Skip to main content
SpringerLink
Log in

Therapeutic Drug Monitoring and Prolonged Infusions of Ceftolozane/Tazobactam for MDR/XDR Pseudomonas aeruginosa Infections: An Observational Study

  • Original Research Article
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Prolonged infusion of ceftolozane/tazobactam (C/T) is a strategy used to increase achievement of pharmacokinetic/pharmacodynamic targets for the treatment of multi- or extensively drug-resistant MDR/XDR Gram-negative microorganisms. The objective of this study was to describe our therapeutic drug monitoring (TDM) experience of C/T administered by prolonged infusion or intermittent infusion to patients with MDR/XDR Pseudomonas aeruginosa infections. Our outcomes of interest were pharmacokinetic/pharmacodynamic target achievement and clinical cure.

Methods

Patients with MDR/XDR P. aeruginosa infections treated with C/T were enrolled between February 2018 and February 2020. Blood samples were obtained as part of a TDM program. The pharmacokinetic/pharmacodynamic therapeutic target of C/T was defined as 100% of the duration of the dosing interval that free concentrations are above the minimum inhibitory concentration (MIC) (100 %ƒT ≥ MIC) of the causative pathogen. Dose changes were performed according to TDM results.

Results

Forty patients were included: 13 (32.5%) with a proven MDR and 27 (67.5%) with a XDR P. aeruginosa infection. C/T was administered by prolonged infusion in 32 (80%) patients and by intermittent infusion in 8 (20%) patients. Lower doses were administered in the prolonged infusion compared to the intermittent infusion group [3 (9.4%) vs. 5 (62.5%] patients received a dose of 9 g/day (ceftolozane 2 g + tazobactam 1 g, every 8 h; p = 0.004). All patients achieved the pharmacokinetic/pharmacodynamic target and C/T concentrations exceeded 10 × MIC in > 50% of patients in both groups. TDM-recommended dose reductions occurred in 19 (47.5%) patients, being 16 (84.2%) in the prolonged infusion group. A high proportion of patients achieved clinical cure (82.5%).

Conclusions

The administration of C/T by prolonged infusion with TDM-guided dosing allowed the achievement of a pharmacokinetic/pharmacodynamic target even at lower doses. C/T showed a high efficacy for treating MDR/XDR P. aeruginosa infections.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Doi Y. Treatment options for carbapenem-resistant gram-negative bacterial infections. Clin Infect Dis. 2019;69:565–75. https://doi.org/10.1093/cid/ciz830.

    Article  CAS  Google Scholar 

  2. Horcajada JP, Montero M, Oliver A, Sorlí L, Luque S, Gómez-Zorrilla S, et al. Epidemiology and treatment of multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa infections. Clin Microbiol Rev. 2019;32:e00031-e119. https://doi.org/10.1128/CMR.00031-19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Miller B, Hershberger E, Benziger D, Trinh M, Friedland I. Pharmacokinetics and safety of intravenous ceftolozane-tazobactam in healthy adult subjects following single and multiple ascending doses. Antimicrob Agents Chemother. 2012;56:3086–91. https://doi.org/10.1128/AAC.06349-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Abdul-Aziz MH, Alffenaar JWC, Bassetti M, Bracht H, Dimopoulos G, Marriott D, et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a position paper. Intensive Care Med. 2020;46:1127–53. https://doi.org/10.1007/s00134-020-06050-1.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Pilmis B, Petitjean G, Lesprit P, Lafaurie M, El Helali N, Le Monnier A, et al. Continuous infusion of ceftolozane/tazobactam is associated with a higher probability of target attainment in patients infected with Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis. 2019;38:1457–61. https://doi.org/10.1007/s10096-019-03573-4.

    Article  CAS  PubMed  Google Scholar 

  6. Natesan S, Pai MP, Lodise TP. Determination of alternative ceftolozane/tazobactam dosing regimens for patients with infections due to Pseudomonas aeruginosa with MIC values between 4 and 32 mg/L. J Antimicrob Chemother. 2017;72:2813–6. https://doi.org/10.1093/jac/dkx221.

    Article  CAS  PubMed  Google Scholar 

  7. McCreary EK, Byers KE, Fernandes C, Kline EG, Nicolau DP, Shields RK. Plasma and cerebrospinal fluid therapeutic drug monitoring of ceftolozane and tazobactam during treatment of multidrug-resistant Pseudomonas aeruginosa meningitis. Open Forum Infect Dis. 2020;7:ofaa549. https://doi.org/10.1093/ofid/ofaa549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Winans SA, Guerrero-Wooley RL, Park SH, Hino G, Forland SC. Continuous infusion of ceftolozane-tazobactam resulted in high cerebrospinal fluid concentrations of ceftolozane in a patient with multidrug-resistant Pseudomonas aeruginosa meningitis. Infection. 2021;49:355–9. https://doi.org/10.1007/s15010-020-01510-8.

    Article  CAS  PubMed  Google Scholar 

  9. Magiorakos AP, 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. https://doi.org/10.1111/j.1469-0691.2011.03570.x.

    Article  CAS  PubMed  Google Scholar 

  10. Zerbaxa. Annex I. Summary of product characteristics. 2021. https://www.ema.europa.eu/en/documents/product-information/zerbaxa-epar-product-information_en.pdf. Accessed Nov 2021.

  11. Sime FB, Lassig-Smith M, Starr T, Stuart J, Pandey S, Parker SL, et al. Population pharmacokinetics of unbound ceftolozane and tazobactam in critically ill patients without renal dysfunction. Antimicrob Agents Chemother. 2019;63:e01265-e1319. https://doi.org/10.1128/AAC.01265-19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Borner K, Borner E, Lode H. Determination of linezolid in human serum and urine by high-performance liquid chromatography. Int J Antimicrob Agents. 2001;18:253–8. https://doi.org/10.1016/S0924-8579(01)00383-1.

    Article  CAS  PubMed  Google Scholar 

  13. Martens-Lobenhoffer J, Hinderhofer M, Tröger U, Bode-Böger SM. Stability of ceftolozane in human plasma and dried blood spots: implications for transport and storage. J Pharmacol Toxicol Methods. 2020;103: 106692. https://doi.org/10.1016/j.vascn.2020.106692.

    Article  CAS  PubMed  Google Scholar 

  14. Delattre IK, Taccone FS, Jacobs F, Hites M, Dugernier T, Spapen H, et al. Optimizing β-lactams treatment in critically-ill patients using pharmacokinetics/pharmacodynamics targets: are first conventional doses effective? Expert Rev Anti Infect Ther. 2017;15:677–88. https://doi.org/10.1080/14787210.2017.1338139.

    Article  CAS  PubMed  Google Scholar 

  15. Cardozo C, Rico V, Agüero D, Soriano A. Antibiotic selection in the treatment of acute invasive infections by Pseudomonas aeruginosa. Rev Esp Quimioter. 2019;32(Suppl 2):32–4.

    PubMed  PubMed Central  Google Scholar 

  16. Caro L, Nicolau DP, De Waele JJ, Kuti JL, Larson KB, Gadzicki E, et al. Lung penetration, bronchopulmonary pharmacokinetic/pharmacodynamic profile and safety of 3 g of ceftolozane/tazobactam administered to ventilated, critically ill patients with pneumonia. J Antimicrob Chemother. 2020;75:1546–53. https://doi.org/10.1093/jac/dkaa049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Clinical Breakpoints-Bacteria. 2021. http://www.eucast.org/clinical_breakpoints/. Accessed Nov 2021.

  18. Benítez-Cano A, Luque S, Sorlí L, Carazo J, Ramos I, Campillo N, et al. Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial. Crit Care. 2020;24:55. https://doi.org/10.1186/s13054-020-2763-4.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sheffield M, Nelson D, O’Neal M, Gould AP, Bouchard J, Nicolau D, et al. Use of continuous-infusion ceftolozane/tazobactam for resistant Gram-negative bacterial infections: a retrospective analysis and brief review of the literature. Int J Antimicrob Agents. 2020;56: 106158. https://doi.org/10.1016/j.ijantimicag.2020.106158.

    Article  CAS  PubMed  Google Scholar 

  20. Haj-Darrah R, et al. Should prolonged infusion of β-lactams become standard of practice? Can J Hosp Pharm. 2017;70:156–60. https://doi.org/10.4212/cjhp.v70i2.1650.

    Article  Google Scholar 

  21. Montero M, VanScoy BD, López-Causapé C, Conde H, Adams J, Segura C, et al. Evaluation of ceftolozane-tazobactam in combination with meropenem against Pseudomonas aeruginosa sequence type 175 in a hollow-fiber infection model. Antimicrob Agents Chemother. 2018;62:e00026-e118. https://doi.org/10.1128/AAC.00026-18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We gratefully received support from the Instituto de Salud Carlos III (ISCIII) (grant number BA18/00005), the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), and the Spanish Society of Hospital Pharmacy (SEFH) thanks to the research travel grant received by SL. J.A. Roberts would like to acknowledge funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP2007007) and an Investigator Grant (APP2009736) as well as an Advancing Queensland Clinical Fellowship.

Author information

Author notes

  1. María Eugenia Navarrete-Rouco and Sònia Luque contributed equally to the article.

Authors and Affiliations

  1. Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain

    María Eugenia Navarrete-Rouco, Sònia Luque & Santiago Grau

  2. Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain

    Sònia Luque, Luisa Sorlí, Adela Benítez-Cano & Santiago Grau

  3. Spanish Network for Research in Infectious Diseases (REIPI), Madrid, Spain

    Sònia Luque, Luisa Sorlí & Santiago Grau

  4. CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain

    Sònia Luque, Luisa Sorlí & Santiago Grau

  5. Infectious Diseases Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain

    Luisa Sorlí

  6. Universitat Pompeu Fabra (UPF), Barcelona, Spain

    Luisa Sorlí & Santiago Grau

  7. Department of Anaesthesiology and Surgical Intensive Care, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain

    Adela Benítez-Cano

  8. University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia

    Jason A. Roberts

  9. Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Australia

    Jason A. Roberts

  10. Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France

    Jason A. Roberts

Authors
  1. María Eugenia Navarrete-Rouco
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sònia Luque
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luisa Sorlí
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adela Benítez-Cano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jason A. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Santiago Grau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sònia Luque.

Ethics declarations

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Code Availability

Not applicable.

Conflict of Interest

None to declare

Funding

No external funding was received for this work.

Ethical Approval

Ethical clearance was obtained from the Ethics Committee of Parc de Salut Mar, Barcelona, on 17 June 2021 (reference no. 2021/9809). This study was conducted in full accordance with the Declaration of Helsinki and International Conference on Harmonization Guidelines in Good Clinical Practice.

Availability of Data and Material

The data generated are available from the corresponding author upon reasonable request.

Author Contributions

SL and SG designed the research protocol. MENR and SL wrote the initial draft of the manuscript. MENR, SL, LS, ABC, JR, and SG wrote and reviewed the manuscript. SL, LS, and ABC performed the research. MENR, SL, and LS analyzed and checked the data.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Navarrete-Rouco, M.E., Luque, S., Sorlí, L. et al. Therapeutic Drug Monitoring and Prolonged Infusions of Ceftolozane/Tazobactam for MDR/XDR Pseudomonas aeruginosa Infections: An Observational Study. Eur J Drug Metab Pharmacokinet 47, 561–566 (2022). https://doi.org/10.1007/s13318-022-00772-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-022-00772-x

Search

Navigation