The central nervous system in pediatric critical illness and injury / , The central nervous system in pediatric critical illness and injury / , کتابخانه دیجیتال جندی شاپور اهواز

The central nervous system in pediatric critical illness and injury

Cerebrospinal fluid isolates of Streptococcus pneumoniae, collected during the years 1997-2000 at more than 100 Belgian laboratories were studied. The 10 most common serotypes-serogroups representing 76% of the isolates were 14, 6, 9, 19, 23, 18, 4, 10, 8 and 12 (in order of frequency). Thirty-six percent of strains were isolated in children 0.06 mg/L), with only 2.1% resistant strains (MIC > 1 mg/L). Twelve strains showed reduced susceptibility to cefotaxime (MIC > 0.5 mg/L). Only three of the 237 strains were intermediately susceptible to meropenem. All strains were susceptible to vancomycin and moxifloxacin. In Belgium, high doses of third generation cephalosporins remain effective for the treatment of pneumococcal meningitis. The new fluoroquinolones seem the most promising agents for the treatment of pneumococcal meningitis in the future.

Antibiotic susceptibility and serotype distribution of 240 Streptococcus pneumoniae causing meningitis in Belgium 1997-2000.

The "magic bullet" theory stated by Paul Ehrlich more than one century ago foresees that drugs need to reach their target to exert their pharmacological activity. When dealing with antibiotics, this implies not only a capacity to interact with bacteria, but also to rejoin them in the infected compartment. The latter property is directly linked to pharmacokinetics. In this Thesis, we have focused our interest on cellular pharmacokinetics of antibiotics in macrophages, reasoning that (i) this model would be relevant for predicting the access of antibiotics to intracellular bacteria, and (ii) deciphering mechanisms of drug entry, distribution, and efflux in single cells would provide pieces of information applicable to the understanding of general pharmaco-kinetics. Accumulation and distribution were studied for oritavancin, a semi-synthetic glycopeptide currently in phase III of clinical development. This molecule is characterized by a highly bactericidal activity against staphylococci, including multiresistant strains, which would be of interest for the eradication of the intracellular forms of these bacteria. We show that oritavancin enters macrophages by adsorptive endocytosis and accumulates to very large amounts in lysosomes, with cellular concentrations as high as 300-fold the extracellular ones. Accordingly, it exerts a concentration-dependent bactericidal activity against Staphylococcus aureus multiplying in phagolysosomes. In parallel, however, it also causes morphological and biochemical alterations, characterized by the deposition of material of heterogeneous aspect and the accumulation of phospholipids and cholesterol. These data point to the difficulty of dissociating high cellular accumulation and cellular toxicity and plead for the interest of in vitro models in the evaluation of the intracellular activity of antibiotics, the early assessment of drug safety profile and the orientation of further in vivo studies. Active efflux was evaluated for macrolides and quinolones, two antibiotic classes accumulating in macrophages and therefore usually considered as useful in the treatment intracellular infections. Macrophages indeed express multidrug transporters in their pericellular membrane, which can extrude a large variety of drugs presenting as common feature an amphiphatic character. We show that macrolides (and azithromycin in particular) are substrates for P-glycoprotein, while quinolones (and ciprofloxacin in particular) are substrates for an MRP-like transporter. Inhibiting these pumps increases the intracellular activity of these antibiotics by enhancing their cellular accumulation. We also describe different mode of transport for these antibiotics, which essentially reflect their variable fluxes through the membrane. These data underline the major role constitutive efflux plays in the modulation of the pharmacokinetics of drugs, and, hence, of their pharmacodynamics. They encourage the setting-up of large-scale screenings aimed at evaluating drug-transporter interactions in lead optimization processes. We may therefore conclude to the usefulness of cellular models in the study of the pharmacokinetics of drugs and of its consequences for pharmacodynamics and toxicity, and suggest the implementation of such models in the early development of new drugs.

Antibiotic accumulation and efflux in eukaryotic cells : a journey at the frontier of pharmacokinetics and pharmacodynamics/

The epidemiology and treatment approach to bacterial meningitis has changed dramatically since the advent of antimicrobial therapy. New vaccines against meningeal pathogens have been implemented into national immunization programs successfully around the world. Antibiotic resistance has had a considerable impact on the efficacy of several therapeutic agents. In this review, the authors will discuss the principles of antibiotic chemotherapy, focusing on new agents for the treatment of penicillin-resistant pneumococci and adjunctive treatments to reduce the inflammatory response to bacterial infection of the meninges.

Current concepts in the treatment of bacterial meningitis beyond the neonatal period.

10 of the Central Nervous System

Failure of cefotaxime and meropenem to eradicate meningitis caused by an intermediately susceptible Streptococcus pneumoniae strain.

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Failure of cefotaxime and meropenem to eradicate meningitis caused by an intermediately susceptible Streptococcus pneumoniae strain.