The pharmacokinetic profiles of azithromycin given as a single-dose regimen (2.0-g extended-release microspheres) were characterized in serum and white blood cells (WBC) and compared with those of a 3-day regimen (a 500-mg immediate-release tablet once daily; total dose, 1.5 g) in an open-label, randomized, parallel-group study of 24 healthy adult subjects. Serial blood samples were collected up to 5 days after the start of dosing for both regimens. Safety assessments were conducted throughout the study. A single 2.0-g dose of azithromycin microspheres achieved significantly higher exposures in serum and WBC during the first 24 h after the start of dosing than a 3-day regimen: an approximately threefold higher area under the curve from time zero to 24 h postdose (AUC 0-24 ) and an approximately twofold higher mean peak concentration on day 1. The single-dose regimen provided total azithromycin exposures in serum and WBC similar to those of the 3-day regimen, as evidenced by the similar AUC 0-120 and trough azithromycin concentrations in serum and WBC (mononuclear leukocytes [MNL] and polymorphonuclear leukocytes [PMNL]). For both regimens, the average total azithromycin exposures in MNL and PMNL were approximately 300-and 600-fold higher than those in serum. Azithromycin concentrations in MNL and PMNL remained above 10 g/ml for at least 5 days after the start of dosing for both regimens. This "front-loading" of the dose on day 1 is safely achieved by the extended-release microsphere formulation, which maximizes the drug exposure at the time when the bacterial burden is likely to be highest.Azithromycin is an azalide, structurally related to the macrolide family of antibiotics. It acts by binding to the 50S ribosomal subunit of susceptible organisms, thereby interfering with protein synthesis. Azithromycin is approved worldwide as a broad-spectrum antibiotic to treat a variety of communityacquired infections. Azithromycin is distributed extensively to a variety of body tissues and fluids. Due to its dibasic structure, azithromycin is actively taken up by a wide variety of cells, including white blood cells (WBC) and fibroblasts, a pattern different from that of the classic macrolide agents (1, 12, 13). The unique pharmacokinetic (PK) properties of azithromycin make short-course therapy possible. For most adult indications, a total of 1.5 g of immediate-release (IR) azithromycin formulations (Zithromax; Pfizer) is administered in divided doses over a period of 3 or 5 days (500 mg once daily [QD] for 3 days, or 500 mg QD on day 1 and 250 mg QD on days 2 to 5) (Zithromax [azithromycin] package insert; Pfizer Inc., New York, NY). The highest approved single oral dose of an azithromycin IR formulation is 2.0 g for the treatment of gonococcal urethritis (Zithromax package insert). The most common adverse events (AEs) of azithromycin are gastrointestinal (GI) in nature and appear to be dose related. The actual use of the 2.0-g dose is limited due to the high incidence of GI AEs such as nausea (18%), diarrhea/loose stool...
This randomized, double-blind, noninferiority study was designed to demonstrate that a single 2.0-g oral dose of a novel microsphere formulation of azithromycin was at least as effective as 7 days of levofloxacin, 500 mg/day, in the treatment of adult patients with mild to moderate community-acquired pneumonia (Fine classes I, II, and III). In total, 427 subjects were randomly assigned to receive either a single 2.0-g dose of azithromycin microspheres (n ؍ 213) or a 7-day regimen of levofloxacin (n ؍ 214). At baseline, 219 of 423 (51.8%) treated subjects had at least one pathogen identified by culture, PCR, or serology. The primary end point was the clinical response (cure or failure) in the "clinical per protocol" population at test of cure (days 13 to 24). Clinical cure rates were 89.7% (156 of 174) for azithromycin microspheres and 93.7% (177 of 189) for levofloxacin (treatment difference, ؊4.0%; 95% confidence interval, ؊9.7%, 1.7%). Bacteriologic success at test of cure in the "bacteriologic per protocol" population was 90.7% (97 of 107) for azithromycin microspheres and 92.3% (120 of 130) for levofloxacin (treatment difference, ؊1.7%; 95% confidence interval, ؊8.8%, 5.5%). Both treatment regimens were well tolerated; the incidence of treatment-related adverse events was 19.9% and 12.3% for azithromycin and levofloxacin, respectively. A single 2.0-g dose of azithromycin microspheres was at least as effective as a 7-day course of levofloxacin in the treatment of mild to moderate community-acquired pneumonia in adult outpatients.
The extended-release microsphere formulation of azithromycin, AZSR, allows administration of an entire therapeutic course of azithromycin as a well-tolerated single 2.0 g dose. This formulation should be administered on an empty stomach and can be co-administered with antacids.
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