Drugs

, Volume 37, Issue 1, pp 8–41

Roxithromycin

A Review of its Antibacterial Activity, Pharmacokinetic Properties and Clinical Efficacy
  • Ronald A. Young
  • John P. Gonzalez
  • Eugene M. Sorkin
Drag Evaluation

DOI: 10.2165/00003495-198937010-00002

Cite this article as:
Young, R.A., Gonzalez, J.P. & Sorkin, E.M. Drugs (1989) 37: 8. doi:10.2165/00003495-198937010-00002
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Summary

Synopsis

Roxithromycin is an acid-stable orally administered antibacterial macrolide structurally related to erythromycin. It has an in vitro antibacterial profile similar to that of erythromycin, with activity against Staphylococcus aureus, S. epidermidis, Streptococcus pneumoniae, S. pyogenes, Branhamella catarrhalis, Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia trachomatis, Gardnerella vaginalis, Haemophilus ducreyi, some anaerobes and other less common pathogens.

Roxithromycin has a pharmacokinetic profile that is characterised by excellent enterai absorption achieving high concentrations in most tissues and body fluids.

The results of clinical studies with roxithromycin have confirmed the potential for its use in a variety of infections, which was suggested by its antibacterial activity in vitro and pharmacokinetic profile. Clinical efficacy has been confirmed in the treatment of respiratory tract infections, including community-acquired and atypical pneumonias, ear, nose and throat infections, genitourinary tract infections, and skin and soft tissue infections. In a relatively small number of patients roxithromycin has generally been shown to be as effective as erythromycin and other appropriate antibacterial drugs in some of the above indications. Roxithromycin is well tolerated and has less potential than erythromycin to produce clinically significant drug interactions. Thus, roxithromycin is an orally active drug which should prove a useful alternative when selecting antibacterial therapy for indications where macrolides are appropriate.

Antibacterial Activity

Roxithromycin is an acid-stable macrolide with an in vitro spectrum of antibacterial activity closely resembling that of erythromycin. Staphylococcus aureus (excluding methicillin-resistant strains) are sensitive to roxithromycin as well as to erythromycin, josamycin and spiramycin. Roxithromycin is slightly less potent than erythromycin against S. epidermidis including strains resistant to penicillin. Streptococci, including Groups A, B and C and S. pneumoniae, but not Group G and the enterococci, are susceptible to roxithromycin, with erythromycin, clindamycin, cefaclor and amoxycillin showing similar activity.

In common with erythromycin, josamycin and doxycycline, roxithromycin is a potent inhibitor of Branhamella catarrhalis, including β-lactamase-producing strains. Roxithromycin produces potent inhibition of Legionella species with similar activity to that of erythromycin. Against Campylobacter species the in vitro activity of roxithromycin is generally lower than that of erythromycin. Gardnerella vaginalis and Haemophilus ducreyi are highly susceptible to roxithromycin and, like erythromycin, josamycin, amoxycillin and tetracycline, roxithromycin produces varying inhibitory activity against Haemophilus influenzae. Isolates of Neisseria gonorrhoeae, including strains resistant to penicillin, are susceptible or moderately susceptible to roxithromycin, with erythromycin and josamycin showing similar inhibitory activities. Neisseria meningitidis is moderately susceptible to roxithromycin but roxithromycin is less potent than erythromycin against Bordetella pertussis and B. parapertussis while B. bronchiseptica is resistant to both macrolides. Roxithromycin is inactive against the enterobacteriaceae Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Providencia stuartii, Salmonella enteritidis and Shigella spp.

Roxithromycin is less potent than rifampicin and isoniazid against Mycobacterium tuberculosis, with strains of M. avium, M. fortuitum and M. chelonae showing resistance to the macrolide. Bacillus cereus, Corynebacterium and Listeria monocytogenes are susceptible to roxithromycin. Among anaerobic species, Bacteroides oralis, B. melaninogenicus, B. ureolyticus, Eubacterium spp., Peptostreptococcus spp., Propionibacterium acnes, Actinomyces spp. and Bifldobacterium spp. were susceptible to roxithromycin; other anaerobes including Bacteroides spp., Clostridium spp., Fusobacterium spp. and Veillonella spp. were generally resistant. Roxithromycin was active against Chlamydia trachomatis, Mycoplasma pneumoniae and Ureaplasma urealyticum, with similar potencies to erythromycin. In general, bacterial strains selected for their resistance to erythromycin are also resistant to roxithromycin.

The in vitro activity of roxithromycin is affected by the biological source and concentration of sera used in the medium. Increases in the inoculum size up to 105 cfu have little effect on the minimum inhibitory concentration (MIC) of roxithromycin. However, when the inoculum size is increased to 107 cfu considerable increases occur in the MIC.

Killing curve studies using conditions simulating serum pharmacokinetics show roxithromycin to be rapidly bactericidal against S. pneumoniae, producing a kill rate which exceeded those of erythromycin, doxycycline and ofloxacin. Roxithromycin produces a postantibiotic effect of up to 9.6 hours after exposure to S. pneumoniae and S. pyogenes.

Roxithromycin produces its antibacterial effect through inhibition of protein synthesis inside the bacterial cell. Roxithromycin is highly concentrated in polymorphonuclear leucocytes and macrophages, and also enhances the adhesive and chemotactic functions of these cells which in the presence of infection produce phagocytosis and bacterial lysis.

Roxithromycin produces good antibacterial activity in experimental models of infection induced by Gram-positive organisms and other infections such as toxoplasmic encephalitis and syphilis.

Pharmacokinetics

Following administration of a single oral dose of roxithromycin 150mg to healthy volunteers, mean plasma concentrations ranging from 6.6 to 7.9 mg/L are reached within 2 hours. Administration of roxithromycin 150mg before a meal had little effect on maximum plasma concentrations and bioavailability. Multiple-dose administration for up to 11 days in healthy volunteers did not produce accumulation at a dosage of 150mg twice a day or 300mg once a day. The area under the plasma concentration-time curve (AUC) following administration of roxithromycin 150mg was 72.6 to 81 mg/L · h compared with 6.97 mg/L · h for erythromycin 500mg.

Roxithromycin is extensively distributed throughout tissue and body fluids with corresponding plasma concentrations being high and greater than the MIC90 values for susceptible bacteria. Maximum concentrations of roxithromycin in pulmonary tissue were 5.6 mg/L 6 hours after administration of 150mg compared with a maximum of 4.2 mg/ L for erythromycin measured 3 hours after a 1g dose. Roxithromycin concentrations in bronchoalveolar lavage cells were 2 and 10 times higher than corresponding levels in plasma and epithelial fluid, respectively. Less than 0.05% of a single dose of roxithromycin 300mg appears in breast milk, with AUC values for breast milk less than 5% of corresponding plasma AUC values.

In urine and faeces 50 and 55% of recovered drug, respectively, appeared as unchanged roxithromycin; 25 and 22%, respectively, as the descladinose derivative, and 5 and 7%, respectively, as the demethylated derivative, with only unchanged roxithromycin detected in plasma. The elimination half-life of roxithromycin following administration of 150 and 300mg doses ranged from 8.4 to 15.5 hours, compared with 1.5 to 3 hours for a 1g dose of erythromycin. The pharmacokinetics of roxithromycin in infants and children are similar to those in adults. No dosage adjustments are required in elderly patients.

Following single doses, maximum plasma concentrations, AUC values and the elimination half-life were increased in patients with renal insufficiency, whereas urinary elimination and renal clearance were reduced. Following the administration of multiple doses no roxithromycin accummulation occurred and the kinetics were not dependent on the degree of renal impairment suggesting no dosage modifications are required in patients with renal impairment. Furthermore, in patients with severe alcoholic cirrhosis maximum plasma concentrations, time to maximum plasma concentrations and the AUC were similar to those of healthy subjects but the elimination half-life increased 2-fold. In these patients roxithromycin dose adjustments are required.

Therapeutic Trials

Oral roxithromycin 150mg twice a day is therapeutically effective in the treatment of several types of infection. In non-comparative studies of respiratory tract infections roxithromycin produced clinical and bacteriological cure rates of 84 to 100% and 91 to 95%, respectively. In comparative studies roxithromycin produced clinical efficacy rates of 78 to 93%, which were similar to those of erythromycin 1g twice a day or 400mg four times a day, doxycycline 200mg daily, amoxycillin 500 twice a day or 750mg 3 times a day, and cephradine 1g twice a day. Compiled results following roxithromycin treatment reveals that 92% of patients with pneumonia caused by common pathogens, 100% with atypical pneumonia, and 85% with acute episodes of chronic obstructive lung disease were clinically cured. Compiled bacteriological eradication rates were 93% for S.pneumoniae, 74% for H. influenzae, 89% for S. aureus, and 92% for S. pyogenes.

High clinical and bacteriological efficacy rates were also obtained in ear, nose and throat infections. Compilation of the results from published studies reveals cure rates of 97% for tonsillitis and pharyngitis, 95% for otitis, and 85% for sinusitis following roxithromycin treatment. In comparative studies similar clinical cure rates of 83 to 100% and 86 to 100%, respectively, were reported for roxithromycin 150mg twice daily and erythromycin 400mg 4 times daily.

Several open and comparative studies have assessed the efficacy of roxithromycin in the treatment of acute or chronic non-gonococcal urethritis, non-gonococcal sexually transmitted infections and cervicovaginitis. In comparative studies clinical cure rates for twice daily administration of roxithromycin 150 and 300mg were 93 and 99%, respectively, compared with 98% for lymecycline 300mg twice a day and 89% for doxycycline 200mg daily. Bacteriological cure rates for roxithromycin ranged in most indications from 86 to 100%, with 97% of C. trachomatis, 88% of U. urealyticum, 73% of M. horninis and 57% of Gardnerella vaginalis isolates eradicated.

In infants and children roxithromycin 2.5 to 5 mg/kg 12-hourly produced clinical cure rates of 83 to 100% for tonsillitis, pharyngitis, superinfected rhinopharyngitis, pneumococcal pneumonia, impetigo, otitis media and pyodermatitis. Bacteriological cure rates were also high, with elimination of 92.3% of S. pyogenes, 79.2% of S. pneumoniae, and 94.3% of S. aureus isolates.

In patients with skin and soft tissue infections both clinical and bacteriological cure rates were 92% for roxithromycin 150mg twice a day and 82% for doxycycline 200mg daily. Overall, in the treatment of skin and soft tissue infections including pyoderma, infective dermatitis and leg ulcers, clinical and bacteriological cure rates were 79 to 100% and 82 to 100%, respectively.

Adverse Effects

Clinically significant adverse effects following treatment with roxithromycin are uncommon. Of 2,917 adults who took part in multicentre studies 4.1% reported adverse effects that were possibly or probably related to treatment. The most common adverse effects encountered were gastrointestinal in nature, with nausea, abdominal pain and diarrhoea the most frequently reported. A total of 0.9% of patients withdrew from treatment as a result of adverse effects. Tolerance and safety in infants and children, and the elderly, were excellent. Abnormalities in liver function tests due to roxithromycin administration were rare.

Dosage and Administration

The recommended oral adult dosage of roxithromycin for all indications is 150mg administered twice a day at least 15 minutes before meals. In infants and children the recommended dose is 2.5 to 5 mg/kg bodyweight twice daily.

No dosage adjustments are required when roxithromycin is administered concurrently with theophylline and carbamazepine, and the drug can be administered simultaneously with warfarin, ranitidine or antacids.

Copyright information

© ADIS Press Limited 1989

Authors and Affiliations

  • Ronald A. Young
    • 1
    • 2
    • 3
  • John P. Gonzalez
    • 1
    • 2
    • 3
  • Eugene M. Sorkin
    • 1
    • 2
    • 3
  1. 1.University of Arkansas for Medical SciencesLittle RockUSA
  2. 2.Manchester International Office CentreADIS Press International LtdWythenshaweEngland
  3. 3.ADIS Drug Information ServicesAucklandNew Zealand