CONTinuous Infusion Versus Intermittent Dosing of ceftaZidime/AVIbactam in Critically Ill Patients

Official title

CONTinuous Infusion Versus Intermittent Dosing of ceftaZidime/AVIbactam in Critically Ill Patients With Klebsiella Pneumoniae OXA-48 or Pseudomonas Aeruginosa Infections: A Single-centre Randomized Open-label Trial (ZAVICONT)

Overview

Ceftazidime/avibactam (CZA) is an essential treatment option for managing infections caused by multidrug-resistant (MDR) gram-negative (G-) bacteria, including Klebsiella pneumoniae OXA-48 and carbapenem-resistant Pseudomonas aeruginosa. Critically ill intensive care unit (ICU) patients frequently exhibit altered pharmacokinetics (PK) of CZA, potentially compromising optimal PK/pharmacodynamic (PD) target attainment with standard dosing regimens. This study compares the efficacy of continuous infusion (CI) versus conventional intermittent dosing (ID) of CZA in critically ill ICU patients with severe infections caused by K. pneumoniae OXA-48 or P. aeruginosa. This single-centre, randomized, open-label trial will be conducted at a tertiary care hospital within the University Hospital Centre in Zagreb, Croatia, with a 1:1 allocation ratio. One hundred forty critically ill ICU patients requiring CZA treatment will be randomized to receive either ID (2 g/0.5 g every 8 hours over 2 hours) or an equivalent dose in CI (6 g/1.5 g continuously over 24 hours). The primary outcome is the microbiological success rate. Secondary outcomes include clinical success rate, time to symptom improvement, length of ICU and hospital stay, 28-day all-cause mortality, pathogen recurrence rate, time to weaning from mechanical ventilation, cumulative vasoactive-inotropic score, adverse events, and the ratio of ceftazidime plasma concentration to the pathogen's minimum inhibitory concentration (C/MIC). This trial seeks to provide evidence on the optimal administration strategy for CZA in critically ill ICU patients with severe infections due to MDR G- pathogens.

Interventions

• Drug Continuos ceftazidime/avibactam infusion
  Continuous infusion will include a loading dose of 2 g/0.5 g administered over 2 hours, followed by continuous infusion of 6 g/1.5 g over 24 hours, equivalent to 0.25 g of ceftazidime per hour. The drug reconstitution and dilution process are shown in Figure 2. The final volume of solution of CZA will be 50 mL, which gives concentration of ceftazidime of 40 mg/mL, with 4:1 concentration ratio for avibactam (10 mg/mL). The solution will be administered via an infusion syringe, with an infusion ra
• Drug Intermitent dosing as per SMPC
  Intermittent dosing, as outlined in the SmPC, consists of 2 g/0.5 g administered by prolonged infusion over 2 hours every 8 hours. Dose adjustments will be applied according to renal function, calculated using Cockroft-Gault formula.

Primary outcome measures

• microbiological success rate [Time frame: 28 days]

Secondary outcome measures (8)

• clinical success rate [Time frame: 28 day]
• time to symptoms improvement [Time frame: 28 day]
• length of ICU stay [Time frame: 28 day]
• length of hospital stay [Time frame: 28 day]
• all-cause 28-day mortality after ceftazidime/avibactam initiation [Time frame: 28 day]
• pathogen recurrence rate on day 28 [Time frame: 28 day]
• time to weaning from mechanical ventilation [Time frame: 28 days]
• cumulative vasoactive-inotropic score (VIS) [Time frame: 28 day]

Eligibility criteria

Inclusion criteria

• General

• Age above or equal to 18 years of age.
• Able to provide informed consent personally or by his/her next of kin, as requested by the Ethics Committee.
• Disease-specific

• Critically ill patients requiring admission to the intensive care unit (medical or surgical).
• Diagnosed with severe infections.
• At least one microbiological sample positive for Klebsiella pneumoniae OXA-48 or Pseudomonas aeruginosa.
• Requiring a prescription for ceftazidime/avibactam, by clinical judgement

Exclusion criteria

• General

• Known or suspected hypersensitivity to ceftazidime/avibactam, excipients, or any other cephalosporin antibacterial agent. Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other β-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems).
• Withdrawal of informed consent.
• Age above 85 years of age.
• Female who is pregnant or breast-feeding.
• Participation (i.e. signed informed consent) in any other interventional clinical trial of an approved or non-approved antibacterial agent within 30 days before screening.
• Any disorder which, in the investigator's opinion, might jeopardize the participant's safety or compliance with the protocol.
• Laboratory values

1\. Severe neutropenia before or during ceftazidime/avibactam administration.

• Medical conditions

• Death within 48 hours following randomization.
• Concomitant acquired immunodeficiency syndrome.
• Presence or history of malignant neoplasms or in situ carcinomas.
• Duration of ceftazidime/avibactam administration is shorter than 72 hours.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007 May;39(2):175-91. doi: 10.3758/bf03193146. PMID 17695343
• Servais H, Tulkens PM. Stability and compatibility of ceftazidime administered by continuous infusion to intensive care patients. Antimicrob Agents Chemother. 2001 Sep;45(9):2643-7. doi: 10.1128/AAC.45.9.2643-2647.2001. PMID 11502544
• Gatti M, Pea F. Continuous versus intermittent infusion of antibiotics in Gram-negative multidrug-resistant infections. Curr Opin Infect Dis. 2021 Dec 1;34(6):737-747. doi: 10.1097/QCO.0000000000000755. PMID 34261906
• Adembri C, Novelli A, Nobili S. Some Suggestions from PK/PD Principles to Contain Resistance in the Clinical Setting-Focus on ICU Patients and Gram-Negative Strains. Antibiotics (Basel). 2020 Oct 6;9(10):676. doi: 10.3390/antibiotics9100676. PMID 33036190
• Lorente L, Jimenez A, Palmero S, Jimenez JJ, Iribarren JL, Santana M, Martin MM, Mora ML. Comparison of clinical cure rates in adults with ventilator-associated pneumonia treated with intravenous ceftazidime administered by continuous or intermittent infusion: a retrospective, nonrandomized, open-label, historical chart review. Clin Ther. 2007 Nov;29(11):2433-9. doi: 10.1016/j.clinthera.2007.11.00 PMID 18158083
• Gomez CM, Cordingly JJ, Palazzo MG. Altered pharmacokinetics of ceftazidime in critically ill patients. Antimicrob Agents Chemother. 1999 Jul;43(7):1798-802. doi: 10.1128/AAC.43.7.1798. PMID 10390248
• Muller AE, Punt N, Mouton JW. Optimal exposures of ceftazidime predict the probability of microbiological and clinical outcome in the treatment of nosocomial pneumonia. J Antimicrob Chemother. 2013 Apr;68(4):900-6. doi: 10.1093/jac/dks468. Epub 2012 Nov 28. PMID 23190766
• Ali A, Imran M, Sial S, Khan A. Effective antibiotic dosing in the presence of resistant strains. PLoS One. 2022 Oct 10;17(10):e0275762. doi: 10.1371/journal.pone.0275762. eCollection 2022. PMID 36215219

Identifiers

NCT: NCT06811727 · ZAVICONT01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗