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Combination therapy for the treatment of nosocomial pneumonia

A technology for acquired pneumonia and hospitals, which is applied in the direction of drug combinations, pharmaceutical formulas, organic active ingredients, etc., and can solve problems such as reduced efficacy

Inactive Publication Date: 2015-10-21
PFIZER ANTI INFECTIVES AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Declining potency of existing empiric treatment regimens (e.g., carbapenems, cephalosporins) has created a significant need for agents active against a broader spectrum of refractory and resistant pathogens than established therapy, such as ceftazidime - Avibactam (CAZ-AVI) combination

Method used

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  • Combination therapy for the treatment of nosocomial pneumonia
  • Combination therapy for the treatment of nosocomial pneumonia
  • Combination therapy for the treatment of nosocomial pneumonia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 - In vitro potency of CAZ-AVI in pulmonary surfactant

[0051] bacterial strain

[0052] The bacterial strains used in this test are part of a microbial culture collection housed at AstraZeneca R&D Boston (AstraZeneca Research Collection, known as ARC). The panel of bacterial isolates used for this test contained 5 CLSI QC reference strains and the remainder were recent clinical isolates expressing β-lactamase or isolates from the primary bacterial screening panel.

[0053] Research design

[0054] MIC values ​​were determined using the CLSI broth microdilution method with small changes. Prepare a stock compound master, and using said master, use a Perkin-Elmer MiniTrak TM The multi-position dispenser dispenses 2 µL aliquots of the 2-fold serial drug dilutions onto columns 1-11 of the 96-well subplate. Column 12 contained no drug and served as a growth control. Use multiple channels 100μL (5×10E 5 CFU / mL) Inoculum volumes in CAMHB containing 0, 1%, 2...

Embodiment 2

[0073] Example 2 - Potential drug interactions with other commonly co-administered agents

[0074] Use a checkerboard assay to test (if present) ceftazidime and ceftazidime-avibactam combinations with 6 established antimicrobials: tobramycin, levofloxacin, vancomycin, linezolid, tigecycline, and colistin interaction between. The MICs of ceftazidime and ceftazidime-avibactam in the presence and absence of various concentrations of these antibacterial agents were compared to generate a series of fractional inhibitory concentration index (FICI) values. The average FICI was taken from each combined board and interpreted according to accepted standards. In cases where antimicrobials were ineffective (vancomycin and linezolid against Gram-negative isolates; colistin against Gram-positive isolates), the individual MICs of ceftazidime and ceftazidime-avibactam were compared with all The above MICs are related to the C of these antimicrobials 最大 and 0.5×C 最大 combination for compa...

Embodiment 3

[0114] Example 3 - CAZ-AVI penetration into ELF

[0115] Pharmacokinetic studies were performed to describe the pulmonary disposition of ceftazidime-avibactam in infected and uninfected mice. Then, the efficacy of ceftazidime and ceftazidime-avibactam against Pseudomonas aeruginosa isolates was studied using a neutropenic lung infection model. No pharmacokinetic differences were observed in serum or ELF between infected and uninfected mice. Using human mock serum doses of 2000 mg ceftazidime and 500 mg avibactam as a 2-h infusion, maximal activity against these isolates was observed at an MIC of 32 μg / mL, where for the upper 95% confidence interval ELF fT > MIC ≥ 19%. Given the MIC of ceftazidime-avibactam 90 At 8 μg / mL, the MIC was higher for few isolates, and even fewer isolates were able to grow in the murine model of lung infection. Therefore, a ceftazidime directed ELF fT > MIC study was performed and showed activity against an MIC of 32 μg / mL with an ELF fT > MIC o...

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Abstract

The present invention relates to a method of treatment of nosocomial pneumonia using a combination of ceftazidime (a third generation cephalosporin) and avibactam (a novel β-lactamase inhibitor), optionally with one or more additional therapeutic agents.

Description

field of invention [0001] The present invention relates to a method of treating nosocomial pneumonia using a combination of ceftazidime (a third generation cephalosporin) and avibactam (a novel beta-lactamase inhibitor) and optionally one or more additional therapeutic agents. Background of the invention [0002] The international microbiological and infectious disease community continues to express serious concern that the continued development of antimicrobial resistance may result in strains of bacteria that are ineffective against currently available antimicrobial agents. The outcome of such events can be associated with considerable morbidity and mortality. [0003] [beta]-lactam antibiotics are important in the fight against bacterial infections. β-lactams are a large class of drugs that all have a β-lactam in their core molecular structure and have generally shown efficacy against a broad spectrum of Gram-positive and Gram-negative bacteria by inhibiting bacterial ce...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/546A61K31/4184A61P11/00
CPCA61K31/546A61K31/529A61K31/439A61K31/5377A61K31/5383A61K31/65A61K31/7036A61P11/00A61P31/04A61P43/00Y02A50/30A61K2300/00A61K31/4184A61K9/0019A61K38/14
Inventor S.达斯J.李J.W.穆顿W.尼克尔斯
Owner PFIZER ANTI INFECTIVES AB
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