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D J Hardy

Publications and source records attributed to D J Hardy.

At least 55 records · Page 3Linked to original sources
PubMed1991

In vitro activity and in vivo efficacy of a new series of 9-deoxo-12-deoxy-9,12-epoxyerythromycin A derivatives.

Analogs of 9-deoxo-12-deoxy-9,12-epoxyerythromycin A with an epimeric hydroxy, amino, or ketone substitution at the 11 position of the macrolide ring and an amino or epimeric hydroxy substitution at the 4" position of the cladinose sugar were synthesized in an attempt to produce acid-stable derivatives of erythromycin with improved bioavailability and activity against gram-negative bacteria. These modifications produced compounds with in vitro activities which were generally similar to that of erythromycin. In mice, however, selected analogs were more active than was erythromycin against staphylococci, streptococci, Haemophilus influenzae, and Legionella pneumophila. In mice, the 11-keto (A-63881), 11-epiamino (A-69334), 11-epiamino-4"-amino (A-71671), and 11-epiamino-4"-epiamino (A-73020) analogs achieved peak concentrations in serum and lung, serum half-lives, and/or areas under the serum curve which were greater than those of erythromycin. Improved pharmacokinetics, as compared with those of erythromycin, may explain the increased in vivo antibacterial activities of these compounds.

Animals↗
PubMed1991

In vitro and in vivo evaluation of tiacumicins B and C against Clostridium difficile.

Tiacumicins B and C are members of a novel group of 18-membered macrolide antibiotics with in vitro activity against Clostridium difficile. The MICs against 15 strains of C. difficile were 0.12 to 0.25 microgram/ml for tiacumicin B, 0.25 to 1 microgram/ml for tiacumicin C, and 0.5 to 1 microgram/ml for vancomycin. The resistance frequency for both compounds against C. difficile was less than 2.8 x 10(-8) at four and eight times the MIC. The in vivo activities of the tiacumicins against two strains of C. difficile were compared with that of vancomycin in a hamster model of antibiotic-associated colitis. Oral therapy with 0.2, 1, or 5 mg of tiacumicin B or C per kg of body weight protected 100% of clindamycin-treated hamsters exposed to C. difficile ATCC 9689. Oral treatment with identical doses of vancomycin produced a prolonged, dose-dependent survival of hamsters, but it did not prevent the development of fatal colitis at doses of up to 5 mg/kg. When clindamycin-treated animals were exposed to another strain of C. difficile, both tiacumicin B and vancomycin were protective at 5 mg/kg, but not at lower doses. Tiacumicin C was not tested in vivo against the second strain of C. difficile. No tiacumicin B or C was detected in the sera of hamsters treated with single oral doses of 25 mg/kg, while antibiotic levels in the ceca of these hamsters reached 248 micrograms/ml and 285 mg/ml for tiacumicins B and C, respectively. The tiacumicins demonstrated in vitro and in vivo potencies against C. difficile and achieved high concentrations in the cecum, but not the serum, of hamsters after oral administration.

Aminoglycosides↗
PubMed1990

Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin, its major metabolite in humans.

MICs of clarithromycin and its major human metabolite, 14-hydroxy-clarithromycin, for Haemophilus influenzae in combination were reduced two- to fourfold compared with the MICs of each compound alone. Serum reduced the MICs of the parent compound and metabolite two- to fourfold compared with the MICs in medium without serum. In serum spiked with clinically relevant concentrations of clarithromycin and 14-hydroxy-clarithromycin at a fixed ratio of 4:1, 15 of 16 strains (94%) were inhibited and killed by combinations containing 1.2 and 0.3 micrograms/ml, respectively. In time kill experiments, the combination of parent compound and metabolite at one-fourth and one-half of their individual MICs, respectively, reduced bacterial counts by greater than 5 log CFU. The postantibiotic effect of clarithromycin combined with 14-hydroxy-clarithromycin was twice that of clarithromycin when tested alone. When orally administered to gerbils with H. influenzae otitis media, the 14-hydroxy metabolite was significantly more active than clarithromycin in reducing bacterial counts from the middle ear. The in vivo activity of the two compounds in combination was synergistic or additive, depending on the level of H. influenzae present at the time treatment was initiated. Significant reductions in bacterial counts and increases in cure rates were observed when clarithromycin at 50 or 100 mg/kg of body weight was combined with 14-hydroxy-clarithromycin at 12 mg/kg or higher. Results from in vitro and in vivo combinations suggest that routine susceptibility tests and animal efficacy studies with clarithromycin alone may underestimate its potential efficacy against H. influenzae.

Animals↗
PubMed1989

New macrolides active against Streptococcus pyogenes with inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance.

Macrolide-resistant bacteria can be classified as inducibly resistant or constitutively resistant. Inducibly resistant bacteria are resistant to 14-membered macrolides, such as erythromycin and clarithromycin (A-56268), but are susceptible to the 16-membered macrolides, such as tylosin and spiramycin, as well as to clindamycin. Constitutively resistant bacteria are resistant to macrolide-lincosamide-streptogramin B antibiotics. In this study, the MICs of several erythromycin and clarithromycin analogs against macrolide-susceptible and macrolide-resistant Streptococcus pyogenes strains were determined. Four 11,12-carbamate analogs of clarithromycin had lower MICs than erythromycin did against S. pyogenes with the inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance. Five 11,12-carbonate analogs of erythromycin with modifications at the 4" position of cladinose had lower MICs than did erythromycin against S. pyogenes with the constitutive type of resistance, and one of these compounds, which had a naphthyl-glycyl substitution at the 4" position, had a lower MIC than erythromycin against both the inducibly resistant and constitutively resistant strains. Two analogs of erythromycin with a modification on the 4" position of cladinose had lower MICs than erythromycin did against the constitutively resistant organisms but not against the inducibly resistant organisms. Thus, 14-membered macrolides can be modified so as to confer a low MIC when tested in vitro.

Aminoglycosides↗
PubMed1989

In vitro and in vivo activities of clarithromycin against Mycobacterium avium.

There is no effective therapy to treat Mycobacterium avium complex infection in patients with acquired immune deficiency syndrome. Clarithromycin (A-56268; TE-031) is a new macrolide which is twofold more active than erythromycin against most aerobic bacteria. In addition, higher levels in serum and tissue are achieved with clarithromycin than with erythromycin. In this study, clarithromycin, erythromycin, difloxacin, temafloxacin, ciprofloxacin, rifampin, amikacin, and ethambutol were tested in vitro and in vivo against the M. avium complex. The MICs for 90% of strains tested were 4 micrograms/ml for clarithromycin, 64 micrograms/ml for erythromycin, 32 micrograms/ml for difloxacin, 8 micrograms/ml for temafloxacin, 4 micrograms/ml for ciprofloxacin, 4 micrograms/ml for rifampin, 32 micrograms/ml for amikacin, and 32 micrograms/ml for ethambutol. Beige mice were infected intravenously with 10(7) CFU of M. avium ATCC 25291. Treatment was started on day 6 after infection and was administered twice a day at 8-h intervals for 9 days. Clarithromycin was the most effective compound in these tests and was effective in reducing the viable bacterial counts in the spleen when it was administered subcutaneously or orally at a dose of 25 mg/kg. Amikacin was the only other compound which showed activity in vivo. The peak concentration in serum at which clarithromycin was active was approximately 1.0 microgram/ml.

Animals↗
PubMed1989

Pacidamycins, a novel series of antibiotics with anti-Pseudomonas aeruginosa activity. III. Microbiologic profile.

Pacidamycins are nucleosidyl-peptide antibiotics which have activity only against Pseudomonas aeruginosa. Their MICs for other organisms such as Enterobacteriaceae, Staphylococcus aureus, most Streptococci and other Pseudomonas species are greater than 100 micrograms/ml. These compounds had no activity against erythromycin-susceptible Streptococci. The MICs for Streptococcus pyogenes with constitutive- and inducible-type of macrolide-lincosamide-streptogramin resistance were 12.5 and 25 micrograms/ml, respectively. The MICs against P. aeruginosa ranged from 8 to 64 micrograms/ml. The activity of these compounds was 1 to 2-fold less in serum than broth. Time-kill curves were performed using 4 and 8 times the MIC of pacidamycin 1. It was bactericidal against P. aeruginosa (3 log10 decrease in 4 to 6 hours). At 24 hours, resistant mutants were found in the cultures. The MICs of piperacillin and gentamicin for these mutants were the same as for the parent strain. The frequency of resistance to these compounds was less than 3.5 x 10(-6). The resistant mutants were stable after 10 transfers in antibiotic-free medium. The pacidamycins were inactive against P. aeruginosa in mouse protection test. After a single subcutaneous injection of 25 mg/kg of pacidamycin 1, the Cmax was approximately 50 micrograms/ml and the serum half-life was 0.5 hour.

Animals↗
PubMed1989

Coumamidines, new broad spectrum antibiotics of the cinodine type. III. Microbiologic activity of coumamidine gamma 1.

The coumamidines are novel antibiotics with activity against a wide spectrum of aerobic Gram-positive and Gram-negative bacteria. All microbiological studies were performed on coumamidine gamma 1. The MIC90s (micrograms/ml) of coumamidine are as follows: Staphylococcus aureus 1.0, Streptococcus pyogenes 8, Enterobacteriaceae 2.0, Pseudomonas aeruginosa 8, Campylobacter jejuni and Campylobacter coli 1, Legionella pneumophila 8, Haemophilus influenzae 0.5, Neisseria gonorrhoeae 0.5. Coumamidine had MICs ranging from 8 to greater 0.5, Neisseria gonorrhoeae 0.5. Coumamidine had MICs ranging from 8 to greater than 64 for most anaerobes, except some Peptostreptococcus strains. The aminoglycoside super-sensitive strain, P. aeruginosa BMH 10, was also super-sensitive to coumamidine (MIC 0.2 micrograms/ml). Coumamidine was rapidly bactericidal for S. aureus. The viable bacterial count in logarithmic phase cultures was reduced to less than 10 cfu within 2 hours after exposure to 4 times the MIC (3.12 micrograms/ml) of coumamidine. The frequency of resistance development was less than 1 X 10(-9) for Escherichia coli and S. aureus when selected at 4 and 8 times the MIC. The Cmax in mouse serum after a single subcutaneous dose of 25 mg/kg of coumamidine was 4.5 micrograms/ml and t1/2 was 1 hour. Coumamidine is stable in serum. In mouse protection tests against S. aureus NCTC 10649 the ED50 was less than 0.6 mg/kg/day when it was administered subcutaneously at 1 and 5 hours after infection. Coumamidine was not absorbed after oral administration. The antibacterial spectrum, bactericidal activity, stability in serum and low frequency of resistance make this an interesting new class of antibiotics.

Aminoglycosides↗
PubMed1989

Phenelfamycins, a novel complex of elfamycin-type antibiotics. III. Activity in vitro and in a hamster colitis model.

Phenelfamycins A, B, C, E, F and unphenelfamycin make up a recently isolated group of elfamycin-type antibiotics. All of the phenelfamycins were active against Gram-positive anaerobes, including Clostridium difficile. Phenelfamycin A was also active in vitro against Neisseria gonorrhoeae and Streptococci. Phenelfamycin A was found to be effective in prolonging the survival of hamsters in an animal model of C. difficile enterocolitis. After oral administration of phenelfamycin A to hamsters, antibiotic was detected in the caecal contents but not in the blood.

Aminoglycosides↗
PubMed1988

Susceptibility of Campylobacter pylori to macrolides and fluoroquinolones.

The in-vitro activities of several 14-, 15- and 16-membered macrolides and fluoroquinolones against Campylobacter pylori were determined. In general, 14-membered macrolides, such as clarithromycin and flurithromycin, were more active than the 15-membered macrolide, azithromycin, which was more active than 16-membered macrolides, such as miocamycin and rokitamycin. Fluoroquinolones, except ciprofloxacin and A-61827, were less active than macrolides. Clarithromycin was the most active of the new compounds against C. pylori and was as active as ampicillin. MICs of all compounds at pH 5.5 were increased when compared to MICs determined at pH 7.3. All compounds had MBCs which were the same as or within one two-fold dilution of their MICs. Frequencies of spontaneous resistance development by C. pylori NCTC 11637 at four and eight times the MIC of the compounds were low and ranged from less than 1 x 10(-9) to 1 x 10(-7).

4-Quinolones↗
PubMed1988

A-61827 (A-60969), a new fluoronaphthyridine with activity against both aerobic and anaerobic bacteria.

A-61827 (A-60969 is the hydrochloric salt of A-61827) is a new aryl-fluoronaphthyridine which is active against aerobic and anaerobic bacteria. The MICs of A-61827 for 90% of strains (MIC90) of staphylococci and streptococci were less than or equal to 1 microgram/ml and were generally 1 to 4 twofold dilutions less than those of ciprofloxacin for these bacteria. The MIC90S of A-61827 for members of the family Enterobacteriaceae and Pseudomonas aeruginosa were also less than or equal to 1 microgram/ml. Ciprofloxacin was 1 to 3 twofold dilutions more active than A-61827 against these gram-negative bacteria. Neisseria gonorrhoeae, Campylobacter jejuni, and Haemophilus influenzae were susceptible to less than 0.06 microgram of A-61827 per ml. The MIC90 of A-61827 for Legionella pneumophila was 0.25 microgram/ml. A-61827 was as potent or 1 to 2 twofold dilutions more potent than ciprofloxacin against these organisms. The MIC90 of A-61827 for all anaerobic bacteria was less than or equal to 4 micrograms/ml compared with less than or equal to 32 micrograms/ml for ciprofloxacin. In mouse protection tests, A-61827 was as active as ciprofloxacin against Escherichia coli, P. aeruginosa, and Salmonella typhimurium and 5 to 10 times more active than ciprofloxacin against Staphylococcus aureus and Streptococcus pyogenes. A-61827 was as active as ciprofloxacin against P. aeruginosa in a mouse pyelonephritis model and more active than ciprofloxacin and metronidazole in a mouse Bacteroides fragilis abscess model. After oral administration of 100 mg/kg to mice, the peak concentrations of A-61827 and ciprofloxacin in serum were 2.3 and 2.4 micrograms/ml and the half-lives in serum were 3.9 and 1.2 h, respectively.

Abscess↗
PubMed1988

Comparative in vitro activities of new 14-, 15-, and 16-membered macrolides.

The in vitro activities of several 14-, 15- and 16-membered macrolides were compared with that of erythromycin. In general, 14-membered macrolides such as erythromycin, clarithromycin, and flurithromycin were more active against streptococci and Bordetella pertussis than was the 15-membered macrolide azithromycin, which was more active than 16-membered macrolides such as miocamycin and rokitamycin. Clarithromycin was the most active compound against Streptococcus pyogenes, pneumococci, Listeria monocytogenes, and Corynebacterium species. Legionella pneumophila was most susceptible to miocamycin, clarithromycin, and rokitamycin. Branhamella catarrhalis, Neisseria gonorrhoeae, and Haemophilus influenzae were most susceptible to azithromycin. Azithromycin and dirithromycin were the most active compounds against Campylobacter jejuni. MICs of 16-membered macrolides for strains expressing inducible-type resistance to erythromycin were less than or equal to 1 microgram/ml, whereas none of the compounds had activity against strains expressing constitutive-type resistance. The MICs of roxithromycin, miocamycin, rokitamycin, and josamycin increased in the presence of human serum, whereas MICs of the other compounds either were unchanged or decreased.

Aminoglycosides↗
PubMed1988

Variability of clarithromycin and erythromycin susceptibility tests with Haemophilus influenzae in four different broth media and correlation with the standard disk diffusion test.

Four separate laboratories performed antimicrobial susceptibility tests with 40 Haemophilus influenzae isolates, each tested in triplicate. Erythromycin and a new macrolide, clarithromycin (A-56268; TE-031), were tested by the disk diffusion method, by the agar dilution procedure in two different media, and by broth microdilution tests in four different media. Erythromycin MICs for 90% of the strains were 16 micrograms/ml in Mueller-Hinton broth with 3% lysed horse blood and NAD, 4.0 micrograms/ml in hemophilus test medium, and 2.0 micrograms/ml in supplemented Schaedler broth or in the fastidious broth medium from Beckman Instruments, Inc. Clarithromycin MICs were generally 1 doubling dilution greater than erythromycin MICs in each of the media. Erythromycin disk tests corresponded best with MICs determined in the fastidious broth medium. In that same medium, clarithromycin MICs were about 1 doubling dilution greater than what would be expected from the results of disk tests. Because there were fewer growth failures, hemophilus test medium is recommended for microdilution tests with H. influenzae. Incubation of all tests for a full 24 h without an increased CO2 atmosphere was needed to achieve maximal precision of the tests. Interlaboratory and intralaboratory reproducibility of all tests was satisfactory.

Clarithromycin↗
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

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

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↗
PubMed1986

Pathophysiology of primary meningococcal pericarditis associated with Neisseria meningitidis group C. A case report and review of the literature.

Pericarditis associated with Neisseria meningitidis in the absence of meningitis or meningococcemia is an extremely rare event. We report herein a case of a 59-yr-old woman with primary meningococcal pericarditis caused by Neisseria meningitidis group C. The patient responded to a course of penicillin therapy and recovery was uncomplicated. The pathophysiologic features underlying or contributing to the disease are discussed and the pertinent literature is reviewed.

Cardiac Tamponade↗