- Brendan J McMullan, Mona Mostaghim
- Aust Prescr 2015;38:87-9
- 1 June 2015
- DOI: 10.18773/austprescr.2015.030
Azithromycin is a broad-spectrum macrolide antibiotic with a long half-life and excellent tissue penetration.
It is primarily used for the treatment of respiratory, enteric and genitourinary infections and may be used in preference to other macrolides for some sexually transmitted and enteric infections.
Azithromycin has additional immunomodulatory effects and has been used in chronic respiratory inflammatory diseases for this purpose.
Potential major adverse effects include cardiovascular arrhythmias and hearing loss. Macrolide resistance is also a problem, as are interactions with commonly prescribed drugs.
Azithromycin is a broad-spectrum macrolide antibiotic with bacteriostatic activity against many Gram-positive and Gram-negative bacteria including Bordetella pertussis and Legionella species. It also has activity against Mycoplasma pneumoniae, Treponema pallidum, Chlamydia species and Mycobacterium avium complex.1
Since the late 1990s, macrolide-resistant Streptococcus pneumoniae and Staphylococcus aureus infections have been increasing in Australia. Over 10% of S. pneumoniae infections and over 15% of S. aureus infections have been reported to be resistant to azithromycin.2,3 Haemophilus influenzae is commonly susceptible to macrolides but resistance rates of 3–15% have been reported in Aboriginal and Torres Strait Islander children.4
Azithromycin reversibly binds to the bacterial ribosome and inhibits protein synthesis.5,6 The drug has an absolute oral bioavailability of 35−42% in healthy volunteers and people with cystic fibrosis7,8 and a long half-life due to extensive uptake in tissue, particularly lung, tonsil and prostate. Tissue concentrations exceed the minimum inhibitory concentration that would inhibit 90% of likely pathogens (MIC90) after a single 500 mg oral dose. Mean concentrations in tissue are 10–100-fold higher than those reached in serum and persist for several days.1 Azithromycin also accumulates in phagocytes, with levels up to 200 times greater than in serum,1 but penetrates poorly into cerebrospinal fluid and peritoneal fluid.
Azithromycin is generally administered orally, but an intravenous formulation exists for patients unable to tolerate oral medications. Duration of treatment varies with indication and severity. Usually a single dose is recommended in some sexually transmitted infections. Several days of treatment is generally appropriate in respiratory tract infections and many months in mycobacterial infections. Guidelines should be consulted for detailed recommendations.9
Unlike clarithromycin, azithromycin does not interact significantly with cytochrome P450 3A4.1 In comparison with erythromycin, it is more acid stable, which simplifies administration around food.
Azithromycin is a pregnancy category B1 drug and is considered safe to use in pregnancy and breastfeeding. However, it may cause diarrhoea in breastfeeding infants.9,10
In Australia, azithromycin is subsidised by the Pharmaceutical Benefits Scheme (PBS) for a number of indications (see Table). It is also recommended for other infections by guidelines, but not specifically approved by the Therapeutic Goods Administration. Infections that may be treated with azithromycin include:
Other recommended uses of azithromycin include treatment of severe infection or persistent lymphadenopathy due to Bartonella henselae (cat-scratch disease), and some tick-borne infections such as Australian tick typhus or scrub typhus. It is also used as part of combination therapy for M. avium complex infections.9
In addition to their antimicrobial properties, there are in vitro and animal data on the immunomodulatory or anti-inflammatory effects of macrolides.1 Effects in humans were initially reported in the treatment of diffuse panbronchiolitis, in which macrolides are associated with improved lung function and prognosis based largely on non-controlled trial data and retrospective studies.1 In cystic fibrosis, treatment for six months is associated with improved respiratory function and reduced respiratory exacerbations.11 Azithromycin produced a small increase in lung function (mean 8.8%) at seven months in patients treated for bronchiolitis obliterans syndrome after lung transplant,12 but was no different compared to placebo for bronchiolitis obliterans syndrome after haematopoetic stem cell transplant.13
Azithromycin and other macrolides have also been proposed for use in sepsis and epidemic respiratory viral infections to prevent cytokine storm.1 It has been used for various respiratory and non-respiratory inflammatory conditions. However, this use has been controversial due to limited direct clinical evidence for many conditions, and concerns about increased antimicrobial resistance.1,14 New non-antibiotic macrolides may provide immunomodulatory benefits without contributing to antimicrobial resistance.14
In non-cystic fibrosis bronchiectasis, three randomised, double-blind, placebo-controlled trials found that azithromycin reduced the number of exacerbations. In adults with bronchiectasis on CT scanning and at least one pulmonary exacerbation treated with antibiotics in the past year, the EMBRACE trial found a reduction in the rate of exacerbations (0.59 vs 1.57) with azithromycin three times weekly for six months compared to placebo.15 The BAT trial found a reduced number of exacerbations (median 0 vs 2) in adults with radiologically confirmed bronchiectasis and at least three respiratory infections treated with antibiotics in the past year (daily azithromycin therapy over 12 months).16 Finally, the Bronchiectasis Intervention Study investigated Australian and New Zealand indigenous children with non-cystic fibrosis bronchiectasis or chronic suppurative lung disease who had had at least one pulmonary exacerbation in the past 12 months. After once-weekly azithromycin for up to 24 months, the incidence of pulmonary exacerbations was half that observed in those given placebo. However, the authors noted a greater incidence of macrolide-resistant bacteria in children treated with azithromycin (46% vs 11%).17
Trials in children and adults with asthma and chronic obstructive pulmonary disease (COPD) have been small with heterogeneous outcomes, and the optimal regimens and subgroups are not yet established. Patients with neutrophilic asthma may benefit from macrolides, but further research is needed.18
A randomised controlled trial of daily azithromycin in patients with variable COPD severity, smoking status and medical management found that azithromycin prolonged time to exacerbation compared to placebo – median 266 days (95% CI* 227–313) versus 174 days (95% CI 143–215) (p<0.001). The rate of exacerbations was 1.48 per patient-year in the azithromycin group, compared with 1.83 in the placebo group (p=0.01). However, there was only a 7% increase in the proportion of people reporting clinically important improvements in quality of life with azithromycin as compared with placebo (43% vs 36%, p=0.03). Patients in the azithromycin arm experienced hearing decrements more frequently (25% vs 20%, p=0.04) and were more likely to be colonised with macrolide-resistant organisms (81% vs 41%, p<0.001). People with a prolonged QT interval were excluded from this study.19
Azithromycin is generally well tolerated, but relatively common adverse effects (1–5% of patients) include gastrointestinal upset, headache and dizziness. Transient increases in transaminases have also been reported in 1.5% of patients.5
Hearing loss or impairment has also been reported with azithromycin, including in patients with COPD and normal hearing at baseline, and appeared to be irreversible in some patients.19,20 Case reports of hearing loss after short-term use have also been published.21
Serious adverse effects include QT prolongation and torsades de pointes resulting in death. The US Food and Drug Administration issued a warning in 2012 to consider the risk of fatal heart rhythms in those:
This advice was primarily based on a large retrospective cohort study that suggested an increase in cardiovascular deaths, and death from any cause, in people treated with a five-day course of azithromycin compared to amoxycillin, ciprofloxacin, or no drug.22
At an individual and a population level, macrolides have been associated with antibiotic resistance in Streptococcus pneumoniae and S. pyogenes, Staphylococcus aureus, Haemophilus species and other organisms.1,14 Patients with chronic lung diseases treated with long-term azithromycin had a 2.7-fold increased risk of macrolide-resistant bacteria, according to a recent meta-analysis.20 This has potential adverse clinical consequences for the individual and the community.
Azithromycin has a number of clinically relevant drug interactions (see Box).23-29 Due to its long half-life, interactions may continue for several days after it has been stopped.10
While there is no clear advantage of azithromycin over other macrolides for most respiratory infections, its pharmacokinetic properties make it useful for treatment of sexually transmitted infections (e.g. single-dose azithromycin for urethritis with Chlamydia trachomatis).9 In addition, its high intracellular concentrations and high potency in vitro are proffered as reasons for use against enteric pathogens such as Salmonella species (which are intrinsically resistant to erythromycin due to active efflux). Azithromycin’s once-daily dosing for the prevention and treatment of M. avium complex and its lack of interactions via cytochrome P450 may make it preferable to clarithromycin in some circumstances.
Azithromycin’s pharmacokinetics and tolerability make it particularly useful in the treatment of sexually transmitted infections, intracellular enteric pathogens and for prophylaxis of mycobacterial disease. It is also useful for treating a range of respiratory diseases. Unfettered use of azithromycin, particularly for its immunomodulatory properties, is of concern in light of macrolide resistance. Novel non-antibiotic macrolides may be used for this role in future.
* CI confidence interval
Conflict of interest: none declared
Staff specialist, Infectious diseases, Sydney Children's Hospital
Antimicrobial stewardship and quality use of medicines pharmacist, Sydney Children's Hospital