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Biomedical subjects

A Bryskier

Publications and source records attributed to A Bryskier.

At least 37 records · Page 2Linked to original sources
PubMed2000

In vivo activity of levofloxacin alone or in combination with imipenem or amikacin in a mouse model of Acinetobacter baumannii pneumonia.

We evaluated the in vivo activity of levofloxacin alone or in combination with imipenem or amikacin in a mouse model of Acinetobacter baumannii pneumonia using a susceptible strain and one with low-level resistance (MIC/MBC of levofloxacin: 0.06/0.06 and 4/4 mg/L, respectively). As demonstrated previously with other pathogens, the AUC/MIC ratio predicted the efficacy of fluoroquinolones against A. baumannii. This parameter correlated with bactericidal effect and survival. Combination therapy did not enhance the efficacy of levofloxacin.

Acinetobacter Infections↗
PubMed2000

In vitro activities of the ketolides telithromycin (HMR 3647) and HMR 3004 compared to those of clarithromycin against slowly growing mycobacteria at pHs 6.8 and 7.4.

The in vitro activities of HMR 3647 (telithromycin) and HMR 3004, two novel semisynthetic ketolides, were investigated and compared with that of the reference macrolide drug, clarithromycin, against 34 strains of slowly growing mycobacteria at pHs 6.8 and 7.4, as determined radiometrically. The MICs at pH 7.4 were about 1 to 2 dilutions lower than those observed at pH 6.8. In terms of the highest to the lowest activity, the three antibiotics could be classified as follows: clarithromycin > HMR 3004 > HMR 3647. Among the species tested, Mycobacterium bovis BCG, M. ulcerans, M. avium, and M. paratuberculosis were moderately susceptible to HMR 3004 and HMR 3647 (MICs at pH 7.4, < or =5.0 and < or =20.0 microg/ml, respectively, versus < or =1.25 microg/ml for clarithromycin), whereas M. tuberculosis, M. africanum, M. bovis, and M. simiae were resistant (MICs, > or =10.0 and > or =40.0 microg/ml, respectively, at pH 7.4). Although not more active than clarithromycin in vitro, the high level of intracellular accumulation of the two ketolides inside phagocytes warrants further screening in experimental animal models.

Anti-Bacterial Agents↗
PubMed2000

In vitro activity of the new ketolide telithromycin compared with those of macrolides against Streptococcus pyogenes: influences of resistance mechanisms and methodological factors.

One hundred and seven clinical isolates of Streptococcus pyogenes, 80 susceptible to macrolides and 27 resistant to erythromycin A (MIC >0.5 microgram/ml), were examined. The erythromycin A-lincomycin double-disk test assigned 7 resistant strains to the M-phenotype, 8 to the inducible macrolide, lincosamide, and streptogramin B resistance (iMLS(B)) phenotype, and 12 to the constitutive MLS(B) resistance (cMLS(B)) phenotype. MICs of erythromycin A, clarithromycin, azithromycin, roxithromycin, and clindamycin were determined by a broth microdilution method. MICs of telithromycin were determined by three different methods (broth microdilution, agar dilution, and E-test methods) in an ambient air atmosphere and in a 5 to 6% CO(2) atmosphere. Erythromycin A resistance genes were investigated by PCR in the 27 erythromycin A-resistant isolates. MICs of erythromycin A and clindamycin showed six groups of resistant strains, groups A to F. iMLS(B) strains (A, B, and D groups) are characterized by two distinct patterns of resistance correlated with genotypic results. A- and B-group strains were moderately resistant to 14- and 15-membered ring macrolides and highly susceptible to telithromycin. All A- and B-group isolates harbored erm TR gene, D-group strains, highly resistant to macrolides and intermediately resistant to telithromycin (MICs, 1 to 16 microgram/ml), were all characterized by having the ermB gene. All M-phenotype isolates (C group), resistant to 14- and 15-membered ring macrolides and susceptible to clindamycin and telithromycin, harbored the mefA gene. All cMLS(B) strains (E and F groups) with high level of resistance to macrolides, lincosamide, and telithromycin had the ermB gene. The effect of 5 to 6% CO(2) was remarkable on resistant strains, by increasing MICs of telithromycin from 1 to 6 twofold dilutions against D-E- and F-group isolates.

Anti-Bacterial Agents↗
PubMed2000

Effect of proinflammatory cytokines on the interplay between roxithromycin, HMR 3647, or HMR 3004 and human polymorphonuclear neutrophils.

Cytokines, the hallmarks of infectious and inflammatory diseases, modify phagocyte activities and thus may interfere with the immunomodulating properties of antibacterial agents. We have investigated whether various proinflammatory cytokines (interleukin 1 [IL-1], IL-6, IL-8, gamma interferon, tumor necrosis factor alpha [TNF-alpha], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) modify two macrolide properties, i.e., inhibition of oxidant production by polymorphonuclear neutrophils (PMN) and cellular uptake. Roxithromycin and two ketolides, HMR 3647 and HMR 3004, were chosen as the test agents. TNF-alpha and GM-CSF (but not the other cytokines) decreased the inhibitory effect of HMR 3647 only on oxidant production by PMN. Fifty percent inhibitory concentrations were, however, in the same range in control and cytokine-treated cells (about 60 to 70 microgram/ml), suggesting that HMR 3647 acts downstream of the priming effect of cytokines. In contrast, the impairment of oxidant production by roxithromycin and HMR 3004 was unchanged (or increased) in cytokine-treated cells. This result suggests that HMR 3004 (the strongest inhibitory drug, likely owing to its quinoline side chain) and roxithromycin act on a cellular target upstream of cytokine action. In addition, TNF-alpha and GM-CSF significantly (albeit moderately) impaired (by about 20%) the uptake of the three molecules by PMN. The inhibitory effect of these two cytokines seems to be related to activation of the p38 mitogen-activated protein kinase. Our data also illuminate the mechanism underlying macrolide uptake: protein kinase A- and tyrosine kinase-dependent phosphorylation seems to be necessary for optimal uptake, while protein kinase C activation impairs it. The relevance of our data to the clinical setting requires further investigations, owing to the complexity of the cytokine cascade during infection and inflammation.

Anti-Bacterial Agents↗
PubMed2000

In vitro activities of telithromycin (HMR 3647) against Rickettsia rickettsii, Rickettsia conorii, Rickettsia africae, Rickettsia typhi, Rickettsia prowazekii, Coxiella burnetii, Bartonella henselae, Bartonella quintana, Bartonella bacilliformis, and Ehrlichia chaffeensis.

In vitro activities of telithromycin compared to those of erythromycin against Rickettsia spp., Bartonella spp., Coxiella burnetii, and Ehrlichia chaffeensis were determined. Telithromycin was more active than erythromycin against Rickettsia, Bartonella, and Coxiella burnetii, with MICs of 0.5 microg/ml, 0.003 to 0.015 microg/ml, and 1 microg/ml, respectively, but was inactive against Ehrlichia chaffeensis.

Anti-Bacterial Agents↗
PubMed2000

Comparative activities of telithromycin (HMR 3647), levofloxacin, and other antimicrobial agents against human mycoplasmas.

The activities of telithromycin and levofloxacin against 99 mycoplasma strains were compared to those of several macrolides, ofloxacin, and doxycycline. Telithromycin MICs of </=0.25 microgram/ml were found for all isolates, except for Mycoplasma hominis, while levofloxacin was active at concentrations of </=1 microgram/ml against all species studied.

Anti-Bacterial Agents↗
PubMed2000

Cephems: fifty years of continuous research.

Since 1964, seven waves of parenteral cephems have been reported. All of them were designed to meet medical needs. The first (group I) and the third (group III) waves were very successful and drugs belonging to group III are widely used in the treatment of severe infections. A new series of compounds (group VII), with a new compound underdevelopment was designed for the treatment of Staphylococcus aureus strain resistant to methicillin but also to glyco- and lipoglycopeptides. By modifying the substituent at position 3 and 7 of the cephems rings optimal moieties have been fixed leading to potent anti-Gram-positive drugs. Alterations of substituents are still in progress to obtain optimal anti-Gram-positive (anti-MRSA) compounds. The first oral cephem cephalexin was introduced in clinical practice in 1967. Since this time, many esterified and non-esterified cephems have been synthesized and introduced in clinics. There are two groups of compounds, alpha-amino and non-alpha-amino cephems which are classified in six groups according to their chemical structure. The absorption route was explored and three transporting systems have been described according to the physico-chemical properties of these compounds, in addition prodrugs are passively absorbed.

Bacteria↗
PubMed1999

Novelties in the field of anti-infectives in 1998.

In 1998, about 30 new medicinal chemical entities in the field of antibacterials and antifungals were presented during the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, held in San Diego. Among these compounds, only a few of them seem to be candidates for preclinical and clinical development: GAR 936, RWJ 54,418, ME 1209, L-084, FK 483, and DC 756. Other compounds seem to be in the preselection stage or potential lead compounds.

Anti-Infective Agents↗
PubMed1999

The suppository form of antibiotic administration: pharmacokinetics and clinical application.

The rectal route of antibiotic administration might be used effectively when other routes of administration are inadequate or unsuitable. With the use of various adjuvants, the rectal route can provide satisfactory pharmacokinetics and acceptable local tolerance. Experiments in animals have demonstrated the influence of the pharmaceutical formulation of suppositories on the rectal absorption and systemic distribution of beta-lactams and aminoglycosides. In healthy volunteers and in children under treatment, similar adjuvants--mainly glyceride mixtures or non-ionic surface agents--have increased the rectal absorption of aminopenicillins, cephalosporins and macrolides. Other antibiotics, including metronidazole and cotrimoxazole, have been investigated in respect of their potential rectal administration.

Animals↗
PubMed1999

The bactericidal activities of HMR 3004, HMR 3647 and erythromycin against gram-positive bacilli and development of resistance.

The bactericidal activities of two new ketolides, HMR 3004 and HMR 3647, and the potential to develop resistance to these two antibiotics were studied in Gram-positive bacilli. As judged by time-kill kinetics both ketolides were mostly bacteriostatic, being bactericidal against only highly susceptible isolates of Corynebacterium striatum (two isolates) and Corynebacterium minutissimum (one isolate). Spontaneous resistant mutants were detected in seven of 30 strains tested, mainly in Rhodococcus equi, C. minutissimum and C. striatum, with a very low frequency of mutation (10(-12)-10(-15)).

Animals↗
PubMed1999

In-vitro antibacterial activity of levofloxacin against hospital isolates: a multicentre study.

The objective of this study was to evaluate the activity of the fluoroquinolone, levofloxacin, against hospital isolates of bacteria. MICs of levofloxacin were determined for 2154 strains by agar dilution. Breakpoints for susceptibility testing were calculated using the agar diffusion technique with 5 micrograms discs. The activity of levofloxacin against nalidixic acid- and pefloxacin-susceptible Enterobacteriaceae (n = 668) was higher (MIC50/90 0.06-0.12 mg/L) than previously reported for ofloxacin. As seen with other fluoroquinolones, this activity was reduced against nalidixic acid-resistant and pefloxacin-intermediate and -resistant strains (MIC 1-8 mg/L). MICs for Pseudomonas aeruginosa (n = 104) were between 0.12 and 128 mg/L. Levofloxacin had good activity against nalidixic acid- and pefloxacin-susceptible Acinetobacter baumannii (n = 12; MIC 0.06-0.25 mg/L), but the activity was reduced against nalidixic acid- and pefloxacin-resistant strains (n = 80; MIC 1-32 mg/L). Haemophilus influenzae (n = 70), Haemophilus parainfluenzae (n = 47) and Moraxella catarrhalis (n = 64) were inhibited by low concentrations of levofloxacin (MICs 0.016-0.03 mg/L, 0.03-0.12 mg/L) and 0.03-0.12 mg/L, respectively). Clostridium perfringens (n = 23; MIC 0.25-1 mg/L) was more susceptible than Bacteroides fragilis (n = 60; MIC 0.5-4 mg/L). Levofloxacin showed superior activity compared with ofloxacin against methicillin-susceptible staphylococci (n = 107; MIC 0.03-0.5 mg/L); the resistant strains (MICs 2-32 mg/L) were usually also resistant to methicillin. Levofloxacin was less effective against enterococci (n = 105; MIC 1-32 mg/L), but streptococci (n = 192) and pneumococci (n = 129), including 58 penicillin-non-susceptible strains, were inhibited by low concentrations (MICs 0.5-2 mg/L). According to the regression curve, zone diameters were usually 20-22 mm, 17-19 mm and 15-16 mm for MICs of 1, 2 and 4 mg/L, respectively. In conclusion, this study, performed on a large number of strains, confirms the superior anti-bacterial activity of levofloxacin compared with ofloxacin, especially against pathogens isolated from respiratory tract infections.

Acinetobacter↗
PubMed1999

A comparative study of the in-vitro activity of levofloxacin against Streptococcus pneumoniae.

In this study, the in-vitro activity of levofloxacin against Streptococcus pneumoniae was compared with the activities of a range of other antibiotics. In total, 320 penicillin-susceptible and 30 penicillin-intermediate clinical isolates of S. pneumoniae were collected in Germany between 1992 and 1994 from patients with bacteraemic pneumonia. MICs were determined using the agar dilution methodology recommended by the NCCLS and the results with levofloxacin compared with those with ofloxacin, D-ofloxacin, ciprofloxacin, amoxycillin, cefpodoxime, cefixime, cefuroxime, faropenem, erythromycin and tetracycline. Levofloxacin (MIC50 1 mg/L) was approximately twice as active against the isolates as ofloxacin (MIC50 2 mg/L). D-ofloxacin (MIC90 32 mg/L) showed no activity, while beta-lactam antibiotics showed elevated MIC90 values against penicillin-intermediate strains (amoxycillin, 1 mg/L; cefpodoxime, 2 mg/L; cefixime, 32 mg/L; cefuroxime, 8 mg/L) in comparison with the MIC90 obtained with penicillin-susceptible strains (amoxycillin, 0.015 mg/L; cefpodoxime, 0.03 mg/L; cefixime, 0.5 mg/L; cefuroxime, 0.03 mg/L). Faropenem showed good activity against pneumococcal isolates (penicillin-susceptible strains, MIC90 0.016 mg/L; penicillin-intermediate strains, MIC90 0.25 mg/L). Erythromycin (MIC90 8 mg/L) and tetracycline (MIC90 64 mg/L) were also less active against penicillin-intermediate pneumococcal isolates. In conclusion, levofloxacin and faropenem may be useful in the treatment of pneumococcal infections caused by organisms with decreased susceptibility to penicillin.

Anti-Bacterial Agents↗
PubMed1999

Relative potential for selection of fluoroquinolone-resistant Streptococcus pneumoniae strains by levofloxacin: comparison with ciprofloxacin, sparfloxacin and ofloxacin.

The aim of this study was to evaluate the relative potential of levofloxacin to select for resistance in Streptococcus pneumoniae in comparison with ciprofloxacin, sparfloxacin and ofloxacin. Two S. pneumoniae strains were studied; HBD 153 (parental strain, serotype 3) and HBD 964 (selected from the parental strain in an experimental mouse peritonitis infection model). MICs for the two strains were, respectively: 2 and 2 mg/L for ciprofloxacin; 2 and 4 mg/L for ofloxacin; 0.5 and 1 mg/L for sparfloxacin; 2 and 2 mg/L for levofloxacin. In-vitro, with 4 x MIC as the selection concentration, no mutant was obtained with strain HBD 153 (mutation frequency < 10(-8). With HBD 964, the mutation frequency was 9 x 10(-7) for ofloxacin, 10(-7) for ciprofloxacin, 4 x 10(-5) for sparfloxacin and < 10(-8) for levofloxacin. In an immunosuppressed mouse peritonitis model (20 mice per dose), the S. pneumoniae strains were studied with sc doses of ciprofloxacin, sparfloxacin and ofloxacin at 50 mg/kg od, and with sc levofloxacin at a dose of 10 and 50 mg/kg od, or 10 and 50 mg/kg bid. The MICs for strains isolated after antibiotic treatment and the mutation frequencies at 4 x MIC were determined. Against HBD 153, sparfloxacin was the most active treatment, followed by levofloxacin 10 mg/kg and 50 mg/kg bid, but strains identical to HBD 964 (showing a resistant variant at 4 x MIC) were selected by sparfloxacin. Against HBD 964, levofloxacin (10 mg/kg and 50 mg/kg) was the most active drug. Highly resistant mutants were selected by ofloxacin and ciprofloxacin, but not by sparfloxacin and levofloxacin. In conclusion, the relative potential of levofloxacin to select for fluoroquinolone-resistant S. pneumoniae is lower than that of ciprofloxacin, ofloxacin and sparfloxacin both in vitro and in vivo.

Anti-Infective Agents↗
PubMed1999

Mechanism underlying levofloxacin uptake by human polymorphonuclear neutrophils.

The mechanism of radiolabeled levofloxacin ([3H]levofloxacin) uptake by human polymorphonuclear neutrophils (PMNs) was investigated by a classical velocity centrifugation technique. PMNs were incubated with levofloxacin for 5 to 180 min under various conditions before centrifugation through an oil cushion. Radioactivity was measured in the cell pellet to determine the amount of cell-associated drug. The uptake of levofloxacin was moderate with a cellular concentration/extracellular concentration ratio of about 4 to 6. Levofloxacin accumulated in PMNs parallel to the extracellular concentration, without saturation, over the range of 2.5 to 200 mg/liter (linear regression analysis: r = 0.92; P < 0.001). The activation energy was low (36 +/- 7.2 kJ/mol). Levofloxacin uptake was increased in Ca(2+)-depleted, EGTA-containing medium by approximately 33% (P = 0.022), while Ni2+, a Ca2+ channel inhibitor, inhibited it in a concentration-dependent manner, with the concentration that inhibited 50% of control uptake being approximately 2.65 mM. Verapamil (an L-type Ca2+ channel inhibitor) and other pharmacologic agents which modify Ca2+ homeostasis did not modify levofloxacin uptake. Interestingly, Ca2+ and Mg2+ inhibited levofloxacin uptake in a concentration-dependent manner. EGTA, Ni2+, and verapamil did not modify levofloxacin efflux; thapsigargin, a Ca2+ pool-releasing agent, modestly increased the intracellular retention of levofloxacin. In addition, contrary to other fluoroquinolones, probenecid at 1 to 10 mM did not modify either levofloxacin uptake or efflux. These data are consistent with a mechanism of passive accumulation of levofloxacin in PMNs. Extracellular Ca2+ and Mg2+ may influence the structural conformation of levofloxacin or the lipophilicity of PMN membranes, thus explaining their effect on levofloxacin uptake.

Anti-Infective Agents↗
PubMed1999

New research in macrolides and ketolides since 1997.

Macrolide and ketolide antibacterials remain a very dynamically active group. To overcome erythromycin A resistance within Gram-positive cocci and bacteria, novel compounds have been semi-synthesised, such as ketolides and C-4'' carbamate erythromycylamine derivatives. The continual efforts of those studying macrolides have led to molecular level investigations into the mechanism of action of these antibacterials. Among all novel derivatives, only telithromycin and AB-773 are currently under development. No real novel developments have been seen with the 15- and 16-membered ring macrolides, however, research is also continuing in this area. This review is an update of our knowledge in the field of macrolides.

Journal Article↗
PubMed1998

Novelties in the field of anti-infectives in 1997.

In 1997, more than 40 new medicinal chemical entities in the field of anti-infectives were presented during the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, held in Toronto. Among these novelties, three compounds could or will be candidates for clinical development: HMR 3647, a ketolide derivative; T-3811, a new quinolone; and GM 237,354, a new antifungal compound. Other molecules are potential lead compounds.

Anti-Infective Agents↗