Ceftazidime-Avibactam PK/PD and Resistance in Hematology Patients

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.