December 2001

With 2001 ending, it is appropriate to review some new drugs that were approved this year for use in children. Readers interested in other newly approved drugs can visit the FDA Web site (www.fda.gov/cder/drug).

Augmentin ES-600

One of the most welcome new drugs for use in children this year is Augmentin ES-600 suspension (amoxicillin-clavulanate extra strength, GlaxoSmithKline). While Augmentin is certainly not new, Augmentin ES-600 is new in the concentration of the amoxicillin and clavulanate components. Clavulanate is a ß-lactamase inhibitor, which extends the antibacterial spectrum of amoxicillin to ß-lactamase-producing organisms, including many Haemophilus influenzae and Moraxella catarrhalis strains. Augmentin ES-600 provides 600 mg of amoxicillin and 42.9 mg of clavulanate in 5 ml. It is indicated at a dose of 90 mg/kg/day for the treatment of recurrent or persistent acute otitis media (AOM) in children due to Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. This includes S. pneumoniae organisms with minimum inhibitory concentrations (MIC) of <2 µg/ml to penicillin (intermediate nonsusceptibility) and ß-lactamase producing H. influenzae and M. catarrhalis. Risk factors for acquiring nonsusceptible pneumococcus pathogens includes antibiotic exposure in the preceding 3 months, being younger than 2 years and day care attendance. Recent recommendations by the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group suggested increasing the dose of amoxicillin to 90 µg/kg/day to provide better activity toward nonsusceptible S. pneumoniae pathogens (penicillin MIC >0.12 mg/ml) in the treatment of AOM. Using previously available amoxicillin-clavulanate formulations dosed at 90 mg/kg/day caused the clavulanate dose to exceed 10 mg/kg/day. Doses above this are thought to increase the risk of gastrointestinal irritation. Augmentin ES-600 dosed at 90 mg/kg/day provides 6.4 mg/kg/day of clavulanate. Thus, Augmentin ES-600 not only provides an increased concentration of amoxicillin, but a reduced amount of clavulanate, at a ratio of 14:1 (amoxicillin:clavulanate). Previously available amoxicillin-clavulanate products provided amoxicillin:clavulanate ratios of 4:1 (125, 250 mg/5 ml products) or 7:1 (200, 400 mg/5 ml products).

Two clinical studies of Augmentin ES-600 led to its approval by the FDA. Ron Dagan, MD, and colleagues published results of an open-label, noncomparative, multicenter study of Augmentin ES-600 in 521 children aged 3-48 months diagnosed with AOM. Augmentin ES-600 was given at 45 mg/kg per dose, twice daily (BID) for 10 days. Tympanocentesis was preformed on all children with an intact tympanic membrane or direct culture of purulent discharge from a ruptured tympanic membrane prior to the first dose. Tympanocentesis was repeated on days 4-6 of treatment if a pathogen was identified initially.

Microbiologic and clinical response was monitored and the primary endpoint was bacteriologic response. H. influenzae was the most common pathogen (31%) identified, and S. pneumoniae isolated in 23% of children. Of the S. pneumoniae isolates, 55% were penicillin-susceptible (MIC <0.06 µg/ml), 18% were penicillin-intermediate nonsusceptible (MIC 0.12-1 mg/ml), and 28% were penicillin-resistant (MIC >2 µg/ml). Pathogens were eradicated from 96% of evaluable children (99% with S. pneumoniae, 92% with H. influenzae). Although there was a statistically significant difference in bacterial eradication rates between children infected with penicillin-susceptible or penicillin-intermediate nonsusceptible S. pneumoniae pathogens (100%) vs. penicillin-resistant pathogens (91%), this bacterial eradication rate of penicillin-resistant pathogens was still relatively high.

Children infected with these resistant pathogens were more likely to have received an antibiotic in the previous 3 months and were younger (mean age 12.8 months). Clinical success occurred in 89% of evaluable children (on days 12-15), including 82% infected with penicillin-resistant S. pneumoniae. Overall, 14% of children experienced an adverse effect related to therapy. Most common were diaper rash (4%), diarrhea (3.6%), and vomiting (2.3%). Diarrhea severe enough to result in study withdrawal occurred in 3% of children.

An additional double-blinded and randomized study compared Augmentin ES-600 (90 mg/kg/day) to Augmentin (45 mg/kg/day) in 450 children aged 3 months to 12 years with AOM. There were no statically significant differences in rates of adverse effects, including protocol-defined diarrhea.

Thus, pediatricians can now choose a therapy specifically formulated for use in children with AOM known or suspected to be caused by a penicillin-nonsusceptible S. pneumoniae. Augmentin ES-600, available as an orange-raspberry flavored suspension, is dosed at 90 mg/kg/day, given BID. Because of differing concentrations of clavulanate, it is important to realize that Augmentin ES-600 is not interchangeable with other Augmentin products.

Cefditoren pivoxil (Spectracef, Tap Pharmaceuticals) is a new orally administered third-generation cephalosporin. It is indicated for ages 12 years and older for acute bacterial exacerbations of chronic bronchitis, pharyngitis/tonsillitis (due to S. pyogenes) and uncomplicated skin and skin-structure infections (due to S. aureus or S. pyogenes). Cefditoren has activity toward ß-lactamase producing H. influenzae, H. parainfluenzae, M. catarrhalis and S. aureus. It is not approved for infections caused by penicillin-nonsusceptible S. pneumoniae.

In clinical studies, cefditoren has been compared with penicillin for the treatment of pharyngitis/tonsillitis. Cefditoren was equally effective in clinical cure, but superior in eradicating S. pyogenes (microbiologic cure). Unlike penicillin, cefditoren has not been evaluated for the prevention of rheumatic fever. Cefditoren was compared with cefadroxil (Duricef, Bristol-Myers Squibb) for skin and skin-structure infections and was equally effective in eradicating pathogens. It has also been compared to cefuroxime (Ceftin, GlaxoSmithKline) and was found to be clinically and microbiologically as effective as cefuroxime.

Cefditoren is available as 200 mg tablets and is dosed 200 mg-400 mg BID. Its adverse effects are typical for a cephalosporin (eg, diarrhea, nausea). Cefditoren contains sodium caseinate, a milk protein, and thus should not be given to patients with milk protein hypersensitivity, which is not synonymous with lactose intolerance. As well, the metabolism of cefditoren results in a reduction of plasma carnitine levels. In clinical studies plasma carnitine levels returned to normal within 10 days of discontinuation of cefditoren. The clinical significance of this reduction is not known. Cefditoren should be taken with meals to enhance absorption and should not be given with aluminum or magnesium-based antacids or H2-antagonists, as a reduction in cefditoren absorption may occur. Cefditoren offers no major advantage over other oral cephalosporins or penicillin.

Formoterol fumarate inhalation powder (Foradil Aerolizer, Novartis) is a new long-acting ß2-agonist indicated at ages 5 years and older for the maintenance treatment of asthma and prevention of exercise-induced bronchospasm. It will be compared with salmeterol (Serevent), another long-acting ß2-agonist. Formoterol is available as a dry powder inhaler, which requires the patient to inhale quickly and deeply. Salmeterol is available as a dry powder inhaler and as a metered-dose inhaler.

Formoterol is similar to salmeterol but they have not been compared in published clinical studies. Both produce bronchodilation for up to 12 hours and should be used in maintenance therapy only. They should not be used for quick relief of symptoms; patients should also have a quick-relief ß-agonist (eg, albuterol) for this purpose. Formoterol’s effects do appear sooner (within several minutes ) as compared with salmeterol (with 10-20 minutes), although this difference is not clinically important in the maintenance treatment of asthma. When used for prophylaxis of exercise-induced bronchospasm, formoterol should be given at least 15 minutes prior to exercise, and offers no advantage over a short-acting ß2-agonist, such as albuterol. Albuterol is less costly for this use. Pediatric dosing for formoterol is 1 inhalation (12 mg) BID. More than 1 inhalation should be not given in a 12 hour period. Because Foradil is available as dry powder inhaler, it is important for patients to understand the proper technique of use (quick and deep inhalation), which differs from MDI technique.

For more information:

• Dagan R. Bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis media. Pediatr Infect Dis J. 2001;20:829-37.
• Bensch G. A randomized 12-week, double-blind, placebo-controlled study comparing formoterol dry powder inhaler with albuterol metered-dose inhaler. Ann Allergy Asthma Immunol. 2001;86:19-27.