The long-term safety of chronic azithromycin use in patients with cystic fibrosis regarding the condition of the kidney, liver and heart

Background: Azithromycin is a widely used macrolide antibiotic in cystic fibrosis (CF), but little is known about the safety of long-term use. Reported side effects only apply to short-term use. The aim of this study is to investigate possible azithromycin-induced toxicity of the kidney, liver and heart during chronic azithromycin therapy and whether long-term use can be considered safe regarding the condition of these organs. Methods: CF patients from two medical centers in the Netherlands were included in this cohort study. Data were retrospectively extracted from January 1, 2008 to December 31, 2015 from hospital electronic patient files and anonymously transferred into the database. Index group participants used azithromycin for at least three uninterrupted years, whereas control group participants did not use azithromycin for at least three uninterrupted years. To reflect renal function, the estimated glomerular filtration rate (eGFR) was used, calculated with the MDRD Equation. To monitor hepatic function, the liver function parameters alanine amino-transferase (ALAT), aspartate amino-transferase (ASAT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and total bilirubin (TB) were used. The QTcinterval was used to determine the condition of the heart. The parameters to reflect renal and hepatic function were analysed with Linear Mixed Models analysis. For the QTc-interval was determined whether population means of index and control group were equal. Results: A total of 91 adult patients, 72 index patients and 19 patients in the control group, were included in the study. The health status of index patients was worse than the condition of patients in the control group, since presence of CF-related diabetes (CFRD) and population means of FEV1 and BMI differed between groups (P=0.001 for CFRD; P=0.002 for FEV1; P=0.027 for BMI). Decline in eGFR over time for the index group did not differ from the control group (P=0.763). During the whole study period the eGFR was higher for the index group (P=0.001). For the liver function parameters there was no difference in course over time between index and control group (P=0.587 for ALAT; P=0.851 for ASAT; P=0.646 for GGT; P=0.209 for ALP; P=0.268 for TB). During the whole study period the GGT was higher for the index group (P=0.005). There was no difference between population means regarding the QTc-interval (P=0.229) nor was this influenced by gender (P=0.660 for males; P=0.190 for females). Conclusion: Chronic azithromycin therapy can be considered safe regarding the risk for kidney, liver and heart. However, it cannot be ruled out that that the elevated GGT in the index group is due to azithromycininduced toxicity from use before the study period. Further research should focus on this possible azithromycin-induced liver toxicity.