Infective endocarditis (IE) is still a serious medical problem. It not only carries significant mortality during the actual period of endocardial infection, but causes morbidity that may persist beyond the duratio

Glauser, M. P.

Malinverni, R.

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European Heart Journal (1987) 8 (Supplement J), 357-359The value of experimental models in the prophylaxisof bacterial endocarditisR. MALINVERNI AND M. P. GLAUSER*Medizinische Universitdtsklinik, Inselspital, CH-30I0 Bern and *Division des Maladies Infectieuses, CentreHospitaller Universitaire Vaudois, CH-1011 Lausanne, SwitzerlandKEY WORDS: Experimental endocarditis, natural history, clinical relevance for prophylaxis.IntroductionInfective endocarditis (IE) is still a serious medicalproblem. It not only carries significant mortalityduring the actual period of endocardial infection, butcauses morbidity that may persist beyond the durationof active infection. Complications such as heartfailure, neurological deficits following central nervoussystem embolism, complications of heart surgery oranticoagulation following valve replacement areconsiderable. Thus it is clear that everything shouldbe done to prevent IE. However, the development ofprophylactic measures implies a precise knowledge ofthe pathogenesis of this disease.Unfortunately, many questions regarding thepathogenesis and the prophylaxis of IE in humansremain unanswered; these include the precise sequenceof events in the establishment of human endocarditisas well as the actual risk of a given invasive procedureto cause transient bacteraemia and endocarditis.Moreover, even the actual risk of development ofendocarditis for a given underlying cardiac conditionis uncertain and controversial. These and similarquestions could only be answered by controlledclinical trials. However, it is unlikely that such clinicalstudies will be performed, mainly because the numberof patients required would be too large1''. Oneapproach to partially solving these questions is abetter understanding of the pathogenesis of IE as seenin experimental models; this may lead to a betterrationale for prophylactic recommendations inDescription of experimental modelsFreedman and coworkers originally developed arabbit model of endocarditis whose rationale wasderived from clinical observations121. They noted theease with which intravenous polyethylene cathetersbecame secondarily infected, resulting in bacteraemiain several patients. They also observed that theirpatients with catheter-induced sepsis had developedinfective endocarditis at the point of contact of theindwelling central venous catheter in the right auricle.They therefore introduced a polyethylene catheter intothe right and left heart of rabbits, filling the catheterwith microorganisms. Durack et al.m changed themodel somewhat in that they injected the bacteriaintravenously, which resulted in a high incidence oftricuspid or aortic valve endocarditis14'. Following asimilar technique we have recently developed a modelin rats, which will be briefly described'5'.A polyethylene catheter is inserted across the aorticvalve through the right carotid artery, resulting in theproduction of sterile valvular vegetations. Theseendocardial lesions resemble those found in humansafter diseases such as rheumatic fever13-"'. Twenty-fourhours after catheterization rats are injected in the tailvein with a given bacterial inoculum of the testorganism. The rats are sacrificed at varying timeintervals after i.v. bacterial challenge; quantitativeblood cultures are then drawn, the aortic vegetationsare excised, weighed, homogenized, serially dilutedand plated. Plates are counted after 48-72 hours ofincubation.Antibiotic prophylaxis is performed by injectingone group of rats with a given dosage of the selectedantibiotic at different time intervals before bacterialchallenge. The dosage and time intervals are chosenso as to result in peak serum levels in rats similar tothose in humans after a recommended dose at the timethe organisms are injected.The relevance of these experimental models to thehuman situation has been questioned mainly for tworeasons1'1.0195-668X/87/08J357 + 03 $02.00/0 1987 The European Society of Cardiology358 R. Malinverni and M. P. Glauser° 40Time after i.v. challenge (min)15Figure I Quantitative determination of bacterial numberscirculating in the blood (log10 c.f.u. ml"') of rats at differenttimes after i.v. challenge with 104 c.f.u. of either S. inlermedius(o), a viridans streptococcal strain, or S. faecalis 1209 (•).Each circle represents values from one rat.S. intermedius S. foecolis 1209100i 80I 60•DCo 40<DO5 20N -- 14/24 18/20Figure 2 Incidence of endocarditis in rats 3days after i.v. challenge with I04 c.f.u. of either5. inlermedius or S.faecalis 1209. The numberof rats with infected vegetations / totalnumber of injected rats is indicated at the baseof each column.THE RELEVANCE OF THE INTRACARDIAC CATHETERIn most experimental studies the catheter has beenleft in place throughout the whole experiment, whilemost frequently there is no intravascular foreign bodypresent in humans. There is experimental evidence,however, that the persistence of the catheter favoursthe development of IE18-91, and that antibioticprophylaxis is facilitated when the catheter isremoved151. Thus, experimental models for theprophylaxis of endocarditis with a catheter in placeprovide a very stringent test of antibiotic prophylaxis.Furthermore, one may argue that it mimics clinicalsituations in humans with prosthetic heart valves orother intravascular foreign bodies.THE MAGNITUDE OF THE BACTERAEMIA USED FORBACTERIAL CHALLENGEThe magnitude of the bacterial inocula injected i.v.to the animals (104-108 c.f.u.) has been consideredirrelevant when compared to bacteraemias observedin humans. Indeed, the magnitude of bacteraemiaobserved in humans after certain procedures such asteeth extractions is generally of the order oflO'-lO2 c.f.u. ml"1 of blood for a given strain'101.However, it must be kept in mind that i.v. bacterialchallenge in rats results in circulating bacterialnumbers that are far below the originally injectedinoculum, due both to a passive haemodilution effectand to an active clearance mechanism by thereticulo-endothelial system'111. Furthermore, it mustbe emphasized that the relationship between themagnitude of bacteraemia and the risk of subsequentdevelopment of IE in humans is unknown. Indeed, itis quite conceivable that those very patients whodevelop endocarditis after a given procedure areprecisely those who presented the highest number ofcirculating bacteria.The properties of various bacterial strains to induceendocarditisThe relationship between the magnitude of transientbacteraemia and the subsequent development ofIE has been carefully investigated in the rat modelof IE. It has been shown that for a given i.v. inocu-lum size of a test strain, the incidence of infection3 days after challenge was fairly constant andreproducible. Wide variations have been observedbetween different bacterial strains in their ability toinduce endocarditis'12 141. Thus, the injection ofsimilar numbers of various strains does not induce ipsofacto the same incidence of endocarditis, although itis likely to induce similar magnitudes of bacteraemias.As an example, Fig. 1 shows the results of quantitativeblood cultures performed in groups of rats injectedwith 104 c.f.u. of either an S. faecalis strain or aviridans streptococcal strain (S. intermedius). As canbe seen, a similar number of S. faecalis and S.intermedius colonies were circulating at different timesafter i.v. challenge and all blood cultures were sterile15 min after injection. Figure 2 shows the incidence ofIE due to both strains 3 days after bacterial challenge.While the S.faecalis strain repeatedly infected 90% ofthe animals (ID 90), only about one-half (58 %) of theanimals had S. intermedius endocarditis. Since theclearance of both organisms from the blood wassimilar, it implies that the two strains had differentpathogenic properties. Indeed, using a modified invitro assay first developed by Scheld el a/.'151, we couldExperimental models of bacterial endocarditis 359demonstrate that the S. faecalis strain adheredsignificantly more to platelet-fibrin matrices in vitrothan the viridans streptococcal strain. Others haveshown similar results in vitro using punch biopsysections of human or canine aortic valveendothelium1161.More importantly, our recent studies on theproduction of endocarditis in rats after the extractionof periodontally diseased teeth have failed todemonstrate a correlation between the total numberof a given streptococcal species that circulatedimmediately after teeth extractions and the likelihoodthat these streptococci will subsequently produceendocarditis11'1. Indeed, some streptococcal strainsthat circulated at barely detectable levels consistentlyproduced endocarditis, while other viridans strep-tococci that were found in much higher numbers inthe blood after extractions only rarely infected thevalves. In these experiments, we could also show thatthe stickiness in vitro of a given bacterial species forplatelet-fibrin matrices predicted best the likelihoodthat this strain would produce IE. Thus thedetermination of the magnitude of bacteraemia aftercertain procedures alone is unlikely to provide reliableinformation on the risk of subsequent development ofIE.ConclusionsExperimental models of IE were developed as aconsequence of careful clinical observations. Thedisease produced in experimental models is much likethe disease observed in humans. Moreover, the role ofan intravascular foreign body can be accuratelyinvestigated. Experimental models of bacterial endo-carditis offer several advantages for studying theprevention of the disease: proper experimentalcontrols can be used and large numbers of animals canbe studied in order to achieve statistically significantresults.More importantly, the model permits comparisonof the efficacy of various antibiotic regimes againstdifferent organisms in vivo and will help unravel themode of action of prophylactic antibiotics, thus givinga rationale for endocarditis prophylaxis recommen-dations in humans which may provide a wide marginof safety.References[I] Durack DT. Prophylaxis of infective endocarditis. In:Mandell GL, Douglas RG, Bennett JE, eds. Principlesand practice of infectious diseases. New York: JohnWiley and Sons, 1985: 539^44.[2] Smits H, Freedman LR. Prolonged venous catheteri-zation as a cause of sepsis. N Engl J Med 1967; 276:1229-33.[3] Durack DT, Beeson PB. Experimental bacterialendocarditis. I. Colonization of a sterile vegetation. BrJ ExpPathol 1972; 53:44-9.[4] Garrison PK, Freedman LR. Experimental endocardi-tis. I. Staphylococcal endocarditis in rabbits resultingfrom placement of a polyethylene catheter in the rightside of the heart. Yale J Biol Med 1970; 42: 394-410.[5] Heraief E, Glauser MP, Freedman LR. Vancomycinprophylaxis of streptococcal endocarditis in rats. In:Nelson JD, Grassi C, eds. Current chemotherapy andinfectious disease. Washington DC: American Societyof Microbiology, 1980: 911-3.[6] McGowan DA. Scanning electron microscopy of heartvalve vegetations. Lancet 1977; 2: 822.[7] Petersdorf RG. Antimicrobial prophylaxis of bacterialendocarditis. Prudent caution or bacterial overkill? AmJ Med 1978; 65: 220-3.[8] Francioli P, Freedman LR. Streptococcal infection ofendocardial and other intravascular vegetations inrabbits: natural history and effects of dexamethasone.Infect Immun 1979; 24: 483-91.[9] Perlman BB, Freedman LR. Experimental endocarditis.III. Natural history of catheter induced endocarditisafter catheter removal. Yale J Biol Med 1971; 44:214-23.[10] Everett ED, Hirschmann JV. Transient bacteremia andendocarditis prophylaxis. A review. Medicine (Balti-more) 1977; 56: 61-77.[11] Bernard JP, Francioli P, Glauser MP. Vancomycinprophylaxis of experimental Streptococcus sunguisendocarditis. Inhibition of bacterial adherence ratherthan bacterial killing. J Clin Invest 1981; 68: 1113-6.[12] Glauser MP, Francioli P. Successful prophylaxis ofexperimental streptococcal endocarditis with bacterio-static antibiotics. J Infect Dis 1982; 146: 806-10.[13] Glauser MP, Bernard JP, Moreillon P, Francioli P.Successful single-dose amoxicillin prophylaxis againstexperimental streptococcal endocarditis: evidence fortwo mechanisms of protection. J Infect Dis 1983; 147:568-75.[14] Francioli P, Moreillon P, Glauser MP. Comparison ofsingle doses of amoxicillin or of amoxicillin-gentamicinfor the prevention of endocarditis caused by Strep-tococcus faecalis and by viridans streptococci. J InfectDis 1985; 152:83-9.[15] Scheld WM, Valone JA, Sande MA. Bacterial adher-ence in the pathogenesis of endocarditis. Interaction ofbacterial dextran, platelets and fibrin. J Clin Invest1978; 61: 1394-404.[16] Gould K, Ramirez-Ronda CH, Holmes RK, SandfbrdJP. Adherence of bacteria to heart valves in vitro. J ClinInvest 1975; 56: 1364-70.[17] Moreillon P, Overholser CD, Bille J, Entenza J,Malinvemi R, Glauser MP. Natural history ofexperimental bacterial endocarditis following dentalextractions in rats with periodontitis (Abstr 465). In:Program and Abstracts of the 25th InterscienceConference on Antimicrobial Agents and Chemo-therapy. Washington, DC: American Society forMicrobiology, 1985.

The value of experimental models in the prophylaxis of bacterial endocarditis

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