Experimental endocarditis: a review of its relevance to human endocarditis

Bacterial endocarditis is a difficult-to-cure infection, owing to (i) poor penetration of antibiotics into infected vegetations; (ii) altered metabolic state of bacteria within the lesion; (iii) absence of adequate host-defence cellular response which could cooperate with antibiotic action. The contribution of infection models to definition and improvement of therapeutic regimens of endocarditis in man remains of great importance because of the difficulties encountered in clinical trials. The advantage of the experimental model is that besides the fact that it closely simulates the characteristics of the infection in humans, it provides clear endpoints which allow statistical comparisons among different therapeutic regimens: number of bacteria/g of tissue, frequency of emergence of resistance, positivity of blood cultures, death vs survival rates, and percentage of relapses after treatment has been stopped. All these parameters are more sensitive and more easy to use than in man. The infection model has definitively established that bactericidal therapy is warranted and that in-vitro susceptibility tests, especially those evaluating the killing rate, have a good predictive value for the therapeutic outcome. Three main aspects are discussed for their influence on human therapy (i) the kinetics of antibiotic diffusion into vegetations, with a special reference to the data obtained by autoradiography, (ii) the specificity of some pharmacodynamic aspects of antibiotics in endocarditis, including the clinical consequences of these two parameters on antibiotic dosing regimens and length of therapy, and (iii) in-vivo synergy. This phenomenon involves a variety of mechanisms which are difficult or even impossible to analyse on the sole basis of in-vitro data: enhanced bactericidal activity (beta-lactam-aminoglycoside), prevention of emergence of resistance (as demonstrated for rifampin, quinolones or fosfomycin) and, as shown with rifampin or quinolones, 'pharmacokinetic synergy'. Animal models have helped to define the importance of antibiotic dosing strategies to achieve in-vivo synergy which appears as essential to increase the rate of both bacteriological and clinical cure rate.