Ceftazidime-Avibactam PK/PD and Resistance in Hematology Patients

Prospective Exploratory Study of Standard-Dose Ceftazidime-Avibactam PK/PD Target Attainment, Clinical Outcomes, and Induced Resistance in Patients With Hematological Malignancies

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.

Inclusion Criteria:

• Age 16 years or older.
• Diagnosed with hematological malignancies (including but not limited to acute leukemia, lymphoma, multiple myeloma, or myelodysplastic syndrome [MDS]) or having received/undergoing autologous or allogeneic hematopoietic stem cell transplantation (HSCT).
• Prescribed ceftazidime-avibactam (CAZ-AVI) therapy for suspected or confirmed Gram-negative bacterial infections based solely on routine clinical decisions.
• Expected duration of CAZ-AVI therapy is no less than 72 hours.
• Willing and able to comply with the study-specified therapeutic drug monitoring (TDM) and microbiological surveillance.

Exclusion Criteria:

• Known severe allergy or hypersensitivity to ceftazidime, avibactam, cephalosporins, or other beta-lactam antibiotics.
• Confirmed infection caused by metallo-beta-lactamase (MBL)-producing pathogens, without receiving appropriate combination therapy.
• Expected survival time of less than 72 hours.
• Inability to complete critical pharmacokinetic (TDM) or microbiological sampling.
• Pregnancy or lactation.
• Any other condition that, in the opinion of the investigator, makes the patient unsuitable for study inclusion.