Treatment with the antibiotic roxithromycin in patients with acute non-Q-wave coronary syndromes. The final report of the ROXIS Study.
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AIMS: Mounting evidence suggests infection, specifically Chlamydia pneumoniae, plays a role in atherosclerosis. We tested whether antibiotic treatment with the macrolide roxithromycin improves clinical outcome in patients with acute non-Q-wave coronary syndromes. Preliminary reports revealed a reduction in events in the roxithromycin group at 30 days. We now report the long-term follow-up results. METHODS AND RESULTS: Sixty-four per cent of the initial 202 patients with unstable angina who were randomly assigned to receive either roxithromycin or placebo for 30 days completed the active treatment period. At day 30, the primary triple and double end-point rates were 9% and 4% in the placebo group compared to 2% and 0% in the roxithromycin group (unadjusted P = 0.032 and 0.058, respectively). The secondary triple and double end-point rates were again higher in the placebo group at day 90 (12.5% and 6.25% vs 4.37% and 0%, unadjusted P = 0.065 and 0.029, respectively), and at day 180 (14.6% and 7.29% vs 8.69% and 2.17%, unadjusted P = 0.259 and 0.17, respectively). Anti-C, pneumoniae IgG titres were unchanged in both groups while C-reactive protein levels decreased in both strategies, with a more significant decrease in the roxithromycin arm (P = 0.03). Elevated C-reactive protein levels predicted the need for revascularization. CONCLUSIONS: In this pilot trial, roxithromycin appears to extend the clinical benefit of preventing death and re-infarction for at least 6 months after initial treatment. (+info)
A new quadruple therapy for Helicobacter pylori: influence of resistant strains on treatment outcome.
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BACKGROUND: There have been no reports concerning the efficacy and safety of a 1-week quadruple therapy regimen of omeprazole, amoxycillin, roxithromycin and metronidazole for Helicobacter pylori infections and the impact of primary resistance on the eradication rate. METHODS: One hundred and sixty-nine consecutive patients with peptic ulcer disease as well as gastritis with biopsy-proven H. pylori infection were entered into an open study of omeprazole 20 mg o.m., amoxycillin 500 mg t.d.s., roxithromycin 150 mg b.d., and metronidazole 250 mg t.d.s. Helicobacter pylori status was determined by urease test, histology and culture. Susceptibility to amoxycillin, metronidazole and roxithromycin was determined by the E-test. RESULTS: H. pylori was eradicated in 155 out of 169 (92%; 95% CI 88-96%) by intention-to-treat analysis, and in 155 out of 163 (95%; 95% CI 92-98%) by per protocol analysis. The prevalence of primary resistance against amoxycillin, roxithromycin and metronidazole was 2 out of 166 (1%), 16 out of 166 (10%) and 27 out of 166 (16%), respectively. H. pylori was eradicated in 25 out of 27 (93%) patients with metronidazole-resistant strains compared with 130 out of 136 (96%) in patients with metronidazole-sensitive strains of H. pylori. It was eradicated in 15 out of 16 (94%) patients with roxithromycin-resistant strains while in 140 out of 147 (95%) patients with roxithromycin-sensitive strains of H. pylori, and in two out of two (100%) patients with amoxycillin-resistant stains compared with 153 out of 161 (95%) in patients with amoxycillin-sensitive strains. H. pylori was eradicated in three out of four (75%) patients with double resistance against metronidazole and roxithromycin compared with 152 out of 159 (96%) patients with sensitive strains to metronidazole and or roxithromycin. None of these differences were statistically significant. Severe side-effects were found in only one out of 169 patients-anaphylaxis due to penicillin. CONCLUSIONS: The 1-week quadruple therapy with omeprazole, amoxycillin, metronidazole and roxithromycin was found to eradicate H. pylori in over 90% of all patients. This regimen was also found to be beneficial for patients with pre-treatment resistant strains to metronidazole, roxithromycin or amoxycillin, and was observed to be safe and well-tolerated. (+info)
Activity of telithromycin (HMR 3647) against anaerobic bacteria compared to those of eight other agents by time-kill methodology.
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Time-kill studies examined the activities of telithromycin (HMR 3647), erythromycin A, azithromycin, clarithromycin, roxithromycin, clindamycin, pristinamycin, amoxicillin-clavulanate, and metronidazole against 11 gram-positive and gram-negative anaerobic bacteria. Time-kill studies were carried out with the addition of Oxyrase in order to prevent the introduction of CO(2). Macrolide-azalide-ketolide MICs were 0.004 to 32.0 microg/ml. Of the latter group, telithromycin had the lowest MICs, especially against non-Bacteroides fragilis group strains, followed by azithromycin, clarithromycin, erythromycin A, and roxithromycin. Clindamycin was active (MIC /=99.9% killing) against 6 strains, with 99% killing of 9 strains and 90% killing of 10 strains. After 24 h at twice the MIC, 90, 99, and 99.9% killing of nine, six, and three strains, respectively, occurred. Lower rates of killing were seen at earlier times. Similar kill kinetics relative to the MIC were seen with other macrolides. After 48 h at the MIC, clindamycin was bactericidal against 8 strains, with 99 and 90% killing of 9 and 10 strains, respectively. After 24 h, 90% killing of 10 strains occurred at the MIC. The kinetics of clindamycin were similar to those of pristinamycin. After 48 h at the MIC, amoxicillin-clavulanate showed 99.9% killing of seven strains, with 99% killing of eight strains and 90% killing of nine strains. At four times the MIC, metronidazole was bactericidal against 8 of 10 strains tested after 48 h and against all 10 strains after 24 h; after 12 h, 99% killing of all 10 strains occurred. (+info)
Clinical and immunoregulatory effects of roxithromycin therapy for chronic respiratory tract infection.
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The clinical and immunoregulatory effects of long-term macrolide antibiotic therapy for patients with chronic lower respiratory tract infections (CLRTI) were investigated. Clinical parameters and neutrophil chemotactic mediators in the epithelial lining fluid (ELF) of CLRTI patients (n = 10) were examined before and after 3 months oral administration of roxithromycin (RXM). The in vitro effects of RXM were also examined on the release of these mediators from alveolar macrophages (AM) and neutrophils. Arterial oxygen tension (p<0.05), vital capacity (VC) (p<0.001), %VC (p<0.05) and forced expiratory volume in one second (p<0.01) were improved after RXM treatment, but airway bacteria were not eradicated. Among the mediators, the levels of interleukin (IL)-8, neutrophil elastase (NE) and leukotriene B4 (LTB4) were higher in ELF than in plasma of CLRTI patients and they decreased after RXM treatment (n = 7, p<0.05 for each). RXM concentrations were significantly increased in the bronchoalveolar lavage cells of the treated patients. In in vitro experiments, RXM showed inhibitory effects on IL-8 release from AM and neutrophils. In conclusion, interleukin-8, neutrophil elastase and leukotriene B4 contribute to the neutrophilic inflammation in the airways of chronic lower respiratory tract infection patients and the clinical effects of roxithromycin may, in part, be attributable to the suppression of excess release of the chemotactic mediators from inflammatory cells. (+info)
Activities of telithromycin (HMR 3647, RU 66647) compared to those of erythromycin, azithromycin, clarithromycin, roxithromycin, and other antimicrobial agents against unusual anaerobes.
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The comparative activity of telithromycin (HMR 3647) against 419 human anaerobic isolates was determined by the agar dilution method. At concentrations of +info)
Chlamydia pneumoniae eradication from carotid plaques. Results of an open, randomised treatment study.
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OBJECTIVE: to determine the effect of specific antibiotic treatment with roxithromycin in the eradication of Chlamydia pneumoniae from carotid artery plaques. DESIGN: prospective open randomised treatment study. PATIENTS AND METHODS: we analysed 32 patients (16 females, mean age 70.1+/-14.7 years) who underwent surgery for the removal of atherosclerotic plaques from carotid arteries. During surgery samples of lingual vein and superior thyroid artery were also taken. Before surgery, patients were randomised to receive either roxithromycin 150 mg twice daily or no treatment. Sixteen patients were treated with antibiotic for a mean of 26 days (range 17-35 days). The two groups of patients were comparable in terms of age, sex, risk factors, and seroprevalence for C. pneumoniae. We applied a semi-nested polymerase chain reaction (PCR) technique to the carotid plaques, lingual vein, and thyroid artery samples. Blood samples were obtained from the patients for the determination of C. pneumoniae IgG, IgA, and IgM antibody titres by a microimmunofluorescence technique. RESULTS: in twelve out of sixteen non-treated patients we found evidence of C. pneumoniae DNA in the carotid plaques. Conversely, C. pneumoniae DNA was detected in only five out of sixteen treated patients (p=0.034, Chi-squared test). In all cases PCR was negative for the lingual vein and thyroid artery samples. CONCLUSIONS: Roxithromycin seems effective in reducing the bacterial burden of C. pneumoniae within atherosclerotic plaques, although extended follow-up is needed to determine whether antibiotic treatment benefits long-term patient outcome. (+info)
Anti-inflammatory activity of macrolide antibiotics.
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The effect of four macrolide antibiotics (roxithromycin, clarithromycin, erythromycin, and azithromycin) on the generation of some mediators and cytokines involved in the inflammatory process has been studied both in vivo and in vitro. Rat carrageenin pleurisy was used as a model of acute inflammation, and the macrolides were administered (10, 20, and 40 mg/kg p.o.) 1 h before the carrageenin challenge. Exudate volume and leukocyte accumulation were both dose-dependently reduced by roxithromycin, clarithromycin and erythromycin in either normal or adrenalectomized animals. Furthermore, in normal rats, prostaglandin (PG)E(2), nitrate plus nitrite, and tumor necrosis factor-alpha levels in pleural exudate were significantly reduced by these macrolides. Roxithromycin appeared more effective than erythromycin and clarithromycin, whereas azithromycin only slightly affected the inflammatory reaction. None of the macrolides were able to modify leukotriene B(4) exudate levels. In vitro experiments have shown that the four macrolides (5-80 microM) reduced in a concentration-dependent manner the production of 6-keto-PGF(1alpha), NO(2)(-), tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 by lipopolysaccharide-stimulated J774 macrophages. In J774 cells, the inhibition of 6-keto-PGF(1alpha) and NO(2)(-) production by roxithromycin and erythromycin was not dependent on direct inhibition of cyclooxygenase-2 and inducible nitric oxide synthase activity because it appears to be related to the inhibition of cyclooxygenase-2 and inducible nitric oxide synthase protein expression. In conclusion, the present study shows that macrolide antibiotics have anti-inflammatory activity, which likely depends on their ability to prevent the production of proinflammatory mediators and cytokines, and suggest that these agents, particularly roxithromycin, can exert therapeutic effects independently of their antibacterial activity. (+info)
Effect of proinflammatory cytokines on the interplay between roxithromycin, HMR 3647, or HMR 3004 and human polymorphonuclear neutrophils.
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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. (+info)