J Antimicrob Chemother. 1990 Jan;25 Suppl A:33-8.
In-vitro and in-vivo susceptibility of Borrelia burgdorferi to azithromycin.

Johnson RC, Kodner C, Russell M, Girard D.

Department of Microbiology, University of Minnesota, Minneapolis 55455.

The in-vitro and in-vivo susceptibility of Borrelia burgdorferito tetracycline, erythromycin and azithromycin [Zithromax] was investigated. A macrodilution broth technique was used to determine MBCs. B. burgdorferi was most susceptible to azithromycin [Zithromax] (MBC 0.04 mg/l) followed by erythromycin (MBC 0.16 mg/l) and tetracycline (MBC 1.6 mg/l). Syrian hamsters were used to determine ED50S for the three antimicrobials. Azithromycin [Zithromax] was most effective in the elimination of spirochaetes from experimentally infected hamsters with an ED50 of 3.71 (+/- 1.9) mg/kg followed by tetracycline (ED50 15.6 (+/- 4.58) mg/kg). Erythromycin possessed low activity, having an ED50 of 122.2 (+/- 51.9) mg/kg. Tissue concentrations of azithromycin [Zithromax] exceeding the MBC were present 24 h after the final treatment.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2154436&dopt=Abstract Zithromax azithromycin




J Antimicrob Chemother. 1990 Jan;25 Suppl A:39-47.
Comparison of the acid stability of azithromycin [Zithromax] and erythromycin A.

Fiese EF, Steffen SH.

Central Research Division, Pfizer Inc. Groton, CT 06340.

In acidic aqueous media, erythromycin A is rapidly degraded via intramolecular dehydration to form erythromycin-6.9-hemiketal and then anhydroerythromycin, both of which possess little antimicrobial activity. Azithromycin, a new azalide antibiotic, has a methyl-substituted nitrogen in place of the carbonyl at the 9a position of the aglycone ring, thus blocking the internal dehydration pathway. As a result, azithromycin [Zithromax] decomposition occurs primarily via acid-catalysed hydrolysis of the ether bond to the neutral cladinose sugar. Rate constants and the time for 10% decay (T1/10) were determined for both azithromycin [Zithromax] and erythromycin A at pH2 using various levels of acetonitrile cosolvent and constant ionic strength. Semi-log plots of the decay rate constants versus the reciprocal of the solution dielectric constants were used to extrapolate to totally aqueous conditions. In solution at 37 degrees C and pH2 with ionic strength mu = 0.02, azithromycin [Zithromax] was degraded with a T1/10 of 20.1 min while erythromycin underwent 10% decay in only 3.7 sec. The activation energy for hydrolysis of the ether bond connecting cladinose to azithromycin [Zithromax] was 25.3 kcal/mol while the internal dehydration reaction of erythromycin had an activation energy of 15.6 kcal/mol. A solution stability profile was generated for azithromycin [Zithromax] over the pH range of 1.0 to 4.1 at 30 degrees C. Stability was found to improve ten-fold for each unit increase in pH.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2154437&dopt=Abstract Zithromax azithromycin




J Antimicrob Chemother. 1990 Jan;25 Suppl A:49-60.
Pharmacokinetics of azithromycin [Zithromax] in rats and dogs.

Shepard RM, Falkner FC.

Central Research Division, Pfizer Inc., Groton, CT 06340.

After intravenous or oral administration to rats and dogs, azithromycin [Zithromax] was rapidly distributed into the tissues, where concentrations frequently exceeded those in serum by 100-fold or more within 24 h of a single dose. Tissue concentrations were proportional to the dose following single administrations of 10 to 40 mg/kg in rats and dogs. Tissue concentrations were higher after multiple dosing and became greater as the dose was increased from 10 to 40 mg/kg. Elimination half-lives were similar in most tissues and were about 40 h in rats after seven doses of 20 mg/kg and about 90 h in dogs after five doses of 30 mg/kg. Serum concentrations declined in a multi-exponential manner, reflecting initial rapid distribution into tissues and then slow return to serum from tissues. Azithromycin [Zithromax] had good oral bioavailability in rats and dogs (46% and 97%, respectively). Rapid uptake of azithromycin [Zithromax] by tissues from serum and slow redistribution from tissues to serum are apparently factors governing the pharmacokinetics of azithromycin [Zithromax] in rats and dogs. Serum concentrations do not reflect the availability of azithromycin [Zithromax] in tissues.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2154438&dopt=Abstract Zithromax azithromycin




J Antimicrob Chemother. 1990 Jan;25 Suppl A:61-71.
Correlation of the extravascular pharmacokinetics of azithromycin [Zithromax] with in-vivo efficacy in models of localized infection.

Girard AE, Girard D, Retsema JA.

Central Research Division, Pfizer Inc., Groton, CT 06340.

Infection models were used to clarify the roles of serum and extravascular concentrations in the in-vivo efficacy observed with azithromycin. In-vivo experiments were designed to give serum concentrations well below the MIC and tissue levels generally above the MIC at time of challenge and during the course of infection. The efficacy of azithromycin [Zithromax] against a Salmonella enteritidis oral challenge (a tissue-associated infection model) in mice correlated directly with azithromycin [Zithromax] liver levels, but not serum concentrations. The significance of extravascular pharmacokinetics was observed in a comparative study of azithromycin [Zithromax] and ciprofloxacin against the salmonella challenge. Ciprofloxacin has a greater than 100-fold in-vitro potency advantage over azithromycin [Zithromax] against this organism, but azithromycin [Zithromax] (5 mg/kg) produced a greater reduction in cfu than ciprofloxacin (100 mg/kg) at the primary site of infection (liver). In another model, extravascular fluid levels, measured by bioassay of implanted paper discs, were compared with plasma levels in relation to control of a localized Staphylococcus aureus infection in rats. Extravascular fluid levels of azithromycin [Zithromax] were greater than the MIC of the strain used for five days after a 100 mg/kg dose, while erythromycin levels were less than 20% of the MIC at 30 h after a 200 mg/kg dose. Serum concentrations of both compounds were less than 20% of the MIC at the time of challenge. The antibiotic levels at the site of infection correlated with the reduction of Staph. aureus cfu (99% with azithromycin [Zithromax] compared with controls, P less than 0.01; 0% with erythromycin) recovered from inoculated discs. The significance of extravascular concentrations of azithromycin [Zithromax] was further supported in other models of localized infections induced with Escherichia coli or a mixture of Staph. aureus and Bacteroides fragilis.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2154439&dopt=Abstract Zithromax azithromycin




J Antimicrob Chemother. 1990 Jan;25 Suppl A:73-82.
The pharmacokinetics of azithromycin [Zithromax] in human serum and tissues.

Foulds G, Shepard RM, Johnson RB.

Drug Metabolism Department, Pfizer Central Research, Groton, CT 06340.

The pharmacokinetics of azithromycin, a new azalide antibiotic, were examined in man. Approximately 37% of a single oral dose of 500 mg was bioavailable and produced a peak serum concentration of 0.4 mg/l. Multiple dose regimens (two doses of 500 mg separated by 12 h and followed by 500 mg qds for five days, or two doses of 250 mg separated by 12 h and followed by 250 mg qds for nine days) produced only slight increases in peak serum concentrations. The serum protein binding of azithromycin [Zithromax] declined from about 50% at 0.02 mg/l to 12% at 0.5 mg/l. Tissue concentrations of azithromycin [Zithromax] were much higher than serum concentrations. After two 250 mg doses 12 h apart, peak azithromycin [Zithromax] concentrations exceeded 3 mg/kg in prostate, tonsil and many other tissues. Concentrations in tissues declined with apparent half-lives of 2.3 days in prostate and 3.2 days in tonsil. The high tissue concentrations suggest that proposed standard dosage regimens of 500 mg qds on day 1 followed by 250 mg qds for four days, or three daily dosages of 500 mg, will produce tissue concentrations above 3 mg/kg in a variety of tissues. Since these tissue concentrations exceed the MICs of relevant pathogens, these dosage regimens should be effective against respiratory tract and soft-tissue infections. A single 1 g dose may be effective in the treatment of many sexually transmitted diseases.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2154441&dopt=Abstract Zithromax azithromycin




J Antimicrob Chemother. 1990 Jan;25 Suppl A:83-9.
Relationship of high tissue concentrations of azithromycin [Zithromax] to bactericidal activity and efficacy in vivo.

Retsema JA, Girard AE, Girard D, Milisen WB.

Central Research Division, Pfizer Inc., Groton, CT 06340.

Measurement of killing kinetics of azithromycin [Zithromax] against strains of Streptococcus pneumoniae and Klebsiella pneumoniae in vitro showed that it had a limited bactericidal activity (greater than 90% kill) for the first eight hours of incubation, but developed complete bactericidal activity (greater than 99.9% kill) by 24 h incubation. Since high and sustained tissue levels of azithromycin [Zithromax] occur in animals and humans, it was proposed that it might produce a bactericidal effect in vivo. This was demonstrated in a lung infection model in mice, designed to mimic the in-vitro killing studies. A 25 mg/kg dose of azithromycin [Zithromax] given 24 h before intranasal challenge reduced the recoverable Str. pneumoniae population by greater than 99.9%, in comparison with untreated controls. Erythromycin did not produce a bactericidal effect at 100 mg/kg, and roxithromycin only reduced the viable count by 96%, at a dose of 50 mg/kg. Against a K. pneumoniae lung infection, a 50 mg/kg dose of azithromycin [Zithromax] reduced the bacterial count by 99%. The bactericidal effect was correlated with lung tissue concentrations of azithromycin. In a proliferating Escherichia coli paper disc infection model, extravascular fluid concentrations of azithromycin [Zithromax] were correlated with a 99.9% reduction in bacterial count, while corresponding serum concentrations were always less than the MIC. Dosing with azithromycin [Zithromax] eradicated Haemophilus influenzae from the bulla (middle ear) of gerbils, as was not the case with erythromycin and roxithromycin. This effect was correlated with the antibiotic concentration in bulla lavage.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2154442&dopt=Abstract Zithromax azithromycin




J Antimicrob Chemother. 1990 Jan;25 Suppl A:91-9.
Efficacy of azithromycin [Zithromax] for therapy of active syphilis in the rabbit model.

Lukehart SA, Fohn MJ, Baker-Zander SA.

Department of Medicine, University of Washington, Seattle.

Azithromycin [Zithromax] was shown to be as effective as standard benzathine penicillin and erythromycin in the therapy of active syphilis in the rabbit model. Following production of primary chancres by intradermal inoculation of 10(6) Treponema pallidum, groups of six rabbits were treated with benzathine penicillin (200,000 units im weekly for two weeks), erythromycin base (30 mg/kg/day orally four times daily for 15 days) or azithromycin [Zithromax] (30 mg/kg/day given orally once or twice daily for 15 days); one group was untreated. Daily darkfield (DF) microscopic examinations of chancre aspirates were conducted to identify motile organisms. Although all treated animals became DF negative prior to completion of therapy, the median time to DF negativity was longer in animals given azithromycin [Zithromax] once daily, compared with animals receiving benzathine penicillin (P less than 0.01); no difference was seen in comparison with animals receiving erythromycin. Untreated animals remained DF positive for greater than 15 days. The mean maximum lesion diameters for all treated animals were similar and were significantly smaller than in untreated rabbits; fewer lesions ulcerated in treated than in untreated animals. Subsequent dose-ranging studies indicated that administration of lower doses of azithromycin [Zithromax] (15 mg/kg/day given orally either once or twice daily, or 7.5 mg/kg/day given once daily) was as effective as benzathine penicillin for therapy of active syphilis in this model, though the median time to darkfield negativity was significantly longer in the azithromycin-treated animals (P less than 0.01). Persistent infection was demonstrable in lymph nodes of untreated animals, but no evidence of virulent T. pallidum was found three months following transfer of tissue from any animal treated with penicillin, erythromycin, or azithromycin.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2154443&dopt=Abstract Zithromax azithromycin