Azithromycin, a novel azalide antibiotic, concentrated in human and mouse polymorphonuclear leukocytes (PMNs), murine peritoneal macrophages, and mouse and rat alveolar macrophages, attaining intracellular concentrations up to 226 times the external concentration in vitro. In murine peritoneal macrophages, azithromycin achieved concentration gradients (internal to external) up to 26 times higher than erythromycin. The cellular uptake of azithromycin was dependent on temperature, viability, and pH and was decreased by 2,4-dinitrophenol. Azithromycin did not decrease phagocyte-mediated bactericidal activity or affect PMN or macrophage oxidative burst activity (H202 release or Nitro Blue Tetrazolium reduction, respectively). Azithromycin remained in cells for several hours, even after extracellular drug was removed. However, its release was significantly enhanced by phagocytosis of Staphylococcus aureus (82 versus 23% by 1.5 h). In vivo, 0.05 ,ig of azithromycin was found in peritoneal fluids of mice 20 h after oral treatment with a dose of 50 mg/kg. Following caseinate-induced PMN infiltration, there was a sixfold increase in peritoneal cavity azithromycin to 0.32 ,ug, most of which was intracellular. Therefore, the uptake, transport, and later release of azithromycin by these cells demonstrate that phagocytes may deliver active drug to sites of infection.

The macrolide antibiotic azithromycin (CP-62,993; 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A; also designated Zagreb, Yugoslavia]) showed a significant improvement in potency against gram-negative organisms compared with erythromycin while retaining the classic erythromycin spectrum. It was up to four times more potent than erythromycin against Haemophilus influenzae and Neisseria gonorrhoeae and twofold more potent against Branhamella catarrhalis, Campylobacter species, and Legionella species. It had activity similar to that of erythromycin against Chiamydia spp. Azithromycin was significantly more potent versus many genera of the family Enterobaeteriaceae; its MIC for 90% of strains of Escherichia, Salmonella, Shigella, and Yersinia was s4 ,ug/ml, compared with 16 to 128 ,ug/ml for erythromycin. Azithromycin inhibited the majority of gram-positive organisms at sl gg/mI. It displayed cross-resistance to erythromycin-resistant Staphylococcus and Streptococcus isolates. It had moderate activity against Bacteroides fragilis and was comparable to erythromycin against other anaerobic species. Azithromycin also demonstrated improved bactericidal activity in comparison with erythromycin. The mechanism of action of azithromycin was similar to that of erythromycin since azithromycin competed effectively for [14C]erythromycin ribosomebinding sites.Erythromycin has been regarded for many years as possessing a good spectrum of activity and safety record for the treatment of respiratory, skin, and soft tissue infections in both adults and children. Recent developments have tended to reinforce the importance of this antibiotic, as erythromycin is now the primary or secondary therapeutic agent for four-prominent infections in humans: Legionnaires disease, Mycoplasma pneumonia, Campylobacter diarrhea, and chlamydial urethritis. However, the potential of erythromycin as a general-use oral antibiotic is limited by its modest potency against Haemophilus influenzae and Neisseria gonorrhoeae and by a low and erratic level in blood following oral administration. More recently, novel formulations or esters of erythromycin have been introduced to improve its pharmacokinetic properties. Each of these has incremental advantages, but none provides the kinetic improvements sufficient to completely incorporate H. influenzae and N. gonorrhoeae into the erythromycin spectrum.Our research in this area has been aimed at identifying novel macrolide antibiotics with in vitro potency and pharmacokinetic properties that would incorporate activity against H. influenzae into the macrolide spectrum and allow for total lower doses. This paper reports the microbiological and biochemical properties of azithromycin (CP-62,993; also designated [Pliva Pharmaceuticals, Zagreb, Yugoslavia]), which differs from erythromycin chemically by a methyl-substituted nitrogen in the macrolide ring (Fig. 1). This difference produces improvements in spectrum and potency compared with erythromycin.( MATERIALS AND METHODS Antibiotics, microorganisms, and chemicals. ...

A series of erythromycin A-derived semisynthetic antibiotics, featuring incorporation of a basic nitrogen atom into a ring expanded (15-membered) macrocyclic lactone, have been prepared and biologically evaluated. Semisynthetic modifications focused upon (1) varied substitution at the macrocyclic ring nitrogen and (2) epimerization or amine substitution at the C-4" hydroxyl site within the cladinose sugar. In general, the new azalides exhibit improved Gram-negative potency, expanding the spectrum of erythromycin A to fully include Haemophilus influenzae and Neisseria gonorrhoeae. Whencompared to erythromycin A, the azalides exhibit substantially increased half-life and area-under-the-curve values in all species studied. The overall in vitro/in vivo performance of TV-methyl, C-4" epimers 3a and 9; and C-4" amine ll identify these compounds as the most interesting erythromycin Asuperior agents. Compound3a has been advanced to clinical study. 1029Erythromycin A is a widely used antibiotic in oral outpatient therapy, including pediatrics. It is frequently the agent of choice for treatment of respiratory, cutaneous, Chlamydia, and Campylobacter infections. However, erythromycin A is not indicated for the treatment of Haemophilus influenzae except with co-administration of sulfonamides. Erythromycin A is also unstable at gastric pH, and is poorly absorbed with oral dosing.In our effort to expand the antimicrobial spectrum and to improve upon the pharmacokinetic properties of erythromycin A, the syntheses of erythromycin A-derived 15-membered aza-macrolides depicted in Schemes 1 and 2 were undertaken. Herein are presented the antibacterial profiles of the series, which features varied alkyl substitution at the 9a-aza site within the macrocyclic ring, and modifications at the C-4" site within the cladinose sugar. Additionally, for selected compounds, antiinfective activity against Staphylococcus aureus in mice, and pharmacokinetic profiles in several species are presented.

Utilizing PMO theory, pyracylene is described as a [12]annulene with an internal vinyl cross-link. As such, it should be an unusually good model for a planar [12]annulene. To examine such a hypothesis, the synthesis of pyracylene, 1,2-dibromopyracylene, and 1,2-diphenylpyracylene was achieved. The key step involved a polybenzylic bromination. After introduction of the first bromine, subsequent hydrogen atom removal involved predominantly, if not exclusively, the ¡3-hydrogen trans to that bromine. Iodide-promoted elimination of the thus formed dibromide introduced the crucial bridging double bonds. Polarographic reduction suggested the presence of an empty approximately nonbonding molecular orbital in agreement with the above model. Dramatic support arose from their nmr spectra which show the protons shifted to exceptionally high fields. These abnormal shifts are interpreted in terms of a paramagnetic ring current-in excellent accord with the proposed peripheral electronic model.

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