Another look at azithromycin

This month’s column will focus on azithromycin and its use for pharyngitis and otitis media.

Issue: December 2002

Azithromycin (Zithromax, Pfizer) is an interesting antibiotic commonly used in the treatment of common pediatric infections. Recently, readers of Infectious Diseases in Children have inquired about the use of azithromycin and its role in the therapy of pharyngitis and acute otitis media (AOM). This month’s column will focus on azithromycin and its use for these common infections.

Microbiology and pharmacokinetics

Azithromycin is classified as an azalide antibiotic, a subclass of the macrolide class, which includes erythromycin and clarithromycin (Biaxin, Abbott). Considered to a have a broad spectrum of antibacterial activity, azithromycin generally is active toward a variety of bacterial pathogens that result in infectious processes in children: Staphylococcus aureus (not methicillin-resistant S. aureus [MRSA]), ß-hemolytic streptococci, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae and Chlamydia pneumoniae, among others. Azithromycin binds to the bacterial 50S ribosomal subunit and inhibits protein synthesis.

The pharmacokinetic profile of azithromycin is interesting and in large part contributes to its usefulness. Azithromycin extensively distributes into various tissues, for its chemical structure includes both hydrophilic and hydrophobic components. Azithromycin remains in these tissues for several days after dosing and after plasma concentrations have decreased. Tissue sites where azithromycin distributes well include lung, tonsil and middle ear fluid. The ratio of azithromycin concentration in some of these tissues compared with plasma concentrations may exceed 100. Additionally, azithromycin concentrates in polymorphonuclear leukocytes, also in amounts that may exceed plasma concentrations by 100 or more. This extensive tissue distribution allows azithromycin to be dosed for one to five day treatment courses, which may be advantageous in some patients. Other than a shortened treatment course, the clinical benefits of azithromycin’s unique pharmacokinetic profile have not been well defined.

A significant disadvantage of the prototypical macrolide, erythromycin, is its propensity for causing clinically significant drug-drug interactions. Through hepatic drug metabolizing enzyme inhibition, concomitant use of erythromycin and numerous other drugs may result in clinically significant untoward effects. Fortunately, azithromycin use does not result in clinically significant interactions with these drugs. The metabolism and plasma concentrations of theophylline and carbamazepine, for example, are not significantly affected by azithromycin.

Clinical uses

Azithromycin has FDA-approved indications in children for AOM (H. influenzae, M. catarrhalis or S. pneumoniae) in ages >6 months; community-acquired pneumonia (M. pneumoniae, S. pneumoniae, C. pneumoniae, H. influenzae) in ages >6 months; and pharyngitis/tonsillitis (Streptococcus pyogenes) in ages >2 years. Dosing for these uses are listed in the Table.

AOM

Source: Edward A. Bell, PharmD, BCPS

Numerous oral antibiotics are currently available to clinicians treating AOM in children. A complete review of these antibiotics is beyond the scope of this column. Advantages of azithromycin include once-daily dosing and FDA-approved shortened treatment courses. From a caregiver’s perspective, this is often a major advantage. Microbiologic activity and clinical efficacy, however, certainly cannot be discounted. Recently published antibiotic susceptibility studies document that resistance toward azithromycin (and other macrolides) is increasing and is significant. Resistance toward azithromycin by S. pneumoniae tends to parallel resistance toward ß-lactam antibiotics, which is also increasing. One surveillance study found resistance by S. pneumoniae toward azithromycin to be up to 30%. These resistance rates can vary geographically throughout the United States. Generally, penicillin/amoxicillin and select cephalosporins (cefuroxime [Zinacef, GlaxoSmithKline], cefpodoxime [Vantin, Pharmacia]) tend to have the most favorable activity toward S. pneumoniae, including nonsusceptible S. pneumoniae. Additionally, nonsusceptibility by S. pneumoniae toward azithromycin may be more difficult to overcome, as compared to nonsusceptibility toward ß-lactam antibiotics. Activity of azithromycin toward H. influenzae documented in recent surveillance studies has been good.

One recent clinical trial evaluating azithromycin in the treatment of AOM used tympanocentesis and compared azithromycin to amoxicillin-clavulanate (Augmentin, GlaxoSmithKline). The trial found azithromycin had reduced microbiologic efficacy toward H. influenzae-infected children. Reduced microbiologic efficacy towards H. influenzae-infected children (the predominant pathogen in this study) was found with azithromycin (P<0.05). No differences in bacterial eradication of S. pneumoniae were found between azithromycin and amoxicillin-clavulanate (P>0.05). Sixty percent of S. pneumoniae pathogens displayed nonsusceptibility to penicillin (34% resistant). Twenty-four percent of S. pneumoniae pathogens displayed resistance to azithromycin (MIC>0.5 µg/ml). The report published by the Drug-resistant S. pneumoniae Therapeutic Working Group in 1999 hesitates to recommend the macrolide antibiotics as front-line therapy because of these concerns.

The pharmacokinetic characteristics of azithromycin and the FDA-approved shortened treatment courses are a potential significant advantage of azithromycin. Other antibiotics given orally have also been evaluated for shortened treatment courses (three to six days), although none are indicated for this use. Over 20 published trials have evaluated various antibiotics in shortened treatment courses, including over 3,000 patients. Many of these trials have been criticized for design flaws, but their results of similar efficacy as 10-day treatment courses suggest that shortened treatment courses with other antibiotics may be appropriate. Children younger than 2 years of age are not considered good candidates for shortened treatment courses with these additional antibiotics. Comparative studies of azithromycin in the product labeling in the treatment of AOM (studies leading to FDA approval) did not assess microbiologic efficacy; such study design may contribute to inflated clinical efficacy (the “Pollyanna phenomenon”). Product labeling information additionally indicates that azithromycin is well tolerated, even when given as a one-time dose (30 mg/kg).

Pharyngitis

The antibiotic of choice in the treatment of bacterial pharyngitis caused by S. pyogenes is penicillin. Penicillin can be given orally or by intramuscular injection with a single dose of benzathine penicillin G. When given orally, penicillin can be dosed twice daily and should be given for 10 days. Although other antibiotics have been advocated in the treatment of pharyngitis, only penicillin has been shown to prevent acute rheumatic fever. If a patient has a history of significant allergy or anaphylaxis with penicillin, erythromycin is generally recommended. The 2000 Red Book recommends erythromycin estolate or ethylsuccinate, which can also be dosed twice daily. Gastrointestinal adverse effects, however, may limit erythromycin’s use. It is important to differentiate, when possible, a patient’s claim of allergy to penicillin from other adverse effects, for studies have documented that most patients claiming an allergy to penicillin do not react to skin testing. Limitations of potential allergies to penicillin, a 10-day treatment course and gastrointestinal adverse effects of erythromycin have prompted studies on the use of other antibiotics. Macrolide and other ß-lactam antibiotics have been evaluated. All of these antibiotics share the limitation of lack of proven prevention of acute rheumatic fever. S. pyogenes resistant to penicillin have not yet been identified. Although resistance by S. pyogenes to alternative antibiotics such as azithromycin is not common, it nonetheless has been documented.

A recently published surveillance study of S. pyogenes documented a 6.2% resistance rate to azithromycin. Regional variation throughout the United States in this study was not large. A similar study of organisms obtained in European countries documented a higher rate of resistance (15.9%) to azithromycin. Advantages of azithromycin in the treatment of pharyngitis include once-daily dosing and a five-day treatment course. Several cephalosporin antibiotics are also FDA-approved for once-daily dosing as 10-day treatment courses: cefixime (Suprax, Lederle), ceftibuten (Cedax, Schering-Plough), cefadroxil (Duricef, BMS) and cefdinir (Omnicef, Parke-Davis). Only cefpodoxime (Vantin, Pharmacia and Upjohn) and cefdinir (both twice daily dosing) are approved for five-day treatment courses. Amoxicillin given once daily (for 10 days) has also recently been shown to be effective.

Relatively few published data are available on the use of azithromycin in the treatment of pharyngitis in children. Unpublished data used in support of FDA approval compared azithromycin with penicillin in the treatment of pharyngitis in children and found azithromycin to be superior to penicillin in bacteriologic eradication and clinical response. It is possible, however, that the increased response seen with azithromycin (or other alternative antibiotics) may be due to their enhanced ability to eliminate streptococcal carrier states in some patients who are entered into clinical trials.

Conclusions

Azithromycin’s unique pharmacokinetic characteristics afford it a significant potential advantage for some patients. One, three and five-day treatment courses are likely to increase compliance, and may be useful for patients that clinicians suspect will be noncompliant with longer treatment courses. Balancing this advantage, however, are concerns over resistance by bacterial pathogens towards azithromycin, its increased cost over other antibiotics (eg, penicillin/amoxicillin, erythromycin), and its broad antibacterial spectrum, which is more likely to promote resistant pathogens. As with any antibiotic, its beneficial characteristics should be applied to select patients. Use of azithromycin may be best suited for children in whom noncompliance is a concern, in children with intolerances to other antibiotics (eg, significant allergy to penicillin, nausea with erythromycin), or in children residing in areas with lower rates of bacterial resistance to macrolides.

For more information:

Dagan R. Bacteriologic and clinical efficacy of amoxicillin/clavulanate vs. azithromycin in acute otitis media. Pediatr Infect Dis J. 2000;19:95-104.

Dagan R. Flaws in design and conduct of clinical trials in acute otitis media. Pediatr Infect Dis J. 2002;21:894-902.

Thornsberry C. Survey of susceptibilities of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis isolates to 26 antimicrobial agents: a prospective US study. Antimicrob Agents Chemother. 1999;43:2612-2623.

Critchley IA. Antimicrobial susceptibilities of Streptococcus pyogenes isolated from respiratory and skin and soft tissue infections: United States LIBRA surveillance data from 1999. Diagn Microbiol Infect Dis. 2002;42:129-135.

Mason EO. Streptococcus pneumoniae in the USA: in vitro susceptibility and pharmacodynamic analysis. J Antimicrob Chemother. 2000;45:623-31.

Gerber MA. New approaches to the treatment of group A streptococcal pharyngitis. Curr Opin Pediatr. 2001;13:51-55.

Still JG. Management of pediatric patients with group A beta-hemolytic Streptoccus pharyngitis: treatment options. Pediatr Infect Dis J. 1995;14:S57-S61.

Feder HM. Once-daily therapy for streptococcal pharyngitis with amoxicillin. Pediatrics. 1999;103:47-51.

Pichichero ME. Shortened course of antibiotic therapy for acute otitis media, sinusitis and tonsillopharyngitis Pediatr Infect Dis J. 1997;16:680-695.