Endocarditis Prophylaxis: From Experimental Models to Human Recommendation

Animal models of endocarditis have helped understanding of the mode of action of antibiotics in prophylaxis. During bacteraemia, some microorganisms will adhere to damaged cardiac valves. The proportion of bacteria that will adhere depends largely on intrinsic properties of the strain. In the absence of antibiotics, the microorganisms will either be eliminated by local host defence mechanisms if the inoculum is low enough or will begin to grow approximately 2 h after the development of bacteraemia and endocarditis. In the presence of antibiotics, the growth of adherent bacteria is inhibited and local host defences have longer to eliminate the bacteria. In cases where the number of adherent bacteria is relatively low, a short period in inhibitory antibiotic activity (6 hours) is sufficient to eliminate the bacteria and lead to successful prophylaxis. If the number of bacteria is high, a longer duration of the inhibitory effect is necessary. These experimental data provide a rationale for practical recommendations for the prophylaxis of endocarditis in human

Successful prophylaxis of experimental streptococcal endocarditis with single doses of sublethal concentrations of penicillin

Penicillin prophylaxis against experimental endocarditis due to a strain of Streptococcus intermedtus isolated from a patient with endocarditis was studied in rats. The minimum bactericidal concentration of penicillin for this strain was more than 64 mg/l and was higher than the peak penicillin serum level obtained in rats 30 min after the iv injection of 60 mg/kg, and in man after an oral dose of 2 g of phenoxymethyl penicillin. Moreover timed kill curves performed in the presence of 64 mg/l of penicillin showed no decrease in the number of colony-forming units during the first 6 h of incubation and only a 95% decrease after 24 h. In addition, no bactericidal activity could be detected in the serum 30 min after penicillin injection, that is at the time of bacterial challenge. Using the minimum bacterial inoculum needed to produce endocarditis in 90% of control animals (ID90), penicillin successfully prevented endocarditis due to this strain. We conclude that penicillin may prevent streptococcal endocarditis by other mechanisms than bacterial killin

Relevance of animal models to the prophylaxis of infective endocarditis

Intravascular or cardiac endothelial lesions may become colonized during bacteraemic episodes and lead to the development of bacterial endocarditis (BE). It has therefore long been recommended that patients with known cardiac lesions receive prophylactic antibiotics before undergoing procedures that might release bacteria into the blood stream. Because clinical trials of antibiotic prophylaxis of endocarditis cannot be conducted in humans for ethical as well as for statistical reasons (Durack, 1985), the questions of which antibiotic, what dosage, and for how long are a matter of controversy. Unfortunately, these questions can only be studied in animals, with all the limitations that this type of approach brings with it. However, animal experimental studies have helped in understanding the conditions and, to some extent, the mode of action of antibiotics in preventing the development of endocardial infection, thus allowing some rationale for devising prophylactic recommendations for the various patients at risk of developing B

Successful Prophylaxis Against Experimental Streptococcal Endocarditis with Bacteriostatic Antibiotics

Because bacteriostatic concentrations of vancomycin are effective in prophylaxis against endocarditis due to Streptococcus sanguis in rats, the efficacy of three other bacteriostatic antibiotics was investigated against three different streptococcal species that cause subacute endocarditis in humans: Streptococcus intermedius, S. sanguis, and Streptococcus mitior. Rats were challenged by intravenous injection of 2 × 105 colony-forming units of streptococci 24 hr after intracardiac insertion of a transaortic catheter and 30 min after intravenous injection of various doses of clindamycin, erythromycin, and doxycycline. Significant protection was achieved with all three antibiotics, but only clindamycin was fully effective against all three species at doses that simulated serum levels achievable in humans after oral administration. Endocarditis was prevented by antibiotic concentrations in serum far below minimal bactericidal concentrations for these streptococci. Furthermore, serum at the time of bacterial challenge was not bactericidal. Therefore, single doses of nonbactericidal antibiotics prevented endocarditis in rats by mechanisms other than bacterial killin

Comparison of Single Doses of Amoxicillin or of Amoxicillin-Gentamicin for the Prevention of Endocarditis Caused by Streptococcus faecalis and by Viridans Streptococci

Recent recommendations for the prophylaxis of endocarditis in humans have advocated single doses or short courses of antibiotic combinations (β-lactam plus aminoglycoside) for susceptible patients in whom enterococcal bacteremia might develop or for patients at especially high risk of developing endocarditis (e.g., patients with prosthetic cardiac valves). We tested the prophylactic efficacy (in rats with catheter-induced aortic vegetations) of single doses of amoxicillin plus gentamicin against challenge with various streptococcal strains (two strains of Streptococcus faecalis, one of Streptococcus bovis, and three of viridans streptococci); we then compared this efficacy with that of single doses of amoxicillin alone. Successful prophylaxis against all six strains was achieved with single doses of both amoxicillin alone and amoxicillin plus gentamicin. This protection, however, was limited, for both regimens, to the lowest bacterial-inoculum size producing endocarditis in 90% of control rats and was not extended to higher inocula by using the combination of antibiotics. We concluded that a single dose of amoxicillin alone was protective against enterococcal and nonenterococcal endocarditis in the rat, but that its efficacy was limited and could not be improved by the simultaneous administration of gentamici

Successful Single-Dose Amoxicillin Prophylaxis Against Experimental Streptococcal Endocarditis: Evidence for Two Mechanisms of Protection

Amoxicillin prophylaxis against experimental endocarditis due to one nontolerant and two tolerant strains of streptococci was studied in rats. Single-dose amoxicillin protected against the two tolerant strains in animals challenged with the 90% infective dose (ID90), but protection diminished with increasing inoculum sizes. Protection against the nontolerant strain was successful with inocula that were 100-and I,OOO-fold larger than the ID90. Close correlation existed between the speed of bacterial killing in vitro, the time of exposure to bactericidal levels in vivo, and the range of inocula against which prophylaxis was effective. Amoxicillin seemed to protect by at least two mechanisms. (1) When in vitro tests indicated adequate bacterial killing, protection was independent of the inoculum size and was probably conferred by bacterial killing. (2) When in vitro tests indicated bacterial inhibition but not. killing, protection was inoculum-dependent and was probably mediated by inhibition of bacterial adherenc

Prophylaxis Failure Is Associated with a Specific Pneumocystis carinii Genotype

To investigate the possible association between Pneumocystis carinii types and various clinical and demographic parameters, we used molecular typing to analyze 93 bronchoalveolar lavage specimens from patients with P. carinii pneumonia (PCP). Multivariate regression analysis revealed an association between being infected with a specific P. carinii genotype and receiving anti-PCP prophylaxis (odds ratio, 4.4; 95% confidence interval, 1.0-18.6; P = .05), although no association with a specific drug was detecte

The Impact of Penicillinase on Cefamandole Treatment and Prophylaxis of Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

β-lactams active against methicillin-resistant Staphylococcus aureus (MRSA) must resist penicillinase hydrolysis and bind penicillin-binding protein 2A (PBP 2A). Cefamandole might share these properties. When tested against 2 isogenic pairs of MRSA that produced or did not produce penicillinase, MICs of cefamandole (8-32 mg/L) were not affected by penicillinase, and cefamandole had a ⩾40 times greater PBP 2A affinity than did methicillin. In rats, constant serum levels of 100 mg/L cefamandole successfully treated experimental endocarditis due to penicillinase-negative isolates but failed against penicillinase-producing organisms. This suggested that penicillinase produced in infected vegetations might hydrolyze the drug. Indeed, cefamandole was slowly degraded by penicillinase in vitro. Moreover, its efficacy was restored by combination with sulbactam in vivo. Cefamandole also uniformly prevented MRSA endocarditis in prophylaxis experiments, a setting in which bacteria were not yet clustered in the vegetations. Thus, while cefamandole treatment was limited by penicillinase, the drug was still successful for prophylaxis of experimental MRSA endocarditi

Role of Amoxicillin Serum Levels for Successful Prophylaxis of Experimental Endocarditis Due to Tolerant Streptococci

The importance of amoxicillin serum profiles for successful prophylaxis of experimental endocarditis in rats was assessed. Animals with catheter-induced vegetations were challenged intravenously with large inocula of Streptococcus sanguis and received one of the following amoxicillin dosages: single or multiple bolus injection of 40 mg/kg; 40 mg/kg administered as a continuous infusion over 12 h; or either 9 or 18 mg/kg administered over 12 or 24 h, respectively. The regimen producing a single transient high peak serum level failed to prevent experimental endocarditis; in contrast, a second injection 6 h after the first resulted in successful prophylaxis. Likewise, the three regimens of continuous, relatively low-dose regimens prevented infections. Thus, the most important parameter for successful prophylaxis was the duration of inhibitory concentration of the drug in the serum. The total dose of antibiotic, the peak serum levels, or the area-under-the-curve values were not predictive of successful prophylaxi