An animal model of ventilator-associated pneumonia was obtained in immunocompetent rabbits. Histopathologic and bacteriologic features were similar to those found in humans. Obviously, pneumonia was more severe when animals underwent mechanical ventilation, especially in terms of systemic spread. Noninfectious lung injury corresponding to ventilation-induced lung injury may explain the difference. This model emphasizes the strong impact of both mechanical ventilation and infection on lung because they seem to act synergistically when causing alveolar damage. Moreover, it seems well suited to testing antimicrobial effectiveness.

In the present study we assessed the use of a new in vitro testing method and graphical representation of the results to investigate the potential effectiveness of combinations of amoxicillin (AMZ) plus ceftriaxone (CRO) and of CRO plus vancomycin (VAN) against strains of Streptococcus pneumoniae highly resistant to penicillin and cephalosporins (PRP strains). We used the fractional maximal effect (FME) method of time-kill curves to calculate adequate concentrations of the drugs to be tested rather than relying on arbitrary choices. The concentrations obtained, each of which corresponded to a fraction of the maximal effect, were tested alone and in combination with the bacterial strains in a broth medium. Synergy was defined as a ratio of observed effect/theoretical effect, called FME, of greater than 1, additivity was defined as an FME equal to 1, and antagonism was defined as an observed effect lower than the best effect of one of the antibiotics used alone. The area between antagonism and additivity is the indifference zone. The well-known synergy between amoxicillin and gentamicin against a reference strain of Enterococcus faecalis was confirmed, with a best FME equal to 1.07. Two strains of PRP, strains PRP-1 and PRP-2, were studied. The MICs for PRP-1 and PRP-2 were as follows: penicillin, 4 and 16 g/ml, respectively; AMZ, 2 and 8 g/ml, respectively, CRO, 1 and 4 g/ml, respectively; and VAN, 0.5 and 0.25 g/ml, respectively. For PRP-1 the best FME for the combination AMZ-CRO was 1.22 with drug concentrations of 1.68 mg/liter for AMZ and 0.17 mg/liter for CRO; the best FME for the combination VAN-CRO was 1.75 with VAN at 0.57 mg/liter and CRO at 0.17 mg/liter. For PRP-2 the best FME obtained for the combination AMZ-CRO was 1.05 with drug concentrations of 11.28 mg/liter for AMZ and 0.64 mg/liter for CRO; the best FME obtained for the combination VAN The emergence of strains of Streptococcus pneumoniae highly resistant to penicillin and cephalosporins (PRP strains) (5, 10) and, often, to other classes of antimicrobial agents (33) complicates empirical treatment of pneumococcal infections. Therefore, all potential modalities for the treatment of these infections must be considered (6). Ceftriaxone or vancomycin is often one of the drugs recommended for the treatment of severe infections due to PRP such as meningitis. However, a combination of amoxicillin and ceftriaxone could also be a candidate for the treatment of such infections.In this context, our purpose was, first, to investigate the in vitro interaction between amoxicillin and ceftriaxone and between vancomycin and ceftriaxone against PRP and, second, to identify the range of concentrations that are of clinical interest.The traditional methods used to test the in vitro interactions between drugs are not very satisfactory, with difficulties in the interpretation of the results (16). All these methods come from two original models: the Loewe additivity model (24), illustrated by isobolograms, and the Bliss independence model (4), illustrated by dose-effe...

Bone marrow aspirates were obtained by sternal puncture prior to sternotomy in 54 volunteers (40 males and 14 females) aged 60 years or more. All underwent surgery for cardiological diseases and had normal blood counts, without any haematological abnormalities. Quantitative examination of these bone marrow aspirates yielded reference ranges for each cell type similar to those obtained in younger adults. However, qualitative analysis revealed certain discrepancies: dysplastic changes were observed frequently, mainly in megakaryocytes and erythroblasts, with a normal growth pattern of haematopoietic progenitor cells. A low proportion of macrophages and mast cells were noted in 30% of the bone marrow aspirates. Lymphoid aggregates, seen in 13% of these samples, were generally of moderate size, contained few mast cells and were non-clonal on immunophenotypic analysis.

An experimental Streptococcus pneumoniae pneumonia model in rabbits was used to assess the efficacy of amoxycillin, erythromycin and a new ketolide, telithromycin (HMR 3647). The MICs of amoxycillin, erythromycin and HMR 3647 for the three clinical S. pneumoniae strains used were, respectively, (mg/L): 0.01, 16 and 0.02 (strain 195); 2, 0.25 and 0.02 (strain 16089); 8, >64 and 0.02 (strain 11724). Antibiotic therapy reproduced human serum pharmacokinetics (amoxycillin 1 g iv tds or erythromycin 500 mg qds or HMR 3647 800 mg bd). Forty-eight hours of therapy with HMR 3647 and amoxycillin resulted in significant bacterial clearance in the lungs and spleen of rabbits infected by S. pneumoniae strain 195 and strain 16089 (at least 3 log(10) cfu/g decrease, P < 0.001). Erythromycin was active against only the erythromycinsusceptible strain (3 log(10) cfu/g decrease at 48 h, P < 0.001). None of the antibiotics showed significant efficacy with strain 11724. All agents produced significant bacterial clearance when time above MBC was >33%, and microbiological failure when it was <25%, whereas MIC was not correlated with microbiological outcome with HMR 3647. Our findings suggest that pharmacodynamic data integrating MBC may be predictive of microbiological success or failure with greater accuracy than with MIC. HMR 3647 produced significant bacterial clearance in both penicillin- and erythromycin-resistant pneumonia, but was less effective against the highly erythromycin-resistant S. pneumoniae strain.

ImportanceExtended-spectrum β-lactamase (ESBL)–producing Escherichia coli is considered a leading pathogen contributing to the global burden of antimicrobial resistance.ObjectiveTo better understand factors associated with the heterogeneity of community-acquired ESBL-producing E coli urinary tract infections (UTIs) in France.Design, Setting, and ParticipantsThis cross-sectional study performed from January 1 to December 31, 2021, was based on data collected via PRIMO (Surveillance and Prevention of Antimicrobial Resistance in Primary Care and Nursing Homes), a nationwide clinical laboratory surveillance system in France. Strains of E coli isolated from community urine samples from January 1 to December 31, 2019, from 59 administrative departments of metropolitan France were included.Main Outcomes and MeasuresQuasi-Poisson regression models were used to assess the associations between several ecological factors available on government and administration websites between 2010 and 2020 (demographic population structure, living conditions, baseline health care services, antibiotic consumptions, economic indicators, animal farming density, and environmental characteristics) and the number of ESBL-producing E coli strains isolated from urine samples of individuals with community-acquired UTI in 2019.ResultsAmong 444 281 E coli isolates from urine samples tested in 1013 laboratories, the mean prevalence of ESBL-producing E coli was 3.0% (range, 1.4%-8.8%). In an adjusted model, the number of community-acquired ESBL-producing E coli UTIs in each department was positively associated with the percentage of children younger than 5 years (adjusted β1 coefficient, 0.112 [95% CI, 0.040-0.185]; P = .004), overcrowded households (adjusted β1 coefficient, 0.049 [95% CI, 0.034 to 0.062]; P &lt; .001), consumption of fluoroquinolones (adjusted β1 coefficient, 0.002 [95% CI, 0.001-0.002]; P &lt; .001), and tetracyclines (adjusted β1 coefficient, 0.0002 [0.00004 to 0.00039]; P = .02), and poultry density (adjusted β1 coefficient, 0.0001 [95% CI, 0.0001-0.0002]; P &lt; .001). The social deprivation index (adjusted β1 coefficient, −0.115 [95% CI, −0.165 to −0.064]; P &lt; .001) and the proportion of water surface area (adjusted β1 coefficient, −0.052 [−0.081 to −0.024]; P = .001) were negatively associated with a higher number of community-acquired ESBL-producing E coli UTIs.Conclusions and RelevanceThe findings of this cross-sectional study suggest that multiple human health, animal health, and environmental factors are associated with the occurence of community-acquired ESBL E coli UTI. Strategies to mitigate ESBL in the community should follow the One Health approach and address the role played by fluoroquinolones, tetracycline use, poultry density, overcrowded households, and preschool-aged children.