Eradication of Streptococcus pneumoniae in the Nasopharyngeal Flora of Children with Acute Otitis Media after Amoxicillin-Clavulanate Therapy

Abstract

Nasopharyngeal cultures were obtained from 60 children with acute otitis media before and after treatment with either 45 or 90 mg of amoxicillin (given as amoxicillin-clavulanate) per kg of body weight per day for 10 days. The number of Streptococcus pneumoniae isolates in the 45-mg/kg group was reduced from 12 to 6 and was reduced from 14 to 1 (P = 0.0261) in the 90-mg/kg group.

The growing resistance of all respiratory tract bacterial pathogens to antimicrobial agents has made the management of acute otitis media (AOM) more difficult. The nasopharynx serves as the reservoir for pathogenic bacteria that can cause respiratory infections, including AOM (11). Potential pathogens can relocate during a viral respiratory infection from the nasopharynx to the middle ear, causing AOM (9). Failure of antimicrobial agents to clear potential pathogens from the nasopharynx can allow the pathogens to initiate a recurrence of the infection (3, 4, 8).

The growing resistance of Streptococcus pneumoniae to penicillin can be overcome by increasing the dose thereof (5). This finding produced the recommendation that the pediatric dose of amoxicillin be increased from 45 to 90 mg per kg of body weight per day. This study was performed to investigate whether the higher dose of amoxicillin is more effective in eradicating the S. pneumoniae from the nasopharynges of children who present with AOM.

The study was conducted between 1 September 2000 and August 2002. The population studied was middle class, residing in suburban locations near Washington, D.C. Included were all children who presented with AOM that received amoxicillin-clavulanate therapy. All presented with clinical signs of active infection (i.e., fever and irritability), including opacified red-gray or yellow bulging tympanic membranes. AOM was defined as the presence of irritability, ear tugging, and/or the presence of middle ear effusion as determined by pneumatic otoscopy. All patients seen prior to 1 December 2001 were treated with 45 mg of amoxicillin-clavulanate/kg/day (400 mg of amoxicillin/57 mg of clavulanate [7:1 formulation] per 5-ml suspension) given twice a day for 10 days, and all children seen after 1 December 2001 were treated with 90 mg of amoxicillin-clavulanate/kg/day (600 mg of amoxicillin/42.9 mg of clavulanate [14:1 formulation] per 5-ml suspension) given twice a day for 10 days. Excluded from analysis were children who had serous ear effusion, otorrhea, tympanostomy tubes, craniofacial anomalies, and chronic medical problems; those who had received antimicrobial agents in the past 3 months who were noncompliant with the current antimicrobial therapy; and those whose first culture did not show any bacterial growth.

A total of 60 children were studied, 30 of whom received 45 mg per kg per day and 30 of whom were treated with 90 mg per kg per day. Compliance was checked by questioning the parents and observing the leftover medication during the return visit. Excluded were seven children who failed to comply with the medication schedule (four in the 45-mg/kg/day group). Patients' ages ranged from 6 months to 6 years and 10 months (average age, 2 years and 7 months), and 43 were males. No differences were noted in the age, gender, and day care attendance distribution between the two groups. No siblings were allowed to be included in the study.

Nasopharyngeal cultures were obtained before therapy and on a follow-up visit 2 to 4 days after completion of 10 days of antimicrobial therapy. These cultures were obtained with calcium alginate swabs that were immediately plated into media supportive of the growth of aerobic and anaerobic bacteria. Specimens were processed semiquantitatively, and organisms were identified by using conventional methods (14). Five colonies of each pathogen were collected for analysis. All isolates of S. pneumoniae were screened for penicillin susceptibility with a 1-μg oxacillin disk by use of the Kirby-Bauer disk diffusion method.

MICs of penicillin, amoxicillin, and amoxicillin-clavulanate were determined by the broth microdilution method by following the guidelines of the National Committee for Clinical Laboratory Standards (NCCLS) with cation-adjusted Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.) supplemented with 5% lysed horse blood for S. pneumoniae and Streptococcus pyogenes (15). Intermediate resistance to penicillin was defined as a MIC of 0.1 to 1.0 μg/ml, and high resistance to penicillin was defined as a MIC of at least 2.0 μg/ml. MICs of amoxicillin and amoxicillin-clavulanate were determined by using Haemophilus test medium for Haemophilus species and Moraxella catarrhalis (15). MICs were interpreted according to the NCCLS M100-S10 MIC testing supplemental tables (18). Beta-lactamase production was determined by using the chromogenic cephalosporin method with nitrocefin as the substrate (14). Statistical analysis was done by using the Fisher exact test (with the P value representing a two-sided test).

Sixty-six potentially pathogenic organisms were isolated: S. pneumoniae (26 isolates), Haemophilus influenzae non-type b (19 isolates), M. catarrhalis (8 isolates), S. pyogenes (7 isolates), and Staphylococcus aureus (6 isolates) (Table 1). All M. catarrhalis, 10 H. influenzae (4 in the 45-mg/kg group and 6 in the 90-mg/kg group), and 3 Staphylococcus aureus (2 in the 45-mg/kg group and 1 in the 90-mg/kg group) isolates produced beta-lactamase. The growth of all isolates was rated moderate to heavy.

TABLE 1.

Recovery of organisms from the nasopharynges of 60 children with acute otitis media

Antimicrobial therapy regimen	No. of patients	No. of isolates recovered on culture day(s)
		S. pneumoniae		H. influenzae		M. catarrhalis		S. pyogenes		S. aureus		Total no. of isolates (%)
		0	12-14	0	12-14	0	12-14	0	12-14	0	12-14	0	12-14
Amoxicillin-clavulanate, 45 mg/kg	30	12	6	10	3	5	0	3	0	2	0	32	9 (28)
Amoxicillin-clavulanate, 90 mg/kg	30	14	1a	9	2	3	0	4	0	4	0	34	3 (9)
Total	60											66

^aP = 0.0261 compared with other group.

Of the 12 S. pneumoniae isolates recovered prior to therapy from the 45-mg/kg group, 6 were resistant to penicillin (4 intermediately resistant and 2 highly resistant). Of the 14 S. pneumoniae isolates in the 90-mg/kg group, 8 were resistant to penicillin (5 intermediately resistant and 3 highly resistant). After treatment, the number of S. pneumoniae isolates in the 45-mg/kg group was reduced from 12 to 6 (3 intermediately resistant and 2 highly resistant). All isolates except one were recovered from the same individuals. In contrast, the number of S. pneumoniae isolates in the 90-mg/kg group after treatment was reduced from 14 to 1 (Table 1 [P = 0.0261]). The number of resistant S. pneumoniae isolates was therefore reduced from six to five in the 45-mg/kg group compared to eight to one in the 90-mg/kg group (P = 0.0256).

No differences were noted in the eradication rate of all other groups of isolates, all of which were susceptible to amoxicillin-clavulanate.

These data illustrate a better efficacy of the 90-mg/kg/day amoxicillin regimen compared to that of the 45-mg/kg/day regimen used in the eradication of S. pneumoniae from the nasopharynges of children with AOM. In contrast, both formulations were equally active in the eradication of H. influenzae, M. catarrhalis, S. pyogenes, and S. aureus.

Our findings support the data reported previously by Ghaffar et al. (12, 13), who observed superior efficacy of amoxicillin at a dosage of 90 mg/kg/day (13) to that of the 45-mg/kg/day (12) dosage in eradicating S. pneumoniae from the nasopharynges of children. The data were generated in two separate studies and were not head-to-head comparisons. The reduction in the rate of recovery of S. pneumoniae after administration of 45 mg/kg/day was from 45 to 12.5% (12) and after 90 mg/kg/day was from 51 to 5% (13).

In an attempt to address the growing problem of penicillin-resistant S. pneumoniae, the Centers for Disease Control Drug-Resistant S. pneumoniae Therapeutic Working Group recommended the use of high-dose amoxicillin-clavulanate (90 mg of amoxicillin/6.4 mg of clavulanate per kg per day) as a second-line agent for empirical treatment of AOM in patients who had not recently received antibiotic therapy and as a first-line agent for those who had received such therapy (10). A new formulation of amoxicillin-clavulanate addresses the growing problem of penicillin-resistant S. pneumoniae and is based on pharmacokinetic and pharmacodynamic considerations (5) and on animal (1, 19), in vitro (1), and clinical data (17). It doubles the concentration of amoxicillin compared with that present in the existing formulation, maintains the same clavulanate concentration, and is divided into two daily doses. This regimen provides amoxicillin concentrations in the middle ear that are sufficiently high to eradicate penicillin-resistant S. pneumoniae, with penicillin and amoxicillin MICs as high as 4 μg/ml (1, 2, 5, 17, 19). The regimen provides amoxicillin concentrations in serum that exceed 4 μg/ml for more than 40% of the dosing interval based on human and animal pharmacokinetic studies and on pharmacokinetic modeling (1, 2, 5, 16, 17, 19).

The superiority of the high-dose 90-mg/kg/day regimen (over the regular 45-mg/kg/day amoxicillin-clavulanate regimen) in the eradication of S. pneumoniae from the middle ear fluid of patients with AOM, while not proven in a comparative prospective study, was shown previously by Dagan et al (6, 7). The high dose of amoxicillin-clavulanate (90 mg of amoxicillin/6.4 mg of clavulanate per kg per day) achieved high bacteriologic and clinical response rates in 521 children with AOM (6). Pathogens were eradicated from 96% of the 180 bacteriologically evaluated children who had repeated incidence of tympanocentesis—a value which is higher than the 83% eradication rate previously noted with amoxicillin-clavulanate (45 mg of amoxicillin/6.4 mg of clavulanate per kg per day in 65 children with AOM) (P = 0.004) (7). The new formulation of amoxicillin-clavulanate also produced high clinical response rates. Clinical success was evident in 89% of the 295 clinically evaluated children on days 12 to 15, including 82% of those infections that were due to penicillin-resistant S. pneumoniae. Further studies of the microbiology and effect of amoxicillin-clavulanate therapy of other respiratory tract infections such as recurrent otitis media and sinusitis are warranted. These studies should investigate whether the use of the higher dose of amoxicillin-clavulanate will be able to enhance recovery and reduce the occurrence of recurrences in these patients.