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.

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CP-65,207 is a new parenteral penem antibiotic with a broad spectrum that includes gram-positive, gram-negative, and anaerobic microorganisms, with MICs for 90% (MIC90s) of the majority of 1,101 clinical pathogens tested being '1 ,ig/ml. The compound was from 10-to 100-fold more active than cefoxitin and broad-spectrum cephalosporins against gram-positive bacteria and anaerobes. CP-65,207 was less active than imipenem for staphylococci, group A streptococci, and Enterococcus faecalis. Against members of the family Enterobacteriaceae, CP-65,207 was in general 100-fold more active than cefoxitin, 5-to 10-fold more active than broad-spectrum cephalosporins, and 2-fold more active than imipenem. Fresh clinical isolates that were resistant to broad-spectrum cephalosporins were highly susceptible to 207 and imipenem (MIC90,1 ,ug/ml). Isolates of Enterococcusfaecalis, Serratia marcescens, and anaerobic Peptococcus spp. had MIC9,s of 8, 2, and 3.12 ,ug/mI, respectively. CP-65,207 was not very active against methicillin-resistant staphylococci or Pseudomonas aeruginosa. Killing kinetics showed that against some strains CP-65,207 is rapidly bactericidal at concentrations well below those required to achieve a similar degree of killing with cefotaxime, ceftazidime, and ceftriaxone. CP-65,207 was only slightly susceptible to hydrolysis by type I cephalosporinases and TEM-1, SHV-1, and PSE-2 plasmid-encoded enzymes. It had the highest affinity for penicillin-binding proteins 2, 1A, 1B, and 3 in cell-free preparations of Escherichia coli W-7.Penems are synthetic beta-lactams that, as a class, possess a number of interesting properties which include a broad antibacterial spectrum and low susceptibility to hydrolysis by ,B-lactamases but, at the same time, are inactivated by renal dipeptidases found in the brush border of the kidney (20). A number of novel penems have been evaluated in the past decade; SCH-29482 and SCH-34343 (2, 10, 11) have rivaled carbapenems like imipenem in antibacterial activity, yet in clinical trials they were found to have undesirable side effects. The broad antibacterial spectrum of penems, however, has encouraged continued research in order to find clinically useful compounds. Two of these penems, FCE-22101 and SUN-5555, are in clinical trials (20). 207 ( Fig. 1) is a new parenteral penem that demonstrates high activity against gram-positive, gram-negative, and anaerobic bacteria that in some itistances is significantly imtproved over cefoxitin and the broad-spectrum cephalosporins. The current study characterizes the in vitro activity of CP-65,207 compared with those of both cephalosporins and imipenem.( Susceptibility studies. Antibiotic susceptibility studies were performed in microdilution trays containing 0.2 ml of unsupplemented Mueller-Hinton broth (MHB) per well with twofold dilutions of antibiotic (3). Inocula were grown overnight in MHB and diluted in broth to give a final inoculum of approximately 7.5 x 105 CFU/ml. Inoculated plates were incubated at 37°C in air for 18 h.

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6,6-dibromopenicillanate was followed by acid rearrangement to afford allyl 7,7-dibromocephalosporinate. Aldol condensation, followed by tin hydride reduction generated all four possible isomers (ll~13). The Scheme 3.

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Objective Recent American College of Rheumatology guidelines emphasise functional improvement as part of osteoarthritis (OA) management. We developed and evaluated a tool to promote provider and patient engagement in functional goal setting in OA care. Methods We developed the Functional Goal‐setting And Self‐management Tool (FAST‐OA) with clinician input and pilot tested it in two US outpatient clinics. Baseline and end‐of‐project surveys addressed attitudes toward incorporating function into care and tool evaluation. We analysed survey data descriptively. Results Nineteen providers and 49 patients completed surveys. At baseline, both groups endorsed the importance of functional assessment and goal setting. Providers perceived challenges to patients' ability to communicate about function. Both patients and providers highly valued the FAST‐OA to promote collaborative discussion and prioritising function. More than half of both groups agreed that they would recommend it to others. End‐of‐project results suggested changes in provider attitudes toward patients' ability to communicate functional progress. While participants valued the FAST‐OA, streamlining content may foster ongoing use. Conclusion This pilot study illustrates the potential of a function‐focused, patient‐facing tool to introduce self‐management goal‐setting strategies into busy clinical workflow, foster the provider‐patient relationship, and encourage alignment with guidelines. These results can inform tailoring of tools for use in practice and to address needs of patients and providers optimally.