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Safety and tolerability of azithromycin in pediatric infectious diseases: 2003 update


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The Pediatric Infectious Disease Journal: February 2004 - Volume 23 - Issue 2 - p S135-S139
doi: 10.1097/01.inf.0000112528.75956.41
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Azithromycin is derived from the macrolide erythromycin and differs from its progenitor by a methyl-substituted nitrogen and an additional carbon atom in the macrolide ring. Compared with erythromycin, azithromycin has improved pharmacokinetic properties, which permit once daily dosing, and improved antimicrobial potency covering all major bacterial pathogens causing respiratory tract infections. Azithromycin has been used in pediatric patients since April 1991. 1 The most common indications have been lower respiratory tract infections, acute otitis media (AOM), streptococcal tonsillopharyngitis and skin and soft tissue infections. 2

The tolerability of azithromycin has been reported in many studies, some of which will be summarized in this review. It is well-established that the 5-and 3-day treatments are well-tolerated, with most adverse events being mild to moderate in severity and gastrointestinal. 3,4 This report provides an update to previously published data, including tolerance data of single dose, high dose, long term and intravenous treatment regimens.


In 1996 Treadway and Pontani 3 analyzed safety data obtained from 43 open label, randomized, comparative pediatric trials conducted in Europe, South Africa, Africa and Asia. A total of 2655 children were treated with azithromycin (10 mg/kg once daily for 3 days). A comparison group contained 1844 children treated with various other antibiotics. The children’s ages ranged from 6 months to 16 years. Most children were treated for upper respiratory tract infections. In the azithromycin group 8.7% of the children experienced adverse effects, compared with 9.8% in the comparator group (Table 1). A second analysis was conducted by Treadway and Reisman 4 in 2001 assessing data from 16 clinical studies. The 3-day azithromycin treatment group consisted of 1213 children, and the comparator group consisted of 1212 children. The occurrence of adverse events was 7.9 and 11.5%, respectively. In each analysis the comparator groups included children who were treated with amoxicillin, amoxicillin/clavulanic acid, cefaclor, clarithromycin, cloxacillin, penicillin V or erythromycin (n >100/group). Placebo-controlled studies are not ethically possible in the treatment of acute bacterial infections, and a proportion of the reported adverse events can be caused by the bacterial/viral infections.

Incidence of adverse events associated with azithromycin (10 mg/kg once daily for 3 days) suspension treatment 2,3

Azithromycin most commonly causes gastrointestinal adverse effects (in 3 to 27% of patients). 5 Abdominal pain, diarrhea, nausea or vomiting occur in 1 to 2% of the children treated with azithromycin. 4 Azithromycin treatment-associated gastrointestinal adverse events are significantly shorter in duration than gastrointestinal adverse events caused by comparator antibiotics (mean, 2.3 and 5.0 days, respectively; P = 0.0001). 4 Allergic reactions caused by azithromycin are rare. According to our clinical experience, most urticarial reactions associated with azithromycin treatment are due to underlying infection and cannot be induced by reexposure to azithromycin. Case reports of hepatotoxicity, ototoxicity and miscellaneous adverse effects have been reported, but with the lack of placebo-controlled studies the real causal relationship has been difficult to evaluate. 5 As is seen with other macrolides, intravenous administration of azithromycin can induce abdominal cramping and nausea; temporary tinnitus has also been reported in adult clinical trials. 6 In a trial of 32 pediatric patients 6 months to <16 years of age who received a single dose of intravenous azithromycin (10 mg/kg; maximum dose, 500 mg), all adverse events were mild to moderate in severity. The most common adverse event was nausea, reported in 8 of 32 (25%) subjects; however, none of the patients with nausea vomited. 7

The tolerability and safety of azithromycin have been compared with those of other antibiotics in several studies. 8–10 Among 4870 patients receiving azithromycin, the discontinuation rate was 0.8% compared with 2.3% for amoxicillin/clavulanic acid, 1.9% for erythromycin, 1.3% for cefaclor, 1% for clarithromycin and 0.6% for amoxicillin or penicillin. 8 In general the occurrence of adverse events associated with azithromycin treatment of 5 to 20% is equivalent to erythromycin and other antibiotics (Table 2). However, azithromycin induces more adverse effects than penicillin V 5,9 but less adverse effects than amoxicillin/clavulanic acid (which induces more gastrointestinal complaints). 5,10 All studies have compared a 10-day amoxicillin/clavulanic acid treatment regimen to azithromycin treatment, yet in Scandinavia the guidelines for AOM recommend only a 5-day amoxicillin/clavulanic acid treatment regimen. Interestingly treatment with erythromycin has been occasionally associated with the development of infantile hypertrophic pyloric stenosis, but no cases have been observed with azithromycin. 11 In contrast a retrospective cohort study of >260000 mother-infant pairs in Tennessee between 1985 and 1997 showed an association between nonerythromycin macrolide use at any time during pregnancy and infantile hypertrophic pyloric stenosis (adjusted odds ratio, 2.77; 95% confidence interval, 1.22, 6.30; P = 0.01). 12

Comparison of adverse events associated with azithromycin (10 mg/kg once daily for 3 days) suspension and other antibiotics 2,3

Prolongation of the Q-T interval is a rare cardiac adverse event that has been reported after erythromycin and clarithromycin treatment and which can lead to ventricular arrhythmia such as torsades des pointes. In a prospective study including 47 healthy subjects, azithromycin treatment (3 g total dose given during 5 days) resulted in a small, nonsignificant prolongation of heart rate corrected Q-T interval. Importantly corrected Q-T intervals greater than the upper normal value of 440 ms were found in the same proportion of patients before and after azithromycin treatment, and no patients developed significant arrhythmias. 13


The most common clinical indication for azithromycin use is AOM, which is typically caused by Streptococcus pneumoniae, nontypable Haemophilus influenzae and Moraxella catarrhalis. Principi and Esposito 5 reviewed seven studies in which azithromycin treatment of AOM was compared with amoxicillin/clavulanic acid (five studies), amoxicillin (one study) or cefaclor (one study) regimens. The occurrence of treatment-associated adverse effects varied from 3 to 12% in the azithromycin study groups. In all comparative studies with amoxicillin/clavulanic acid, significantly fewer adverse reactions were recorded in azithromycin treatment groups. In the treatment of AOM, azithromycin appears to have a safety profile comparable with those of amoxicillin and cefaclor. Recent studies have shown that a single dose (30 mg/kg) of azithromycin is effective in the treatment of AOM. 14,15 The adverse events associated with azithromycin treatment with different durations of treatment are shown in Table 3. Single dose treatment induces more adverse events than 3-day and 5-day treatments but is still well-tolerated. In a trial of single dose azithromycin vs. amoxicillin/clavulanate (45 mg/kg/day given twice a day for 10 days), nearly all cases of vomiting in the azithromycin group occurred on the first day, whereas vomiting with amoxicillin/clavulanate occurred during 9 days. 14 In addition the 12.7% rate of drug-related diarrhea in the amoxicillin/clavulanate group, which is similar to rates reported for amoxicillin/clavulanate in other studies, 16 was twice that of azithromycin.

Azithromycin (total dose, 30 mg/kg) associated adverse events according to duration of treatment*

Group A beta-hemolytic Streptococcus-induced tonsillopharyngitis is a common infection in children. Penicillin V is the drug of choice for treatment of streptococcal tonsillitis, but azithromycin is a practical alternative in many countries. It is well-known that azithromycin (10 mg/kg for 3 days) is clinically effective and well-tolerated, although it can be associated with more treatment-related adverse effects than penicillin V. 5,9 In addition azithromycin 10 mg/kg for 3 days has been less effective in eradicating group A beta-hemolytic Streptococcus. 17,18 A recent study showed that a 3-day azithromycin 20-mg/kg/day regimen was more effective than 10 mg/kg/day. 9 Importantly the treatment-related adverse events were similar in both treatment groups but higher than in the penicillin V group (Fig. 1). 9

Fig. 1:
Adverse effects of standard and high dose azithromycin treatment of pharyngitis. d, day. Data adapted from Cohen et al. 9 and data on file, Pfizer Global Pharmaceuticals, Pfizer Inc.

Azithromycin (20 mg/kg/day once daily for 3 days) has also been used in the treatment of recurrent or persistent AOM. Azithromycin was compared with high dose amoxicillin/clavulanate (90 mg/kg given in two divided doses for 10 days); the most common adverse event was diarrhea, which occurred in 30 of 153 (19.6%) children in the azithromycin arm compared with 44 of 147 (29.9%) in the amoxicillin/clavulanate arm (P = 0.045). 19

The antibacterial spectrum of azithromycin encompasses the most common causative bacterial agents of acute lower respiratory tract infections. 2 Harris et al. 20 showed that a 5-day azithromycin regimen was effective in the treatment of community-acquired pneumonia. Adverse events were recorded in 35 of 310 (11%) children in the azithromycin group compared with 46 of 146 (31%) children in the comparator (erythromycin estolate or amoxicillin/clavulanate) group. A recent double blind, double dummy study by Ferwerda et al. 10 found azithromycin treatment-related adverse events in 19% of children (n = 56) with lower respiratory tract infection compared with 43% (n = 54) in an amoxicillin/clavulanate group. Both studies concluded that azithromycin is a safe and well-tolerated drug in the treatment of lower respiratory tract infections in children.


Forty-one children with cystic fibrosis, ages 8 to 18 years, received either azithromycin (body weight 40 kg, 250 mg daily; body weight >40 kg, 500 mg daily) or placebo for 6 months. 21 Side effects were assessed by audiometry and liver enzymes before, during and on completion of treatment. No side effects were recorded, and the drug was well-tolerated. Using pure tone audiometry, minor changes were found in 12 of 190 (6%) children; in all cases retesting results were normal after 2 months. One child had increased liver enzymes values, which were normalized within 2 months. The mean forced expiratory volume in 1 s was consistently greater in the azithromycin group, and authors state that azithromycin is justified in children with cystic fibrosis, who do not respond to conventional treatment. In a recent randomized, double blind, placebo-controlled trial, 87 patients with cystic fibrosis and Pseudomonas aeruginosa infection were treated with oral azithromycin 3 days a week for 168 days. 22 Nausea occurred in 17% more participants in the azithromycin group, diarrhea in 15% more and wheezing in 13% more than in the placebo group. Azithromycin treatment was associated with a significant increase in forced expiratory volume in 1 s compared with placebo (P = 0.009). Daily azithromycin (250 mg/day) as prophylaxis against malaria in adults was well-tolerated during 20 weeks, but azithromycin recipients complained more frequently of heartburn, paresthesia and itching than the comparator doxycycline prophylaxis group. No evidence of hearing loss or hematologic, hepatic or renal toxicity was found. 23 These findings suggest that daily long term azithromycin treatment is well-tolerated.


Erythromycin and to a certain extent clarithromycin interact with several other drugs including theophylline, cyclosporin, carbamazepine, phenytoin, warfarin and terfenadine. Most interactions are the result of inhibition of drug metabolism via cytochrome P450 microsomal enzymes. There is no evidence that azithromycin inhibits this enzyme system, and no significant interactions with other drugs have been found. 24 Monitoring of serum cyclosporin concentration during azithromycin treatment has been recommended. 5 In addition azithromycin can interact with antacids, which may decrease serum azithromycin concentrations. 25 The clinical significance of this finding is not clear.


The palatability of antibiotic suspensions is crucial for compliance in young children. The color, flavor and taste of azithromycin have been found to be acceptable. In one study children preferred the taste of azithromycin to that of cefprozil, cefpodoxime and clarithromycin. Loracarbef and cefixime were considered better tasting than azithromycin. 26


The safety and tolerability of 3- and 5-day azithromycin regimens in children are well-established. The unique pharmacokinetics and pharmacodynamics of azithromycin support single dose (30 mg/kg) regimens that are clinically effective and offer improved patient compliance. Single dose azithromycin is associated with slightly increased rates of adverse events but is still very well-tolerated. High dose azithromycin (20 mg/kg/day once daily for 3 days) has an adverse event profile that is equivalent to the standard 3-day azithromycin regimen (10 mg/kg/day once daily for 3 days) and caused significantly fewer cases of diarrhea compared with high dose amoxicillin/clavulanate (P = 0.045).


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Azithromycin; pediatric; children, safety, tolerability

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