Azithromycin powder reviews

Azithromycin powder reviews DEFAULT

Clinical applications of azithromycin microspheres in respiratory tract infections

Int J Nanomedicine. 2007 Dec; 2(4): 551–559.

Published online 2007 Dec.

Francesco Blasi,Stefano Aliberti, and Paolo Tarsia

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Institute of Respiratory Diseases, University of Milan, IRCCS Fondazione Policlinico-Mangiagalli-Regina Elena Milano, Italy

Correspondence: Francesco Blasi, Istituto di Tisiologia e Malattie, dell’Apparato Respiratorio, Università degli Studi di Milano, Pad. Sacco, Fondazione Policlinico-Mangiagalli-Regina Elena Milano, via F. Sforza, 35 I-20122 Milano, Italy, Tel +39 02 50320623, Fax +39 02 50320628, Email [email protected]

Copyright © 2007 Dove Medical Press Limited. All rights reserved

This article has been cited by other articles in PMC.


Few adequately designed clinical trials have addressed optimal treatment duration in lower respiratory tract infections. Drugs possessing favourable pharmacokinetic and pharmacodynamic profiles may obtain early bacterial eradication allowing shorter treatment duration. This may be associated with a number of advantages including reduced resistance induction, increased compliance, lesser adverse events, and cost containment. Recently, a novel 2.0 g single dose of azithromycin microspheres has been compared with 7-day levofloxacin 500 mg or extended release clarithromycin in over 400 patients with community-acquired pneumonia. Clinical cure and bacteriological eradication rates, hospitalizations, and deaths were similar between azithromycin and comparators. Azithromycin 2.0 g microspheres proved as effective as 7 days of levofloxacin 500 mg in acute exacerbation of chronic bronchitis patients across all degrees of obstruction severity. In both settings Azithromycin microspheres obtained clinical cure in most patients harbouring macrolide-resistant Streptococcus pneumoniae strains. The drug was well tolerated in clinical studies and in healthy volunteers with modest and transitory adverse events. An undoubted advantage of single-dose azithromycin administration is the facility in ensuring that patients complete their prescribed course of therapy. A further advantage of single-dose therapy is the potential for use as directly-observed therapy, which may be useful in specific clinical conditions.

Keywords: azithromycin microspheres, pneumonia, COPD exacerbations


The last 50 years have witnessed an impressive evolution in the antibiotic armamentarium at the clinician’s disposal. The availability of effective antibiotic treatment has substantially impacted on overall mortality of patients with lower respiratory tract infections (LRTIs). International guideline drafting and implementation have been important in highlighting key factors in improving care in community-acquired pneumonia (CAP) and acute exacerbation of chronic bronchitis (AECB) (Woodhead et al 2005; Mandell et al 2007). Remarkably, guidelines contain few indications regarding the appropriate duration of antibiotic therapy. This reflects the paucity of appropriately designed large scale clinical trials addressing such an important treatment issue. Conventionally, antibiotics are continued until clinical and laboratory indices of infection are normal in patients with LRTIs. It is recognized that patients tend to interupt treatment once they feel better, decreasing compliance to treatment after that time point.

Antibiotic exposure is unavoidably associated with the phenomenon of antibiotic resistance due to a selection pressure on bacterial strains with natural or acquired resistance. Ideally, antibiotics should be maintained only up until bacteria are effectively cleared as further protraction of therapy increases unnecessary bacterial exposure to drugs. Currently, antimicrobial resistance is a global problem resulting in high hospitalization rates, mortality and costs in LRTIs (Sahm 2003). It has been suggested that shortening antimicrobial treatment duration may benefit resistance patterns. For example, low dose and prolonged duration of β-lactam antibiotic treatment may contribute to promoting pharyngeal carriage of drug-resistant Streptococcus pneumoniae (Guillemot et al 1998), whereas high-dose short course amoxicillin may be associated with significantly lower penicillin-resistant S. pneumoniae carriage (Schrag et al 2001).

Patient adherence to prescribed antibiotic regimens is affected by variables including dosing interval, treatment duration, adverse effects, and palatability in pediatric patients. Adherence to once-daily regimens has been shown to be far superior to that of twice- (Kardas 2007) or thrice-daily dosing schemes (Claxton et al 2001). It is fairly well established that patient compliance with antibiotic therapy begins to drop after 3–7 days of treatment (Kardas 2002). Additional potential benefits of short course antibiotic therapy in LRTIs patients include diminished impact on human endogenous flora, decreased total drug exposure with reduced side effects, reduced health care worker time expenditure, and reduced costs.

In order to avoid falling short of effectively controlling infection, short-course antibiotic therapy should be based on robust pharmacokinetic and pharmacodynamic considerations. Candidate drugs for short-course regimens should be able to achieve adequate tissue penetrations and concentrations at the site of infection for a sufficiently long length of time to ensure bacterial eradication (Nicolau 2001). The development of an effective short course regimen requires a concentration-dependent antimicrobial effect. The rate and extent of bacterial killing increase with increasing drug concentrations. For such agents the pharmacodynamic/pharmacokinetic predictors of efficacy are the area under the concentration-time curve/MIC ratio (AUC/MIC) and the maximal serum drug concentration/MIC ratio (Cmax/MIC) (Nicolau 2001).

Short-course azithromycin treatment in lower respiratory tract infections

Azithromycin is an azalide antibiotic exerting activity against most pathogens commonly involved in LRTIs. It acts by interfering with bacterial protein synthesis through binding of the 50S ribosomal subunit of susceptible microorganisms. Azithromycin is an ideal candidate for short-course antibiotic regimens for a number of reasons. Compared with earlier macrolides, azithromycin shows improved pharmacokinetic/dynamic properties that determine a prolonged half-life and excellent tissue penetration. The drug rapidly moves from the bloodstream into the interstitial compartment resulting in low serum concentrations but high and persistent tissue concentrations (Amsden et al 1997). Characteristically, azithromycin concentration in lung tissue may be over a 100-fold greater than in the circulation. High tissue concentrations are maintained for extended periods of time due to slow release. Considering that respiratory tract infections reside in the interstitial space, tissue accumulation of azithromycin may guarantee high drug concentrations in the active site of infection. A further interesting characteristic is the ability of azithromycin to concentrate within inflammatory cells, particularly neutrophils and monocytes within the bloodstream, and tissue macrophages (Mandell et al 2001). The ongoing inflammatory process in the lung recalls azithromycinladen neutrophils from the circulation which then unload the drug in the presence of bacteria within inflammation sites (Hand et al 2001). Inflammatory cells therefore act as a “Trojan horse” delivering local concentrations of azithromycin that are several orders of magnitude greater than that in plasma. Neutrophil unloading and the extended half life of azithromycin (~60 hours) sustain therapeutic drug concentrations at the site of infection for prolonged periods of time (Blumer 2005). Furthermore, inflammatory cell uptake of azithromycin is non-saturable and concentration dependent, suggesting that administration of higher doses of the drug early in the course of the infection may result in even greater drug concentration at the sites of infection.

Short-course treatment of CAP patients with azithromycin has been shown to be effective, with the 3-day (500 mg single daily dose) regimen and the 5-day (500 mg first day, 250 mg following days) regimens obtaining comparable results (Socan 1998). Clinical studies have shown that a 3-day or 5-day treatment with azithromycin is at least as effective as more prolonged regimens of benzylpenicillin or erythromycin (Bohte et al 1995), and clarithromycin (O’Doherty et al 1998). Azithromycin and comparators were similar in terms of clinical, microbiological, and radiological results in outpatient or hospitalized cases of mild-to moderate CAP. Similarly, 3 or 5-day azithromycin regimens were clinically and microbiologically as effective as more prolonged treatment with amoxicillin-clavulanic acid (Hoepelman et al 1997), levofloxacin (Amsden et al 2003), clarithromycin (Bradbury et al 1993) or 5-day courses of moxifloxacin (DeAbate et al 2000) or dirithromycin (Castaldo et al 2003) in patients with AECB. Table 1 shows a summary of clinical data for the quoted studies on azithromycin versus comparators in LRTIs.

Table 1

Clinical success rates in studies evaluating azithromycin against comparators in the treatment of lower respiratory tract infections

First author, yearSettingAzithromycin dosing schemeComparator/s dosing schemeNo. of treated patientsClinical success rate
Bohte 1995CAP500 mg once daily, 3 daysBenzylpenicillin i.v.35 azitromycin vsAzithromycin 83% vs
Erythromycin29 benzylpenicillinBenzylpenicillin 66%
19 azithromycin vsAzithromycin 79% vs
21 erythromycinErythromycin 76%
O’Doherty 1998CAP500 mg once daily, 3 daysClarithromycin 250 mg twice daily, 10 days101 azithromycinAzithromycin 94%
102 clarithromycinClarithromycin 95%
Bradbury 1993LRTI500 mg once daily, 3 daysClarithromycin 250 mg twice daily, 10 days252 azithromycinAzithromycin 94%
258 clarithromycinClarithromycin 97%
Hoepelman 1997LRTI500 mg once daily, 3 daysAmoxi/clav acid 625 mg 3 times daily, 10 days62 azithromycinAzithromycin 95%
61 amoxi/clav acidAmoxi/clav 90%
DeAbate 2000AECB500 mg day 1, 250 mg days 2–5Moxifloxacin 400 mg once daily, 5 days243 azithromycinAzithromycin 92%
221 moxifloxacinMoxifloxacin 90%
Amsden 2003AECB500 mg day 1, 250 mg days 2–5Levofloxacin 500 mg once daily, 7 days118 azithromycinAzithromycin 89%
117 levofloxacinLevofloxacin 92%
Castaldo 2003AECB500 mg day 1, 250 mg days 2–5Dirithromycin 500 mg once daily, 5 days46 azithromycinAzithromycin 86.5%
40 dirithromycinDirithromycin 95.5%

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Given its prolonged half-life, propensity to accumulate in tissues and inflammatory cells, and post antibiotic effect, attempts have been made to condense conventional treatment into single large dose schemes of azithromycin (1.5 g in adults, 30 mg/kg in children) for the management of LRTIs. Administration of a single, higher dose of azithromycin has been shown to achieve more rapid bacterial eradication and enhanced survival than the same dose divided over several days in pre-clinical infection models of otitis media, murine pneumonia and septicemia (Girard et al 2005, Babl et al 2002). This suggests that antibiotic “front-loading”, attaining higher systemic exposure early in the course of infection (ie, the AUC from time zero to 24 hours [AUC0–24] post dosing), may result in more rapid and efficient bacterial clearance following the single-dose regimen. This may offer benefits in terms of minimizing emergence of resistance.

In an open randomized study, the efficacy and safety of a single 1.5 g oral dose of azithromycin was compared with the standard 3-day regimen in the treatment of 100 patients with community-acquired atypical pneumonia (Schönwald et al 1999). Clinical success was obtained in 97.9% of patients in both groups. Side effects were observed in 2 patients in the single-dose group, and one patient in the 3-day group. Due to the relatively small number of patients studied, the safety evaluation of the single-dose regimen is inconclusive. However, the study does indicate that a single 1.5 g dose of azithromycin may be an alternative to the standard 3-day azithromycin regimen in the treatment of outpatients with atypical pneumonia syndrome. A later study analyzed the serum and white blood cell pharmacokinetic behavior of 1.5 g single dose azithromycin compared to the same dose over 3 days (Amsden et al 2001). The single drug bolus resulted in significantly higher peak serum concentration compared to the 3-day regimen, although the subjects’ overall drug exposure did not differ significantly. At 10 days from the start of therapy both regimens showed intracellular white blood cell concentrations that were above the MIC90 values of the vast majority of community-acquired respiratory pathogens.

The highest single oral dose of azithromycin currently approved is an immediate-release 2.0 g sachet formulation of oral powder for suspension in the treatment of chlamydial and gonococcal urethritis and cervicitis (Handsfield et al 1994). The reported 34% incidence of nausea and 14% incidence of diarrhea indicate that this formulation is likely to achieve limited clinical diffusion due to the high level of gastrointestinal intolerance.

Azithromycin microsphere formulation

Recently, microspheres have been developed as a means of effectively delivering antibiotics in periodontal (Paquette 2007) and ocular diseases (Pijls et al 2006), for minimizing toxicity of antimycobacterial treatment (Rastogi et al 2006), and as an aid in Helicobacter pylori eradication (Patel et al 2007). A novel azithromycin microsphere formulation (recently approved as Zmax in the USA) has been developed to address the challenge of administering a higher oral dose of the drug as a single dose while maintaining tolerability. The characteristics of the microspheres, with a mean diameter ranging from approximately 100–300 μm, were selected based on a combination of palatability, release profile, and manufacturability. Azithromycin is released slowly via diffusion through pores formed in-situ in the microspheres. Alkalinizing agents (sodium phosphate tribasic and magnesium hydroxide) were incorporated in the formulation. Following ingestion, the alkaline nature of the microsphere formulation delays initial release of drug in the stomach. Azithromycin is thus released over 2 hours after ingestion in the small intestine. This allows by-passing of the motilin receptors in the upper gastrointestinal tract. Local drug activation of the motilin receptors is thought to mediate much of the macrolide-related gastrointestinal side effects (Takeshita et al 2006). Motilin receptor density is maximal in the antrum and decreases in the aboral direction. All the drug is released prior to the colon, thus ensuring maximal bioavailability (approximately 83%) (Chandra et al 2007). In an open-label, randomized, parallel-group study of 24 healthy adult subjects the pharmacokinetic profiles of azithromycin given as 2.0 g microspheres were characterized in serum and white blood cells and compared with those of a 3-day regimen totaling 1.5 g (Liu et al 2007). Compared with the conventional 3-day 1.5 g azithromycin treatment, the single-dose 2.0 g microsphere formulation obtained a 2-fold higher maximum plasma concentration (Cmax) and a 3-fold higher 24-hour area under the concentration-time curve (AUC0–24) at day 1. The total systemic exposure in serum over 5 days following the start of dosing (AUC0–120) was similar for the two regimens. Similarly, in white blood cells, threefold higher drug exposure and maximal concentrations were found at day 1 following single dose administration compared with the 3-day regimen.

In an observer-blind, parallel group, single-dose study, the tolerability profiles of azithromycin 2.0 g microspheres were compared with the immediate-release azithromycin 2.0 g sachet formulation of oral powder for suspension (Chandra et al 2007). This was a complex study that also evaluated pharmacokinetic profiles of the two compounds and the effect of food (high fat meal and a standard meal) and an antiacid on the rate of drug absorption. A total of 377 healthy male and female volunteers were recruited. Compared with the sachet oral powder suspension, the microsphere formulation was associated with a slower absorption rate (57% decrease in mean Cmax with a 2.5 hour delay in time to reach Cmax). However, because the AUC values were comparable, overall drug exposure was similar. The incidence of gastrointestinal side effects (abdominal pain, nausea, vomiting, and diarrhea) was significantly lower with azithromycin microspheres compared to the immediate-release formulation. One non-gastrointestinal adverse event common to azithromycin slow-release and immediate release was headache (12% and 6%, respectively). In both groups over 90% of adverse events were mild in intensity and occurred within the first 2 hours after dosing. Both the high fat meal and the standard meal increased the rate of drug absorption (2-fold higher Cmax values, and 2- to 4-hour shortening of time to maximal concentration) but were associated with an increased incidence of nausea and vomiting. It was assumed that meal-triggered gastric acid secretions led to faster release of azithromycin from the microspheres (Chandra et al 2007). Because of the decreased tolerability of the formulation when taken with food, it was suggested that azithromycin micro-spheres be taken on an empty stomach. Pharmacokinetic properties of the azithromycin microspheres were not significantly affected by co-administration of an antiacid.

Azithromycin microspheres in community-acquired pneumonia

Two phase III multinational, multicenter, double-blind, double-dummy studies analyzed the efficacy and safety of a new microsphere (MS) formulation of azithromycin, 2.0 g given as a single dose, compared with either the extended-release formulation of clarithromycin) (1 g od for 7 days) (Drehobl et al 2005) or with levofloxacin (500 mg od for 7 days) (D’Ignazio et al 2005) in the treatment of adults with mild-to-moderate CAP.

In the clarithromycin extended-release comparator trial, eligible subjects were required to be 16 years of age or older, with cough productive of sputum and a diagnosis of pneumonia as demonstrated by two or more of the following signs or symptoms: auscultatory findings on pulmonary examination of rales and/or evidence of pulmonary consolidation; dyspnea or tachypnea; body temperature >38 °C (oral); or an elevated total peripheral white blood cell count (>10,000/mm3) or >15% immature neutrophils (bands). In addition, subjects had to have a prospectively calculated Modified Fine Risk score of ~70 (Fine Classes I and II) (Fine et al 1997). A total of 501 subjects were randomized and 499 were treated. Patients were recruited at 58 centers in 7 countries among the US, Canada, Europe, and Asia. In the levofloxacin trial, subjects were aged 18 years or older with a clinical diagnosis of mild-to-moderate CAP with a Fine mortality risk class of I, II, or III (ie, a risk score of ~90). In total, 427 patients were randomized, of whom 423 received study medication. Patients were enrolled at 56 centers in 8 countries among North and South America, Europe, and Asia.

In both studies, clinical assessments were conducted at baseline (Day 1), during treatment (Days 3–5), at the end of treatment (Days 8–11), post treatment at the test of cure (TOC) visit (Days 14–21) and at a long-term follow-up visit (Days 28–35). Clinical efficacy was assessed at the TOC visit. Subjects with a clinical response of cure at the TOC visit were assessed for relapse at the long-term follow-up visit (Days 28–35). Bacteriological response was assessed in those subjects from whom a pathogen was identified at baseline. Table 2 shows the demographics and baseline characteristics of the patients enrolled in the two studies. No differences in terms of either clinical response or bacteriological response were noted between azithromycin microspheres and comparators at the TOC visit (Days 14–21) (Table 3).

Table 2

Demographics and baseline characteristics of patients included in two comparative phase III community-acquired pneumonia studies of 2 g single-dose azithromycin microspheres (D’Ignazio et al 2005; Drehobl et al 2005)

Drehobl et al 2005
D’Ignazio et al 2005
Azithromycin microspheres (n = 247)Clarithromycin XL 1.0 g (n = 252)Azithromycin microspheres (n = 211)Levofloxacin 500 mg (n = 212)
Mean age (years)45.643.648.249.0
No. of subjects ≥65 years (%)32 (13%)26 (10.3%)49 (23.2%)48 (22.6%)
History of diabetes13112027
Unilobar disease211219172181

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Table 3

Clinical and bacteriological response rates at days 14–21 in two studies comparing azithromycin 2.0 g microspheres with either extended release clarithromycin or levofloxacin in patients with community-acquired pneumonia (D’Ignazio et al 2005; Drehobl et al 2005)

Drehobl et al 2005
D’Ignazio et al 2005
Azithromycin microspheresClarithromycin XL 1.0 gAzithromycin microspheresLevofloxacin 500 mg
Clinical response92.6% (n = 202)94.7% (n = 209)89.7% (n = 174)93.7% (n = 209)
Bacteriological response93.0% (n = 100)92.1 (n = 127)90.1% (n = 91)92.3% (n = 104)
Clinical response by pathogen
  Haemophilus influenzae14/15 (93%)23/26 (88%)14/15 (93%)8/8 (100%)
  Moraxella catarrhalis8/8 (100%)3/5 (60%)7/7 (100%)2/2 (100%)
  Streptoccoccus pneumoniae17/19 (89%)25/27 (93%)11/14 (79%)10/12 (83%)
  Chlamydia pneumoniae19/21 (90%)29/31 (94%)18/19 (94%)21/22 (95%)
  Mycoplasma pneumoniae25/26 (96%)20/21 (95%)5/7 (71%)18/18 (100%)

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In the azithromycin vs clarithromycin study, at the long-term follow-up visit (days 28–35), only 1 subject (0.6%) in the azalide study arm and 5 subjects (2.8%) in the clarithromycin study arm were classified as having relapsed. Clinical cure rates in patients with multilobar pneumonia were only slightly lower than those in patients with single lobe pneumonia (88.5% vs 94.4%). Two azithromycin-treated subjects and one clarithromycin-treated subject were hospitalized for worsening of pneumonia. In this study there were 4 deaths, all of which were in the clarithromycin extended release arm. None of the deaths were attributed to study therapy or progression of CAP. In the study comparing azithromycin microspheres with levofloxacin, 6 subjects (2 azithromycin and 4 levofloxacin) were hospitalized for worsening pneumonia; 2 of the levofloxacin-treated and 1 of the azithromycin-treated subjects ultimately died of causes other than pneumonia.

In the azithromycin vs clarithromycin study a pathogen was identified in 281/499 (56%) of treated patients, with evidence of mixed infection in 16%. An atypical pathogen was identified in 24% of azithromycin-treated subjects. In the azithromycin vs levofloxacin study a pathogenic microrganism was identified in 219/423 (52%) of treated patients, a mixed infection being present in 11%. Atypical pneumonia was identified in 27% of the azithromycin arm cases. Data on S. pneumoniae eradication rates and clinical response, according to bacterial susceptibility to macrolides and penicillin, were analyzed in both studies (Tables 4 and ​5). No clear relationship between resistance patterns and clinical and bacteriological outcomes was observed. In the two studies combined, 13 azithromycin-resistant S. pneumoniae strains were found, 7 of which were treated with azithromycin, with clinical cure and bacteriological eradication (presumed or documented) being obtained in 4/7.

Table 4

Antimicrobial susceptibility of the 56 Streptococcus pneumioniae isolates identified in the study comparing azithromycin 2.0 g microspheres with extended release clarithromycin (Drehobl et al 2005)

Penicillin38 (68%)16 (29%)2 (4%)
Azithromycin49 (88%)1 (2%)6a (11%)
Clarithromycin50 (89%)06 (11%)

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Table 5

Antimicrobial susceptibility of the 28 Streptococcus pneumioniae isolates identified in the study comparing azithromycin 2.0 g microspheres with extended release clarithromycin (D’Ignazio et al 2005)

Penicillin19 (68%)8 (29%)1 (4%)
Azithromycin21 (75%)07a (25%)
Levofloxacin28 (100%)00

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Macrolide-resistant pneumococci are increasing worldwide (Gay et al 2000). However, the clinical significance of this finding is still debated as resistance has been associated with clinical failure in some (Fogarty et al 2000) but not all studies (Aspa et al 2004). Particularly, treatment failure is not unusual in cases of bacteremic pneumococcal pneumonia (Lonks 2002), although most clinical failures showed underlying conditions that would have contraindicated the empirical choice of a macrolide as first line treatment. As mentioned above, the administration of a single high dose of azithromycin is likely to result in concentrations of azithromycin in lung tissue and fluids that would be effective against S. pneumoniae with low-level macrolide resistance.

The safety and tolerability of this novel azithromycin formulation were excellent. The majority of all reported adverse events were mild or moderate in severity. For azithromycin microspheres, most adverse events occurred on the day of administration and resolved within 2 days. There were no clinically significant changes in clinical laboratory parameters. Table 6 shows the adverse reactions recorded in the two studies. In both studies, the azithromycin group showed a greater number of diarrhea and loose stools adverse events. In most cases the effect was limited to the day of therapy or the following day.

Table 6

Incidence of adverse events in two studies comparing azithromycin 2.0 g microspheres with either extended release clarithromycin or levofloxacin in patients with community-acquired pneumonia (D’Ignazio et al 2005; Drehobl et al 2005)

Drehobl et al 2005
D’Ignazio et al 2005
Azithromycin microspheres (n = 247)Clarithromycin XL 1.0 g (n = 252)Azithromycin microspheres (n = 211)Levofloxacin 500 mg (n = 212)
Diarrhea/loose stools30 (12.1%)19 (7.5%)27 (12.8%)11 (5.2%)
Nausea9 (3.6%)8 (3.2%)3 (1.4%)2 (0.9%)
Abdominal pain9 (3.6%)3 (1.2%)4 (1.9%)2 (0.9%)
Rash3 (1.2%)1 (0.4%)1 (0.5%)0
Taste perversion3 (1.2%)9 (3.6%)01 (0.5%)
Vomiting2 (0.8%)2 (0.8%)4 (1.9%)2 (0.9%)

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Owing to the single-dose nature of the regimen, all azithromycin-treated patients completed the treatment course, whereas 15 of 254 subjects (5.9%) randomized to the clarithromycin XL arm did not complete the entire 7-day course of active treatment and 10 of the 212 levofloxacin-treated subjects (4.7%) did not complete the full 7-day treatment course.

The results of these controlled trials in CAP demonstrated that a single 2.0 g dose of azithromycin microspheres is at least as effective as a 7-day treatment with either clarithromycin extended release or levofloxacin, confirming the suitability of the new formulation of azithromycin.

Azithromycin microspheres in acute exacerbations of chronic bronchitis

Proper management of an AECB should result in rapid resolution of the acute episode and decrease in the likelihood of treatment failure and of an early recurrence (Martinez 2005). The role of antibiotic treatment in AECB is less straightforward than in CAP. It is felt that only approximately 50% of exacerbations are sustained by bacteria (Monso et al 1995) and the issue is complicated by the fact that approximately 25%–40% of COPD patients present stable bacterial colonization of the airways outside periods of acute deterioration (Cabello et al 1997). Attempts have been made to identify patients more likely to present bacterial aetiology of an exacerbation based on the presence of at least 2 out of 3 of the clinical Anthonisen criteria (increased cough, increased in sputum production, change in sputum color) (Anthonisen et al 1987). Among the three symptoms, sputum purulence has been most strongly associated with bacterial exacerbation (Stockley et al 2000; Allegra et al 2005). Additionally, patient baseline severity must also be considered as antibiotics have a greater beneficial effect in patients with more severe disease (Allegra et al 2001), which translates into a survival advantage in those sufficiently severe to require mechanical ventilation (Nouira et al 2001). Regrettably, in most older antibiotic efficacy studies on patients with exacerbations a precise definition of COPD was often absent, with enrolment of young, non-obstructed never-smokers, unsatisfactory definitions of exacerbation, high population severity heterogeneity, and lacked stratification for steroid use.

A recent double-blind, double-dummy study compared azithromycin microspheres (2 g single dose) with levofloxacin (500 mg once daily for 7 days) in patients with AECB (Zervos et al 2005). Patients were clearly defined with stratification for the use of systemic steroids, and strict inclusion and exclusion criteria. A total of 551 subjects were randomized and 438 were treated at 62 centers in 13 countries. Most enrolled subjects were advanced-age patients with a past history of smoking, documented airflow obstruction, at least one AECB in the previous year, and presented all three cardinal Anthonisen symptoms in the current exacerbation. Patient baseline demographic characteristics are shown in Table 7.

Table 7

Patient baseline demographics in a study comparing azithromycin 2.0 g microspheres with levofloxacin 500 mg in acute exacerbations of chronic bronchitis (Zervos et al 2005)

CharacteristicAzithromycin microspheres (n = 268)Levofloxacin 500 mg (n = 2742)
Mean age (years)62.361.7
Systemic steroids27 (10.1%)27 (9.9%)
FEV1 % predicted
  >8044 (16.4%)35 (12.8%)
  <80 and >6050 (18.7%)57 (20.8%)
  <60 and >30111 (41.4%)110 (40.1%)
  <3031 (11.6%)38 (13.9%)
  Missing32 (11.9%)34 (12.4%)
Smoking history
  Smoker156 (58.2%)163 (59.5%)
  Ex-smoker109 (40.7%)111 (40.5%)
  Never-smoker3 (1.1%)0 (0%)
Anthonisen criteria
  Presence of all three criteria263 (98.1%)269 (98.2%)
  Presence of two criteria5 (1.9%)4 (1.5%)
  Presence of one criterion0 (0%)1 (0.4%)
No. AECB in the previous year
  1–4213 (79.5%)218 (79.6%)
  >421 (7.8%)21 (7.7%)
  None34 (12.7%)34 (12.4%)

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The clinical cure rate at the test-of-cure (TOC) visit (Days 14–21) in the treated population was comparable between the two agents (93.6% for azithromycin compared with 92.7% for levofloxacin). Baseline microbiological testing yielded positive results in approximately 49% of subjects. In these patients, the overall bacteriological eradication rate was comparable between the two treatment regimens (91.9% for azithromycin versus 94.4% for levofloxacin).

Additional post hoc analyses of the 272 subjects in this study with spirometric evidence of airway obstruction suggests equal efficacy of azithromycin microspheres compared with levofloxacin across all strata of COPD severity using the GOLD and ATS/ERS stratification schemes (Pauwels et al 2001; Celli et al 2004) (Table 8). The majority of enrolled patients presented advanced disease severity. During the course of the trial and the follow-up period, 12 patients needed hospitalization. Eight of these occurred in the levofloxacin-treated arm while 4 occurred in azithromycin microsphere-treated patients. There was no clear pattern noted, although the majority of hospitalized patients had more severe airway obstruction at baseline.

Table 8

Subset analysis of favourable clinical response rates (expressed as percentage) of azithromycin 2.0 g microspheres or levofloxacin 500 mg in 272 AECB patients with differing degrees of airway obstruction (Zervos et al 2005)

Azithromycin microspheres (n = 136)Levofloxacin 500 mg (n = 136)
Degree of airway obstruction
  Very severe88.5%89.7%

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Among the patients treated with azithromycin microspheres, 5 were found to harbor macrolide-resistant S. pneumoniae strains. All patients were reported as clinically cured. In 1 patient with the highest macrolide MIC values (>256 μg/mL), persistence of the baseline pathogen was established at the 10-day TOC visit despite clinical resolution of the acute symptoms.


Optimal duration for antimicrobial treatment in lower respiratory tract infections (LRTIs) is still undetermined. Short-course treatments may be a means for maintaining clinical efficacy while containing antibiotic resistance spread, increasing patient compliance, and limiting drug-related adverse events. As recently pointed out by Thomas M. File (File 2004), the basic rationale behind short-course antibiotic treatment in CAP is to “hit hard and stop early”. Candidate drugs must show favorable pharmacokinetic and pharmacodynamic properties allowing high and prolonged antimicrobial concentrations at the site of infection.

The novel azithromycin microsphere formulation takes the concept of short-course treatment one step further by allowing single-dose antibiotic administration in LRTIs. Use of this formulation allows greater peak concentrations of the drug early in the course of infection with similar overall total antimicrobial exposure compared to traditional 3- to 5-day dosing regimens. This may allow sufficiently high concentration to effectively eradicate even moderately resistant organisms. The results of controlled trials in CAP and COPD exacerbations demonstrate that a single dose of azithromycin microspheres is at least as effective and well tolerated as a 7-day treatment with either extended release clarithromycin or levofloxacin.

An undoubted advantage of single-dose azithromycin administration is the facility in ensuring that patients complete their prescribed course of therapy. Failure to complete therapy may be associated with deterioration in the patient’s condition, treatment failure, and increased use and cost of healthcare resources such as the requirement for additional drugs and hospital admission. Incomplete treatment may also increase the likelihood that bacteria will develop resistance. Another advantage of single-dose therapy is the potential for use as directly observed therapy (DOT). The use of a DOT in LRTIs is intriguing, particularly in congested clinical situations (such as emergency departments) where assuring patient compliance may be troublesome or barriers to filling prescriptions may exist.

Predictably, such a form of treatment may encounter some resistance among interested parties. Physicians may be doubtful as to whether a single dose regimen may be reliable and effective for the treatment of their patients with LRTIs. Similarly, patients are accustomed to taking medications everyday while they are sick, with interruption of treatment often coinciding with symptom resolution. Clearly, further sound clinical demonstration of efficacy and recognition of patient subsets most likely to benefit are needed before widespread use of this approach to LRTIs can be considered.


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Articles from International Journal of Nanomedicine are provided here courtesy of Dove Press


Azithromycin (Zithromax) Reviews

2 Stars

Posted 1 months ago (9/20/2021)2

Rated for Otitis Media Report

Bad diarrhea and lack of appetite. Feel out of it and overall weakness.


1 Stars

Posted 1 months ago (9/12/2021)1

Rated for Pneumonia Report

I was given this to treat COVID. Was given a 5 day dose. The 1st day I didn’t notice any side effects, it was on the 2nd day when shit hit the fan. I woke up nauseous with stomach cramps and diarrhea, loss of appetite and whatever I did manage to eat I would then immediately run to the toilet. I also noticed my heart rate was a lot lower than normal. I’ve also noticed I have insomnia now and on my 4th day had an anxiety attack (not normal for me). I’m on day 5 today but going to stop taking this stuff. I’m crossing my fingers my heart rate goes back to normal and my stomach doesn’t feel off.


1 Stars

Posted 1 months ago (9/9/2021)1

Rated for Bacterial Infection Report

Took the 2 pill dosage with a lot of food. My stomach started getting big and was gassy and then diarrhea hit. Then it hit again. I feel a lot better that the cold is gone but now it feels like I have the flu and fever. I started to get swelling of the lips, dry mouth, dehydration, dizziness, anxiety, sweating, agitation, no appetite, headache, and itchy. I've been in bed for 2 days now freaking out. Doctor called and told me to stop taking it but wouldn't prescribe anything else so now I screwed because that means I'm antibiotic-resistant. I wish I didn't start this. I'm with kaiser and the doctor didn't even see me just prescribed it. I've taken it in the past no problem but it doesn't seem to be the same medication anymore.


1 Stars

Posted 4 months ago (6/27/2021)1

Rated for Sinusitis Report

I wouldn’t give this to my worst enemy. After day one, I had really bad anxiety that lasted for 3 days until I convinced my doctor I couldn’t take it. I went to the ER 3 times because my pulse and BP would get really high, causing me to feel dizzy. I couldn’t eat anything after taking my pill in the morning, and had to force myself to eat before taking the pill. Nothing helped with the join pain I was feeling in all my joints, not even medical marijuana. This stuff needs to be outlawed because I’m still having stomach issues.


1 Stars

Posted 4 months ago (6/27/2021)1

Rated for Chlamydophila Pneumoniae Report

I took this medicine back in may it’s June now I still feel the same it won’t go away I feel swelling in my stomach it feel like pressure all the time I feel nauseous all the time especially in the morning I have different poops all the time sometimes I have normal one or it’s diarrhea I feel like I have lost of air and can’t breathe my stomach switches and I have no clue why besides the medicine messed me up I am a 16 year old and I don’t think anyone should go threw this I just want to know when this will stop I feel anxious anxiety and nervousness all the time I have had like 100 mental breakdowns I do not recommend and you should look for other medicines that you can use besides this !!!!!


1 Stars

Posted 4 months ago (6/16/2021)1

Rated for Sinusitis Report

The worst antibiotic ever!!!! I was prescribed a week with the first day having 2 pills. Then one for each of the other days. Within an hour my face felt like it was on fire. The worst pain I have ever experienced. I've had 2 kids... it felt like I was getting labotomies and having someone gouge my ear drums out all at the same time. Nothing otc touched the pain. So the next day I split the pill in half. Figured it would be less so it would be as harsh. WRONG. Complete cranial pain and swelling. I called my Dr told him he said that is just it working to continue the treatment. So... I crushed it up and could taste the tiniest amount throughout the day. Now 2 months later I still have nerve pain in my face and no one can explain why. UM HI ITS THE ZPACK. But.... no one has listened yet. Stay far from this. I still can't take some otc meds now when I have had no problems in the past. Ruined everything. Idk how this drug is legal...


5 Stars

Posted 5 months ago (5/23/2021)5

Rated for Chlamydial Infection Prophylaxis Report

The meds work and they work fast as far as symptoms of std. but the day you take it your stomach is on fire I’m having cramps so bad It feels like when I was in labor. Straight pooping water and every few mins I’m having pains so bad I stop breathing. If I had known it would be this bad I wouldn’t take it first thing in the morning knowing I have kids to tend to omfg only take if you can lay in bed all day. Also I ate before hand had a cheeseburger and frys so light and greasy thinking it would help ugh


1 Stars

Posted 5 months ago (5/20/2021)1

Rated for Chlamydial Infection Prophylaxis Report

Within an hour of taking this my Stomach pains were out of this world!! I took 2 (500mg) in one dosage! I'm 30 weeks pregnant & I called labor and delivery because pain was unbearable in my stomach! They told me it was just side effects and they couldn't do much! Nothing eases the pain! Worked very well in curing my situation but in the most painful way! Never wanna have to take this again!


1 Stars

Posted 5 months ago (5/18/2021)1

Rated for Legionella Pneumonia Report

I started taking thus drug for pneumonia 4 days ago its a horrible horrible drug J think it gets the job done but you pay a price for it! I Felt like my chest was blowing up or my lungs were blowing up inside my chest,along with heart palpitations,swollen glands, and just feeling sick but I finished the 4 day treatment because I sure as heck wanted the pneumonia gone.but dam the Xithromax truly sucks!!!!!.


1 Stars

Posted 5 months ago (5/18/2021)1

Rated for Pneumonia Report

Taking the first 2 pills had a pounding heart and severe sweating. The doctor wanted me to finish it. Completed medication for 5 days. After 5 days I noticed a racing heart even when resting it was 130 to 140 bpm. Went to ER. They took several tests, ex-ray, ultrasound, they said the heart was normal and it was beating fast due to an infection and I was hospitalized for a week. No reaction to treatment. They discharged me. I still have a fast heart rate of 130 bpm after 2 weeks from this med. Please do not take this. I also took this along with amoxicillin. I'm not sure if this is a combined side effect.


1 Stars

Posted 5 months ago (5/9/2021)1

Rated for Dental Infection Report

So I took this to prevent a dental infection after my wisdom teeth were removed . I took this before last year and I didn’t have any side effects at all! so I figured this one is okay but oh my goodness. BOY was I wrong. the first pill I took nauseous , got sweaty , I want to say palpitations??? I went to the er because I also had wisdom teeth pain and this mixed together wasn’t good for my system so I told the doc I’ve taken this before so I’m not sure what what’s happening but he said if I vomited or diarrhea I said no so he said to still take It I will never take this again , The next couple of days stomach cramping pain . and head aches . I just want this out my system .


1 Stars

Posted 5 months ago (5/4/2021)1

Rated for Bacterial Endocarditis Prophylaxis Report

I've taken and tolerated this drug in the past, but this time was different. I took the first two pills the day before yesterday (250 mg). An hour later, I started having nausea and dizziness. I took the third pill yesterday, and it got even worse. Today I woke up with chest pain, no appetite, heart palpations, severe headache, shakiness, dizziness, and anything I eat makes me instantly nauseated. I almost had my husband take me to the ER since I was convinced I was having a heart attack. I decided to stop taking it at this point because I need this out of my body as soon as possible! These side effects are much worse than the sinus infection I am being treated for.


1 Stars

Posted 5 months ago (5/3/2021)1

Rated for Bacterial Endocarditis Prophylaxis Report

I took four pills at once each at 250mg to treat an std. The drug was effective and worked but I will never take this again and definitely do NOT recommend. After 2 hours of having it in my system , I was extremely nauseous and feel like I couldn’t even look straight. I also got very sweaty and then I had diarrhea that was basically water. I felt like I was about to throw up for 5 hours straight and had extreme stomach cramping. I sat by the toilet and hope that I could just throw up already so that I could feel better, instead I passed out next to the toilet and woke up an hour later feeling a bit better. I tried a bath but it didn’t help the stomach pain. Will not ever be taking this again.


5 Stars

Posted 6 months ago (4/19/2021)5

Rated for Sinusitis Report

I was prescribed 250mg, 6 pills. I took 2 on day 1 and 1 a day for next 4 days. I started feeling better, from the sinus infection with in 2 days. I literally thought I was going to die from the pain in my face. I did have side effects though. I have felt nauseated since the first pill. That is how I found this site. Trying to find out how long after final dose does the nausea go away. I hate it. I have also had a migraine every single day. Even with these side effects though, I would do it all over again if I was in pain like I was prior to this medication. I just want to feel better, completely better. I hate being sick. I have 3 daughters and a husband, a house to clean and laundry to do. I know you all understand what I mean, too much to do to be feeling like this. It's going on 2 weeks between the infection and the side effects.


1 Stars

Posted 6 months ago (4/11/2021)1

Rated for Bacterial Endocarditis Prophylaxis Report

Terrible I would recommend complete abstinence makes you so sick


3 Stars

Posted 6 months ago (4/2/2021)3

Rated for Chlamydial Infection Prophylaxis Report

After I took it I was fine but until an hour went by & I got in my bed everything went downhill... my anxiety raised up & then I started to feel hella nauseous to the point where I was sitting on the floor in my bathroom by my toilet waiting for it to come out, but it didn’t! After another hour went by , that’s when it subsided & I was able to get back in bed to go to sleep!


1 Stars

Posted 6 months ago (4/1/2021)1

Rated for Chlamydial Infection Prophylaxis Report

Ok I think my doctor is trying to kill me because they made me take 8 (yes I said 8) of the 250 MG. Which is 2000 at once. Immediately my stomach hurts so bad and I have bad diarrhea. Haven’t thrown up yet, and I ate a small meal before taking it, but Jesus I’ll neverrrrrr do this again.


3 Stars

Posted 7 months ago (3/30/2021)3

Rated for Chlamydial Infection Prophylaxis Report

I took 2 tablets of 1000mg after I ate dinner. I wish I had something a little lighter and filled with carbs. About an hour or two after taking it I had extreme pain in my stomach with diarrhea. I felt like I was going to throw up. I walked around instead of lying down and drank mint tea (suppose to help with stomach aches) I then laid down and put a heating pad on my stomach and passed out. I was a little queasy the next day, but was fine. The pain lasted around 30 minutes or so.


1 Stars

Posted 7 months ago (3/24/2021)1

Rated for Bacterial Endocarditis Prophylaxis Report

Omg this is a nightmare!!! STOMACH IS KILLING ME!!! I’m super nauseas. Before taking drug I ate really well. In bed wishing I never took this. This pill should not be allowed to be prescribed! Dentist prescribed with knowing I also have anxiety. Terrible. I’m not gonna get any sleep tonight and terrified to take this again


5 Stars

Posted 7 months ago (3/24/2021)5

Rated for Gonococcal Infection -- Uncomplicated Report

A fast smooth acting drug that gets results after taking 1G that is 2 tablets 500mg.


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What to know about azithromycin

Azithromycin (Zithromax) is an antibiotic that can help treat certain bacterial infections. It is generally safe to use while breastfeeding, but people with existing heart conditions should avoid this drug.

Azithromycin is an antibiotic in the macrolides class. The Food and Drug Administration (FDA) first approved azithromycin in 1991.

Like all antibiotics, azithromycin can only fight certain bacteria. For this reason, it is important to talk to a doctor before taking the drug. It is not effective against viral infections or as a pain reliever.

This article provides an overview of azithromycin, including its uses, side effects, warnings, and drug interactions.

What does azithromycin treat?

Azithromycin can fight a wide range of bacteria, including many in the Streptococcus family. It can stop harmful bacteria from growing.

Healthcare providers tend to use this drug to treat mild-to-moderate infections of the lungs, sinuses, skin, and other body parts.

A doctor may prescribe azithromycin to treat the following bacterial infections:

  • sinus infections related to Moraxella catarrhalis or Streptococcus pneumoniae
  • community-acquired pneumonia related to Chlamydia pneumoniae, Haemophilus influenzae, or S. pneumoniae
  • chronic obstructive pulmonary disease (COPD) complications related to M. catarrhalis or S. pneumoniae
  • some skin infections related to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae
  • tonsillitis related to S. pyogenes
  • urethritis and cervicitis related to Chlamydia trachomatis
  • chancroid genital ulcers (in males) related to Haemophilus ducreyi
  • certain ear infections in children aged 6 months and over, such as those related to M. catarrhalis

How to take it

Azithromycin is a prescription medication. Therefore, people should not take it without a prescription.

The drug is available in the form of a tablet, an oral suspension solution, an eye drop, and an injection. The best type and dosage depends on the infection a person has.

People can take the drug with or without food. They should thoroughly shake the liquid form before use.

Some examples of common dosages include:

community-acquired pneumonia
skin infections
an initial dose of 500 milligrams (mg) followed by 250 mg once daily until day 5
mild-to-moderate bacterial COPD exacerbations500 mg per day for 3 days
an initial dose of 500 mg followed by 250 mg once daily until day 5
sinus infections500 mg per day for 3 days
chancroid genital ulcersa single dose of 1 gram (g)
a single dose of 1 g
gonococcal urethritis
a single dose of 2 g

Using antibiotics incorrectly to the development of drug-resistant strains of bacteria, meaning that antibiotics no longer work against them. This is called antibiotic resistance.

When taking azithromycin or any other antibiotic, people should heed the following precautions:

  • Take the entire course of antibiotics the doctor recommends, even when starting to feel better.
  • Do not take antibiotics without a prescription. Not all antibiotics can treat all bacteria.
  • Do not share antibiotics.
  • Do not take antibiotics on a different dosing schedule than the one a doctor prescribes.
  • Immediately call a doctor if side effects develop.
  • Go to the emergency room for symptoms of an allergic reaction, such as trouble breathing.

Learn more about antibiotic resistance here.

What are the side effects?

Like all drugs, azithromycin can have certain side effects. These are usually minor. In clinical trials, only 0.7% of people stopped taking Zithromax because of its side effects.

Most of the side effects that led people to stop taking the drug were gastrointestinal, such as:

  • nausea
  • vomiting
  • diarrhea
  • pain in the abdomen

Less common side effects, occurring in up to 1% of cases, include:

Serious side effects are rare but can include:

  • liver damage, especially in people with a history of liver health problems
  • heart rhythm changes, which are more likely in people who take heart rhythm medications, older people, and those with low blood potassium
  • serious allergic reactions


People who have myasthenia gravis, a condition that causes muscle weakness, may develop worsening symptoms or breathing problems.

People with a history of allergic reactions to macrolides or ketolides should not take azithromycin.

Doctors should not prescribe this drug to treat pneumonia if a person:

  • has cystic fibrosis
  • has a hospital-acquired infection
  • has bacteremia
  • requires a stay in the hospital
  • is older or debilitated
  • has a significant underlying health problem, such as immune system problems

People should not rely on azithromycin to treat syphilis.

A person should speak to a doctor about any existing heart, kidney, and liver conditions before taking azithromycin, including an irregular heartbeat and especially QT prolongation.

What does the research say?

A large 2012 cohort study found a small increase in the risk of cardiovascular death among people taking azithromycin. The risk was higher among those with other risk factors for heart disease, such as smoking, low physical activity levels, and a high body mass index (BMI).

The study reported that when compared with amoxicillin, there were 47 additional cardiovascular deaths per 1 million azithromycin prescriptions. Among people with the highest risk of heart disease, there were 245 more deaths per 1 million courses of azithromycin.

This suggests that other antibiotics, such as amoxicillin, may be a safer option for people with heart disease or certain types of heart arrythmias.

, the FDA issued a warning about the long term use of azithromycin in people with certain blood or lymph node cancers who have stem cell transplants. Emerging research has suggested that azithromycin may increase the risk of cancer relapse in these people.

Following a stem cell transplant, some people take azithromycin to reduce the risk of an inflammatory lung condition called bronchiolitis obliterans syndrome. The FDA have not approved azithromycin for this use, however.

Rarely, azithromycin can cause liver toxicity. People should stop taking the drug and call their doctor if they develop any symptoms of liver problems, including dark urine, itching, or yellow eyes.

In newborns younger than 42 days old, azithromycin may cause a dangerous condition called infantile hypertrophic pyloric stenosis. Caregivers should contact a doctor if a baby becomes irritable or vomits when eating.

Drug interactions

Azithromycin may interact with other medications a person is taking.

For example, using azithromycin while taking nelfinavir, which is a drug that helps treat HIV, can increase the risk of liver abnormalities and hearing problems.

Azithromycin can also increase the effects of blood thinners such as warfarin.

Other drugs that may interact with azithromycin include:

  • digoxin, a heart medication
  • colchicine, a gout medication
  • phenytoin, a seizure medication
  • antacids that contain magnesium or aluminum

A person should tell a doctor about all current medications, supplements, and remedies before taking azithromycin. Always speak to a doctor before stopping taking medications.

Pregnancy and breastfeeding

Azithromycin may be safe to use during pregnancy and while breastfeeding.

Studies of animals who received very large doses of azithromycin did not find an increased risk of miscarriage or birth defects.

However, there have been no high quality studies in pregnant humans, so the drug label currently states that “azithromycin should be used during pregnancy only if clearly needed.”

Azithromycin can transfer into breast milk and may remain present for 48 hours following a person’s last dose. Although it is generally safe to use when breastfeeding, azithromycin may cause diarrhea, vomiting, or a rash in some babies.

A person should tell a doctor if they are pregnant, might be pregnant, or are breastfeeding before taking azithromycin. If a nursing infant develops side effects while the parent is taking azithromycin, call a doctor for advice.


The brand name version of azithromycin (Zithromax) is typically more expensive than the generic version.

However, the price may vary depending on the pharmacy, a person’s insurance coverage and deductibles, and their geographic location.

Azithromycin vs. other antibiotics

Azithromycin treats many of the same infections that drugs such as penicillin and amoxicillin can treat.

A doctor may prescribe azithromycin as an alternative to other antibiotics because it typically requires a shorter course. It is also a good option for people with a history of allergies to other medications, or when other antibiotics do not work.

Because the risk of heart health problems is higher with azithromycin than with some other antibiotics, people with heart disease or arrhythmias should ask their doctor about trying a different antibiotic.


Azithromycin is an antibiotic that can treat many types of bacterial infection. It can also prevent these infections from getting worse or spreading.

Like all antibiotics, it presents some risks, so it is important to only take it under the guidance of a medical professional.


On and began to pull off the dress from Vera, the girl stopped sucking, and getting up from her knees obediently threw off the dress, remaining completely naked, the girl lay on the floor and spread her legs and beckoned the man with her finger. Nikolai Petrovich went down to the floor and stood between Vera's legs, she took his penis and directed it into her pussy, the man slowly began to.

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Have already touched so closely that you can feel how my penis pressed tightly against your bosom. I plunge my hand deep into the water and look for it, find your most delicate petals and slowly smooth them with my fingers. They are also wet, but not from water.

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