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Biomedical subjects

C W Ford

Publications and source records attributed to C W Ford.

At least 19 recordsLinked to original sources
PubMed2001

Carbon-carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria.

In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon-carbon linked pyrazolylphenyl analogues has been prepared. The alpha-N-substituted methyl pyrazole (10alpha) in the C3-linked series exhibited very good Gram-positive activity with MICs <or=0.5-1 microg/mL and moderate Gram-negative activity with MICs=2-8 microg/mL against Haemophilus influenzae and Moraxella catarrhalis. This analogue was also found to have potent in vivo activity with an ED(50)=1.9 mg/kg. Beta-substitution at the C3-linked pyrazole generally results in a loss of activity. The C4-linked pyrazoles are slightly more potent than their counterparts in the C3-linked series. Most of the analogues in the C4-linked series exhibited similar levels of activity in vitro, but lower levels of activity in vivo than 10alpha. In addition, incorporation of a thioamide moiety in selected C4-linked pyrazole analogues results in an enhancement of in vitro activity leading to compounds several times more potent than eperezolid, linezolid and vancomycin. The thioamide of the N-cyanomethyl pyrazole analogue (34) exhibited an exceptional in vitro activity with MICs of <or= 0.06-0.25 microg/mL against Gram-positive pathogens and with MICs of 1 microg/mL against fastidious Gram-negative pathogens.

Anti-Bacterial Agents↗
PubMed2001

Oxazolidinones: a new class of antibacterials.

The oxazolidinones represent the first truly new class of antibacterial agents to reach the marketplace in several decades. They have a unique mechanism of action involving inhibition of the initiation step of protein synthesis and are not cross-resistant to other classes of antibiotics. The first marketed member of that class, linezolid (Zyvox), shows good efficacy with an impressive antibacterial spectrum (including activity against gram-positive organisms resistant to other drugs), and a pharmacodynamic/pharmacokinetic relationship best characterized by time above the minimum inhibitory concentration. The agent is effective by both the intravenous and oral route of administration. Although technically classified as bacteriostatic against a number of pathogens in vitro, linezolid behaves in vivo like a bactericidal antibiotic.

Animals↗
PubMed2001

Efficacy of linezolid in a staphylococcal endocarditis rabbit model.

A rabbit endocarditis model was used to test the efficacy of oral linezolid and iv vancomycin. Twenty-four hours after catheter placement across the aortic valve, rabbits were infected with 3.5 x 10(6) cfu of Staphylococcus aureus (UC-9258). Two days after infection, control rabbits were killed, and treated rabbits were given 5 days of therapy with linezolid at 8 h intervals (tds) using either 25, 50 or 75 mg/kg/dose, or vancomycin at 12 h intervals (bd) using 25 mg/kg/dose. Linezolid at 75 and 50 mg/kg, and vancomycin significantly reduced S. aureus in aortic valve vegetations compared with the control. Linezolid at 25 mg/kg was ineffective. The efficacy of 75 and 50 mg/kg linezolid was related to maintenance of plasma drug levels near or above the linezolid MIC for UC-9258 (2 mg/L).

Acetamides↗
PubMed2001

Efficacy of linezolid in treatment of experimental endocarditis caused by methicillin-resistant Staphylococcus aureus.

The efficacies of orally (p.o.) dosed linezolid and intravenously (i.v.) dosed vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) in rabbits with experimental aortic-valve endocarditis were investigated. After endocarditis was established with a recent clinical MRSA isolate, rabbits were dosed for 5 days with linezolid (p.o., three times a day) at either 25, 50, or 75 mg/kg of body weight or vancomycin (i.v., twice a day) at 25 mg/kg. The 25-mg/kg linezolid group had a high mortality rate and bacterial counts in the valve vegetations that were not different from those of the controls. Linezolid dosed p.o. at 50 and 75 mg/kg and i.v. vancomycin produced statistically significant reductions in bacterial counts compared to those of the untreated controls. The reduced bacterial counts and culture-negative valve rates for the animals treated with linezolid at 75 mg/kg were similar to those for the vancomycin-treated animals. Concentrations of linezolid in plasma were determined at several points in the dosing regimen. These results suggest that the efficacy of linezolid in this infection model is related to trough levels in plasma that remain above the MIC for this microorganism. At the ineffective dose of linezolid (25 mg/kg) the concentration at sacrifice was 0.045 times the MIC, whereas the concentrations of linezolid in plasma in the 50- and 75-mg/kg groups were 2 and 5 times the MIC at sacrifice, respectively. The results from this experimental model suggest that the oxazolidinone linezolid may be effective for the treatment of serious staphylococcal infections when resistance to other antimicrobials is present.

Acetamides↗
PubMed2000

Substituent effects on the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis.

A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has been prepared in an effort to expand the spectrum of activity of this class of antibiotics to include Gram-negative organisms. Pyrrole, pyrazole, imidazole, triazole, and tetrazole moieties have been used to replace the morpholine ring of linezolid (2). These changes resulted in the preparation of compounds with good activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. The unsubstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae = 4 microgram/mL and M. catarrhalis = 2 microgram/mL. Various substituents were also placed on the azole moieties in order to study their effects on antibacterial activity in vitro and in vivo. Interesting differences in activity were observed for many analogues that cannot be rationalized solely on the basis of sterics and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime, and cyano azoles generally led to dramatic improvements in activity against both Gram-positive and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with interesting antibacterial activity in vitro and in vivo. In particular, the 3-cyanopyrrole, 4-cyanopyrazole, and 4-cyano-1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus MICs </= 0.5-1 microgram/mL and H. influenzae and M. catarrhalis MICs = 2-4 microgram/mL. These analogues are also very effective versus S. aureus and S. pneumoniae in mouse models of human infection with ED(50)s in the range of 1. 2-1.9 mg/kg versus 2.8-4.0 mg/kg for the eperezolid (1) control.

Administration, Oral↗
PubMed2000

MICs of oxazolidinones for Rhodococcus equi strains isolated from humans and animals.

Eperezolid and linezolid are representatives of a new class of orally active, synthetic antimicrobial agents. The in vitro activity values (MICs) of linezolid, eperezolid, and comparator antibiotics against 102 strains of Rhodococcus equi isolated from humans and animals were determined. Linezolid was more active than eperezolid against the strains tested; premafloxacin was the most active comparator antibiotic.

Acetamides↗
PubMed1998

Piperazinyl oxazolidinone antibacterial agents containing a pyridine, diazene, or triazene heteroaromatic ring.

Oxazolidinones are a novel class of synthetic antibacterial agents active against gram-positive organisms including methicillin-resistant Staphylococcus aureus as well as selected anaerobic organisms. Important representatives of this class include the morpholine derivative linezolid 2, which is currently in phase III clinical trials, and the piperazine derivative eperezolid 3. As part of an investigation of the structure-activity relationships of structurally related oxazolidinones, we have prepared and evaluated the antibacterial properties of a series of piperazinyl oxazolidinones in which the distal nitrogen of the piperazinyl ring is substituted with a six-membered heteroaromatic ring. Compounds having MIC values </= 2 microg/mL vs selected gram-positive pathogens were discovered among each of the pyridine, pyridazine, and pyrimidine structural classes. Among these the cyanopyridine 17, the pyridazines 25 and 26, and the pyrimidine 31 exhibited in vivo potency vs S. aureus comparable to that of linezolid.

Acetamides↗
PubMed1998

Synthesis and antibacterial activity of [6,5,5] and [6,6,5] tricyclic fused oxazolidinones.

A series of conformationally restricted, [6,5,5] and [6,6,5] tricyclic fused oxazolidinones were synthesized and tested for antibacterial activity. Several compounds in the trans-[6,5,5] series demonstrated potent in vitro and in vivo activity. This work provides valuable information regarding the preferred conformational orientation of the oxazolidinones at the binding site.

Animals↗
PubMed1997

Oxazolidinones: new antibacterial agents.

The oxazolidinones are a new chemical class of synthetic antibacterial agents that are active orally or intravenously against multidrug-resistant Gram-positive bacteria. Their unique mechanism of action and activity against bacteria that pose therapeutic problems in hospital and community treatments make them promising candidates for antimicrobial agents.

Anti-Bacterial Agents↗
PubMed1997

Identification of Staphylococcus aureus virulence genes in a murine model of bacteraemia using signature-tagged mutagenesis.

Signature-tagged mutagenesis with transposon Tn917 was used to identify genes of Staphylococcus aureus required for virulence in a murine model of bacteraemia. Screening 1248 mutant strains in pools of 96 resulted in the provisional identification of 50 mutants attenuated in virulence. Subsequent individual analysis of many of these mutants confirmed that they are attenuated in virulence. DNA sequence analysis of regions flanking their transposon insertion points revealed that approximately half of them represent genes with unknown function, while most of the remainder are involved in nutrient biosynthesis and cell surface metabolism. Three mutants were found with transposon insertions in different positions in femA, and one mutant had an insertion in femB. Both femA and femB are involved in the formation of cell wall peptidoglycan pentaglycine cross-bridges. A further mutation occurred in a previously unknown gene that shares significant similarity to femB. Mutations were also obtained in recA and lsp (encoding the S. aureus prolipoprotein signal peptidase). On the basis of sequence similarities to proteins of known function, the products of other genes are probably involved in the synthesis of diaminopimelic acid (a component of peptidoglycan), maintenance of surface adhesins and cell surface membrane transport, showing that many components of the S. aureus cell surface are critical for the survival and replication of this pathogen in blood.

Animals↗
PubMed1996

Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant gram-positive bacterial infections.

Bacterial resistance development has become a very serious clinical problem for many classes of antibiotics. The 3-aryl-2-oxazolidinones are a relatively new class of synthetic antibacterial agents, having a new mechanism of action which involves very early inhibition of bacterial protein synthesis. We have prepared two potent, synthetic oxazolidinones, U-100592 and U-100766, which are currently in clinical development for the treatment of serious multidrug-resistant Gram-positive bacterial infections caused by strains of staphylococci, streptococci, and enterococci. The in vitro and in vivo (po and iv) activities of U-100592 and U-100766 against representative strains are similar to those of vancomycin. U-100592 and U-100766 demonstrate potent in vitro activity against Mycobacterium tuberculosis. A novel and practical asymmetric synthesis of (5S)-(acetamidomethyl)-2-oxazolidinones has been developed and is employed for the synthesis of U-100592 and U-100766. This involves the reaction of N-lithioarylcarbamates with (R)-glycidyl butyrate, resulting in excellent yields and high enantiomeric purity of the intermediate (R)-5-(hydroxymethyl)-2-oxazolidinones.

Acetamides↗
PubMed1996

Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity.

During the course of our investigations in the oxazolidinone antibacterial agent area, we have identified a subclass with especially potent in vitro activity against mycobacteria. The salient structural feature of these oxazolidinone analogues, 6 (U-100480), 7 (U-101603), and 8 (U-101244), is their appended thiomorpholine moiety. The rational design, synthesis, and evaluation of the in vitro antimycobacterial activity of these analogues is described. Potent activity against a screening strain of Mycobacterium tuberculosis was demonstrated by 6 and 7 (minimum inhibitory concentrations or MIC's < or = 0.125 micrograms/mL). Oxazolidinones 6 and 8 exhibit MIC90 values of 0.50 micrograms/mL or less against a panel of organisms consisting of five drug-sensitive and five multidrug-resistant strains of M. tuberculosis, with 6 being the most active congener. Potent in vitro activity against other mycobacterial species was also demonstrated by 6. For example, 6 exhibited excellent in vitro activity against multiple clinical isolates of Mycobacterium avium complex (MIC's = 0.5-4 micrograms/mL). Orally administered 6 displays in vivo efficacy against M. tuberculosis and M. avium similar to that of clinical comparators isoniazid and azithromycin, respectively. Consideration of these factors, along with a favorable pharmaco-kinetic and chronic toxicity profile in rats, suggests that 6 (U-100480) is a promising antimycobacterial agent.

Acetamides↗
PubMed1996

In vivo activities of U-100592 and U-100766, novel oxazolidinone antimicrobial agents, against experimental bacterial infections.

The Upjohn oxazolidinones, U-100592 and U-100766, are orally bioavailable synthetic antimicrobial agents with spectra of activity against antibiotic-susceptible and -resistant gram-positive pathogens. In several mouse models of methicillin-resistant Staphylococcus aureus infection, U-100592 and U-100766 yielded oral 50% effective doses (ED50) ranging from 1.9 to 8.0 mg/kg of body weight, which compared favorably with vancomycin subcutaneous ED50 values of 1.1 to 4.4 mg/kg. Similarly, both compounds were active versus a Staphylococcus epidermidis experimental systemic infection. U-100592 and U-100766 effectively cured an Enterococcus faecalis systemic infection, with ED50 values of 1.3 and 10.0 mg/kg, and versus a vancomycin-resistant Enterococcus faecium infection in immunocompromised mice, both drugs effected cures at 12.5 and 24.0 mg/kg. Both compounds were exceptionally active in vivo against penicillin- and cephalosporin-resistant Streptococcus pneumoniae, with ED50 values ranging from 1.2 to 11.7 mg/kg in systemic infection models. In soft tissue infection models with S. aureus and E. faecalis, both compounds exhibited acceptable curative activities in the range of 11.0 to 39.0 mg/kg. U-100766 was also very active versus the Bacteroides fragilis soft tissue infection model (ED50 = 46.3 mg/kg). In combination-therapy studies, both U-100592 and U-100766 were indifferent or additive in vivo against a monomicrobic S. aureus infection in combination with other antibiotics active against gram-positive bacteria and combined as readily as vancomycin with gentamicin in the treatment of a polymicrobic S. aureus-Escherichia coli infection. U-100592 and U-100766 are potent oxazolidinones active against antibiotic-susceptible and -resistant gram-positive pathogens in experimental systemic and soft tissue infections.

Acetamides↗
PubMed1996

College student's blood donation behavior: relationships to demographics, perceived risk, and incentives.

A study was undertaken to empirically investigate whether the student market could be further segmented into blood donor and nondonor markets based on their demographic characteristics, perceived risks, and influence on non-monetary incentives. While significant differences were found between donors and nondonors based on their gender, blood type, student classification, and influence of incentives, no differences were found between the four (physical, psychological, social, or time) dimensions of perceived risk. Discussion focuses on strategies for blood collection agencies for student markets.

Adolescent↗
PubMed1994

Effect of tumor necrosis factor-alpha, interleukin-1 beta, and antibiotics on the killing of intracellular Staphylococcus aureus.

A bovine blood polymorphonuclear neutrophil system was used to determine the ability of cytokines, alone or in combination with various antibiotics, to enhance the intracellular killing of Staphylococcus aureus sequestered within these phagocytes. Pretreatment of blood polymorphonuclear neutrophils with human recombinant tumor necrosis factor-alpha, bovine macrophage supernatant tumor necrosis factor-alpha, or human recombinant interleukin-1 beta enhanced the killing of S. aureus by the phagocytes compared with that of untreated polymorphonuclear neutrophils. This enhancement was dose-dependent and required 30 min of contact between the cytokine and the blood polymorphonuclear neutrophils. However, mammary gland polymorphonuclear neutrophils, macrophages, and blood monocytes showed no enhanced killing activity following pretreatment with tumor necrosis factor. Pretreatment of polymorphonuclear neutrophils with tumor necrosis factor and subsequent exposure to various antibiotics after infection with S. aureus enhanced intracellular bacterial killing by certain antibiotics, including paldimycin, rifampin, and ciprofloxacin (antibiotics that normally kill intracellular S. aureus). However, no enhancement occurred with antibiotics that do not normally kill intracellular S. aureus. Cytokine therapy may be a useful adjunct to antibiotic therapy in the treatment of bovine staphylococcal infection and mastitis.

Animals↗
PubMed1994

Efficacy of tumor necrosis factor-alpha and antibiotics in therapy of experimental murine staphylococcal mastitis.

The mouse model was used to determine the efficacy of the cytokine, tumor necrosis factor-alpha, and antibiotic in treatment of experimentally induced staphylococcal mastitis. Recombinant human tumor necrosis factor-alpha alone administered to the mammary glands of lactating mice recruited significantly more polymorphonuclear neutrophils into the gland by 4 h posttreatment than did the untreated control. One hundred times less recombinant mouse tumor necrosis factor-alpha than human tumor necrosis factor-alpha was required to enhance the killing of Staphylococcus aureus within the gland. Human tumor necrosis factor-alpha effectively enhanced the killing of the bacteria when it was administered 4 to 0 h prior to infection, but not 4 h after infection. When mice were first pretreated with tumor necrosis factor-alpha, infected, and then treated with antibiotics (ciprofloxacin and pirlimycin, but not cloxacillin), the combination of antibiotic and cytokine significantly reduced the number of bacteria within the gland compared with that for mice treated with antibiotic alone, cytokine alone, or placebo. Recombinant tumor necrosis factor-alpha may be an effective adjunct to antimicrobial therapy in treatment of staphylococcal mastitis in the bovine.

Animals↗