This is a prospective, single-arm, observational, exploratory clinical study to evaluate whether the standard fixed dose of ceftazidime-avibactam (CAZ-AVI) achieves sufficient drug exposure (pharmacokinetic/pharmacodynamic, or PK/PD targets) in patients with blood cancers (or those undergoing stem cell transplantation). Patients with hematological malignancies are at high risk for severe, drug-resistant Gram-negative bacterial infections due to weakened immune systems. CAZ-AVI is a critical antibiotic used to treat these infections. However, there is limited evidence on whether the standard recommended dose achieves adequate drug concentrations for both ceftazidime and avibactam simultaneously in this specific patient group, and whether low drug exposure drives the development of antibiotic resistance during treatment. This study will enroll 60 participants who are already prescribed CAZ-AVI by their treating physicians based on routine clinical needs. The study will not change or interfere with any clinical treatment decisions. To measure drug levels, 5 small blood samples (about 2-3 mL each) will be collected within one dosing interval after the drug reaches a steady level in the body (typically 48 to 72 hours after starting treatment). Microbiological samples (such as blood cultures or swabs) will also be collected at multiple time points to monitor bacterial clearance and detect any newly developed resistance. Participants will be followed up for clinical outcomes and survival status up to 30 days after the completion of treatment. The primary goal of this study is to determine the percentage of patients who achieve the target drug exposure for both ceftazidime and avibactam simultaneously. The secondary goals are to observe clinical cure rates, bacterial clearance rates, 30-day survival, and the rate of newly induced antibiotic resistance during therapy.
Background and Rationale: Patients with hematological malignancies or those undergoing hematopoietic stem cell transplantation (HSCT) are highly vulnerable to drug-resistant Gram-negative bacterial infections due to prolonged neutropenia, mucosal barrier damage, and frequent broad-spectrum antibiotic exposure. Ceftazidime-avibactam (CAZ-AVI) is a key therapeutic option for managing these infections. While the efficacy of CAZ-AVI is well established, real-world data suggest that drug exposure may vary significantly in this patient population. Furthermore, standard dosing may not guarantee joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment for both ceftazidime (a beta-lactam) and avibactam (a beta-lactamase inhibitor) simultaneously, potentially leading to treatment failure or the emergence of resistance. This study employs an "explore first, intervene later" stepwise strategy to systematically assess joint PK/PD target attainment and its clinical/microbiological correlates in a real-world setting. Study Objectives: The primary objective is to evaluate the proportion of patients achieving the pre-defined joint PK/PD target of CAZ-AVI during the early phase of therapy (48-72 hours). Secondary objectives include assessing the rate of induced resistance, 7-day clinical response, defervescence rate, microbiological clearance, 7-day re-fever rate, infection-related shock, and 30-day all-cause mortality, as well as exploring the association between drug under-exposure and adverse clinical or microbiological outcomes. Study Design and Flow: This is a prospective, single-arm, observational, exploratory clinical study. The study does not interfere with clinical decisions regarding the initiation, dosing, renal adjustments, combination therapy, or duration of CAZ-AVI. 1. Patient Enrollment: A total of 60 patients who meet the inclusion criteria and are prescribed CAZ-AVI for suspected or confirmed Gram-negative infections will be enrolled. 2. Pharmacokinetic Sampling (TDM): Blood samples (2-3 mL each, K2-EDTA anticoagulated plasma) will be collected at 5 specific time points within a single dosing interval after reaching steady state (typically 48-72 hours, corresponding to the 4th or 5th dose): pre-dose (trough), 2 hours (end of infusion), 4 hours, 6 hours, and 7.5 hours. Plasma concentrations of both ceftazidime and avibactam will be quantified using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. 3. Microbiological Surveillance: Blood cultures, infection site cultures, and oropharyngeal/perianal colonization swabs will be systematically collected at Baseline, Day 3±1, Day 7±1, End of Therapy (EOT), and 7 days post-therapy. Separated key pathogens (focusing on Pseudomonas aeruginosa and Klebsiella pneumoniae complex) will undergo susceptibility testing. Minimum inhibitory concentrations (MICs) will be verified using the broth microdilution (BMD) method at a fixed concentration of 4 mg/L avibactam. 4. Clinical Follow-up: Daily body temperature, symptoms, inflammatory markers, and hemodynamics will be recorded. Patients will be followed up for 30 days post-infection to determine survival status. PK/PD Target Attainment Definitions: * Joint PK/PD Target (Primary Endpoint): Defined as ceftazidime achieving free drug concentration above the MIC for at least 50% of the dosing interval (50% fT\>MIC) AND avibactam free drug concentration remaining above 1 mg/L for at least 50% of the dosing interval (50% fT\>1 mg/L) simultaneously. * Exploratory Optimized Joint Target: Ceftazidime achieving 100% fT\>MIC and avibactam achieving 100% fT\>1 mg/L. Further strict targets (e.g., ceftazidime 100% fT\>4xMIC and avibactam 100% concentration \> 4 mg/L) will be evaluated in exploratory analyses. Key Definitions: * Induced Resistance: Transition of a pathogen from CAZ-AVI susceptible/non-resistant at baseline to non-susceptible/resistant during therapy or within 7 days post-therapy. * 7-day Clinical Response: Satisfaction of at least two of the following criteria within 7 days: temperature normalization or significant decrease, clinical symptom improvement, decrease in inflammatory markers, and hemodynamic stability. Statistical Considerations: The sample size of 60 is based on the precision of estimating the primary endpoint (early joint PK/PD target attainment rate), assuming a conservative target attainment rate (p = 0.5) to yield a 95% confidence interval half-width of approximately 13.9% with a final analysis set of 50 patients, allowing for a 10%-15% drop-out rate. Descriptives will be presented as mean±SD or median (IQR) for continuous variables, and counts (%) with 95% CIs for categorical variables. Fisher's exact test and exploratory logistic regression will be used to explore associations between target attainment and outcomes.
Study Type
OBSERVATIONAL
Enrollment
60
Patients receive standard-dose ceftazidime-avibactam (CAZ-AVI) intravenously. The standard recommended dosage for adults is 2.5 g (ceftazidime 2.0 g and avibactam 0.5 g) administered every 8 hours via a 2-hour intravenous infusion, with adjustments made for renal impairment according to the drug's official product label. This study is purely observational; the initiation, dosing regimen, combination with other antibiotics, and duration of therapy are determined entirely by the treating physicians based on clinical routine, without any study-active interference.
Auxiliary non-interventional procedures added to routine care: 1) Standardized TDM sampling: 5 blood samples (2-3 mL each, total \~15 mL) collected within a single dosing interval at steady state (48-72 hours after treatment initiation, typically after the 4th or 5th dose) to measure ceftazidime and avibactam plasma concentrations via LC-MS/MS. 2) Microbiological surveillance: longitudinal collection of blood cultures, clinical infection site specimens, and oropharyngeal/perianal colonization swabs at Baseline, Day 3±1, Day 7±1, end of therapy, and 7 days post-therapy to monitor bacterial clearance and screen for newly induced resistance.
Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences
Tianjin, Tianjin Municipality, China
Joint Pharmacokinetic/Pharmacodynamic (PK/PD) Target Attainment Rate of Ceftazidime-Avibactam
The percentage of patients who simultaneously achieve the target drug exposure for both ceftazidime and avibactam in plasma during the early phase of therapy. The joint PK/PD target attainment is defined as meeting both of the following criteria concurrently within a single dosing interval: 1. Ceftazidime free drug concentration remains above the Minimum Inhibitory Concentration (MIC) of the pathogen for at least 50% of the dosing interval (50% fT \> MIC). 2. Avibactam free drug concentration remains above 1 mg/L for at least 50% of the dosing interval (50% fT \> 1 mg/L). The pathogen's MIC is determined under a fixed concentration of 4 mg/L avibactam using the broth microdilution (BMD) method.
Time frame: 48 to 72 hours after starting ceftazidime-avibactam therapy (assessed over a single dosing interval at steady state, typically after the 4th or 5th dose).
Incidence of Induced Resistance to Ceftazidime-Avibactam During Therapy
The percentage of patients who experience a transition of their baseline pathogen from ceftazidime-avibactam susceptible/non-resistant to non-susceptible/resistant. This is defined as isolating the same pathogen species during the therapy period or within 7 days post-therapy that exhibits ceftazidime-avibactam non-susceptibility/resistance, whereas the baseline isolate was susceptible/non-resistant.
Time frame: From baseline up to 7 days after completion of ceftazidime-avibactam therapy.
7-Day Clinical Response Rate
The percentage of patients achieving clinical response within 7 days of starting therapy. Clinical response is defined as meeting at least two of the following criteria: 1. Temperature normalization (body temperature \< 38.0°C) or significant decrease; 2. Improvement of infection-related clinical symptoms; 3. Decrease in inflammatory markers; 4. Hemodynamic stability.
Time frame: 7 days after starting ceftazidime-avibactam therapy.
Microbiological Clearance Rate
The percentage of patients achieving microbiological clearance. This is defined as the target Gram-negative pathogen culture turning negative in follow-up clinical specimens, or when follow-up specimens are no longer obtainable due to clinical resolution of the infection site.
Time frame: Up to 7 days after completion of ceftazidime-avibactam therapy.
7-Day Re-fever Rate
The percentage of patients who experience a recurrence of infection-related fever (body temperature ≥ 38.0°C) within 7 days after initial defervescence (fever resolution) during the treatment period.
Time frame: Up to 7 days after initial defervescence during the therapy period.
30-Day All-Cause Mortality Rate
The percentage of patients who die from any cause within 30 days after the initiation of ceftazidime-avibactam therapy.
Time frame: 30 days after the initiation of ceftazidime-avibactam therapy.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.