Prophylaxis of Experimental Endocarditis

The evidence supporting the use of prophylactic antibiotic regimens in humans derives from its proven efficacy in animal models. Experimental IE has been typically produced in rabbits (e.g., New Zealand white rabbit [11]) or rats (e.g., female Wistar rats [12]) via catheter-induced damage to cardiac valves and subsequent intravenous challenge with various amounts of bacterial inocula. These experimental conditions allowed IE to be more effectively and reliably induced than in other models, with a predictable time of onset, thus facilitating analyses. Antibiotics are administered at the same or similar weight-based dose as in humans. The experimental IE is followed with serial blood cultures, with eventual sacrifice of the animal and quantitative culture of the valvular vegetations. Such experiments have helped to elucidate a hierarchy in the infectivity of the pathogens [13]. Adherence of circulating bacteria to the valvular endothelium/thrombotic vegetation is the most critical factor early in the pathogenesis of infective endocarditis [14,15]. Indeed, S. aureus, the VGS, and Enterococcus spp., which collectively account for the majority of cases of IE, do so specifically because of virulence factors that permit ligand-receptor interactions between bacterial surface components and constituents of damaged valves. However, the inoculum size (i.e., magnitude of the bacteremia) [13,16], as well as the duration of the bacteremia after inoculation, are also important determinants of infectivity [13].

Based on such models, antimicrobial prophylactic regimens should be predicted to be efficacious by interfering with one or more of these factors. A previously held belief was that antibiotics prevented IE via elimination of the post-procedure transient bacteremia by killing the microorganisms before, as they entered, or while they were circulating in the bloodstream, before they seeded the endocardial surface. It seems unlikely, however, that any prophylactic agent could prevent the actual lodgement of circulating bacteria on a suitable nidus: seeding of the vegetation occurs within 30 minutes of the bacteria entering the circulation [17], while antibiotics usually require hours to exert their antibacterial effect [18]. The notion that prophylaxis is mediated by a bactericidal effect is the result of misinterpretation of negative blood culture results in earlier studies, which resulted from the continued elimination of the bacteria by the antibiotic after transfer of blood (and antimicrobial) to culture media. Indeed, animal [19,20] and human [21-24] studies with improved culture methods confirm that prophylaxis does not consistently and significantly reduce the incidence of post-procedure bac-teremia. Therefore, the operative mechanism by which antibiotic prophylaxis is successful occurs by other means. Prevention of bacterial adherence has been proposed to explain the success of experimental prophylaxis. It was previously demonstrated that inhibitors of cell wall synthesis, such as P-lactams [25] and glycopep-tides [20], have the capacity to decrease the adherence of bacteria to platelet-fibrin clots in vitro, possibly by inducing the release of lipoteichoic acid [26]. However, Moreillon and colleagues [27] elegantly demonstrated in the rat model of amoxicillin prophylaxis that inhibition of adherence was not an important mechanism, as the decrease was very marginal and did not prevent infection. Alternatively, successful prophylaxis is mediated by the ability of the administered antibiotic to facilitate elimination of bacteria subsequent to attachment to the vegetation. Studies have demonstrated that such an effect likely occurs by the prolonged inhibition of bacterial growth after inoculation. The determinants of the inhibitory effect include characteristics of the organism (e.g., tolerance), the challenge dose (i.e., the ID90, that is, the minimum inoculum producing IE in 90% of control animals), and the duration of time the serum concentration of the antibiotic remains above the MIC of the pathogen. Studies have shown that for inocula >ID90, the longer the duration of growth inhibition, the greater the likelihood of successful prophylaxis [27-29]. Thus, when VGS or enterococci tolerant to amoxicillin are inoculated into the rat model, single-dose prophylaxis with amoxicillin was efficacious only at the ID90 [16,30,31]. Against higher inocula, multiple doses of amoxicillin for VGS or amoxicillin and gentamicin for entero-cocci were necessary for successful prophylaxis [32]. Pharmacokinetic properties inherent in the administered antimicrobial assist in determining the dosage scheme to maximize growth inhibition. For example, single-dose aminopenicillin prophylaxis for Enterococcus spp. is likely not effective because blood antibiotic levels are not sustained long enough completely to eliminate the bacteria from the vegetation, whereas singledose teicoplanin was efficacious [33]. For organisms with demonstrated in vitro susceptibility, amoxicillin has a duration of inhibition of > 10 hours [13]. These features identified from experimental models have thus allowed recommendations for prophylaxis in humans to be devised. What remains unclear, though, is the mechanism by which prolonged serum inhibitory activity eliminates bacteria adherent to vegetation. It had been postulated that growth-inhibited surface organisms would be susceptible to post-antibiotic leukocyte-enhanced opsonophagocytic activity. Animal studies [28], including a neutropenic endocarditis model [16], have demonstrated that poly-morphonuclear leukocytes do not play a role in eliminating bacteria adhered to the vegetation. Therefore, the mechanism by which antibiotic prophylaxis is effective remains undefined.

Although the principle of prophylaxis dictates to administer the antimicrobial agent before commencement of the procedure, experimental studies have demonstrated that prophylaxis may also be effective if given shortly after the procedure. In the rat model, efficacy of prophylaxis could still be maintained if the antibiotic was administered within two hours of the bacteremia-inducing procedure [16]. Administration of antimicrobials at four to six hours post-procedure was not effective in preventing IE [16,34]. Also, although the dogma in the treatment of IE is to use a bactericidal antimicrobial regimen, this philosophy may not necessarily apply to IE prophylaxis, particularly given the lack of evidence that bactericidal properties mediate prophylaxis. In fact, animal studies have confirmed that while bactericidal antimicrobial agents are required for large inocula, bacteriostatic antimicrobial agents are effective for inoculum sizes < ID90 [35]—hence, the rationale for agents, such as the macrolides (e.g., clarithromycin [36]) and lincosamides (e.g., clindamycin [37]) for penicillin allergic patients.

The applicability of the results from animal studies to humans remains debated. Major issues relate to the size of the inoculum used and the route of challenge. The bacteremia post-procedure in human is estimated to be <1 x 102 CFU/mL of blood [9], whereas in experimental models, the inocula used is in the order of 106-108 CFU/mL [38]. Such large inocula are required to ensure that IE consistently developed in all (90%) of tested animals, but it may lead to an inaccurate model of disease. Furthermore, most animal models are challenged via the intravenous route to mimic a presumed mucosal micro-trauma-related bact-eremia, again potentially introducing sources of error. Lastly, the experimental models used (i.e., rabbits, rats) may not reliably reproduce the pharmacokinetics of the antibiotics in humans, since these small animals clear drugs from their blood more quickly than humans [2].

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