Optimal Dose of Amoxicillin in Treatment of Otitis Media Caused by a Penicillin-Resistant Pneumococcus Strain in the Gerbil Model

Abstract

Amoxicillin at doses of 0.2 to 5 mg/kg of body weight was administered for the treatment of pneumococcal otitis media in a gerbil model. Doses greater than or equal to 2.5 mg/kg, which resulted in concentrations in middle ear fluid of >1.4 g/ml and concentrations in serum higher than the MIC (1 g/ml) for >14% of the dosing interval, were both clinically and bacteriologically effective.The emergence of penicillin-insensitive Streptococcus pneumoniae strains is now a worldwide problem and causes great concern (2, 3, 12). To overcome this problem in cases of acute otitis media (AOM), a proposal has been made to increase the amoxicillin dose (5) in order to achieve concentrations in serum above the MIC for the pathogen during at least 40% of the dosing interval (4).The aim of this work was to determine, by means of an experimental model of AOM caused by a penicillin-resistant pneumococcus (penicillin MIC, 2 g/ml), the minimum dose of amoxicillin able to achieve both clinical and bacteriological success.One S. pneumoniae serotype 23F strain was used. Amoxicillin trihydrate (SmithKline Beecham Pharmaceuticals, Worthing, England) was used for in vitro studies. For in vivo studies, vials of commercially produced amoxicillin (Clamoxyl; SmithKline Beecham Pharmaceuticals, Toledo, Spain) were employed.MICs and minimum bactericidal concentrations were determined five times by a microdilution method (10, 11), and median values were considered. Eight-to 9-week-old adult female Mongolian gerbils were inoculated bilaterally with ϳ5 ϫ 10 6 S. pneumoniae CFU per 20 l, as previously reported (13). AOM and otitis media with effusion (OME) were defined as previously described (13).The antibiotic was tested at doses of 0.2, 0.4, 0.8, 1.25, 2.5, and 5 mg/kg of body weight and administered subcutaneously (s.c.) in 500-l volumes at 2, 10, and 18 h postinoculation (p.i.). Animals in the control group received apyrogen sterile distilled water. Treated and control animals were studied daily for otorrhea, weight, and behavior. On day 2 p.i., ears were examined with an otoscope and middle ear (ME) samples were obtained by washing the ME fossa with 20 l of saline solution (ME with wash fluid [MEWF] samples) for determining the volume and presence of bacteria and cells. Amoxicillin levels in serum at 15, 30, 60, and 120 min after drug administration were determined in groups of six healthy animals after single s.c. injections of the doses that had demonstrated the highest efficacies.Concentrations of the antibiotic in ME fluid without washing (MEF samples) were also determined for groups of 10 bilaterally inoculated animals. Single s.c. doses of the antibiotic or control were administered 46 h after bacterial inoculation. MEF samples were obtained 90 min later, and aliquots were pooled for determination of the antibiotic concentrations.Antibiotic concentrations were determined by using Micrococcus luteus ATCC 9341. Assay variability for individual samples was Ͻ10%.Differences in eradication (and presence of otorrhea at day 1) were analyzed by ...

Does Acetaminophen Interfere in the Antibiotic Treatment of Acute Otitis Media Caused by a Penicillin-Resistant Pneumococcus Strain? A Gerbil Model

“…from 15% to 25% of the dosing interval), a value lower than that previously suggested (21). However, these data corroborated the results obtained by our group in a previous animal model of AOM caused by penicillin-resistant pneumococci treated with low doses of amoxicillin (22). The concentrations of both amoxicillin/clavulanic acid and erythromycin in the ME, as well as the percentages of penetration, were very similar to rates reported in children with AOM (18 -20).…”

Effect of Antibiotic Treatment Delay on Therapeutic Outcome of Experimental Acute Otitis Media Caused by Streptococcus pneumoniae Strains with Different Susceptibilities to Amoxicillin

“…The 5-mg/kg amoxicillin dose was chosen because it achieves serum and MEF drug concentrations in gerbils similar to those obtained in children receiving a standard dose for the treatment of AOM (4,12,21). This dose administered 2 h after bacterial inoculation prevented the development of AOM and, when administered 5 h after bacterial inoculation, was efficacious in the treatment of AOM.…”

“…For these reasons, we have studied the effect of delayed antibiotic administration on the course of experimental AOM caused by both penicillinsensitive and -resistant S. pneumoniae strains. This model has been very useful for evaluating antibiotic treatment either for AOM or for otitis media with effusion (OME) (1,2,4,21,23,25). Most of these experimental models have shown that many organisms inoculated into the middle ear (ME) are cleared by antibiotics active in vitro, but in most published studies the antibiotics were administered very early.…”

Animal Models ofStreptococcus pneumoniaeDisease

“…Infection was carried out by instilling bacteria directly into the ME by transbullar challenge (81). This system was employed in investigations on the efficacy and pharmacokinetics of ␤-lactams against otitis media caused by penicillin-and cephalosporin-resistant S. pneumoniae (17,18,54,190). Intrabullar challenge of gerbils with virulent pneumococci was also carried out to investigate the pathogenesis of pneumococcal meningitis secondary to otitis media (160,170).…”