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PubMed2004

Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the leading cause of late mortality after lung transplantation. METHODS: We added azithromycin (AZI) (250 mg/day for 5 days, followed by 250 mg every other day) to the current immunosuppressive therapy in eight lung transplant recipients (mean age 36 years) with established BOS in an attempt to prevent further decline of the forced expiratory volume in 1 sec (FEV1). RESULTS: Before the administration of AZI, there was a gradual decline of the FEV1 (-34.4%+/-14.7%) compared with the patients' best postoperative values. Twelve weeks after AZI had been added, there was a significant increase in the FEV1 (+18.3%+/-14.6%, P <0.0001, analysis of variance) with an absolute increase of 328+/-305 mL. This increase persisted in three patients during 9 months of follow-up. CONCLUSIONS: AZI is a promising drug for some patients with BOS after lung transplantation. The exact mechanism of action is unknown at the present time.

Adolescent↗
PubMed2005

Kinetic bactericidal activity of telithromycin, azithromycin and clarithromycin against respiratory pathogens.

The present study assessed the comparative in vitro killing kinetics of telithromycin, azithromycin and clarithromycin. Minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) were determined against Streptococcus pneumoniae, beta-haemolytic streptococci, Haemophilus influenzae and Moraxella catarrhalis strains characterized by different susceptibilities to beta-lactams and macrolides. For each bacterial species, representative strains were chosen for time-kill studies. Telithromycin showed high activity against all the tested strains with MIC ranging from < or = 0.004 to 0.5 mg/L for streptococci, from 0.008 to 8 mg/L for H. influenzae, and from 0.008 to 0.5 mg/L for M. catarrhalis. In time-kill studies, telithromycin showed an overall superior bactericidal activity in respect to macrolides, particularly against resistant strains. In conclusion, telithromycin proved to possess bactericidal activity against a wide range of respiratory pathogens, including strains resistant to common macrolides.

Anti-Bacterial Agents↗
PubMed1992

[Effect of azithromycin on human serum sensitivity of Pseudomonas aeruginosa].

We examined the effect of azithromycin (AZM), a 15-membered azalide newly synthesized from erythromycin (EM), on serum sensitivity of 6 strains of Pseudomonas aeruginosa. Incubation for 48 h on agar with EM 12 micrograms/ml or AZM 1.6 micrograms/ml induced increased serum sensitivity in 2 of 6 strains (S-6, PA-103), but there were no changes in any strains with josamycin (JM) 12 micrograms/ml. Although EM 12 micrograms/ml induced increased serum sensitivity of S-6 after more than 36 h incubation, AZM 1.6 micrograms/ml induced increased serum sensitivity of this strain at 12 h incubation. AZM 0.8 microgram/ml (1/62.5 MIC) showed more potent activity to enhance serum sensitivity of S-6 than that of EM 12 micrograms/ml (1/8 MIC) after 48 h incubation. P. aeruginosa S-6 incubated with EM 12 micrograms/ml or AZM 1.6 micrograms/ml for 48 h was less hydrophobic than that of control bacteria, but there was little change in the hydrophobicity of the strain incubated with JM 12 micrograms/ml. These results show that AZM has more potent activity to enhance serum sensitivity of P. aeruginosa than that of EM. Since decrease of cell surface hydrophobicity of P. aeruginosa S-6 was correlated with increased serum sensitivity, EM and AZM may induce enhanced serum sensitivity by changing cell surface structure of P. aeruginosa.

Azithromycin↗
PubMed1995

[Study on azithromycin in treatment of diffuse panbronchiolitis].

In the treatment of diffuse panbronchiolitis, azithromycin (AZM), a new macrolide antibiotic with 15-membered lactone ring, was studied for its efficacy and safety. AZM, 250 mg, was intermittently administered to a total of 60 patients twice a weeks, for 3 months as a rule, and its efficacy was clinically evaluated in 52 patients and the safety in 55. The rate of efficacy was 84.6% (44/52). Clinical findings 12 weeks after the start of administration showed a decrease in sputum volume in 30 of 46 patients and amelioration of dyspnea on exertion in 23 of 46 patients, and no worsening of symptoms was observed in the patients. Vital capacity (4/22), FEV1.0 (6/21), cold agglutination reaction (22/28), and CRP (16/36) were also improved. The rate of eradication of organisms isolated from the sputum except for indigenous organisms was 39.5% (15/38); 4 of the 22 strains of Pseudomonas aeruginosa were eradicated. Adverse reactions were observed in 4 of the 55 patients (7.3%), 1 patient each with rash, itching, diarrhea, and a gastric symptom (heavy feeling in the stomach). 4 of the 54 patients (7.4%) exhibited abnormal changes in clinical laboratory test values values. These were an increase in eosinophil count in 2, elevation of GOT in 1, and elevation of Al-P in 1. These adverse reactions and abnormal changes in laboratory tests were mild or moderate. Therefore, long-term intermittent administration of AZM, twice a week, is expected to have the same effect in the treatment of diffuse panbronchiolitis as long-term small-dose administration of 14-membered macrolides such as erythromycin and clarithromycin, whose effects have already been established.

Adolescent↗
PubMed2004

[Efficacy of azithromycin as the empiric therapy in children with community-acquired pneumonia who were isolated macrolide resistant Streptococcus pneumoniae from nasopharynx].

Identification of pathogens in childhood community-acquired pneumonia (CAP) is not easy. However, it is believed that nasopharyngeal colonization of pathogenic bacteria leads to childhood CAP, so the etiology is inferred by the isolates obtained from nasopharynx of children with CAP. Among the pathogens of childhood CAP, Streptococcus pneumoniae (SP) is the most important agent and macrolides resistant SP (MRSP) is increasingly reported. We investigated the characterization of the mechanism of macrolide resistance in isolates of MRSP by the presence of the ermB gene or the mefA gene and clindamycin (CLDM) resistance. In addition, we also assessed the efficacy of azithromycin (AZM) in children with CAP who were isolated MRSP from nasopharynx. During a 6 month period between January and June in 2002, children with CAP who were treated with a 3 day regimen of AZM and isolated SP from nasopharynx were enrolled. Clinical outcome was based on assessment of fever on the fourth day of treatment. MIC measurements were obtained by broth microdilution and interpreted according to NCCLS criteria. 53 patients were enrolled and MRSP were isolated in 41 children. Of 41 MRSP isolates, 25 isolates were identified CLDM resistance. The AZM MIC90 of CLDM resistant MRSP isolates was 128 microg/ml. On the other hand, that of CLDM sensitive MRSP isolates was 8 microg/ml. However, AZM was effective in 20 children isolated CLDM resistant MRSP and 15 out of 16 children isolated CLDM sensitive MRSP. On this background, despite high rates of MRSP in Japan, AZM continues to be clinically effective for the treatment of childhood CAP.

Anti-Bacterial Agents↗
PubMed2007

Azithromycin selectively reduces tumor necrosis factor alpha levels in cystic fibrosis airway epithelial cells.

Azithromycin (AZM) ameliorates lung function in cystic fibrosis (CF) patients. This macrolide has been suggested to have anti-inflammatory properties as well as other effects potentially relevant for therapy of CF. In this study, we utilized three CF (IB3-1, 16HBE14o- AS3, and 2CFSMEo-) and two isogenic non-CF (C38 and 16HBE14o- S1) airway epithelial cell lines to investigate whether AZM could reduce tumor necrosis factor alpha (TNF-alpha) mRNA and protein levels by real-time quantitative PCR analysis and an enzyme-linked immunosorbent assay (ELISA), respectively. We studied the effects on the DNA binding of NF-kappaB and specificity protein 1 (Sp1) by an ELISA. Non-CF cells express significantly lower TNF-alpha mRNA and protein levels than an isogenic CF cell line. In CF cells, AZM treatment causes a 30% reduction of TNF-alpha mRNA levels (P < 0.05) and a 45% decrease in TNF-alpha secretion (P < 0.05), reaching approximately the levels of the untreated isogenic non-CF cells. In CF cells, NF-kappaB and Sp1 DNA binding activities were also significantly decreased (about 45 and 60%, respectively; P < 0.05) after AZM treatment. Josamycin, a macrolide lacking clinically described anti-inflammatory effects, was ineffective. Finally, AZM did not alter the mRNA expression levels of interleukin-6, a proinflammatory molecule not differentially expressed in CF and isogenic non-CF cells. The results of our study support the anti-inflammatory activities of this macrolide, since we show that AZM reduced the levels of TNF-alpha and propose inhibitions of NF-kappaB and Sp1 DNA binding as possible mechanisms of this effect.

Anti-Bacterial Agents↗
PubMed1990

Erythromycin and azithromycin transport into Haemophilus influenzae ATCC 19418 under conditions of depressed proton motive force (delta mu H).

The effect of collapsing the electrochemical proton gradient (delta mu H) on [3H]erythromycin and [14C]azithromycin transport in Haemophilus influenzae ATCC 19418 was studied. The proton gradient and membrane potential were determined from the distribution of [2-14C]dimethadione and rubidium-86, respectively. delta mu H was reduced from 124 to 3 mV in EDTA-valinomycin-treated cells at 22 degrees C with 150 mM KCl and 0.1 mM carbonyl cyanide m-chlorophenylhydrazone. During the collapse of delta mu H, macrolide uptake increased. Erythromycin efflux studies strongly suggested that this increase was not due to an energy-dependent efflux pump but was likely due to increased outer membrane permeability. These data indicated that macrolide entry was not a delta mu H-driven active transport process but rather a passive diffusion process.

Azithromycin↗
PubMed1992

Once-a-week azithromycin in AIDS patients: tolerability, kinetics, and effects on zidovudine disposition.

Toxoplasmic encephalitis is one of the leading causes of morbidity in patients with AIDS. Lifelong treatment is needed to prevent relapses, and primary prevention is desirable in high-risk patients, but the available drugs are often poorly tolerated. Azithromycin (AZM) has been considered a drug candidate because of its efficacy in the animal model and its kinetic properties, which would allow intermittent administration. The tolerability and kinetics of AZM and its effect on the disposition of zidovudine (ZVD) were therefore evaluated in a preliminary open study in nine human immunodeficiency virus-infected patients. AZM was administered once weekly for 5 weeks 2 h before the usual morning ZVD dose. The day before and on the first and fifth AZM dosings, blood samples were drawn every 30 min during 5 h for determination of the concentrations of ZVD and its glucuronide metabolite. Blood samples were drawn for AZM measurement over 72 and 360 h on the first and fifth AZM administrations, respectively, as well as before and 3 h after dosing on the second, third, and fourth AZM dosings. After the first and fifth administrations, maximum AZM concentrations in serum were 0.6 +/- 0.1 and 0.8 +/- 0.2 microM (mean +/- standard error of the mean), respectively; times to peak concentration in serum were 3.7 +/- 0.2 and 2.9 +/- 0.4 h, respectively; areas under the plasma concentration-time curves were 9.2 +/- 1.6 and 9.3 +/- 2.0 micrograms.h/ml, respectively; and half-lives were 61.0 +/- 5.4 and 63.8 +/- 6.7 h, respectively. On days -1, 1, and 29, ZVD kinetic parameters were as follows: maximum concentrations in serum, 3.1+/- 0.6, 4.3 +/- 0.6, and 4.2 +/- 0.9 microM, respectively; times to maximum concentrations in serum, 1.1 +/- 0.4, 0.8 +/- 0.2, and 1.2 +/- 0.3 h, respectively: areas under the plasma concentration-time curves, 5.3 +/- 0.9, 5.9 +/- 0.6, and 5.7 +/- 0.8 microgram . h/ml, respectively; and half-lives, 1.3 +/- 0.08, 1.4 +/- 0.04, and 1.3 +/- 0.04 h, respectively. Except for transient mild abdominal cramps that occurred at 2 to 3 h postdose (6 of 45 exposures) and nausea (4 of 45 exposures), neither subjective nor objective side effects were observed. The kinetics of AZM were similar after the first and repeated administrations, and the disposition of ZVD was not altered by this treatment. The efficacy of AZM in preventing cerebral toxoplasmosis can therefore be safely tested in human immunodeficiency virus-infected patients concomitantly treated with zidovudine.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Comparative in vitro exoenzyme-suppressing activities of azithromycin and other macrolide antibiotics against Pseudomonas aeruginosa.

The inhibitory effects of azithromycin (AZM), a new 15-membered macrolide antibiotic, on the production of exotoxin A, total protease, elastase, and phospholipase C by Pseudomonas aeruginosa were determined, and the virulence-suppressing effects of AZM were compared with those of erythromycin (EM), roxithromycin (RXM), and rokitamycin (RKM). The effect of exposure of P. aeruginosa PA103 or B16 in cultures to sub-MICs of these macrolide antibiotics on the production of exoenzymes was determined. AZM suppressed the in vitro production of extracellular and intracellular exotoxin A by P. aeruginosa PA103 more than did EM, even at a concentration of only 2 micrograms/ml. At concentrations of between 4 and 32 micrograms/ml, AZM also inhibited total protease, elastase, and phospholipase C production by P. aeruginosa B16 more than did EM, RXM, and RKM. AZM was effective in suppressing exotoxin A and total protease production through 24 h of incubation in the presence of drug at sub-MICs, but it had no significant effect on either the growth of P. aeruginosa or its total protein production. Moreover, at a concentration of 4 micrograms/ml, AZM suppressed exoenzyme production by other strains of P. aeruginosa more than did EM. These findings indicate that AZM, EM, RXM, and RKM each has an inhibitory effect on exoenzyme production separate from the antimicrobial effect and that, of these macrolides, AZM has the strongest virulence-suppressing effect.

ADP Ribose Transferases↗
PubMed1994

Comparative activities of azithromycin and clarithromycin against Mycobacterium avium infection in beige mice.

The comparative activities of azithromycin (AZI) and clarithromycin (CLA) against eight Mycobacterium avium complex (MAC) isolates were evaluated in the beige mouse model of disseminated infection. Mice were infected intravenously with approximately 10(7) viable MAC isolate. AZI at 100 or 200 mg/kg of body weight or CLA at 200 mg/kg of body weight was given by gavage daily for 10 days starting at 7 days postinfection. In each study, groups of treated mice were compared with untreated control animals. A dose-related reduction in organism cell counts in the spleens between the groups receiving AZI at 100 and 200 mg/kg was observed. AZI at 200 mg/kg was more active than CLA at 200 mg/kg against six of eight MAC isolates in the spleens. CLA at 200 mg/kg was more active than AZI at 200 mg/kg against three of eight MAC isolates in the lungs. The difference between AZI at 200 mg/kg and CLA at 200 mg/kg against organisms in the lungs was not significant for the remaining five isolates. Clinical trials comparing the activities of AZI and CLA in combination with other agents in patients with disseminated MAC infection are necessary to ascertain any clinically significant differences in the efficacies of these agents.

Animals↗
PubMed1994

Activities of azithromycin and clarithromycin against nontuberculous mycobacteria in beige mice.

The comparative activities of azithromycin (AZI) and clarithromycin (CLA) were evaluated against nontuberculous mycobacteria in a murine model of disseminated infection. Four-week-old beige mice (C57BL/6J bgj/bgj) were infected intravenously with approximately 10(7) viable Mycobacterium kansasii, M. xenopi, M. simiae, or M. malmoense. Treatment with AZI at 200 mg/kg, CLA at 200 mg/kg, ethambutol at 125 mg/kg, rifampin at 20 mg/kg, or clofazimine at 20 mg/kg of body weight was started 7 days postinfection, and the treatments were administered 5 days per week for 4 weeks. Control groups were sacrificed at the start and end of the treatments. Spleens and lungs were homogenized, and viable cell counts were determined by serial dilution and plating onto 7H10 agar. AZI and CLA had activities comparable to or better than that of rifampin, ethamutol, or clofazimine against these nontuberculous mycobacteria in the beige mouse test system. AZI at 200 mg/kg was more active than CLA at 200 mg/kg against organisms in the spleens for M. xenopi and M. malmoense. The activities of AZI and CLA were comparable against organisms in the spleens for M. kansasii and M. simiae. The activities of these two agents were comparable against organisms in the lungs for all four nontuberculous mycobacterial species. AZI or CLA in combination with other agents may be useful for the therapy of nontuberculous mycobacterial infections in humans.

Animals↗
PubMed1994

Intermittent azithromycin for treatment of Mycobacterium avium infection in beige mice.

The activity of azithromycin (AZI) was evaluated in the beige mouse model of disseminated Mycobacterium avium infection. Mice were infected intravenously with approximately 10(7) viable avium ATCC 49601. AZI at 50, 100, or 200 mg/kg of body weight or clarithromycin (CLA) at 200 mg/kg was given by gavage 5 days per week for 4 weeks. Groups of treated mice were compared with untreated control animals. A dose-related reduction in cell counts in organs was observed with AZI treatment. AZI at 200 mg/kg was more active than CLA at 200 mg/kg against organisms in spleens. The activities of these two agents at 200 mg/kg were comparable against organisms in lungs. In a second study, AZI at 200 mg/kg was given daily for 5 days; this was followed by intermittent AZI treatment for the next 3 weeks. The activities of AZI given on a three-times- and five-times-per-week basis in the continuation phase were comparable. AZI given on a once-weekly basis was less active. The regimen of AZI given in combination with rifapentine on a once-weekly basis for 8 weeks showed promising activity. Clinical evaluation of AZI and rifapentine will help to define the roles of these agents in the treatment of disseminated M. avium complex infection.

Animals↗
PubMed1996

Comparison of bronchopulmonary pharmacokinetics of clarithromycin and azithromycin.

The bronchopulmonary and plasma pharmacokinetics of clarithromycin (CLA; 500 mg given twice daily for nine doses) or azithromycin (AZ; 500 mg for the first dose and then 250 mg once daily for four doses) were assessed in 41 healthy nonsmokers. Bronchoalveolar lavage was performed at 4, 8, 12, or 24 h after administration of the last dose. The concentrations (mean +/- standard deviation) of CLA, 14-hydroxyclarithromycin, and AZ were measured in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) cells by high-performance liquid chromatography assay. The concentrations of CLA achieved in ELF were 34.02 +/- 5.16 micrograms/ml at 4 h, 20.63 +/- 4.49 micrograms/ml at 8 h, 23.01 +/- 11.9 micrograms/ml at 12 h, and 4.17 +/- 0.29 microgram/ml at 24 h, whereas at the same time points AZ concentrations remained below the limit of assay sensitivity (0.01 microgram/ml) for all but two subjects. The concentrations of CLA in the AM cells were significantly higher than those of AZ at 8 h (703 +/- 235 and 388 +/- 53 micrograms/ml, respectively). However, the ratio of the concentration in AM cells/concentration in plasma was significantly higher for AZ than for CLA for all time points because of the lower concentration of AZ in plasma. These results indicate that while AZ has higher tissue concentration to plasma ratios, as shown by other investigators, the absolute concentrations of CLA in AM cells and ELF are higher for up to 8 and 12 h, respectively, after administration of the last dose.

Adult↗
PubMed1996

In vitro activities of azithromycin, clarithromycin, and other antibiotics against Chlamydia pneumoniae.

The in vitro susceptibilities of Chlamydia pneumoniae isolates to macrolide, tetracycline, and quinolone antibiotics were determined. Tetracycline, clarithromycin, and erythromycin had the lowest MICs in the first cell culture passage. Azithromycin required the lowest concentration for complete inhibition of inclusion formation on the second pass into antibiotic-free medium, likely reflecting its high intracellular concentrations.

4-Quinolones↗
PubMed1996

In vitro activities of azithromycin and doxycycline against 15 isolates of Chlamydia pneumoniae.

Fourteen isolates of Chlamydia pneumoniae, 12 from clinically ill patients and 2 from subjectively healthy individuals from an area within a 400-km proximity of Gävle, Sweden, and strain IOL-207, originally from the eye of an Iranian child, were tested for susceptibilities to the antibiotics doxycycline and azithromycin. MICs and minimum chlamydiacidal concentrations were found to correlate well with values reported earlier by other investigators. In addition to MIC and minimum chlamydiacidal concentration testing, testing for the viability of C. pneumoniae after exposure to antibiotic concentrations as high as 50 mg/liter was carried out by passaging antibiotic-treated, infected cell cultures four times in the absence of antibiotics. It was found that all Chlamydia strains were viable after four passages, regardless of antibiotic concentration in the cell culture.

Anti-Bacterial Agents↗
PubMed1997

Cellular accumulation of the new ketolide RU 64004 by human neutrophils: comparison with that of azithromycin and roxithromycin.

We analyzed the uptake of RU 64004 by human neutrophils (polymorphonuclear leukocytes [PMNs]) relative to those of azithromycin and roxithromycin. RU 64004 was strongly and rapidly accumulated by PMNs, with a cellular concentration/extracellular concentration ratio (C/E) of greater than 200 in the first 5 min, and this was followed by a plateau at 120 to 180 min, with a C/E of 461 +/- 14.8 (10 experiments) at 180 min. RU 64004 uptake was moderately sensitive to external pH, and activation energy was also moderate (63 +/- 3.8 kJ/mol). RU 64004 was mainly located in PMN granules (about 70%) and egressed slowly from loaded cells, owing to avid reuptake. The possibility that PMN uptake of RU 64004 and other macrolides occurs through a carrier-mediated system was suggested by three key results. First, there existed a strong interindividual variability in uptake kinetics, suggesting variability in the numbers or activity of a transport protein. Second, macrolide uptake displayed saturation kinetics characteristic of that of a carrier-mediated transport system: RU 64004 had the highest Vmax value (3,846 ng/2.5 x 10(6) PMNs/5 min) and the lowest Km value (about 28 microM), indicating a high affinity for the transporter. Third, as observed previously with other erythromycin A derivatives, Ni2+ (a blocker of the Na+/Ca2+ exchanger which mediates Ca2+ influx in resting neutrophils) impaired RU 64004 uptake by PMNs, with a 50% inhibitory concentration of about 3.5 mM. In addition, we found that an active process is also involved in macrolide efflux, because verapamil significantly potentiated the release of all three macrolides tested. This effect of verapamil does not seem to be related to an inhibition of Ca2+ influx, because neither EGTA [ethylene glycol-bis (beta-aminoethyl ether)-N,N',N'-tetraacetic acid] nor Ni2+ modified macrolide efflux. The nature and characteristics of the entry- and efflux-mediating carrier systems are under investigation.

Anti-Bacterial Agents↗
PubMed1998

Postantibiotic effect and postantibiotic sub-MIC effect of levofloxacin compared to those of ofloxacin, ciprofloxacin, erythromycin, azithromycin, and clarithromycin against 20 pneumococci.

The postantibiotic effect (PAE) (10 times the MIC of quinolones, 5 times the MIC of macrolides) and postantibiotic sub-MIC effect (PAE-SME) at 0.125, 0.25, and 0.5 times the MIC were determined for levofloxacin, ciprofloxacin, ofloxacin, erythromycin, azithromycin, and clarithromycin against 20 pneumococci. Quinolone PAEs ranged between 0.5 and 6.5 h, and macrolide PAEs ranged between 1 and 6 h. Measurable PAE-SMEs (in hours) at the three concentrations were 1 to 5, 1 to 8, and 1 to 8, respectively, for quinolones and 1 to 8, 1 to 8, and 1 to 6, respectively, for macrolides.

Anti-Bacterial Agents↗
PubMed1999

Beneficial effect of adjunctive azithromycin in treatment of mucoid Pseudomonas aeruginosa pneumonia in the murine model.

While a time-kill methodology noted no appreciable improvement in bactericidal activity with the addition of azithromycin (AZM) to a ceftazidime (CAZ) regimen, data from the murine pneumonia model showed that the addition of AZM significantly improved survival compared to treatment with CAZ alone. These data suggest that AZM might be a useful adjunctive therapy in the management of pneumonia resulting from mucoid isolates of Pseudomonas aeruginosa.

Animals↗