Impact of Renal-adjusted Ceftazidime/avibactam in Patients with KPC-producing Bloodstream Infection: a Retrospective Cohort Study

Overview

Journal JAC Antimicrob Resist

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2024 Dec 18

PMID 39691790

Authors

A Oliva

L Volpicelli

A Gigante

M Di Nillo

S Trapani

A Viscido

F Sacco

C M Mastroianni

Affiliations

Soon will be listed here.

Abstract

Background: Bloodstream infections (BSIs) caused by KPC-producing (KPC-Kp) are still associated with high mortality, and the game-changing drug ceftazidime/avibactam has shown suboptimal pharmacokinetics in some clinical settings. Ceftazidime/avibactam renal dose adjustment has recently been identified as an independent risk factor for mortality.

Objectives: To investigate the effect of ceftazidime/avibactam renal dose adjustment on mortality.

Methods: Patients with KPC-Kp BSI treated with a ceftazidime/avibactam-based regimen were retrospectively collected and analysed. The primary outcome was mortality at 7, 14 and 30 days after the start of definitive ceftazidime/avibactam antibiotic therapy. Renal function was estimated using the CKD-EPI equation.

Results: One hundred and ten patients with KPC-Kp BSI treated with a ceftazidime/avibactam-based regimen were included. Full-dose ceftazidime/avibactam (7.5 g daily) was prescribed to 82 patients (74.5%), while 28 patients (25.5%) received a renal-adjusted dose (17 patients due to chronic renal disease or haemodialysis, 11 patients due to infection-related acute kidney injury), with a median of 1.9 g daily. At multivariable analysis, receiving a reduced dose of ceftazidime/avibactam was independently associated with mortality (HR 4.47, 95% CI 1.09-18.03, = 0.037), along with intra-abdominal or lower respiratory tract infections as source of BSI (HR 5.42, 95% CI 1.77-16.55, = 0.003), septic shock (HR 6.99, 95% CI 1.36-35.87, = 0.020) and SARS-CoV-2 coinfection (HR 10.23, 95% CI 2.69-38.85, = 0.001).

Conclusions: Dose reduction of ceftazidime/avibactam according to renal function in patients with KPC-Kp BSI seems to be independently associated with higher mortality. This may be possibly due to inadequate exposure provided by the recommended doses for renal impairment.

References

Gatti M, Fornaro G, Viale P, Pea F, Giannella M . Clinical efficacy of renal dosing adjustments of ceftazidime-avibactam in patients affected by carbapenem-resistant Gram-negative infections: A systematic review and meta-analysis of observational studies. Br J Clin Pharmacol. 2022; 89(2):617-629. DOI: 10.1111/bcp.15586. View

Gutierrez-Gutierrez B, Salamanca E, Cueto M, Hsueh P, Viale P, Pano-Pardo J . Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study. Lancet Infect Dis. 2017; 17(7):726-734. DOI: 10.1016/S1473-3099(17)30228-1. View

Inker L, Eneanya N, Coresh J, Tighiouart H, Wang D, Sang Y . New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. N Engl J Med. 2021; 385(19):1737-1749. PMC: 8822996. DOI: 10.1056/NEJMoa2102953. View

Tumbarello M, Raffaelli F, Giannella M, Mantengoli E, Mularoni A, Venditti M . Ceftazidime-Avibactam Use for Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae Infections: A Retrospective Observational Multicenter Study. Clin Infect Dis. 2021; 73(9):1664-1676. DOI: 10.1093/cid/ciab176. View

Camargo M, Mistro S, Oliveira M, Passos L . Association between increased mortality rate and antibiotic dose adjustment in intensive care unit patients with renal impairment. Eur J Clin Pharmacol. 2018; 75(1):119-126. DOI: 10.1007/s00228-018-2565-7. View

Charlson M, Pompei P, Ales K, MacKenzie C . A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40(5):373-83. DOI: 10.1016/0021-9681(87)90171-8. View

Cleri D, Corrado M, SELIGMAN S . Quantitative culture of intravenous catheters and other intravascular inserts. J Infect Dis. 1980; 141(6):781-6. DOI: 10.1093/infdis/141.6.781. View

Falcone M, Bassetti M, Tiseo G, Giordano C, Nencini E, Russo A . Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae. Crit Care. 2020; 24(1):29. PMC: 6993311. DOI: 10.1186/s13054-020-2742-9. View

Boattini M, Bianco G, Charrier L, Comini S, Iannaccone M, Almeida A . 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(4):431-439. DOI: 10.1007/s10096-023-04577-x. View

10.

Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith C, French C . Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021; 47(11):1181-1247. PMC: 8486643. DOI: 10.1007/s00134-021-06506-y. View

11.

Crass R, Rodvold K, Mueller B, Pai M . Renal Dosing of Antibiotics: Are We Jumping the Gun?. Clin Infect Dis. 2018; 68(9):1596-1602. DOI: 10.1093/cid/ciy790. View

12.

Bidell M, Lodise T . Suboptimal Clinical Response Rates with Newer Antibiotics Among Patients with Moderate Renal Impairment: Review of the Literature and Potential Pharmacokinetic and Pharmacodynamic Considerations for Observed Findings. Pharmacotherapy. 2018; 38(12):1205-1215. DOI: 10.1002/phar.2184. View

13.

Ehmann L, Zoller M, Minichmayr I, Scharf C, Maier B, Schmitt M . Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients: a prospective observational study. Crit Care. 2017; 21(1):263. PMC: 5651591. DOI: 10.1186/s13054-017-1829-4. View

14.

. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024; 105(4S):S117-S314. DOI: 10.1016/j.kint.2023.10.018. View

15.

Jorgensen S, Trinh T, Zasowski E, Lagnf A, Bhatia S, Melvin S . 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(2):291-304. PMC: 7223509. DOI: 10.1007/s40121-020-00288-4. View

16.

Karampatakis T, Tsergouli K, Lowrie K . Efficacy and safety of ceftazidime-avibactam compared to other antimicrobials for the treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae strains, a systematic review and meta-analysis. Microb Pathog. 2023; 179:106090. DOI: 10.1016/j.micpath.2023.106090. View

17.

Fresan D, Luque S, Benitez-Cano A, Sorli L, Montero M, De-Antonio M . Pharmacokinetics/pharmacodynamics and therapeutic drug monitoring of ceftazidime/avibactam administered by continuous infusion in patients with MDR Gram-negative bacterial infections. J Antimicrob Chemother. 2023; 78(3):678-683. DOI: 10.1093/jac/dkac439. View

18.

Singer M, Deutschman C, Seymour C, Shankar-Hari M, Annane D, Bauer M . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):801-10. PMC: 4968574. DOI: 10.1001/jama.2016.0287. View

19.

Waikar S, Bonventre J . Creatinine kinetics and the definition of acute kidney injury. J Am Soc Nephrol. 2009; 20(3):672-9. PMC: 2653692. DOI: 10.1681/ASN.2008070669. View

20.

Li J, Lovern M, Riccobene T, Carrothers T, Newell P, Das S . Considerations in the Selection of Renal Dosage Adjustments for Patients with Serious Infections and Lessons Learned from the Development of Ceftazidime-Avibactam. Antimicrob Agents Chemother. 2020; 64(4). PMC: 7179271. DOI: 10.1128/AAC.02105-19. View