Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy.

RATIONALE: Xanthomatosis associated with monoclonal gammopathy includes hyperlipidaemic xanthoma (HX), normolipidaemic xanthoma (NX) and necrobiotic xanthogranuloma (NXG). All three pathologies are characterized by skin or visceral lesions related to cholesterol accumulation, monoclonal immunoglobulin (MIg) and hypocomplementemia. The pathophysiology underlying NXG remains unknown although the involvement of MIg is suspected. OBJECTIVE: To provide further insights into the pathophysiology of NXG, we evaluated the plasma lipid phenotype, mechanisms involved in cellular cholesterol accumulation and role of MIg in an analysis of blood and plasma markers of inflammation in 16 patients with xanthomatosis [NXG (n = 8) and NX (n = 8)] associated with monoclonal IgG relative to the relevant controls. RESULTS: The lipid profile of patients with NXG was characterized by a low HDL-C phenotype and an abnormal distribution of HDL particles. Sera from patients with NXG induced cholesterol accumulation in human macrophages. This accumulation was due in part to a significant reduction in the HDL capacity to promote cholesterol efflux from macrophages, which was not found in the case of NX. The MIg of NXG and NX patients was tested positively by ELISA to recognize a large spectrum of lipoproteins. High plasma levels of pro-inflammatory cytokines (TNFα and IL-6), soluble cytokine receptors (sIL-6R, sTNFRI and sTNFRII), adhesion molecules (VCAM-1 and ICAM-1) and chemokines (MCP-1, IL-8 and MIP-1α) were observed in both patients with NXG and NX, revealing a specific xanthoma inflammatory signature which was inversely correlated with plasma levels of anti-inflammatory HDL. However, patients with NXG were distinguished by elevated levels of IL-15 and a marked increase in the rate of intermediate CD14++CD16+ monocytes. CONCLUSION: This study revealed that NXG is characterized by impaired macrophage lipid homeostasis associated with a systemic inflammatory profile that may result from the interaction of MIg and lipoproteins.

[Bactericidal effect of daptomycin (LY 146032) compared with vancomycine and teicoplanin against gram-positive bacteria]. / Activité bactéricide de la daptomycine (LY 146032) comparée à celle de la vancomycine et de la teicoplanine sur les bactéries à gram positif.

Daptomycin (LY 146032) is a semi-synthetic antibiotic whose structure consists of a cyclic peptide with a lipophilic chain. It inhibits synthesis of the bacterial wall differently than vancomycin and teicoplanin. The bactericidal activity of daptomycin was compared with that of vancomycin and of teicoplanin with regard to 54 Gram positive strains of bacteria: (S. aureus meti S and meti R; S. epidermidis meti S and meti R; E. faecalis, E. faecium, and Corynebacterium group JK). Vancomycin and teicoplanin have the same slow and time-dependent bactericidal activity. The activity of daptomycin is different: rapid and concentration-dependent, similar to that of the aminoglycosides. In the case of the Corynebacteria, however, the activity of daptomycin is comparable to that of vancomycin and of teicoplanin slow and time-dependent.

[Theoretical bases for the combination of ceftazidime with other antibiotics. Synergism research]. / Bases théoriques de l'association de la ceftazidime avec les autres antibiotiques. Recherche de synergie.

Combinations of antibiotics have always been difficult to study, and the available methods often give discordant results making interpretation uneasy in the absence of in vitro-in vivo correlations. By studying the bactericidal effects of combinations a better definition of interactions between two antibiotics can be obtained if the concept of dominance is taken into account. Ceftazidime, a time-dependent antibiotic, acts synergistically with aminoglycosides, notably against moderately sensitive strains. This synergistic effect results from acceleration of the early bacterial kill and from blockage of the late regrowths. With quinolones, the synergistic effect does not result from blockage of late regrowths. However, the significance of these results needs to be confirmed by clinical trials.

[Kinetics of ofloxacin-amoxicillin and ofloxacin-clavulanic acid combinations against pathogenic bacteria of the respiratory tract]. / Cinétiques des associations ofloxacine-amoxicilline et ofloxacine-acide clavulanique sur les bactéries pathogènes du tractus respiratoire.

Ofloxacin exhibit a good activity against the pathogen bacteria of the respiratory tract, except for S. pneumoniae. Its use is interesting because it has a good diffusion into respiratory tissues. However, the combination with an another antibiotic was necessary to spread the activity spectrum and to prevent the resistant variants. By the new killing curve checkerboard method, these 2 combinations are studied against 8 strains: 4 H. influenzae (2 beta-lactamase producers), 2 S. pneumoniae and 2 K. pneumoniae, at 0, 2, 4, 6 and 24 hours, a viable bacteria counting is executed by a microdilution method and is subcultured with a Steers-type multiple inoculator. With K. pneumoniae, ofloxacin has a dose dependent bactericidal activity which is maximum at 1 mg/l, While augmentin has a time-dependent activity. In the combination the synergy is rare. With H. influenzae, the results are the same; the bactericidal activity is less rapid but it is better than the ones with amoxicillin and clavulanic acid. With S. pneumoniae, the 2 antibiotics have the same activity. No antagonism is observed. And the antibiotic which has a better bactericidal activity determine the viable bacteria count.

[Comparison of the bactericidal activity of three aminosides: gentamicin, tobramycin and amikacin]. / Comparaison de l'activité bactéricide de trois aminosides: gentamicine, tobramycine, amikacine.

Bactericidal action of antibiotics seems to be a test for the choice of antibiotic used and its dosage's adjustment. However, its use is limited by the determination's methods employed until now. By a viable bacteria counting micromethod, bactericidal action of three aminoglycosides: gentamicin, tobramycin and amikacin, is studied towards 48 bacterial strains. For each strain and each antibiotic, 11 antibiotic's concentration have been used, in a dilution range varying from 0.06 to 256 mg x l-1. Viable bacteria counting is executed after 1.5 h, 3 h and 5 hours of incubation. These antibiotics have a dose-dependent action. Regarding the smallest concentration of antibiotic permitted to lower to 3 log10 the bactericidal initial population, one can see that a concentration of 4 mg x l-1 is sufficient for 50% of strains with gentamicin and tobramycin, while a concentration of 16 mg x l-1 is necessary for amikacin. This result is corroborated by a statistical analysis carrying out by a variance analysis: it is showing a little significant difference between gentamicin and tobramycin, and very much significant differences between amikacin and the two others antibiotics.

Dynamics of ceftazidime-pefloxacin interaction shown by a new killing curve-chequerboard method.

Since in-vitro methods for studying drug interactions are difficult to evaluate and different results occur with the chequerboard (isobolograms-FIC index) and killing curve methods, a new approach associating these two methods was used to study the ceftazidime-pefloxacin interaction. In 64 tubes in a chequerboard pattern, viable bacteria were counted at 0, 2.5, 5 and 24 h, by a microdilution method and a multiple inoculator replicating method. The bacterial inoculum consisted of 5 X 10(6)-10(7) cfu/ml. Twelve strains belonging to six genera were tested: Acinetobacter, Citrobacter, Enterobacter, Klebsiella, Serratia and Pseudomonas. During the first 5 h no antagonism was noted, but few differences in viable count equal to or greater than 2 log10 were observed. The results of the drug interaction were equivalent to those of the more rapid bactericidal antibiotic concentrations (ceftazidime or pefloxacin). At 24 h, synergy was observed: ceftazidime prevented the late regrowth noted with pefloxacin, but with Citrobacter spp. regrowth was also observed with ceftazidime and none of the combinations were bactericidal.

[Bactericidal effect of piperacillin alone and combined]. / Activité bactéricide de la pipéracilline seule et associée.

The bactericidal activity of piperacillin was evaluated by the kill rate kinetics method. Piperacillin compared with amoxicillin, amdinocillin, mezlocillin, cefotaxime, ceftazidime and latamoxef. Against E. coli, piperacillin and antibiotics electively bound to penicillin-binding protein (PBP) 3 had the same, mainly time-dependent, bactericidal activity. Antibiotics bound to PBP 1 and 2 mainly have a dose-dependent activity. The bactericidal activity of piperacillin against E. coli was enhanced when the drug was combined with amoxicillin and amdinocillin; in contrast, the kill rate remained unmodified when piperacillin was combined with latamoxef. When the piperacillin-amikacin combination was tested against Pseudomonas aeruginosa, Enterobacter cloacae, Escherichia coli and Serratia marcescens, early synergism (5th hour), was weak, but after 24 hours piperacillin reduced the regrowth observed with the aminoglycoside, and synergism was much more pronounced irrespective of the species investigated.