ECFS 2020 - Optimizing pharmaceutical care in cystic fibrosis

48    www.ecfs.eu OPTIMIZING PHARMACEUTICAL CARE IN CYSTIC FIBROSIS PK AND PD TO GUIDE ANTIBACTERIAL THERAPY IN CF CHAPTER 3 increase the degree of ionization of basic drugs (e.g. aminoglycosides) and their renal CL. However the lower degree of ionization in acidic urine could favor tubular reabsorp- tion of weakly acidic drugs (e.g. beta-lac- tams), reducing CL. CFTR also acts as an ABC-transporter for anions other than Cl - . The CFTR defect in CF patients implies, in theory, that bidirec- tional transport of organic anions could be reduced; this would justify the increased renal CL, which is often observed for some beta-lactams [18]. The two contrasting mechanisms described may partially explain why renal CL does not significantly differ between CF and healthy subjects. Some drugs, such as beta-lactams can fail due to augmented renal clearance (CL>130-160 mL/min/1.73m 2 , according to different definitions) [19]. This should be considered in when treating CF patients with severe infections. 3 Using PK/PD parameters to optimize antibiotic therapy In CF, the airways often become the site of chronic polymicrobial infection and inflam- mation. Antibiotics are widely prescribed to eradicate pathogens or control acute respi- ratory exacerbations [20] and are adminis- tered repeatedly, with prolonged cycles. This practice has substantially contributed to increased life expectancy [21]. However, it has also been observed that the diverse microbiota observed in younger patients narrows over lifetime, with establishment of specialized communities of pathogens associated with poor pulmonary function relationship between possibly increased enzyme activity, mediated by cytochromes CY1A2 and CYP2C8, and CF disease (severity, genotype) has not yet been defined, with only divergent evidence from small studies available. 2.4. Kidney changes In the kidney, CFTR is highly expressed in the apical membrane of all segments of the nephron, where it mediates the secretion of Cl - in the distal tubule [14]. CFTR is also expressed in the main cells of the collecting duct, and modulates the activity of other ion channels, in particular reducing ENaC activity. Changes in cell membrane compo- sition and tubular transport characteristics seem to be the basis of increased Na + reabsorption in the proximal tubule in CF patients. These changes appear to reduce Na + delivery to the distal convoluted tubule and to increase glomerular filtrate (GFR) through a feedback tubuloglomerular mech- anism or through the activation of the atrial natriuretic peptide secondary to hyper- volemia [16]. Glomerulomegaly, glomerular hyperfiltration and abnormalities in renal tubular function, which precede microal- buminuria and the following nephropathy, have been described in adults with CF, in association with disease severity. However, the supporting studies do not include a control group, are based on historical controls, or use non-comparable equations for the estimation of GFR. The mecha- nisms involved in renal drug elimination are glomerular filtration, active secretion and tubular reabsorption. It has been shown that people with CF have more acidic urine than healthy volunteers [17], which would