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Discovered that there could be a 'division of labour' in bacterial biofilm populations such that a subset that remained attached could degrade the chitin substratum and provide nutrients for a detached, planktonic subset. Edwards, K. An archaeal iron-oxidizing extreme acidophile important in acid mine drainage. Article Google Scholar. Klausen, M. Biofilm formation by Pseudomonas aeruginosa wild type, flagella and type IV pili mutants.
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Stewart, P. Antibiotic resistance of bacteria in biofilms. IE is associated with significant morbidity and mortality. In most cases, prolonged courses of broad-spectrum antimicrobials fail to eradicate the infection, making surgical intervention the only solution. They have submitted their findings to the Journal of Thoracic and Cardiovascular Surgery.
The term biofilm describes a surface mode of infection in which microbes attach to a surface and grow in self-contained micro-colonies with a protective extracellular polymeric matrix — also referred to as a slime layer. Located near the surface of the biofilm are free planktonic cells that can spread to colonize surrounding structures and other organs.
The bigger problem lies deep within the biofilm structure, where so-called persister cells rebuild and develop the biofilm. The National Institutes of Health reports that up to 80 percent of clinical infections involve biofilm bacterial phenotypes, particularly those associated with IE and implanted medical devices.
Biofilm has been identified on cardiac pacemakers, prosthetic heart valves, vascular grafts, intravascular catheters, orthopaedic implants, sternal fixation wires and endotracheal tubes.
The most common biofilm-forming organisms are Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus species, Pseudomonas aeruginosa and Enterobacteriaceae microorganisms. Immune complexes may be found within the lesions. Janeway lesions are caused by septic emboli and are characterized by the presence of bacteria, neutrophils, necrosis and subcutaneous haemorrhage Ocular manifestations. Patients with IE may have Roth spots in their eyes.
These immunological phenomena appear on funduscopic examination as retinal haemorrhages with a pale centre Fig. Microscopically, they consist of fibrin—platelet plugs or lymphocytes surrounded by oedema and haemorrhage in the nerve fibre layer of the retina Endophthalmitis is especially prevalent with S. For instance, in a prospective cohort of patients with S. The diagnosis of IE typically requires a combination of clinical, microbiological and echocardiography results.
Historically, and as is probably still the case in resource-limited settings, IE was diagnosed clinically based on classic findings of active valvulitis such as cardiac murmur , embolic manifestations and immunological vascular phenomena in conjunction with positive blood cultures. These manifestations were the hallmarks of subacute or chronic infections, most often in young patients with rheumatic heart disease.
However, in the modern era in developed countries, IE is usually an acute disease with few of these hallmarks because the epidemiology has shifted towards health care-associated IE, often with early presentations due to S.
In this context, fever is the most common presenting symptom but is nonspecific 4. The presence of other risk factors, such as IDU or the presence of intravascular prosthetic material, should increase the clinical suspicion for IE in a febrile patient.
This clinical variability complicates efforts to identify patients with IE who would benefit from early effective antibiotics or cardiac valve surgery. The ability to reliably exclude IE is also important, both to avoid extended courses of unnecessary antibiotics and to focus diagnostic considerations onto other possibilities.
Diagnostic techniques. Blood culture is the most important initial laboratory test in the work-up of IE. Bacteraemia is usually continuous 92 and the majority of patients with IE have positive blood cultures 4. If antibiotic therapy has been administered before the collection of blood cultures, the rate of positive cultures declines Modern blood culture techniques now enable isolation of most pathogens that cause IE.
For this reason, practices that were traditionally used to facilitate isolation of fastidious pathogens, such as the use of specific blood culture bottles or extending incubation beyond 5 days, are no longer generally recommended In cases of suspected IE when cultures are negative 95 , other microbiological testing approaches may be useful Table 1.
For example, serological testing is necessary for the diagnosis of Q fever, murine typhus 96 and psittacosis In addition, Bartonella spp. Culture of valvular tissue may yield a causative organism when blood cultures are negative, and microscopy for fastidious or intracellular pathogens may also be diagnostic 76 , Molecular techniques to recover specific DNA or 16S ribosomal RNA from valve tissue and blood or serum samples 20 have been helpful in selected cases.
Other investigative techniques have been reported Table 1 , although they are not widely available. Echocardiography is the second cornerstone of diagnostic efforts and should be performed in all patients in whom IE is suspected , Transthoracic echocardiography TTE may enable visualization of vegetations in many patients Fig.
The sensitivity of TTE is variable and is highest in right-sided IE owing to the proximity of the tricuspid and pulmonic valves to the chest wall.
Transoesophageal echocardiography TOE is more sensitive than TTE for the detection of vegetations and other intracardiac manifestations of IE, especially in the setting of prosthetic valves In this setting, the ESC guidelines recommend subsequent TOE in almost all cases to detect local valvular complications, such as abscess or fistula. Owing to its relative convenience, TTE is often performed first, although TOE may be the appropriate initial test in a difficult imaging candidate, such as an obese patient or a patient with a prosthetic valve.
In addition, the timing of echocardiography is important. Echocardiography findings may be negative early in the disease course. Thus, repeat echocardiography after several days is recommended in patients in whom the initial echocardiography is negative but high suspicion for IE persists , Intraoperative TOE can help to identify local complications and is recommended in all cases of IE that requires surgery. Patients with S. TTE may be adequate in a carefully selected minority of patients who do not have a permanent intracardiac device, have sterile follow-up blood cultures within 4 days after the initial set, are not haemodialysis dependent, have nosocomial acquisition of bacteraemia, do not have secondary foci of infection and do not have clinical signs of IE To differentiate patients with S.
Using PET-CT, inflammatory leukocytes are visualized after taking up radiolabeled glucose, showing an area of active infection on the aortic valve blue circle. Image in part b courtesy of A.
Bruun, Gentofte Hospital, Copenhagen, Denmark. Other imaging modalities have been evaluated for the diagnosis of IE in a preliminary manner. The use of multimodality imaging is likely to increase in the future if additive benefits can be demonstrated, and the ESC guidelines have incorporated these modalities into the diagnostic algorithm of PVIE Diagnostic criteria. The original and subsequently modified Duke criteria provide the current gold-standard diagnostic strategy, which is both sensitive and specific for IE.
The original Duke criteria were evaluated in multiple studies — from geographically and clinically diverse populations, confirming their high sensitivity and specificity. Microbiological criteria form the first major criterion, with diagnostic weight accorded to bacteraemia with pathogens that typically cause IE.
For organisms with a weaker association with IE, persistently positive blood cultures are required. The second major criterion is evidence of endocardial involvement, as demonstrated by echocardiography or findings of new valvular regurgitation.
Minor criteria include a predisposing heart condition or IDU, fever, vascular phenomena, immunological phenomena or microbiological evidence that does not meet a major criterion.
Thus, IE diagnosis cannot be made on the basis of a single symptom, sign or diagnostic test. Rather, the diagnosis requires clinical suspicion, most commonly triggered by systemic illness in a patient with risk factors, followed by evaluation according to the diagnostic schema outlined in the modified Duke criteria.
It is worth keeping in mind that the Duke criteria were originally developed to facilitate epidemiological and clinical research efforts and that the application of the criteria to the clinical practice setting is more difficult. The heterogeneity of patient presentations necessitates clinical judgement in addition to application of the criteria.
Moreover, the criteria may be further modified as evidence accrues for new microbiological and imaging modalities.
Adapted from Ref. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. The substantial morbidity and mortality of IE has inspired efforts to prevent its occurrence in at-risk individuals. Based on the assumption that dental procedures may lead to IE in patients with underlying cardiac disease, the AHA and other major society guidelines previously recommended prophylactic antibiotic therapy to prevent IE in patients with underlying cardiac conditions who underwent dental procedures More recently, however, this recommendation has come into question.
There is now substantial evidence that transient bacteraemia is common with normal daily activities, including tooth brushing, flossing and chewing food, and the efficacy of antimicrobial prophylaxis is unknown In a departure from previous guidance, the French IE prophylaxis guidelines were the first to dramatically reduce dental prophylaxis indications The AHA guidelines reduced the recommended scope of cardiac conditions for which dental prophylaxis is reasonable to four clinical settings: patients with prosthetic valves or valve material; patients who had previous IE; patients with a subset of congenital heart disease; and cardiac transplantation recipients who develop cardiac valvulopathy Prophylaxis is no longer recommended for gastrointestinal or genitourinary procedures.
Guidelines from the ESC similarly recommended using dental prophylaxis only for those with highest risk of developing IE Recommendations of the UK National Institute for Health and Clinical Excellence NICE were published in and were even more restrictive, advising against IE prophylaxis for any dental, gastrointestinal, genitourinary or respiratory tract procedures Subsequent to the NICE guidelines, there was a highly significant With 2 years of follow-up data after guideline publication, there did not seem to be an appreciable increase in IE cases or deaths Similarly reassuring data were reported following the introduction of the revised French and AHA guidelines 16 , However, poor adherence to the AHA guidelines complicates interpretation of these results in the United States Recently, increasing concerns have accompanied the availability of longer durations of follow-up.
After extending the follow-up period in England through , the number of IE cases seemed to increase significantly over the projected historical trend, leading to an estimated additional 35 more cases per month than would have been expected if prior prophylaxis rates had continued However, this study did not contain organism-specific data, so it was not possible to tell whether this increase was due to VGS — which might plausibly have been prevented by dental prophylaxis — or to other pathogens, such as S.
However, it was noted that enterococci were included in the streptococcal category and that the apparent increase in streptococcal IE might thus be owing to rising enterococcal IE rates To date, at least nine population-based studies have examined IE rates before and after guideline changes Table 2. Taken together, these data indicate that there may be both efficacy and risk in the form of antibiotic-related adverse events associated with antibiotic prophylaxis.
Importantly, all of the available evidence derives from observational cohorts, with imprecise microbiological data. Furthermore, even if IE rates did increase following guideline changes, a causal relationship cannot be established. No prospective randomized controlled studies to assess the efficacy of prophylaxis have been performed, despite calls for such a trial for at least the past 25 years In a review of the prior guidelines, the NICE elected not to change any of the prior recommendations and reiterated the need for a randomized controlled trial comparing prophylaxis with no prophylaxis, including long-term follow-up for incident IE In addition to dental prophylaxis, efforts at prevention of intravascular catheter-related bacteraemia may also reduce the incidence of health care-associated IE.
Bacteraemia rates are reduced by quality improvement interventions, such as care bundles or checklists that consist of strict hand hygiene, use of full-barrier precautions during the insertion of central catheters, cleaning the skin with chlorhexidine, avoiding the femoral site if possible and removing unnecessary catheters Confirmatory data on the effect of these interventions on IE incidence are not available.
In the modern era, management of IE typically requires a multidisciplinary team, including, at a minimum, an infectious disease specialist, a cardiologist and a cardiac surgeon All patients should receive antimicrobial therapy and a subset may benefit from cardiovascular surgical intervention.
The primary purpose of antimicrobial therapy is to eradicate infection. As a result, extended courses of parenteral therapy with bactericidal or fungicidal agents are typically required.
Duration of therapy. The duration of therapy must be sufficient to completely eradicate microorganisms within cardiac vegetations. Owing to poor penetration of antibiotics into these vegetations and the slowly bactericidal properties of some of the commonly used drugs such as vancomycin , extended courses of antibiotics are usually required. When bactericidal activity is rapid, shorter courses may be feasible. For example, combination therapy with penicillin or ceftriaxone and an aminoglycoside is synergistic for VGS-associated IE, enabling effective courses as short as 2 weeks for susceptible strains Right-sided vegetations tend to have lower bacterial densities than left-sided vegetations and may also be amenable to shorter course therapy.
The duration of antimicrobial therapy is generally calculated from the first day on which blood cultures are negative. Blood cultures should be obtained every 24—72 hours until it is demonstrated that the bloodstream infection has cleared , If operative valve tissue cultures are positive, an entire antimicrobial course should be considered following cardiovascular surgery.
Selection of the appropriate antimicrobial agent. Therapy should be targeted to the organism identified in blood cultures or serological studies. While awaiting microbiological results, an empirical regimen may be selected based on epidemiological and patient demographic features.
As most IE cases are caused by Gram-positive bacteria, vancomycin is often an appropriate empirical choice. However, other empirical agents may also be appropriate based on local microbiology and susceptibility patterns.
Detailed recommendations for antimicrobial treatment of specific pathogens are comprehensively addressed in recent treatment guidelines , , Key points are summarized in Table 3. Considerations for prosthetic valves and implantable cardiac devices. Infections of cardiac implantable electronic devices such as pacemakers and defibrillators may occur with or without associated valvular IE There are limited clinical data to inform the optimal duration of antibiotic therapy for cardiac device infections; at least 4—6 weeks, using the same antibiotics as for valvular IE, are recommended for lead endocarditis The crucial distinction in selecting antibiotic therapy for S.
However, among patients with a reported penicillin allergy, most do not have a true allergy when skin testing is performed , and skin testing seemed to be cost-effective in decision analyses for treating MSSA bactaeremia and IE For MRSA IE, vancomycin has historically been the antibiotic of choice and it remains a first-line therapy in treatment guidelines , , , Recent reports have raised the concern that after decades of use, the vancomycin minimum inhibitory concentration MIC for S.
Increased vancomycin MICs, even among isolates still classified as susceptible, might be associated with worse outcomes in MRSA bacteraemia, although meta-analyses have reached different conclusions , In light of this finding, it seems that a higher vancomycin MIC may be a surrogate marker for host-specific or pathogen-specific factors that lead to worse outcomes.
Ultimately, the clinical response of the patient should determine the continued use of vancomycin, independent of the MIC Daptomycin seems to be safe and effective at these higher doses — Gentamicin is not recommended for staphylococcal NVIE because it is associated with nephrotoxicity and does not have robust data to support clinical benefit Similarly, rifampin is also not recommended as an adjunct therapy for NVIE because it has been associated with adverse effects and prolonged bacteraemia and should be avoided in staphylococcal NVIE unless there is another indication for its use, such as concurrent osteoarticular infection.
For staphylococcal PVIE, weak evidence supports the use of both gentamicin and rifampin A large trial examining the role of adjunctive rifampin for S. Observational data have been reported for other antibiotic combinations. For example, ceftaroline is a cephalosporin antibiotic active against MRSA and has been used as salvage therapy for IE alone or in combination with other anti-staphylococcal antibiotics , Recommended treatment regimens for coagulase-negative staphylococci are the same as those for S.
The addition of an aminoglycoside may enable a shorter 2-week course of therapy when administered once daily in combination with ceftriaxone for streptococcal NVIE , For streptococcal isolates with an increased penicillin or ceftriaxone MIC, gentamicin should be added From the early days of the antibiotic era, clinicians noted that penicillin worked less well for enterococci than for streptococci and combination therapy with an aminoglycoside was therefore recommended Although this has remained the standard approach, increasing rates of aminoglycoside resistance and the toxicity associated with this class of antibiotics have spurred efforts to find alternative therapeutic options.
Recent data indicate that the combination of ampicillin and ceftriaxone may be effective for IE due to ampicillin-susceptible Enterococcus faecalis , particularly in patients with aminoglycoside resistance, or in whom there is concern for nephrotoxicity with an aminoglycoside , Vancomycin-resistant enterococcal IE is fortunately rare but has been successfully treated with linezolid and daptomycin If daptomycin is used, high-dose therapy may be considered Other organisms.
Thus, HACEK organisms should be considered ampicillin-resistant and ceftriaxone is the preferred treatment. A duration of 4 weeks of therapy is generally sufficient for these organisms Consequently, optimal management strategies are not defined. Cardiac surgery combined with prolonged antibiotic therapy is considered a reasonable strategy in many cases Fungal IE is also rare but outcomes are poor. Valve surgery is often used, but this approach is not clearly associated with improved outcomes Following initial parenteral therapy with an amphotericin-based regimen or an echinocandin, indefinite azole therapy is recommended, particularly if valve surgery is not performed , Culture-negative IE.
Culture-negative IE cases are particularly challenging to manage. Although sterile blood cultures are most commonly due to patient receipt of antibiotics before obtaining blood cultures, they may also arise from inadequate microbiological techniques, infection with fastidious organisms or non-infectious causes of valvular vegetations, such as marantic or Libman—Sacks IE.
Choosing an antibiotic regimen in these cases requires balancing the need for empirical therapy for all the likely pathogens with the potential adverse effects of using multiple antibiotics. The rate of early valve replacement or repair has increased over time 4 in keeping with the prevailing opinion that surgery is a key component of the management of many complicated IE cases.
However, the evidence base for this practice is decidedly mixed. A single randomized trial demonstrated a significant reduction in the composite outcome of in-hospital deaths and embolic events with early surgery While clearly transformational, study generalizability was nonetheless questioned. Study subjects were younger, healthier and infected with less-virulent pathogens for example, VGS than contemporary patients with IE encountered in general practice For most patients with IE, recommendations for surgery are based on observational studies and expert opinion.
The principal consensus indications for valve surgery are heart failure, uncontrolled infection and prevention of embolic events in patients at high risk of IE. Uncontrolled infection may be related to paravalvular complications, such as abscess, an enlarging vegetation or dehiscence of a prosthetic valve.
In addition, uncontrolled infection may be manifested by ongoing systemic illness with persistent fevers and positive blood cultures despite appropriate antibiotic therapy. The timing of cardiac surgery for patients with IE and neurovascular complications remains controversial. A large prospective cohort study of patients with IE complicated by ischaemic stroke without haemorrhagic conversion found that no patient benefit was gained from delaying surgery On the basis of these observational data, the AHA currently recommends that valve surgery may be considered in patients with IE who also have stroke or subclinical cerebral emboli without delay if intracranial haemorrhage has been excluded by imaging studies and neurological damage is not severe such as coma.
In patients with major ischaemic stroke or intracranial haemorrhage, AHA guidelines currently state that delaying valve surgery for at least 4 weeks is reasonable However, these pathogen-specific recommendations for surgery have been recently called into question in favour of an individualized decision-making approach based on haemodynamic and structural indications , Patients with PVIE who are receiving oral anticoagulants may be at an increased risk of death from cerebral haemorrhage Antiplatelet therapies are not currently recommended for IE.
A single randomized trial examined the role of mg of aspirin daily for patients with IE. The incidence of embolic events was similar between aspirin-treated and placebo-treated patients, and there was a non-significant increase in the rate of cerebral bleeding episodes However, there are several limitations to this study, including the dose of aspirin used and the delayed initiation of aspirin.
For patients with another indication for antiplatelet therapy, it may be reasonable to continue the antiplatelet agent unless bleeding complications develop. Similarly, it is not recommended to initiate anticoagulant therapy such as warfarin for the purpose of treating IE. In patients with IE who have another indication for anticoagulation therapy, such as a mechanical valve, data are contradictory on whether to continue anticoagulation during acute therapy , , and bridging therapy with heparin products has not been studied.
Management of metastatic foci. Metastatic foci of infection frequently complicate IE. As with any infection, recognition of these foci of infection is important so that targeted interventions, such as drainage of abscesses or removal of infected prosthetic material, may be undertaken. This is of crucial importance in patients who require valve surgery because a persistent source of infection may serve as a source from which a recently placed prosthetic valve or annuloplasty ring becomes infected , Some metastatic foci, such as vertebral osteomyelitis, may require additional antibiotic therapy beyond what is typically indicated for IE There is currently insufficient evidence to recommend specific imaging strategies to look for metastatic foci in all patients with IE.
Most patients with IE in the modern era are cured and attention can eventually turn to a follow-up plan. Elements of follow-up may include an echocardiogram at the completion of antimicrobial therapy to establish a new baseline for subsequent comparison, referral to a drug cessation programme for patients with IDUs and a thorough dental evaluation.
A comprehensive search for the initial portal of pathogen entry may be undertaken so that this can be addressed to minimize repeat episodes of IE. Routine blood cultures at completion of antibiotic therapy are not recommended given a very low rate of positivity in patients with no signs of active infection.
Patients should also be monitored for complications of IE, including relapse, incident heart failure and complications of antibiotic therapy, such as audiological toxicity from aminoglycosides or incident Clostridium difficile infection. In addition to the stress associated with being diagnosed with a potentially lethal infection, patients with IE routinely experience prolonged hospitalizations and adverse reactions to treatment, and undergo multiple invasive procedures.
For instance, treatment for left-sided IE requires extended courses of intravenous antibiotics, which involves long-term venous access and probably diminishes patient quality of life QOL.
To what extent these factors may impair the QOL of patients after they are discharged from the hospital is not well known, as only a few studies have addressed these issues — In addition, life-threatening illness may cause post-traumatic stress disorder PTSD , which has been shown to impair patient well-being in survivors of various life-threatening infectious diseases.
In one study of QOL in survivors of left-sided NVIE, 55 out of 86 eligible adults completed questionnaires 3 and 12 months after discharge from hospital and 12 more patients completed the month questionnaires only. Given the low number of patients evaluated, the effect of factors, such as causative microorganisms or valve surgery, on QOL and on the rate of PTSD could not be assessed.
In one study conducted in patients without IE who had undergone mitral valve surgery, the type of surgery replacement versus repair had no effect on the QOL of patients Whether a comprehensive cardiac rehabilitation programme which typically involves exercise and information sessions may improve the QOL of patients surviving IE is currently being explored through a randomized clinical trial the CopenHeart IE study , in which patients treated for left-sided NVIE or PVIE or cardiac device IE will be randomized to either cardiac rehabilitation or usual care In a qualitative evaluation of 11 patients recovering from IE, Rasmussen et al.
These feelings subsided quickly for a few, whereas most patients experienced a persisting weakness and felt frustrated about the prolonged recovery phase. Finally, patients expressed that support from relatives and health care professionals, as well as one's own actions, were important in facilitating recovery. This original study emphasized the need for research in follow-up care to support a patient's ability to cope with potential physical and psychoemotional consequences of IE Given the scarcity of data on the subject, future studies are needed to define the effect of IE on patient QOL.
Engage patient networks and advocacy groups for input on priorities in infective endocarditis IE research. Future treatments for IE will emphasize pragmatism. For example, an effective treatment strategy for left-sided IE that avoids long-term venous access would be an important advance. In addition, two newly approved anti-staphylococcal antibiotics — dalbavancin and oritavancin — might eventually represent alternatives to the current standard intravenous treatment strategies for IE.
Along these lines, the POET study uses a non-inferiority, multicentre, prospective, randomized, open-label study design to test the hypothesis that partial oral antibiotic treatment is as safe and effective as parenteral therapy in left-sided IE A total of stable patients with streptococcal, staphylococcal or enterococcal aortic or mitral valve IE will be randomized to receive a full 4—6 weeks of intravenous antibiotics or to receive oral antibiotics after a minimum of 10 days of parenteral therapy.
Patients will be followed up for 6 months after completion of antibiotic therapy. The primary end point is a composite of all-cause mortality, unplanned cardiac surgery, embolic events and relapse of positive blood cultures with the primary pathogen. In this study, subjects with IE due to MSSA will receive at least 10 days of intravenous antibiotic therapy, then will be randomized to complete a full 4—6 weeks of intravenous therapy or to receive oral levofloxacin and rifampin for at least 14 additional days.
Dalbavancin and oritavancin, which are lipoglycopeptide-class antibiotics that were approved in by the FDA for the treatment of acute bacterial skin and skin structure infections ABSSSIs , represent potential improvements to the current options of intravenous therapy for IE. An important property is their extremely long half-life, estimated to be 10—14 days , , which allows infrequent administration. Dalbavancin is approved by the FDA for the treatment of ABSSSIs using a single 1, mg dose or with a two-dose strategy: a 1, mg loading dose on day 1 followed by a mg infusion 1 week later , These dosing strategies might ultimately avoid the need for home health or skilled nursing facility care for outpatient intravenous antibiotics.
Although no data are currently available for the efficacy of such treatment strategies in IE, the pharmacokinetics of dalbavancin dosed at 1, mg of dalbavancin on day 1 followed by mg weekly for 7 additional weeks seemed to be favourable in one phase I study In addition, dalbavancin was studied in catheter-associated bloodstream infection Therapies not requiring extended intravenous access, such as dalbavancin or oritavancin, could be especially advantageous in treating IE in patients with IDU or who have limited options for intravascular line placement.
The best way to treat IE is to prevent it. Although most efforts to date on IE prevention have focused on infection control and dental prophylaxis, considerable resources have also been invested in vaccine development that targets common bacterial causes of IE.
Success has been mixed and none of these agents is currently commercially available. Nonetheless, future prevention strategies for some causes of IE are likely to include vaccines. Although vaccine candidates for pathogens such as VGS and C. Passive immunization strategies for staphylococcal infections.
At least ten studies have tested vaccines or immunotherapeutics for the prevention or treatment of S. Efforts to date have pursued two approaches: passive immunization with existing antibodies or active immunization by stimulating a host antibody response in a classic vaccine design. Two passive immunization strategies have been attempted: treatment of active staphylococcal infections as an adjunct in addition to standard treatment; and prevention of staphylococcal infections in patients deemed to be at high risk of developing infection.
Each approach has strengths and limitations. Treatment strategies provide the design advantage of a relatively small sample size and relative ease of enrolment owing to provision of standard of care treatment in both arms, but will require demonstrating superiority over standard of care therapy for FDA approval. Although three immunotherapeutic compounds to date have been evaluated as treatment adjuncts in patients with S. A fourth compound, G3, is currently undergoing evaluation in a phase II safety and efficacy study in hospitalized patients with S.
Three passive immunotherapeutic compounds have undergone clinical trials to prevent staphylococcal infections aimed at both S. None exhibited significant protection. Pagibaximab, a humanized murine chimeric monoclonal antibody that targets lipoteichoic acid in the cell wall of S.
Active immunization strategies for staphylococcal infections. Two S. A third registrational trial is underway All three trials focus on specific adult populations at high risk for S. StaphVAX Nabi Biopharmaceuticals, Rockville, Maryland, USA is a bivalent vaccine of capsular polysaccharides 5 and 8 that was tested in 1, patients with a primary fistula or synthetic graft vascular access undergoing haemodialysis.
Thus, a second trial of StaphVAX in 3, patients undergoing haemodialysis was undertaken. In this second study, the primary efficacy end point was set at 6 months. Unfortunately, this unpublished trial also failed to demonstrate protection against the development of S. V is a vaccine that targets the cell wall constitutive iron-regulatory protein IsdB and was tested in patients undergoing median sternotomy. The study was terminated after approximately 8, patients were enrolled owing to lack of efficacy and also to a higher rate of multiple organ system failure-related deaths among patients who received V In post-hoc analyses, patients that received V and subsequently became infected with S.
The reason for this increased mortality is unknown. This study aims to test the efficacy and safety of a vaccine that targets S. Unlike previous S. At least two other S. Candidate vaccine NDV-3 contains the amino-terminal portion of the C.
Preclinical studies have demonstrated that the Als3p vaccine antigen protects mice from mucocutaneous and intravenous challenge with both C. The vaccine has been shown to be safe and immunogenic in healthy adults Most recently, a multi-subunit vaccine that targets five known S. When formulated with a novel Toll-like receptor 7-dependent agonist, the five antigens provided high levels of T helper 1-driven protection against S.
Although much has changed since Osler elucidated its fundamental disease mechanisms in the late s, IE remains a disease of high morbidity and mortality with far-reaching effects on the QOL of survivors. In the near term, the epidemiology will continue to reflect the epidemiological and microbiological effect of health care contact.
Improved algorithms for the diagnosis of IE will incorporate new microbiological techniques, especially for blood culture-negative cases.
We can safely assume that imaging technology will continue to advance, and further research is needed to define which patients with suspected IE should undergo TOE and which patients may benefit from newer imaging modalities.
Novel Gram-positive antibiotics are promising but as yet untested in IE. If proven to be effective, they might enable simpler and more-patient-friendly treatment regimens.
It is likely that the debate around IE prophylaxis will continue until prophylaxis strategies are compared prospectively. Vaccine development has not yet yielded an effective and commercially available product, but numerous candidates are in the pipeline. Contrepois, A. Towards a history of infective endocarditis. Osler, W. The Gulstonian Lectures, on malignant endocarditis. Bin Abdulhak, A. Global and regional burden of infective endocarditis, — a systematic review of the literature.
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This prospective cohort study of 2, adults with definite IE demonstrates that IE had shifted from a subacute disease of younger people with rheumatic valvular abnormalities to one in which the presentation is more acute and is characterized by a high rate of S.
Thayer, W. Studies on bacterial infective endocarditis. Johns Hopkins Hosp. Google Scholar. Fowler, V. Jr et al. Staphylococcus aureus endocarditis: a consequence of medical progress.
JAMA , — This prospective cohort study of 1, patients with definite IE demonstrates that S. Rabinovich, S. A long-term view of bacterial endocarditis. Watt, G. Greenspon, A. Thiene, G. Pathology and pathogenesis of infective endocarditis in native heart valves. Clemens, J.
A controlled evaluation of the risk of bacterial endocarditis in persons with mitral-valve prolapse. Kaye, D. Changing pattern of infective endocarditis. Movahed, M. Mitral annulus calcification is associated with valvular and cardiac structural abnormalities. Ultrasound 5 , 14 Benito, N. Health care-associated native valve endocarditis: importance of non-nosocomial acquisition.
Federspiel, J. Jr Increasing US rates of endocarditis with Staphylococcus aureus : — Duval, X. Temporal trends in infective endocarditis in the context of prophylaxis guideline modifications: three successive population-based surveys.
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Veloso, T. Use of a human-like low-grade bacteremia model of experimental endocarditis to study the role of Staphylococcus aureus adhesins and platelet aggregation in early endocarditis.
Forner, L. Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. Lockhart, P. The risk for endocarditis in dental practice.
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