Using a rabbit model of meningitis, we sought to determine whether concomitant use of dexamethasone affects the penetration and efficacy of ceftriaxone or vancomycin in cerebrospinal fluid. Rabbits were inoculated with a penicillin-sensitive strain of Streptococcus pneumoniae and treated with ceftriaxone or vancomycin with or without dexamethasone. In the ceftriaxone-treated groups, no statistically significant differences were seen between the group treated with dexamethasone and that without dexamethasone; however, in the vancomycintreated groups we found statistically significant lower cerebrospinal fluid vancomycin levels at 2 h in the dexamethasone-treated rabbits and differences in bacterial killing.Dexamethasone (DEX) has been shown to down modulate inflammatory activity in experimental bacterial meningitis, to reduce neurological sequelae in pediatric Haemophilus influenzae and pneumococcal meningitis, and to reduce mortality in adult pneumococcal meningitis (5,7,9,10,12,14). However, the routine use of DEX as adjunctive therapy in bacterial meningitis is not yet widely accepted because of (i) its potential adverse effects, especially the possibility of gastrointestinal bleeding; (ii) the difficulties in assessing adequately the clinical evolution of meningitis, since DEX is associated with a more rapid decrease in fever; (iii) the possibility of deleterious effects in cases of viral meningitis; and (iv) the concerns of some about the possibility of DEX interfering with an adequate penetration of antibiotics in cerebrospinal fluid (CSF) (1, 13).In 1988 we carried out a study using vancomycin (VAN) in the therapy of adult pneumococcal meningitis (15) in order to explore real alternatives in the therapy of such an infection. The study was discontinued after 11 patients had been treated because of four therapeutic failures, all of them following an initial improvement. VAN levels in CSF were erratic, and the concomitant use of DEX, which was used in all cases as an early adjunctive therapy, was invoked as a possible explanation.On the other hand, ceftriaxone (CRO) is being widely used as a therapy of bacterial meningitis because of its broad spectrum of activity, its safety, and its efficacy, so we wanted to study the possible influence of DEX when used with either antibiotic in the therapy of pneumococcal meningitis. Recently, Paris et al. (11) published a work in which the rabbit model of pneumococcal meningitis was used to study the problem of the penetration in CSF of antibiotics used in conjunction with DEX. The experiments covered 24 h of therapy and showed a decrease in VAN penetration in CSF.
Using a rabbit model of meningitis, we sought to determine the efficacy of LY333328, a semisynthetic glycopeptide, in the treatment of cephalosporin-resistant pneumococcal meningitis. LY333328 was administered at a dose of 10 mg/kg of body weight/day, alone and in combination with ceftriaxone at 100 mg/kg/day with or without dexamethasone at 0.25 mg/kg/day. The therapeutic groups were treated with LY333328 with or without dexamethasone and LY333328-ceftriaxone with or without dexamethasone. Rabbits were inoculated with a cephalosporin-resistant pneumococcal strain (ceftriaxone MIC, 2 g/ml; penicillin MIC, 4 g/ml; LY333328 MIC, 0.008 g/ml) and were treated over a 26-h period beginning 18 h after inoculation. The bacterial counts in cerebrospinal fluid (CSF), the white blood cell count, the lactic acid concentration, the CSF LY333328 concentration, and bactericidal and bacteriostatic activities were determined at different time points. In vitro, LY333328 was highly bactericidal and its use in combination with ceftriaxone at one-half the MIC was synergistic. In the rabbit model, LY333328 alone was an excellent treatment for cephalosporin-resistant pneumococcal meningitis, with a rapid decrease in colony counts and no therapeutic failures. The use of LY333328 in combination with ceftriaxone improved the activity of LY333328, but no synergistic effect was observed. The combination of LY333328 with dexamethasone was also rapidly bactericidal, but two therapeutic failures were observed. The combination of LY333328 with ceftriaxone and dexamethasone was effective, without therapeutic failures.The treatment of cephalosporin-resistant pneumococcal meningitis is a challenging issue. High doses of cefotaxime have been successfully used to treat infections caused by organisms with intermediate resistance to expanded-spectrum cephalosporins, but sporadic failures have also occurred (3,6,24). Experience with the treatment of adult patients with systemic vancomycin alone is very limited, and therapeutic failures have been reported (23), especially when vancomycin is used in combination with dexamethasone. Some experimental studies have suggested that vancomycin plus ceftriaxone would be synergistic against pneumococci (11), and most experts recommend use of this combination for the empirical therapy of pneumococcal meningitis (12, 16).LY333328 is a semisynthetic glycopeptide antibiotic derived from LY264826, which is active in vitro against gram-positive pathogens including methicillin-and amynoglycoside-resistant Staphylococcus aureus; coagulase-negative staphylococci; enterococci, including some enterococci resistant to vancomycin; and susceptible and penicillin-and cephalosporin-resistant Streptococcus pneumoniae (2,10,13,20,22). LY333328 has been demonstrated to have efficacy in animal models of S. pneumoniae septicemia, vancomycin-resistant enterococcal endocarditis, S. aureus endocarditis, S. aureus catheter-related infections, S. aureus soft tissue infections, and S. aureus foreign body-related skin infections (1, 17). A...
The object of the study was to assess the efficacy of rifampicin and the combination of rifampicin plus vancomycin in a rabbit model of experimental penicillin-resistant pneumococcal meningitis. We also studied the effect of concomitant dexamethasone on the CSF antibiotic levels and inflammatory parameters. The rabbit model of pneumococcal meningitis was used. Groups of eight rabbits were inoculated with 106 cfu/mL of a cephalosporin-resistant pneumococcal strain (MIC of cefotaxime/ceftriaxone 2 mg/L). Eighteen hours later they were treated with rifampicin 15 mg/kg/day, vancomycin 30 mg/kg/day or both plus minus dexamethasone (0.25 mg/kg/day) for 48 h. Serial CSF samples were withdrawn to carry out bacterial counts, antibiotic concentration and inflammatory parameters. Rifampicin and vancomycin promoted a reduction of >3 log cfu/mL at 6 and 24 h, and cfu were below the level of detection at 48 h. Combination therapy with vancomycin plus rifampicin was not synergic but it had similar efficacy to either antibiotic alone and it was able to reduce bacterial concentration below the level of detection at 48 h. Concomitant use of dexamethasone decreased vancomycin levels when it was used alone (P< 0.05), but not when it was used in combination with rifampicin. Rifampicin alone at 15 mg/kg/day produced a rapid bactericidal effect in this model of penicillin-resistant pneumococcal meningitis. The combination of vancomycin and rifampicin, although not synergic, proved to be equally effective. Using this combination in the clinical setting may allow rifampicin administration without emergence of resistance, and possibly concomitant dexamethasone administration without significant interference with CSF vancomycin levels.
This article provides an overview of the evolution of the in-situ consolidation (ISC) process over time. This evolution is intimately linked with the advancements in each of the steps of the ISC manufacturing process, is additive in nature, and is limited by the orthotropic nature of composite materials and the physicochemical behavior of the thermoplastic matrix. This review covers four key topics: (a) Thermal models—simulation tools are critical to understand a process with such large spatial gradients and fast changes. Heating systems once marked a turning point in the development of industrial ISC systems. Today, lasers are the most recent trend, and there are three key issues being studied: The absorption of energy of light by the material, the laser profile, and the laser focusing. Several approaches have been proposed for the distributed temperature measurements, given the strong temperature gradients. (b) Adhesion—this refers to two subsequent mechanisms. In the first place, the process of intimate contact is one by which two surfaces of thermoplastic pre-impregnated composite materials are brought into contact under pressure and temperature. This enables closure of the existing gaps between the two microscopic irregular surfaces. This process is then followed by the healing or diffusion of polymer molecules across the interface. (c) Crystallinity—mostly influenced by the cooling rate, and strongly affects the mechanical properties. (d) Degradation—this refers to the potential irreversible changes in the polymer structure caused by the high temperatures required for the process. Degradation can be avoided through adequate control of the process parameters. The end goal of the ISC manufacturing process is to achieve a high product quality with a high deposition rate through an industrial process competitive with the current manufacturing process for thermoset composites.
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