Impact of Aggressive Empiric Antibiotic Therapy and Duration of Therapy on the Emergence of Antimicrobial Resistance During the Treatment of Hospitalized Subjects With Pneumonia Requiring Mechanical Ventilation
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 43
- 试验地点
- 11
- 主要终点
- Number of Participants With Suppression and Emergence of Resistance
研究概览
简要总结
The primary objective of this study is to demonstrate a low rate of emergence of antibiotic resistance in P. aeruginosa and Acinetobacter spp during the treatment of hospitalized patients with pneumonia requiring mechanical ventilation treated with PD optimized meropenem administered as a prolonged infusion in combination with a parenteral aminoglycoside plus tobramycin by inhalation (Group 1) compared to therapy with meropenem alone (Group 2 - control arm).
详细描述
The goal of this clinical study is to demonstrate that the application of pharmacodynamic dosing principles to the antibiotic treatment of hospitalized subjects with culture-documented pneumonia (including HABP, VABP and HCAP) requiring mechanical ventilation can inhibit the emergence of antibiotic-resistant organisms during treatment and therefore may improve the rate of a satisfactory clinical response. Antibiotic resistance is defined as an increase in meropenem or aminoglycoside MIC by two tube dilutions (fourfold) from baseline. In animal models of infection, the pharmacodynamic driver for bactericidal effect by β lactam antibiotics such as meropenem is the proportion of the dosing interval during which plasma drug levels are maintained above the MIC of the causative pathogen. The hypothesis of this study is that prolongation of time above MIC by increasing total meropenem dose and the duration of infusion will counter-select for the emergence of antimicrobial resistance during the treatment of hospitalized subjects with pneumonia (i.e. HABP, VABP and HCAP) caused by P.aeruginosa, Acinetobacter species (spp), or other pathogens with intermediate susceptibility to meropenem, and that the addition of parenteral aminoglycosides (amikacin, tobramycin or gentamicin) and nebulized aminoglycoside (tobramycin) given along optimal pharmacodynamic principles will further reduce the likelihood of resistance emergence, particularly among the non-fermenting Gram-negative bacilli, such as Pseudomonas aeruginosa and Acinetobacter spp. The observed incidence of resistance emergence to meropenem will be compared across therapeutic regimens.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
This is an open-label study with 1:1 randomization between two active treatment groups.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Subjects with pneumonia caused by pathogens resistant to meropenem (MIC greater than or equal to 16µg/ml) or a prior meropenem therapy failure.
- •Subjects with contra-indications to ANY study medication, in particular with known or suspected allergy or hypersensitivity.
- •Women who are pregnant or lactating.
- •Subjects taking anticonvulsant medications for a known seizure disorder.Patients with a history of seizures, AND who are stabilized on anti-seizure medication, may be enrolled into the study at the discretion of the site investigator.
- •Subjects with known or suspected community acquired bacterial pneumonia (CABP) or viral pneumonia; or Subjects with acute exacerbation of chronic bronchitis without evidence of pneumonia.
- •Subjects with primary lung cancer or another malignancy metastatic to the lungs.
- •Subjects who were previously enrolled in this study.
- •Subjects who have had an investigational drug or have used an investigational device within 30 days prior to entering the study.
- •Subjects with another focus of infection requiring concurrent antibiotics that would interfere with evaluation of the response to study drug.
- •Subjects with cystic fibrosis, AIDS with a CD4 lymphocyte count <200 cells/µl, neutropenia (absolute neutrophil count <500 cells/ml), known or suspected active tuberculosis.
- •Subjects with little chance of survival for the duration of study therapy.
- •Subjects with an APACHE II score >
- •Subjects with underlying condition(s) which would make it difficult to interpret response to the study drugs.
- •Subjects with hypotension or acidosis despite attempts at fluid resuscitation. Subjects requiring ongoing treatment with vasopressors will be eligible for the study if their hypotension is controlled and acidosis has resolved. Subjects with intractable septic shock are not eligible for enrollment.
- •Subjects who have undergone bone marrow transplantation.
- •Subjects with profound hypoxia as defined by a PaO2/FiO2 ratio <100.
研究组 & 干预措施
IV meropenem; parenteral aminoglycoside
Subjects assigned to this group will receive:
- IV meropenem (2 g infused over 3 hrs q 8 hr);
- a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h)
- tobramycin nebulization
Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens.
干预措施: IV meropenem (Drug)
IV meropenem; parenteral aminoglycoside
Subjects assigned to this group will receive:
- IV meropenem (2 g infused over 3 hrs q 8 hr);
- a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h)
- tobramycin nebulization
Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens.
干预措施: Parenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24h (Drug)
IV meropenem; parenteral aminoglycoside
Subjects assigned to this group will receive:
- IV meropenem (2 g infused over 3 hrs q 8 hr);
- a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h)
- tobramycin nebulization
Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens.
干预措施: Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage. (Drug)
IV meropenem; parenteral aminoglycoside
Subjects assigned to this group will receive:
- IV meropenem (2 g infused over 3 hrs q 8 hr);
- a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h)
- tobramycin nebulization
Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens.
干预措施: tobramycin nebulization (Device)
I.V. Meropenem
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).
Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat Gram-positive pathogens.
**NOTE: Empiric MRSA coverage is allowed in both arms. This therapy is advised for any subjects with known or suspected MRSA entering the study. Once microbiologic results are available, this coverage may be discontinued at the investigator's discretion.
干预措施: I.V. Meropenem (Drug)
I.V. Meropenem
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).
Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat Gram-positive pathogens.
**NOTE: Empiric MRSA coverage is allowed in both arms. This therapy is advised for any subjects with known or suspected MRSA entering the study. Once microbiologic results are available, this coverage may be discontinued at the investigator's discretion.
干预措施: Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage. (Drug)
结局指标
主要结局
Number of Participants With Suppression and Emergence of Resistance
时间窗: up to 28 days after enrollment
The emergence of resistance is defined as a change of meropenem MIC or aminoglycoside MIC by two tube dilutions (fourfold) from baseline when assessed at the second BAL procedure on day 5/early extubation. Patients are evaluable for this endpoint IF they had baseline BAL and Day 5/early extubation and if they had positive cultures on baseline and Day/EE.
次要结局
- Clinical Response(End of treatment - up to 28 days after enrollment)
- Clinical Response in Subjects Who Received Prior Antibiotics(End of treatment - up to 28 days after enrollment)
- Overall Microbiologic Response(End of treatment - up to 28 days after enrollment)
- Pretreatment Pathogen Response(End of treatment - up to 28 days after enrollment)
- Suppression of the Emergence of Resistance in Other Gram-negative Pathogens(Day 5/Early Extubation)
- Occurrence of Repeat Negative Cultures(Day 5/Early Extubation)
- Mortality(28 days)