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PubMed1992

Postantibiotic sub-MIC effects of vancomycin, roxithromycin, sparfloxacin, and amikacin.

The sub-MIC effects (SMEs) and the postantibiotic sub-MIC effects (PA SMEs) of vancomycin, roxithromycin, and sparfloxacin for Streptococcus pyogenes and Streptococcus pneumoniae and of amikacin for Escherichia coli and Pseudomonas aeruginosa were investigated. A postantibiotic effect was induced by exposing strains to 10x the MIC of the antibiotic for 2 h in vitro. After the induction, the exposed cultures were washed to eliminate the antibiotics. Unexposed controls were treated similarly. Thereafter, the exposed cultures (PA SME) and the controls (SME) were exposed to different subinhibitory concentrations (0.1, 0.2, and 0.3x the MIC) of the same drug and growth curves for a period of 24 h were compared. In general, the PA SMEs were much more pronounced than the SMEs. However, for amikacin and E. coli the SME of 0.2 and 0.3x the MIC also had an initial bactericidal effect. The longest PA SMEs were demonstrated for the combinations with the most pronounced killing during the induction and for the combinations which exhibited the longest PAEs.

Amikacin↗

PubMed1993

Outer membrane permeability barrier to azithromycin, clarithromycin, and roxithromycin in gram-negative enteric bacteria.

Mutations which severely affect the function of the outer membrane of Escherichia coli and Salmonella typhimurium (lpxA and firA mutations of lipid A synthesis and rfaE mutation of the lipopolysaccharide inner-core synthesis) were found to decrease the MICs of erythromycin, roxithromycin, clarithromycin, and azithromycin by factors of 32 to 512, 32 to 1,024, 64 to 512, and 16 to 64, respectively. The sensitization factors for three other hydrophobic antibiotics (rifampin, fusidic acid, and mupirocin) ranged from 16 to 300. The outer membrane permeability-increasing agents polymyxin B nonapeptide (3 micrograms/ml) and deacylpolymyxin B (1 microgram/ml) sensitized wild-type E. coli to azithromycin by factors of 10 and 30, respectively. Quantitatively very similar sensitization to the other macrolides took place. Polymyxin-resistant pmrA mutants of S. typhimurium displayed no cross-resistance to azithromycin. Proteus mirabilis mutants which were sensitized to polymyxin by a factor of > or = 300 to > or = 1,000 had a maximal two- to fourfold increase in sensitivity to azithromycin. These results indicate that azithromycin and the other new macrolides use the hydrophobic pathway across the outer membrane and that the intact outer membrane is an effective barrier against them. Furthermore, the results indicate that azithromycin, in contrast to polymyxin, does not effectively diffuse through the outer membrane by interacting electrostatically with the lipopolysaccharide.

Azithromycin↗

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

Reaction of roxithromycin and clarithromycin with macrolide-inactivating enzymes from highly erythromycin-resistant Escherichia coli.

The activities of two new 14-membered-ring macrolide antibiotics, roxithromycin (RXM) and clarithromycin (CAM), against highly erythromycin (EM)-resistant Escherichia coli strains were evaluated. Pretreatment of macrolide phosphotransferase (MPH) (2') I-producing strains with EM increased the MICs of EM and CAM without any noticeable change in the MIC of RXM. The MPH (2') II-producing strain was more susceptible to CAM, while the EM esterase-producing strains were more susceptible to RXM than EM. Pretreatment of these latter two strains with EM did not alter their susceptibility to either RXM or CAM. In addition, the compounds were assessed as substrates for inactivation by crude enzyme preparations. Of the 14-membered-ring macrolides, RXM was the least favored substrate for MPH (2') I or II. CAM and RXM were substrates for the EM esterase but were the least preferred of the 14-membered-ring macrolides.

Anti-Bacterial Agents↗

PubMed1996

Effects of roxithromycin and erythromycin on interleukin 8-induced neutrophil recruitment and goblet cell secretion in guinea pig tracheas.

Inhaled interleukin 8 caused an increase in goblet cell secretion in guinea pig tracheas, which was accompanied by mucosal infiltration of neutrophils. These responses were inhibited by pretreatment with roxithromycin or erythromycin in a dose-dependent fashion. Macrolides may thus be a value in protecting against neutrophil-associated airway hypersecretion.

Animals↗

PubMed1997

Cellular accumulation of the new ketolide RU 64004 by human neutrophils: comparison with that of azithromycin and roxithromycin.

We analyzed the uptake of RU 64004 by human neutrophils (polymorphonuclear leukocytes [PMNs]) relative to those of azithromycin and roxithromycin. RU 64004 was strongly and rapidly accumulated by PMNs, with a cellular concentration/extracellular concentration ratio (C/E) of greater than 200 in the first 5 min, and this was followed by a plateau at 120 to 180 min, with a C/E of 461 +/- 14.8 (10 experiments) at 180 min. RU 64004 uptake was moderately sensitive to external pH, and activation energy was also moderate (63 +/- 3.8 kJ/mol). RU 64004 was mainly located in PMN granules (about 70%) and egressed slowly from loaded cells, owing to avid reuptake. The possibility that PMN uptake of RU 64004 and other macrolides occurs through a carrier-mediated system was suggested by three key results. First, there existed a strong interindividual variability in uptake kinetics, suggesting variability in the numbers or activity of a transport protein. Second, macrolide uptake displayed saturation kinetics characteristic of that of a carrier-mediated transport system: RU 64004 had the highest Vmax value (3,846 ng/2.5 x 10(6) PMNs/5 min) and the lowest Km value (about 28 microM), indicating a high affinity for the transporter. Third, as observed previously with other erythromycin A derivatives, Ni2+ (a blocker of the Na+/Ca2+ exchanger which mediates Ca2+ influx in resting neutrophils) impaired RU 64004 uptake by PMNs, with a 50% inhibitory concentration of about 3.5 mM. In addition, we found that an active process is also involved in macrolide efflux, because verapamil significantly potentiated the release of all three macrolides tested. This effect of verapamil does not seem to be related to an inhibition of Ca2+ influx, because neither EGTA [ethylene glycol-bis (beta-aminoethyl ether)-N,N',N'-tetraacetic acid] nor Ni2+ modified macrolide efflux. The nature and characteristics of the entry- and efflux-mediating carrier systems are under investigation.

Anti-Bacterial Agents↗

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↗

PubMed2000

Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats.

In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats. Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously injected for 90 min to obtain the time courses of drug concentrations in plasma and the changes in the Q-T intervals during and after the drug injections. Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prolongation at concentrations higher than their clinical ranges. The potencies for Q-T interval prolongation, assessed as the slope of the concentration-response relationship, were 6.09, 0.536, and 0.989 ms. ml/microg for CAM, RXM, and AZM, respectively. There was hysteresis between the change in the Q-T intervals and the time course of the plasma concentration of each drug. The rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM. In conclusion, RXM and AZM were estimated to be less potent at provoking arrhythmia than EM and CAM. These results should be useful for making a safer choice of an appropriate agent for patients with electrocardiographic risk factors.

Algorithms↗

PubMed2003

In vitro effects of ciprofloxacin and roxithromycin on apoptosis of jurkat T lymphocytes.

Ciprofloxacin (CPFX) and roxithromycin (RXM) induced apoptosis of activated Jurkat T cells in vitro. CPFX showed concentration-dependent acceleration of apoptosis of activated Jurkat T cells by enhancing the expression of FasL and activities of caspase-3 and -8. RXM accelerated cell death, enhanced expression of FasL and caspase-3 but not caspase-8, and did not show the concentration dependency.

Anti-Bacterial Agents↗

PubMed1995

Susceptibilities of 201 anaerobes to erythromycin, azithromycin, clarithromycin, and roxithromycin by oxyrase agar dilution and E test methodologies.

The susceptibility of 201 anaerobes to erythromycin, azithromycin, clarithromycin, and roxithromycin was tested by agar dilution and E test methods by using a commercially available plate and dish system (OxyDish) to provide anaerobic conditions. Plates were incubated for 48 h. MICs for 50% of strains tested and MICs for 90% of strains tested by agar dilution and E test methods corresponded within 1 doubling dilution for all compounds. When all antibiotics were considered together, agar and E test MICs were within 1 and 2 doubling dilutions of each other in 84 to 91% and > 99% of cases, respectively.

Agar↗

PubMed2001

Improvement in right lung atelectasis (middle lobe syndrome) following administration of low-dose roxithromycin.

Middle lobe syndrome is a distinct clinical entity characterized by right middle lobe atelectasis. Prompt diagnosis and initiation of medical therapy including the administration of antibiotics and the avoidance of irritating agents may be effective. However, abnormal shadows on chest radiography remain unchanged even when acute symptoms have disappeared, suggesting latent lesional inflammation or recurrence. We describe 2 cases of atelectasis in the middle lobe of the right lung which resolved completely after administration of low-dose roxithromycin. Thus, low-dose therapy with a macrolide could be of interest or some value in these cases, but it is too early to draw a definite conclusion.

Aged↗

PubMed1994

Antiasthmatic activity of a macrolide antibiotic, roxithromycin: analysis of possible mechanisms in vitro and in vivo.

This study was designed to examine the possible mechanisms by which macrolide antibiotics favorably influence the clinical course of asthmatic patients. In the first set of experiments, we investigated the effect of roxithromycin (RXM), a newly synthesized macrolide antibiotic, on in vitro cytokine secretion by mitogen-activated human peripheral blood leukocytes. RXM suppressed the secretion of T cell cytokine interleukins (IL) 2-4 and monocyte cytokine tumor necrosis factor alpha. This inhibitory effects on cytokine secretion was dose dependent and firstly noted at a concentration of as little as 0.5 microgram/ml which is much lower than therapeutic blood levels. In the second part of experiments, we examined the influence of RXM on cytokine appearance in mouse lung extract induced by lipopolysaccharide (LPS) inhalation and on bronchial responsiveness to methacholine in LPS-treated mice. As compared with mice pretreated with phosphate-buffered saline, RXM administered orally at a single dose of 5 mg/kg once a day for 21 days inhibited the appearance of IL-3, IL-4, IL-5, and tumor necrosis factor alpha in aqueous lung extracts. Pretreatment with RXM also decreased the bronchial responsiveness to methacholine induced by intratracheal injection of LPS. We conclude that the attenuating effect of macrolide antibiotics on asthmatic syndromes might be explained partially by their inhibitory effects on cytokine secretion from leukocytes.

Animals↗

PubMed1991

Penetration of roxithromycin into bronchial secretions.

The penetration of an antibacterial agent into the bronchial secretions is a crucial factor in determining its clinical efficacy in the treatment of bacterial respiratory infections. Roxithromycin is a novel macrolide compound active against the most frequent respiratory pathogens. Following administration of 150 mg p.o., we observed a prompt penetration of the compound into bronchial secretions of critically ill patients. Elevated concentrations above the MICs of the commonest susceptible pathogens are reached and maintained until the next administration.

Absorption↗

PubMedDate not supplied

Effects of long-term administration of roxithromycin on neutrophil count and interleukin-8 level in endometrial cavity subjected to pyometra.

We investigated the effect of long-term administration of roxithromycin (RXM) on clinical responses and immune responses to chronic intrauterine infection, pyometra. One hundred and fifty milligrams of RXM were orally administered once a day for 3 months to patients with pyometra. Neutrophils and interleukin-8 (IL-8), which is a neutrophil chemotactic factor, in the lavage fluid of the uterine endometrial cavity obtained from 5 normal women and 18 patients with pyometra were investigated. Sixteen (88.9%) of the 18 patients showed a clinical improvement at the end of treatment. The immune responses occurred in the lavage fluid from the uterine endometrial cavity. Neutrophils accumulated in the lavage fluid of the uterine endometrial cavity before RXM treatment (p < 0.001 vs. normal subjects and decreased after RXM treatment (p < 0.001). The levels of IL-8 were significantly higher in the lavage fluid of pyometra patients than in normal women (p < 0.001), and tended to decrease after RXM treatment (p < 0.01). These results indicate that RXM decreases uterine endometrial cavity inflammation through reduction of neutrophil migration in inflammatory sites and is effective in treating chronic intrauterine infection.

Aged↗

PubMedDate not supplied

The effect of roxithromycin on the generation of reactive oxygen species in vitro.

The effect of roxithromycin (ROM), a new oral semi-synthetic macrolide, on the generation of reactive oxygen species (ROS), using human neutrophils and a cell-free, xanthine-xanthine oxidase system was examined. The species investigated were the superoxide radical anion (O2-), hydrogen peroxide (H2O2), and the hydroxyl radical (OH.). ROM effectively inhibited the generation of O2-, H2O2 and OH. by human neutrophils. On the other hand, the drug did not markedly affect the ROS levels generated in the xanthine-xanthine oxidase system. The present study indicates that ROM may exert an anti-inflammatory action by inhibiting neutrophil oxygen radical generation at the sites of inflammation.

Anti-Bacterial Agents↗

PubMed2001

A multicenter study on the clinical efficacy and safety of roxithromycin in the treatment of ear-nose-throat infections: comparison with amoxycillin/clavulanic acid.

This multicenter, randomized open-label study compared the efficacy and safety of roxithromycin tablets 300 mg once a day (Rx) and amoxicillin/clavulanic acid tablets 875+125 mg twice a day (Acx), administered for a mean of 7 days. The study was carried out in five centers on 100 in- or out-patients of both sexes, aged between 18 and 91 years (mean 38+/-14). All patients suffered from ENT diseases, 85% with acute otitis media, 31% pharyngotonsillitis and 11% rhinosinusitis. The patients were divided into two randomized groups of 50 patients each. Clinical evaluations (signs and symptoms) were performed before, during and at the end of therapy. At the end of therapy, for intent-to-treat and per-protocol populations, a satisfactory overall clinical response was achieved by 82% of patients in the Rx group and 78% in the Acx group with similar reductions in signs and symptoms of disease in both groups. Safety was good, with only 2 patients of the Rx group and 4 patients of the Acx group presenting side effects, involving mainly the gastrointestinal system. Rx appears to be active and safe in the therapy of ENT diseases exhibiting similar effects on the reduction of signs and symptoms as Amx but with better compliance because of once-a-day administration.

Acute Disease↗

PubMed1995

Effects of roxithromycin on proliferation of peripheral blood mononuclear cells and production of lipopolysaccharide-induced cytokines.

Roxithromycin (RXM), a new macrolide antibiotic, has a 14-member macrocycline ring structure which is similar to that of erythromycin. We investigated the effects of RXM on the proliferation of peripheral blood mononuclear cells (PBMCs) and the production of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) by PBMCs stimulated with lipopolysaccharide (LPS). At concentrations greater than 25.0 micrograms/ml, RXM suppressed the proliferation of PBMCs stimulated with phytohemagglutinin, probably due to cytotoxicity. When the PBMCs were incubated with RXM for 7 d, the number of adherent cells (monocyte/macrophages) increased. Incubation with RXM at a concentration of 25.0 micrograms/ml induced the greatest increase (p < 0.05). IL-1 beta and TNF-alpha were present 3 h after LPS-stimulation, and IL-1 beta production reached a peak at 12 h and TNF-alpha production at between 6 and 12 h, and then their production declined. RXM (25 micrograms/ml) suppressed the production of IL-1 beta and TNF-alpha slightly during the entire course of the incubation. This suppression was dose-dependent. Anti-human granulocyte-macrophage colony-stimulating factor and anti-human macrophage colony stimulating factor antibodies had no effect on the RXM-induced proliferation of adherent cells. Suppression of the production of IL-1 beta and TNF-alpha by RXM suggested that this drug might have anti-inflammatory and immunosuppressive effects.

Anti-Bacterial Agents↗

PubMed1996

The macrolide antibiotic, roxithromycin suppresses IFN-gamma-mediated immunological functions of cultured normal human keratinocytes.

The effects of the macrolide antibiotic, roxithromycin (RXM) on immunological functions of cultured normal human keratinocytes (NHK) were studied. RXM neither modulated the expression of intercellular adhesion molecule-1 (ICAM-1) and human histocompatibility leukocyte antigen (HLA)-DR nor mobilized intracellular free calcium in NHK that were cultured in medium alone. However, the ICAM-1 and HLA-DR expression induced by cultivation with interferon-gamma (IFN-gamma) was upregulated and suppressed, respectively, by pretreatment of NHK with RXM. Whereas ICAM-1 upregulation was observed with RXM at a concentration as high as 0.1 mM, the inhibition of HLA-DR expression by RXM was virtually dose-dependent at doses ranging from 100 nM to 0.1 mM. Accessory cell function of major histocompatibility complex (MHC) class II-bearing NHK in terms of the T-cell response to staphylococcal enterotoxin B was suppressed by pretreatment of NHK with RXM, indicating the functional consequence of RXM-induced reduction of MHC class II molecules. Furthermore, RXM inhibited IFN-gamma-mediated upregulation of IL-1 alpha secretion by NHK. These results show that RXM suppresses immunological functions of keratinocytes triggered by IFN-gamma and suggest the therapeutic relevance of RXM to T cell-mediated inflammatory skin diseases and T cell malignancies such as atopic dermatitis, psoriasis and cutaneous T cell lymphoma, which can be exacerbated by keratinocytes immunologically modulated by exposure to IFN-gamma.

Animals↗