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| Name | Class |
|---|---|
| UHC Zagreb, Zagreb, Croatia | OTHER_GOV |
| Daniel Lovrić | UNKNOWN |
| Mirna Momčilović | UNKNOWN |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Continuos ceftazidime/avibactam infusion | Experimental | 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 a solution of CZA will be 50 mL, which gives the concentration of ceftazidime 40 mg/mL, with a 4:1 concentration ratio for avibactam (10 mg/mL). The solution will be administered via an infusion syringe with an infusion rate of 6.25 mL/h. Dose adjustments will be applied according to renal function, calculated using the Cockroft-Gault formula |
|
| Intermitent dosing as per SMPC | Active Comparator | 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 the Cockroft-Gault formula. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Continuos ceftazidime/avibactam infusion | Drug | 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 rate of 6.25 mL/h. Dose adjustments will be applied according to renal function, calculated using Cockroft-Gault formula |
| Measure | Description | Time Frame |
|---|---|---|
| microbiological success rate | The aim of this study is to investigate efficacy of continuous infusion of ceftazidime/avibactam compared to conventional intermittent dosing, in treating critically ill ICU patients with severe infections caused by Klebsiella pneumoniae OXA-48 or Pseudomonas aeruginosa. The primary outcome of the study is microbiological success rate, defined by proportion of patients in whom the causative pathogen is absent from specimen at the site of infection. | 28 days |
| Measure | Description | Time Frame |
|---|---|---|
| clinical success rate | The clinical success rate is the proportion of patients who achieve clinical cure or clinical improvement evaluated at the end of therapy. Clinical cure is the complete resolution of all signs and symptoms, with no evidence of ongoing infection. Clinical improvement is a significant reduction in infection-related signs and symptoms such that the patient demonstrates considerable progress towards recovery. |
| Measure | Description | Time Frame |
|---|---|---|
| adverse events | Any adverse event that can be attributed to ceftazidime/avibactam | 28 day |
| the ratio of ceftazidime plasma concentration to the pathogen's minimum inhibitory concentration (C/MIC) | The ratio of ceftazidime plasma concentration to the pathogen's minimum inhibitory concentration (C/MIC). |
Inclusion Criteria:
General
Disease-specific
Exclusion Criteria:
General
Laboratory values
1. Severe neutropenia before or during ceftazidime/avibactam administration.
Medical conditions
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Ivan Šitum, MD | Contact | 0915143620 | ivsitum@gmail.com | |
| Daniel Lovrić, MD, PhD | Contact | 385914488350 | daniel@lovric.net |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17695343 | Background | 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. | |
| 11502544 | Background | 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. |
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| ID | Term |
|---|---|
| D007239 | Infections |
| D016638 | Critical Illness |
| D011552 | Pseudomonas Infections |
| ID | Term |
|---|---|
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D016905 | Gram-Negative Bacterial Infections |
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Patients will not be informed of their group assignment to maintain study integrity. We opted for this study design, which is not fully blinded, for several practical and clinical reasons. First, the dosing regimen of the drug is complex. According to the SmPC, ceftazidime/avibactam is administered as a prolonged infusion over 2 hours every 8 hours. In a placebo-controlled design, all patients would require an additional infusion, either placebo or the active drug, following the initial 2-hour infusion. By not including a placebo, the control group will follow the SmPC dosing regimen (2-hour infusions every 8 hours), while the intervention group will receive the drug as a continuous infusion over 24 hours. Second, the study involves administration in cardiac and cardiac surgery intensive care units, where patients are at a more significant risk of volume overload. The study was designed without a placebo-controlled arm to minimise unnecessary fluid administration.
|
| Intermitent dosing as per SMPC | Drug | 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. |
|
| 28 day |
| time to symptoms improvement | Patients who achieve clinical cure or clinical improvement | 28 day |
| length of ICU stay | Length of ICU stay is defined as the total number of days from the day of the first CZA administration (study day on 0) until either: Discharge from the ICU (if the patient is transferred out of the ICU before day 28) Day 28 (for patients who remain in the ICU beyond this time) | 28 day |
| length of hospital stay | Length of hospital stay is defined as the total number of days from the day of the first CZA administration (study day on 0) until either: Discharge from the hospital (if the patient is discharged before day 28) Day 28 (for patients who remain hospitalized beyond this time) | 28 day |
| all-cause 28-day mortality after ceftazidime/avibactam initiation | All-cause 28-day mortality is defined as death at any point up to and including study day 28. The 28-day mortality rate will be calculated as the number of deaths divided by the total number of patients in the group, expressed as a percentage. | 28 day |
| pathogen recurrence rate on day 28 | The pathogen recurrence rate on day 28 is defined as the proportion of patients who have a recurrence of the initial causative pathogen from clinical or surveillance microbiological samples taken by study day 28 after completion of CZA therapy. | 28 day |
| time to weaning from mechanical ventilation | time in hours from the start of the trial to the end of mechanical ventilation | 28 days |
| cumulative vasoactive-inotropic score (VIS) | The vasoactive-inotropic score is a quantitative measure that evaluates the cumulative effect of vasoactive and inotropic medications. It is calculated using the following formula: VIS = dobutamine dose (μg/kg/min) + adrenaline dose (μg/kg/min) x 100 + noradrenaline dose (μg/kg/min) x 100 + vasopressin dose (IU/kg/min) x 10 + angiotensin II dose (ng/kg/min) x 10000 24-hour VIS quantifies the overall cardiovascular support required over 24 hours. The average daily VIS score will be calculated using the following formula: Daily VIS=∑ (VIS for each interval × interval duration (hours)/24 An interval is defined as the period where drug doses remain constant. | 28 day |
| 28 day |
| 34261906 | Background | 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. |
| 33036190 | Background | 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. |
| 18158083 | Background | 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.2007.11.003. |
| 10390248 | Background | 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. |
| 23190766 | Background | 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. |
| 36215219 | Background | 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. |
| 37007043 | Background | Ghazi IM, El Nekidy WS. Editorial: Advances in antimicrobial therapy and combating resistance. Front Pharmacol. 2023 Mar 16;14:1170289. doi: 10.3389/fphar.2023.1170289. eCollection 2023. No abstract available. |
| 36845830 | Background | Batchelder JI, Hare PJ, Mok WWK. Resistance-resistant antibacterial treatment strategies. Front Antibiot. 2023;2:1093156. doi: 10.3389/frabi.2023.1093156. Epub 2023 Jan 30. |
| 21747788 | Background | Poole K. Pseudomonas aeruginosa: resistance to the max. Front Microbiol. 2011 Apr 5;2:65. doi: 10.3389/fmicb.2011.00065. eCollection 2011. |
| 29165604 | Background | Bonomo RA, Burd EM, Conly J, Limbago BM, Poirel L, Segre JA, Westblade LF. Carbapenemase-Producing Organisms: A Global Scourge. Clin Infect Dis. 2018 Apr 3;66(8):1290-1297. doi: 10.1093/cid/cix893. |
| 36946763 | Background | Chen T, Xu H, Chen Y, Ji J, Ying C, Liu Z, Xu H, Zhou K, Xiao Y, Shen P. Identification and Characterization of OXA-232-Producing Sequence Type 231 Multidrug Resistant Klebsiella pneumoniae Strains Causing Bloodstream Infections in China. Microbiol Spectr. 2023 Apr 13;11(2):e0260722. doi: 10.1128/spectrum.02607-22. Epub 2023 Mar 22. |
| 37272914 | Background | Garcia-Gonzalez N, Fuster B, Tormo N, Salvador C, Gimeno C, Gonzalez-Candelas F. Genomic analysis of the initial dissemination of carbapenem-resistant Klebsiella pneumoniae clones in a tertiary hospital. Microb Genom. 2023 Jun;9(6):mgen001032. doi: 10.1099/mgen.0.001032. |
| 37512889 | Background | Ceron S, Salem-Bango Z, Contreras DA, Ranson EL, Yang S. Clinical and Genomic Characterization of Carbapenem-Resistant Klebsiella pneumoniae with Concurrent Production of NDM and OXA-48-like Carbapenemases in Southern California, 2016-2022. Microorganisms. 2023 Jun 30;11(7):1717. doi: 10.3390/microorganisms11071717. |
| Background | European Medicines Agency (EMA). Summary of Product Characteristics - Zavicefta 2 g/ 0.5 g powder for concentrate for solution for infusion. https://www.ema.europa.eu/en/documents/product-information/zavicefta-epar-product-information_en.pdf. (accessed 9.11.2024.) |
| 40852616 | Derived | Momcilovic M, Situm I, Erceg A, Siroglavic M, Lovric M, Nizic Nodilo L, Hafner A, Lovric J, Turcic P, Fabijanovic D, Marinic A, Nedeljkovic V, Pasalic M, Percin L, Sipus D, Milicic D, Lovric D. Continuous infusion versus intermittent dosing of ceftazidime/avibactam in critically ill patients with Klebsiella pneumoniae OXA-48 or Pseudomonas aeruginosa infections: a single-center randomized open-label trial (ZAVICONT). Rationale and design. Front Pharmacol. 2025 Aug 7;16:1618987. doi: 10.3389/fphar.2025.1618987. eCollection 2025. |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |