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1.  Revised structure for the phenazine antibiotic from Pseudomonas fluorescens 2-79 (NRRL B-15132). 
Antimicrobial Agents and Chemotherapy  1987;31(12):1967-1971.
A phenazine antibiotic (mp, 243 to 244 degrees C), isolated in a yield of 134 micrograms/ml from cultures of Pseudomonas fluorescens 2-79 (NRRL B-15132), was indistinguishable in all of its measured physicochemical (melting point, UV and infrared spectra, and gas chromatography-mass spectrometry data) and biological properties from synthetic phenazine-1-carboxylic acid. Gurusiddaiah et al. (S. Gurusiddaiah, D. M. Weller, A. Sarkar, and R. J. Cook, Antimicrob. Agents Chemother. 29:488-495, 1986) attributed a dimeric phenazine structure to an antibiotic with demonstrably similar properties obtained from the same bacterial strain. Direct comparison of the physicochemical properties of the authentic antibiotic obtained from D. M. Weller with synthetic phenazine-1-carboxylic acid and with the natural product from the present study established that all three samples were indistinguishable within the experimental error of each method. No evidence to support the existence of a biologically active dimeric species was obtained. Phenazine-1-carboxylic acid has a pKa of 4.24 +/- 0.01 (25 degrees C; I = 0.09), and its carboxylate anion shows no detectable antimicrobial activity compared with the active uncharged carboxylic acid species. These data suggest that phenazine-1-carboxylic acid is probably not an effective biological control agent for phytopathogens in environments with a pH greater than 7.
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PMCID: PMC175836  PMID: 3125789
4.  Correction for bacterial loss in in vitro dilution models. 
Antimicrobial Agents and Chemotherapy  1987;31(11):1859-1860.
A new method to correct for bacteria lost to dilution in in vitro kinetic models is presented which includes the influence of the stationary bacterial growth phase. The method imposes an upper limit on bacterial density, in contrast to previous methods.
PMCID: PMC175055  PMID: 3324963
5.  Effect of calcium on in vitro activity of LY146032 against Clostridium difficile. 
The in vitro MICs of LY146032 against 63 isolates of Clostridium difficile tested in Wilkins-Chalgren broth ranged from 0.5 to greater than 32 micrograms/ml, with MICs of 4 and 8 micrograms/ml for 50 and 90% of the isolates, respectively. However, when the test medium was supplemented with physiologic concentrations of calcium, the MIC for 90% of the isolates was reduced to less than or equal to 0.12 microgram/ml.
PMCID: PMC174753  PMID: 3034146
6.  Antagonism of wild-type and resistant Escherichia coli and its DNA gyrase by the tricyclic 4-quinolone analogs ofloxacin and S-25930 stereoisomers. 
Antimicrobial Agents and Chemotherapy  1987;31(11):1861-1863.
The mechanism of action of the quinolone analogs ofloxacin and S-25930, which are unusual because of the presence of a third ring with an asymmetric carbon, was studied. Drug-resistant strains of Escherichia coli were selected by serial passage in the presence of ofloxacin, and a mutation was mapped near the gyrA gene of DNA gyrase. DNA gyrase containing the A subunit purified from this strain as compared with the isogenic wild-type strain exhibited increased resistance to ofloxacin, proving that the mutation was located in the gyrA gene. For S-25930, the S stereoisomer was more potent than the R isomer in inhibiting wild-type E. coli and DNA gyrase containing an A subunit isolated from this strain. Both isomers had decreased potency against the isogenic ofloxacin-resistant (gyrA) strain and its purified enzyme, but the S isomer remained more potent than the R isomer. These studies, using a combined genetic and biochemical approach, demonstrate (i) that DNA gyrase is a target of the tricyclics ofloxacin and S-25930, (ii) that serial exposure to ofloxacin can select resistance to tricyclic quinolone agents by mutation in the gyrA gene, and (iii) that the more potent antibacterial activity of S relative to R S-25930 correlates with increased activity against DNA gyrase for both wild-type and ofloxacin-resistant (gyrA) isogenic strains.
PMCID: PMC175056  PMID: 2829717
8.  In vitro susceptibility of 96 Capnocytophaga strains, including a beta-lactamase producer, to new beta-lactam antibiotics and six quinolones. 
The in vitro activities of new beta-lactam antibiotics and new quinolones were studied against 96 Capnocytophaga strains, including a beta-lactamase-producing strain which was resistant to ampicillin, amoxicillin, carbenicillin, cephalothin, and cefamandole. All strains were susceptible to the combination of amoxicillin and clavulanic acid, ureidopenicillins, cefoxitin, broad-spectrum cephalosporins, and imipenem. Cephalothin and cefamandole did not show good activity against most strains. All Capnocytophaga spp. were uniformly susceptible to the five new quinolones tested.
PMCID: PMC174921  PMID: 3498438
9.  Praziquantel and clonorchiasis. 
PMCID: PMC174924  PMID: 3631948
12.  Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against gram-negative organisms. 
Antimicrobial Agents and Chemotherapy  1987;31(12):1939-1947.
The macrolide antibiotic azithromycin (CP-62,993; 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A; also designated XZ-450 [Pliva Pharmaceuticals, 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 Chlamydia spp. Azithromycin was significantly more potent versus many genera of the family Enterobacteriaceae; its MIC for 90% of strains of Escherichia, Salmonella, Shigella, and Yersinia was less than or equal to 4 micrograms/ml, compared with 16 to 128 micrograms/ml for erythromycin. Azithromycin inhibited the majority of gram-positive organisms at less than or equal to 1 micrograms/ml. 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.
PMCID: PMC175832  PMID: 2449865
14.  Molecular epidemiology of trimethoprim resistance among coagulase-negative staphylococci. 
Antimicrobial Agents and Chemotherapy  1987;31(11):1683-1688.
A 42% (70 of 167 isolates) incidence of resistance to 20 micrograms of trimethoprim per ml was found among clinical isolates of coagulase-negative staphylococci from two hospitals. A specific trimethoprim resistance gene probe from a conjugative Staphylococcus aereus plasmid was used to investigate the location of the trimethoprim resistance gene among 29 isolates. In 14 trimethoprim-resistant isolates, the probe hybridized with only chromosomal DNA, in 9 it hybridized with only plasmid DNA, and in 1 isolate both plasmid and chromosomal sequences showed hybridization. In five isolates there was no hybridization of the probe with either chromosomal or plasmid DNA. Four of these five nonhybridizing isolates were Staphylococcus haemolyticus. In contrast, all 22 Staphylococcus epidermidis isolates tested hybridized with the probe. The presence of the trimethoprim resistance gene in a chromosomal location was correlated with a lower MIC (median, 80 micrograms/ml) than when it was plasmid encoded (median, 1,250 micrograms/ml). Restriction endonuclease mapping as well as DNA hybridization of cloned plasmid and chromosomal DNA showed that there were 2.7 kilobases of common DNA in the two loci. This included the 500 base pairs of DNA mediating trimethoprim resistance and a total of 2.2 kilobases of 3'- and 5'-flanking sequences. The presence of the same gene and flanking sequences in chromosomal and plasmid locations suggests that the trimethoprim resistance determinant is translocated among different genetic loci.
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PMCID: PMC175020  PMID: 3435115
15.  Production of low-affinity penicillin-binding protein by low- and high-resistance groups of methicillin-resistant Staphylococcus aureus. 
Methicillin- and cephem-resistant Staphylococcus aureus (137 strains) for which the cefazolin MICs are at least 25 micrograms/ml could be classified into low-resistance (83% of strains) and high-resistance (the remaining 17%) groups by the MIC of flomoxef (6315-S), a 1-oxacephalosporin. The MICs were less than 6.3 micrograms/ml and more than 12.5 micrograms/ml in the low- and high-resistance groups, respectively. All strains produced penicillin-binding protein 2' (PBP 2'), which has been associated with methicillin resistance and which has very low affinity for beta-lactam antibiotics. Production of PBP 2' was regulated differently in low- and high-resistance strains. With penicillinase-producing strains of the low-resistance group, cefazolin, cefamandole, and cefmetazole induced PBP 2' production about 5-fold, while flomoxef induced production 2.4-fold or less. In contrast, penicillinase-negative variants of low-resistance strains produced PBP 2' constitutively in large amounts and induction did not occur. With high-resistance strains, flomoxef induced PBP 2' to an extent similar to that of cefazolin in both penicillinase-producing and -negative strains, except for one strain in which the induction did not occur. The amount of PBP 2' induced by beta-lactam antibiotics in penicillinase-producing strains of the low-resistance group correlated well with resistance to each antibiotic. Large amounts of PBP 2' in penicillinase-negative variants of the low-resistance group did not raise the MICs of beta-lactam compounds, although these strains were more resistant when challenged with flomoxef for 2 h. Different regulation of PBP 2' production was demonstrated in the high- and low-resistance groups, and factor(s) other than PBP 2' were suggested to be involved in the methicillin resistance of high-resistance strains.
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PMCID: PMC174932  PMID: 3499861
16.  Oral ribavirin treatment of influenza A and B. 
A loading dose and short-term administration of oral ribavirin significantly improved symptoms and signs of influenza type A or B infection in 25 patients. The antiviral effect was not significant. No adverse clinical effects or significant laboratory values were observed. Oral treatment of patients with influenza A or B infection might be possible with ribavirin.
PMCID: PMC174922  PMID: 3307623
17.  Activity of LY146032 in vitro and in experimental enterococcal pyelonephritis. 
The efficacy of LY146032 (LY), a new lipopeptide antibiotic, was compared with that of vancomycin, ciprofloxacin, ceftriaxone, imipenem, and gentamicin and combinations of LY-ceftriaxone, LY-imipenem, and LY-gentamicin against 15 strains of Streptococcus (Enterococcus) faecalis by microtiter dilution and checkerboard techniques. LY was effective within a very narrow range of drug concentrations (from 0.125 to 2.0 micrograms/ml) and was more active than other agents tested against S. faecalis. Enhanced inhibition of S. faecalis was seen more frequently with combinations of either penicillin or ampicillin and an aminoglycoside than with combinations of LY and gentamicin, imipenem, or ceftriaxone. The in vivo efficacy of LY was compared with that of vancomycin and ampicillin alone and combinations of vancomycin-gentamicin, ampicillin-gentamicin, and LY-gentamicin in a rat model of chronic enterococcal pyelonephritis. At a dose of 10 mg/kg given twice daily, LY reduced the number of organisms per kidney significantly compared with that in infected untreated controls within 48 h after the initiation of therapy. At 20 mg/kg given once a day, LY was less effective but reduced colony counts significantly after 4 days of therapy, and its activity was comparable to that of vancomycin or vancomycin-gentamicin given twice daily. LY may be a promising agent for the treatment of enterococcal infections.
PMCID: PMC174903  PMID: 2820299
18.  Improved sensitivity in assays for binding of novel beta-lactam antibiotics to penicillin-binding proteins of Escherichia coli. 
Tigemonam and temocillin, but not aztreonam, bound to penicillin-binding proteins (PBPs) 1a and 3 of Escherichia coli with apparent improved affinity when challenged with benzylpenicillin at lowered temperatures. Half times for deacylation of the tigemonam-PBP complexes were shorter than were those of the corresponding aztreonam-PBP complexes. The implications of the routine testing of PBP affinities are discussed.
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PMCID: PMC174917  PMID: 3307621
19.  Human pharmacokinetics and tolerance of oral ganciclovir. 
Ganciclovir is a nucleoside analog which inhibits the replication of herpesviruses in vitro and which has been effective by intravenous administration for the treatment of severe cytomegalovirus infection in immunocompromised patients. Because most patients with acquired immunodeficiency syndrome and severe cytomegalovirus infection have required lifelong daily suppressive ganciclovir therapy to control disease progression, oral therapy appears to have practical advantages. We studied the pharmacokinetics of orally administered ganciclovir in four patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. Repeated oral ganciclovir doses (10 to 20 mg/kg every 6 h) were well tolerated. With a 20-mg/kg dose given every 6 h, mean steady-state peak and trough levels were 2.96 and 1.05 microM, respectively, and the area under the concentration-time curve from 0 to 24 h was 47 microM X h. Calculated absorption was 3.0%, based on urinary excretion. Because the levels achieved in serum with oral ganciclovir approximated those required to inhibit cytomegalovirus in vitro, a trial of oral maintenance therapy in immunocompromised patients with severe cytomegalovirus infections seems warranted.
PMCID: PMC174913  PMID: 2820301
21.  Treatment of Clostridium difficile colitis in hamsters with a lipopeptide antibiotic, LY146032. 
LY146032, an acidic lipopeptide antibiotic which inhibits the biosynthesis of cell wall peptidoglycan, was found to be effective in delaying death in a hamster model of pseudomembranous colitis. A dose of 0.05 mg/day was effective. The equivalent protection with vancomycin required a dose 100-fold higher, i.e., 5 mg/day.
PMCID: PMC174884  PMID: 2821892
22.  Inhibition of peptidoglycan biosynthesis in gram-positive bacteria by LY146032. 
LY146032, a cyclic lipopeptide antibiotic, is an inhibitor of cell wall peptidoglycan biosynthesis in gram-positive bacteria. Although LY146032 at relatively high concentrations inhibited the in vitro polymerization of UDP-linked sugar precursors, inhibition of cell wall formation in intact Staphylococcus aureus and Bacillus megaterium cells did not lead to the accumulation of UDP-N-acetyl-muramyl (MurNAc)-peptide(s). Experiments that measured formation of UDP-MurNAc-peptides revealed that LY146032 inhibited the formation of these nucleotide-linked intermediates. This antibiotic had a disruptive effect on membrane permeability as evidenced by the loss of intracellular potassium immediately after exposure to the drug. The lack of any major disruption of the phosphoenolpyruvate:sugar phosphotransferase system indicated that the membrane is not likely a lethal target for this antibiotic. The findings are consistent with a mechanism by which LY146032 inhibits the formation of precursor molecules utilized in peptidoglycan biosynthesis. The observed membrane effects likely result from transit of the inhibitor to its lethal target site.
PMCID: PMC174877  PMID: 2821889
23.  In vitro and in vivo antibacterial activities of CS-807, a new oral cephalosporin. 
CS-807 is a new oral prodrug of R-3746, a cephalosporin derivative, with potent in vitro and in vivo antibacterial activity against both gram-positive and gram-negative bacteria. The susceptibility of about 1,200 clinical isolates to R-3746 was determined by the agar dilution method. Ninety percent or more of pathogens such as Staphylococcus aureus, streptococci, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, indole-positive and indole-negative Proteus spp., Providencia rettgeri, and Haemophilus influenzae were inhibited at concentrations ranging less than or equal to 0.01 to 1.56 micrograms/ml. Furthermore, at a concentration of 3.13 micrograms/ml, 50% or more of Staphylococcus epidermidis, Morganella morganii, Citrobacter freundii, and Serratia marcescens strains were also inhibited. Pseudomonas aeruginosa and Xanthomonas maltophilia were resistant to R-3746. The activity of R-3746 was scarcely influenced by several growth conditions. R-3746 was highly resistant to hydrolysis by beta-lactamases derived from various species of bacteria. Killing-curve studies demonstrated bactericidal activity of R-3746 at concentrations above the MIC. R-3746 showed high affinity for penicillin-binding proteins 1, 3, and 4 of Staphylococcus aureus and 1A, 1Bs, and 3 of Escherichia coli. Systemic infections in mice caused by various pathogens, including beta-lactamase-producing strains, responded well to therapy with oral doses of CS-807.
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PMCID: PMC174876  PMID: 3310868
24.  Characterization of a staphylococcal trimethoprim resistance gene and its product. 
Resistance to trimethoprim (Tp) is mediated by a plasmid-encoded gene in staphylococci. The gene is responsible for high-level resistance (MIC, greater than 1,000 micrograms/ml) in both its native host and when cloned on high-copy-number vectors in Escherichia coli. Analysis of subclones of the staphylococcal Tp gene on E. coli expression vectors and estimation of the size of full and truncated proteins produced in E. coli minicells generated an approximate size limit of 505 base pairs for the gene and 18,500 daltons for the gene product. Crude extracts of E. coli containing the cloned gene had dihydrofolate reductase (DHFR) specific activity that was more than 100 times greater than that of control cells and more than 1,000 times more resistant to trimethoprim inhibition. The amount of trimethoprim required for a 50% reduction in the specific activity of staphylococcal DHFR differed from those of cells containing DHFR types I, II, or III, enzymes mediating Tp in members of the family Enterobacteriaceae. In addition, the size of the monomeric staphylococcal DHFR protein was larger than that of any of the gram-negative DHFRs both compared with published sequence data and as observed by direct comparison on polyacrylamide gels. Finally, there was no homology between a DNA fragment containing the cloned staphylococcal gene and DNA encoding any of the gram-negative DHFRs. Thus, the staphylococcal Tp gene codes for a single protein with DHFR activity that appears to be unrelated to DHFR genes that mediate Tp in members of the Enterobacteriaceae.
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PMCID: PMC174866  PMID: 2821886
25.  In vitro activity of systemic antifungal agents against Malassezia furfur. 
The activity of four antifungal agents against 15 systemic (blood and vascular catheter) and 10 superficial (skin) Malassezia furfur isolates was evaluated. MIC ranges were similar for the two groups of organisms: amphotericin B, 0.3 to 2.5 micrograms/ml; flucytosine, greater than 100 micrograms/ml; miconazole, 0.4 to 1.5 micrograms/ml; and ketoconazole, 0.025 to 0.4 micrograms/ml.
PMCID: PMC284220  PMID: 3619430

Results 1-25 (449)