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.
In mid-January 2000, the reappearance of Japanese encephalitis (JE) virus activity in the Australasian region was first demonstrated by the isolation of JE virus from 3 sentinel pigs on Badu Island in the Torres Strait. Further evidence of JE virus activity was revealed through the isolation of JE virus from Culex gelidus mosquitoes collected on Badu Island and the detection of specific JE virus neutralizing antibodies in 3 pigs from Saint Pauls community on Moa Island. Nucleotide sequencing and phylogenetic analyses of the premembrane and envelope genes were performed which showed that both the pig and mosquito JE virus isolates (TS00 and TS4152, respectively) clustered in genotype I, along with northern Thai, Cambodian, and Korean isolates. All previous Australasian JE virus isolates belong to genotype II, along with Malaysian and Indonesian isolates. Therefore, for the first time, the appearance and transmission of a second genotype of JE virus in the Australasian region has been demonstrated.
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