How is azithromycin excretion

In tonsils, mean 4 h post dose parent and metabolite concentrations were 5. Parent and metabolite concentrations in nasal mucosa 4 h post dose were 5. In lung tissue, parent and metabolite concentrations 4 h post dose were Tissue distribution of clarithromycin and azithromycin Adapted from [ 20 ]. In a recent study conducted in the United Kingdom, pulmonary tissue concentrations of azithromycin were measured in 22 patients Up to 96 h after a single mg dose, the following findings were observed: mean peak concentration of the drug in sputum, 1.

Serum concentrations were significantly lower 0. The concentration of azithromycin in most tissues has been shown to exceed serum concentrations by to fold 7.

Mean concentrations for a single tissue type are usually greater than 2. One may question whether such an extended half-life is completely beneficial.

Although intraphagocytic bioactivity is not a common property of antimicrobial agents 11 , the newer macrolide antibiotics achieve high intracellular concentrations. Both clarithromycin and azithromycin have been shown to penetrate macrophages and leukocytes, which makes them particularly effective against intracellular pathogens such as Legionella pneumophila and Chlamydia species 5. In contrast, penicillin and cephalosporin antibiotics are not actively concentrated by phagocytes, and they possess only modest, if any, intracellular activity Anderson and colleagues 11 observed that erythromycin was rapidly concentrated by neutrophils, with an intracellular to extracellular I:E ratio of The I:E ratio for clarithromycin was These investigators concluded that the superior pharmacokinetic properties of clarithromycin will lead to increased intraphagocytic accumulation and bioactivity in vivo.

Therapeutic concentrations of clarithromycin have also been found to stimulate protein kinase C activity in polymorphonuclear leukocytes PMNLs. Thus, in addition to its antimicrobial activity, the drug stimulates cellular host defense mechanisms involving the activation of protein kinase C It was recently shown that, among all macrolides tested so far, azithromycin provides the highest I:E ratio, confirmed both in vitro and in vivo, with values of approximately obtained in vitro for azithromycin The theory that onsite, intraphagocytic delivery of azithromycin provides a significant amount of bioactive antimicrobial agent has been demonstrated in vitro and in vivo However, this concept applies to all macrolides, including erythromycin, that are known to accumulate in phagocytic cells.

Although the metabolism of the macrolide antibiotics has not been extensively studied, it is known that a portion of the dose is metabolized in the liver. Macrolide antibiotics are demethylated by the cytochrome PIII microsomal enzyme system.

Clarithromycin is metabolized to eight metabolites, but only one, the hydroxy metabolite, has been shown to have antibacterial activity. The activity of this metabolite is comparable to or greater than that of the parent compound. It is not known whether any of the metabolites of azithromycin are active 5. The pharmacokinetics of clarithromycin appear to be dose-dependent and nonlinear, apparently as a result of capacity-limited saturation of metabolic pathways.

However, such nonlinearity is slight at the recommended dosages. Similar dose dependency has been observed with the hydroxy metabolite 1. In individuals with normal renal function, the half-lives of clarithromycin and its hydroxy metabolite after a mg dose are 5 and 7 h, respectively As renal function declines, the serum half-lives of these compounds increase to 7. For hydroxy clarithromycin at the lower creatinine clearance, the half-life is 47 h. Clearly, regimen alteration would be advisable in patients with severely impaired renal function.

Severe hepatic impairment could theoretically alter the pharmacokinetics of clarithromycin and its metabolite so that less metabolite would be formed, and renal clearance of the parent compound would increase.

Steady-state levels of unchanged clarithromycin in hepatically impaired patients are similar to those in normal subjects, so if renal function is normal, the drug can be administered without dose adjustment Azithromycin elimination is polyphasic: the initial rapid decline in drug serum levels is followed by multiple-phase distribution and elimination.

After a single mg dose, terminal half-life probably exceeds 40 h When azithromycin metabolism occurs, demethylation is the primary route. The metabolites, which may number as many as 10, are not thought to have any significant antimicrobial activity 3. The feces are an important route of elimination for azithromycin; binary concentrations of the drug far exceed serum concentrations, suggesting binary excretion. Over half the drug-related material in the bile is unchanged.

Transin-testtnal excretion may be the primary route of elimination of the unchanged compound 3. The antibiotic is metabolized through the liver and excreted in active form in the bile.

Azithromycin may be given as a single 1 g dose in specific instances, but the more common regimen is a five-day course of therapy, beginning with a mg dose on day 1, followed by daily mg doses on days 2 through 5 1 , 8. For clarithromycin, the usual adult dose for infections of the respiratory tract and the skin and soft tissues is to mg every 12 h for seven to 14 days.

In patients with both hepatic and renal impairment, or in the presence of severe renal impairment, decreased dosage or prolonged dosing intervals may be appropriate The pharmacokinetic advantages and superior spectra of activity of clarithromycin and azithromycin over erythromycin base and esters are well delineated; however, it is my opinion that differences between clarithromycin and azithromycin are not as dramatic as they may appear to be. When evaluating tissue penetration of clarithromycin and azithromycin, one would prefer data from the same investigators under similar study conditions.

Comparative studies are currently under way and are likely to provide further insights into understanding these new compounds. Both clarithromycin and azithromycin offer therapeutic advantages in certain areas, and they are likely to become first-line therapy in a number of situations Thus synthesis of proteins is inhibited. At high concentrations azithromycin is bactericidal against susceptible strains. Cells are substantially more permeable to the unionized form of azithromycin, which possibly explains the augmented antimicrobial activity at alkaline pH.

Azithromycin usually is less active than erythromycin against gram-positive organisms and slightly more active than either clarithromycin or erythromycin against H. It has good activity against M. It has enhanced activity against M. It is also more active than erythromycin against Chlamydia trachomatis and Ureaplasma urealyticum, and Mycobacterium avium complex.

Erythromycin-resistant gram-positive strains are cross resistant to azithromycin. Beta-lactamase production does not affects azithromycin. The most common type of resistance is a plasmid-mediated ability to methylate ribosomal RNA, resulting in decreased binding of the antimicrobial drug. This can lead to cross-resistance between erythromycin, other macrolides, lincosamides, and streptogramin B, as they share a common binding site on the ribosome and this pattern of resistance is known as the MLSB phenotype.

Incidence of resistance to azithromycin and other macrolides is higher among penicillin-resistant strains than among penicillin-sensitive strains. Absorption from capsules, but not tablets or suspension, is decreased by food. Peak plasma concentrations occur two to three after an oral dose and 1 to 2 hours after intravenous dosage.

Concentrations are higher in tissues than in blood. It concentrates in WBCs, phagocytes and fibroblasts which contribute to drug distribution to inflamed tissues. Although slightly less potent than erythromycin against gram-positive organisms, azithromycin demonstrates superior activity in vitro against a wide variety of gram-negative bacilli, including Haemophilus influenzae. Metabolism is predominantly hepatic to inactive metabolites , with biliary excretion a major pathway of elimination.

Drug elimination is biphasic, with a terminal half-life of up to 5 days. Published trials have examined the efficacy and safety of azithromycin in the treatment of adults with upper and lower respiratory tract infections, skin and skin structure infections, streptococcal pharyngitis, and sexually transmitted diseases.