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The spectrum of antimalarial activity of the new macrolide antibiotic azithromycin [Zithromax] was evaluated against blood- and sporozoite-induced infections with a chloroquine-resistant strain of Plasmodium yoelii nigeriensis (N-67) in Swiss mice and with simian parasite Plasmodium cynomolgi B in rhesus monkeys. Against experimental rodent malaria, a 70 mg/kg/day dose showed curative blood-schizontocidal activity in a four-dose regimen administered orally from day 0 to day 3 or from day 2 to day 5 to mice harboring established infection. The curative response was also obtained with a 40 mg/kg/day dose administered in an extended seven-dose (days 0-6) regimen. Azithromycin [Zithromax] was also effective in the causal prophylactic test, since a 50 mg/kg dose from day -1 to day +2 protected mice against P. y. nigeriensis (N-67) sporozoite challenge. In comparison, erythromycin did not show either of the above activities up to a 405 mg/kg/day dose in identical regimens. Comparison of the ED(90) values showed that azithromycin [Zithromax] was 31-fold more effective than erythromycin as a blood schizontocide. In the simian model, trophozoite-induced infections of P. cynomolgi B were cured with 25 mg/kg/day azithromycin [Zithromax] administered for 7 days. In the causal prophylactic test, the prepatent period was significantly extended in monkeys challenged with P. cynomolgi B sporozoites, presumably because of the growth inhibition of preerythrocytic schizonts in hepatocytes. Azithromycin [Zithromax] did not exhibit any hypnozoitocidal (dormant exoerythrocytic stages) activity at 25 mg/kg/day in a seven-dose regimen. Copyright 2000 Academic Press.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10631075&dopt=Abstract Zithromax azithromycin




Br J Clin Pharmacol. 1996 Apr;41(4):277-84.
A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin [Zithromax] and cefixime examined by observational cohort studies.

Wilton LV, Pearce GL, Mann RD.

Drug Safety Research Unit, Southampton, UK.

1. The safety in everyday clinical usage of three 4-quinolone antibiotics, (ciprofloxacin, norfloxacin and ofloxacin), was compared with similar data for azithromycin [Zithromax] and cefixime, each agent being examined by Prescription-Event Monitoring (PEM) during the early post-marketing period. 2. In PEM the exposure data are derived from general practitioner prescriptions confidentially provided by the Prescription Pricing Authority. Outcome data are provided by questionnaires (green forms) on which the prescribing medical practitioner records event data. When necessary, further information is obtained from a number of sources which include follow-up of all pregnancies and the patients' life-time medical record. 3. The main outcome measures were demographic information, including the patient's date of birth and sex; the indication for prescribing the drug being monitored; the reason for stopping treatment; the start and stop dates of treatment and the events recorded during and after treatment. 4. The final cohort for each of the five antibiotics exceeded 11000 patients. The only event significantly related to the use of all five antibiotics was nausea/vomiting. This was also the most frequent adverse event causing treatment to be discontinued with norfloxacin, ofloxacin and azithromycin [Zithromax] (relevant information was not requested in the studies of ciprofloxacin and cefixime). Vaginal candidiasis was significantly more frequently associated with the use of the three 4-quinolones than with azithromycin [Zithromax] and cefixime but it was frequently delayed until the week or two after the cessation of therapy. Within each event, as recorded in these studies, the highest event rates (the number of events per 1000 patients) in the week following the start of therapy were: 9.2 for diarrhoea with cefixime; 4.9 for nausea/vomiting with ofloxacin; 2.4 for rash with azithromycin; 2.2 for abdominal pain with norfloxacin; 1.5 for headache/migraine with ofloxacin; 1.4 for malaise/lassitude with ofloxacin; 1.2 for dizziness with norfloxacin. Uncommon events (reported in less than 1:1000 patients) included rare cases of allergic phenomena, convulsions and pseudomembranous colitis. There were no reports of tendinitis, tenosynovitis or tendon rupture in children but tendon disorders were reported in the two months following the start of treatment in 20 adults. A total of 307 pregnancies were reported. Thirty-eight of the 55 women who received these drugs during the first trimester of pregnancy gave birth to healthy babies. No congenital abnormalities were reported. Apart from one case of unconfirmed pseudomembranous colitis, none of the other 2468 deaths that occurred in these studies was attributed to the antibiotics. 5. These five antibiotics are acceptably safe antimicrobial agents when used in general medical practice. PEM is an effective method for monitoring the safety of recently introduced antimicrobial agents.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8730972&dopt=Abstract Zithromax azithromycin




J Clin Microbiol. 1996 Feb;34(2):479-81.
Evaluation of in vitro spectra of activity of azithromycin, clarithromycin, and erythromycin tested against strains of Neisseria gonorrhoeae by reference agar dilution, disk diffusion, and Etest methods.

Mehaffey PC, Putnam SD, Barrett MS, Jones RN.

Medical Microbiology Division, University of Iowa College of Medicine, Iowa City 52242, USA.

The macrolide-azilide susceptibility testing (agar dilution, disk diffusion, Etest) criteria for 105 Neisseria gonorrhoeae strains were evaluated. In addition, the potencies of azithromycin, clarithromycin, and erythromycin were studied. The most active macrolide-azilide agent was azithromycin [Zithromax] (MIC at which 90% of the isolates are inhibited [MIC90], 0.5 microgram/ml) compared with clarithromycin (MIC90, 1.5 to 2 micrograms/ml) and erythromycin (MIC90, 2 to 4 micrograms/ml). The Etest (AB Biodisk, Solna, Sweden) was observed to produce MIC results very similar to those of the reference agar dilution test (GC agar base), with 100% of the results within 1 log2 dilution step of the reference MICs. The disk diffusion test zone diameters for all three drugs correlated at an acceptable level (r = -0.81 to -0.92) with the reference agar dilution MICs. Interpretive criteria for susceptibility were proposed for azithromycin [Zithromax] at a MIC of < or = 2 micrograms/ml and a disk diffusion test zone of > or = 25 mm. No category for resistance was proposed because of the paucity of strains for which MICs were > 2 micrograms/ml. These tentative criteria should be further validated by correlations with clinical trial data for gonococcal strains (as they emerge) that have azithromycin [Zithromax] MICs above the proposed susceptible category range.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8789046&dopt=Abstract Zithromax azithromycin




Antimicrob Agents Chemother. 1996 Jul;40(7):1617-22.
Single-dose intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime in volunteer subjects.

Conte JE Jr, Golden J, Duncan S, McKenna E, Lin E, Zurlinden E.

Department of Epidemiology and Biostatistics, University of California, San Francisco 94143-0208, USA.

The intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime were studied in 68 volunteers who received single, oral doses of azithromycin [Zithromax] (0.5 g), clarithormycin (0.5 g), ciprofloxacin (0.5 g), or cefuroxime (0.5 g). In subgroups of four subjects each, the subjects underwent bronchoscopy and bronchoalveolar lavage at timed intervals following drug administration. Drug concentrations, including those of 14-hydroxyclarithromycin (14H), were determined in serum, bronchoalveolar lavage fluid, and alveolar cells (ACs) by high-pressure liquid chromatography. Concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The maximum observed concentrations (mean +/- standard deviation) of azithromycin, clarithromycin, 14H, ciprofloxacin, and cefuroxime in serum were 0.13 +/- 0.07, 1.0 +/- 0.6, 0.60 +/- 0.41, 0.95 +/- 0.32, and 1.1 +/- 0.3 microgram/ml, respectively (all at 6 h). None of the antibiotics except clarithromycin (39.6 +/- 41.1 micrograms/ml) was detectable in ELF at the 6-h bronchoscopy. The movement into and persistence in cells was different for azithromycin [Zithromax] and clarithromycin. In ACs azithromycin [Zithromax] was not detectable at 6 h, reached its highest concentration at 120 h, and exhibited the greatest area under the curve (7,403 micrograms.hr ml-1). The peak concentration of clarithromycin (181 +/- 94.1 micrograms/ml) was greater and occurred earlier (6 h), but the area under the curve (2,006 micrograms.hr ml-1) was less than that observed for azithromycin. 14H was detectable in ACs at 6 h (40.3 +/- 5.2 micrograms/ml) and 12 h (32.8 +/- 57.2 micrograms/ml). The peak concentration of ciprofloxacin occurred at 6 h (4.3 +/- 5.2 micrograms/ml), and the area under the curve was 35.0 micrograms.hr ml-1. The data indicate that after the administration of a single dose, azithromycin, clarithromycin, and ciprofloxacin penetrated into ACs in therapeutic concentrations and that only clarithromycin was present in ELF. The correlation of these kinetic observations with clinical efficacy or toxicity was not investigated and is unclear, but the data provide a basis for further kinetic and clinical studies.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8807050&dopt=Abstract Zithromax azithromycin




J Antimicrob Chemother. 1996 Jun;37 Suppl C:9-19.
Correlation of increased azithromycin [Zithromax] concentrations with phagocyte infiltration into sites of localized infection.

Girard AE, Cimochowski CR, Faiella JA.

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

Azithromycin [Zithromax] reaches high concentrations in phagocytic and other host cells, suggesting that they may transport this agent to specific sites of infection. Models of localized infection (Haemophilus influenzae middle ear infection in gerbils, Streptococcus pyogenes implanted contaminated paper disc and Streptococcus pneumoniae pneumonia in mice) that induced severe inflammatory response after challenge were used to explore this hypothesis. Animals were given a single 100 or 50 mg/kg po dose of azithromycin [Zithromax] at various times from 2 to 120 h following introduction of a pathogen or sterile medium. When azithromycin [Zithromax] was given during a period of little or no inflammation, there was marginal difference between concentrations found in infected or non-infected sites (bulla, disc, lung). However, when the compound was given during a period of inflammation, considerably higher drug concentrations were found in infected sites than in non-infected sites at 5-24 h after dosing (0.38-0.44 mg/c compared with 0.07-0.14 mg/L of bulla wash; 1.01-1.75 micrograms compared with < or = 0.01-0.03 microgram at the disc site; 1.72-5.28 mg/kg compared with 0.7-1.53 mg/kg of lung). When the observation periods were extended to include 48, 56 or 96 h after dosing, the ratio of azithromycin [Zithromax] infection site concentration: serum concentration steadily increased with time in all model systems (middle ear, implanted disc and pneumonia), reflecting the maintenance of concentrations at the sites of infection, while serum concentrations declined. Bioassay of cell pellets and supernatants, obtained from pooled bulla washes of gerbils treated with azithromycin [Zithromax] during a period of inflammation, revealed that cellular components accounted for about 75% of the azithromycin [Zithromax] detected. These data show that increased azithromycin [Zithromax] concentrations occur at sites of localized infection. This correlates with the presence of inflammation and is associated with the cellular components of the inflammatory response. Therefore, phagocytes may be important vehicles for delivering azithromycin [Zithromax] to and sustaining azithromycin [Zithromax] concentrations at sites of infection.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8818842&dopt=Abstract Zithromax azithromycin




J Antimicrob Chemother. 1996 Jun;37 Suppl C:21-35.
Influence of immunosuppression on the pharmacokinetics and pharmacodynamics of azithromycin [Zithromax] in infected mouse tissues.

Girard D, Regan PA, Milisen WB, Retsema JA, Swindell AC.

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

Azithromycin [Zithromax] has been shown to preferentially distribute to infection loci. Due to the potential contribution of phagocytes as transporters of drug to these sites, there has been some concern that immunosuppression of the cellular arm of the host defence system would greatly reduce the delivery of azithromycin [Zithromax] to sites of infection and hence impair efficacy. Therefore, we evaluated the pharmacokinetics and pharmacodynamics of azithromycin [Zithromax] in a Staphylococcus aureus intramuscular infection model in normal and immunosuppressed mice, employing therapeutic and prophylactic regimens. Immunosuppression was induced by daily doses of cyclophosphamide that culminated in leucopenia with an underlying granulocytopenic condition, with circulating peripheral granulocytes numbering from < or = 0.1-0.3 x 10(9)/L. Azithromycin [Zithromax] tissue levels were not reduced in infection loci in granulocytopenic mice but moderate increases in Cmax and AUC values were observed, relative to similar tissues from normal mice. The tissue half-life of azithromycin [Zithromax] in infected tissues in a therapeutic mode (75 h) was three-fold longer than in a prophylactic mode (25 h); this correlated with the degree of inflammation (therapy was withheld until inflammation was evident; i.e., prophylaxis reduced inflammation). Histological examination of infected tissues from normal and leucopenic mice was indistinguishable despite a 70%-85% reduction in circulating granulocytes. Compared with untreated infected controls, bactericidal activity was noted following prophylaxis with azithromycin [Zithromax] and bacteraemia was suppressed in mice receiving azithromycin [Zithromax] therapeutically. In summary, these data indicate that azithromycin [Zithromax] delivery and efficacy in a moderately immunosuppressed animal model are unimpaired.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8818843&dopt=Abstract Zithromax azithromycin




Int J Dermatol. 2000 Jan;39(1):45-50.
Azithromycin [Zithromax] for the treatment of acne.

Fernandez-Obregon AC.

Hudson Dermatology & Skin Center, Hoboken, NJ 07030, USA.

BACKGROUND: Acne affects a large number of young adults, including women, who often present with facial as well as truncal involvement. Systemic antimicrobial agents currently used for the reduction of inflammatory papules and cysts require frequent administration and are sometimes associated with uncomfortable side-effects contributing to a decrease in compliance. METHODS: Ninety-nine episodes of inflammatory acne in 79 patients treated with oral antimicrobial agents were studied retrospectively over a period of 46 weeks. Patients were treated with tetracycline, erythromycin, minocycline, and doxycycline, the most commonly prescribed oral antimicrobials used to treat acne. Individuals that were unable to tolerate this therapy or had failed conventional therapy were treated with the azalide antibiotic azithromycin, given in a single oral 250-mg dose three times a week. The other agents were administered daily in divided doses as is current practice. Patients were also on topical care. RESULTS: The efficacy and reported side-effects were examined for all agents. Significant improvement was noted in 4 weeks. All agents were effective in reducing inflammatory lesions and improving acne. Azithromycin [Zithromax] produced a slightly higher percentage of patients with a greater than 80% reduction in their inflammatory acne lesions (85.7%) vs. an average of 77.1% for all other agents. All differences observed were not statistically significant. CONCLUSIONS: The results show that azithromycin [Zithromax] is a safe and effective alternative in the treatment of inflammatory acne with few side-effects and good compliance, and suggest the need for further investigation with a clinical trial that will compare the long-term efficacy and tolerability.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10651967&dopt=Abstract Zithromax azithromycin