Roxithromycin

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Abstract
Roxithromycin is a derivative of the macrolide antibacterial erythromycin with in vitro antibacterial activity resembling that of the parent compound. The drug has activity against some Staphylococcus spp., many Streptococcus spp., Moraxella (Branhamella) catarrhalis, Mycoplasma pneumoniae, Legionella pneumophila and Chlamydia trachomatis as well as many less common organisms. Measured using recently proposed guidelines, roxithromycin has in vitro activity against Haemophilus influenzae. In comparison with that of its parent compound, the pharmacokinetic profile of roxithromycin is characterised by high plasma, tissue and body fluid concentrations and a long half-life permitting an extended dosage interval. Roxithromycin has proven clinical efficacy in upper and lower respiratory infections, skin and soft tissue infections, urogenital infections and orodental infections, and appears to be as effective as more established treatments including erythromycin, amoxicillin/clavulanic acid and cefaclor. The drug has also shown promise in a variety of more specialised indications including opportunistic infections in human immunodeficiency virus (HlV)-positive patients and as part of a Helicobacter pylori eradication regimen. Roxithromycin is very well tolerated with an overall incidence of adverse events of approximately 4%. Thus, roxithromycin is an attractive therapeutic alternative in its established indications, especially when the option of once-daily administration is considered. Roxithromycin is an ether oxime derivative of erythromycin with in vitro activity resembling that of the parent compound. MIC90 (minimum concentration required to inhibit 90% of strains) values of ≤2 mg/L and 2 to 4 mg/L are indicative, respectively, of full and moderate susceptibility to the drug. Roxithromycin has variable activity against methicillin-susceptible Staphylococcus aureus but methicillin-resistant S. aureus, as well as S. epidermidis, S. haemolyticus and S. hominis, are not susceptible to the drug. Erythromycin-susceptible isolates of coagulase-negative staphylococci are susceptible to roxithromycin but erythro-mycin-resistant isolates are not. Roxithromycin is active against Streptococcus agalactiae, S. pneumoniae, S. pyogenes, Lancefield group C and viridans group streptococci. It is generally inactive against Lancefield group G Streptococcus and enterococci. The activity of roxithromycin against Listeria monocytogenes is broadly similar to that of erythromycin, with most isolates being inhibited at a concentration of 1 or 2 mg/L. Roxithromycin MIC90 values for Neisseria gonorrhoeae are similar to those of erythromycin; Neisseria meningitidis is slightly less susceptible with an MIC range of 0.3 to 4 mg/L. Roxithromycin has borderline activity in vitro against Haemophilus influenzae when measured using current susceptibility guidelines; however, a higher susceptibility breakpoint of ≤16 mg/L has recently been proposed. The drug has good in vitro activity against Bordetella pertussis, B. parapertussis, Borrelia burgdorferi, Moraxella catarrhalis and Legionella pneumophila. Roxithromycin MIC90 values against Chlamydia trachomatis range between 0.25 and 1 mg/L. Roxithromycin had an MIC90 value of 16 mg/L against 28 Mycobacterium avium complex strains isolated from patients with acquired immune deficiency syndrome, compared with values of 8, 32 and ≥64 mg/L for clarithromycin, azithromycin and erythromycin, respectively. Roxithromycin MIC90 values against Bacteroides spp. and Clostridium difficile are high. Roxithromycin exerts its action by disrupting bacterial protein synthesis. It is also concentrated in human polymorphonuclear leucocytes and macrophages. The drug has demonstrated good activity in animal models of Gram-positive and other infections such as toxoplasma encephalitis, Legionnaires’ disease, Mycobacterium leprae infection, syphilis and chlamydial urogenital infection. The pharmacokinetic profile of roxithromycin differs substantially from that of its parent compound, erythromycin. Mean plasma roxithromycin concentrations ranging between 6.6 and 7.9 mg/L are achieved within 2 hours after administration of a single oral 150mg dose. In a direct comparison, the area under the plasma concentration versus time curve produced by roxithromycin 150mg was 16.2-fold greater than that produced by erythromycin 250mg. Multiple doses produced similar differences. The drug is strongly, specifically and saturably bound to a 1-acid glycoprotein in plasma. The plasma clearance of roxithromycin appears to be dose- or plasma concentration-dependent. Concentrations achieved in tissues and body fluids are generally higher than MIC90 values for susceptible organisms. In a study assessing elimination, 74.2% of a radiolabeled roxithromycin dose was accounted for: 53.4% in faeces; 13.4% as expired carbon dioxide and 7.4% in the urine. The mean elimination half-life of roxithromycin (8.4 to 15.5 hours) is much longer than that recorded for erythromycin (1.5 to 3 hours). Its pharmacokinetics appear to be nonlinear and may include a saturable process involving plasma a 1-acid glycoprotein releasing bound drug for distribution and elimination. The pharmacokinetic profile of roxithromycin in children is generally similar to that in adults. Dosage adjustment is not required in the elderly or in patients with renal impairment. Roxithromycin has produced efficacy rates of between 71 and 96% in patients with tonsillitis or sinusitis and resolved or improved the signs and symptoms of pharyngotonsillitis and sinusitis significantly more effectively than clarithromycin in 1 study. Clinical efficacy rates were >90% in almost 10 000 patients with acute bronchitis who received roxithromycin in noncomparative studies. The clinical efficacy of roxithromycin was very similar to that of amoxicillin/clavulanic acid, cefaclor and azithromycin in comparative studies. Roxithromycin is also an effective treatment for exacerbations of chronic bronchitis, producing clinical efficacy rates ranging between 83.3 and 89% in 4 noncomparative trials involving >4000 patients, and having clinical efficacy similar to that of amoxicillin/clavulanic acid, oxycycline, cefaclor and azithromycin in comparative studies. Roxithromycin has demonstrated similar clinical efficacy to amoxicillin/clavulanic acid, azithromycin, clarithromycin, cefaclor, erythromycin and midecamycin acetate in patients with pneumonia. The drug is also an effective treatment for patients with pneumonia caused by atypical organisms such as chlamydia, mycoplasma, Legionella spp., rickettsia and Coxiella burnetii. Roxithromycin 300 mg/day was equally effective administered either once or twice daily to 1588 patients with various infections. One study has shown roxithromycin to be as effective as josamycin as treatment for patients with suppurative skin and soft tissue infections and as effective as penicillin in patients with erysipelas. The clinical efficacy of roxithromycin was similar to that of amoxicillin, erythromycin and josamycin as treatment for orodental and odontological infections and was also comparable with spiramycin as prophylaxis prior to dental surgery. In patients with urogenital or gynaecological infections, roxithromycin has produced clinical response rates ranging between 71 and 100%, and was as effective as doxycycline and minocycline in comparative studies. The drug was equally effective administered either once or twice daily in patients with nongonococcal urethritis. Roxithromycin has good in vitro activity against Borrelia burgdorferi and, in combination with cotrimoxazole (trimethoprim/sulfamethoxazole), was an effective treatment for late Lyme disease. In a pilot study the drug effectively prevented pneumocystosis and cerebral toxoplasmosis in human immunodeficiency virus (HlV)-positive patients, either alone or in combination with pentamidine aerosol. Roxithromycin 300 mg/day in combination with omeprazole and bismuth subni-trate eradicated confirmed Helicobacter pylori infection in patients with peptic ulcers and gastritis more effectively than omeprazole monotherapy. Although recent paediatric studies are limited, roxithromycin 5 to 10 mg/kg/day has demonstrated efficacy in the treatment of respiratory tract and skin and soft tissue infections in children and, compared with placebo, has significantly reduced the duration of diarrhoea and faecal excretion of Campylobacter in children with campylobacter-associated enteritis. Gastrointestinal symptoms are the most common adverse events during roxithromycin therapy. Large noncomparative studies have reported an overall incidence of adverse events of around 4%, with gastrointestinal symptoms accounting for 75 to 80% of these. The overall incidence of adverse events in patients treated with roxithromycin has compared favourably with those of other antibacterial drugs and appears to be lower than that of erythromycin. The adverse event profile of the drug in children is similar to that in adults. Isolated cases of cholestatic hepatitis and 1 case of fulminant acute hepatitis have been reported in patients receiving roxithromycin. The drug appears to have less effect on gastrointestinal motility and faecal bacterial flora than erythromycin. Roxithromycin 300 mg/day, administered once-daily or in 2 divided doses, is the recommended adult dosage for all indications. The recommended dose for infants and children is 5 to 8 mg/kg body weight per day administered in 2 divided doses. The drug should be given at least 15 minutes before food. A 50% dosage reduction has been recommended for patients with hepatic insufficiency. Dosage modifications are not required in elderly patients or in patients with renal insufficiency.

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