Oral Administration Of Azithromycin Research Articles

Lactoferrin Ameliorates Azithromycin-induced Cardiac Injury: Insight into Oxidative Stress/TLR4 /NF-κB Pathway

Introduction: Azithromycin, a widely used antibacterial agent, is also considered the cornerstone of the management protocols for COVID-19 infection, particularly in Egypt, due to its antiviral impact and preventive effects against secondary bacterial infections. However, even at pharmacological doses, azithromycin develops rapid cardiac toxicity. Objectives: Our study here aims at investigating the cardioprotective potentials of lactoferrin, a natural compound used primarily for boosting intestinal iron absorption, to counteract azithromycin-induced cardiac toxicity in experimental rats when administered concurrently. Methods: Male Sprague Dawley rats received either lactoferrin (200 mg/kg/day, orally) or saline for 10 days. Induction of cardiac toxicity was initiated on the 6th day via oral administration of azithromycin (20mg/kg/day, orally) for 5 successive days, concurrently with either lactoferrin or vehicle. Cardiac injuries were confirmed via Electrocardiogram (ECG) recording, assessment of cardiac function biomarkers, assessment of cardiac expression of nuclear factor erythroid 2–related factor 2 (Nrf2), interleukin-1β (IL-1β) and IL-10, measurement of cardiac oxidant/antioxidant balance, immunohistochemical staining against toll-like receptor-4 (TLR4), and nuclear factor-κB (NF-κB), and histopathological examination of HE-stained cardiac specimens. Results: Administration of azithromycin denoted a significant cardiac tissue injury as demonstrated by upregulated serum levels of cardiac biomarkers, namely total creatine Kinase (CK), Creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and Alkaline phosphatase (ALP). Furthermore, it upregulated cardiac content of malondialdehyde (MDA) and nitric oxide (NO) and cardiac inflammatory markers, such as TLR4, NF-κB, and IL-1β. Similarly, azithromycin-downregulated reduced glutathione (GSH) cardiac content and the anti-inflammatory protective indicators, IL-10 and Nrf2. Additionally, azithromycin-induced cardiotoxicity was evinced by ECG pattern and histopathologic deterioration. Oral Lactoferrin showed cardioprotective potentials and counteracted the azithromycin-induced cardiac toxicity, downregulating cardiac biomarkers. Moreover, it restored cardiac oxidant/antioxidant balance, decreased cardiac TLR4, NF-κB, and IL-1β expression, and increased IL-10 and Nrf2 expression. Lactoferrin Cardioprotective potentials were also evinced by enhanced ECG pattern and histopathological examination. Conclusion: Finally, we support the use of lactoferrin with azithromycin intake that induced cardiac toxicity.

Abstract 1227: Identification of the molecular target of azithromycin as an autophagy inhibitor and its potential application in cancer therapeutics

Abstract Autophagy is a self-digestive cellular mechanism that enables survival under nutrient depleted conditions. In normal cells, autophagy has been known to prevent tumorigenesis by removal of genotoxicity-causing mitochondria, as well as transformed cells. In contrast, once cancer has been established, autophagy appears to play a cytoprotective role to adapt to the insufficiently vascularized hypoxic and low nutrient environment; and also works for metastasis and therapeutic resistance. Therefore, autophagic inhibitors could be suitable candidates for cancer therapeutics. However, the only two autophagic inhibitors clinically available at present are chloroquine (CQ) and hydroxychloroquine (HCQ). We previously reported that azithromycin (AZM), a macrolide antibiotic, has an inhibitory effect on autophagy and that combined administration of AZM with various anti-cancer drugs, such as a tyrosine kinase inhibitor and a proteasomal inhibitor, appears to enhance the anti-cancer effect. With an aim to explore the clinical application of AZM for cancer therapy, we attempted to identify the molecular target of AZM for autophagy inhibition. High throughput affinity purification using AZM-conjugated magnetic nano-beads was used to identify several candidates for the AZM-binding protein involved in autophagy inhibition from human NSCLC-derived A549 cell lysates. Knockdown of one of the candidate genes resulted in a prominent accumulation of autophagosomes and lysosomes, leading to autophagy inhibition. Fluorescence microscopic observation of A549 cells expressing GFP-LC3 and LAMP1-mCherry markers suggested that AZM suppressed the fusion between autophagosomes and lysosomes. Comparison of autophagy inhibitory capacity using the GFP-LC3/RFP-LC3ΔG fluorescent reporter system revealed an almost equivalent autophagic inhibition between AZM and HCQ but less cytotoxicity by itself at the same concentrations. Suppression of lysosomal acidification was not observed upon AZM administration as same as in the case of HCQ administration. However, unlike HCQ, AZM did not increase the levels of HIF-1α and phospho-ERK1/2. This indicates the existence of different autophagy inhibitory mechanisms for AZM and HCQ. In the A549 murine xenograft model, daily oral administration of AZM (100 μg/g/day) significantly suppressed tumor cell growth. These results from the present study encourage the use of AZM as an autophagy inhibitor for cancer therapy. Citation Format: Naoharu Takano, Yumiko Yamada, Mayumi Tokuhisa, Hirotsugu Hino, Masaki Hiramoto, Keisuke Miyazawa. Identification of the molecular target of azithromycin as an autophagy inhibitor and its potential application in cancer therapeutics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1227.

Antimicrobial prophylaxis in tonsillectomy: the efficacy of preoperative single-dose oral administration of azithromycin in preventing surgical site infection

Conclusion: The results indicate that oral administration of azithromycin (AZM) is equivalent to intravenous administration of cefazolin (CEZ) for preventing surgical site infection (SSI) in patients undergoing tonsillectomy, and should be used as cost-effective antimicrobial prophylaxis. Objective: Staphylococcus aureus, Streptococcus spp., and pharyngeal anaerobes have been described as major pathogens causing SSI in transpharyngeal operations such as tonsillectomy. The purpose of this study was to explore whether administration of AZM, an oral antimicrobial agent, might be equivalent to intravenous administration of a first-generation cefem antimicrobial agent for preventing SSI in patients undergoing tonsillectomy. Methods: Patients undergoing tonsillectomy were divided into an AZM-treated group and a CEZ-treated group, for intergroup comparison of responses. AZM was administered once orally, 2 days before the operation, whereas patients in the CEZ-treated group received CEZ intravenously 30 min before the operation, 4 h postoperatively, and then twice daily for 3 consecutive days beginning the day after the operation. Results: There were no significant intergroup differences in mean duration of hospitalization after the operation, incidence of postoperative hemorrhage, postoperative analgesic effect, or hematologic/blood biochemical findings. The incidence of postoperative fever was significantly lower in the AZM-treated group. Diarrhea occurred as an adverse drug reaction in the AZM-treated group, but no clinically significant adverse reactions were noted.

Azithromycin Inhibits Mucus Hypersecretion from Airway Epithelial Cells

To examine the in vivo effects of the 15-member macrolide, azithromycin (AZM), on mucus hypersecretion, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal instillation of ovalbumin (OVA) in OVA-sensitized rats, or by intranasal lipopolysaccharides (LPS) instillation. Oral administration of AZM (5–10 mg/kg) or clarithromycin (CAM, 5–10 mg/kg) significantly inhibited OVA- and LPS-induced mucus production, whereas josamycin (JM) or ampicillin (ABPC) showed no effect. In vitro effects of AZM on airway epithelial cells were examined using NCI-H292 cells and human nasal epithelial cells cultured in air-liquid interface. Mucus secretion was evaluated by enzyme-linked immunosorbent assay using an anti-MUC5AC monoclonal antibody. AZM or CAM significantly inhibited tumor necrosis factor-α (TNF-α) (20 ng/mL)-induced MUC5AC secretion from NCI-H292 cells at 10−6–10−7 M, whereas JM or ABPC showed no effect. AZM significantly inhibited TNF-α (20 ng/mL)-induced MUC5AC secretion from human nasal epithelial cells at 10−4 M. MUC5AC mRNA expression was also significantly inhibited. These results indicate that the 15-member macrolide, AZM, exerts direct inhibitory effects on mucus secretion from airway epithelial cells and that it may be useful for the treatment of mucus hypersecretion caused by allergic inflammation and LPS stimulation.

Azithromycin novel drug delivery system for ocular application

Background:Azithromycin (AZT) is a macrolide antibiotic derived from and similar in structure to erythromycin. Oral administration of AZT is effective for the treatment of trachoma; however, topical formulations are difficult to develop because of the drug's hydrophobicity. The aim of this study is to formulate a novel topical ophthalmic delivery system of AZT.Materials and Methods:In the present study, ocular inserts of AZT are prepared using alginate, carbopol, and hydroxypropyl methylcellulose (HPMC) to solve the said formulation problem of drug and to facilitate ocular bioavailability. Ocular inserts were prepared by film casting method and the prepared films were subjected to investigations for their physical and mechanical properties, swelling behaviors, ex vivo bioadhesion, and in vitro drug release. Ocular irritation of the developed formulation was also checked by hen's egg chorioallantoic membrane test for ocular irritation potential.Results:The physicochemical, bioadhesive, and swelling properties of films were found to vary significantly depending on the type of polymers used and their combinations. The alginate films exhibited greater bioadhesion and showed higher tensile strength and elasticity than the carbopol films. HPMC addition to the films significantly affected the properties of ocular inserts. Carbopol:HPMC (30:70)-based ocular inserts sustained drug release for longest span of 6 h. The release profile of AZT showed that drug release was by both diffusion and swelling. The formulation was found to be practically nonirritant in ocular irritation studies.Conclusion:AZT can therefore be developed as an ocular insert delivery system for the treatment of ocular surface infections.

Effects of Irrigation With an Antiseptic and Oral Administration of Azithromycin on Bacteremia Caused by Scaling and Root Planing

Transient bacteremia frequently occur secondary to several periodontal procedures. The purpose of the present study is to investigate the effects of irrigation with an essential oil-containing antiseptic (EO) and oral administration of azithromycin (AZM) on bacteremia caused by scaling and root planing (SRP). Thirty patients with chronic periodontitis were randomly assigned to three groups (control, EO, and AZM). The EO group received quadrant subgingival irrigation with EO, and mouthrinsing was continued at home for 1 week. Oral administration of AZM was started 3 days before SRP in the AZM group. No adjunctive treatment was performed before SRP in the control group. Peripheral blood and subgingival plaque were collected at baseline and after 1 week. The second blood sample was taken 6 minutes after the initiation of quadrant SRP. The blood samples were cultured and analyzed for bacteremia. Quantitative analysis of periodontopathic bacteria in the sulcus was performed using the polymerase chain reaction Invader method. Bacteremia incidence rates were 90%, 70%, and 20% for the control, EO, and AZM groups, respectively. Significant reduction of the incidence of bacteremia was shown in the AZM group only (P <0.01). Subgingival bacterial counts significantly decreased in both the EO and AZM groups (P <0.01). Quadrant SRP frequently induced bacteremia. Although AZM was effective in reducing bacteremia incidence, EO showed less effectiveness.

Development of a Topical Polymeric Mucoadhesive Ocular Delivery System for Azithromycin

Azithromycin is an azalide class of antibiotic with pharmacodynamics that have made it a valuable agent in the treatment of soft tissue infections. In ophthalmology, oral administration of azithromycin has been proven effective for the treatment of trachoma. However, topical formulations of azithromycin to treat ocular surface infections have been challenging to develop because of the drug's hydrophobicity and instability in aqueous solutions at pH levels that are comfortable in the eye. The design of a polycarbophil polymer-based delivery system for a topical formulation of azithromycin was evaluated for its ability to provide drug stability, comfort, and increased retention of the formulation in the eye. Formulations of 0.5% and 1.0% azithromycin were created in polycarbophil, a lightly cross-linked polyacrylic acid polymer that was adjusted to a viscosity, pH, and osmolality that are suitable for dispensing in the eye. The polycarbophil-based ophthalmic delivery system, DuraSite (InSite Vision, Alameda, CA), helps solubilize azithromycin and retard its degradation in aqueous solution. The formulation was stable at room temperature as well as 5 degrees C. Upon administration of a single drop of 1% azithromycin in DuraSite ophthalmic solution in rabbits' eyes, tear concentrations of azithromycin ranged from 87 to 288 microg/g and high concentrations were sustained for over a 24-h period. Azithromycin can be developed as an eyedrop in an aqueous ocular delivery system for the treatment of ocular surface infections. The ocular delivery system, DuraSite solubilizes azithromycin at a high concentration in an aqueous solution and protects it from degradation during manufacture and storage. The development of azithromycin in this delivery system enhances the antibiotic's usefulness in ophthalmology for the topical treatment of ocular surface bacterial infections and lid margin diseases.

Effect of Jieze No.1 (洁泽 号) on cervicitis caused by ureaplasma urealyticum and on ureaplasma urealyticum in vitro

To observe the clinical therapeutic effect of Jieze No. 1 ( I ) on cervicitis caused by ureaplasma urealyticum and its inhibitory effect on ureaplasma urealyticum (Uu) in vitro. A total of 393 patients suffering from cervicitis induced by ureaplasma urealyticum without other complications were randomly assigned to 3 groups, the combined treatment group: 140 patients treated with Chinese herbs Jieze No.1 by vaginal lavage, 30 min each time, once a day for 10 consecutive days and oral administration of Azithromycin, 1.0 g once every 72 h for three times; Jieze group: 115 patients were treated with Jieze No.1 alone by vaginal lavage, 30 min each time, once a day for 10 consecutive days; and the Azithromycin group: 138 patients were treated with oral administration of Azithromycin, 1.0 g once in 72 h for three times. All the patients were treated for 1 therapeutic course and condom were used for contraception during the treatment course. The Uu patients were examined again after 21 days of treatment. The therapeutic effect on cervicitis was observed. The experimental study of Jieze No. 1 on the Uu strain separated from the secretion of the urogenital tract was also observed. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the Uu were investigated. The total effective rate of the combined group was 85.3%, showing a significant difference compared with the Jieze group (67.8%) and the Azithromycin group (60.3%, both P<0.01). There was no statistical significance between the latter two groups (P>0.05). The clearing rate of Uu in the combined group was 78.4%, that of the Jieze group was 60.9% and the Azithromycin group was 47.9%. The combined group also showed a significant difference in comparison with the other two groups (all P<0.01). Especially for the drug-resistant strain, the clearing rate of Uu reached 48.1% in the combined group, 42.1% in the Jieze group, and 16.1% in the Azithromycin group, respectively. The clearing rate of Uu for the drug-resistant strain in the former two groups had significant differences in comparison with the latter (P<0.01, P<0.05), while there was no significant difference between the former two (P>0.05). The range of MIC and MBC of Jieze No. 1 to the drug-resistant strain of Uu was 15.62-250.00 mg/mL. To the non-drug-resistant MIC and MBC strain, it was 15.62-125.00 mg/mL. For the drug-resistant strain, MIC(50) was < or = 31.25 mg/mL, MBC(50) was < or = 62.50 mg/mL, MIC(90) was < or = 125.00 mg/mL and MBC(90) was 250.00 mg/mL. For the non-drug-resistant strain, MIC(50) was < or = 31.25 mg/mL, MBC50 was< or = 62.50 mg/mL, MIC(90) was< or = 62.50 mg/mL and MBC(90) was < or = 125.00 mg/mL. Jieze No.1 combined with Azithromycin can effectively treat cervicitis caused by Uu. The laboratory study confirms that Jieze No. 1 has an inhibitory effect on ureaplasma urealyticum strain. It has a remarkably effective therapeutic effects on drug-resistant strains, which is worthy of further research.

Efficacy of azithromycin in the treatment of guinea pigs infected with Legionella pneumophila by aerosol

Azithromycin and erythromycin were compared for efficacy in guinea pigs infected with an aerosol containing Legionella pneumophila. When administered intraperitoneally, azithromycin was very effective in the treatment of experimental Legionnaires' disease. Even at the low dose of 3.6 mg/kg/day it gave 100% survival and eliminated lung infectivity two days following infection. In contrast, erythromycin at a much higher dose (96 mg/kg/day) gave only 83.3% survival and failed to eliminate organisms from the lung six days after infection. The histological findings confirmed the superiority of azithromycin. A single dose of azithromycin given intraperitoneally at 3.6 or 14.4 mg/kg gave survival rates of 83.3 and 100%, respectively. Azithromycin was also found to be superior to erythromycin in eliminating lung infectivity and reducing mortality, when administered orally. However, oral administration of azithromycin was not as effective as intraperitoneal when assessed by lung histopathology, although it was still superior to oral erythromycin treatment.