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Biomedical subjects

A Bryskier

Publications and source records attributed to A Bryskier.

At least 55 records · Page 3Linked to original sources
PubMed1998

Roxithromycin: review of its antimicrobial activity.

Roxithromycin is a semi-synthetic 14-membered-ring macrolide antibiotic in which the erythronolide A lactone ring has been altered to prevent inactivation in the gastric milieu. The in-vitro activity of roxithromycin is well documented and similar to that of other macrolide antibiotics. Roxithromycin is active against gram-positive and gram-negative cocci, gram-positive bacilli and some gram-negative bacilli, but has no significant effect on the predominant faecal flora. It also displays good activity against atypical pathogens, such as Mycobacterium avium complex, Helicobacter pylori and Borrelia spp. It penetrates and accumulates within cells, such as macrophages and polymorphonuclear neutrophils (PMNs), where it is distributed between the cytosol and cellular granules. Once inside the cells, it is active against intracellular pathogens, such as Legionella, Chlamydia, Mycobacterium, Rickettsia and Borrelia spp. Like other macrolides, roxithromycin displays a significant post-antibiotic effect which is dependent on the pathogens under study, the concentration of roxithromycin and the duration of exposure. In vivo, roxithromycin is as effective or more effective than other macrolides in a wide range of infections.

Anti-Bacterial Agents↗
PubMed1998

In-vitro antimicrobial activity of HMR 3004 (RU 64004) against erythromycin A-sensitive and -resistant Corynebacterium spp. isolated from clinical specimens.

We studied the in-vitro activity of HMR 3004 (RU 64004), a new ketolide, against 161 clinical isolates of Corynebacterium spp. including isolates resistant to erythromycin A, josamycin and lincomycin. HMR 3004 was active against all erythromycin A-sensitive isolates as well as against 75.8% and 45.4% of erythromycin A-intermediate and -resistant isolates, respectively. In contrast, HMR 3004 was active against 40 (46.5%) of 86 isolates resistant to erythromycin A, josamycin and lincomycin as well as against two isolates that were resistant to erythromycin A and lincomycin but not resistant (i.e. susceptible or intermediate) to josamycin.

Anti-Bacterial Agents↗
PubMed1998

Use of ketolides in combination with other drugs to treat experimental toxoplasmosis.

Because combination therapy is required to treat human toxoplasmosis, we examined combinations of the ketolides HMR 3004 and HMR 3647 with atovaquone, clindamycin or sulphadiazine in a murine model of toxoplasmosis. An oral dose of 50 mg/kg/day of HMR 3004 protected 30% of mice lethally infected with Toxoplasma gondii. The same dose protected 100% of infected mice when administered in combination with non-protective doses of atovaquone, clindamycin or sulphadiazine. Similar results were noted with 25 mg/kg/day of HMR 3647. These results demonstrate that these drug combinations are highly effective for treating toxoplasmosis in mice.

Animals↗
PubMed1998

In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to two ketolides (HMR 3004 and HMR 3647), four macrolides (azithromycin, clarithromycin, erythromycin A, and roxithromycin), and two ansamycins (rifampin and rifapentine).

When tested by agar dilution on Mueller-Hinton agar supplemented with 5% horse blood, the ketolides HMR 3004 and HMR 3647 were slightly more active (MIC at which 90% of the isolates were inhibited [MIC90], 0.03 microg/ml) against Bordetella pertussis than azithromycin, clarithromycin, erythromycin A, and roxithromycin. Azithromycin (MIC90, 0.06 microg/ml) was the most active compound against B. parapertussis. Rifampin and rifapentine were considerably less active.

Anti-Bacterial Agents↗
PubMed1998

In vitro activities of the new ketolide antibiotics HMR 3004 and HMR 3647 against Streptococcus pneumoniae in Germany.

The comparative in vitro activity of HMR 3004 and HMR 3647, new ketolide antibiotics, was tested by a standard agar dilution technique against 221 pneumococcal strains, including isolates with intermediate levels of resistance to penicillin and erythromycin-resistant isolates. The ketolides were more active than other macrolides and showed excellent activity against erythromycin-resistant strains. All the strains were inhibited by < or = 2 micrograms of HMR 3004/ml or by < or = 0.5 microgram of HMR 3647/ml.

Anti-Bacterial Agents↗
PubMed1998

Interactions between HMR 3647, a new ketolide, and human polymorphonuclear neutrophils.

HMR 3647, a new ketolide, is active upon intracellular pathogens. We previously demonstrated that HMR 3004 (RU 64004), another ketolide, is highly concentrated by human polymorphonuclear neutrophils (PMNs). This prompted us to evaluate whether the presence of a 3-keto group instead of an L-cladinose, a neutral sugar characteristic of erythromycin A derivatives, confers peculiar pharmacokinetic properties with regard to cellular accumulation and efflux. After incubation with the radiolabelled drug, HMR 3647 uptake was determined by a velocity gradient centrifugation technique. HMR 3647 was avidly concentrated by PMNs, without saturation, over a 3-h incubation period, with cellular-to-extracellular concentration ratios of 31 +/- 4.2 at 5 min and up to 348 +/- 27.1 at 180 min. About 60% of HMR 3647 was located in the granular compartment; less than 6% was associated with the membranes. HMR 3647 gradually egressed from loaded cells placed in drug-free medium. Uptake was dependent on environmental temperature (activation energy, 128 +/- 9. 4 kJ/mol) but not on extracellular pH. HMR 3647 displayed Michaelis-Menten saturation kinetics with a mean Vmax of 2315 ng/2.5 x 10(6) PMNs/5 min and a mean Km of 117 mg/liter (144 microM). As already observed with erythromycin A-derived macrolides, extracellular Ca2+ was necessary for optimal uptake of HMR 3647. Interestingly, verapamil increased the uptake of HMR 3647 at 5 min, but this was followed by gradual inhibition at later incubation times, a phenomenon probably related to stimulation of drug efflux. The impact of intracellular accumulation of HMR 3647 on PMN functions was also investigated. In contrast to other erythromycin A derivatives, HMR 3647 only weakly triggered granule exocytosis, but it inhibited superoxide anion production in a time- and concentration-dependent manner, with concentrations which inhibited 50% of control response of 55 (67 microM) (5 min) and 30 (36 microM) (30 min) mg/liter for formyl-methionyl-leucyl-phenylalanine stimulation and 117 (143 microM) (5 min) and 44 (54 microM) (30 min) mg/liter for phorbol myristate acetate stimulation.

Anti-Bacterial Agents↗
PubMed1997

Bactericidal activity of cefodizime on Enterobacteriaceae in an in-vitro model simulating plasma pharmacokinetics in humans.

An in-vitro dialysis model was employed to assess the feasibility of once-daily dosing of cefodizime in the treatment of infections caused by various Enterobacteriaceae: Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Serratia marcescens, Providencia stuartii and Enterobacter cloacae. This model simulated the concentrations of cefodizime detected in human blood after an intravenous (i.v.) bolus injection of 1 g or 2 g of the antibiotic. Validation of the model was undertaken to confirm its utility. Based on the data obtained with this model, once-daily dosing with 1 g cefodizime (i.v.) should be effective against infections due to the commonest Gram-negative bacteria (E. coli, K. pneumoniae, M. morganii). For infections caused by Enterobacteriaceae strains that produce large quantities of Class I beta-lactamases, twice-daily (P. stuartii or S. marcescens) or four times daily (E. cloacae) administration of 1 g cefodizime may be required.

Cefotaxime↗
PubMed1997

The ketolide antibiotics HMR 3647 and HMR 3004 are active against Toxoplasma gondii in vitro and in murine models of infection.

Ketolides are a new class of macrolide antibiotics that have been shown to be active against a variety of bacteria including macrolide-resistant bacteria and mycobacteria. We examined two ketolides, HMR 3647 and HMR 3004, for their in vitro and in vivo activities against the protozoan parasite Toxoplasma gondii. In vitro, both ketolides at concentrations as low as 0.05 microg/ml markedly inhibited replication of tachyzoites of the RH strain within human foreskin fibroblasts. HMR 3004 demonstrated some toxicity for host cells after they were exposed to 5 microg of the drug per ml for 72 h. In contrast, HMR 3647 did not show any significant toxicity even at concentrations as high as 25 microg/ml. In vivo, both ketolides provided remarkable protection against death in mice lethally infected intraperitoneally with tachyzoites of the RH strain or orally with tissue cysts of the C56 strain of T. gondii. A dosage of 100 mg of HMR 3647 per kg of body weight per day administered for 10 days protected 50% of mice infected with tachyzoites. The same dosage of HMR 3004 protected 100% of the mice. In mice infected with cysts, a dosage of 30 mg of HMR 3647 per kg per day protected 100% of the mice, whereas a dosage of 40 mg of HMR 3004 per kg per day protected 75% of the mice. These results demonstrate that HMR 3647 and HMR 3004 possess excellent activities against two different strains of T. gondii and may be useful for the treatment of toxoplasmosis in humans.

Animals↗
PubMed1997

Dual beta-lactam-fluoroquinolone compounds: a novel approach to antibacterial treatment.

Codrugs comprise a beta-lactam-fluoroquinolone antibacterial hybrid. These new agents have been developed with the aim of enhancing the antibacterial spectrum of current therapies, overcoming intrinsic and acquired resistance, and diminishing severe side-effects. A few compounds, including Ro 23-9424, have entered Phase I clinical trials. Furthermore, a series of oral codrugs have been synthesised, although clear oral bioavailability has not yet been demonstrated. New drugs are urgently needed to treat Gram-positive resistant bacteria.

Journal Article↗
PubMed1997

Novelties in the field of macrolides.

Research in the field of macrolide antibiotics has continued. The aims of research efforts are quite different with 14-, 15- and 16-membered ring macrolides. A review of 14- and 15-membered ring macrolides covering the period up to 1995 was published in a previous issue of this journal.

Journal Article↗
PubMed1997

Novelties in the field of parenteral cephem antibacterials since 1993.

There is still considerable interest in cephem antibacterial agents. In fact, there are a significant number of patents submitted for this antibacterial class. All the new cephem derivatives, independent of which group they belong to (III to V), possess a 2-amino-5-thiazolyl or a 5-amino-2-thiadiazolyl ring with an oxime group (at position 7 of the cephem nucleus). At position 3, they have a C-3' quaternary ammonium moiety. Research has focused on the following structural modifications: the nature of the oxime residues and the charged azolium heterocycle, and the addition of the vinylogous chain. The aim of researchers is to increase the overall activity of these compounds against Gram-negative bacilli, including against isolates producing type 1 beta-lactamases or extended spectrum beta-lactamases (Enterobacteriaceae). Non-fermentative Gram-negative bacilli are now included in the first screening process, in addition to Pseudomonas aeruginosa. Extensive research is ongoing with the aim of solving the MRSA problem. New promising entities have been reported.

Journal Article↗
PubMed1997

Novelties in the field of fluoroquinolones.

The field of fluoroquinolone research is rapidly expanding. Bacterial targets are constantly changing to meet the demands of resistance. At present, new compounds are targeting respiratory pathogens, such as Streptococcus pneumoniae. However, problems such as phototoxicity, cardiotoxicity and CNS disturbances must be overcome. New promising fluoroquinolones include: HSR 903, LB 20304 and BAY 12-8039. Research in the field of mycobacteria, especially for Mycobacterium tuberculosis, is also underway.

Journal Article↗
PubMed1996

Spectrum of activity of levofloxacin against nontuberculous mycobacteria and its activity against the Mycobacterium avium complex in combination with ethambutol, rifampin, roxithromycin, amikacin, and clofazimine.

The spectrum of activity of levofloxacin was initially determined against 29 strains belonging to 16 species of atypical mycobacteria by measuring radiometric MICs. Levofloxacin MICs were 1 to 2 dilutions lower compared with those obtained for ofloxacin and 8 to 64 dilutions lower compared with those obtained for its D-isomer. Levofloxacin MICs were below its peak level in serum (5.5 micrograms/ml following administration of a single oral dose of 350 mg) for 25 of 29 isolates tested. It possessed MICs below its peak level in serum for M. scrofulaceum, M. szulgai, M. malmoense, M. xenopi, M. marinum, M. kansasii, M. chelonei, M. abcessus, M. fortuitum, and M. peregrinum. Regarding the M. avium complex, the MICs of levofloxacin for 11 clinical isolates (7 from human immunodeficiency virus-positive patients and 4 from human immunodeficiency virus-negative patients) were 1 to 2 dilutions lower than those of ofloxacin. Among 20 isolates belonging to 12 pathogenic mycobacterial species, the MBC/MIC ratios varied from 1 to 4 for levofloxacin and 2 to 4 for ofloxacin. When drug combinations were screened by using the radiometric x/y quotient methodology against five M. avium complex isolates, levofloxacin activity against all five isolates was enhanced by ethambutol and activity against three isolates was enhanced by clofazimine. Screening of three-drug combinations showed that the combination levofloxacin-ethambutol with a third potential anti-M. avium drug (rifampin, roxithromycin, amikacin, or clofazimine) resulted in enhanced activity for all 20 drug combinations screened.

Amikacin↗
PubMed1996

In vitro activities of 14 antibiotics against 100 human isolates of Yersinia pestis from a southern African plague focus.

A limited repertoire of antimicrobial agents is currently in use for the treatment of plague. We investigated the in vitro activities of some newer antimicrobial agents against Yersinia pestis. Among the injectable agents tested, cefotaxime was the most active, and among the oral agents, both levofloxacin and ofloxacin were highly active, with MICs at which 90% of isolates are inhibited of < 0.03 microgram/ml. the susceptibilities to the ketolide RU004 and the penem faropenem warrant attention. The enhanced activities of quinolones against Y. pestis suggest that these agents should be further investigated for the treatment of human plague in the future.

Africa, Southern↗
PubMed1996

In vitro susceptibility of penicillin-resistant Streptococcus pneumoniae to levofloxacin, selection of resistant mutants, and time-kill synergy studies of levofloxacin combined with vancomycin, teicoplanin, fusidic acid, and rifampin.

Among 180 clinical isolates of pneumococci, no strains were found to be resistant to levofloxacin (MIC, > or = 4 micrograms/ml) whereas 9% were resistant to ofloxacin and 7% were resistant to ciprofloxacin. Synergism was demonstrated by time-kill studies in nine of nine strains for the combination of levofloxacin and vancomycin and in six of nine strains for levofloxacin plus teicoplanin. The combinations of levofloxacin with rifampin or fusidic acid were indifferent. Resistant mutants could be selected using incremental concentrations of levofloxacin. For two of nine strains that were initially susceptible to levofloxacin, the MICs reached the resistance range (> or = 4 micrograms/ml). In contrast, ciprofloxacin and ofloxacin selected mutants from the susceptible to the resistant range more frequently (four of six and six of seven strains, respectively). These data argue for further study of levofloxacin against penicillin-resistant pneumococci.

Anti-Bacterial Agents↗
PubMed1996

In vitro activities of levofloxacin used alone and in combination with first- and second-line antituberculous drugs against Mycobacterium tuberculosis.

By using the radiometric BACTEC 460-TB methodology, the inhibitory and bactericidal activity of the optically active L-isomer of ofloxacin (levofloxacin) was compared with those of the D-isomer and the commercially available mixture containing equal amounts of DL-isomers (ofloxacin) against the Mycobacterium tuberculosis complex (type strain H37Rv, a panel of drug-susceptible and -resistant clinical isolates including multidrug-resistant isolates of M. tuberculosis, as well as M. africanum, M. bovis, and M. bovis BCG). Levofloxacin MICs (range 0.50 to 0.75 microgram/ml) were about 1 dilution lower than those of ofloxacin (MIC range, 0.75 to 1.00 microgram/ml) and 5 to 6 dilutions lower than those of the D-isomer (MIC range, 32 to 60 micrograms/ml). The MICs of levofloxacin, ofloxacin, and D-ofloxacin at which 90% of the strains are inhibited were 0.50, 1.00, and 64 micrograms/ml, respectively. The multidrug-resistant M. tuberculosis strains resistant to first-line drugs were as susceptible to quinolones as the wild-type drug-susceptible isolates. Levofloxacin at 0.5 microgram/ml showed bactericidal activity comparable to the activities of 1.0 microgram of ofloxacin per ml and 64 micrograms of D-ofloxacin per ml, with MBCs within the range of 0.5 to 2.0 micrograms/ml, compared with MBCs of 0.75 to 4.0 micrograms of ofloxacin per ml for M. tuberculosis, M. africanum, M. bovis BCG. Combination testing of sub-MICs of levolofoxacin with other first-line (isoniazid, rifampin, and ethambutol) and second-line (amikacin and clofazimine) antituberculous drugs was evaluated with various two-, three-, and four-drug combinations; enhanced drug activity was observed in 8 of 25, 12 of 20, and 8 of 15 tests, respectively, indicating that levofloxacin acts in synergy with other antituberculous drugs.

Anti-Infective Agents↗
PubMed1995

[Antibiotherapy in the past, present and future].

The antibiotic era started in 1941. Several antibiotics were obtained from the fermentation broth, either from moulds (penicillin) or from Actinomyces species (erythromycin). Numerous antibacterial agents were prepared synthetically such as benzylpyrimidines, 4-quinolones, nitroheterocyclic derivatives, have been developed. Consecutive "waves" of newer antibiotics was helpful to solve some infectious problems but simultaneous emergence of resistant strains has occurred amongst initially susceptible bacteria. This imposes reconsideration of our therapeutic armamentarium and a search for new compounds as well as for new concepts in anti-infective therapy.

Anti-Bacterial Agents↗