Azithromycin

Abstract

Synopsis

Azithromycin is an acid stable orally administered macrolide antimicrobial drug, structurally related to erythromycin, with a similar spectrum of antimicrobial activity. Azithromycin is marginally less active than erythromycin in vitro against Gram-positive organisms, although this is of doubtful clinical significance as susceptibility concentrations fall within the range of achievable tissue azithromycin concentrations. In contrast, azithromycin appears to be more active than erythromycin against many Gram-negative pathogens and several other pathogens, notably Haemophilus influenzae, H. parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Ureaplasma urealyticum and Borrelia burgdorferi. Like erythromycin and other macrolides, the activity of azithromycin is unaffected by the production of β-lactamase. However, erythromycin-resistant organisms are also resistant to azithromycin. Following oral administration, serum concentrations of azithromycin are lower than those of erythromycin, but this reflects the rapid and extensive movement of the drug from the circulation into intracellular compartments resulting in tissue concentrations exceeding those commonly seen with erythromycin. Azithromycin is subsequently slowly released, reflecting its long terminal phase elimination half-life relative to that of erythromycin. These factors allow for a single dose or single daily dose regimen in most infections, with the potential for increased compliance among outpatients where a more frequent antimicrobial regimen might traditionally be indicated. The potential disadvantage of low azithromycin serum concentrations, however, is that breakthrough bacteraemia may occur in patients who are severely ill; nevertheless, animal studies suggest that tissue concentrations of azithromycin are more important than those in serum when treating respiratory and other infections.

The clinical efficacy of azithromycin has been confirmed in the treatment of infections of the lower and upper respiratory tracts (the latter including paediatric patients), skin and soft tissues (again including paediatric patients), in uncomplicated urethritis/cervicitis associated with N. gonorrhoeae, Chlamydia trachomatis or U. urealyticum and in the treatment of early Lyme disease. Azithromycin was as effective as erythromycin and other commonly used drugs including clarithromycin, β-lactams (penicillins and cephalosporins), and quinolone and tetracycline antibiotics in some of the above infections. Some patients with acute exacerbations of chronic bronchitis due to H. influenzae may be refractory to therapy with azithromycin (as is the case with erythromycin) indicating the need for physician vigilance, although it should be noted that azithromycin is of equivalent efficacy to amoxicillin in the treatment of such patients. In the therapy of urethritis/cervicitis associated with C. trachomatis, N. gonorrhoea or U. urealyticum, a single dose azithromycin regimen offers a distinct advantage over currently available pharmacological options, while providing effective therapy. Furthermore, it is likely that azithromycin may supersede erythromycin in the treatment of early Lyme disease and become an alternative to therapy with penicillin or tetracycline antibiotics in this condition. Similarly, if the finding of clinical efficacy of azithromycin in a preliminary study of chancroid is sustained in further clinical trials, then the use of azithromycin might supplant the traditional use of a more frequent erythromycin regimen in this condition.

Small initial trials have shown azithromycin to be effective at least in the amelioration of Mycobacterium avium infection in AIDS patients.

Comparative clinical trials have shown azithromycin to be better tolerated than erythromycin, principally through fewer gastrointestinal disturbances. Such studies have also shown the tolerability profile of azithromycin to be superior to that of cefaclor, doxycycline or amoxicillin plus probenecid.

In conclusion, with its broad spectrum of antimicrobial activity, proven efficacy in a wide range of community-acquired infections, improved tissue pharmacokinetic and tolerability profiles, and suitability for once daily dosing, azithromycin provides a useful alternative to erythromycin and other macrolides with similar activity. In patients with uncomplicated urethritis or cervicitis associated with C. trachomatis, N. gonorrhoeae or U. urealyticum, azithromycin as a single dose regimen offers distinct advantages over current pharmacological options and should therefore be considered as a first-line therapy.

Antimicrobial Activity

Azithromycin has a spectrum of in vitro activity similar to that of erythromycin, although differences in activity have been recorded for particular organisms.

Azithromycin was active against isolates of Staphylococcus aureus, including β-lactamase producing strains, although less so than clarithromycin and roxithromycin. Azithromycin was also active against some S. epidermidis isolates and other coagulase-negative staphylococci; however, staphylococcal resistance to macrolides was often encountered, and azithromycin was also inactive in these instances. Azithromycin was active against streptococci Groups A,B,C,F,G, other oral streptococci and Streptococcus bovis included among other strains tested together. However, Group A streptococci that were resistant to erythromycin were also resistant to azithromycin. Azithromycin was inactive against Enterococci (group D streptococci). Although S. viridans was resistant overall to azithromycin in the analysis, both susceptibility and resistance were reported in the individual studies analysed. S. pneumoniae strains susceptible to erythromycin and those not selected for antimicrobial sensitivity or resistance were susceptible to azithromycin although more so to the other macrolides tested. S. pneumoniae erythromycin-resistant strains were also resistant to azithromycin. Isolates of Listeria monocytogenes were moderately susceptible to azithromycin but were more susceptible to erythromycin, clarithromycin or roxithromycin. Corynebacterium species were generally resistant to azithromycin.

Azithromycin was active against Bordetella pertussis (particularly) and B. parapertussis and was marginally more active than other macrolides tested against the latter organism. Clinical isolates of Campylobacter jejuni were more susceptible to azithromycin than to erythromycin, roxithromycin or clarithromycin. Helicobacter pylori isolates were also susceptible to azithromycin and similarly susceptible to erythromycin and roxithromycin although more so to clarithromycin. Azithromycin was more active against this organism than rifampin, metronidazole and a selection of quinolone antimicrobials. Azithromycin showed greater activity than other macrolides against isolates of Haemophilus influenzae and H. parainfluenzae, including β-lactamase producing strains, although the microbiologically active 14-hydroxy metabolite of clarithromycin showed similar activity to azithromycin against H. influenzae. Azithromycin was particularly active against H. ducreyi; the susceptibility of this organism to azithromycin was not affected by β-lactamase production or tetracycline resistance. Moraxella catarrhalis strains, including those producing β-lactamase, were susceptible to azithromycin and most other macrolides, although less so to erythromycin, roxithromycin or clindamycin. Azithromycin was also more active than benzyl penicillin against M. catarrhalis, even when isolates producing β-lactamase were excluded from the analysis. Azithromycin was active against Neisseria gonorrhoeae (including β-lactamase producing strains) and N. meningitidis and was more active than erythromycin against these pathogens. Legionella species were susceptible to azithromycin, although these organisms were more susceptible to erythromycin and other macrolides. Azithromycin was particularly active against Gardnerella vaginalis and Mobiluncus species and was also active against Actinobacillus actinomycetemcomitans and Bruceila melitensis.

Pooled results of in vitro tests against Bacteroides species showed overall resistance to azithromycin; however, when species were tested individually, either susceptibility or resistance were recorded. Clostridium species were moderately susceptible to azithromycin overall, although in the majority of individual studies these isolates were susceptible. Azithromycin was active against C. perfringens and active or moderately active against C. difficile. Azithromycin was highly active against Propionibacterium acnes, although only moderate activity was recorded against anaerobic Gram-positive cocci (including Peptococcus and Peptostreptococcus species).

Azithromycin was active against the commonly isolated urogenital pathogens C. trachomatis and U. urealyticum, and was also active against the atypical respiratory pathogens C. pneumoniae and Mycoplasma pneumoniae. M. hominis isolates were either moderately susceptible or resistant to azithromycin, although consistently resistant to erythromycin. Mycobacterium avium complex isolates were resistant to azithromycin, but the replication rate of this organism was slowed by azithromycin in cultured macrophages. Isolates of Borrelia burgdorferi were notably more susceptible to azithromycin than to either benzyl penicillin or tetracycline. Treponema pallidum protein synthesis was inhibited by azithromycin, however, the effective concentration range exceeded clinically relevant concentrations. Like metronidazole, azithromycin inhibited the growth of Entamoeba histolytica, although unlike metronidazole, azithromycin showed considerable variation in activity against Giardia duodenalis. Azithromycin had only a minimal effect on the growth of G. lamblia. Azithromycin appears to be parasitostatic against Toxoplasma gondii.

In general, bacterial strains resistant to erythromycin are also resistant to azithromycin, although bacterial strains resistant to penicillins are susceptible to azithromycin where macrolide resistance is absent. Therefore, the resistance mechanism involving the production of β-lactamase alone does not appear to influence susceptibility to azithromycin.

Azithromycin is bactericidal against a variety of organisms including S. aureus, S. epidermidis, S. pneumoniae, H. influenzae, Klebsiella pneumoniae, Bordetella species, L. pneumophila, M. catarrhalis, C. trachomatis, C. pneumoniae, M. avium complex and B. burgdorferi. A postantibiotic effect of 1.7 to 3.9 hours was recorded for azithromycin against S. pyogenes, S. pneumoniae, H. influenzae, M. catarrhalis, K. oxytoca, and K. pneumoniae.

Azithromycin produces its antibacterial effect by inhibition of protein synthesis.

Azithromycin has demonstrated antimicrobial activity in experimental models of infection induced by a variety of Gram-positive and Gram-negative organisms (including Staphylococci, Streptococci, H. influenzae, L. pneumophila) and other organisms including T. gondii, T. pallidum, B. burgdorferi, C. trachomatis and M. avium complex.

Pharmacokinetic Properties

Azithromycin is considerably more stable than erythromycin at low pH. Following oral administration to healthy volunteers, the bioavailability of azithromycin was estimated as 37%. The pharmacokinetic profile of azithromycin appears to be characterised by rapid and extensive uptake from the circulation into intracellular compartments followed by slow release. This may explain the low peak plasma concentration (C_max) of about 0.4 mg/L attained within approximately 2.5 hours of a 500mg oral dose, relative to those achieved following administration of other commercially available macrolide drugs at therapeutic doses. Similarly, area under the plasma concentration-time curve (AUC) was 2- to 39-fold lower for azithromycin than for other macrolides. In multiple dose studies, azithromycin 500mg twice daily on day 1 followed by 500 mg/ day for a further 4 days resulted in mean AUC values rising from 1.77 mg/L · h on day 1 to 3.18 mg/L· h on day 5, and mean C_max increased from 0.41 to 0.62 mg/L over the same period. A similar trend was seen with administration of azithromycin 250mg twice daily on day 1 followed by 250 mg/day for a further 8 days.

Azithromycin appears to be widely distributed throughout the body, generally achieving higher concentrations in tissues, organs, tissue fluids and a variety of cell types including phagocytes, than in blood. Indeed, the reported values for volume of distribution have been large — 23 to 31 L/kg. Binding of azithromycin to human plasma proteins was 50% at a concentration of 0.02 to 0.05 mg/L, reducing to 7% at 1 mg/L. The degree of binding of azithromycin is much lower than that of erythromycin (72% at 0.4 mg/L) or roxithromycin (96% at 2.5 mg/L), suggesting the capacity for higher concentrations of free azithromycin to be available for distribution to infection sites.

Available pharmacokinetic data suggest that azithromycin is mainly excreted unchanged, principally in the faeces and to a lesser extent in the urine. Transintestinal excretion may be the primary elimination mechanism for the unchanged compound. The elimination of azithromycin from serum follows a polyphasic pattern, with values for terminal phase elimination half-life ranging from 10 to 57 hours depending on the dose regimen and sampling interval.

The pharmacokinetic profile of azithromycin is not altered significantly in elderly patients with mild renal impairment, nor in patients with mild to moderate hepatic impairment. Pharmacokinetic data are not available for paediatric patients, or for patients with more severe renal or hepatic dysfunction.

Therapeutic Efficacy

Azithromycin is effective in the treatment of several types of infection when administered as a 1.5g total dose over 3 or 5 days to adults and as a 30 mg/kg total dose over 3 or 5 days to children. In the treatment of urogenital and sexually transmitted infections, a single 1g dose appears to be as effective as a 3-day regimen (500mg on day 1 then 250 mg/day for an additional 2 days), while AIDS patients with M. avium complex infection have benefited from an azithromycin regimen of 500 mg/day for 10 to 30 days.

In comparative (mostly nonblind) studies of patients with lower respiratory tract infections, treatment with azithromycin was associated with clinical cure rates of 36 to 80%, clinical success (cure plus improvement) rates of 92 to 100% and bacteriological eradication rates of 52 to 93%. In these investigations, the clinical efficacy of azithromycin was judged to be equivalent to that of erythromycin, josamycin, amoxicillin (with or without clavulanic acid) or cefaclor. In 2 non-comparative studies of patients with lower respiratory tract infections clinical cure and/or bacteriological eradication rates were high; 95 and 91%, respectively. However, in the treatment of patients with acute purulent exacerbations of chronic bronchitis the cure rate declined from 55% at the end of treatment to 33% 1 month after initiation of therapy, reflecting the incidence of reinfection. Furthermore, the development of H. influenzae resistance to azithromycin appeared to be a major factor in the failure of this antibiotic. Azithromycin, however, was at least as effective as amoxicillin in the treatment of patients with (mainly severe) acute exacerbations of chronic bronchitis when assessed 12 days after initiation of therapy (clinical cure and success rates; 64 and 96% vs 52 and 80%, and bacteriological eradication rates; 52 vs 40%, respectively). Furthermore, in this study, eradication rates for Haemophilus spp. were similar for the 2 antimicrobials.

Upper respiratory tract infections (including those of the middle ear) also responded to therapy with azithromycin. In comparative (mostly nonblind) studies that recruited adults, azithromycin therapy resulted in clinical cure and success rates of 66 to 81% and 93 to 100% in patients with acute maxillary sinusitis, 76 to 87% and 96 to 99% of patients with acute streptococcal pharyngitis and/or tonsillitis, and 79 and 97% of patients with acute otitis media. In paediatric patients with acute otitis media azithromycin was clinically curative for 78 to 95% and clinically successful for 93 to 99% of children. Azithromycin was also effective in the treatment of paediatric pharyngitis and/or tonsillitis with clinical cure rates of 86 to 93% and clinical success rates of 95 to 98%. Bacteriological eradication rates in adults ranged from 87 to 100%, while in children with bacterial pharyngitis, eradication rates ranged from 91 to 95%.

Therapy with azithromycin in adults and/or children was considered equivalent to a standard regimen of amoxicillin or clarithromycin in patients with acute sinusitis, phenoxymethyl penicillin, erythromycin or clarithromycin in patients with bacterial pharyngitis and/or tonsillitis, erythromycin in patients with acute sinusitis and other upper respiratory tract infections and clarithromycin in patients with acute otitis media.

Azithromycin has also shown clinical efficacy in the treatment of urogenital and other sexually transmitted infections. In comparative studies, the clinical cure and rates for azithromycin in patients with urethritis and/or cervicitis associated with C. trachomatis, N. gonorrhoeae or U. urealyticum ranged from 56 to 100% when assessed within 28 days of initiating therapy, although in most studies clinical cure was noted for more than 90% of patients. Bacteriological eradication rates were either comparable with, or exceeded, clinical cure rates, and almost invariably surpassed 90%. In these comparative studies, azithromycin 1g was equally effective whether administered in a single or dose or as a 3-day regimen. Furthermore, azithromycin was at least as effective as doxycycline and tended to show superior efficacy to ciprofloxacin when these drugs were given in standard 7-day regimens.

In the treatment of adults with skin and soft tissue infections, therapy with azithromycin was associated with clinical cure rates of 53 to 83%, clinical success rates of 86 to 99%, and bacteriological eradication rates of 60 to 99%. Treatment with azithromycin was considered to be as effective as a standard regimen of cloxacillin, cephalexin or erythromycin.

In the treatment of early Lyme disease azithromycin was considered to be at least as effective as phenoxymethyl penicillin, doxycycline or amoxicillin plus probenecid.

A preliminary study of AIDS patients with M. avium infection has revealed azithromycin 500mg to be effective in reducing mycobacteraemia and the clinical symptoms of this infection when administered over a 10- to 30-day period.

Tolerability

In comparative studies involving a total of 3995 patients who were treated with azithromycin 1.5g in divided doses over 5 days, the overall adverse effect rate was 12%; this decreased to 9.3% in patients aged ⩾ 65 years and 5.4% in patients aged ⩽ 14 years. The overall incidence of adverse effects was comparable to, or lower than, that reported for other antibacterial agents studied.

The most common adverse effects were gastrointestinal (9.6%), followed by central and peripheral nervous system effects (1.3%). Most adverse effects were mild or moderate, with only 6% rated as severe (predominantly gastrointestinal disturbances, dizziness, headache, fatigue and cutaneous events). Treatment was discontinued in 0.7% of patients because of adverse events; this compares with 1.3 to 15.2% for most of the comparator drugs studied. Fewer discontinuations were noted during the first 5 days of therapy in azithromycin recipients compared with the majority of other antibacterial drugs.

Dosage and Administration

The recommended adult oral dosage regimen for azithromycin in the treatment of infections, excluding those transmitted sexually, is 500mg once daily for 3 days or 500mg as a single dose on day 1 followed by 250mg once daily for a further 4 days. Both dosage regimens have been shown to provide target tissue concentrations of azithromycin above the MIC values for key pathogens during and for 5 to 10 days following therapy. Chlamydial urethritis or cervicitis may be treated with a single oral dose of 1g; this dose also appears effective in the treatment of chancroid and uncomplicated gonorrhoea. In paediatric patients, an oral dosage regimen of 10 mg/kg on the first day and 5 mg/kg for a further 4 days is recommended. However, children weighing more than 45kg should receive the adult dosage. In the treatment of Lyme disease, a standard 5-day azithromycin regimen or azithromycin 250mg twice daily for 2 days followed by 250mg daily for 8 days has proven effective. Preliminary studies indicate that azithromycin 500mg daily for 10 to 30 days has a beneficial effect in the treatment of M. avium complex infection in patients with AIDS. Studies have indicated that dosage adjustment is not necessary in elderly patients with mild renal impairment or in patients with mild to moderate hepatic dysfunction; however, the manufacturer recommends that azithromycin be used with caution in patients with creatinine clearance rates <2.4 L/h, and patients with hepatic disease should not be administered the drug. Azithromycin is contraindicated in patients with known macrolide hypersensitivity and in those receiving ergot alkaloids; serum concentrations of cyclosporin or digoxin should be monitored when coadministered with azithromycin. Azithromycin should be given at least 1 hour before or 2 hours after food or antacids.