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Experimental endocarditis in rabbits. 2. Course of untreated Streptococcus faecalis infection.

Insertion of a polyethylene catheter in the left side of the heart was used to induce sterile endocarditis in 34 rabbits. Bacterial endocarditis was established by injection of approximately 10(8) Streptococcus faecalis into the blood stream simultaneous with the removal of the catheter which had been in place for 3 days. The course of the bacterial endocarditis was examined by autopsy of rabbits sacrificed at regular intervals after the infection. The results showed that the presence of the catheter was not essential for the induction or maintenance of the infection. Growth of the bacteria took place in the preformed vegetations in the aorta, on the aortic valves and in the left ventricle. However, increases in the size of the vegetations, a high density of bacteria in the vegetations and secondary spreading were found only on the aortic valves. The extracardial manifestations of left-sided S. faecalis endocarditis included constant bacteriaemia, a high frequency of septic kidney infarcts and enlargement of the spleen. This form of experimentally provoked bacterial endocarditis in rabbits provides a good imitation of human subacute endocarditis, and would thus seem to be suitable for further study of the pathophysiology of endocarditis and evaluation of the effect of treatment with antibiotics.

Animals

Fate of circulating immune complexes in infective endocarditis.

To examine the role of circulating immune complexes (CIC) in infective endocarditis, we studied 64 patients with infective endocarditis for the presence of CIC by the polyethylene-glycol (PEG)-precipitation test and the Clq binding test. This study was repeated during the course of the disease in 23 patients. CIC were found in 84 per cent of patients (66 per cent with acute infective endocarditis, 89 per cent with subacute infective endocarditis) during the active phase of the disease. Higer PEG precipitates were associated with typical cutaneous signs, cryoglobulins and nonstreptococcic culture-positive infective endocarditis. Under appropriate antibiotic treatment, the PEG precipitate levels of 17 patients fell within 1 month to the normal range, with a concomitant drop in cryoglobulinemia and rheumatoid factor. Conversely, uncontrolled sepsis always (six of six) yielded a rising level of CIC. These findings support the hypothesis that CIC may be important in the pathogenesis of peripheral lesions in infective endocarditis.

Adolescent

Endocarditis caused by coagulase-negative staphylococci.

Sixteen patients with coagulase-negative staphylococcal endocarditis were treated at the University of Minnesota Hospitals between January 1970 and September 1977. In six patients, endocarditis developed after prosthetic valve surgery; among the other ten patients (the medical group), eight had known antecedent valvular disease. The skin was thought to be the source of infection in eight patients, suggesting that prompt treatment of skin infections and avoidance of injections in patients with valvular disease are important measures in the prevention of this disease. Patients with prosthetic valve endocarditis were infected with antibiotic-resistant organisms and had a higher mortality than those in the medical group (83% versus 20%). Bacterial isolates from three patients with prosthetic valve endocarditis were resistant to methicillin, and two of these three isolates also were resistant to cephalothin by quantitative susceptibility testing. The only patient with prosthetic valve endocarditis to survive was operated upon early in the course of his illness. These observation, coupled with the high mortality in this series and in others, has prompted us to advocate early surgery in prosthetic valve endocarditis.

Adolescent

[Bacterial endocarditis: clinical and bacteriological aspects and prognostic factors].

The microbiological, clinical and therapeutic aspects of all (71) cases of bacterial endocarditis admitted to the Hôpital cantonal, Geneva, between August 1970 and October 1974 were reviewed: there was a definite trend towards higher prevalence of acute cases compared to subacute cases. The pathogenic role of S. epidermidis, mostly in cases of prosthetic valve endocarditis, could be demonstrated in several cases. When defined initially by microbiological criteria only, acute endocarditis were characterized by rapid evolution, destruction of the valvular structures (especially aortic valve), and by further evolution under adequate antibiotic therapy: thus, 10/25 patients with acute endocarditis died, whereas the mortality rate in the subacute cases was only 10/46. Many cases in our series showed one or more often frequent embolic phenomena: 70% of the cured cases and 80% of the patients with a fatal outcome. An unfavorable evolution could be correlated with neurologic involvement, cardiac rhythm or conduction disturbances, and/or heart failure; indeed, heart failure due to various mechanisms was the single most frequent cause of death and is presently the main therapeutic problem. Thus, acute infection leading to destruction of the aortic valve and to heart failure still carries a bad prognosis, even if emergency valve replacement is attempted. Finally, 22/30 patients who developed a bacterial endocarditis after oral or urological procedures knew about a heart murmur, but did not receive antibiotic prophylaxis. This clearly shows that emphasis should be put on the elaboration and diffusion of adequate prophylactic regimens.

Adult

Bacterial endocarditis in idiopathic hypertrophic subaortic stenosis.

Bacterial endocarditis complicating idiopathic hypertrophic subaortic stenosis (IHSS) is uncommon but endocarditis may be the first clinical manifestation of IHSS. In this report of such a case, the aortic and the mitral valves were the sites of the bacterial infection. Many chordae tendineae to the mitral valve were ruptured from the extension of the infectious process. The endothelial lesions, which served as the seat for the bacterial infection on the anterior mitral leaflet, likely resulted from its abutting action against the septal prominence. Damage to the aortic valve leaflet may have resulted from abnormal valve motion caused by IHSS and created an environment conducive to endocarditis. This patient developed aortic insufficiency during the course of bacterial endocarditis, suggesting that the occasional association of aortic insufficiency in patients with IHSS may be secondary to healed endocarditis of the aortic valve.

Adult

Effect of type-specific active immunization on the development and progression of experimental Pseudomonas aeruginosa endocarditis.

Rabbits with intracardiac catheters were immunized with heat-killed Pseudomonas aeruginosa or saline and challenged with either 10(9) (high inoculum) or 10(7) (low inoculum) pseudomonas. Immunization did not decrease the incidence of endocarditis when compared with controls, but it did significantly prolong survival. The longer survival of immunized rabbits after high-inoculum challenge was not due to prolongation of the course of endocarditis but to type-specific protection from early, overwhelming bacteremia. However, after low-inoculum challenge there were no early deaths and there was a significantly (P < 0.01) longer survival of immunized (17.4 days) than unimmunized (10.6 days) animals dying of endocarditis. Increased survival was associated with higher total and 2-mercaptoethanol-resistant hemagglutinating antibody titers 1 week after challenge in immunized as compared with unimmunized rabbits. Early (48 h after challenge) vegetation colonization was also significantly (P < 0.05) greater after type-specific as opposed to non-type-specific or saline immunization and low-inoculum challenge. However, whereas 67% of type-specifically immunized rabbits had colonized vegetations at 48 h, only 38.9% died with bacteremic endocarditis. Another 19.2% of immunized rabbits had vegetations colonized with > 10(5) colony-forming units of pseudomonas at elective sacrifice 2 weeks after challenge but no bacteremia; no unimmunized rabbit exhibited similar late colonization. Preexisting antibody may be important in the pathogenesis of pseudomonas endocarditis in drug addicts, and its presence may explain the subacute and often protracted course of the disease.

Animals

Staphylococcal endocarditis: clinical observations on 113 patients.

A 10-year analysis of 113 cases of staphylococcal endocarditis seen in two Washington, D.C., hospitals is presented. 96% of the cases occurred in parenteral drug addicts, but 4% complicated septicemia from known foci of infection. Coagulase positive staphylococcus was responsible for 97% of the infection, and the rest were caused by coagulase negative staphyloccus. Except in four patients with previously known cardiac murmurs, infection occurred on normal valves in these patients. Infection was isolated to the tricuspid valve in 71%, to the mitral valve in 6% and to the aortic valve in 3.5% of our cases; and more than one cardiac valve was affected in the remaining patients. All patients were treated with antibiotics based on bacterial sensitivity testing. The mortality from isolated tricuspid endocarditis was 5%, from isolated mitral endocarditis 33%, and from isolated aortic valve endocarditis 100%. The overall mortality was 18%. The better prognosis documented for acute tricuspid endocarditis is related to the much less severe haemodynamic consequences of acute tricuspid regurgitation, and the probably milder consequences of septic pulmonary embolism compared with coronary or cerebral embolism.

Adolescent

Vancomycin therapy of bacterial endocarditis.

Fifteen patients with bacterial endocarditis were treated with vancomycin between 1967 and 1976. The indications for vancomycin therapy were penicillin-cephalosporin allergy in six patients, antibiotic resistant bacteria in six, initial therapy in one and culture-negative endocarditis in two. The causative microorganisms were Staph. epidermidis (four patients), Staph. aureus (two patients), diphtheroids (four patients), viridans streptococci (two patients) and enterococci (one patient). Minimum inhibitory concentrations of vancomycin for these organisms ranged from 0.8 to 3.1 micrograms/ml. The patients received vancomycin for two to 10 weeks (mean five weeks). Cure was achieved in 13 patients, including six with prosthetic valve endocarditis (PVE). Two patients had a relapse of PVE and cultures of blood or heart valve were positive within two months of vancomycin therapy. Vancomycin serum levels did not exceed 50 micrograms/ml, and no serious drug toxicity was encountered in any patient. Three patients had minimal audiogram changes beyond the social hearing range. One patient had mild phlebitis and a rash, and one patient had a transient leukopenia. Vancomycin is an effective nontoxic antibiotic in patients with endocarditis when penicillin or cephalosporin therapy is not appropriate.

Adult

Infective endocarditis in the narcotic addict.

As long as the illicit use of heroin and other drugs continues in our society, infective endocarditis will remain a significant medical problem in the drug-using population. The majority of infections are produced by S. aureus, and the tricuspid valve is most commonly involved. Addicts, unlike the general population, may also develop endocarditis with a variety of gram-negative bacilli and have a higher incidence of fungal infection. The outcome of each individual infection is dependent on the prompt recognition of the underlying valvular infection and the institution of antimicrobial therapy. Infection of the tricuspid valve has a much more favorable prognosis than does infection of the aortic or mitral valves. Fungal endocarditis, and frequently gram-negative bacillary endocarditis, require valvular surgery to effect a cure.

Adult

Synergy between carbenicillin and an aminoglycoside (gentamicin or tobramycin) against Pseudomonas aeruginosa isolated from patients with endocarditis and sensitivity of isolates to normal human serum.

Isolates from the blood of 30 patients with endocarditis due to Pseudomonas aeruginosa were tested for synergy between carbenicillin and an aminoglycoside, either gentamicin or tobramycin, by in vitro checkerboard methods in modified (cation-supplemented) Mueller-Hinton broth. Twenty-five of the 30 isolates were affected synergistically. Whether given low (2.5--5 mg/kg) or high (8 mg/kg) doses of aminoglycoside along with 30 g of carbenicillin daily, all of the five patients infected with pseudomonads that were not synergistically affected were refractory to treatment with pseudomonads that were not synergistically affected were refractory to treatment with the carbenicillin-gentamicin combination, whereas the finding of synergy of carbenicillin with gentamicin (or tobramycin) did not assure a medical cure. Tests for synergy between carbenicillin and gentamicin yielded different results in Mueller-Hinton agar than in modified Mueller-Hinton broth. The majority (28) of 30 isolates of endocarditis-producing P. aeruginosa were resistant to the bactericidal effects of 50% pooled normal serum that had been freshly separated. One of the endocarditis-producing strains that was sensitive to 50% serum was resistant to 10% serum. However, sensitivity or resistance to freshly separated, pooled normal human serum did not predict the outcome of antibacterial therapy for pseudomonas endocarditis.

Aminoglycosides

Beta hemolytic streptococcal endocarditis: predominance of non-group A organisms.

Identification of beta hemolytic streptococci (BHS) as group A or non-group A on the basis of bacitracin sensitivity rather than Lancefield serogrouping may lead to misidentification of the pathogen. In four recent cases of endocarditis due to BHS, the pathogens initially were identified as group A; Lancefield serogrouping showed all four to be group G. All four patients presented with a syndrome characteristic of acute bacterial endocarditis. Review of all cases of endocarditis at our institution for the past five years showed none due to group A BHS. In 166 previously reported cases of endocarditis due to BHS, 68 pathogens were serogrouped: 53 belonged to groups B, C, G, or H; only five were group A. Our four cases and review of the literature demonstrate the need for Lancefield serogrouping in serious beta hemolytic streptococcal infections, rather than reliance on bacitracin sensitivity.

Acute Disease

Penicillin and netilmicin in treatment of experimental enterococcal endocarditis.

Successful therapy of enterococcal endocarditis requires the use of a combination of penicillin plus an aminoglycoside. The effectiveness of penicillin (Pen), streptomycin (Str), and netilmicin (Net), a new aminoglycoside, alone and in combination, were studied in vitro and in the treatment of left-sided enterococcal endocarditis in rabbits. In vitro Pen+Str or Net resulted in a more rapid and more complete bactericidal effect than Pen, Str, or Net alone against a Str-susceptible strain of enterococcus (strain 1). Against a highly Str-resistant strain (strain 2), Pen+Net showed an advantage over Pen, Str, or Net alone, or Pen+Str. Endocarditis was produced in rabbits with strain 1 or 2, and treatment was initiated 24 h later. Rabbits were treated for 48 h or 5 days with procaine Pen, Pen+Str, or Pen+Net. With strain 1, numbers of enterococci in the vegetations decreased more rapidly with Pen+Str or Pen+Net treatment than with Pen, Str, or Net alone. With strain 2, Pen+Net showed a clear advantage over Pen, Str, Net, or Pen+Str. Net in combination with Pen showed synergistic in vitro activity and was more effective than Pen alone in the treatment of enterococcal endocarditis in rabbits caused by both Str-susceptible and Str-resistant strains.

Animals

Musculoskeletal manifestations of bacterial endocarditis.

The records of 180 patients out of 247 with bacterial endocarditis were examined. 50 patients had rheumatic manifestations. In 10 there was arthritis of 2-12 weeks' duration before diagnosis; 19 had myalgia/arthralgia; 17 had back or neck pain; 14 had demonstrable arthritis; and 2 tenosynovitis of the foot. Of the 14 patients with arthritis, 8 had monarticular arthritis and 6 polyarticular. All but one patient had a raised erythrocyte sedimentation rate, and in one patient rheumatoid factor was positive. The rheumatic features responded when the endocarditis was treated. Some of the symptoms undoubtedly resulted from the infection and fever of the endocarditis, and emboli may have caused the transient aches but there was no evidence that they caused the synovitis in the patients with arthritis. The rheumatic manifestations of bacterial endocarditis can mimic other rheumatic diseases and disguise the underlying disease.

Adolescent

Scanning electron microscopy of infective endocarditis.

As part of a study of the development of infective endocarditis in ncarcotic addicts, we sought to establish the feasibility of using scanning electron microscopy (SEM) to view the surface characteristics of human heart valves obtained at autopsy. Normal and infected heart valves from humans and animals were obtained at autopsy, fixed in formalin, and processed for SEM. Parallel samples from immediately adjacent regions were processed for light microscopy. Active and healed endocarditis were readily recognizable by SEM, and the observations correlated well with those made by light microscopy. The advantage of SEM in the study of endocarditis is that it provides significant information about damage to the endocardial surface across the entire valve. The relative proportions of fibrin, platelets, leukocytes, exposed stromal connective tissue and bacteria on the surface of a lesion can easily be analysed. SEM may prove particularly useful in the study of the pathogenesis of the early lesions of infective endocarditis on previously "undamaged" valves.

Animals

[Therapy of bacterial endocarditis].

The successful treatment of bacterial endocarditis requires a close cooperation to a clinical microbiological laboratory. This performs blood cultures, estimation of sensitivity to the different antibiotics, if anyhow possible also quantitatively, and supervision of therapy by serum bactericidal tests. Synergistic combinations by adding one of the aminoglycosides bring the best chances for therapeutic success. Special advices are given in dependence of the numerous causative bacterial agents. Rare ones are sufficiently taken into consideration. If blood cultures remain negative, empiricial chemotherapy is recommended. Surgical treatment by operative replacement of the infected heart valves and insertion of prosthetic ones is indicated in uncontrolled infection, in severe heart failure caused by valve perforation, and in recurrent embolism. Early interventions have a much better prognosis. Special problems are connected to bacterial endocarditis in prosthetic valves. Bacterial endocarditis in drug addicts is of relatively good prognosis in spite of the frequent complications. Patients with suspicious or evident bacterial endocarditis should be transferred to centers owing sufficient diagnostic and therapeutic experiences.

Administration, Oral

Diffuse glomerulonephritis in rabbits with Streptococcus viridans endocarditis.

Intravenous administration of live microorganisms to rabitts with cardiac catheters produces an experimental model of infective endocarditis. Despite the development of infected valvular vegetations, positive blood cultures, splenomegaly, and focal embolic renallesions, glomerulonephritis has not been found in these animals. In the present study, acute diffuse proliferative glomerulonephritis, featuring endothelial and mesangial proliferation, capillary occlusion, and leukocytic infiltration was produced in rabbits immunized withthe infecting agent prior to the establishment of left sided alpha-streptococcal endocarditis. Controls receiving immunization alone, immunization and sterileendocarditis, or infective endocarditis alone did not develop diffuse glomerulonephritis. Electron microscopic findings of occasional subendothelial electron-dense deposits and immunofluorescence deposition of IgG and C3 in a peripheral granular capillary pattern were consistent with an immune complex type nephritis. Decreased serum complement levels were demonstrated in those animals developing diffuse glomerulonephritis, and some animals developed circulating rheumatoid factor. In view of the morphologic findings and the necessity of preimmunization for development of glomerular changes, it is concluded that immune mechanisms play a role in the diffuse glomerulonephritis associated with this model of infective endocarditis.

Animals

A genome-wide in vivo screen reveals fitness pathways required for streptococcal infective endocarditis.

Infective endocarditis (IE) is a life-threatening disease most often caused by blood-borne bacteria that infect previously damaged cardiac tissue. Despite the importance of this disease, the genetic basis for IE-associated fitness remains poorly defined. Here, we present the first genome-wide in vivo analysis of bacterial fitness in a vertebrate model of IE. We identified 146 genes in Streptococcus sanguinis required for IE fitness, the majority of which had not previously been linked to endocarditis. These determinants cluster into conserved metabolic, cell envelope, transport, and regulatory pathways, representing a vast reservoir of potential targets for novel antimicrobial intervention. A subset of these genes was examined in Streptococcus mutans; all were found to be essential for IE fitness in this distantly related oral species as well, suggesting broad conservation. Using experimental evolution, we further show that disruption of key fitness pathways triggers reproducible compensatory "bypass" mechanisms. Together, these findings provide a comprehensive, genome-wide map of the bacterial niche-requirements for streptococcal infective endocarditis.

Animals

Nonbacterial Thrombotic Endocarditis Unmasking Concomitant Monoclonal Gammopathy of Undetermined Significance (MGUS) by Manifesting as Stroke.

Nonbacterial thrombotic endocarditis (NBTE) is a rare condition characterized by sterile platelet-fibrin vegetations on cardiac valves in the absence of systemic infection. The pathogenesis of marantic endocarditis is driven by endothelial dysfunction and a systemic hypercoagulable state. In contrast to infective endocarditis, vegetations in NBTE lack significant inflammatory infiltrates and do not yield positive blood cultures. NBTE typically comes to clinical attention via systemic embolic events, with cerebrovascular accidents serving as a clinical hallmark and constituting over 50% of cases. While NBTE is commonly associated with mucin-producing adenocarcinomas of the lung, pancreas, and gastrointestinal tract, its occurrence secondary to hematological malignancies or precursor plasma cell dyscrasias like monoclonal gammopathy of undetermined significance (MGUS) is exceedingly rare, particularly in young individuals. We report the case of a previously healthy 35-year-old woman who presented with acute-onset blurred vision. Neuroimaging via magnetic resonance imaging (MRI) revealed an acute left occipital infarct along with multiple chronic infarcts, raising a strong suspicion of a recurrent embolic process. A transesophageal echocardiogram (TEE) demonstrated two vegetations on the aortic valve with moderate transvalvular regurgitation; in the context of persistent negative blood cultures, these findings supported the diagnosis of NBTE. The patient was managed with systemic anticoagulation. A comprehensive hypercoagulable and autoimmune workup revealed an elevated lambda free light chain level with a decreased kappa/lambda ratio. Subsequent bone marrow biopsy and cytogenetic analysis established a diagnosis of MGUS featuring high-risk genomic aberrations, specifically an immunoglobulin heavy chain/musculoaponeurotic fibrosarcoma (IGH/MAF) rearrangement and the loss of chromosome 13 in a polyploid (3n, 4n) background, findings consistent with plasma cell neoplasia. The prevalence of MGUS in individuals under the age of 40 is exceptionally low, estimated at less than 0.3%. This case underscores NBTE as a critical finding that can unmask underlying, atypical plasma cell neoplasms. It highlights the necessity of an exhaustive diagnostic evaluation for occult hematological disorders and high-risk cytogenetic features in young patients presenting with multi-territory embolic strokes.

igh/maf rearrangement