Prospective Exploratory Study of Standard-Dose Ceftazidime-Avibactam PK/PD Target Attainment, Clinical Outcomes, and Induced Resistance in Patients With Hematological Malignancies
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Joint Pharmacokinetic/Pharmacodynamic (PK/PD) Target Attainment Rate of Ceftazidime-Avibactam
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
CAZ-AVI Single-Arm Observation Group
Patients with hematological malignancies or those undergoing hematopoietic stem cell transplantation (HSCT) who are prescribed standard-dose ceftazidime-avibactam (CAZ-AVI) for suspected or confirmed Gram-negative bacterial infections based solely on routine clinical decisions [4, 6.1, 17]. This group will undergo standard-of-care antibiotic therapy combined with protocol-specified therapeutic drug monitoring (TDM) and microbiological surveillance.
干预措施: Ceftazidime-avibactam (Drug)
CAZ-AVI Single-Arm Observation Group
Patients with hematological malignancies or those undergoing hematopoietic stem cell transplantation (HSCT) who are prescribed standard-dose ceftazidime-avibactam (CAZ-AVI) for suspected or confirmed Gram-negative bacterial infections based solely on routine clinical decisions [4, 6.1, 17]. This group will undergo standard-of-care antibiotic therapy combined with protocol-specified therapeutic drug monitoring (TDM) and microbiological surveillance.
干预措施: Therapeutic Drug Monitoring (TDM) and Microbiological Surveillance (Procedure)
结局指标
主要结局
Joint Pharmacokinetic/Pharmacodynamic (PK/PD) Target Attainment Rate of Ceftazidime-Avibactam
时间窗: 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).
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.
次要结局
- Incidence of Induced Resistance to Ceftazidime-Avibactam During Therapy(From baseline up to 7 days after completion of ceftazidime-avibactam therapy.)
- 7-Day Clinical Response Rate(7 days after starting ceftazidime-avibactam therapy.)
- Microbiological Clearance Rate(Up to 7 days after completion of ceftazidime-avibactam therapy.)
- 7-Day Re-fever Rate(Up to 7 days after initial defervescence during the therapy period.)
- 30-Day All-Cause Mortality Rate(30 days after the initiation of ceftazidime-avibactam therapy.)
研究者
Sizhou Feng
Director, Chief Physician, Professor
Institute of Hematology & Blood Diseases Hospital, China