppl 5):91–7.

    Article  CAS  PubMed  Google Scholar 

  10. Bauernfeind A. Bacteriostatic and bactericidal activity of penicillins at constant and variable concentrations. Drugs. 1985;29(Suppl 5):9–14.

    Article  CAS  PubMed  Google Scholar 

  11. Bonacorsi S, Fitoussi F, Lhopital S, Bingen E. Comparative in vitro activities of meropenem, imipenem, temocillin, piperacillin, and ceftazidime in combination with tobramycin, rifampin, or ciprofloxacin against Burkholderia cepacia isolates from patients with cystic fibrosis. Antimicrob Agents Chemother. 1999;43:213–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Acker HV, Snick EV, Nelis HJ, Coenye T. In vitro activity of temocillin against planktonic and sessile Burkholderia cepacia complex bacteria. J Cyst Fibros. 2010;9:450–4.

    Article  PubMed  Google Scholar 

  13. Van Landuyt HW, Boelaert J, Piot P, Verbist L. In vitro activity of temocillin against clinical isolates. Drugs. 1985;29(Suppl 5):1–8.

    Article  PubMed  Google Scholar 

  14. Jephcott AE, Egglestone SI. In vitro activity of temocillin against Neisseria gonorrhoeae including penicillinase-producing strains. Drugs. 1985;29(Suppl 5):18–23.

    Article  CAS  PubMed  Google Scholar 

  15. Fuchs PC, Barry AL, Jones RN, Thornsberry C. Temocillin: in vitro activity against 734 selected clinical isolates, including beta-lactamase-producing strains. Diagn Microbiol Infect Dis. 1984;2:55–63.

    Article  CAS  PubMed  Google Scholar 

  16. Verbist L. In vitro activity of temocillin (BRL 17421), a novel beta-lactamase-stable penicillin. Antimicrob Agents Chemother. 1982;22:157–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ghathian K, Calum H, Gyssens IC, Frimodt-Møller N. Temocillin in vitro activity against recent clinical isolates of Neisseria gonorrhoeae compared with penicillin, ceftriaxone and ciprofloxacin. J Antimicrob Chemother. 2016;71:1122–3.

    Article  CAS  PubMed  Google Scholar 

  18. Matagne A, Ghuysen M-F, Frère J-M. Interactions between active-site-serine beta-lactamases and mechanism-based inactivators: a kinetic study and an overview. Biochem J. 1993;295:705–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Woodford N, Pike R, Meunier D, Loy R, Hill R, Hopkins KL. In vitro activity of temocillin against multidrug-resistant clinical isolates of Escherichia coli, Klebsiella spp. and Enterobacter spp., and evaluation of high-level temocillin resistance as a diagnostic marker for OXA-48 carbapenemase. J Antimicrob Chemother. 2014;69:564–7.

    Article  CAS  PubMed  Google Scholar 

  20. Fournier D, Chirouze C, Leroy J, Cholley P, Talon D, Plésiat P, et al. Alternatives to carbapenems in ESBL-producing Escherichia coli infections. Médecine Mal Infect. 2013;43:62–6.

    Article  CAS  Google Scholar 

  21. Mischnik A, Baumert P, Hamprecht A, Rohde A, Peter S, Feihl S, et al. Susceptibility to penicillin derivatives among third-generation cephalosporin-resistant Enterobacteriaceae recovered on hospital admission. Diagn Microbiol Infect Dis. 2017;87(1):71–3.

    Article  CAS  PubMed  Google Scholar 

  22. Rodriguez-Villalobos H, Malaviolle V, Frankard J, de Mendonça R, Nonhoff C, Struelens MJ. In vitro activity of temocillin against extended spectrum β-lactamase-producing Escherichia coli. J Antimicrob Chemother. 2006;57:771–4.

    Article  CAS  PubMed  Google Scholar 

  23. Tärnberg M, Östholm-Balkhed A, Monstein H-J, Hällgren A, Hanberger H, Nilsson LE. In vitro activity of beta-lactam antibiotics against CTX-M-producing Escherichia coli. Eur J Clin Microbiol Infect Dis. 2011;30:981–7.

    Article  PubMed  Google Scholar 

  24. Livermore DM, Hope R, Fagan EJ, Warner M, Woodford N, Potz N. Activity of temocillin against prevalent ESBL- and AmpC-producing Enterobacteriaceae from south-east England. J Antimicrob Chemother. 2006;57:1012–4.

    Article  CAS  PubMed  Google Scholar 

  25. Glupczynski Y, Huang T-D, Berhin C, Claeys G, Delmée M, Ide L, et al. In vitro activity of temocillin against prevalent extended-spectrum beta-lactamases producing Enterobacteriaceae from Belgian intensive care units. Eur J Clin Microbiol Infect Dis. 2007;26:777–83.

    Article  CAS  PubMed  Google Scholar 

  26. Adams-Haduch JM, Potoski BA, Sidjabat HE, Paterson DL, Doi Y. Activity of temocillin against KPC-Producing Klebsiella pneumoniae and Escherichia coli. Antimicrob Agents Chemother. 2009;53:2700–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mutters NT, Zimmermann S, Kaase M, Mischnik A. Activity of temocillin, mecillinam, ceftazidime, and ceftazidime/avibactam against carbapenem-non-susceptible Enterobacteriaceae without carbapenemase production. Eur J Clin Microbiol Infect Dis. 2015;34:2429–37.

    Article  CAS  PubMed  Google Scholar 

  28. Zykov IN, Sundsfjord A, Småbrekke L, Samuelsen Ø. The antimicrobial activity of mecillinam, nitrofurantoin, temocillin and fosfomycin and comparative analysis of resistance patterns in a nationwide collection of ESBL-producing Escherichia coli in Norway 2010–2011. Infect Dis. 2016;48:99–107.

    Article  CAS  Google Scholar 

  29. Buyck JM, Guénard S, Plésiat P, Tulkens PM, Bambeke FV. Role of MexAB-OprM in intrinsic resistance of Pseudomonas aeruginosa to temocillin and impact on the susceptibility of strains isolated from patients suffering from cystic fibrosis. J Antimicrob Chemother. 2012;67:771–5.

    Article  CAS  PubMed  Google Scholar 

  30. Chalhoub H, Pletzer D, Weingart H, Braun Y, Tunney MM, Elborn JS, et al. Mechanisms of intrinsic resistance and acquired susceptibility of Pseudomonas aeruginosa isolated from cystic fibrosis patients to temocillin, a revived antibiotic. Sci Rep. 2017;7:40208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Soubirou JF, Rossi B, Couffignal C, Ruppé E, Chau F, Massias L, et al. Activity of temocillin in a murine model of urinary tract infection due to Escherichia coli producing or not producing the ESBL CTX-M-15. J Antimicrob Chemother. 2015;70:1466–72.

    Article  CAS  PubMed  Google Scholar 

  32. Alexandre K, Chau F, Guérin F, Massias L, Lefort A, Cattoir V, et al. Activity of temocillin in a lethal murine model of infection of intra-abdominal origin due to KPC-producing Escherichia coli. J Antimicrob Chemother. 2016;71:1899–904.

    Article  CAS  PubMed  Google Scholar 

  33. Gupta ND, Smith RE, Balakrishnan I. Clinical efficacy of temocillin. J Antimicrob Chemother. 2009;64:431–3.

    Article  CAS  PubMed  Google Scholar 

  34. Just HM, Becker C, Gieringer J, Wenz A, Bassler M, Daschner F. In vitro combination-effect of temocillin with ticarcillin and aminoglycosides on gram-negative and gram-positive bacteria. Drugs. 1985;29(Suppl 5):74–7.

    Article  CAS  PubMed  Google Scholar 

  35. De Jongh R, Hens R, Basma V, Mouton JW, Tulkens PM, Carryn S. Continuous versus intermittent infusion of temocillin, a directed spectrum penicillin for intensive care patients with nosocomial pneumonia: stability, compatibility, population pharmacokinetic studies and breakpoint selection. J Antimicrob Chemother. 2008;61:382–8.

    Article  PubMed  Google Scholar 

  36. Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect. 2014;20:862–72.

    Article  CAS  PubMed  Google Scholar 

  37. Basker MJ, Merrikin DJ, Ponsford RJ, Slocombe B, Tasker TCG. BRL 20330, an oral prodrug of temocillin: bioavailability studies in man. J Antimicrob Chemother. 1986;18:399–405.

    Article  CAS  PubMed  Google Scholar 

  38. Overbosch D, van Gulpen C, Mattie H. Renal clearance of temocillin in volunteers. Drugs. 1985;29(Suppl 5):128–34.

    Article  CAS  PubMed  Google Scholar 

  39. Hampel B, Feike M, Koeppe P, Lode H. Pharmacokinetics of temocillin in volunteers. Drugs. 1985;29(Suppl 5):99–102.

    Article  CAS  PubMed  Google Scholar 

  40. Höffler D, Koeppe P. Temocillin pharmacokinetics in normal and impaired renal function. Drugs. 1985;29(Suppl 5):135–9.

    Article  PubMed  Google Scholar 

  41. Baert L, Aswarie H, Verbist L, Horton R. Penetration of temocillin into prostatic tissue after intravenous dosing. Acta Clin Belg. 1989;44:358–9.

    Article  CAS  PubMed  Google Scholar 

  42. Spelsberg F, Bauernfeind A, Wiest W, Hanser P. Biliary concentrations of temocillin. Drugs. 1985;29(Suppl 5):122–7.

    Article  PubMed  Google Scholar 

  43. Poston GJ, Greengrass A, Moryson CJ. Biliary concentrations of temocillin. Drugs. 1985;29(Suppl 5):140–5.

    Article  PubMed  Google Scholar 

  44. Wise R, Donovan IA, Drumm J, Dyas A, Cross C. The intraperitoneal penetration of temocillin. J Antimicrob Chemother. 1983;12:93–6.

    Article  CAS  PubMed  Google Scholar 

  45. Wittke RR, Adam D, Klein HE. Therapeutic results and tissue concentrations of temocillin in surgical patients. Drugs. 1985;29(Suppl 5):221–6.

    Article  PubMed  Google Scholar 

  46. Cowan W, Baird A, Sleigh JD, Gray JM, Leiper JM, Lawson DH. Lung tissue penetration of temocillin. Drugs. 1985;29(Suppl 5):151–3.

    Article  PubMed  Google Scholar 

  47. Legge JS, Reid TM, Palmer JB. Clinical efficacy, tolerance and pharmacokinetics of temocillin in patients with respiratory tract infections. Drugs. 1985;29(Suppl 5):118–21.

    Article  PubMed  Google Scholar 

  48. Brückner O, Trautmann M, Borner K. A study of the penetration of temocillin in the cerebrospinal fluid. Drugs. 1985;29(Suppl 5):162–6.

    Article  PubMed  Google Scholar 

  49. Leroy A, Humbert G, Fillastre J-P, Borsa F, Godin M. Pharmacokinetics of temocillin (BRL 17421) in subjects with normal and impaired renal function. J Antimicrob Chemother. 1983;12:47–58.

    Article  CAS  PubMed  Google Scholar 

  50. Boelaert J, Daneels R, Schurgers M, Lambert AM, Van Landuyt HW, Mellows G, et al. The pharmacokinetics of temocillin in patients with normal and impaired renal function. J Antimicrob Chemother. 1983;11:349–56.

    Article  CAS  PubMed  Google Scholar 

  51. Vandecasteele SJ, Miranda Bastos AC, Capron A, Spinewine A, Tulkens PM, Van Bambeke F. Thrice-weekly temocillin administered after each dialysis session is appropriate for the treatment of serious Gram-negative infections in haemodialysis patients. Int J Antimicrob Agents. 2015;46:660–5.

    Article  CAS  PubMed  Google Scholar 

  52. Roberts JA, Paul SK, Akova M, Bassetti M, Waele JJD, Dimopoulos G, et al. DALI: defining antibiotic levels in intensive care unit patients: are current β-Lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58:1072–83.

    Article  CAS  PubMed  Google Scholar 

  53. Craig WA. Basic pharmacodynamics of antibacterials with clinical applications to the use of beta-lactams, glycopeptides, and linezolid. Infect Dis Clin N Am. 2003;17:479–501.

    Article  Google Scholar 

  54. Leggett JE, Fantin B, Ebert S, Totsuka K, Vogelman B, Calame W, et al. Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models. J Infect Dis. 1989;159:281–92.

    Article  CAS  PubMed  Google Scholar 

  55. Laterre P-F, Wittebole X, Van de Velde S, Muller AE, Mouton JW, Carryn S, et al. Temocillin (6 g daily) in critically ill patients: continuous infusion versus three times daily administration. J Antimicrob Chemother. 2015;70:891–8.

    Article  CAS  PubMed  Google Scholar 

  56. Balakrishnan I, Awad-El-Kariem FM, Aali A, Kumari P, Mulla R, Tan B, et al. Temocillin use in England: clinical and microbiological efficacies in infections caused by extended-spectrum and/or derepressed AmpC-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother. 2011;66:2628–31.

    Article  CAS  PubMed  Google Scholar 

  57. Habayeb H, Sajin B, Patel K, Grundy C, Al-Dujaili A, Van de Velde S. Amoxicillin plus temocillin as an alternative empiric therapy for the treatment of severe hospital-acquired pneumonia: results from a retrospective audit. Eur J Clin Microbiol Infect. 2015;34:1693–9.

    Article  CAS  Google Scholar 

  58. Muller AE, Theuretzbacher U, Mouton JW. Use of old antibiotics now and in the future from a pharmacokinetic/pharmacodynamic perspective. Clin Microbiol Infect. 2015;21:881–5.

    Article  CAS  PubMed  Google Scholar 

  59. Bergan T, Olszewski WL, Engeset A. Temocillin penetration of peripheral lymph. Drugs. 1985;29(Suppl 5):114–7.

    Article  CAS  PubMed  Google Scholar 

  60. British Society for Antimicrobial Chemotherapy. BSAC Clinical Breakpoints [Internet]. 2015. Available at: http://www.bsac.org.uk/wp-content/uploads/2012/02/BSAC-Susceptibility-testing-version-143.pdf.

  61. Société Française de Microbiologie. Comité de l’antibiogramme de la Société Française de Microbiologie. 2017. Available at: http://www.sfm-microbiologie.org/UserFiles/files/casfm/CASFMV1_0_MARS_2017.pdf. Accessed 28 Apr 2017.

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Authors and Affiliations

  1. Infectious Diseases Department, Rouen University Hospital, GRAM (EA2656), Rouen, France

    Kevin Alexandre

  2. Univ. Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, 75018, Paris, France

    Bruno Fantin

  3. Service de Médecine Interne, Hôpital Beaujon, AP-HP, 100 boulevard du Général Leclerc, 92110, Clichy, France

    Bruno Fantin

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Correspondence to Bruno Fantin.

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No funding was received in the preparation of this manuscript.

Conflict of interest

Bruno Fantin received funding from Eumedica pharmaceuticals for part of the temocillin experimental studies performed in the laboratory [31, 32]. Dr Kevin Alexandre has no conflicts of interest to declare regarding this manuscript.

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Alexandre, K., Fantin, B. Pharmacokinetics and Pharmacodynamics of Temocillin. Clin Pharmacokinet 57, 287–296 (2018). https://doi.org/10.1007/s40262-017-0584-7

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