The 2-pyridones are a new class of broad-spectrum orally bioavailable antibacterial agents. These compounds are potent bacterial DNA gyrase inhibitors which differ from fluoroquinolones by placement of the nitrogen atom in the ring juncture. ABT-719 is an S isomer and a representative 2-pyridone. ABT-719 administered orally or subcutaneously was 4- to 10-fold more effective than ciprofloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes infections in normal mice. ABT-719 was equivalent in efficacy to ciprofloxacin for treatment of gram-negative bacterial infections caused by Pseudomonas aeruginosa or Escherichia coli. The racemate and R forms of ABT-719 produced similar results against gram-positive and gram-negative bacterial infections. The 50% effective doses of ABT-719 were at least threefold lower than those of ciprofloxacin for therapy of intracellular infections caused by Salmonella typhimurium or Listeria monocytogenes. In immunosuppressed mice, ABT-719 was more effective than ciprofloxacin against quinolone-sensitive S. aureus, Enterococcus faecalis, and Enterococcus faecium. The pharmacokinetic properties of ABT-719 were consistent with its relative efficacy. The 2-pyridones are potent, orally available antibacterial agents with efficacy against gram-positive and gram-negative bacterial infections in mice.

The efficacy of clarithomycin and sulphamethoxazole for treatment of experimental Pneumocystis carinii infection was investigated. Rats were immunosuppressed with dexamethasone and inoculated intratracheally with 5 x 10(6) P. carinii cysts. After 2 weeks, the lung tissues were assayed for P. carinii cyst burden. The combination of clarithromycin and sulphamethoxazole caused a significantly greater reduction in cyst burden than either drug alone. Up to 50% of the rats treated with the combination of clarithromycin and sulphamethoxazole were negative for P. carinii cysts. Equivalent doses of the individual drugs given alone did not produce cures. The combination of clarithromycin and sulphamethoxazole was more than twice as effective as either drug alone. Clarithromycin combined with sulphamethoxazole in treatment of P. carinii infection could be especially useful since clarithromycin monotherapy provides safe and effective treatment against many other pathogens, including several that are associated with AIDS.

The effects of enteral formulations on the response of mice to infectious challenge with Listeria monocytogenes, influenza A or Candida albicans were studied to test the efficacy of specialized ingredients. CF-1 outbred female mice (12-15 g) were fed nonpurified diet (Purina No. 5002) or commercially available liquid formulas: Osmolite HN, Perative or Impact. There were no differences between the groups fed the liquid formulas with regards to mean survival time or percentage of survivors in any of these models of infection. Examination of spleens from the groups challenged with L. monocytogenes, lungs from mice infected with Influenza A and kidneys from the groups challenged with C. albicans revealed no differences in cure rate of survivors. Pre-feeding periods of up to 8 d before infection produced similar results for mice fed enteral formulations compared to nonpurified diet. Contrary to previous reports, the use of Impact did not improve resistance to disease in mice challenged with lethal doses of L. monocytogenes, as compared with mice fed Osmolite HN. Additionally, mice fed Impact, Perative, or nonpurified diet responded similarly to challenge with L. monocytogenes, C. albicans or influenza A. The results indicate that these acute lethal animal models of infectious challenge may be of limited use to distinguish effects of modified nutrient composition of enteral formulas.

ChemInformVolume 21, Issue 48 Natural Products ChemInform Abstract: Cyclobut-A (I) and Cyclobut-G (II): Broad-Spectrum Antiviral Agents with Potential Utility for the Therapy of AIDS. D. W. NORBECK, D. W. NORBECK Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorE. KERN, E. KERN Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorS. HAYASHI, S. HAYASHI Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorW. ROSENBROOK, W. ROSENBROOK Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorH. SHAM, H. SHAM Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorT. HERRIN, T. HERRIN Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorJ. J. PLATTNER, J. J. PLATTNER Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorJ. ERICKSON, J. ERICKSON Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorJ. CLEMENT, J. CLEMENT Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorR. SWANSON, R. SWANSON Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorN. SHIPKOWITZ, N. SHIPKOWITZ Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorD. HARDY, D. HARDY Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorK. MARSH, K. MARSH Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorG. ARNETT, G. ARNETT Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorW. SHANNON, W. SHANNON Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorS. BRODER, S. BRODER Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorH. MITSUYA, H. MITSUYA Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this author D. W. NORBECK, D. W. NORBECK Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorE. KERN, E. KERN Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorS. HAYASHI, S. HAYASHI Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorW. ROSENBROOK, W. ROSENBROOK Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorH. SHAM, H. SHAM Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorT. HERRIN, T. HERRIN Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorJ. J. PLATTNER, J. J. PLATTNER Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorJ. ERICKSON, J. ERICKSON Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorJ. CLEMENT, J. CLEMENT Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorR. SWANSON, R. SWANSON Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorN. SHIPKOWITZ, N. SHIPKOWITZ Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorD. HARDY, D. HARDY Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorK. MARSH, K. MARSH Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorG. ARNETT, G. ARNETT Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorW. SHANNON, W. SHANNON Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorS. BRODER, S. BRODER Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorH. MITSUYA, H. MITSUYA Anti-Infect. Res. Div., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this author First published: November 27, 1990 https://doi.org/10.1002/chin.199048292AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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The in vitro and in vivo antibacterial activity of A-56268 (TE-031), the 6-O-methyl derivative of erythromycin, was compared with those of erythromycin and other reference drugs. A-56268 had the same spectrum of antibacterial activity as erythromycin. A-56268 was generally 1 log2 dilution more potent or equal to erythromycin against all organisms except haemophilus influenzae and Propionibacterium acnes, for which A-56268 was 1 log2 dilution and 3 log2 dilutions, respectively, less potent. The MBC of A-56268 and erythromycin was not significantly different from the MIC against Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus epidermidis, and H. influenzae but was more than 2 log2 dilutions higher than the MICs for some Staphylococcus aureus strains. Human serum at a concentration of 50% did not change the in vitro potency of A-56268 or erythromycin. A-56268 was similar to erythromycin in being more active at pH 8.0 than at the physiologic pH of 7.3. The activity of A-56268 was synergistic with sulfamethoxazole against 4 of 12 strains of H. influenzae. In mouse protection tests, when administered orally A-56268 was more potent than erythromycin against H. influenzae, S. pyogenes, S. pneumoniae, and S. aureus. After subcutaneous administration the potencies of A-56268 and erythromycin were not statistically different from each other. A-56268 was more potent than erythromycin against Legionella infection in guinea pigs. The concentration of A-56268 in the serum and lung was higher than that of erythromycin after intraperitoneal administration. In A-56268 in the serum and lung was higher than that of erythromycin after intraperitoneal administration. In mice, the peak levels in serum of A-56268 and erythromycin were similar after subcutaneous administration and seven times higher for A-56268 after oral administration. The serum half-life of A-56268 was approximately twice that of erythromycin after administration by both routes.

The MICs of difloxacin (A-56619), A-56620 and ofloxacin were similar or within one to two-fold dilutions against a variety of anaerobic bacteria. Ciprofloxacin was slightly less active (two- to four-fold dilutions) than difloxacin, A-56620 and ofloxacin. Norfloxacin was less active than the other fluoroquinolones tested against anaerobic bacteria. The MICs of norfloxacin, A-56620, ciprofloxacin and ofloxacin against most anaerobes, except the Gram-positive cocci, were lower at pH 8.1 than at pH 6.6. MICs of the fluoroquinolones against anaerobic cocci were the same at pH 6.6, 7.3 and 8.1. Norfloxacin and ciprofloxacin were most affected by the acidic pH. Ofloxacin and A-56620 were affected to a lesser extent by an acidic pH than norfloxacin and ciprofloxacin. The potency of difloxacin was similar at the three pHs tested. A subcutaneous anaerobic infection model in mice was used to determine the in-vivo efficacy of the new fluoroquinolones against Bacteroides fragilis. Difloxacin was the most potent compound in this test.

The effects of enterai formulations on the response of mice to infectious challenge with Listeria mortocytogenes, influenza A or Candida albicans were studied to test the efficacy of specialized ingredients. CF-1 outbred female mice (12-15 g) were fed nonpu- rified diet (Purina No. 5002) or commercially available liquid formulas: Osmolite HN®, Perative®or Impact®. There were no differences between the groups fed the liquid formulas with regards to mean survival time or percentage of survivors in any of these models of in fection. Examination of spleens from the groups challenged with L monocytogcncs, lungs from mice in fected with Influenza A and kidneys from the groups challenged with C. albicans revealed no differences in cure rate of survivors. Pre-feeding periods of up to 8 d before infection produced similar results for mice fed enterai formulations compared to nonpurified diet. Con trary to previous reports, the use of Impact®did not improve resistance to disease in mice challenged with lethal doses of L. monocytogenes, as compared with mice fed Osmolite HN. Additionally, mice fed Impact®, Perative®,or nonpurified diet responded similarly to challenge with L monocytogenes, C. albicans or in fluenza A. The results indicate that these acute lethal animal models of infectious challenge may be of limited use to distinguish effects of modified nutrient compo sition of enterai formulas. J. Nutr. 124: 2156-2162, 1994.