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P B Fernandes

Publications and source records attributed to P B Fernandes.

At least 55 records · Page 3Linked to original sources
PubMed1988

Structure-activity relationships in quinolone antibacterials: design, synthesis and biological activities of novel isothiazoloquinolones.

Over the past years it was found that modification of the 3-carboxylic acid group of quinolones generally produced compounds with a substantial decrease in antibacterial activity. The 3-carboxylic acid moiety together with the 4-carbonyl function are believed to be the most structurally critical sites for this class of compounds to DNA gyrase. The authors have designed and synthesized a series of quinolone analogues in which the 3-carboxylic acid group has been modified. These compounds, 2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-diones, possess biological activities far superior to their parent counterparts. For example, the MICs (microgram/ml) for A-62824 (ciprofloxacin 3-carboxylic acid modified analogue) and ciprofloxacin against some organisms are as follows: S. aureus ATCC 6538P (0.02, 0.2); S. epidermidis 3519 (0.05, 0.2); E. coli Juhl (0.005, 0.01); P. aeruginosa A5007 (0.05, 0.1) and Acinetobacter sp. CMX 699 (0.05, 0.78). This investigation has produced the first successful modification of the 3-carboxylic acid group of quinolones resulting in a series of extremely potent antibacterials. The design and synthesis as well as the biological activities of these new derivatives are described.

Anti-Infective Agents↗
PubMed1988

Effect of dosing intervals on efficacy of clarithromycin and erythromycin in mouse infection models.

Clarithromycin is a new macrolide with a serum half-life which is at least twice that of erythromycin. In order to select the appropriate dosing intervals, the in vitro post-antibiotic effect (PAE) of clarithromycin and erythromycin were compared and the efficacies of clarithromycin and erythromycin when administered once (q.d.), twice (b.i.d.) and three (t.i.d.) times a day in mouse protection tests were measured. The doses were selected from achievable peak serum concentrations in man and were 18 mg/kg for clarithromycin which gave a peak blood level of 2.0 micrograms/ml and a serum half-life of 0.82 h, and 10 mg/kg for erythromycin which gave a peak blood level of 0.9 microgram/ml and a serum half-life of 0.46 h. The PAE of clarithromycin for Staph. aureus is 6.25 h compared to 2.35 h for erythromycin. Clarithromycin was effective against Staph. aureus, Strep. pyogenes and Strep. pneumoniae when administered q.d., b.i.d. and t.i.d. and there was no difference in the cumulative mortalities in the three treatment groups. For erythromycin, there was also no difference in the survival of Strep. pyogenes and Strep. pneumoniae-infected mice, but when tested against Staph. aureus it was more effective when administered t.i.d. than b.i.d., and b.i.d. was more effective than q.d. Clarithromycin administered q.d. was more effective than erythromycin administered t.i.d. against Staph. aureus.

Animals↗
PubMed1988

Correlation of in vitro activities of the fluoroquinolones to their in vivo efficacies.

The new fluoroquinolones have activity against Gram-positive and Gram-negative bacteria. In order to differentiate between the compounds, the authors have compared their in vitro activities and correlated these results with their in vivo efficacies. Norfloxacin (N), pefloxacin (P), enoxacin (E), ofloxacin (O), difloxacin (D), ciprofloxacin (C), fleroxacin (F), A-61827 (A), temafloxacin (T) and lomefloxacin (L) were used in these studies. In vitro, C was the most active compound against Gram-negative aerobic bacteria and A was the most active compound against Gram-positive cocci and anaerobic bacteria. In mouse protection tests, C, D, A, O, T and F had similar activities against Escherichia coli and Pseudomonas aeruginosa. D, T and A were the most active quinolones against Staphylococcus aureus and Streptococcus pyogenes and Strep. pneumoniae in mouse protection tests. D was the most active agent against intracellular infection with Salmonella typhimurium, followed by O, T, A and F. The other compounds were ineffective in this test. All the quinolones were effective in treating E. coli pyelonephritis in mice. The doses required to treat P. aeruginosa pyelonephritis in mice were four times greater than those required to treat E. coli. Resistant P. aeruginosa mutants could be isolated from the kidneys after quinolone treatment. Systemic infections with E. coli, Staph. aureus and P. aeruginosa in neutropenic mice required high doses of the fluoroquinolones and F, T and A were ineffective at doses of 100 mg/kg against P. aeruginosa in this model. Differences in in vitro potencies were not reflected in in vivo efficacies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Comparative in vitro potencies of nine new macrolides.

The in vitro activities of the 14-membered macrolides (14M) clarithromycin (CL), roxithromycin (RO), dirithromycin (DI) and flurithromycin (FL), a 15-membered macrolide (15M) azithromycin (AZ), and the 16-membered macrolides (16M) josamycin (JM), spiramycin (SP), miocamycin (MI) and rokitamycin (RK) were compared with erythromycin (ER). CL was two- to four-fold more potent than ER against all organisms except Haemophilus and Campylobacter jejuni against which it was two-fold less active. RO and DI were generally two- to four-fold less active than ER. FL was two-fold less active than ER. AZ was equal to or two-fold less active than ER against Gram-positive bacteria and two- to four-fold more active than ER against Gram-negative bacteria, such as Haemophilus, Neisseria gonorrhoeae and Branhamella. The 16M were generally four- to eight-fold less active than ER against most aerobic bacteria and two-fold less active than ER against anaerobic bacteria. RK was generally two-fold more active than the other 16M. Bacteria carrying a constitutive-type of MLS resistance were resistant to the 14M, 15M and 16M, whereas bacteria with an inducible-type of resistance were susceptible to the 16M but resistant to the 14M and 15M. Addition of serum to the medium increased the activity of ER, CL, DI, FL, AZ and SP. The activity of RO was reduced four- to six-fold and the activity of MI was reduced by two-fold by adding serum to the medium. The activity of JO was unaffected by serum. All the macrolides were one- to four-fold more active at pH 8.0 than at pH 6.5. All the macrolides were bacteriostatic against Staphylococcus aureus 553, except RO and MI which were slowly bactericidal. All the macrolides were slowly bactericidal against Haemophilus influenzae 1435.

Aminoglycosides↗
PubMed1987

Synthesis and structure-activity relationship of 1-aryl-6,8-difluoroquinolone antibacterial agents.

A series of new arylfluoroquinolones has been prepared. These derivatives are characterized by having fluorine atoms at the 6- and 8-positions, substituted amino groups at the 7-position, and substituted phenyl groups at the 1-position. The in vitro antibacterial potency is greatest when the 1-substituent is 2,4-difluorophenyl and the 7-substituent is a 3-amino-1-pyrrolidinyl group. 1-(4-Fluorophenyl)-6,8-difluoro-7-piperazin-1-yl-1,4-dihydro-4-oxo quinoline-3- carboxylic acid (22) was found to possess excellent in vitro potency and in vivo efficacy.

Animals↗
PubMed1987

The frequency of in-vitro resistance development to fluoroquinolones and the use of a murine pyelonephritis model to demonstrate selection of resistance in vivo.

The frequency of development of resistance to the fluoroquinolones in vitro was generally low with Escherichia coli (in the order of 10(-7) to less than 10(-9) and high with Pseudomonas aeruginosa (in the order of 10(-5) to 10(-7)). Susceptibility to the fluoroquinolones also decreased after serial transfer in increasing concentrations of the drug. Although the MICs for the resistant E. coli variants were higher than that of the parent organism, they were still susceptible to achievable serum concentrations of all the quinolones except nalidixic acid. On the other hand some of the P. aeruginosa variants selected for resistance were resistant to achievable serum concentrations of all the quinolones. When E. coli pyelonephritis in mice was treated with the fluoroquinolones, difloxacin, A-56620, and ciprofloxacin were more effective than norfloxacin and nalidixic acid in lowering viable bacterial counts in the kidneys. The susceptibility of E. coli isolated from kidneys of mice treated with the quinolones was the same as that of the parent strain. When P. aeruginosa pyelonephritis in mice was treated with the fluoroquinolones an initial reduction in the cell count was seen, followed by an increase in the number of resistant variants. The resistant variants differed in their colony morphology and cell envelope proteins. The levels of resistance for the P. aeruginosa variants ranged from a two- to a 64-fold increase in the MIC.

Animals↗
PubMed1987

Comparative antibacterial activities of temafloxacin hydrochloride (A-62254) and two reference fluoroquinolones.

The in vitro and in vivo properties of a new 1-difluorophenyl-6-fluoroquinolone, temafloxacin hydrochloride (A-62254), were compared with those of difloxacin and ciprofloxacin. Temafloxacin hydrochloride was as active as ciprofloxacin and difloxacin against staphylococci and as active as ciprofloxacin and 2 twofold dilutions more active than difloxacin against streptococci. Against gram-negative enteric bacteria and Pseudomonas aeruginosa, temafloxacin hydrochloride was 2 twofold dilutions more active than difloxacin but 2 to 4 twofold dilutions less active than ciprofloxacin. The MICs of temafloxacin hydrochloride and difloxacin were increased by 2 to 5 twofold dilutions in urine at pH 6.5 compared with 4 to 5 twofold-dilution increases in the MICs of ciprofloxacin. The MICs of temafloxacin hydrochloride, difloxacin, and ciprofloxacin were increased by 1 to 3 twofold dilutions in serum. The MICs of temafloxacin hydrochloride, difloxacin, and ciprofloxacin were the same or within 1 to 2 twofold dilutions at pHs 6.5, 7.2, and 8.0. When administered orally in mouse protection tests, temafloxacin hydrochloride was as active as difloxacin and 5 to 10 times more active than ciprofloxacin against infections with Staphylococcus aureus and streptococci. Against infections with gram-negative enteric bacteria and P. aeruginosa, temafloxacin hydrochloride was as active as difloxacin and ciprofloxacin. Temafloxacin hydrochloride was three times less active than difloxacin but was five times more active than ciprofloxacin against infections with Salmonella typhimurium. Temafloxacin hydrochloride was as active as difloxacin and ciprofloxacin against P. aeruginosa and Proteus mirabilis pyelonephritis in mice. The peak serum concentration and serum half-life of temafloxacin hydrochloride in mice were approximately one-half and one-sixth, respectively, that of difloxacin after oral administration. The peak serum concentration of temafloxacin hydrochloride in mice after oral administration was six times higher than that of ciprofloxacin, and the serum half-life was equal to that of ciprofloxacin.

Animals↗
PubMed1987

Susceptibility testing of macrolide antibiotics against Haemophilus influenzae and correlation of in vitro results with in vivo efficacy in a mouse septicemia model.

There is poor correlation between the MICs and zone sizes obtained for erythromycin against Haemophilus influenzae. The effect of two media, Mueller-Hinton medium supplemented with 3% lysed horse blood and 10 micrograms of NAD per ml (MHA + LYHB) and Mueller-Hinton agar supplemented with 1% bovine hemoglobin and 1% IsoVitaleX (MHA + HGB), on the MICs and zone sizes of erythromycin against H. influenzae was determined. The effect of three different methods for inoculum preparation on the susceptibility of H. influenzae was also determined. The MICs were independent of the method of inoculum preparation, but the zone sizes were smaller if the inoculum was carefully adjusted to contain approximately 10(8) CFU/ml. MICs were higher and zone sizes were smaller when MHA + HGB was used instead of MHA + LYHB. Good correlation was found when MHA + LYHB was used for determining the MIC and MHA + HGB was used for determining susceptibility by the disk method. When the inoculum was adjusted to match a McFarland 0.5 standard, the viable counts had to be approximately 10(8) CFU/ml for good correlation between MICs and zone sizes. A-56268, a new macrolide antibiotic, was tested against H. influenzae, and its MICs and tentative breakpoints against this organism were determined. The MICs obtained by various methods were correlated with in vivo efficacy by using a mouse septicemia model. MICs obtained on MHA + HGB or MHA + LYHB incubated without a 5% CO2 atmosphere showed the best correlation with in vivo efficacy.

Animals↗
PubMed1987

Regression analysis, proposed interpretative zone size standards, and quality control guidelines for a new macrolide antimicrobial agent, A-56268 (TE-031).

A-56268 is a 6-O-methyl derivative of erythromycin A which has a spectrum of activity similar to that of erythromycin and is 1 log2 dilution more potent than erythromycin against most organisms that have been tested. The correlation of zone size diameters and MICs of A-56268 for 461 strains of bacteria isolated from clinical specimens was investigated. Based on anticipated levels in human serum of 2 micrograms/ml, 15-microgram disks have been recommended with zone size standards of greater than or equal to 15 mm for susceptibility (MIC correlate, less than or equal to 2.0 micrograms/ml) and less than or equal to 11 mm for resistance (MIC correlate, greater than or equal to 8 micrograms/ml). Selection of these tentative breakpoints resulted in no very major errors (false susceptible), a major error (false resistant) rate of 0.22%, and an acceptable minor error (intermediate) rate of 2.82%. MIC ranges and zone diameter limits for quality control organisms used in the standardized agar dilution and disk diffusion susceptibility tests with A-56268 are given.

Clarithromycin↗
PubMed1987

Coloradocin, an antibiotic from a new Actinoplanes. I. Taxonomy, fermentation and biological properties.

Coloradocin was discovered in a screen for anti-anaerobe activity. The producing organism was determined to be a new species of Actinoplanes, designated Actinoplanes coloradoensis sp. nov. Coloradocin inhibits Bacteroides, Clostridium and other anaerobes. It does not inhibit most aerobic bacteria but is effective against Neisseria gonorrhoeae and Haemophilus influenzae. Coloradocin has low acute toxicity.

Actinomycetales↗
PubMed1986

Synthesis and biological activity of benzothiazolo[3,2-a]quinolone antibacterial agents.

A new class of heterocyclic compounds with potent antibacterial activity, namely, 2-substituted amino-3-fluoro-5,12-dihydro-5-oxobenzothiazolo[3, 2-a]quinoline-6-carboxylic acids, is described. The compounds are conformationally restricted analogues of 7-substituted amino-6-fluoro-1-aryl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acids. Compounds 7 and 10, having a 4-methylpiperazinyl and a piperazinyl substitution at the 2-position, respectively, possess in vitro antibacterial activities comparable to norfloxacin (15). Compound 8, which has a 4-acetylpiperazinyl substitution at the 2-position, is active against Gram-positive organisms and nearly inactive against Gram-negative organisms. An efficient and short synthesis of this novel heterocyclic system via an intramolecular nucleophilic displacement cyclization reaction is reported.

Acinetobacter↗
PubMed1986

Synthesis and structure-activity relationships of new arylfluoronaphthyridine antibacterial agents.

Novel arylfluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids have been prepared and their antibacterial activity evaluated. These derivatives are characterized by having a fluorine atom at the 6-position, substituted amino groups at the 7-position, and substituted phenyl groups at the 1-position. The in vitro antibacterial potency is greatest when the 1-substituent is either p-fluorophenyl or o,p-difluorophenyl and the 7-substituent is a 3-amino-1-pyrrolidinyl group. 1-(2,4-Difluorophenyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid (38) was found to possess excellent in vitro potency and in vivo efficacy.

Anti-Bacterial Agents↗
PubMed1986

In-vitro and in-vivo potency of five new fluoroquinolones against anaerobic bacteria.

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.

Anti-Bacterial Agents↗
PubMed1986

Evaluation of aztreonam, cefoperazone, latamoxef and ceftazidime in the hamster colitis model.

Aztreonam, ceftazidime, cefoperazone and latamoxef (moxalactam) were evaluated in a hamster model for antibiotic-associated colitis. Aztreonam, a novel monocyclic beta-lactam antibiotic specifically directed against aerobic Gram-negative bacteria with limited activity against Gram-positive and anaerobic bacteria did not cause haemorrhagic caecitis and death in hamsters when administered intraperitioneally or orally. Quantitative caecal cultures showed no changes in the anaerobic caecal microflora of hamsters treated intraperitoneally with aztreonam and only a temporary decrease in anaerobic Gram-negative bacilli in hamsters treated orally. Clostridium difficile and its cytotoxin were not present in these animals. Parenteral administration of ceftazidime also did not affect the anaerobic caecal microflora or cause caecitis. However, when given orally, ceftazidime suppressed the anaerobic caecal microflora and a lethal C. difficile-induced caecitis developed. Latamoxef or cefoperazone given parenterally resulted in caecitis and death in five days with marked changes in the anaerobic caecal microflora and C. difficile present in the caecal contents of these animals. The lethal haemorrhagic caecitis observed in this study was indistinguishable from that seen in the clindamycin-induced colitis model in the hamster. The possible correlation of these findings to gastrointestinal disturbances as a complication of antibiotic therapy in humans is discussed.

Administration, Oral↗
PubMed1986

In vitro evaluation of A-56619 (difloxacin) and A-56620: new aryl-fluoroquinolones.

The in vitro antibacterial potencies of A-56619 and A-56620, two new aryl-fluoroquinolones, were compared with the potency of norfloxacin against a broad spectrum of organisms. Cefotaxime, aztreonam, piperacillin, imipenem, penicillin, and gentamicin were also tested for reference purposes. The MICs required to inhibit at least 90% of the strains tested ranged from 0.25 to 4 micrograms/ml for A-56619 and from 0.06 to 0.5 microgram/ml for A-56620 for members of the Enterobacteriaceae. A-56619 was generally twofold less potent and A-56620 was twofold more potent than norfloxacin against most aerobic gram-negative bacilli, including members of the Enterobacteriaceae and Pseudomonas aeruginosa. Against indole-positive Proteus, Morganella, Providencia rettgeri, and Serratia strains, A-56619 was at least 8- to 16-fold less potent than norfloxacin. A-56619 and A-56620 were four- to eightfold more potent than norfloxacin against Staphylococcus aureus and equally potent to fourfold more potent against Streptococcus species, Haemophilus influenzae, and Neisseria gonorrhoeae. The MICs of A-56619 and A-56620 were only slightly affected by increased inoculum size or by the addition of various cations at physiologic concentrations. A-56619 was three- to fivefold less active at pH 8.0 than at pH 6.5 or 7.2. A-56620 was twofold less active at pH 6.5 than at pH 8.0 or 7.2 against members of the Enterobacteriaceae and Pseudomonas aeruginosa; similar pH variations did not affect A-56620 activity against gram-positive cocci. The potencies of A-56619, A-56620, and norfloxacin were less in urine than in Mueller-Hinton broth; however, this effect was more pronounced with norfloxacin. Human serum at a concentration of 50% caused a 4- to 64- fold decrease in the potency of A-56619 and an average 4-fold decrease in the potency of A-56620, compared with no effect on the potency of norfloxacin. A-56619, A-56620, and norfloxacin were bactericidal and, at four times the MIC, reduced the viable cell counts of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa by approximately 99.9% within 2 h. A-56619, A-56620, and norfloxacin showed no significant synergistic activity and no antagonism when they were aminoglycoside or beta-lactam antimicrobial agents.

Anti-Infective Agents↗
PubMed1986

In vivo evaluation of A-56619 (difloxacin) and A-56620: new aryl-fluoroquinolones.

A-56619 and A-56620 are two new aryl-fluoroquinolones which are as potent as or more potent than norfloxacin when administered orally and subcutaneously in mouse protection tests against Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae. A-56619 and A-56620 were more potent than norfloxacin when administered orally against Escherichia coli, Proteus mirabilis, Serratia marcescens, and Pseudomonas aeruginosa. A-56620 was as potent or two- to threefold more potent than norfloxacin when administered subcutaneously against members of the family Enterobacteriaceae and Pseudomonas aeruginosa. Infection with Salmonella typhimurium was more effectively treated with A-56619 (50% effective dose [ED50], 1.4 mg/kg per day) than with norfloxacin (ED50, 62.8 mg/kg per day). E. coli or Pseudomonas pyelonephritis in mice was more effectively treated with A-56619 or A-56620 than with norfloxacin. After oral treatment, the ED50s of A-56619 and A-56620 were less than 12.5 mg/kg per day against E. coli and 62.9 and 38 mg/kg per day against P. aeruginosa pyelonephritis, respectively. Norfloxacin was ineffective at 200 mg/kg per day against E. coli or P. aeruginosa pyelonephritis. A-56619 and A-56620 were also more potent than norfloxacin in treatment of mixed bacterial pyelonephritis caused by E. coli and Streptococcus faecalis. A-56619 was at least 30 times more potent than norfloxacin and A-56620 was 4 to 11 times more potent than norfloxacin when administered against Klebsiella pneumonia in mice. A-56619 and A-56620 were at least 2 to 10 times more potent than norfloxacin against Staphylococcus aureus infections in immunosuppressed mice. A-56619 was equally potent in all in vivo tests when administered orally or subcutaneously, whereas A-56620 was similar to norfloxacin in being more potent when administered subcutaneously. The peak serum levels after subcutaneous and oral administration of A-56619 and A-56620 were higher than that of norfloxacin. The serum hal-lives of A-56619 and A-56620 after subcutaneous and oral administration were longer than the serum half-life of norfloxacin.

Animals↗