Skip to main content
SpringerLink
Log in

Ceftazidime-avibactam combination therapy versus monotherapy for treating carbapenem-resistant gram-negative infection: a systemic review and meta-analysis

  • Review
  • Published:
Infection Aims and scope Submit manuscript

  • 23 Altmetric

Abstract

Background

This meta-analysis was conducted to compare the efficacy of ceftazidime-avibactam combination therapy with that of monotherapy in the treatment of carbapenem-resistant Gram-negative bacterial (CR-GNB).

Methods

A literature search of PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov was conducted until September 1, 2023. Only studies that compared CZA combination therapy with monotherapy for CR-GNB infections were included.

Results

A total of 25 studies (23 retrospective observational studies and 2 prospective studies) involving 2676 patients were included. There was no significant difference in 30-day mortality between the study group receiving combination therapy and the control group receiving monotherapy (risk ratio [RR] 0.91; 95% confidence interval [CI] 0.71–1.18). In addition, no significant differences were observed between the study and the control group in terms of in-hospital mortality (RR 1.00; 95% CI 0.79–1.27), 14-day mortality (RR 1.54; 95% CI 0.24–9.91), 90-day mortality (RR 1.18; 95% CI 0.62–2.22), and clinical cure rate (RR 0.95; 95% CI 0.84–1.08). However, the combination group had a borderline higher microbiological eradication rate than the control group (RR 1.15; 95% CI 1.00–1.32).

Conclusions

Compared to monotherapy, CZA combination therapy did not yield additional clinical benefits. However, combination therapy may be associated with favorable microbiological outcomes.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

Our study is a Systematic Review/Meta-analysis. The datasets analyzed during the current study are available in the published pooled study. Also, the datasets used and analyzed during the current study available from the corresponding author on reasonable request.

References

  1. Murray CJL, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar G, Gray A, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet. 2022;399:629–55.

    Article  CAS  Google Scholar 

  2. Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018;18:318–27.

    Article  PubMed  Google Scholar 

  3. Martin A, Fahrbach K, Zhao Q, Lodise T. Association between carbapenem resistance and mortality among adult, hospitalized patients with serious infections due to enterobacteriaceae: results of a systematic literature review and meta-analysis. Open Forum Infect Dis. 2018;5:ofy150.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kempf M, Arhin FF, Stone G, Utt E. Ceftazidime-avibactam activity against Gram-negative respiratory isolates collected between 2018 and 2019. J Glob Antimicrob Resist. 2022;31:239–47.

    Article  CAS  PubMed  Google Scholar 

  5. La Bella G, Lopizzo T, Lupo L, Angarano R, Curci A, Manti B, et al. In vitro activity of ceftazidime/avibactam against carbapenem-nonsusceptible Klebsiella penumoniae isolates collected during the first wave of the SARS-CoV-2 pandemic: a Southern Italy, multicenter, surveillance study. J Glob Antimicrob Resist. 2022;31:236–8.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Tsai CH, Lee NY, Chao CM, Chen CC, Lai CC, Ho CH, et al. Emergence and dissemination of multidrug-resistant escherichia coli ST8346 coharboring bla(NDM-5) and bla(OXA-181) in Southern Taiwan, 2017–2021. J Infect Public Health. 2023;16:1675–81.

    Article  PubMed  Google Scholar 

  7. Wise MG, Karlowsky JA, Lemos-Luengas EV, Valdez RR, Sahm DF. Epidemiology and in vitro activity of ceftazidime-avibactam and comparator agents against multidrug-resistant isolates of enterobacterales and Pseudomonas aeruginosa collected in Latin America as part of the atlas surveillance program in 2015–2020. Braz J Infect Dis. 2023;27: 102759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wise MG, Karlowsky JA, Mohamed N, Kamat S, Sahm DF. In vitro activity of aztreonam-avibactam against enterobacterales isolates collected in Latin America, Africa/Middle East, Asia, and eurasia for the atlas global surveillance program in 2019–2021. Eur J Clin Microbiol Infect Dis. 2023;42:1135–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Carmeli Y, Armstrong J, Laud PJ, Newell P, Stone G, Wardman A, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis. 2016;16:661–73.

    Article  CAS  PubMed  Google Scholar 

  10. Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind Phase II trial. J Antimicrob Chemother. 2013;68:1183–92.

    Article  CAS  PubMed  Google Scholar 

  11. Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, et al. Efficacy and safety of ceftazidime-avibactam Plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis. 2016;62:1380–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Qin X, Tran BG, Kim MJ, Wang L, Nguyen DA, Chen Q, et al. A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia. Int J Antimicrob Agents. 2017;49:579–88.

    Article  CAS  PubMed  Google Scholar 

  13. Torres A, Zhong N, Pachl J, Timsit JF, Kollef M, Chen Z, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2018;18:285–95.

    Article  CAS  PubMed  Google Scholar 

  14. Vazquez JA, González Patzán LD, Stricklin D, Duttaroy DD, Kreidly Z, Lipka J, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin. 2012;28:1921–31.

    Article  CAS  PubMed  Google Scholar 

  15. Wagenlehner FM, Sobel JD, Newell P, Armstrong J, Huang X, Stone GG, et al. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: recapture, a phase 3 randomized trial program. Clin Infect Dis. 2016;63:754–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gaibani P, Lewis RE, Volpe SL, Giannella M, Campoli C, Landini MP, et al. In vitro interaction of ceftazidime-avibactam in combination with different antimicrobials against KPC-producing Klebsiella pneumoniae clinical isolates. Int J Infect Dis. 2017;65:1–3.

    Article  CAS  PubMed  Google Scholar 

  17. Mataracı Kara E, Yılmaz M, Özbek ÇB. In vitro activities of ceftazidime/avibactam alone or in combination with antibiotics against multidrug-resistant Acinetobacter baumannii isolates. J Glob Antimicrob Resist. 2019;17:137–41.

    Article  PubMed  Google Scholar 

  18. Gaudereto JJ, PerdigãoNeto LV, Leite GC, RuedasMartins R, do BoasPrado GV, Rossi F, et al. Synergistic effect of ceftazidime-avibactam with meropenem against panresistant, carbapenemase-harboring acinetobacter baumannii and serratia marcescens investigated using time-kill and disk approximation assays. Antimicrob Agents Chemother. 2019. https://doi.org/10.1128/AAC.02367-18.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kroemer N, Martens M, Decousser JW, Grégoire N, Nordmann P, Wicha SG. Evaluation of in vitro pharmacodynamic drug interactions of ceftazidime/avibactam and fosfomycin in escherichia coli. J Antimicrob Chemother. 2023;78:2524–34.

    Article  CAS  PubMed  Google Scholar 

  20. Romina PE, Lucía A, Leticia C, Federica F, Pablo Á, Verónica S, et al. In vitro effectiveness of ceftazidime-avibactam in combination with aztreonam on carbapenemase-producing Enterobacterales. J Glob Antimicrob Resist. 2023;35:62–6.

    Article  CAS  PubMed  Google Scholar 

  21. Boattini M, Bianco G, Charrier L, Comini S, Iannaccone M, Almeida A, et al. Rapid diagnostics and ceftazidime/avibactam for KPC-producing Klebsiella pneumoniae bloodstream infections: impact on mortality and role of combination therapy. Eur J Clin Microbiol Infect Dis. 2023;42:431–9.

    Article  CAS  PubMed  Google Scholar 

  22. Alqahtani H, Alghamdi A, Alobaidallah N, Alfayez A, Almousa R, Albagli R, et al. Evaluation of ceftazidime/avibactam for treatment of carbapenemase-producing carbapenem-resistant Enterobacterales with OXA-48 and/or NDM genes with or without combination therapy. JAC Antimicrob Resist. 2022;4:dlac104.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lin J, Zhang L, Zhou M, Tian X, Chen J, Lu M, et al. Combination therapy of ceftazidime/avibactam for the treatment of patients infected with carbapenem-resistant klebsiella pneumoniae: a multicenter retrospective study. Infect Dis Ther. 2023;12:2165–77.

    Article  PubMed  PubMed Central  Google Scholar 

  24. King M, Heil E, Kuriakose S, Bias T, Huang V, El-Beyrouty C, et al. Multicenter study of outcomes with ceftazidime-avibactam in patients with carbapenem-resistant enterobacteriaceae infections. Antimicrob Agents Chemother. 2017;61:10–128.

    Article  Google Scholar 

  25. Sousa A, Pérez-Rodríguez MT, Soto A, Rodríguez L, Pérez-Landeiro A, Martínez-Lamas L, et al. Effectiveness of ceftazidime/avibactam as salvage therapy for treatment of infections due to OXA-48 carbapenemase-producing enterobacteriaceae. J Antimicrob Chemother. 2018;73:3170–5.

    Article  CAS  PubMed  Google Scholar 

  26. Tumbarello M, Trecarichi EM, Corona A, De Rosa FG, Bassetti M, Mussini C, et al. Efficacy of ceftazidime-avibactam salvage therapy in Patients with infections caused by klebsiella pneumoniae carbapenemase-producing k pneumoniae. Clin Infect Dis. 2019;68:355–64.

    Article  CAS  PubMed  Google Scholar 

  27. Tumbarello M, Raffaelli F, Giannella M, Mantengoli E, Mularoni A, Venditti M, et al. Ceftazidime-avibactam use for klebsiella pneumoniae carbapenemase-producing k pneumoniae Infections: a retrospective observational multicenter study. Clin Infect Dis. 2021;73:1664–76.

    Article  CAS  PubMed  Google Scholar 

  28. Li D, Fei F, Yu H, Huang X, Long S, Zhou H, et al. ceftazidime-avibactam therapy versus ceftazidime-avibactam-based combination therapy in patients with carbapenem-resistant gram-negative pathogens: a meta-analysis. Front Pharmacol. 2021;12: 707499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fiore M, Alfieri A, Di Franco S, Pace MC, Simeon V, Ingoglia G, et al. Ceftazidime-avibactam combination therapy compared to ceftazidime-avibactam monotherapy for the treatment of severe infections due to carbapenem-resistant Pathogens: a systematic review and network meta-analysis. Antibiotics (Basel). 2020;9:388.

    Article  CAS  PubMed  Google Scholar 

  30. Onorato L, Di Caprio G, Signoriello S, Coppola N. Efficacy of ceftazidime/avibactam in monotherapy or combination therapy against carbapenem-resistant gram-negative bacteria: a meta-analysis. Int J Antimicrob Agents. 2019;54:735–40.

    Article  CAS  PubMed  Google Scholar 

  31. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The Prisma 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10:89.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Jonathan ACS, Miguel AH, Barnaby CR, Jelena S, Nancy DB, Meera V, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355: i4919.

    Google Scholar 

  33. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. Clin Infect Dis Dio. 2023. https://doi.org/10.1093/cid/ciad428.

    Article  Google Scholar 

  34. Shields RK, Nguyen MH, Chen L, Press EG, Kreiswirth BN, Clancy CJ. Pneumonia and renal replacement therapy are risk factors for ceftazidime-avibactam treatment failures and resistance among Patients with carbapenem-resistant enterobacteriaceae infections. Antimicrob Agents Chemother. 2018;62:10–128.

    Article  Google Scholar 

  35. Nagvekar V, Shah A, Unadkat VP, Chavan A, Kohli R, Hodgar S, et al. Clinical outcome of patients on ceftazidime-avibactam and combination therapy in carbapenem-resistant enterobacteriaceae. Indian J Crit Care Med. 2021;25:780–4.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Davido B, Crémieux AC, Vaugier I, De Truchis P, Hamami K, Laurent F, et al. Efficacy of ceftazidime/avibactam in various combinations for the treatment of experimental osteomyelitis in rabbits caused by OXA-48-/ESBL-producing escherichia coli. J Antimicrob Chemother. 2023;78:1211–8.

    Article  CAS  PubMed  Google Scholar 

  37. Mantzana P, Protonotariou E, Kassomenaki A, Meletis G, Tychala A, Keskilidou E, et al. In Vitro synergistic activity of antimicrobial combinations against carbapenem- and colistin-resistant acinetobacter baumannii and klebsiella pneumoniae. Antibiotics (Basel). 2023;12:93.

    Article  CAS  PubMed  Google Scholar 

  38. Shields RK, Potoski BA, Haidar G, Hao B, Doi Y, Chen L, et al. Clinical outcomes, drug toxicity, and emergence of ceftazidime-Avibactam resistance among patients treated for carbapenem-resistant enterobacteriaceae infections. Clin Infect Dis. 2016;63:1615–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Both A, Büttner H, Huang J, Perbandt M, Belmar Campos C, Christner M, et al. Emergence of ceftazidime/avibactam non-susceptibility in an MDR klebsiella pneumoniae isolate. J Antimicrob Chemother. 2017;72:2483–8.

    Article  CAS  PubMed  Google Scholar 

  40. Mishuk AU, Strich J, Warner S, Sun J, Malik S, Lawandi A, et al. 652. Ceftazidime-avibactam alone or as combination therapy? Multicenter retrospective cohort analysis of clinical outcomes in patients with carbapenem-resistant Gram-negative Infection. Open Forum Infect Dis. 2022. https://doi.org/10.1093/ofid/ofac492.704.

    Article  PubMed Central  Google Scholar 

  41. Zhang F, Zhong J, Ding H, Liao G. Efficacy of ceftazidime-avibactam in the treatment of carbapenem-resistant klebsiella pneumoniae infection after kidney transplantation. Infect Drug Resist. 2021;14:5165–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kuang H, Zhong C, Wang Y, Ye H, Ao K, Zong Z, et al. Clinical characteristics and outcomes of patients with multidrug-resistant gram-negative bacterial infections treated with ceftazidime/avibactam. J Glob Antimicrob Resist. 2020;23:404–7.

    Article  PubMed  Google Scholar 

  43. De la Calle C, Rodríguez O, Morata L, Marco F, Cardozo C, García-Vidal C, et al. Clinical characteristics and prognosis of infections caused by OXA-48 carbapenemase-producing enterobacteriaceae in patients treated with ceftazidime-avibactam. Int J Antimicrob Agents. 2019;53:520–4.

    Article  PubMed  Google Scholar 

  44. Jorgensen SCJ, Trinh TD, Zasowski EJ, Lagnf AM, Bhatia S, Melvin SM, et al. Evaluation of the INCREMENT-CPE, pitt bacteremia and qPitt scores in patients with carbapenem-resistant enterobacteriaceae infections treated with ceftazidime-avibactam. Infect Dis Ther. 2020;9:291–304.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Castón JJ, Gallo M, García M, Cano A, Escribano A, Machuca I, et al. Ceftazidime-avibactam in the treatment of infections caused by KPC-producing klebsiella pneumoniae: factors associated with clinical efficacy in a single-center cohort. Int J Antimicrob Agents. 2020;56: 106075.

    Article  PubMed  Google Scholar 

  46. Ackley R, Roshdy D, Meredith J, Minor S, Anderson WE, Capraro GA, et al. Meropenem-vaborbactam versus ceftazidime-avibactam for treatment of carbapenem-resistant enterobacteriaceae infections. Antimicrob Agents Chemother. 2020;64:10–128.

    Article  Google Scholar 

  47. Chen L, Han X, Li Y, Li M. Assessment of mortality-related risk factors and effective antimicrobial regimens for treatment of bloodstream infections caused by carbapenem-resistant enterobacterales. Antimicrob Agents Chemother. 2021;65: e0069821.

    Article  PubMed  Google Scholar 

  48. Zheng G, Zhang J, Wang B, Cai J, Wang L, Hou K, et al. Ceftazidime-avibactam in combination with In vitro Non-susceptible antimicrobials versus ceftazidime-avibactam in monotherapy in critically ill patients with carbapenem-resistant klebsiella pneumoniae infection: a retrospective cohort study. Infect Dis Ther. 2021;10:1699–713.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Gu J, Xu J, Zuo TT, Chen YB. Ceftazidime-avibactam in the treatment of infections from carbapenem-resistant klebsiella pneumoniae: ceftazidime-avibactam against CR-KP infections. J Glob Antimicrob Resist. 2021;26:20–5.

    Article  CAS  PubMed  Google Scholar 

  50. Rathish B, Wilson A, Warrier A, Prakash S, Babu R, Joy S. Clinical outcomes in carbapenem-resistant enterobacteriaceae infections treated with ceftazidime-avibactam: a single-center observational study. Cureus. 2021;13: e13081.

    PubMed  PubMed Central  Google Scholar 

  51. Zheng G, Cai J, Zhang L, Chen D, Wang L, Qiu Y, et al. Ceftazidime/avibactam-based versus polymyxin B-based therapeutic regimens for the treatment of carbapenem-resistant klebsiella pneumoniae infection in critically Ill patients: a retrospective cohort study. Infect Dis Ther. 2022;11:1917–34.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Luterbach CL, Qiu H, Hanafin PO, Sharma R, Piscitelli J, Lin FC, et al. A systems-based analysis of mono- and combination therapy for carbapenem-resistant klebsiella pneumoniae bloodstream infections. Antimicrob Agents Chemother. 2022;66: e0059122.

    Article  PubMed  Google Scholar 

  53. Zhuang HH, Chen Y, Hu Q, Long WM, Wu XL, Wang Q, et al. Efficacy and mortality of ceftazidime/avibactam-based regimens in carbapenem-resistant Gram-negative bacteria infections: a retrospective multicenter observational study. J Infect Public Health. 2023;16:938–47.

    Article  PubMed  Google Scholar 

  54. Pérez-Nadales E, Fernández-Ruiz M, Natera AM, Gutiérrez-Gutiérrez B, Mularoni A, Russelli G, et al. Efficacy of ceftazidime-avibactam in solid organ transplant recipients with bloodstream infections caused by carbapenemase-producing klebsiella pneumoniae. Am J Transplant. 2023;23:1022–34.

    Article  PubMed  Google Scholar 

  55. Zhen S, Zhao Y, Chen Z, Zhang T, Wang J, Jiang E, et al. Assessment of mortality-related risk factors and effective antimicrobial regimens for treatment of bloodstream infections caused by carbapenem-resistant Pseudomonas aeruginosa in patients with hematological diseases. Front Cell Infect Microbiol. 2023;13:1156651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Hospital Medicine, Chi Mei Medical Center, Tainan, Taiwan

    Wei Hsu, Min-Hsiang Chuang, Hsin-Yu Lai & Hung-Jen Tang

  2. Department of Neurology, Chi Mei Medical Center, Tainan, Taiwan

    Wen-Wen Tsai

  3. Department of Intensive Care Medicine, Chi Mei Medical Center, Tainan, Taiwan

    Chih-Cheng Lai

Authors
  1. Wei Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min-Hsiang Chuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen-Wen Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chih-Cheng Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hsin-Yu Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hung-Jen Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WH, HYL and HJT: conception or design of the work. WH, MHC, WWT, and CCL: analysis, WH and CCL: interpretation of data for the work; WH and HYL: Drafting the work. HYL and HJT: Reviewing it critically for important intellectual content. All authors had final approval of the version to be published and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding authors

Correspondence to Hsin-Yu Lai or Hung-Jen Tang.

Ethics declarations

Conflict of interest

All authors declare that there was no conflict of interest.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 456 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hsu, W., Chuang, MH., Tsai, WW. et al. Ceftazidime-avibactam combination therapy versus monotherapy for treating carbapenem-resistant gram-negative infection: a systemic review and meta-analysis. Infection (2024). https://doi.org/10.1007/s15010-024-02277-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s15010-024-02277-y

Keywords

Search

Navigation