, Volume 46, Issue 2, pp 239–244 | Cite as

Beta-lactams in continuous infusion for Gram-negative bacilli osteoarticular infections: an easy method for clinical use

  • Alba Ribera
  • Laura Soldevila
  • Raul Rigo-Bonnin
  • Fe Tubau
  • Ariadna Padullés
  • Joan Gómez-Junyent
  • Javier Ariza
  • Oscar Murillo
Original Paper


Continuous infusion (CI) of beta-lactams could optimize their pharmacokinetic/pharmacodynamic indices, especially in difficult-to-treat infections.


To validate an easy-to-use method to guide beta-lactams dosage in CI (formula).


A retrospective analysis was conducted of a prospectively collected cohort (n = 24 patients) with osteoarticular infections caused by Gram-negative bacilli (GNB) managed with beta-lactams in CI. Beta-lactams dose was calculated using a described formula (daily dose = 24 h × beta-lactam clearance × target “steady-state” concentration) to achieve concentrations above the MIC. We correlated the predicted concentration (Cpred = daily dose/24 h × beta-lactam clearance) with the patient’s observed concentration (Cobs) measured by UPLC–MS/MS (Spearman’s coefficient).


The most frequent microorganism treated was P. aeruginosa (21 cases; 9 MDR). Beta-lactams in CI were ceftazidime (n = 14), aztreonam (7), and piperacillin/tazobactam (3), mainly used in combination (12 with colistin, 5 with ciprofloxacin) and administered without notable side effects. The plasma Cobs was higher overall than Cpred; the Spearman correlation between both concentrations was rho = 0.6 (IC 95%: 0.2–0.8) for all beta-lactams, and rho = 0.8 (IC 95%: 0.4–1) for those treated with ceftazidime.


The formula may be useful in clinical practice for planning the initial dosage of beta-lactams in CI, while we await a systematic therapeutic drug monitoring. The use of beta-lactams in CI was safe.


Beta-lactams Continuous infusion Biofilm-related infections Osteoarticular infections Gram-negative bacilli Antibiotic plasma levels 



We thank Michael Maudsley for helping with the English in this manuscript.


This work was supported by Ministerio de Economía y Competitividad, Instituto de Salud Carlos III—co-financed by the European Development Regional Fund ‘A way to achieve Europe’ ERDF, Spanish Network for Research in Infectious Diseases (REIPI RD12/0015). A. R. was supported by a research grant from the Bellvitge Biomedical Research Institute (IDIBELL).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and informed consent

The research was conducted in accordance with the Declaration of Helsinki and national and institutional standards. The approval was obtained from Hospital Universitari de Bellvitge Ethics Committee, a tertiary-care hospital (Barcelona).


  1. 1.
    Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1–10.CrossRefPubMedGoogle Scholar
  2. 2.
    Eagle H, Fleischman R, Musselman AD. Effect of schedule of administration on the therapeutic efficacy of penicillin; importance of the aggregate time penicillin remains at effectively bactericidal levels. Am J Med. 1950;9:280–99.CrossRefPubMedGoogle Scholar
  3. 3.
    Drusano GL. Antimicrobial pharmacodynamics: critical interactions of “bug and drug”. Nat Rev Microbiol. 2004;2:289–300.CrossRefPubMedGoogle Scholar
  4. 4.
    Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig WA. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis. 1988;158:831–47.CrossRefPubMedGoogle Scholar
  5. 5.
    McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T > MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents. 2008;31:345–51.CrossRefPubMedGoogle Scholar
  6. 6.
    Van Herendael B, Jeurissen A, Tulkens PM, Vlieghe E, Verbrugghe W, Jorens PG, et al. Continuous infusion of antibiotics in the critically ill: the new holy grail for beta-lactams and vancomycin. Ann Intensive Care. 2012;2:22.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mohd Hafiz A-A, Staatz CE, Kirkpatrick CMJ, Lipman J, Roberts JA. Continuous infusion vs. bolus dosing: implications for beta-lactam antibiotics. Minerva Anestesiol. 2012;78:94–104.PubMedGoogle Scholar
  8. 8.
    Mouton JW, Vinks AA. Continuous infusion of beta-lactams. Curr Opin Crit Care. 2005;13:598–606.CrossRefGoogle Scholar
  9. 9.
    Alou L. Is there a pharmacodynamic need for the use of continuous versus intermittent infusion with ceftazidime against Pseudomonas aeruginosa? An in vitro pharmacodynamic model. J Antimicrob Chemother. 2005;55:209–13.CrossRefPubMedGoogle Scholar
  10. 10.
    Cappelletty DM, Kang SL, Palmer SM, Rybak MJ. Pharmacodynamics of ceftazidime administered as continuous infusion or intermittent bolus alone and in combination with single daily-dose amikacin against Pseudomonas aeruginosa in an in vitro infection model. Antimicrob Agents Chemother. 1995;39:1797–801.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Mouton JW, Vinks AA. Is continuous infusion of beta-lactam antibiotics worthwhile? Efficacy and pharmacokinetic considerations. J Antimicrob Chemother. 1996;38:5–15.CrossRefPubMedGoogle Scholar
  12. 12.
    Dulhunty JM, Roberts JA, Davis JS, Webb SAR, Bellomo R, Gomersall C, et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis. 2013;56:236–44.CrossRefPubMedGoogle Scholar
  13. 13.
    Roberts JA, Abdul-Aziz M-H, Davis JS, Dulhunty JM, Cotta MO, Myburgh J, et al. Continuous versus intermittent β-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med. 2016;194:681–91.CrossRefPubMedGoogle Scholar
  14. 14.
    Gilbert P, Collier PJ, Brown MR. Influence of growth rate on susceptibility to antimicrobial agents: biofilms, cell cycle, dormancy, and stringent response. Antimicrob Agents Chemother. 1990;34:1865–8.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gilbert P, Brown MR. Biofilms and beta-lactam activity. J Antimicrob Chemother. 1998;41:571–2.CrossRefPubMedGoogle Scholar
  16. 16.
    Ribera A, Benavent E, Lora-Tamayo J, Tubau F, Pedrero S, Cabo X, et al. Osteoarticular infection caused by MDR Pseudomonas aeruginosa: the benefits of combination therapy with colistin plus β-lactams. J Antimicrob Chemother. 2015;70:3357–65.PubMedGoogle Scholar
  17. 17.
    Moriyama B, Henning SA, Childs R, Holland SM, Anderson VL, Morris JC, et al. High-dose continuous infusion beta-lactam antibiotics for the treatment of resistant Pseudomonas aeruginosa infections in immunocompromised patients. Ann Pharmacother. 2010;44:929–35.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Huttner A, Harbarth S, Hope WW, Lipman J, Roberts JA. Therapeutic drug monitoring of the β-lactam antibiotics: what is the evidence and which patients should we be using it for? J Antimicrob Chemother. 2015;70:3178–83.PubMedGoogle Scholar
  19. 19.
    Georges B, Conil J-M, Seguin T, Ruiz S, Minville V, Cougot P, et al. Population pharmacokinetics of ceftazidime in intensive care unit patients: influence of glomerular filtration rate, mechanical ventilation, and reason for admission. Antimicrob Agents Chemother. 2009;53:4483–9.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014;14:498–509.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Magiorakos A-P, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18:268–81.CrossRefPubMedGoogle Scholar
  22. 22.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.CrossRefPubMedGoogle Scholar
  23. 23.
    Xu H, Zhou W, Zhou D, Li J, Al-Huniti N. Evaluation of aztreonam dosing regimens in patients with normal and impaired renal function: a population pharmacokinetic modeling and monte carlo simulation analysis. J Clin Pharmacol. 2017;57:336–44.CrossRefPubMedGoogle Scholar
  24. 24.
    Hayashi Y, Roberts JA, Paterson DL, Lipman J. Pharmacokinetic evaluation of piperacillin-tazobactam. Expert Opin Drug Metab Toxicol. 2010;6:1017–31.CrossRefPubMedGoogle Scholar
  25. 25.
    Moriyama B, Henning SA, Neuhauser MM, Danner RL, Walsh TJ. Continuous-infusion beta-lactam antibiotics during continuous venovenous hemofiltration for the treatment of resistant gram-negative bacteria. Ann Pharmacother. 2009;43:1324–37.CrossRefPubMedGoogle Scholar
  26. 26.
    Roberts JA, Webb S, Paterson D, Ho KM, Lipman J. A systematic review on clinical benefits of continuous administration of β-lactam antibiotics. Crit Care Med. 2009;37:2071–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Rigo-Bonnin R, Cobo-Sacristán S, Padullés A, Ribera A, Arbiol-Roca A, Murillo Ó, et al. Measurement of ceftazidime concentration in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry. Application to critically ill patients and patients with osteoarticular infections. Biomed Chromatogr. 2016;30:410–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Rigo-Bonnin R, Ribera A, Arbiol-Roca A, Cobo-Sacristán S, Padullés A, Murillo Ò, et al. Development and validation of a measurement procedure based on ultra-high performance liquid chromatography-tandem mass spectrometry for simultaneous measurement of β-lactam antibiotic concentration in human plasma. Clin Chim Acta. 2017;468:215–24.CrossRefPubMedGoogle Scholar
  29. 29.
    Roberts JA, Paratz J, Paratz E, Krueger WA, Lipman J. Continuous infusion of beta-lactam antibiotics in severe infections: a review of its role. Int J Antimicrob Agents. 2007;30:11–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Hoiby N, Bjarnsholt T, Moser C, Bassi GL, Coenye T, Donelli G, et al. ESCMID guideline for the diagnosis and treatment of biofilm infections 2014. Clin Microbiol Infect. 2015;21:S1–25.CrossRefPubMedGoogle Scholar
  31. 31.
    Klinger-Strobel M, Stein C, Forstner C, Makarewicz O, Pletz M. Effects of colistin on biofilm matrices of Escherichia coli and Staphylococcus aureus. Int J Antimicrob Agents. 2017;49:472–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Alba Ribera
    • 1
  • Laura Soldevila
    • 1
  • Raul Rigo-Bonnin
    • 2
  • Fe Tubau
    • 3
    • 4
  • Ariadna Padullés
    • 5
  • Joan Gómez-Junyent
    • 1
  • Javier Ariza
    • 1
  • Oscar Murillo
    • 1
  1. 1.Infectious Diseases DepartmentIDIBELL-Hospital Universitari de BellvitgeBarcelonaSpain
  2. 2.Clinical Laboratory DepartmentIDIBELL-Hospital Universitari de BellvitgeBarcelonaSpain
  3. 3.Microbiology DepartmentIDIBELL-Hospital Universitari de BellvitgeBarcelonaSpain
  4. 4.Ciber de Enfermedades Respiratorias ISCIIIMadridSpain
  5. 5.Pharmacy DepartmentIDIBELL-Hospital Universitari de BellvitgeBarcelonaSpain

Personalised recommendations