Skip to main content

Advertisement

SpringerLink
Log in

Ceftolozane/tazobactam for the treatment of XDR Pseudomonas aeruginosa infections

  • Original Paper
  • Published:
Infection Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study was to evaluate the effectiveness of ceftolozane/tazobactam (C/T) for treating extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) infections, and to analyze whether high C/T dosing (2 g ceftolozane and 1 g tazobactam every 8 h) and infection source control have an impact on outcome.

Methods

Retrospective study of all consecutive patients treated with C/T for XDR-PA infection at a tertiary referral hospital (November 2015–July 2017). Main clinical and microbiological variables were analyzed.

Results

Thirty-eight patients were included. Median age was 59.5 years and Charlson Comorbidity Index was 3.5. Fourteen (36.8%) patients had respiratory tract infection, six (15.8%) soft tissue, and six (15.8%) urinary tract infection. Twenty-three (60.5%) received high-dose C/T and in 24 (63.2%) C/T was combined with other antibiotics. At completion of treatment, 33 (86.8%) patients showed clinical response. At 90 days of follow-up, 26 (68.4%) achieved clinical cure, and 12 (31.6%) had clinical failure because of persistent infection in one patient, death attributable to the XDR-PA infection in four, and clinical recurrence in seven. All-cause mortality was 5 (13.2%). Lower C/T MIC and adequate infection source control were the only variables significantly associated with clinical cure.

Conclusions

C/T should be considered for treating XDR-PA infections, with infection source control being an important factor to avoid failure and resistance.

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

Similar content being viewed by others

References

  1. Sader HS, Farrell DJ, Castanheira M, Flamm RK, Jones RN. Antimicrobial activity of ceftolozane/tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with various resistance patterns isolated in European hospitals (2011–2012). J Antimicrob Chemother. 2014;1:2713–22. https://doi.org/10.1093/jac/dku184.

    Article  CAS  Google Scholar 

  2. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolozane–tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in US hospitals (2011–2012). Antimicrob Agents Chemother. 2013;1:6305–10. https://doi.org/10.1128/AAC.01802-13.

    Article  CAS  Google Scholar 

  3. Liscio JL, Mahoney MV, Hirsch EB. Ceftolozane/tazobactam and ceftazidime/avibactam: two novel β-lactam/β-lactamase inhibitor combination agents for the treatment of resistant Gram-negative bacterial infections. Int J Antimicrob Agents. 2015;46:266–71. https://doi.org/10.1016/j.ijantimicag.2015.05.003.

    Article  PubMed  CAS  Google Scholar 

  4. Munita JM, Aitken SL, Miller WR, Perez F, Rosa R, Shimose LA, et al. Multicenter evaluation of ceftolozane/tazobactam for serious infections caused by carbapenem-resistant Pseudomonas aeruginosa. Clin Infect Dis. 2017;65:158–61. https://doi.org/10.1093/cid/cix014.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Peghin M, Maiani M, Castaldo N, Givone F, Righi E, Lechiancole A, et al. Ceftolozane/tazobactam for the treatment of MDR Pseudomonas aeruginosa left ventricular assist device infection as a bridge to heart transplant. Infection. 2017. https://doi.org/10.1007/s15010-017-1086-0.

    Article  PubMed  Google Scholar 

  6. Dinh A, Wyplosz B, Kernéis S, Lebeaux D, Bouchand F, Duran C, et al. Use of ceftolozane/tazobactam as salvage therapy for infections due to extensively drug-resistant Pseudomonas aeruginosa. Int J Antimicrob Agents. 2017;49:782–3. https://doi.org/10.1016/j.ijantimicag.2017.04.001.

    Article  PubMed  CAS  Google Scholar 

  7. Castón JJ, De la Torre Á, Ruiz-Camps I, Sorlí ML, Torres V, Torre-Cisneros J. Salvage therapy with ceftolozane–tazobactam for multidrug-resistant Pseudomonas aeruginosa infections. Antimicrob Agents Chemother. 2017;61:e02136-16. https://doi.org/10.1128/AAC.02136-16.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sousa Dominguez A, Perez-Rodríguez MT, Nodar A, Martinez-Lamas L, Perez-Landeiro A, Crespo Casal M. Successful treatment of MDR Pseudomonas aeruginosa skin and soft-tissue infection with ceftolozane/tazobactam. J Antimicrob Chemother. 2017;72:1262–3. https://doi.org/10.1093/jac/dkw526.

    Article  PubMed  CAS  Google Scholar 

  9. Hernández-Tejedor A, Merino-Vega CD, Martín-Vivas A, Ruiz de Luna-González R, Delgado-Iribarren A, Gabán-Díez Á, et al. Successful treatment of multidrug-resistant Pseudomonas aeruginosa breakthrough bacteremia with ceftolozane/tazobactam. Infection. 2017;45:115–7. https://doi.org/10.1007/s15010-016-0944-5.

    Article  PubMed  CAS  Google Scholar 

  10. Haidar G, Philips NJ, Shields RK, Snyder D, Cheng S, Potoski BA, et al. Ceftolozane–tazobactam for the treatment of multidrug-resistant Pseudomonas aeruginosa infections: clinical effectiveness and evolution of resistance. Clin Infect Dis. 2017;65:110–20. https://doi.org/10.1093/cid/cix182.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kuti JL, Ghazi IM, Quintiliani R, Shore E, Nicolau DP. Treatment of multidrug-resistant Pseudomonas aeruginosa with ceftolozane/tazobactam in a critically ill patient receiving continuous venovenous haemodiafiltration. Int J Antimicrob Agents. 2016;48:342–3. https://doi.org/10.1016/j.ijantimicag.2016.06.00512.

    Article  PubMed  CAS  Google Scholar 

  12. Vickery SB, McClain D, Wargo KA. Successful Use of Ceftolozane–tazobactam to treat a pulmonary exacerbation of cystic fibrosis caused by multidrug-resistant Pseudomonas aeruginosa. Pharmacother J Hum Pharmacol Drug Ther. 2016;36:e154–9. https://doi.org/10.1002/phar.1825.

    Article  CAS  Google Scholar 

  13. Xiao AJ, Miller BW, Huntington JA, Nicolau DP. Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. J Clin Pharmacol. 2016;56:56–66. https://doi.org/10.1002/jcph.5666.

    Article  PubMed  CAS  Google Scholar 

  14. Gelfand MS, Cleveland KO. Ceftolozane/tazobactam therapy of respiratory infections due to multidrug-resistant Pseudomonas aeruginosa. Clin Infect Dis. 2015;61:853–5.

    Article  PubMed  Google Scholar 

  15. 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. https://doi.org/10.1111/j.1469-0691.2011.03570.x.

    Article  PubMed  CAS  Google Scholar 

  16. Centers for Disease Control and Prevention. National Healthcare Safety Network surveillance definitions for specific types of infections [Internet]. 2016 [cited 2017 23]. Available at: http://www.cdc.gov/nhsn/PDFs/pscManual/17pscNosInfDef_current.pdf.

  17. Marshall JC, Maier RV, Jimenez M, Dellinger EP. Source control in the management of severe sepsis and septic shock: an evidence-based review. Crit Care Med. 2004;32:S513–26.

    Article  PubMed  Google Scholar 

  18. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Fifth Informational Supplement MS100-S25. CLSI, Wayne, PA, USA, 2015. [Internet]. [cited 2017 29] http://shop.clsi.org/site/Sample_pdf/M100S25_sample.pdf.

  19. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard M07-A10–Tenth Edition. NCCLS, Wayne, PA, USA, 2015. [Internet] [cited 2017 29] http://shop.clsi.org/site/Sample_pdf/M07A10_sample.pdf.

  20. EUCAST: Clinical breakpoints [Internet] [cited 2017 29] http://www.eucast.org/clinical_breakpoints//.

  21. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J. Chronic Dis. 1987;40:373–83.

    Article  PubMed  CAS  Google Scholar 

  22. Linden PK, Kusne S, Coley K, Fontes P, Kramer DJ, Paterson D. Use of parenteral colistin for the treatment of serious infection due to antimicrobial-resistant Pseudomonas aeruginosa. Clin Infect Dis. 2003;1:e154–60. https://doi.org/10.1086/37961.

    Article  Google Scholar 

  23. Dalfino L, Puntillo F, Ondok MJM, Mosca A, Monno R, Coppolecchia S, et al. Colistin-associated acute kidney injury in severely ill patients: a step toward a better renal care? A prospective cohort study. Clin Infect Dis. 2015;15:1771–7. https://doi.org/10.1093/cid/civ717.

    Article  CAS  Google Scholar 

  24. Nation RL, Garonzik SM, Li J, Thamlikitkul V, Giamarellos-Bourboulis EJ, Paterson DL, et al. Updated US and European dose recommendations for intravenous colistin: how do they perform? Clin Infect. Dis. 2016;62:552–8. https://doi.org/10.1093/cid/civ964.

    Article  Google Scholar 

  25. US National Institutes of Health. ClinicalTrials.gov. Safety and efficacy study of ceftolozane/tazobactam to treat ventilated nosocomial pneumonia (MK-7625A-008)(ASPECT-NP). [Internet]. https://www.clinicaltrials.gov/ct2/show/ NCT02070757?term“ceftolozane?tazobactam&rank”3.

  26. Martínez ML, Ferrer R, Torrents E, Guillamat-Prats R, Gomà G, Suárez D, et al. Impact of source control in patients with severe sepsis and septic shock. Crit Care Med. 2017;45:11–9. https://doi.org/10.1097/CCM.0000000000002011.

    Article  PubMed  Google Scholar 

  27. Fraile-Ribot PA, Cabot G, Mulet X, Periañez L, Martín-Pena ML, Juan C, et al. Mechanisms leading to in vivo ceftolozane/tazobactam resistance development during the treatment of infections caused by MDR Pseudomonas aeruginosa. J Antimicrob Chemother. 2017. https://doi.org/10.1093/jac/dkx424/4629302.

    Article  PubMed  Google Scholar 

  28. Berrazeg M, Jeannot K, Ntsogo Enguéné VY, Broutin I, Loeffert S, Fournier D, et al. Mutations in β-lactamase AmpC increase resistance of Pseudomonas aeruginosa isolates to antipseudomonal cephalosporins. Antimicrob Agents Chemother. 2015;59:6248–55. https://doi.org/10.1128/AAC.00825-15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Cabot G, Bruchmann S, Mulet X, Zamorano L, Moya B, Juan C, et al. Pseudomonas aeruginosa ceftolozane–tazobactam resistance development requires multiple mutations leading to overexpression and structural modification of AmpC. Antimicrob Agents Chemother. 2014;1:3091–9. https://doi.org/10.1128/AAC.02462-13.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Celine Cavallo for English language support.

Funding

Supported by Plan Nacional de I + D+I 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0003)—co-financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014-2020. MSD provided medical writing support but was not involved in the content of the manuscript.

Author information

Authors and Affiliations

  1. Infectious Diseases Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Passeig Vall d’Hebron 119-129, 08035, Barcelona, Spain

    Laura Escolà-Vergé, Carles Pigrau, Ibai Los-Arcos, Oscar Len & Benito Almirante

  2. Pharmacy Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

    Ángel Arévalo & David Campany

  3. Microbiology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

    Belen Viñado & Nieves Larrosa

  4. Intensive Care Department and SODIR Research Group, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

    Xavier Nuvials & Ricard Ferrer

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

    Laura Escolà-Vergé, Carles Pigrau, Belen Viñado, Nieves Larrosa & Benito Almirante

Authors
  1. Laura Escolà-Vergé
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carles Pigrau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ibai Los-Arcos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ángel Arévalo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Belen Viñado
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Campany
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nieves Larrosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xavier Nuvials
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ricard Ferrer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Oscar Len
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Benito Almirante
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benito Almirante.

Ethics declarations

Conflict of interest

CP. has received honoraria for talks on behalf of Angelini, MSD, Novartis, Pfizer, Salvat, and Zambon. O.L. has received honoraria for talks on behalf of Astellas, MSD and Pfizer. R.F. has received honoraria for talks on behalf of MSD, Pfizer, Estor and Orion. B.A. has received grant support from Gilead Sciences, Pfizer, and the Instituto de Salud Carlos III. He has received honoraria for talks on behalf of Gilead Sciences, Merck Sharp & Dohme, Pfizer, Astellas Pharma, Novartis, and Angelini. The other authors have no declarations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Escolà-Vergé, L., Pigrau, C., Los-Arcos, I. et al. Ceftolozane/tazobactam for the treatment of XDR Pseudomonas aeruginosa infections. Infection 46, 461–468 (2018). https://doi.org/10.1007/s15010-018-1133-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s15010-018-1133-5

Keywords

Search

Navigation