Antibiotic Therapy of Pulmonary Infections In Cystic Fibrosis
Dotage Schedules and Duration of Tteatment
It is widely agreed that antibiotic therapy is beneficial in the treatment of exacerbations of pulmonary infections in patients with cystic fibrosis (CF). Frequent antibiotic treatments have been shown to increase patient survival. Randomized, double-blind, crossover trials, which have shown the benefit of antibiotic therapy in acute exacerbations in patients with chronic obstructive pulmonary disease, have usually been considered unethical in CF. Difficulties in eradicating the colonizing microorganism from the lower respiratory tract have led to interest being focused on the dosages of antibiotics or special characteristics of the bacteria involved, but little attention has been devoted to the characteristics of the internal environment of the bronchi in the patients.
General Views on Dosage
Most studies on duration of therapy have recommended 2 weeks of treatment, and long-term prophylactic use of antibiotics is today seldom advocated. One reason to avoid long-term use of antibiotics in CF patients is the difficulty of obtaining adequate serum concentrations compared to those in healthy individuals or patients with other diseases. This problem, including enhanced clearance, has been shown to occur not only with antibiotics, but also with other drugs. The increased renal clearance in CF is attributed to an increased glomerular filtration rate and a disturbed tubular function. The cause of the increased nonrenal clearance is probably multifactorial. A changed distribution volume, related to a decreased lean body mass, and induction of microsomal enzymes in the liver, kidney, and lung—suggested to be the result of long-term pancreatic enzyme supplementation—have been proposed to account for the rapid clearance. The different explanations and conflicting results obtained in different studies might be related to the severity of the disease. Essential fatty acids are important constituents of membranes. Patients with CF develop an essential fatty acid deficiency, which might be related to the basic defect* and not secondary to malabsorption.- This deficiency may influence the clearance of drugs through several membranes in the body. further
Antibiotics are given to treat infection in the lower respiratory tract. Difficulties in obtaining adequate concentrations in the bronchial secretion, ie, concentrations exceeding the minimal inhibitory concentration (MIC) values of the bacteria, might be one of many possible explanations for failure to achieve more than temporary eradication of bacteria. The factors determining the penetration of antibiotics into the bronchial lumen are largely unknown. Sputum levels are usually low; the need to obtain sputum concentrations as high as possible means trying to achieve high antibiotic serum levels with minimal toxic side effects. When aminoglycosides are used, the postantibiotic effect and the area under the curve are probably more important than the peak value, while for p-lactams the time of exposure to concentrations above the MIC values is probably the most important factor for efficacy. By using a combination of a (3-lactam and an aminoglycoside, a synergistic effect is obtained. Attacking the bacteria with 2 different kinds of antibiotics may further reduce the risk of development of resistance. The principle of antibiotic treatment should therefore be high-dosage combined therapy for short periods during exacerbations, irrespective of whether these are primarily of viral or bacterial origin. If the time of treatment is limited, fewer pure cultures and resistant strains will develop and superinfection with fungi is reduced.