María José Giménez

Role of Streptococcus pneumoniae and Haemophilus influenzae in the Development of Acute Otitis Media and Otitis Media with Effusion in a Gerbil Model

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 (P</=.001) after administration of 5 mg/kg of either drug (amoxicillin/clavulanate, 100% vs. 10%; cefuroxime, 73.3% vs. 10%). Efficacy was predicted by the relation of in vitro susceptibility and ME antibiotic concentration, which was 2.7 times higher in AOM than in OME. In the mixed otitis model, the most efficacious antibiotic was able to prevent AOM, but >80% of animals developed culture-negative OME.

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 μg/ml and concentrations in serum higher than the MIC (1 μg/ml) for ≥14% of the dosing interval, were both clinically and bacteriologically effective.

Efficacy and pharmacodynamics of gemifloxacin versus levofloxacin in guinea pig pneumococcal pneumonia induced by strains with decreased ciprofloxacin susceptibility

Quinolone in vivo bactericidal activity was investigated in a guinea pig pneumonia model using three Streptococcus pneumoniae strains with decreasing susceptibility to ciprofloxacin. Treatment regimens resulted in values of AUC(0-24 h) and C(30 min) similar to those of standard oral regimens in human serum. Efficacy was defined as a significant difference in number of viable bacteria in the lungs compared with the control. Ciprofloxacin, levofloxacin and gemifloxacin were effective against the levofloxacin-susceptible strain. Only gemifloxacin achieved a >/=99.9% reduction versus control against the levofloxacin intermediate-resistant strain. Gemifloxacin achieved a 99.69% reduction and was the only quinolone significantly different from the control (P<0.05) against the levofloxacin-resistant strain. Gemifloxacin offers in vivo activity against ciprofloxacin- to levofloxacin-resistant pneumococci.

Influence of diminished susceptibility of Streptococcus pneumoniae to ciprofloxacin on the serum bactericidal activity of gemifloxacin and trovafloxacin after a single dose in healthy volunteers

The serum bactericidal activity against 2 Streptococcus pneumoniae strains (ciprofloxacin MIC 1 and 4 mg/l) was measured in 12 volunteers who received oral single doses of gemifloxacin 320 mg and trovafloxacin 200 mg in a crossover fashion. The 4-fold increase in ciprofloxacin MIC from the susceptible to the resistant strain resulted in a 2-fold increase in MIC (from 0.015 to 0.03 mg/l), a 2-fold decrease in C(max)/MIC (104 vs 52) and in AUC(0-24 h)/MIC (532 vs 266), but a 5.6-fold decrease in area under the bactericidal curve (AUBC: 168 vs 30) for gemifloxacin. Trovafloxacin showed a 4-fold higher MIC (0.25 vs 0.06 mg/l), a 4-fold lower C(max)/MIC (8.6 vs 36), a 4-fold lower AUC(0-24 h)/MIC (85 vs 356) and a 11-fold lower AUBCs (2 vs 22) against the resistant isolate compared with the susceptible one. Trovafloxacin serum bactericidal titres against the ciprofloxacin-resistant strain were measurable generally only at 1 h after dosing (median titre=2). Gemifloxacin showed similar ex vivo bactericidal activity against the ciprofloxacin-resistant strain to that of trovafloxacin against the ciprofloxacin-susceptible strain.

Antibacterial Properties of Gemifloxacin and Trovafloxacin in Urine Ex Vivo: Phase I Study

ABSTRACT Urine bactericidal titers (UBTs) againstEscherichia coli ATCC 25922 and Staphylococcus saprophyticus ATCC 1970 were determined after the administration of single oral doses of gemifloxacin at 320 mg and trovafloxacin at 200 mg to healthy volunteers. Gemifloxacin presented significantly lower experimental versus mathematically predicted UBTs over 72 h, due to the effect of urine on the susceptibility of the E. colistrain. Experimental UBTs were significantly higher for gemifloxacin than trovafloxacin against both strains over 72 h.

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

The possible interference of acetaminophen, combined with antibiotics, in the treatment of acute otitis media (AOM) caused by a penicillin-resistant (minimal inhibitory concentration [MIC], 2 μg/mL), amoxicillin/clavulanic acid– and erythromycin-sensitive pneumococcus was evaluated in a gerbil model. Animals were challenged with ∼5 × 106 bacteria in each ear through transbullar instillation. Acetaminophen was administered s.c. at 50 mg/kg 30 min before each antibiotic dose. Amoxicillin/clavulanic acid and erythromycin (2.5 and 10 mg/kg) were administered s.c. at 2, 10, and 18 h after inoculation. Samples were obtained from the middle ear (ME) on day 2 after inoculation for bacterial count. The overall results showed no difference between animals that received acetaminophen, with or without antibiotics, and those that did not receive acetaminophen. The antibiotic concentrations in the ME were practically identical in both groups of animals, so acetaminophen did not interfere with the pharmacokinetics of antibiotics in the ME. However, both antibiotics significantly reduced the number of culture-positive and the bacterial concentration in ME samples when compared with antibiotic-untreated animals. Both antibiotics, whether combined with acetaminophen or not, lowered the number of AOM to <25%, but >75% of animals presented otitis media with effusion, and no differences were shown between groups. A high rate of bacterial eradication from the ME correlated with antibiotic serum concentrations being over the MIC of the infecting organism for only >15% of the dose interval and with an ME concentration exceeding the MIC by a factor of 1.7. In this experimental model, acetaminophen had neither a synergistic nor an antagonistic effect on the antibiotics tested.

Effects of Single Oral Doses of Gemifloxacin (320 Milligrams) versus Trovafloxacin (200 Milligrams) on Fecal Flora in Healthy Volunteers

ABSTRACT Gemifloxacin and trovafloxacin were administered to 12 volunteers in a randomized crossover trial with a 2-week washout period. Stool samples were collected predose and 1, 2, and 3 days postdose. Both quinolones reduced the number of organisms of the familyEnterobacteriaceae and aerobic gram-positive organisms. Escherichia coli reduction was greater with gemifloxacin than with trovafloxacin, with postdose isolation of quinolone-resistant strains for which MICs of trovafloxacin were higher than those of gemifloxacin.

Pulmonary Damage and Bacterial Load in Assessment of the Efficacy of Simulated Human Treatment-Like Amoxicillin (2,000 Milligrams) Therapy of Experimental Pneumococcal Pneumonia Caused by Strains for Which Amoxicillin MICs Differ

ABSTRACT An experimental rat pneumonia model using two amoxicillin-susceptible (MICs, ≤0.015 and 2 μg/ml) and two non-amoxicillin-susceptible (MIC, 4 μg/ml) Streptococcus pneumoniae strains was developed for testing the efficacy of amoxicillin administered to simulate human serum kinetics after treatment with amoxicillin-clavulanate (2,000 and 125 mg, respectively, twice a day, for 2.5 days). The end points for efficacy were reductions in bacterial loads in the lungs and reductions in levels of pulmonary damage. For the amoxicillin-susceptible strains (serotypes 23F and 14), a decrease greater than 4.5 log10 CFU/pair of lungs was obtained, and the time for which the serum antibiotic concentration (SAC) was higher than the MIC (TSAC>MIC) was greater than 60% of the dosing interval. For non-amoxicillin-susceptible strains, the decrease in bacterial load was 1.34 to 1.75 log10 CFU/pair of lungs, with a TSAC>MIC of 46.7% of the dosing interval. An in vitro study showed that serotype 9V non-amoxicillin-susceptible strains behaved as tolerant-like to concentrations similar to those in the in vivo model. The high and maintained SACs (TSAC>MIC, >46% for all strains) significantly diminished lung injury (affected area of the lung and lung weight), compared to that in controls, by all strains, regardless of the MIC, bactericidal behavior in in vitro killing curves, or the serotype of the infecting strain. These results show the importance of host therapeutic end points in the evaluation of antibiotic efficacy. The antibiotic was more efficacious, for one nonsusceptible strain tested, when the treatment was started early (1 h postinoculation [p.i.]) than when treatment was delayed (24 h p.i.).

Opsonophagocytosis versus complement bactericidal killing as effectors following Neisseria meningitidis group C vaccination

Abstract.Background: Opsonophagocytosis and complement-mediated Neisseria meningitidis killing after vaccination were investigated. Methods: Twelve seronegative healthy volunteers received one dose of polysaccharide A/C vaccine and were followed for 3 years. Ex vivo serum killing rates with polymorphonuclear cells (PMN) and/or complement were performed at 0, 1.5, 6, 12, 18, 24, 30 and 36 months. Results: High mean total and median bactericidal antibodies were detected over time in all subjects. Considerable reduction of the initial inoculum was obtained only in the presence of complement, with or without PMN (with significant differences compared to curves without complement) a long time after vaccination. Conclusion: PMN did not increase post-vaccination bacterial killing, suggesting that antibody complement-mediated killing, and not opsonophagocytosis, is the main immune effector of the vaccine protection against N. meningitidis.

Ex vivo bactericidal activity against group C Neisseria meningitidis in seronegative subjects.

SummaryBackground: To determine the anti-meningococcal C immunological activity by adding functional tests (opsonophagocytosis) to the classical serology techniques. Subjects and Methods: 42 adult volunteers were screened using serological methods (determination of total and bactericidal antibodies). Seronegative subjects were tested by opsonophagocytosis. Results: 24 subjects (57%) showed serological evidence of previous contact with Neusseria meningitidis group C antigens: 19 subjects had both total and bactericidal antibodies, two subjects had only total antibodies and three subjects had only bactericidal antibodies. Of the 18 seronegative subjects, five showed ex vivo activity in killing curves with or without polymorphonuclear cells: two subjects exhibited only complement-mediated bactericidal activity, one subject only opsonophagocytosis, and two subjects exhibited both activities. Conclusion: The addition of functional tests to the classical serological determination increases the evidence of previous contact with N. meningitidis antigens by 12%.