Cystic fibrosis antimicrobials

The spectrum of respiratory tract infections (RTI) can vary from the common cold to acute or chronic bronchitis to community-acquired pneumonia to nosocomial pneumonia and aspiration pneumonia to ventilator-associated pneumonia to chronic pneumonia (in cystic fibrosis, histoplasmosis, tuberculosis, etc.). Important complications are lung abscess and pleural empyema that will often need drainage and prolonged antimicrobial treatment (>6 weeks). 

Canton R, Cobos N, de Gracia J, et al. Antimicrobial therapy for pulmonary pathogenic colonisation and infection by Pseudomonas aeruginosa in cystic fibrosis patients. Clin Microbiol Infect. 2005 11 690-703. 

Schultz MJ. Macrolide activities beyond their antimicrobial effects macrolides in diffuse panbronchiolitis and cystic fibrosis. J Antimicrob Chemother. 2004 54 21-28. 

Topical uses. Neomycin and framycetin, whilst too toxic for systemic use, are effective for topical treatment of infections of the conjunctiva or external ear. They are sometimes used in antimicrobial combinations selectively to decontaminate the bowel of patients who are to receive intense immunosuppressive therapy. Tobramycin is given by inhalation for therapy of infective exacerbations of cystic fibrosis. 

Nebulizers are generally used to treat acute exacerbations of asthma or chronic obstructive pulmonary disease. Other indications include long-term bronchodilator treatment of chronic airflow obstruction prophylactic treatment for asthma antimicrobial drugs for cystic fibrosis, bronchiectasis, and HIV/AIDS and symptomatic relief in palliative care. 

Part Three is the most extensively modified in the second edition. In the early 1990s asthma was the only disease that was being treated systematically with aerosols. Throughout the decade the concept of treating diabetes with insulin aerosols, cystic fibrosis by gene transfection, and infectious diseases with antimicrobials gained ground. Many of these approaches have yet to be commercial or therapeutic success stories, but by the time this book is in print they may be available to the clinician. Consequently, sections on these topics have been added. 

A number of antibiotics have been used as aerosol therapies. Examples include beta lactam agents, polymycin antimicrobials, neomycin, gentamicin, and tobramycin. Many of the early efforts were reported as case studies, and observations and data regarding safety and efficacy were lacking. Controlled clinical trials were not conducted until the middle of the 1980s. More recent evaluations have focused on the role of inhaled tobramycin used as suppressive therapy for cystic fibrosis patients colonized with Pseudomonas aeruginosa. 

The search for useful inhaled antibiotics has been driven, in part, by a concern about the adequacy of systemic antimicrobial therapy for respiratory infections. Some agents, including aminoglycoside antibiotics, exhibit limited penetration into respiratory tract secretions. In fact, aminoglycosides may achieve sputum concentrations that are 12% of related serum concentrations. In addition, cystic fibrosis patients are often colonized with mucoid strains of Pseudomonas aeruginosa. This phenotype is associated with a further reduction in penetration of antibiotics. 

The potential benefit of aerosolized antibiotic therapy is dependent on three factors characteristics of the disease, aerosol delivery system, and properties of the antimicrobial agent [5]. Diseases that are likely to respond better cause infection in the airway without significant parenchymal or systemic involvement (e.g., cystic fibrosis). There is a significant need for research and scientific advances in the area of aerosol delivery of these therapies. Delivery systems that produce reliable, consistent, and reproducible aerosols are essential. Formulation of drug products requires attention to integrity, stability, tolerability, and overall suitability for aerosolization. 

Some progress has been made in developing alternative devices for the delivery of inhaled antimicrobial therapies. Colistin has been formulated in a dry powder inhaler and evaluated in healthy individuals and patients with cystic fibrosis [40]. Peak semm concentrations of colistin were 2.5-5 times higher when 25 mg of colistin sulfate dry powder was inhaled compared to 160 mg of colistin sulfomethate delivered by nebulization. Some patients experienced a decrease in pulmonary function and severe cough with the dry powder however, the investigators felt that this may be improved with a reduction in dose. 

Initial experiences with aerosolized antimicrobial therapies appeared in the literature more than 50 years ago. Until the early 1990s, the quality of the evidence supporting this strategy in the management of lung infections was poor. Recently, results from well-controlled clinical trials have established a role for inhaled antibiotics, particularly aminoglycosides, as suppressive therapy for patients with cystic fibrosis. Cyclic therapy with inhaled tobramycin reduces the frequency of pulmonary exacerbations and improves lung function. 

O Riordan TG. Inhaled antimicrobial therapy from cystic fibrosis to the flu. Respir Care 45(7) 836-845, 2000. 

Bosso JA, Walker KB. Lack of correlation between objective indicators and clinical-response scores during antimicrobial therapy for acute pulmonary exacerbations of cystic fibrosis. Clin Pharm 1988 7 897-901. 

Beringer PM. New approaches to optimizing antimicrobial therapy in patients with cystic fibrosis. Curr Opin Pulm Med 1999 5 371-377. 

Schaefer, H.G., Stass, H., Wedgwood, J., Hampel, B., Fischer, C., Kuhlmann, J., and Schaad, U.B. Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients. Antimicrobial Agents and Chemotherapy 1996 40 29-34. 

Bronchial asthma has been described in a mother who had opened capsules of pancreatic extract, which had been prescribed for her children suffering from cystic fibrosis (Sakula 1977). Piperazine is an anthelmintic drug. Single cases of angioedema, urticaria, exanthema, and erythema multiforme have been reported in Sweden. Suppositories and ointments used for the anal region can cause allergic contact dermatitis. Procaine, benzocaine, cinchocaine, and antimicrobial agents are the most common offenders. We have seen two cases of purpura and one case of urticaria caused by such suppositories. 

Many papers showed that NHC-silver(I) could be effective broad-spectrum antimicrobials. NHC-Ag compounds were used in in vivo studies to treat multidrug-resistant pulmonary infections found in cystic fibrosis patients, and in vitro and in vivo studies on several strains of cancerous cells. ... 

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