Summary and conclusions

This is the authors' abstract. We don't add key points for this paper.

This publication of the material presented at the meeting held in New York in July 2003 provides a state-of-the art report on the use of azithromycin in the treatment of acute otitis media and tonsillopharyngitis. Usage of azithromycin has undergone substantial changes since it was introduced in April 1991. The novel pharmacokinetics of azithromycin has resulted in United States Food and Drug Administration approval of two new dosage schedules for management of acute otitis media: a single dose regimen (30 mg/kg); and a 3-day regimen (10 mg/kg/day once daily for 3 days), in addition to the original 5-day regimen (10 mg/kg once daily on Day 1, followed by 5 mg/kg/day once daily on Days 2 to 5). Other challenges since introduction of azithromycin include the increased incidence of multidrug-resistant pneumococci that has raised concerns about appropriate usage of all antimicrobial agents including the macrolides. The presentations at the symposium reviewed the latest information about azithromycin: pharmacokinetic/pharmacodynamic data; safety and tolerability in infants and children; pneumococcal resistance; clinical studies of single dose azithromycin in the treatment of uncomplicated acute otitis media; optimal therapy of acute otitis media relapse and recurrence; and optimal treatment regimens for acute tonsillopharyngitis. Although azithromycin is a mature product with extensive clinical experience in infants and children, the interested practitioner should be alert for surprises that might modify management decisions. For example the intriguing observations by Saiman et al. 1 that patients with cystic fibrosis who were chronically infected with Pseudomonas aeruginosa had clinical improvement after a course of azithromycin. Change is constant, and the informed reader must be ready to absorb and utilize new and useful information about management of infectious diseases. PHARMACOKINETICS AND PHARMACODYNAMICS: AZITHROMYCIN CONCENTRATES IN TISSUES Dr. Blumer (with Dr. Gordon) 2 underlined the importance of distinguishing the azalides from the beta-lactam antibiotics. Whereas the beta-lactam antibiotics have relatively high extracellular fluid concentrations, azithromycin concentrates in neutrophils and macrophages and has relatively low concentrations in plasma. The actions of beta-lactams are predictable on the basis of their plasma concentrations, but the activity of azithromycin is dependent on the inflammatory response elicited by the microbial pathogen and concentration of the drug to which the inflammatory cells are exposed before reaching the site of infection. Dr. Blumer characterized the high concentration of azithromycin in neutrophils and macrophages as a “Trojan Horse” phenomenon. Azithromycin-laden neutrophils are recruited to the sites of bacterial infection where the drug is released, resulting in local free concentrations of drug. Giving higher doses up front (e.g. 30 mg/kg as a single dose regimen) or as a shorter course (e.g. 10 mg/kg once daily for 3 days) combined with the long elimination half-life of azithromycin are the theoretical bases for the efficacy of shorter treatment courses for acute otitis media. MULTIDRUG-RESISTANT PNEUMOCOCCI: ARE WE WINNING THE BATTLE? Dr. Amsden 3 provided an update on resistance of pneumococci to antimicrobial agents and efforts to limit the annual increments that had been identified in the 1990s. The Centers for Disease Control, the World Health Organization and other groups have targeted physicians and consumers with educational programs to decrease inappropriate use of antibiotics. Decreased antibiotic use is likely to result in decreased selective pressure for development of resistant bacterial pathogens in the patient and the community. Educational efforts in Tennessee, New England and Northern Wisconsin have been successful in decreasing antibiotic prescription rates. Data from the National Ambulatory Medical Care Survey documented a remarkable decrease in antibiotic prescriptions of ∼40% for infections of the respiratory tract during the period 1989 to 2000. The answer to the question are we winning the battle appears to be YES, but national and local will on the part of all stakeholders remains necessary to achieve a sustained reduction of unnecessary use of antimicrobial agents. SINGLE DOSE ANTIBIOTIC THERAPY WORKS FOR UNCOMPLICATED ACUTE OTITIS MEDIA Single dose therapy has been successful for a variety of infections including benzathine penicillin for group A streptococcal pharyngitis, various drugs for gonorrhea, syphilis, parasitic infections such as filariasis (Ivermectin) and Ancylostoma caninem (Albendazole) and a single dose of intramuscular ceftriaxone for acute otitis media. Arguedas et al. 4 discussed 3 studies of single dose azithromycin for the treatment of uncomplicated acute otitis media. One study was noncomparative for documentation of clinical and microbiologic efficacy of the single dose regimen. The other 2 studies compared single dose azithromycin with 3-day azithromycin or single dose ceftriaxone or 10-day amoxicillin/clavulanate. The results of the comparative studies demonstrated the clinical equivalence of the 4 regimens. The clinical response rates stratified by pathogen are provided in Table 3 of the accompanying paper by Arguedas et al. In the comparative trial all isolates of Haemophilus influenzae were susceptible in vitro to azithromycin and ceftriaxone; all but 2 of the 60 isolates of Streptococcus pneumoniae were susceptible to azithromycin, and all were susceptible to ceftriaxone. Thus the clinical results in the otitis media trials were based on infections caused by susceptible strains of the major pathogens. The results of the comparative trials demonstrated clinical equivalence of each regimen. Thus azithromycin treatment of uncomplicated acute otitis media can be added to the list of approved single dose therapies. MANAGEMENT OF SEVERE AND RECURRENT ACUTE OTITIS: STILL CONTROVERSIAL The various options for treatment of the child with severe and recurrent acute otitis media are reviewed by Arrieta and Singh. 5 The authors’ review comes at an opportune time with the publication of the guidelines for management of acute otitis media prepared by committees of the American Academy of Pediatrics and the American Academy of Family Physicians. 6 The guidelines are based on an evidence-based review; high dosage amoxicillin (80 to 90 mg/kg/day twice daily for 10 days) was recommended as the regimen of choice for children with uncomplicated acute otitis media. Children who fail an initial course of high dosage amoxicillin can be managed with high dosage amoxicillin/clavulanate, an oral cephalosporin (cefdinir, cefpodoxime or cefuroxime) or intramuscular ceftriaxone; children who have had a serious adverse event associated with allergy to a beta-lactam drug should be managed with a macrolide (azithromycin, clarithromycin or erythromycin-sulfisoxazole) or trimethoprim-sulfamethoxazole. The susceptibility patterns have varied over time and place, and national and regional surveillance will dictate the continued value of these recommendations. AZITHROMYCIN IS WELL-TOLERATED AND HAS A FAVORABLE ADVERSE EVENT PROFILE Ruuskanen 7 reviewed the results of >50 clinical studies with safety and tolerability data for azithromycin. He noted that >80 million azithromycin prescriptions have been written for children during the 12 years since its introduction. Adverse effects were mostly mild to moderate gastrointestinal upsets that rarely required discontinuation of treatment. PENICILLIN REMAINS THE DRUG OF CHOICE FOR STREPTOCOCCAL PHARYNGITIS, BUT BACTERIOLOGIC CURE RATES ARE HIGHER WITH CEPHALOSPORINS AND MACROLIDES Cohen 8 reviewed the clinical and microbiologic data available in recent studies of therapy of acute streptococcal pharyngitis. Although all authoritative groups including the Centers for Disease Control and the American Academy of Pediatrics continue to recommend penicillin as the drug of choice for therapy of acute streptococcal pharyngitis, the microbiologic results are consistent in documenting over the years that higher rates of microbiologic cure follow use of various cephalosporins and macrolides when compared with penicillin. However, only one penicillin, an intramuscular formulation that is no longer available, has been documented to prevent rheumatic fever. This formulation was evaluated in a placebo-controlled trial performed at Warren Air Force Base in Wyoming in the early 1950s. No other studies have had sufficient power to evaluate the role of any antimicrobial agent in preventing this nonsuppurative sequela of streptococcal pharyngitis. The argument over the optimal agent for group A streptococcal pharyngitis will continue, and the interested reader should review the Cohen paper as well as a recent review by Pichichero et al. 9