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Biomedical subjects

C Ponte

Publications and source records attributed to C Ponte.

At least 19 recordsLinked to original sources
PubMed2003

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.

Animals↗
PubMed2002

Effect of dexamethasone and pentoxifylline in combination with amoxicillin in the treatment of penicillin-insensitive pneumococcal pneumonia in guinea pigs.

A fatal guinea pig model of pneumococcal pneumonia was developed in order to evaluate the efficacy of amoxicillin combined with either pentoxifylline or dexamethasone. Parameters assessed were survival time and lung changes (alterations, bacterial colony counts, inducible nitric oxide synthase [iNOS] and cyclooxygenase-2 [COX-2] protein expression). Animals receiving pentoxifylline (50 mg/kg) showed higher survival rates than controls (p < 0.05). Animals which received amoxicillin (50 mg/kg), alone or combined, showed significantly higher survival rates than controls (p < 0.05). Animals dying in spite of receiving amoxicillin alone or combined had lung colony counts significantly lower than those that did not receive the antibiotic (p < 0.001), but their lungs showed identical changes. The correlation between COX-2 protein expression and mortality was rather high (r = 0.75). The addition of either dexamethasone or pentoxifylline to amoxicillin improved neither survival rates nor lung pathology when compared with the antibiotic alone.

Amoxicillin↗
PubMed2001

Effects of single oral doses of gemifloxacin (320 milligrams) versus trovafloxacin (200 milligrams) on fecal flora in healthy volunteers.

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 family Enterobacteriaceae 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.

Anti-Infective Agents↗
PubMed2001

Antibacterial properties of gemifloxacin and trovafloxacin in urine ex vivo: phase I study.

Urine bactericidal titers (UBTs) against Escherichia 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. coli strain. Experimental UBTs were significantly higher for gemifloxacin than trovafloxacin against both strains over 72 h.

Administration, Oral↗
PubMed2000

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.

Acute Disease↗
PubMed1999

Antimicrobial treatment of an experimental otitis media caused by a beta-lactamase positive isolate of Haemophilus influenzae.

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.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed1998

In vivo efficacies of amoxicillin and cefuroxime against penicillin-resistant Streptococcus pneumoniae in a gerbil model of acute otitis media.

The comparative efficacies of amoxicillin and cefuroxime against acute otitis media caused by a penicillin-resistant (MIC, 2 micrograms/ml) Streptococcus pneumoniae strain were assessed in a gerbil model by challenging each ear with 10(7) bacteria through transbullar instillation. Each antibiotic was tested at two doses (5 and 20 mg/kg of body weight) administered at 2, 10, and 18 h postinoculation. Samples were obtained from the middle ear (ME) on days 3 and 7 postinoculation for determination of bacterial counts. Only amoxicillin, at both doses, was able to significantly halt the weight loss in animals, reducing both the number of culture-positive animals and the bacterial concentration in ME samples versus the values for untreated animals. Comparison of the efficacies between the antibiotics, determined by their ability to achieve culture-negative ME specimens, showed that amoxicillin at 5 mg/kg was significantly more active than cefuroxime at the same dose. The use of higher doses of either amoxicillin or cefuroxime did not produce significantly better results than those obtained with the lower dose but caused a greater inflammatory response. The more favorable results obtained with amoxicillin compared with those obtained with cefuroxime could be related to the antimicrobial susceptibility of the pneumococcal strain (MICs and minimum bactericidal concentrations of 1 and 1 microgram/ml and 4 and 4 micrograms/ml for amoxicillin and cefuroxime, respectively) as well as to the better pharmacokinetic parameters obtained with amoxicillin.

Acute Disease↗
PubMed1997

A thyroxine dosage of 8 micrograms/kg per day is appropriate for the initial treatment of the majority of infants with congenital hypothyroidism.

UNLABELLED: The adequate L-thyroxine dosage for the initial treatment of infants with congenital hypothyroidism is a subject of controversy. Some recommend higher dosages (> 10 micrograms/kg/day) to ensure adequate levels, while others advocate lower dosages to permit normalisation of thyroid status. The aim of this study was to evaluate the results of a treatment strategy using an initial dosage of 7.5-8.0 micrograms/kg per day, TSH measurements being taken at 15 and 30 days of treatment. Fifty one newborns infants with primary congenital hypothyroidism detected by neonatal screening were treated with the same therapeutic strategy. A mean L-thyroxine dosage of 7.9 micrograms/kg per day at the onset of treatment and 6.6 micrograms/kg/d at 2 months, normalised the FT4 and FT3 levels at 15 days in 100% and TSH levels at 2 months in 90% of cases. Many patients showed elevated levels of FT4 and a systematic higher initial dosage could expose many infants to a dangerous hyperthyroidism. Patients with abnormal TSH levels at 2 months already had higher TSH levels in the first 8 weeks of life and, despite higher L-thyroxine dosage, also exhibited lower FT4 and FT3 levels. These patients who needed an early increase in dosage had already shown a more profound ante and neonatal hypothyroidism. This subgroup of patients require a higher dosage of thyroxine and early assessment of FT4, FT3 and TSH levels are required for optimum dosage choice. CONCLUSION: Even though a subgroup of patients may require a higher dosage of L-thyroxine, an initial dosage of 7.5-8.0 micrograms/kg per day, with an early assessment of FT4, FT3, and TSH levels, is adequate for the treatment of the majority of infants with congenital hypothyroidism.

Congenital Hypothyroidism↗
PubMed1997

[Induction of interleukin-6 by Borrelia burgdorferi in different cell cultures].

BACKGROUND: To determine variability, if exists, in interleukin-6 (IL-6) response by different cell cultures stimulated by Borrelia burgdorferi. METHODS: Five human embryonic diploid fibroblast cell lines (three of them of lung origin) and four human synovial cell cultures were used. Induction of IL-6 was made with B. burgdorferi B31 culture and E. coli lipopolysaccharide (LPS). IL-6 was determined by a commercial EIA (Coaliza IL-6). RESULTS: All cell cultures produced IL-6 under basal conditions and responded after adding E. coli LPS. The IL-6 production after B. burgdorferi stimulation was higher than that induced by LPS with three out the four synovial cell cultures and lowest with lung fibroblasts. CONCLUSIONS: The ability of B. burgdorferi to stimulate IL-6 production depends on the nature and origin of cell cultures. This variability and the fact that the most reactive cell cultures were those of synovial precedence may correlated with some clinical aspects of the Lyme disease.

Borrelia burgdorferi Group↗
PubMed1997

In vitro antibiotic sensitivity testing breakpoints and therapeutic activity in induced infections in animal models.

Antimicrobial susceptibility breakpoints are artificially designated to classify organisms as susceptible, intermediate or resistant but such values may differ according to the relative weight given to the microbiological, pharmacological and clinical information. Animal models of bacterial infections are considered necessary to establish tentative breakpoints before initiating clinical trials in humans. Studies in animals provide a preliminary indication of the most effective and least toxic concentration of the antibiotic and give a rational basis for the selection of dosages and schedules. Animal models of therapeutic efficacy have demonstrated the importance of the inoculum effect, showing that the minimum inhibitory concentration (MIC) determined with high inoculum (10(7)-10(8) CFU/ml) is, under some experimental conditions, a better predictor of therapeutic efficacy than the value obtained with standard (10(4)-10(5) CFU/Ml) inoculum. Studies in animals have demonstrated the failure of some fluoroquinolones in respiratory tract infections where Streptococcus pneumoniae was present or the efficacy of penicillins and third-generation cephalosporins for treating respiratory tract infections and meningitis by pneumococci with diminished susceptibility to such agents. Although most therapeutic models in animals should be carried out during preclinical studies, many are done during later phases of antibiotic development, as explicate models of what is seen in clinical practice.

Animals↗
PubMed1996

Three years of GH treatment in Turner's syndrome: complex effect of GH dosage on growth parameters. French Pediatric Clinics and Sanofi-Winthrop.

OBJECTIVE: There have been few studies of GH dose responses in Turner's syndrome. We have therefore compared the growth effect of two doses of subcutaneous GH: 0.45 (D1) or 0.90 (D2) IU/kg/week. DESIGN: Multicentre study with two parallel randomized groups treated with D1 or D2 dose for one year, then with D2 for the second and third years in both groups. PATIENTS: Ninety-seven girls with Turner's syndrome aged from 4.8 to 16.5 years. RESULTS: The first mean height velocity (HV) was significantly higher with D2. At one year the girls changed from D1 to D2 showed a further acceleration in HV. During second and third years HV remained above the mean for untreated Turner girls, in both groups. Mean cumulative height gains over the 3 years were 1.06 and 1.17 SDS/CA (Ranke's Turner standard) in groups G1 and G2 respectively. Bone maturation, over 36 months, was 33.7 (G1) and 31.9 (G2) months. CONCLUSION: These results suggest that, if a higher initial GH dose is associated with a greater net initial height gain, the duration of treatment might affect the long-term results. Intermittent treatment should be considered.

Adolescent↗
PubMed1996

Correlation of in-vitro activity and pharmacokinetic parameters with in-vivo effect of amoxycillin, co-amoxiclav and cefotaxime in a murine model of pneumococcal pneumonia.

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.

Amoxicillin↗
PubMed1996

Correlation of pharmacodynamic parameters of five beta-lactam antibiotics with therapeutic efficacies in an animal model.

The MIC is the main microbiologic parameter used to predict the efficacies of antibiotics. However, it is well known that MICs may vary according to the inoculum size used (inoculum effect), especially with some beta-lactam antibiotics. In order to correlate the pharmacologic and microbiologic properties of some beta-lactams, an experimental model of intraperitoneal infection caused by Escherichia coli in nonneutropenic and neutro-penic mice was developed. The animals were treated with three different doses of either ampicillin, piperacillin, aztreonam, cefazolin, or cefotaxime. The linear regression analysis obtained in our model shows a better correlation between in vitro activity and efficacy when the MICs considered were those obtained with a large inoculum (ca. 1 x 10(8) CFU/ml) instead of the standard inoculum (5 x 10(5) CFU/ml). The correlations for the MICs obtained with the large inoculum were 0.78 for log2 maximum concentration of drug in serum (Cmax)/ MIC, 0.72 the time that the concentrations exceeded the MIC, and 0.79 for log2 area under the serum concentration-time curve (AUC)/MIC at 24 h in nonneutropenic mice. The corresponding values in neutropenic mice, also for the MICs obtained with the large inoculum, were 0.54, 0.68, and 0.64, respectively, at 24 h. A good correlation was also obtained for the same parameters in nonneutropenic mice at 48 h. The values of Cmax, AUC, and the time that the concentrations exceeded the MIC were parallel among the antibiotics studied, and our study confirms that the time that the levels in serum exceed the MIC is a significant parameter determining the efficacies of beta-lactam antibiotics, but the correlation is much better when the MICs obtained with the large inoculum instead of those obtained with the standard (low) inoculum are considered.

Ampicillin↗
PubMed1996

Development of experimental pneumonia by infection with penicillin-insensitive Streptococcus pneumoniae in guinea pigs and their treatment with amoxicillin, cefotaxime, and meropenem.

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↗
PubMed1996

Follow-up of three years of treatment with growth hormone and of one post-treatment year, in children with severe growth retardation of intrauterine onset.

Seventy-eight prepubertal, non-GH-deficient children aged 8.1 +/- 0.2 y, with very short stature (mean, -3.2 SD) of intrauterine onset, were treated for 3 y with GH [0.4 (dose D1) or 1.2 (dose D2) IU/kg/wk] and 66 were followed during a 4th y without GH therapy. A 2-y intermediary report had demonstrated a GH dose-dependent acceleration of growth. During the 3rd y on GH, patients D2 (1.2 IU/kg/wk) continued with the same dose, whereas patients D1 (0.4 IU/kg/wk) were randomized to either continue on D1 (group D1) or be increased to D2 (group D1D2). After 3 y on GH, patients' mean height (SD) reached -2.37 (D1), -2.17 (D1D2), and -1.58 (D2) with a total mean height gain of 0.77 (D1), 0.93 (D1D2) (difference NS), and 1.61 SD (D2 significantly higher than D1 and D1D2, p < or = 0.0001). During the off-treatment year, mean growth rate (cm/y) decreased to 3.4 in patients D1, 3.7 in D1D2, and 4.1 in D2 (NS). During the 4 y, bone age advanced of 4.6, 4.6, and 5.3 y in D1, D1D2, and D2, respectively, and puberty started in 34 patients (10 during the off-treatment year). Age at onset of puberty, apparently within normal range, did not relate either to the dose or the duration of treatment. Clinical and biologic tolerance of treatment was good. In conclusion this study demonstrates a GH dose-dependent effect on growth acceleration in persistent postnatal severe growth retardation of intrauterine onset. This effect was sustained for 3 y at 1.2 IU/kg/wk followed by a peculiar growth deceleration at treatment discontinuation. Additional studies are necessary to optimize long-term GH treatment regimen and to document its effects on final height.

Body Height↗