The efficacy of amoxicillin/clavulanate and cefuroxime was determined in a gerbil model of otitis media with a mixed Streptococcus pneumoniae plus Haemophilus influenzae middle ear (ME) infection. Results were compared with those obtained in a previous single H. influenzae model. All untreated animals inoculated with the mixed inoculum developed acute otitis media (AOM), whereas 86.7% of those inoculated with H. influenzae developed otitis media with effusion (OME). Antibiotics eradicated H. influenzae from the ME more efficiently in AOM than in OME, and this difference was highly significant (P80% of animals developed culture-negative OME.

In an attempt to determine the susceptibility breakpoints for amoxycillin, co-amoxiclav and cefotaxime in pneumococcal pneumonia, a neutropenic mouse model was established and tested with two strains having different susceptibility to penicillins and cefotaxime. With a penicillin-sensitive strain (MIC/MBC = 0.01/0.01 mg/L) the minimum dosage tested achieving significant cure was 2 mg/kg for amoxycillin, co-amoxiclav and cefotaxime. For the penicillin-insensitive strain (MIC/MBC = 1/2 mg/L), the minimum dosage tested giving significant cure was 50 mg/kg for amoxycillin and co-amoxiclav but 100 mg/kg for cefotaxime. Our results support the belief that MICs of amoxycillin, co-amoxiclav and cefotaxime for pneumococcal strains of < or = 0.5 or < or = 1 mg/L can be considered as clinically relevant susceptibility breakpoints.

Acute respiratory infection with penicillin-insensitive Streptococcus pneumoniae (MIC and MBC, 1 and 2 micrograms/ml, respectively) was established in guinea pigs. Intratracheal instillation of 0.5 ml of an overnight culture of S. pneumoniae concentrated 25 times (approximately 3 x 10(9) CFU) induced a bacteremic and fatal pneumonia in > 85% of untreated animals within 46 h, with a mean +/- standard deviation bacterial count of 8.83 +/- 1.11 log10 CFU in lung homogenates. This model was used to evaluate the efficacies of two doses each of amoxicillin, cefotaxime, and meropenem given 1 h after bacterial inoculation. The antibiotics were given at 8-h intervals for up to a total of four injections. The dose of 50 mg of any antibiotic per kg of body weight gave 66.6% survival, compared with 5.05% survival for untreated control animals (P < 0.001). A dose of 200 mg/kg gave a survival rate of 77.8% for meropenem and 83.3% for amoxicillin and cefotaxime, while survival for untreated controls was 11.1% (P < 0.001). Although antibiotic treatment decreased mortality compared with that in untreated controls, the antibiotics contributed to a high early (less than 9 h after bacterial inoculation) mortality, being 53.5% compared with only 6.06% for the untreated controls (P < 0.001). Quantitative cultures of the lungs of animals that died during the 46-h observation period or that were killed after this time showed a significant reduction in the numbers of organisms among treated animals compared with numbers among the control animals (P < 0.001). The described model is an appropriate system for evaluating antibiotic efficacy in invasive pulmonary infection caused by penicillin-insensitive S. pneumoniae.

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 ...

A gerbil model of otitis media induced by a beta-lactamase producing and non-serotypeable isolate of Haemophilus influenzae was used to assess the in-vivo efficacy of co-amoxiclav and cefuroxime at low (5 mg/kg) and high (20 mg/kg) doses. The MIC of the antibiotics tested against the pathogen was 1 mg/L (1/0.5 mg/L for co-amoxiclav). The organism was inoculated (+/-10(6) cfu) by transbullar challenge directly in the middle ear and antibiotic treatment was commenced 2 h post-inoculation and continued at 8 h intervals for three doses. Only high dose co-amoxiclav significantly reduced the number of culture-positive specimens as compared with untreated animals or with other treatment groups (91.7% as compared with 36.7% for high dose cefuroxime). The results obtained in any treatment group were related to middle ear antibiotic level/MIC. Antibiotic concentrations in the middle ear 90 min after administration were about 10% of serum levels at 15 min, probably related to a slight inflammatory response. Only after high dose co-amoxiclav did the concentration in the middle ear exceed the MIC by a factor of four. In otitis media with effusion, if indicated, antibiotics active in vitro should be administered in high doses and, to avoid side effects, probably in short courses.