Vet Res Commun. 2000 Apr;24(3):169-77.
Evaluation of the efficacy of atovaquone alone or in combination with azithromycin [Zithromax] against acute murine toxoplasmosis.

Moshkani SK, Dalimi A.

Parasitology Department, Medical Science Faculty, Tarbiat Modarres University, Tehran, IR, Iran.

Mice were infected intraperitoneally with 10,000 tachyzoites of Toxoplasma gondii (RH) strain and, 24 h later, were treated orally for 10 days with atovaquone and azithromycin, either alone or in combination. Evaluation of the efficacy of the drugs was performed by microscopic examination of smears prepared from the organs of the mice, and by subinoculation of visceral and brain suspensions from surviving mice into healthy mice at the end of the experiments. It was found that 58%, 83% and 100% of the mice survived after administration of 75, 150 or 200 mg/kg per day of azithromycin, respectively. Moreover, 8%, 17% and 25% of the mice survived after treatment with atovaquone at 20, 50 or 100 mg/kg per day, respectively. No synergistic or additive effects of combinations of atovaquone and azithromycin [Zithromax] were observed. However, azithromycin [Zithromax] did not eradicate the parasite from the brain and viscera of the infected mice, whereas atovaquone at 20, 50 and 100 mg/kg per day removed the parasite from viscera and at 100 mg/kg per day eradicated the parasite from the brain of infected mice. The combinations of atovaquone and azithromycin [Zithromax] failed to completely eradicate the parasite from the brain and viscera of infected mice.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10836275&dopt=Abstract Zithromax azithromycin

ncsu.edu

Dogs were experimentally inoculated with Rickettsia rickettsii (canine origin) in order to compare the efficacies of azithromycin [Zithromax] and trovafloxacin to that of the current antibiotic standard, doxycycline, for the treatment of Rocky Mountain spotted fever. Clinicopathologic parameters, isolation of rickettsiae in tissue culture, and PCR amplification of rickettsial DNA were used to evaluate the response to therapy or duration of illness (untreated infection control group) in the four groups. Concentrations of the three antibiotics in plasma and blood cells were measured by high-performance liquid chromatography. Doxycycline and trovafloxacin treatments resulted in more-rapid defervescence, whereas all three antibiotics caused rapid improvement in attitudinal scores, blood platelet numbers, and the albumin/total-protein ratio. Based upon detection of retinal vascular lesions by fluorescein angiography, trovafloxacin and doxycycline substantially decreased rickettsia-induced vascular injury to the eye, whereas the number of ocular lesions in the azithromycin [Zithromax] group did not differ from that in the infection control group. As assessed by tissue culture isolation, doxycycline resulted in the earliest apparent clearance of viable circulating rickettsiae; however, rickettsial DNA could still be detected in the blood of some dogs from all four groups on day 21 postinfection, despite our inability to isolate viable rickettsiae at that point. As administered in this study, trovafloxacin was as efficacious as doxycycline but azithromycin [Zithromax] proved less efficacious, possibly due to the short duration of administration.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10103185&dopt=Abstract Zithromax azithromycin




BJOG. 2000 Jun;107(6):770-5.
The transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin.

Heikkinen T, Laine K, Neuvonen PJ, Ekblad U.

Department of Obstetrics and Gynaecology, University of Turku, Finland.

OBJECTIVE: To investigate the transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin. METHODS: Twenty-one term placentas were obtained with maternal consent immediately after delivery and a two-hour nonrecirculating perfusion of a single placental cotyledon was performed. Erythromycin (2 microg/mL), roxithromycin (2 microg/mL) and azithromycin [Zithromax] (0.3 microg/mL) were infused to the maternal inflow at a constant rate, with antipyrine as a reference compound, and their appearance in the fetal circulation was followed. Drug concentrations were measured by high performance liquid chromatography for 120 min. RESULTS: The mean transplacental transfers (TPT(SS)) for erythromycin, roxithromycin and azithromycin [Zithromax] were 3.0%, 4.3% and 2.6%, respectively, calculated as the ratio between the steady state concentrations in fetal venous and maternal arterial sides. Similar results were obtained when the TPT was calculated as the absolute amount of drug transferred across the placenta during 2-hour perfusion (TPT(A)). No significant differences were found among the three macrolides in TPT(SS) (P = 0.39) or TPT(A) (P = 0.35). The TPT(SS) of erythromycin, roxithromycin and azithromycin [Zithromax] were 41%, 35% and 32% of the freely diffusable reference compound antipyrine, respectively. Steady state was reached in 60 minutes in each perfusion indicating sufficient perfusion time. CONCLUSION: The limited transplacental transfer of erythromycin, roxithromycin and azithromycin [Zithromax] suggests compromised efficacy in the treatment of fetal infections. On the other hand, the placenta seems to produce an effective barrier reducing the fetal exposure when these three macrolides are used to treat maternal infections.

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Pharmacotherapy. 2000 Jun;20(6):657-61.
Comparison of the serum and intracellular pharmacokinetics of azithromycin [Zithromax] in healthy and diabetic volunteers.

Ernst EJ, Klepser ME, Klepser TB, Nightingale CH, Hunsicker LG.

Division of Clinical and Administrative Pharmacy, University of Iowa, College of Pharmacy, Iowa City 52242, USA.

STUDY OBJECTIVE: To compare serum and intracellular pharmacokinetics of azithromycin [Zithromax] in healthy volunteers and patients with diabetes. DESIGN: Open-label, parallel study. SETTING: Clinical research center. SUBJECTS: Twelve patients with diabetes and 12 healthy volunteers. INTERVENTIONS: Subjects were given a single 500-mg dose of azithromycin [Zithromax] followed by 250 mg/day for 2 days. Blood samples were obtained just before and after the third dose for up to 24 hours for serum and 168 hours for intracellular measurement of azithromycin. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic parameters were calculated by noncompartmental methods and compared with a t test. The groups did not differ in maximum concentration, time to maximum concentration, or area under the concentration-time curve in serum or polymorphonuclear cells (PMNs). Differences in the PMN:serum ratio were observed at the 24-hour time point (healthy 1209 +/- 432, diabetic 859 +/- 286, p=0.051). CONCLUSION: In general, the pharmacokinetics of azithromycin [Zithromax] are comparable in diabetics and healthy volunteers. Accumulation of drug in macrophages was slightly lower in patients.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10853621&dopt=Abstract Zithromax azithromycin




Int J Technol Assess Health Care. 1999 Summer;15(3):531-47.
The cost-effectiveness of prophylaxis for Mycobacterium avium complex in AIDS.

Scharfstein JA, Paltiel AD, Weinstein MC, Seage GR, Losina E, Craven DE, Freedberg KA.

Johns Hopkins School of Public Health, USA.

OBJECTIVE: To develop a simulation model to project costs, life expectancy, and cost-effectiveness in discounted dollars per quality-adjusted life-year (QALY) saved for clinical strategies to prevent Mycobacterium avium complex (MAC) in patients with AIDS. METHODS: We used natural history data from the Multicenter AIDS Cohort Study, efficacy and toxicity data from randomized clinical trials, and cost data from the AIDS Cost and Services Utilization Survey. The model permits timing of prophylaxis to be stratified by CD4 count (201-300, 101-200, 51-100, and < or = 50/mm3), and allows combinations of prophylaxis, crossover to second- and third-line agents for toxicity, and consideration of adherence, resistance, and quality of life. RESULTS: The model projects that the average HIV-infected patient with a beginning CD4 count between 201 and 300/mm3 has total lifetime costs of approximately $43,150 and a quality-adjusted life expectancy of 42.35 months. If azithromycin [Zithromax] prophylaxis for M. avium complex is begun after the CD4 declines to 50/mm3, costs and quality-adjusted survival increase to approximately $44,040 and 42.78 months, respectively, for an incremental cost-effectiveness ratio of $25,000/QALY compared with no M. avium complex prophylaxis. Other prophylaxis options (i.e., rifabutin, clarithromycin, and combination therapies) either cost more but offer shorter survival, or have cost-effectiveness ratios above $260,000/QALY. Sensitivity analysis reveals that, for reasonable assumptions about quality of life, risk of infection, prophylaxis cost, adherence, and resistance, azithromycin [Zithromax] remains the most cost-effective prophylaxis option. CONCLUSIONS: Azithromycin [Zithromax] prophylaxis, begun after the CD4 count has declined to 50/mm3, is the most cost-effective M. avium complex prophylaxis strategy. Consistent with new United States Public Health Service guidelines, it should be the first-line prophylaxis option.

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J Antimicrob Chemother. 2000 Jul;46(1):19-26.
Apoptosis, oxidative metabolism and interleukin-8 production in human neutrophils exposed to azithromycin: effects of Streptococcus pneumoniae.

Koch CC, Esteban DJ, Chin AC, Olson ME, Read RR, Ceri H, Morck DW, Buret AG.

Department of Biological Sciences, The University of Calgary, Alberta, Canada, T2N 1N4.

Pathogen virulence factors and the host inflammatory response cause tissue injury associated with respiratory tract infections. The azalide azithromycin [Zithromax] has demonstrated efficacy in the treatment of these infections. It has been demonstrated previously that induction of polymorphonuclear leucocyte (PMN) apoptosis is associated with minimization of tissue damage and inflammation in the lung. We hypothesized that, in addition to its antibacterial effects, azithromycin [Zithromax] may promote apoptosis. The aim of the study was to determine the effects of azithromycin [Zithromax] on PMN apoptosis, oxidative function and interleukin-8 (IL-8) production in the presence or absence of Streptococcus pneumoniae, in comparison with penicillin, erythromycin, dexamethasone or phosphate-buffered saline. Human circulating PMNs were assessed for apoptosis (by annexin V labelling and ELISA), oxidative function (by nitroblue tetrazolium reduction) and IL-8 production (by ELISA). Azithromycin [Zithromax] significantly induced PMN apoptosis in the absence of S. pneumoniae after 1 h (10.27% +/- 1.48%, compared with 2.19% +/- 0.42% in controls) to levels similar to those after 3 h induction with tumour necrosis factor-alpha (8. 73% +/- 1.86%). This effect was abolished in the presence of S. pneumoniae. Apoptosis in PMNs exposed to the other drugs was not significantly different from that in controls. Azithromycin [Zithromax] did not affect PMN oxidative metabolism or IL-8 production. In summary, azithromycin-induced PMN apoptosis may be detected in the absence of any effect on PMN function, and the pro-apoptotic properties of azithromycin [Zithromax] are inhibited in the presence of S. pneumoniae.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10882684&dopt=Abstract Zithromax azithromycin




Toxicol Appl Pharmacol. 1999 Apr 15;156(2):129-40.
Interactions of macrolide antibiotics (Erythromycin A, roxithromycin, erythromycylamine [Dirithromycin], and azithromycin) with phospholipids: computer-aided conformational analysis and studies on acellular and cell culture models.

Montenez JP, Van Bambeke F, Piret J, Brasseur R, Tulkens PM, Mingeot-Leclercq MP.

Unite de Pharmacologie Cellulaire et Moleculaire, Universite Catholique de Louvain, Brussels, B-1200, Belgium.

The potential of 14/15 membered macrolides to cause phospholipidosis has been prospectively assessed, and structure-effects examined, using combined experimental and conformational approaches. Biochemical studies demonstrated drug binding to phosphatidylinositol-containing liposomes and inhibition of the activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the bilayer, in close correlation with the number of cationic groups carried by the drugs (erythromycin A </= roxithromycin < erythromycylamine </= azithromycin). In cultured cells (fibroblasts), phospholipidosis (affecting all major phospholipids except sphingomyelin) was observed after 3 days with the following ranking: erythromycin A </= roxithromycin < erythromycylamine < azithromycin [Zithromax] (roxithromycin could, however, not be studied in detail due to intrinsic toxicity). The difference between erythromycylamine and azithromycin [Zithromax] was accounted for by the lower cellular accumulation of erythromycylamine. In parallel, based on a methodology developed and validated to study drug-membrane interactions, the conformational analyses revealed that erythromycin A, roxithromycin, erythromycylamine, and azithromycin [Zithromax] penetrate into the hydrophobic domain of a phosphatidylinositol monolayer through their desosamine and cladinose moieties, whereas their macrocycle is found close to the interface. This position allows the aminogroups carried by the macrocycle of the diaminated macrolides (erythromycylamine and azithromycin) to come into close contact with the negatively charged phosphogroup of phosphatidylinositol, whereas the amine located on the C-3 of the desosamine, common to all four drugs, is located at a greater distance from this phosphogroup. Our study suggests that all macrolides have the potential to cause phospholipidosis but that this effect is modulated by toxicodynamic and toxicokinetic parameters related to the drug structure and mainly to their cationic character. Copyright 1999 Academic Press.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10198278&dopt=Abstract Zithromax azithromycin