Master Program in Pharmaceutical Sciences Assignment

Assignment Task

Introduction

A large portion of gram negative bacteria considered responsible for the lower respiratory infections in multiple conditionIncluding Cystic Fibrosis, Chronic obstructive pulmonary disease (COPD) Ventilator associated pneumonia (VAP) and bronchiectasis is conditions where pseudomonas aeruginosa infects the organ chronically leading serious consequences.  Additionall intrinsic strain of resistant organisms like Staphylococcus aureus, Mithillin resistant aureu Stenotrophomonas maltophilia Achromobactor Anaerobes and fungal and viral infections are frequent in CF lungs. The internally colonized bacteria within the airways where only limited molecules of drug can reach are hard to eradicate completely. The shunting and chemokine induced inflammation can further reduce the amount of drug. Additionally the common respiratory pathogens are able to survive and grow in the epithelial lining fluid (ELF). Multiple reasons support the fact that pulmonary barrier is the most complex to penetrate by systemic antibiotics. (Wenzler et al., 2016) 4 Mostly the systemic antibiotics have poor penetration in lung parenchyma and narrow therapeutic index between efficacy and toxicity. The natural defense mechanism of lungs comprises mucus clearance in airways making lungs clear to perform complex pulmonary functions (Kurbatova et al., 2015).  5   Regularity of these functions depends on the fluid balance of the organs through the regular process of absorption and secretion of salt and fluid. The CFTR- channel is a Camp-activated chloride and bicarbonate channel essential for lung homeostasis. CFTR performs the essential role during the minute transportation of ions in the epithelial tissues of air ways, gastro intestinal tract, reproductive tracts, and sweat glands. (Saint-Criq & Gray, 2017) 6   The functional role covers the liquid hydration and pH. of airway surface, regulation of inflammatory responses in the lungs.  Defects or loss in the CFTR leads to mucus stasis, chronic bacterial infections and eventually lung destruction.

Aztreonam

Aztrreonam for inhalation solution, brand name as Cayston from Gilead Sciences Inc. Anecdotal reports are showed to have positive results for the chronic Burkholderia infections. The report demonstrates the in vitro activity of inhaled solution against Burkholderia spp. considering possible therapeutic application of AZLI.  Aztreonam is an antibiotic of class monobactams antibiotic acts against gram negative bacteria. It binds to Penicillin-binding proteins of susceptible bacteria leading the inhibition of bacterial cell wall synthesis and cell death.  In 1986 Aztreonam was first approved by FDA to treat bacterial infections. The IV dose was formulated with Arginine, which was showing inflammation; hence it was again reformulated as a lysine salt for inhalation.  Aztreonam activity is not affected by the presence of the CF lung secretions. Preclinical study shows that the formulation of intravenous substance to nebulized aerosols had minor changes in the efficacy of drug. The dose can be delivered in less than 3 minutes for each dose.

Pharmacokinetics

Clinical trial shows the considerable variability of sputum Aztreonam concentrations in the patients treated with Aztreonam( Brand Name: Cayston 75 mg) The mean sputum concentration 10 minutes following the first dose of CAYSTON (n = 195 patients with CF) was 726 mcg/g. Mean sputum concentrations of Aztreonam in patients receiving CAYSTON 3 times a day for 28 days were 984 mcg/g, 793 mcg/g, and 715 mcg/g 10 minutes after dose administration on Days 0, 14, and 28, respectively, indicating no accumulation of Aztreonam in sputum.

Statistical analyse

Analyses included subjects receiving ≥1 dose of AZLI/placebo. Missing data were not imputed. A sample size of 50 subjects per treatment group was estimated as providing ≥80% power to detect an 8.5% difference between groups in mean AUC_ave of relative change from baseline in FEV₁% predicted through week 24 (2-sided, 0.05-level), assuming a common standard deviation (SD) of 15. The primary analysis used a parametric analysis of covariance (ANCOVA) model (2-sided, 0.05-level); baseline FEV₁% predicted was a covariate.  A family alpha spending rule controlled the Type 1 error rate (α = 0.05), with the primary endpoint analysis serving as gatekeeper, and key secondary endpoints tested sequentially (α = 0.05) based upon the closed testing procedure.

The Intravenous Combination therapy of Antibiotic with Aztreonam

The intravenous combination antibiotic therapy proved successfully effective with the combination of Aztreonam with Ceftazidime/Avibactam. The report presents the   favorable response to ceftazidime/avibactam, used in combination with aztreonam, in a patient with CF and an XDR Burkholderia multivorans infection.

over the prior 12 months) in prior sputa, which had chronic colonization for more than ten years. Pseudomonas aeruginosa was found in 50% of specimens. The B. multivorans had earlier been demonstrated to be susceptible to ceftazidime, but had been resistant to aztreonam in the six years prior to presentation.

Sputum culture on admission to hospital produced a heavy growth of B. multivorans resistant to amikacin, aztreonam, ceftazidime, chloramphenicol, ciprofloxacin, colistin, gentamicin, meropenem, piperacillin/tazobactam and tobramycin. Scanty growths of P. aeruginosa (susceptible to ceftazidime and aztreonam) and Candida albicans were also identified. For the B. multivorans, the MIC of ceftazidime/avibactam was determined to be 2.0 mg/L by MIC test strip. Intravenous ceftazidime/avibactam at 2 g q8h plus aztreonam at 2 g q8h were commenced. The patient made rapid clinical improvement and suffered no adverse effects. After 2 weeks of therapy, the patient’s FEV1 (forced expiratory volume in 1 s) improved from a baseline of 0.9 to 1.24 L (39% of predicted), achieving the best spirometric values for 3 years; in the 5 months since treatment the patient has not been readmitted to hospital.

Results and Discussion:

Combination Therapy of  inhaled Tobramycin and amiloride solution for BCC infection

In vitro study This is a previous study where cepacia and maltophilia strains were defined as the pseudomonas isolates and the results are presented exclusively for the positive effect of combination inhaled solution for cepacia strain. In this study twenty three strains of p. cepacia isolated from the patient of Cystic fibrosis were studied. Per patient only one isolated strain was tested. Separate MIC for Amiloride and tobramycin were determined by agar dilution. MIC defined as the lowest concentration of the drug to completely inhibit the bacterial growth. Overnight broth culture of each strain was diluted comparable to 0.5 McFarland and inoculated to Muller-Hinton Agar with doubled dilution of tobramycin (0.5 to 128, ug/ml) and Amiloride (200 to 1,600 jig/ml). The final inoculum was 104 CFU per spot. Incubation followed at 35°C for 48 h.  

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