The Weight of Evidence From Electrophysiology, Observational, and Cardiovascular End Point Studies Demonstrates the Safety of Azithromycin.

Increased use of azithromycin (AZ) in treating infections associated with coronavirus disease 2019 (COVID-19) and reports of increased incidence of prolonged corrected QT (QTc) interval associated with AZ used with hydroxychloroquine prompted us to review the latest evidence in the literature, present additional analyses of human cardiovascular (CV) electrophysiology studies, and to describe sequential steps in research and development that were undertaken to characterize the benefit-risk profile of AZ. Combined QTc findings from electrocardiograms taken during oral and i.v. pharmacokinetic-pharmacodynamic studies of AZ suggest that clinically meaningful QTc prolongation is unlikely. Findings from several observational studies were heterogeneous and not as consistent as results from at least two large randomized controlled trials (RCTs). The QTc findings presented and observational data from studies with large numbers of events are not consistent with either a proarrhythmic action of AZ or an increase in frequency of CV deaths. Well-powered RCTs do not suggest a presence of increased risk of CV or sudden cardiac death after short-term or protracted periods of AZ usage, even in patients at higher risk from pre-existing coronary disease.

A paradigm shift in drug development for treatment of rare multidrug-resistant gram-negative pathogens.

Multidrug-resistant (MDR) gram-negative pathogens pose a major threat to patients worldwide. Although the organisms remain relatively uncommon overall, their incidence is steadily increasing with associated increases in mortality and pharmacoeconomic impact. As evidenced by the dearth of new products in the pipeline or in clinical use, the conventional paradigm for the development of drugs against such pathogens is generally ineffectual. We advocate the need for a shift in the current paradigm and propose innovative development programs that involve implementation of a graduated approval process. The initial phase of the proposed regulatory paradigm includes early approval of a new drug based on a robust nonrandomized study, buttressed by data from concurrent controls and a pharmacokinetic-pharmacodynamic package generated from nonclinical studies. The postapproval commitment phase will include a randomized controlled trial, when disease prevalence permits, as well as continued assessment of risks and benefits under "real world" settings.

The effect of azithromycin on ivermectin pharmacokinetics--a population pharmacokinetic model analysis.

BACKGROUND: A recent drug interaction study reported that when azithromycin was administered with the combination of ivermectin and albendazole, there were modest increases in ivermectin pharmacokinetic parameters. Data from this study were reanalyzed to further explore this observation. A compartmental model was developed and 1,000 interaction studies were simulated to explore extreme high ivermectin values that might occur. METHODS AND FINDINGS: A two-compartment pharmacokinetic model with first-order elimination and absorption was developed. The chosen final model had 7 fixed-effect parameters and 8 random-effect parameters. Because some of the modeling parameters and their variances were not distributed normally, a second mixture model was developed to further explore these data. The mixture model had two additional fixed parameters and identified two populations, A (55% of subjects), where there was no change in bioavailability, and B (45% of subjects), where ivermectin bioavailability was increased 37%. Simulations of the data using both models were similar, and showed that the highest ivermectin concentrations fell in the range of 115-201 ng/mL. CONCLUSIONS: This is the first pharmacokinetic model of ivermectin. It demonstrates the utility of two modeling approaches to explore drug interactions, especially where there may be population heterogeneity. The mechanism for the interaction was identified (an increase in bioavailability in one subpopulation). Simulations show that the maximum ivermectin exposures that might be observed during co-administration with azithromycin are below those previously shown to be safe and well tolerated. These analyses support further study of co-administration of azithromycin with the widely used agents ivermectin and albendazole, under field conditions in disease control programs.

Pharmacokinetics of azithromycin and the combination of ivermectin and albendazole when administered alone and concurrently in healthy volunteers.

Azithromycin is a critical component of an integrated disease elimination program against trachoma. This study was conducted to evaluate whether azithromycin has a pharmacokinetic interaction with the combination of ivermectin and albendazole. Eighteen healthy volunteers were administered single doses of azithromycin, ivermectin/albendazole, and the combination of the three agents in random, crossover fashion. To assess the presence of interactions, test (combination) and reference (single dose) data were compared using an estimation approach. Compared with reference phases, the geometric mean values for the combination arm's azithromycin AUC(0-t) and C(max) were increased approximately 13% and 20%, respectively, albendazole AUC(0-t) decreased by approximately 3% and C(max) increased approximately 3%, and ivermectin AUC(0-t) and C(max) were increased 31% and 27%, respectively. Albendazole sulfoxide AUC(0-t) and C(max) were decreased approximately 16% and 14%, respectively. All treatments were well tolerated. The interactions for azithromycin and albendazole were minimal although the increase in ivermectin exposure requires further study.

Comparative efficacies and tolerabilities of intravenous azithromycin plus ceftriaxone and intravenous levofloxacin with step-down oral therapy for hospitalized patients with moderate to severe community-acquired pneumonia.

OBJECTIVE: To compare the efficacy and tolerability of ceftriaxone plus azithromycin with those of levofloxacin in the treatment of hospitalized patients with moderate to severe community-acquired pneumonia (CAP). DESIGN: Randomized, open-label multicenter trial with 1 : 1 treatment allocation in an inpatient setting. PATIENTS: 212 male or female inpatients with a clinical diagnosis of CAP were included in the study. In each treatment group >50% of patients had a pneumonia severity index of IV or V. INTERVENTIONS: Open-label treatment with either intravenous (IV) ceftriaxone 1g and IV azithromycin 500 mg daily or IV levofloxacin 500 mg daily. Patients who improved clinically were switched to oral follow-on therapy with either azithromycin 500 mg/day or levofloxacin 500 mg/day. At the clinician's discretion, oral cefuroxime axetil was added to the treatment regimen of patients who received oral azithromycin if a macrolide resistant pneumococcal isolate was documented. RESULTS: Overall, both study treatments were well tolerated. Favorable clinical outcomes in clinically evaluable patients were demonstrated in 91.5% of patients treated with ceftriaxone plus azithromycin and 89.3% (95% CI -7.1%, 11.4%) of patients treated with levofloxacin at the end of therapy visit and in 89.2% and 85.1% (95% CI -6.7%, 14.8%) patients, respectively, at the end of study visit. Bacteriological eradication rates for both treatments were equivalent with the exception of Streptococcus pneumoniae; 44% of isolates were eradicated with levofloxacin compared with 100% of isolates with ceftriaxone plus azithromycin. CONCLUSIONS: As acknowledged by international CAP treatment guidelines, the combination of a third-generation cephalosporin and a macrolide is at least as efficacious as monotherapy with a fluoroquinolone with enhanced anti-pneumococcal activity, for hospitalized patients with moderate to severe CAP. Combined medication with a macrolide and third-generation cephalosporin may be preferred over fluoroquinolones as first-line therapy of hospitalized patients with CAP to minimize the development of multiresistant nosocomial Gram-negative bacilli.

The possibility of eliminating blinding trachoma.

Global elimination of blinding trachoma, the world's leading preventable cause of blindness, now seems possible. The disease, which persists most severely in the poorest parts of Africa and Asia, is already eliminated in North America and Europe. On a scientific basis, the case for elimination was outlined at a WHO global scientific meeting in 1996. To facilitate action, WHO founded the Alliance for Global Elimination of Trachoma by 2020 (GET 2020) in 1997. In 1998 a World Health Assembly resolution called for member states to take steps to eliminate blinding trachoma by 2020 using the WHO recommended SAFE strategy (surgery of late stage disease, antibiotics for acute infection, and improved facial hygiene and environmental change-ie, improved access to water and sanitation). These developments contributed to the decision by Pfizer Inc to donate azithromycin in support of national programmes implementing SAFE and, with the Edna McConnell Clark Foundation, to found the International Trachoma Initiative as a charity dedicated to the elimination of blinding trachoma by 2020. Reports of the early programme scope and impact are encouraging. In ten national programmes currently underway (constituting about 50% of the global burden) more than 55,000 lid surgeries have halted further corneal damage and prevented blindness, and more than 6 million treatments with azithromycin have been given with reductions in acute infections of around 50% in children. Morocco, one of the first countries to implement SAFE with azithromycin, has achieved remarkable results and expects to eliminate blinding trachoma by 2005. If political will and public-health support can be mobilised, the goal of eliminating this cause of blindness can become a reality by 2020.