MIDDLE EAR FLUID CONCENTRATIONS OF AMOXICILLIN AFTER LARGE DOSAGES IN CHILDREN WITH ACUTE OTITIS MEDIA

Abstract

The rising incidence of penicillin-resistant isolates of Streptococcus pneumoniae has made treatment of acute otitis media difficult. This is because resistance has been associated with prior beta-lactam treatment, a common occurrence in infants and children with recurrent otitis media, and because many penicillin-resistant isolates are also resistant to the orally administered cephalosporins. For an antibiotic to be effective in patients with acute otitis media it should achieve concentrations in middle ear fluid (MEF) that equal or exceed the MIC for the otitic pathogen. With amoxicillin therapy MEF concentrations should equal or exceed 1.0 and 2.0 μg/ml to be effective against intermediate and resistant strains of pneumococcus, respectively.1 In one study MEF concentrations were from 0.3 to 4.0 μg/ml after a standard amoxicillin dosage of 15 mg/kg, and the concentrations in 6 of 12 specimens were <1.0 μg/ml.2 In the present study we determined the MEF concentrations of amoxicillin in infants and children with acute otitis media after administration of 35 or 45 mg/kg amoxicillin combined with potassium clavulanate in 7:1 and 14:1 formulations, respectively. Methods. Children from 1 to 130 months of age (mean, 34 months; 48% ≤24 months), with acute otitis media with effusion who were seen in the Emergency Referral Center of Children's Medical Center of Dallas, April 1, 1995, to May 5, 1996, were eligible for enrollment in the study. Written, informed consent was obtained from parents or guardians of the patients, and the protocol was approved by the Institutional Review Board of The University of Texas Southwestern Medical Center. The diagnosis was based on otoscopic findings of bulging and red-orange discoloration with immobility of the tympanic membrane observed by pneumatic otoscopy plus the presence of fluid behind the membrane. The initial antibiotic dose was administered orally in the emergency department. Twenty-five patients were given the 35/5 mg/kg doses and 30 were given the 45/3.2 mg/kg dosages of amoxicillin/clavulanate potassium. Specimens from 17 patients in the lower dosage group were inadvertently destroyed by a reference laboratory and one patient was excluded from the larger dosage group because of vomiting after the dose was given. From 1 to 3 h after administration of the antibiotic, venipuncture and tympanocentesis were performed by a study investigator to obtain plasma and MEF samples. The patients were then discharged with study medication to complete a 10-day course of amoxicillin/clavulanate potassium in daily dosages of 70/10 mg/kg or 90/6.4 mg/kg, given in two divided doses. Plasma and MEF specimens were stored at −70°C. The concentrations of amoxicillin in the body fluids were determined by a standard disk diffusion microbioassay using Micrococcus lutea (ATCC 9341).3 To correct for the presence of blood in MEF, the hemoglobin concentration in MEF was measured by a colorimetric technique based on the catalytic action of hemoglobin on the oxidation of benzidine by hydrogen peroxide (Sigma Diagnostics, St. Louis, MO), and the amoxicillin value in MEF was adjusted for the concentration contained in that amount of blood. Results. Specimens from 27 children with acute otitis media were available for study. Seven patients were excluded, two because an inadequate volume of MEF was obtained and five because the MEF was grossly bloody. Thus samples from 20 patients were available for assay; 6 patients had received 35 mg/kg and 14 had received 45-mg/kg dosages. All 20 patients tolerated the medication well and completed 10 days of treatment successfully. Concentrations of amoxicillin in MEF (Fig. 1) exceeded 1.0 μg/ml in 18 specimens (90%) and 4.0 μg/ml in 8 specimens (40%), the amoxicillin MIC90 values for penicillin-intermediate and penicillin-resistant strains, respectively.4, 5 The lowest value was 0.2 μg/ml at 1 h after a 45-mg/kg dose. The mean plasma concentrations after the larger dosage were 7.6 μg/ml at 1 h, 15.7 μg/ml at 2 h and 13 μg/ml at 3 h. With the 35-mg/kg dosage the mean plasma concentration was 7.7 μg/ml at 3 h; only 2 patients had samples available at 2 h (6.0 and 11.0 μg/ml).Fig. 1: Concentrations of amoxicillin in MEF of children with acute otitis media. Two amoxicillin-clavulanate potassium formulations (7:1 and 14:1 mixtures) were administered in amoxicillin dosages of 35 or 45 mg/kg/dose. Specimens were obtained at the times indicated after the first dose. Dashed lines represent the National Committee for Clinical Laboratory Standards breakpoints for intermediate (A) and resistant (B) strains of S. pneumoniae for amoxicillin.Comment. Beta-lactam antibiotics are believed to exert antimicrobial activity in a concentration-independent fashion, meaning that the bactericidal effect is most closely associated with the time that the concentration of the drug at the site of infection remains above the MIC for the pathogen.6 For amoxicillin therapy of acute otitis media, 80 to 85% bacteriologic eradication occurs when values in serum exceed the MIC for 40 to 50% of the dosing interval, or as a surrogate marker, when peak concentrations in MEF exceed the MIC by 3- to 6-fold.7 With the use of the cutoff values for amoxicillin susceptibilities of pneumococci established recently by the National Committee for Clinical Laboratory Standards,1 the amoxicillin MEF concentrations after the 45-mg/kg dose equaled or exceeded by 3-fold the breakpoint for intermediate resistant strains (1 μg/ml) in 9 of 14 specimens (64%) and for resistant strains (2 μg/ml) in 4 specimens (29%); 3 of these latter 4 MEF specimens were obtained at 3 h after the larger dosage. It is possible that some specimens obtained at 4 h would have also had concentrations exceeding 6 μg/ml. On the basis of serum concentrations of free drug, Craig and Andes7 predicted successful outcome with conventional amoxicillin therapy (13.3 mg/kg/dose given three times daily) for many intermediate resistant strains and for a few resistant strains. Clinical correlations of the pharmacodynamic data from the current study are uncertain, but it is likely that the 45-mg/kg dosage of amoxicillin, whether or not combined with clavulanate, would be effective for approximately two-thirds of the intermediate resistant pneumococcal strains and for approximately one-third of resistant strains causing acute middle ear infection. Acknowledgment. The study was supported by a grant from SmithKline Beecham Pharmaceuticals. Kathleen Seikel, M.D. Sharon Shelton, M.A. George H. McCracken Jr., M.D. Department of Pediatrics; The University of Texas Southwestern Medical; Center at Dallas; Dallas, TX