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Antimicrobial agents

Multi-resistance is a feature of both Gram-negative and Gram-positive pathogens. However, Gram-positive bacteria have been the major causative pathogens of severe disease in nosocomial settings in recent years. In the community, Streptococcus pneumoniae and Streptococcus pyogenes are the lead causative pathogens of ear, nose and throat infections as well as severe pneumonia and meningitis in both children and adults. S. pneumoniae are often resistant to multiple drugs including commonly used beta-lactams and macrolides. In addition, S. pyogenes is resistant to macrolides in up to 40% of cases in certain countries. Even mouth-colonizing streptococci, which are the leading cause of infectious endocarditis, are becoming resistant to beta-lactams and numerous other drugs. In the hospital, Staphylococcus spp. and Enterococcus spp. have become the primary cause of nosocomial bacteremia and pneumonia. Staphylococcus aureus resistant to methicillin (methicillin-resistant S. aureus or MRSA) occur in up to 50% of cases. MRSA are commonly co-resistant to all other available drugs except for vancomycin. However, vancomycin-resistant MRSA with intermediate-level and high-level resistance have emerged in several countries, indicating that this last-resort drug will sooner or later become obsolete as well. In parallel, gut-colonizing enterococci have become resistant to virtually every existing antibiotic including vancomycin. Multi-drug resistant enterococci may be responsible for having transferred the genes essential for vancomycin resistance to more virulent S. aureus.

The emergence of bacterial resistance to most classes of antibiotics has stimulated the search of new compounds that may overcome this problem. Our laboratory has gained expertise in the study of the activity of new antimicrobial agents against multi drug-resistant Gram-positive pathogens, and has become a leading group in this domain, using the rat model of endocarditis.

Therapeutic investigations of experimental endocarditis focused on the search for alternative antibiotic regimens against multi-resistant bacteria such as MRSA, penicillin-resistant S. pneumoniae and streptococci. For instance, therapeutic experiments against MRSA have focused on the investigation of the efficacy of (i) cell wall-active drugs such as the "old-fashioned" beta-lactams penicillin G, amoxicillin and amoxicillin-clavulanate, and the novel cephalosporins BAL9141 and LB11058, (ii) ribosome-inhibitors such as the streptogramin quinupristin-dalfopristin, and (iii) DNA-inhibitors such as the quinolones ciprofloxacin, levofloxacin, moxifloxacin and garenoxacin.

The rat model of experimental endocarditis is particularly well suited to investigate the intrinsic power of new antibacterial drugs. First, the model is therapeutically relevant because it mimics infectious endocarditis in humans. Second, the model is particularly stringent for antibiotic efficacy, because successful treatment of endocarditis essentially relies on the sole ability of the antibacterial drug to kill the bacteria inside the infected vegetations. Third, it allowed evaluating the therapeutic effect both in a PMN-free infection system, i.e., inside the cardiac vegetation, and a PMN-rich system in the infected spleens. Finally, we use a programmable infusion pump system to deliver the antibiotics, which allows to exactly simulate in animals the pharmacokinetics produced by standard administration of the compounds in humans. All in all, these advantages make the model of experimental endocarditis in rats a good predictor of the response to therapy in humans.

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Marlyse Giddey

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Jacques Vouillamoz

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