Roxithromycin

Roxithromycin is a semi-synthetic macrolide antibiotic. Roxithromycin is bacteriostatic at low concentrations and bactericidal at high concentrations. It binds to the 50S subunit of the 70S ribosome, thereby disrupting bacterial protein synthesis.

Microbiology

At plasma concentrations achieved with the recommended therapeutic doses, roxithromycin has been demonstrated to have in vitro and clinical activity against the following micro-organisms: Streptococcus pneumoniae, Strep. pyogenes, Mycoplasma pneumoniae, Moraxella catarrhalis, Ureaplasma urealyticum and Chlamydia sp.

Roxithromycin has been demonstrated to have clinical activity against the following micro-organisms which are partially sensitive in vitro to roxithromycin: Haemophilus influenzae and Staphylococcus aureus, except methicillin resistant Staph. aureus (MRSA).

The following strains of micro-organisms are resistant: multi-resistant Staph. aureus, Enterobacteriaceae, Pseudomonas sp. and Acinetobacter sp.

Susceptibility tests

Using the National Committee for Clinical Laboratory Standards (NCCLS), method of susceptibility testing with a 15 microgram roxithromycin disc, susceptible organisms other than Haemophilus influenzae produce zones of inhibition of diameter 21 mm or greater. A zone diameter of 10 to 20 mm should be considered intermediate and a zone diameter of 9 mm or less indicates resistance. A bacterial isolate may be considered susceptible if the minimal inhibitory concentration (MIC) value for roxithromycin is less than or equal to 1 mg/L. Organisms are considered resistant if the MIC value is greater than 8 mg/L.

For H. influenzae, zones of inhibition of diameter 10 mm or greater indicate susceptibility when CO₂ incubation and the HTM agar is used with a 15 microgram roxithromycin disc. An isolate may be considered susceptible if the MIC value for roxithromycin is less than or equal to 8 mg/L.

Note: The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.

Absorption

Roxithromycin is absorbed after oral administration with an absolute bioavailability of approximately 50%. Peak plasma concentrations following administration of 150 and 300 mg film coated tablets are achieved in young and elderly adult patients approximately one to two hours post-dose.

As food intake delays absorption, roxithromycin should be administered at least 15 minutes before food or, alternatively, on an empty stomach (i.e. more than three hours after a meal).

Absorption is not linear; with increasing doses in the range 150 to 300 mg, peak plasma levels and area under the curve (AUC) do not increase in proportion to the dose.

After repeated administration of 2.5 mg/kg every twelve hours to children, the average peak plasma concentration at steady state was 9 mg/L and the AUC was 61 mg.hour/L.

Following administration of a single oral dose of roxithromycin 150 mg to healthy young adults, the mean peak plasma concentration was 6.6 mg/L and the AUC was 69 mg.hour/L. At steady state following doses of 150 mg twice daily, the mean peak plasma concentration was 9.3 mg/L and the AUC was 71 mg.hour/L.

In elderly patients the mean peak plasma concentration following a single 150 mg dose was 9.1 mg/L and the AUC was 148 mg.hour/L. At steady state, a dosage regimen of 150 mg twice daily produced a mean peak plasma concentration of 11.3 mg/L and an AUC of 83 mg.hour/L.

Following administration of a single oral dose of roxithromycin 300 mg to healthy young adults, the mean peak plasma concentration was 10.7 mg/L and the AUC was 146.0 mg.hour/L. At steady state following doses of 300 mg once daily, the mean peak plasma concentration was 10.9 mg/L and the AUC was 77 mg.hour/L.

In elderly patients, the mean peak plasma concentration following a single 300 mg dose was 10.8 mg/L and the AUC was 197 mg.hour/L.

Distribution

Roxithromycin is 92 to 96% bound to plasma proteins (principally alpha-1-acid glycoprotein, but also albumin) at concentrations less than 4.2 mg/L. The binding is saturable. In subjects with normal plasma levels of alpha-1-acid glycoprotein, the extent of binding decreases when plasma concentrations of roxithromycin exceed 4.2 mg/L. At plasma concentration of 8.4 mg/L approximately 87% of the drug is protein bound.

Roxithromycin is highly concentrated in polymorphonuclear leucocytes and macrophages, where levels 30 times those in serum have been reported.

After a single oral dose of 150 mg roxithromycin, good concentrations are reached in respiratory tract tissues and secretions, male and female genital tracts, tonsils and paranasal sinuses, synovial fluid and the skin. Roxithromycin is not detected in saliva.

Metabolism

The mean half-life of roxithromycin is approximately 12 hours in young adults and 20 hours in children. The apparently longer half-life in children does not cause excessive accumulation; minimum concentration (C_min) and AUC values are comparable for adults and children.

The half-life is prolonged to 25 hours in patients with impaired hepatic function and 18 hours in patients with renal insufficiency. The mean half-life in elderly patients is approximately 27 hours.

Roxithromycin undergoes limited metabolism in the body, presumably in the liver. The major metabolite is descladinose roxithromycin. Two minor metabolites have also been identified. Plasma levels of roxithromycin are approximately twice those of all metabolites; a similar ratio is seen in the urine and faeces.

Excretion

Approximately 7% of a dose is excreted in the urine and 13% is eliminated via the lungs. Faecal excretion, which represents the unabsorbed fraction and the small proportion excreted by the liver, accounts for approximately 53% of the dose. The fate of the remainder is unknown.

When roxithromycin plasma levels are above 4.2 mg/L, renal clearance increases because reduced plasma protein binding (see Distribution) causes increased levels of unbound roxithromycin which may be excreted by the kidneys.

None.