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. ...

Three derivatives of oleandomycin in which the C"-4 hydroxyl moiety was replaced for the first time with a nitrogen functionality have been compared with erythromycin base and oleandomycin base. The minimum inhibitory concentrations of these derivatives for 90% of a group of clinical isolates of Staphylococcus aureus were one-half to one-fourth those of erythromycin. The minimum inhibitory concentrations of the experimental macrolides for 50% of a group of S. aureus isolates resistant to greater than 12.5 micrograms of erythromycin per ml ranged from 0.2 to 0.39 micrograms/ml. The activities of these experimental compounds were equivalent to the activities of erythromycin against Staphylococcus epidermidis, Bacteroides fragilis, and Haemophilus influenzae isolates. In general, erythromycin was more active against Streptococcus species. Each experimental macrolide was superior to erythromycin in inhibiting RNA-directed, cell-free polypeptide synthesis. The three experimental compounds were markedly more active than erythromycin base after oral administration to mice infected with S. aureus. The 50% protective doses of the experimental compounds ranged from 27.4 to 45.7 mg/kg; that of erythromycin was approximately 100 mg/kg.