Journal of Antimicrobial Chemotherapy

doi: 10.1093/jac/41.suppl_2.iiipmid: N/A

This content is only available as a PDF. © 1998 The British Society for Antimicrobial Chemotherapy

Bryskier,, A

doi: 10.1093/jac/41.suppl_2.1pmid: 9579708

Abstract 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. This content is only available as a PDF.

Brett,, M;Short,, P;Beatson,, S

doi: 10.1093/jac/41.suppl_2.23pmid: 9579709

Abstract In spite of vaccination programmes, whooping cough epidemics continue to occur. The disease affects all age groups, although its severity is greatest in the young, with infants being particularly vulnerable. Erythromycin is generally accepted as the drug of choice both for treatment and for prophylaxis during epidemics. Roxithromycin is a macrolide with pharmacokinetic advantages over erythromycin; it is well absorbed, produces high serum concentrations, has a long half-life and penetrates respiratory secretions well. There are no accepted standards for testing the sensitivity of Bordetella pertussis to antibiotics, and reports of the activity of roxithromycin and erythromycin are variable. Using Isosensitest agar supplemented with 5% horse blood and an inoculum of 10(4) cfu, 88 strains of B. pertussis were tested for their sensitivity to roxithromycin, erythromycin, rifampicin and trimethoprim/sulphamethoxazole. The range of MICs was 0.12-0.5 mg/L for both roxithromycin and erythromycin. Roxithromycin was bactericidal, with an MBC of 1 mg/L (as compared with 0.5 mg/L for erythromycin). Since roxithromycin is well tolerated by children when used for respiratory tract infections, the good in-vitro activity against B. pertussis, combined with its favourable pharmacokinetics, suggest it may be a good candidate for use in the treatment and prophylaxis of whooping cough. This content is only available as a PDF.

Malizia,, T;Tejada,, M;Marchetti,, F;Favini,, P;Pizzarelli,, G;Campa,, M;Senesi,, S

doi: 10.1093/jac/41.suppl_2.29pmid: 9579710

Abstract Thirty-eight clinical strains of Helicobacter pylori were isolated from patients with chronic gastritis and gastroduodenal ulceration, and their susceptibility to macrolide antibiotics (roxithromycin, flurithromycin, azithromycin, erythromycin) in combination with proton-pump inhibitors (lansoprazole and omeprazole) and bismuth subcitrate was assayed. Chequerboard titration was used to analyse the results of antimicrobial interactions and showed that the activity of macrolides was enhanced by combining them with lansoprazole, omeprazole or, to a lesser extent, bismuth subcitrate. While the interactions between erythromycin and the proton-pump inhibitors or bismuth subcitrate were always additive, the combinations of roxithromycin-lansoprazole, flurithromycin-omeprazole and azithromycin-lansoprazole acted synergically on 82%, 60% and 60% of H. pylori strains, respectively. These results may, in part, account for the enhanced clinical efficacy of macrolides administered with proton-pump inhibitors in the treatment of H. pylori-associated diseases. This content is only available as a PDF.

Labro, M, T

doi: 10.1093/jac/41.suppl_2.37pmid: 9579711

Abstract The important role played by macrolides in the chemotherapy of infectious diseases is well established, but there is still much speculation about their anti-inflammatory potential. A review of in-vitro and ex-vivo studies reported in the literature shows that macrolides have potentially relevant immunomodulatory effects. In-vitro data suggest that erythromycin A derivatives have a direct effect on neutrophil function and the production of cytokines involved in the inflammation cascade. The ex-vivo results indicate that short-term administration of macrolides may enhance the immune response while long-term administration results in immunosuppression. Further research is required to improve our understanding of the therapeutic activity of macrolides. This content is only available as a PDF.

Scaglione,, F;Rossoni,, G

doi: 10.1093/jac/41.suppl_2.47pmid: 9579712

Abstract There are many published reports on the anti-inflammatory effects of macrolides, some dating back to the introduction of erythromycin. Macrolides have been shown to affect a number of the processes involved in inflammation, including the migration of neutrophils, the oxidative burst in phagocytes and the production of various cytokines, although the precise mechanisms are not clear. These effects have been linked to the ability of macrolides to accumulate in mammalian cells. Roxithromycin, a macrolide with better plasma concentrations and higher tissue concentrations than erythromycin, has been tested in a standard animal model used for evaluating anti-inflammatory drugs. When rats were given a prophylactic dose (20 mg/kg), roxithromycin suppressed the oedema produced by injecting carrageenin into the paw with effects almost equal to that seen with the non-steroidal anti-inflammatory drug nimesulide. Azithromycin and clarithromycin, macrolides with better pharmacokinetics than erythromycin, only showed slight anti-inflammatory effects. These results confirm that roxithromycin has anti-inflammatory properties in vivo and encourage the investigation of its mode of action. This content is only available as a PDF.

Favre-Bonté,, S;Forestier,, C;Joly,, B

doi: 10.1093/jac/41.suppl_2.51pmid: 9579713

Abstract The effect of subinhibitory concentrations of roxithromycin on the adhesion of three strains of Klebsiella pneumoniae to Int-407 cells was studied. Adherence was markedly inhibited and the effect was increased when roxithromycin was added to the cell culture medium rather than to the bacterial growth medium. Several assays were performed in order to understand the mechanism by which roxithromycin exerted this inhibitory effect. The greatest effect was obtained when roxithromycin was concentrated in the extracellular compartment; when roxithromycin was concentrated in the intracellular compartment, the inhibitory effect was reduced. The analysis of adhesion factors of bacteria showed that exposure to roxithromycin did not alter their apparent structure or quantity. Roxithromycin appears to interfere in the interaction between bacteria and eukaryotic receptors. This content is only available as a PDF.

Brun-Pascaud,, M;Chau,, F;Derouin,, F;Girard, P, M

doi: 10.1093/jac/41.suppl_2.57pmid: 9579714

Abstract We have developed a dual infection model in immunosuppressed rats for evaluating drugs against Pneumocystis carinii and Toxoplasma gondii, two important opportunistic pathogens in patients with AIDS. Using this model, we reported that the macrolide roxithromycin was effective at a daily dose of 400 mg/kg in preventing the development of T. gondii infection but did not have a prophylactic effect against P. carinii in the same rats. A lower dose (200 mg/kg/day) had only marginal effects. Extending these experiments, we have now shown that roxithromycin at doses of 400 or 200 mg/kg/day combined with dapsone at doses of 5, 25 or 50 mg/kg/day completely prevented the development of T. gondii infection, with no parasites being detected in any of the tissues sampled. Roxithromycin at either dose combined with dapsone at 25 or 50 mg/kg/day was also effective in preventing the development of P. carinii infection in the lungs. The lowest dose of dapsone (5 mg/kg/day) was not fully effective. Pyrimethamine-dapsone, a combination used clinically, was tested in the same experiment, and gave results comparable to those with roxithromycin-dapsone combinations. In a further experiment combining roxithromycin with sulphamethoxazole, roxithromycin was effective in preventing the T. gondii infection, even when given at only 200 mg/kg/day with 20 mg/kg/day of sulphamethoxazole. When the dose of sulphamethoxazole was reduced to 2 mg/kg/day and given with roxithromycin 200 mg/kg/day, T. gondii infection developed in two of the five rats treated. P. carinii infection was prevented by sulphamethoxazole at 20 mg/kg/day but not completely by 2 mg/kg/day. Roxithromycin also has activity against Mycobacterium avium, another important cause of opportunistic infections in AIDS patients, and the compound penetrates mammalian cells well. Taken together with the favourable pharmacokinetic profile of roxithromycin, these results suggest that it may have a clinical utility, when used with other agents, in controlling the development of opportunistic infections caused by M. avium complex, T. gondii and P. carinii in HIV-infected individuals. This content is only available as a PDF.

Bouvier d'Yvoire, M, J;Dresco, I, A;Tulkens, P, M

doi: 10.1093/jac/41.suppl_2.63pmid: 9579715

Abstract The relative in-vivo intracellular concentration of various macrolides in phagocytes cannot be directly extrapolated from in-vitro experiments that use a fixed and constant extracellular concentration for all compounds, since this fails to consider different rates of intracellular penetration, dosage regimens and pharmacokinetic data. In the proposed model, which takes into account the free plasma concentrations and accumulation characteristics of three antibiotics, roxithromycin, azithromycin and erythromycin, we show that roxithromycin and azithromycin may reach similar concentrations in human polymorphonuclear leucocytes when conditions mimic clinical administration of these drugs, while erythromycin concentrations are lower. This approach may be useful to predict the behaviour of other drugs or other cells, and to assist in the design of rational treatment schemes. This content is only available as a PDF.

Tatsis,, G;Tsoukalas,, G;Boulbasakos,, G;Platsouka,, E;Anagnostopoulou,, M;Pirounaki,, M;Paniara,, O;Sioula,, E;Raptis,, J;Saroglou,, G

doi: 10.1093/jac/41.suppl_2.69pmid: 9579716