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PubMed2004

Azithromycin inhibits interleukin-6 but not fibrinogen production in hepatocytes infected with cytomegalovirus and chlamydia pneumoniae.

Chlamydia pneumoniae and cytomegalovirus (CMV) have been associated with the development of atherosclerosis. Inflammatory stimuli initiate the biosynthesis of fibrinogen, interleukin (IL)-6 and plasminogen activator inhibitor (PAI)-1 in the liver. Chronic infection may perpetuate the inflammatory status. We hypothesized that infection of human hepatocytes with the intracellular pathogens C pneumoniae and CMV accelerates biosynthesis of fibrinogen, IL-6, and PAI-1 but that this biosynthesis can be reduced with the use of azithromycin. HepG2 human hepatocytes were infected with C pneumoniae and CMV in vitro in the presence of 0, 0.016, 0.125, or 1 microg/mL azithromycin. We measured IL-6, PAI-1, and fibrinogen after 24, 48, 72, and 96 hours. C pneumoniae-infected hepatocytes produce IL-6 (2667 +/- 309 pg/mL vs 137 +/- 120 pg/mL in uninfected cells after 96 hours. Incubation with 0.016 microg/mL azithromycin decreased IL-6 levels to a mean of 1516 +/- 402 pg/mL, and incubation with 0.125 and 1 microg/mL azithromycin decreased IL-6 to 871 +/- 364 and 752 +/- 403 pg/mL, respectively. C pneumoniae-induced IL-6 production was time- and dose-dependent. The interaction of C pneumoniae with azithromycin treatment was significant, indicating an inhibitory effect of azithromycin on C pneumoniae-induced IL-6 production. CMV infection did not lead to IL-6 production by hepatocytes. C pneumoniae and CMV infection did not induce any changes in PAI-1 production. Fibrinogen production was increased by CMV infection after 72 hours (838 +/- 88 ng/mL; P <.01) and after 96 hours by infection with both C pneumoniae and CMV (765 +/- 100 and 846 +/- 123 ng/mL, respectively; P <.05). Azithromycin did not suppress CMV- or C pneumoniae-induced fibrinogen production. Moreover, we could not confirm an antiinflammatory effect of azithromycin in experiments with cross-titrations of azithromycin against either IL-1 or IL-6 (P >.05). Azithromycin reduces C pneumoniae-induced IL-6 production, but not fibrinogen production, by human hepatocytes. This is a result of the antimicrobial properties of azithromycin and not a direct antiinflammatory effect.

Anti-Bacterial Agents↗
PubMed2005

Higher dosages of azithromycin are more effective in treatment of group A streptococcal tonsillopharyngitis.

BACKGROUND: Azithromycin has become a frequent choice for the treatment of group A streptococcal (GAS) tonsillopharyngitis. In this study, our objective was to determine the optimal dose of azithromycin for treatment of GAS tonsillopharyngitis in children and adults by analyzing trials that used different dose regimens. METHODS: We performed a meta-analysis of randomized, controlled trials that involved bacteriological confirmation of GAS tonsillopharyngitis, random assignment to receive either azithromycin or a 10-day comparator antibiotic, and assessment of bacteriological eradication by throat culture after therapy. The primary outcomes of interest were bacteriological and clinical cure rates. RESULTS: Nineteen trials involving 4626 patients were included in the analysis. One trial used 10-day course of 2 different comparator antibiotics, and 2 trials compared 2 dose regimens of azithromycin with a 10-day course of comparator antibiotic; all other trials compared 1 dose regimen of azithromycin with a single 10-day course of comparator antibiotic. In children, azithromycin administered at 60 mg/kg per course was superior to the 10-day courses of comparators (P < .00001), with bacterial failure occurring 5 times more often in patients receiving the 10-day courses of antibiotics. Azithromycin administered at 30 mg/kg per course was inferior to the 10-day courses of comparators (P = .02), with bacterial failure occurring 3 times more frequently in patients receiving azithromycin. Three-day regimens were inferior to 5-day regimens (P = .002). In adults, no studies compared dosages by weight. Three-day regimens of 500 mg/day showed a trend favoring azithromycin over the 10-day courses of comparators (P = .14); 5-day regimens were inferior to 3-day regimens (P = .006). Clinical cure rates were significantly different for the different azithromycin regimens, with differences that resembled those for bacterial cure rate. CONCLUSION: This analysis suggests that azithromycin administered at a dosage of 60 mg/kg in children or administered for 3 days at a dosage of 500 mg/day in adults is more effective than other treatment regimens in producing eradication and clinical cure of GAS tonsillopharyngitis.

Adult↗
PubMed2006

Traveler's diarrhea in Thailand: randomized, double-blind trial comparing single-dose and 3-day azithromycin-based regimens with a 3-day levofloxacin regimen.

BACKGROUND: Traveler's diarrhea in Thailand is frequently caused by Campylobacter jejuni. Rates of fluoroquinolone (FQ) resistance in Campylobacter organisms have exceeded 85% in recent years, and reduced fluoroquinolone efficacy has been observed. METHODS: Azithromycin regimens were evaluated in a randomized, double-blind trial of azithromycin, given as a single 1-g dose or a 3-day regimen (500 mg daily), versus a 3-day regimen of levofloxacin (500 mg daily) in military field clinics in Thailand. Outcomes included clinical end points (time to the last unformed stool [TLUS] and cure rates) and microbiological end points (pathogen eradication). RESULTS: A total of 156 patients with acute diarrhea were enrolled in the trial. Campylobacter organisms predominated (in 64% of patients), with levofloxacin resistance noted in 50% of Campylobacter organisms and with no azithromycin resistance noted. The cure rate at 72 h after treatment initiation was highest (96%) with single-dose azithromycin, compared with the cure rates of 85% noted with 3-day azithromycin and 71% noted with levofloxacin (P=.002). Single-dose azithromycin was also associated with the shortest median TLUS (35 h; P=.03, by log-rank test). Levofloxacin's efficacy was inferior to azithromycin's efficacy, except in patients with no pathogen identified during the first 24 h of treatment or in patients with levofloxacin-susceptible Campylobacter isolates, in whom it appeared to be equal to azithromycin. The rate of microbiological eradication was significantly better with azithromycin-based regimens (96%-100%), compared with levofloxacin (38%) (P=.001); however, this finding was poorly correlated with clinical outcome. A higher rate of posttreatment nausea in the 30 min after receipt of the first dose (14% vs. <6%; P=.06) was observed as a mild, self-limited complaint associated with single-dose azithromycin. CONCLUSIONS: Single-dose azithromycin is recommended for empirical therapy of traveler's diarrhea acquired in Thailand and is a reasonable first-line option for empirical management in general.

Adult↗
PubMed1996

Doxycycline compared with azithromycin for treating women with genital Chlamydia trachomatis infections: an incremental cost-effectiveness analysis.

OBJECTIVE: To compare the economic consequences of doxycycline therapy with those of azithromycin therapy for women with uncomplicated cervical chlamydial infections. DESIGN: Decision analysis in which the health outcomes, costs, and cost-effectiveness of two provider-administered treatment strategies for women with uncomplicated cervical chlamydial infections were compared: 1) initial therapy with doxycycline, 100 mg orally twice daily for 7 days (estimated cost, $5.51) and 2) initial therapy with azithromycin, 1 g orally administered as a single dose (estimated cost, $18.75). RESULTS: Under baseline assumptions, the azithromycin strategy incurred fewer major and minor complications and was less expensive overall than the doxycycline strategy despite a higher initial cost for acquiring antibiotic agents. In univariate sensitivity analyses, the azithromycin strategy prevented more major complications but was more expensive than the doxycycline strategy when doxycycline effectiveness was greater than 0.93. In a multivariate sensitivity analysis combining 11 parameter estimates selected so that the cost-effectiveness of the doxycycline strategy would be maximized relative to that of the azithromycin strategy, the azithromycin strategy resulted in fewer complications but was more costly. The incremental cost-effectiveness was $521 per additional major complication prevented. However, if the difference in the cost of azithromycin and doxycycline decreased to $9.80, the azithromycin strategy was less expensive and more effective, even under these extreme conditions. CONCLUSIONS: On the basis of the best available data as derived from the literature and experts, the azithromycin strategy was more cost-effective than the doxycycline strategy for women with uncomplicated cervical chlamydial infections. Despite the dominance of the azithromycin strategy over the doxycycline strategy, the adoption of the azithromycin strategy may be limited by the practical financial constraints of our currently fragmented health care system, in which the costs and benefits of preventing chlamydia sequelae are often incurred by different components of the system.

Analysis of Variance↗
PubMed2005

Azithromycin prophylaxis and treatment of murine toxoplasmosis.

OBJECTIVE: To evaluate the azithromycin effects alone and in combination with other agents in the prophylaxis and treatment of murine toxoplasmosis. METHODS: A total of 280 BALB/c mice were included, and 2 x 103 Toxoplasma organisms of the RH strain Toxoplasma gondii strain ATCC50174 were given intraperitoneally to each mouse. In experiment one, 40 animals were given azithromycin 200 milligram/kilogram/daily for 3 days starting the day of inoculation, 40 mice were control. In experiment 2, the treatment was started 48 hours after inoculation and given daily for 3 days: one group received azithromycin 200 milligram/kilogram/day, the second group received pyrimethamine 25 milligram/kilogram/day, and the sulfadiazine 100 milligram/kilogram/day. The third group was control. In experiment 3, 7 groups of animals received one of the following (1) none, (2) azithromycin 200 milligram/kilogram/day, (3) pyrimethamine 25 milligram/kilogram/day and sulfadiazine 100 milligram/kilogram/day, (4) azithromycin and sulfadiazine, (5) azithromycin and pyrimethamine, (6) azithromycin with sulfadiazine and pyrimethamine, (7) sulfadiazine alone. Treatment was initiated 72 hours after inoculation for 3 days. The study was conducted at the Animal Care Facility of King Saud University, Riyadh, Kingdom of Saudi Arabia. RESULTS: Animals that received azithromycin simultaneously with inoculation survived, and all control animals died. All animals died in groups receiving single drug therapy. Animals treated with azithromycin and sulfadiazine showed a survival rate of 40%, sulfadiazine and pyrimethamine 40%, or azithromycin with sulfadiazine and pyrimethamine 95% (p<0.0001). CONCLUSION: Azithromycin alone was found to be effective in the prophylaxis of murine toxoplasmosis. Combination therapy was effective in the treatment of murine toxoplasmosis.

Animals↗
PubMed2001

In vitro activity and pharmacodynamics of azithromycin and clarithromycin against Streptococcus pneumoniae based on serum and intrapulmonary pharmacokinetics.

BACKGROUND: Multidrug-resistant strains of Streptococcus pneumoniae are increasingly common worldwide, but the clinical significance of their resistance to the macrolide antibiotics is controversial. Applying pharmacokinetic and pharmacodynamic principles can assist in the selection of appropriate antimicrobial therapy. OBJECTIVES: The purpose of this study was to determine the in vitro activity of penicillin, azithromycin, clarithromycin, and clindamycin against clinical isolates of S. pneumoniae and to evaluate the pharmacodynamics of azithromycin and clarithromycin based on serum and epithelial lining fluid (ELF) concentrations. METHODS: The minimum inhibitory concentrations (MICs) of penicillin, azithromycin, clarithromycin, and clindamycin were determined for 307 isolates of S. pneumoniae using broth microdilution. Using serum and ELF concentrations after standard dosing, we calculated the proportion of isolates against which it would be possible to obtain a ratio of azithromycin area under the curve to MIC > or =25 and clarithromycin concentrations that exceeded the MIC for > or =40% of the dosing interval. RESULTS: Overall, 19.5%, 25.4%, 25.1%, and 7.2% of the 307 pneumococcal isolates were resistant to penicillin, azithromycin, clarithromycin, and clindamycin, respectively. However, 71.7% of penicillin-resistant strains were also resistant to azithromycin and clarithromycin. Based on serum concentrations, clarithromycin achieved its pharmacodynamic target in 76.9% of isolates, compared with 59.9% for azithromycin. Based on ELF concentrations, clarithromycin achieved its pharmacodynamic target in 93.5% of isolates, compared with 74.6% for azithromycin. Based on ELF concentrations, clarithromycin achieved its pharmacodynamic target in 86.7% of penicillin-resistant isolates, compared with 28.3% for azithromycin. CONCLUSIONS: On the basis of serum and ELF concentrations, clarithromycin achieved pharmacodynamic targets against a greater proportion of S. pneumoniae isolates than did azithromycin. Clinical studies are needed to determine the efficacy of these agents against pneumococci that demonstrate in vitro resistance using current susceptibility breakpoints.

Anti-Bacterial Agents↗
PubMed2003

A comparison of 5-day courses of dirithromycin and azithromycin in the treatment of acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Short-term use of antibiotics has become a common component of the management of acute exacerbations of chronic bronchitis (AECB), particularly in complex cases with productive cough or purulent phlegm. The macrolide antibiotics, particularly second-generation agents such as dirithromycin and azithromycin, are among the antibiotic classes frequently recommended and used to treat upper and lower respiratory infections, including AECB. OBJECTIVE: This study compared the clinical efficacy and tolerability of 5-day courses of dirithromycin and azithromycin given once daily for the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD). METHODS: This randomized, investigator-blinded, parallel-group clinical trial was conducted at 5 centers in the United States. Eligible patients were adult (age >35 years) smokers or ex-smokers (smoking history of at least 10 pack-years) with chronic bronchitis and an acute exacerbation, defined by the occurrence of increased dyspnea and/or productive cough and feverishness within 48 hours of enrollment. Before randomization, an attempt was made to obtain a sputum specimen from each patient for Gram's staining and culture. Patients were randomized to receive dirithromycin 500 mg QD for 5 days or azithromycin 500 mg QD on day 1 and 250 mg QD on days 2 to 5. Clinical efficacy was assessed separately by patients and physicians at early (days 7-10) and late (days 25-35) posttreatment visits. RESULTS: Eighty-six patients (48 women, 38 men; mean age, 55 years) with a mean smoking history of 31 pack-years were included in the intent-to-treat analysis. Forty-six (54%) patients were randomized to dirithromycin and 40 (47%) patients to azithromycin. Clinical efficacy was reported in a high proportion of patients in both treatment groups, both at the early posttreatment visit (84.8% dirithromycin, 75.7% azithromycin; difference dirithromycin - azithromycin, 9.1%; 95% CI, -8.2 to 26.4) and the late posttreatment visit (95.5% and 86.5%, respectively; difference dirithromycin - azithromycin, 9.0%; 95% CI, -3.7 to 21.6). A similar proportion of patients required a second course of antibiotics over the study period (20.5% dirithromycin, 27.0% azithromycin; difference dirithromycin - azithromycin, -6.6%; 95% CI, -25.2 to 12.1). Only 42 (48.8%) patients were able to produce a sputum sample before receiving study treatment, and of these, only 20 (47.6%) demonstrated a preponderance of neutrophils on Gram's staining. Both treatments were well tolerated. CONCLUSIONS: The results of this study suggest comparable clinical efficacy between 5-day courses of once-daily dirithromycin and azithromycin in acute exacerbations of COPD. There were insufficient data to permit meaningful comparison of the bacteriologic efficacy of these macrolide antibiotics.

Acute Disease↗
PubMed1999

Combined activity of azithromycin and lansoprazole against Helicobacter pylori.

BACKGROUND: Due to its unique pharmacokinetic properties, azithromycin may be an attractive combination partner for H. pylori eradication regimens. However, up to 15% of clinical isolates are primarily resistant to azithromycin as well as to other macrolide antibiotics. Combination therapy with lansoprazole, a proton pump inhibitor known to have intrinsic antibacterial activity against H. pylori, may be useful to counteract such resistance. We therefore evaluated the combined effects of azithromycin and lansoprazole in vitro. MATERIALS AND METHODS: Minimal inhibitory concentrations (MICs) of azithromycin and lansoprazole alone and in combination were determined for 106 clinical H. pylori isolates by means of an agar dilution technique. Killing kinetics of seven isolates were also studied in fluid medium. RESULTS: MIC values for 50 and 90% of the isolates (MIC50, MIC90) were 0.19 and 0.5 mg/l for azithromycin, and 44.5 and 104 mg/l for lansoprazole. Nine strains (8.5%) had an MIC of azithromycin > or = 16 mg/l and were regarded as resistant. An additive interaction between the two drugs was found in 72 (68%), and indifferent effects in 24 strains (23%). Three of 9 azithromycin-resistant strains regained sensitivity in the presence of lansoprazole. In fluid culture, synergism between the two drugs occurred in 6 out of 7 strains tested. CONCLUSION: In the majority of strains, lansoprazole and azithromycin interacted in an additive or synergistic manner depending on the test method employed. Addition of lansoprazole restored in vitro sensitivity to azithromycin in 3 out of 9 azithromycin-resistant strains. Such effects may enhance the elimination of H. pylori during clinical eradication therapy.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1996

Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group.

BACKGROUND: Azithromycin is active in treating Mycobacterium avium complex disease, but it has not been evaluated as primary prophylaxis in patients with human immunodeficiency virus (HIV) infection. Because the drug is concentrated in macrophages and has a long half-life in tissue, there is a rationale for once-weekly dosing. METHODS: We compared three prophylactic regimens in a multicenter, double-blind, randomized trial involving 693 HIV-infected patients with fewer than 100 CD4 cells per cubic millimeter. The patients were assigned to receive rifabutin (300 mg daily), azithromycin (1200 mg weekly), or both drugs. They were monitored monthly with blood cultures for M. avium complex. RESULTS: In an intention-to-treat analysis, the incidence of disseminated M. avium complex infection at one year was 15.3 percent with rifabutin, 7.6 percent with azithromycin, and 2.8 percent with both drugs. The risk of the infection in the azithromycin group was half that in the rifabutin group (hazard ratio, 0.53; P = 0.008). The risk was even lower when two-drug prophylaxis was compared with rifabutin alone (hazard ratio, 0.28; P<0.001) or azithromycin alone (hazard ratio, 0.53; P = 0.03). Among the patients in whom azithromycin prophylaxis was not successful, 11 percent of M. avium complex isolates were resistant to azithromycin. Dose-limiting toxic effects were more common with the two-drug combination than with azithromycin alone (hazard ratio, 1.67; P=0.03). Survival was similar in all three groups. CONCLUSIONS: For protection against disseminated M. avium complex infection, once-weekly azithromycin is more effective than daily rifabutin and infrequently selects for resistant isolates. Rifabutin plus azithromycin is even more effective but is not as well tolerated.

AIDS-Related Opportunistic Infections↗
PubMed1992

Azithromycin and clarithromycin: overview and comparison with erythromycin.

Azithromycin and clarithromycin are erythromycin analogues that have recently been approved by the FDA. These drugs inhibit protein synthesis in susceptible organisms by binding to the 50S ribosomal subunit. Alteration in this binding site confers simultaneous resistance to all macrolide antibiotics. Clarithromycin is several-fold more active in vitro than erythromycin against gram-positive organisms, while azithromycin is 2- to 4-fold less potent. Azithromycin has excellent in vitro activity against H influenzae (MIC90 0.5 microgram/ml), whereas clarithromycin, although less active against H influenzae (MIC90 4.0 micrograms/ml) by standard in vitro testing, is metabolized into an active compound with twice the in vitro activity of the parent drug. Both azithromycin and clarithromycin are equivalent to standard oral therapies against respiratory tract and soft tissue infections caused by susceptible organisms, including S aureus, S pneumoniae, S pyogenes, H influenzae, and M catarrhalis. Clarithromycin is more active in vitro against the atypical respiratory pathogens (e.g., Legionella), although insufficient in vivo data are available to demonstrate a clinical difference between azithromycin and clarithromycin. Superior pharmacodynamic properties separate the new macrolides from the prototype, erythromycin. Azithromycin has a large volume of distribution, and, although serum concentrations remain low, it concentrates readily within tissues, demonstrating a tissue half-life of approximately three days. These properties allow novel dosing schemes for azithromycin, because a five-day course will provide therapeutic tissue concentrations for at least ten days. Clarithromycin has a longer serum half-life and better tissue penetration than erythromycin, allowing twice-a-day dosing for most common infections. Azithromycin pharmacokinetics permit a five-day, single daily dose regimen for respiratory tract and soft tissue infections, and a single 1 g dose of azithromycin effectively treats C trachomatis genital infections; these more convenient dosing schedules improve patient compliance. Azithromycin and clarithromycin also are active against some unexpected pathogens (e.g., B burgdorferi, T gondii, M avium complex, and M leprae). Clarithromycin, thus far, appears the most active against atypical mycobacteria, giving new hope to what has become a difficult group of infections to treat. Gastrointestinal distress, a well known and major obstacle to patient compliance with erythromycin, is relatively uncommon with the new macrolides. Further clinical data and experiences may better define and expand the role of these new macrolides in the treatment of infectious diseases.

Azithromycin↗
PubMed2000

In vitro development of resistance to ceftriaxone, cefprozil and azithromycin in Streptococcus pneumoniae.

Approval of ceftriaxone for the treatment of otitis media has led to fear of selection of resistant mutants owing to widespread use. To test this, we examined the ability of sequential subcultures in sub-MICs of ceftriaxone, cefprozil and azithromycin to select resistant mutants in 12 pneumococci. Daily subculturing was performed 50 times or until mutants with raised ceftriaxone, cefprozil or azithromycin MICs were selected. Of eight ceftriaxone-susceptible parents, ceftriaxone did not select for any resistant mutants, while cefprozil selected for four mutants (MICs 2-4 mg/L after 21-50 subcultures). Among four ceftriaxone-resistant parents, subculturing in ceftriaxone selected for one stable mutant with raised ceftriaxone MIC (>16 mg/L after 21 subcultures) and subculturing in cefprozil selected for one mutant with raised cefprozil MIC (64 mg/L after 44 subcultures). Mutations were observed in pbp2x and pbp1a. Among six azithromycin-susceptible parents, subculturing in azithromycin selected for five resistant mutants (MIC 0.5-32 mg/L after 10-42 passages) and among six azithromycin-resistant strains, subculturing selected for mutants with raised azithromycin MICs in all six strains (MIC 16-32 mg/L after 4-18 passages). All azithromycin-resistant mutants derived from azithromycinsusceptible parents had mutations in domain V of 23S rRNA while all azithromycin-resistant parents and derived mutants had mefE. Single-step mutation rates among the 12 strains at the MIC ranged from 1.5 x 10(-6) to <6.2 x 10(-10) for ceftriaxone, >1.3 x 10(-5) to 8.9 x 10(-8) for cefprozil and >1.1 x 10(-6) to 6.7 x 10(-10) for azithromycin. Multi-step and single-step testing showed that ceftriaxone selected for resistant mutants less often than cefprozil and azithromycin.

Anti-Bacterial Agents↗
PubMed1996

A multicenter, open label trial of azithromycin vs. amoxicillin/ clavulanate for the management of acute otitis media in children.

OBJECTIVE: This randomized, open label study compared the efficacy and safety of a 5-day course of once daily azithromycin to those of a 10-day course of three times daily amoxicillin/ clavulanate. METHODS: One hundred sixty-nine children with confirmed acute bacterial otitis media were randomized to treatment with 10 mg/kg of azithromycin oral suspension on Day 1, followed by 5 mg/kg once daily for the next 4 days or 40 mg/kg/ day of amoxicillin/clavulanate suspension in three divided doses for 10 days. Clinical efficacy and safety were evaluated on Days 11 and 30. RESULTS: Analysis of evaluable patients 11 days after the start of treatment demonstrated that 87.8% of patients treated with azithromycin and 100.0% of the patients treated with amoxicillin/ clavulanate were cured or improved. Presumed bacteriologic eradication of the baseline pathogens Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes was comparable in the two groups: 87.8% in patients treated with azithromycin; and 100.0% in patients receiving amoxicillin/clavulanate. At Day 30, 82.2% of patients treated with azithromycin and 80.0% of patients treated with amoxicillin/clavulanate were cured or improved. Presumed bacteriologic eradication of the base-line pathogens was similar in the two groups: 82.2% in patients treated with azithromycin; and 81.1% in patients receiving amoxicillin/clavulanate. Relapses occurred in 5.1% of patients receiving azithromycin and 21.1% of patients taking amoxicillin/clavulanate (P = 0.047). Treatment-related side effects occurred in 3.5% of the azithromycin patients compared with 31.0% of amoxicillin/clavulanate patients (P < 0.001). CONCLUSIONS: Azithromycin was comparable to amoxicillin/clavulanate in achieving clinical cure or improvement and presumed eradication of baseline pathogens in pediatric patients with acute otitis media. Azithromycin was significantly better tolerated and was associated with fewer relapses than seen after amoxicillin/clavulanate therapy.

Acute Disease↗
PubMed1996

A multicenter, randomized, open label comparison of azithromycin and amoxicillin/clavulanate in acute otitis media among children attending day care or school.

OBJECTIVE: This multicenter, randomized, open label study compared the efficacy and safety of azithromycin and amoxicillin/clavulanate for the treatment of acute otitis media among children who were attending a day-care facility or school. METHODS: Eligible children with acute otitis media from 21 US centers were randomized to treatment with 10 mg/kg of azithromycin oral suspension on Day 1, followed by 5 mg/kg once daily for the next 4 days or approximately 40 mg/kg/day of amoxicillin/clavulanate suspension in 3 divided doses for 10 days. Clinical efficacy was evaluated on Days 14, 30 and 45. Acceptance and convenience of the medications were assessed on Day 14 by parent interviews with a standardized questionnaire. RESULTS: Of the 263 children enrolled in the study, 233 were evaluable at the primary evaluation 45 days after the start of treatment. Satisfactory clinical response rates (cure, delayed cure and improvement) were 60.5% in patients treated with azithromycin and 64.9% in patients treated with amoxicillin/clavulanate. Satisfactory clinical response rates at secondary evaluations were also comparable: 92.2% vs. 90.0% at Day 14 and 66.7% vs. 72.7% at Day 30 in patients treated with azithromycin and amoxicillin/clavulanate, respectively. No significant differences in treatment failures, relapses or recurrences were noted with either medication. Azithromycin was significantly better tolerated and caused fewer treatment-related adverse events (7.2%) than amoxicillin/clavulanate (17.1%) (P < 0.001). In response to the interview and questionnaire, parents of children treated with azithromycin noted less need for special arrangements to give medication (2.0% vs. 14.9%). Children liked the taste of azithromycin (89.2%) and did not have to be forced to take the medication (2.4%). Parents of children receiving amoxicillin/clavulanate noted that 61.8% liked the medication and 19.4% of children had to be forced to take it. CONCLUSIONS: This study demonstrates that azithromycin was comparable to amoxicillin/clavulanate in achieving satisfactory clinical response rates in children with acute otitis media attending day care or school. Azithromycin was significantly better tolerated than amoxicillin/ clavulanate. Parents considered azithromycin to be significantly more convenient to administer and more acceptable to children.

Acute Disease↗
PubMed2005

A randomized, multicenter, double blind, double dummy trial of single dose azithromycin versus high dose amoxicillin for treatment of uncomplicated acute otitis media.

BACKGROUND: High dose amoxicillin is recommended for the initial treatment of children with acute otitis media (AOM), particularly patients at risk for having drug-resistant Streptococcus pneumoniae. Single dose azithromycin (30 mg/kg) is considered an alternative agent for the treatment of AOM. OBJECTIVE: To compare the clinical efficacy and safety of single dose azithromycin with that of high dose amoxicillin among children with uncomplicated AOM. METHODS: This was a double blind, double dummy, multinational, clinical trial in which children (6-30 months of age) with AOM were randomized to treatment with single dose azithromycin (30 mg/kg) or high dose amoxicillin (90 mg/kg/d, in 2 divided doses) for 10 days. Tympanocentesis was performed at baseline and clinical responses were assessed at days 12-14 (end of therapy) and at days 25-28 (end of study). RESULTS: The study enrolled 313 patients, and 83% of the patients were < or =2 years of age. A total of 158 patients in the azithromycin group and 154 in the amoxicillin group were considered clinical modified intent-to-treat patients. A middle ear pathogen was detected for 212 patients (68%). Haemophilus influenzae was the most common pathogen (isolated for 96 patients), followed by S. pneumoniae (92 patients), Moraxella catarrhalis (23 patients) and Streptococcus pyogenes (23 patients). beta-Lactamase production was observed for 17% of H. influenzae isolates and 100% of M. catarrhalis isolates. Thirty-five (38%) S. pneumoniae isolates were penicillin-nonsusceptible and 24 (26%) isolates were macrolide-resistant. At the end of therapy, clinical success rates for azithromycin and amoxicillin were comparable for all patients (84 and 84%, respectively) and for children < or =2 years of age (82 and 82%, respectively). At the end of therapy and end of study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithromycin (80%) and patients treated with amoxicillin (83%). The rates of treatment-related adverse events for azithromycin and amoxicillin were 20% and 29%, respectively (P = 0.064). Diarrhea was more common in the amoxicillin group than in the azithromycin group (17.5 and 8.2%, respectively) (P = 0.017). Compliance, defined as completion of > or =80% of the study medication, was higher in the azithromycin group (100%) than in the amoxicillin group (90%) (P = 0.001). CONCLUSIONS: In this study, single dose azithromycin was as effective as high dose amoxicillin for the treatment of children with AOM, whereas rates of adverse events were lower and compliance improved with the simplified single dose regimen.

Amoxicillin↗
PubMed2007

Maintenance azithromycin treatment in pediatric patients with cystic fibrosis: long-term outcomes related to macrolide resistance and pulmonary function.

BACKGROUND: Maintenance azithromycin therapy may improve pulmonary function in patients with cystic fibrosis (CF) with Pseudomonas aeruginosa infection because of its antiinflammatory properties. However, azithromycin therapy might increase macrolide resistance in Staphylococcus aureus cultured from respiratory secretions. We studied the emergence of macrolide resistance in S. aureus and correlated this to pulmonary function decline in pediatric patients with CF on daily azithromycin therapy. METHODS: Respiratory cultures of 100 patients with CF were analyzed for S. aureus colonization and its resistance pattern before and during 3 years after initiation of azithromycin maintenance therapy. Mean annual change in forced expiratory volume as percent of predicted (FEV1 %) was calculated to compare pulmonary function before and after azithromycin therapy. RESULTS: Staphylococcal colonization did not significantly decrease after initiation of azithromycin (50% versus 48%). Before start of therapy, 10% of patients with staphylococcal colonization had macrolide-resistant strains. Staphylococcal resistance increased to 83% in the first year; 97% in the second and 100% in the third year after initiation of azithromycin therapy (P < 0.001). Half of macrolide-resistant S. aureus comprised the macrolide-lincosamide-streptogramin phenotype. Percent forced expiratory volume in 1 second improved in the first year after initiation of azithromycin (mean annual change: -4.75% before versus +3.09% after initiation; P < 0.01) but decreased during the second and third years after initiation (-5.15% and -3.65%, respectively). Emergence of macrolide-resistant S. aureus was not related to pulmonary function decline. CONCLUSION: Maintenance azithromycin therapy in patients with CF leads to macrolide resistance in nearly all S. aureus carriers. Pulmonary function improvement after initiation of azithromycin therapy seems to be temporary and appears not to be related to macrolide resistance of S. aureus.

Adolescent↗
PubMed1987

Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution.

Azithromycin (CP-62,993), a new acid-stable 15-membered-ring macrolide, was well absorbed following oral administration in mice, rats, dogs, and cynomolgus monkeys. This compound exhibited a uniformly long elimination half-life and was distributed exceptionally well into all tissues. This extravascular penetration of azithromycin was demonstrated by tissue/plasma area-under-the-curve ratios ranging from 13.6 to 137 compared with ratios for erythromycin of 3.1 to 11.6. The significance of these pharmacokinetic advantages of azithromycin over erythromycin was shown through efficacy in a series of animal infection models. Azithromycin was orally effective in treating middle ear infections induced in gerbils by transbulla challenges with amoxicillin-resistant Haemophilus influenzae or susceptible Streptococcus pneumoniae; erythromycin failed and cefaclor was only marginally active against the H. influenzae challenge. Azithromycin was equivalent to cefaclor and erythromycin against Streptococcus pneumoniae. In mouse models, the new macrolide was 10-fold more potent than erythromycin and four other antibiotics against an anaerobic infection produced by Fusobacterium necrophorum. Similarly, azithromycin was effective against established tissue infections induced by Salmonella enteritidis (liver and spleen) and Staphylococcus aureus (thigh muscle); erythromycin failed against both infections. The oral and subcutaneous activities of azithromycin, erythromycin, and cefaclor were similar against acute systemic infections produced by Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, or S. aureus, whereas azithromycin was more potent than erythromycin and cefaclor against the intracellular pathogen Listeria monocytogenes. The pharmacokinetic advantage of azithromycin over erythromycin in half-life was clearly demonstrated in prophylactic treatment of an acute mouse model of S. aureus infection. These properties of azithromycin strongly support the further evaluation of this new macrolide for use in community-acquired infections of skin or soft tissue and respiratory diseases.

Animals↗
PubMed2002

In vitro selection of resistance in Haemophilus influenzae by amoxicillin-clavulanate, cefpodoxime, cefprozil, azithromycin, and clarithromycin.

Abilities of amoxicillin-clavulanate, cefpodoxime, cefprozil, azithromycin, and clarithromycin to select resistant mutants of Haemophilus influenzae were tested by multistep and single-step methodologies. For multistep studies, 10 random strains were tested: 5 of these were beta-lactamase positive. After 50 daily subcultures in amoxicillin-clavulanate, MICs did not increase more than fourfold. However, cefprozil MICs increased eightfold for one strain. Clarithromycin and azithromycin gave a >4-fold increase in 8 and 10 strains after 14 to 46 and 20 to 50 days, respectively. Mutants selected by clarithromycin and azithromycin were associated with mutations in 23S rRNA and ribosomal proteins L4 and L22. Three mutants selected by clarithromycin or azithromycin had alterations in ribosomal protein L4, while five had alterations in ribosomal protein L22. Two mutants selected by azithromycin had mutations in the gene encoding 23S rRNA: one at position 2058 and the other at position 2059 (Escherichia coli numbering), with replacement of A by G. One clone selected by clarithromycin became hypersusceptible to macrolides. In single-step studies azithromycin and clarithromycin had the highest mutation rates, while amoxicillin-clavulanate had the lowest. All resistant clones were identical to parents as observed by pulsed-field gel electrophoresis. The MICs of azithromycin for azithromycin-resistant clones were 16 to >128 micro g/ml, and those of clarithromycin for clarithromycin-resistant clones were 32 to >128 micro g/ml in multistep studies. For strains selected by azithromycin, the MICs of clarithromycin were high and vice versa. After 50 daily subcultures in the presence of drugs, MICs of amoxicillin-clavulanate and cefpodoxime against H. influenzae did not rise more than fourfold, in contrast to cefprozil, azithromycin, and clarithromycin, whose MICs rose to variable degrees.

Amino Acid Sequence↗
PubMed2004

Enhanced hypoprothrombinemia with warfarin due to azithromycin.

OBJECTIVE: To report a case of probable azithromycin-warfarin drug interaction with enhanced hypoprothrombinemic effect of warfarin. CASE SUMMARY: An 83-year-old African American man stabilized on warfarin therapy (10 mg on Wednesdays, 7.5 mg on other days) developed a prolonged prothrombin time one day after starting azithromycin 500 mg. The elevated prothrombin time normalized 3 days after azithromycin was discontinued. After the initial increase in the international normalized ratio, the absence of any significant confounding factors affecting the anticoagulant effect of warfarin in our patient and the numerous reports of such interactions indicate that an interaction between azithromycin and warfarin may have been responsible for the elevated prothrombin time seen in this patient. An objective causality assessment revealed that the adverse event was probably related to the combination of these drugs. DISCUSSION: Azithromycin, unlike erythromycin and clarithromycin, is not known to inhibit the cytochrome P450 enzyme system and is presumed to be the macrolide of choice in patients already on warfarin. However, previously reported cases of azithromycin-warfarin interactions support the possibility that azithromycin does interact with warfarin, although the exact mechanism is not understood. CONCLUSIONS: Azithromycin may interact with warfarin and enhance its hypoprothrombinemic effects. This effect may be delayed for 4-8 days after a course of azithromycin has been completed. Periodic monitoring of the prothrombin time is recommended when using azithromycin in patients taking warfarin.

Aged↗