| Azithromycin, a second generation broad spectrum macrolide, can achieve high tissue concentrations, good adherence for medication and has unique pharmacokinetic properties. It is one of the most widely used antibacterials in the world and has received increasing attention in recent years because of its additional effects on immunoregulation and chronic human diseases. Azithromycin shares the similar mechanism of action as other macrolide antibiotics, but accumulates more effectively in cells, particularly phagocytes, thus being delivered in high concentrations to sites of infection. Azithromycin also inhibits bacterial quorum-sensing and reduces formation of biofilm and mucus production, which extend its range of antibacterial. As a result, it is also active against gram-negative bacteria such as Haemophilus influenzae and Helicobacter pylori (HP). In addition, azithromycin has rapid plasma clearance and high volume of distribution as reflected in extensive tissue distribution, leading to high concentration in lung, bronchus mucous membrane and gastric tissues. Compared with older generation macrolides, azithromycin has a longer half-life, allowing for once a day or even single dose treatment and ensuring patients receive their regular medications.Azithromycin is well tolerated and has a very good record of safety, has always been considered one of the safest antimicrobial agents for many years. The U.S. Food and Drug Administration (FDA) warned the public in March 2013 that azithromycin can increase the risk of cardiovascular mortality. However, subsequent studies pointed out that these effect on cardiovascular mortality was limited to patients with cardiovascular disease. Drug interactions (DI) are also important causes of adverse drug reactions (ADR). Though azithromycin exhibits few metabolic interactions with most other commonly used drugs, with its widely application, we should still pay attention to the existence of potential metabolic interference to certain drug with a narrow therapeutic range for preventing adverse events. As an antibiotic, azithromycin is most commonly used to treat respiratory infections. Additional immunoregulatory and anti-inflammatory effects facilitates its long-term use in chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis and non-cystic fibrosis bronchiectasis. Oral theophylline is aslo used for long-term control of COPD and asthma. Therefore, azithromycin in combination with theophylline for the treatment of respiratory diseases is very common. As we know, older macrolide antibiotics can increase the plasma levels of theophylline. Many researchers suggest that patients should not receive azithromycin and theophylline concomitantly to avoid adverse drug reactions. Accordingly, there is still a need for further research to assess whether azithromycin could affect the metabolism of theophylline.In addition to be used for treat respiratory diseases, azithromycin has attracted many researchers’ interest in the eradication of HP. Azithromycin is a potential attractive therapeutic agent for HP given its good in vitro activity against HP as well as its high concentrations in gastric tissue, and long biological half-life. However, results of eradication rates from the available published trials utilizing azithromycin are conflicting. Further research is needed to evaluate whether azithromycin based triple therapy could be better than the current triple therapy.According to the clinical applications of azithromycin, we conducted this research. First, we established an method for the simultaneous determination of plasma levels of theophylline (TP) and its main metabolite. Then we conducted a drug interaction study to evaluate the effect of azithromycin on the steady-state plasma levels of theophylline and its main metabolite in a Chinese population. This would provide the theoretical basis for the combined medication. Second, we collected randomized clinical tirals utilizing azithromycin based triple therapy and conducted a systematic review to evaluate the efficacy and safety of azithromycin based triple therapy for HP eradication. This would provide a basis for evidence-based practice.Objectives1. Quantitative determination:To determine the plasma levels of theophylline and its metabolite 1,3-dimethyluric acid (1,3-DMU) simultaneously and to provide an experimental basis for further clinical trial, a method of quantitative determination was established.2. Clinical trial:By comparing the difference of steady state plasma concentration of theophylline and 1,3-DMU in patients administered theophylline alone and in combination with azithromycin. The aim of this study was to determine whether azithromycin can effect theophylline metabolism.3. Systematic review:To evaluate the efficacy and safety of azithromycin based triple therapy versus clarithromycin based triple therapy for Helicobacter pylori eradication.Methods1. The HPLC analysis was performed on an Elite HypersilBDS C18 column (250 mmx4.6 mm,5μm) with a mobile phase consisting of acetonitrile and water (7:93). Column temperature:25℃, flow rate:1mL·min-1, detection wavelength: 280nm.2. In this non-blinded, auto-control study, outpatients with respiratory disease served as their own controls during the 2-week treatment phase. The subjects were co-administered oral doses of sustained release theophylline (100mg bid; 8:00 am,8:00 pm) and azithromycin (500mg qd; 8:00 pm) in the first week. Then patients received theophylline therapy alone with the same dose in the second week. Blood samples for the measurement of theophylline plasma concentrations were collected on Days 8 and 15 prior to dosing. Steady state plasma concentration of theophylline and 1,3-DMU in patients administered theophylline alone and in combination with azithromycin were measured by HPLC. The 1,3-DMU/theophylline ratio was viewed as a indicator of theophylline metabolic clearance. Data were analyzed using SPSS version 13.0 software and paired sample T test method was used.3. We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Biomedical Database, Wanfang database and CNKI for potentially relevant articles published prior to January 2015, with no lower date limit applied. The RCTs included in our study were assessed for methodological quality. All statistical analyses were conducted by using Review Manager 5.2.4.Results1. Quantitative determinationThe linear ranges of theophylline and 1,3-DMU were 0.20-10.00 (r=0.9998) and 0.05～2.00 (r=0.9996)μg·mL-1 , respectively. The intra and inter-assay precision for this analysis were less than 12.91%. The extraction recovery was 77.52%～79.22% for theophylline and 71.69%～74.02% for 1,3-DMU.2. The effect of azithromycin on theophylline metabolismFifty patients fulfilled the inclusion criteria and entered the clinical trial. Of these patients,10 were withdrawn from the study in the second stage, and 40 completed the the study in total but 5 of them didn’t obey the dosing regimen. Thus, 35 patients (20 males and 15 females) were involved in the analysis in final. The results showed that the average steady-state plasma concentration of theophylline was 3.45±1.30μg·mL-1 in the presence of azithromycin, slightly higher than that of using theophylline alone (3.25±1.06μg·mL-1) but the difference did not achieve statistical significance (P=0.225). The average steady-state plasma concentration of 1,3-DMU were 0.19±0.10μg·mL-1 and 0.18±0.10μg·mL-1 in patients with or without azithromycin, and the difference was not statistically significant (P=0.474). The average 1,3-DMU/TP ratio were 0.059±0.038 and 0.060±0.048 in patients with or without azithromycin, and no significant difference was found between groups (P=0.821).3. A systematic review of azithromycin based triple therapy for Helicobacter pylori eradicationNine studies involving 864 participants fulfilled the inclusion criteria and were selected for meta-analysis. Overall, clarithromycin based triple therapy resulted in a significantly higher HP eradication rate (82.1%) than azithromycin based triple therapy (68.9%), and the odds ratio (OR) was 0.43 (95%CI:0.31-0.60, P<0.00001). But azithromycin based triple therapy resulted in a significantly lower occurrence of side effects (20.5%) than clarithromycin based triple therapy (28.5%), the OR was 0.67 (95%CI:0.47-0.96, P=0.03). There was no significant difference between the two groups in terms of the incidence of diarrhea (OR=0.94,95%CI:0.41-2.18, P=0.89). But the incidence of taste disturbance in azithromycin based triple therapy group (1.7%) was significantly lower than the control group (9.7%), the OR was 0.18 (95%CI:0.06-0.60, P=0.005). Subgroup analysis:(1) Different courses of azithromycin. Long-course azithromycin based triple therapy resulted in a significantly lower HP eradication rate (66.4%) than the control group (80.9%), the OR was 0.43 (95%CI:0.30-0.61, P<0.00001). There was no significant difference in HP eradication rate between the short-course azithromycin based triple therapy (78.9%) and the control group (87.5%), the OR was 0.46 (95%CI:0.19-1.10, P=0.08). (2) Different regions. Azithromycin based triple therapy in Asia (Iran and China) resulted in similar HP eradication rate (81.3%) as compared to the control group (85.9%), the OR was 0.70 (95%CI:0.40-1.22, P=0.21). Azithromycin based triple therapy in Europe and America resulted in a significantly lower HP eradication rate (58.3%) as compared to the control group (79.5%), the OR was 0.33 (95%CI: 0.22-0.50, P<0.00001). (3) Different regimen. The HP eradication rate of azithromycin+amoxicillin subgroup (69.5%) was significantly lower than the control group (80.8%), the OR was 0.48 (95%CI:0.33-0.68, P<0.0001). The HP eradication rate of azithromycin+metronidazole subgroup (66.7%) was lower than the control group (87.6%), but the difference did not achieve statistical significance (OR=0.20, 95%CI:0.02-2.06, P=0.18).Conclusions1. The HPLC method used in our study is precise, rapid and easily operated and is suitable for simultaneous determination of human plasma levels of theophylline and 1,3-dimethyluric acid.2. Azithromycin has no significant effect on the steady-state plasma concentration of theophylline and its metabolic clearance. They can be used together with high security.3. Based on the current evidence available, azithromycin cannot take the place of clarithromycin in triple therapy for HP eradication but can be used as as a second-line antimicrobial agent. Azithromycin has a lower occurrence of side effects and better compliance than clarithromycin. In some regions, azithromycin based triple therapy was equally effective in eradication of HP compared with clarithromycin based triple therapy and this may be related to regional differences of Helicobacter pylori resistance to azithromycin. More high quality trials are required to validate the efficacy and safety of azithromycin in triple therapy for HP eradication. The results and conclusions will be updated with the emergence of new clinical evidence. |
PDF Full Text Request