July 01, 2014
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The role of azithromycin in pediatrics

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The azalide antibiotic azithromycin, a subclass of the macrolide antibiotics, is commonly used in the pediatric population and is described as one of the most frequently prescribed oral antibiotics — within the top three antibiotics — in pediatrics in recent studies and rankings.

Why is azithromycin so often prescribed? Its popularity is likely due to its simple daily dosing schedule of 1, 3 or 5 days for common ambulatory infections; its relatively pleasant liquid taste; and its safety profile. Azithromycin is available generically as several different oral, liquid and tablet dosage forms. Other than these practical benefits, however, what are the pharmacologic and clinical advantages (and disadvantages) of using azithromycin, and do these characteristics justify its common use?

The FDA has labeled azithromycin for the following indications in the pediatric population: acute otitis media and community-acquired pneumonia (CAP) for children aged at least 6 months, and pharyngitis (as an alternative to first-line therapy) for children aged at least 2 years. Although these indications are labeled by the FDA, recently published clinical practice guidelines on common pediatric infectious diseases have described azithromycin as having a very limited role.

Differences in guidelines

In 2013, the AAP updated its clinical practice guideline on the diagnosis and management of AOM. Initial antibiotics of choice recommended in this guideline include amoxicillin or amoxicillin/clavulanate, as these agents have good activity toward the major bacterial pathogens — Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis — and are well tolerated.

Azithromycin and the macrolide class are not recommended for any role in this guideline, with the justification that these antibiotics have poor activity toward these bacterial pathogens. In 2011, the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America published a clinical practice guideline on the management of CAP in infants and children older than 3 months. As S. pneumoniae is the predominant bacterial pathogen in CAP, amoxicillin is the preferred antibiotic described in this guideline. Alternative antibiotics include cefpodoxime, cefuroxime or cefprozil; levofloxacin or linezolid may be used for highly non-susceptible strains (minimum inhibitory concentration ≥4 mcg/mL).

Edward A. Bell

Edward A. Bell

Azithromycin is recommended in the CAP guideline and is the preferred antibiotic, but only when the suspected pathogen is Mycoplasma pneumoniae, Chlamydia trachomatis or Chlamydophila pneumoniae (formally C. pneumoniae). CAP caused by M. pneumoniae and C. pneumoniae is more likely to occur in school-aged children/adolescents, whereas C. trachomatis is more likely to occur in infants. In older children and adolescents, atypical pneumonia is often described as slowly progressing, mild and self-limiting, although cough may persist for several weeks.

Azithromycin is not recommended in the treatment of CAP when the suspected pathogen is S. pneumoniae, as resistance to azithromycin and the macrolide class is common in many strains of this pathogen.

Azithromycin may serve a specific, limited role in the treatment of another common pediatric infectious disease — pharyngitis — when the proven cause is bacterial (group A streptococci, or Streptococcus pyogenes [GAS]). First-line antibiotics for streptococcal pharyngitis are penicillin or amoxicillin, as these antibiotics are effective, safe and have a narrow spectrum of activity.

GAS strains have never been documented to be resistant to penicillin or amoxicillin, additionally supporting their first-choice use. In a 2012 clinical practice guideline by IDSA, azithromycin is described as an alternative antibiotic for individuals with penicillin allergy. Some GAS strains, however, have been documented to be resistant to azithromycin and the macrolides.

Azithromycin is not labeled for use in the treatment of bacterial sinusitis in children. However, the package insert for azithromycin includes information describing a 3-day dosage regimen for children aged at least 6 months for the treatment of sinusitis, based upon extrapolated data from adult studies. In a 2013 AAP clinical practice guideline on the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years, azithromycin is described as having no role in the treatment of sinusitis, including penicillin-allergic individuals, as resistance by S. pneumoniae and H. influenzae to azithromycin is significant.

Thus, when considering the treatment of several bacterial infectious diseases common in the pediatric population — AOM, CAP, pharyngitis and sinusitis — recently published clinical practice guidelines describe a limited, specific role (eg, atypical pneumonia, pharyngitis in penicillin-allergic individuals) or no role (AOM, sinusitis) for azithromycin.

Azithromycin resistance

Reasoning for not recommending azithromycin use in several of the clinical practice guidelines described above includes resistance to azithromycin and the macrolide class by common pediatric respiratory pathogens, including S. pneumoniae, H. influenzae and GAS. Data to support this reasoning include published susceptibility studies and clinical studies documenting macrolide resistance and decreased therapeutic efficacy. Harrison and colleagues isolated several hundred S. pneumoniae, H. influenzae and M. catarrhalis isolates from two pediatric hospitals and tested the activity of commonly used antibiotics to these pathogens. Using pharmacokinetic/pharmacodynamic (PK/PD) breakpoints, the researchers calculated antibiotic percent-susceptibility to these antibiotics for S. pneumoniae, H. influenzae and M. catarrhalis.

For azithromycin, S. pneumoniae isolates displayed 56.7% susceptibility (compared with 89.4% susceptibility for high-dose amoxicillin); H. influenzae isolates displayed 0% susceptibility (compared with 100% susceptibility for high-dose amoxicillin/clavulanate); and M. catarrhalis isolates displayed 98.4% susceptibility (compared with 100% susceptibility for high-dose amoxicillin/clavulanate). Concern has also been raised in the medical literature on the influence of the unique pharmacokinetic profile of azithromycin to antibiotic resistance. Azithromycin displays a relatively long elimination half-life due to its uptake into intracellular compartments and polymorphonuclear neutrophils, with resultant concentrations much greater than serum. This prolonged elimination half-life and subsequent exposure to respiratory mucosa have been shown to alter the selection for resistant bacterial pathogens.

Penicillin allergy conundrum

Pediatric clinicians may traditionally use azithromycin and other macrolide antibiotics when treating common infectious diseases in children who are “penicillin allergic.” When evaluating antibiotic choice and use in these individuals, several considerations should be assessed, including the individual’s allergy history and severity, the likelihood of an immunologic, severe allergic reaction to penicillin (type I, anaphylactic), and the potential for other antibiotics (eg, beta-lactam antibiotics) to cross-react. It is also important to consider data from several published studies that have demonstrated the majority of individuals claiming a penicillin allergy do not display positive reactions to penicillin skin testing or other testing for immunologic reactivity.

Recent studies have shown that the use of cephalosporin antibiotics with differing chemical structures than penicillin or amoxicillin, such as select second- and third-generation cephalosporins (cefuroxime, cefdinir, cefpodoxime and ceftriaxone), in individuals with reliable penicillin allergy histories, is highly unlikely to result in severe allergic reactions.

Data published this year on ambulatory antibiotic use in children demonstrate interesting trends in antibiotic use overall, and in the use of specific antibiotic classes. Vaz and colleagues evaluated changes in antibiotic-dispensing rates among children aged 3 months to 18 years from three health plans in the United States during a 10-year period. Overall, antibiotic dispensing slowed or reversed between 2000-2001 and 2009-2010. Azithromycin use increased from 2000-2001 to 2009-2010 in children aged 4 to younger than 6 years, 6 to younger than 12 years, and in adolescents 12 to 18 years. Clinical diagnoses most commonly treated when azithromycin was used included AOM for children younger than 6 years, pharyngitis for children aged 6 to younger than 12 years, and pneumonia, sinusitis and pharyngitis for children 12 to younger than 18 years.

It’s important to note that azithromycin was frequently prescribed in children aged 4 to 18 years with presumed viral respiratory tract infections as well.

Conclusions

Despite several published clinical practice guidelines describing azithromycin as having a limited, specific role for some infectious diseases, or no role for other infectious diseases, azithromycin continues to be commonly prescribed. This may result from the perceived ease of use of azithromycin, including 1-, 3- and 5-day once-daily dosing regimens, and a relatively pleasant tasting liquid dosage form.

Although these characteristics are beneficial to promote treatment adherence, other important characteristics should be considered when choosing an antibiotic for a specific patient. Antimicrobial susceptibility by common bacterial pathogens and resultant clinical efficacy are clearly important. Numerous published studies have implied or demonstrated that azithromycin is less likely to be clinically effective for many of these common infectious diseases. Azithromycin can play an important role in the treatment of select common infectious diseases, such as atypical CAP in school-aged children. Azithromycin use for many common infections may please parents and caregivers when administering an antibiotic; clinical efficacy, however, may be compromised.

References:

Bradley JS. Clin Infect Dis. 2011;53:e25-e76.
Harrison CJ. J Antimicrob Chemother. 2009;63:511-519.

Liberthal AS. Pediatrics. 2013;131:e964-e999.

Shulman ST. Clin Infect Dis. 2012;55:1279-1282.

Vaz LE. Pediatrics. 2014;133:375-385.

Wald ER. Pediatrics. 2013;132:e262-e280.

For more information:

Edward A. Bell, PharmD, BCPS, is professor of pharmacy practice at Drake University College of Pharmacy and Health Sciences and Blank Children’s Hospital and Clinics, Des Moines, Iowa. He also is a member of the Infectious Diseases in Children Editorial Board. Bell can be reached at ed.bell@drake.edu.

Disclosure: Bell reports no relevant financial disclosures.

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