Nonvalvular cardiovascular device-related infections.

Abstract

HomeCirculationVol. 108, No. 16Nonvalvular Cardiovascular Device–Related Infections Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBNonvalvular Cardiovascular Device–Related Infections Larry M. Baddour, MD, Michael A. Bettmann, MD, Ann F. Bolger, MD, Andrew E. Epstein, MD, Patricia Ferrieri, MD, Michael A. Gerber, MD, Michael H. Gewitz, MD, Alice K. Jacobs, MD, Matthew E. Levison, MD, Jane W. Newburger, MD, Thomas J. Pallasch, DDS, Walter R. Wilson, MD, Robert S. Baltimore, MD, Donald A. Falace, DMD, Stanford T. Shulman, MD, Lloyd Y. Tani, MD and Kathryn A. Taubert, PhD Larry M. BaddourLarry M. Baddour Search for more papers by this author , Michael A. BettmannMichael A. Bettmann Search for more papers by this author , Ann F. BolgerAnn F. Bolger Search for more papers by this author , Andrew E. EpsteinAndrew E. Epstein Search for more papers by this author , Patricia FerrieriPatricia Ferrieri Search for more papers by this author , Michael A. GerberMichael A. Gerber Search for more papers by this author , Michael H. GewitzMichael H. Gewitz Search for more papers by this author , Alice K. JacobsAlice K. Jacobs Search for more papers by this author , Matthew E. LevisonMatthew E. Levison Search for more papers by this author , Jane W. NewburgerJane W. Newburger Search for more papers by this author , Thomas J. PallaschThomas J. Pallasch Search for more papers by this author , Walter R. WilsonWalter R. Wilson Search for more papers by this author , Robert S. BaltimoreRobert S. Baltimore Search for more papers by this author , Donald A. FalaceDonald A. Falace Search for more papers by this author , Stanford T. ShulmanStanford T. Shulman Search for more papers by this author , Lloyd Y. TaniLloyd Y. Tani Search for more papers by this author and Kathryn A. TaubertKathryn A. Taubert Search for more papers by this author Originally published21 Oct 2003https://doi.org/10.1161/01.CIR.0000093201.57771.47Circulation. 2003;108:2015–2031More than a century ago, Osler took numerous syndrome descriptions of cardiac valvular infection that were incomplete and confusing and categorized them into the cardiovascular infections known as infective endocarditis. Because he was both a clinician and a pathologist, he was able to provide a meaningful outline of this complex disease. Technical advances have allowed us to better subcategorize infective endocarditis on the basis of microbiological etiology. More recently, the syndromes of infective endocarditis and endarteritis have been expanded to include infections involving a variety of cardiovascular prostheses and devices that are used to replace or assist damaged or dysfunctional tissues (Table 1). Taken together, infections of these novel intracardiac, arterial, and venous devices are frequently seen in medical centers throughout the developed world. In response, the American Heart Association’s Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease wrote this review to assist and educate clinicians who care for an increasing number of patients with nonvalvular cardiovascular device–related infections. Because timely guidelines1,2 exist that address the prevention and management of intravascular catheter–related infections, these device-related infections are not discussed in the present Statement. TABLE 1. Nonvalvular Cardiovascular Device–Related InfectionsType of DeviceIncidence of Infection, %*Closure device use ≤1.9%.Intracardiac Pacemakers (temporary and permanent)0.13–19.9 Defibrillators0.00–3.2 LVADs25–70 Total artificial heartsTo be determined Ventriculoatrial shunts2.4–9.4 PledgetsRare Patent ductus arteriosus occlusion devices (investigational in the United States: plugs, double umbrellas, buttons, discs, embolization coils)Rare Atrial septal defect and ventricular septal defect closure devices (Bard clamshell occluders, discs, buttons, double umbrellas)Rare ConduitsRare PatchesRareArterial Peripheral vascular stentsRare Vascular grafts, including hemodialysis1.0–6 Intra-aortic balloon pumps≤5–26 Angioplasty/angiography-related bacteremias<1* Coronary artery stentsRare Patches1.8Venous Vena caval filtersRareThis review is divided into two broad sections. The first section examines general principles for the evaluation and management of infection that apply to all nonvalvular cardiovascular devices. Despite the marked variability in composition, structure, function, and frequency of infection among the various types of nonvalvular cardiovascular devices reviewed in this article, there are several areas of commonality for infection of these devices. These include clinical manifestations, microbiology, pathogenesis, diagnosis, treatment, and prevention. The second section addresses each device and describes unique clinical features of infection. Each device is placed into one of 3 categories—intracardiac, arterial, or venous—for discussion.General PrinciplesClinical ManifestationsThe specific signs and symptoms associated with an infection of a nonvalvular cardiovascular device depend on the location of the infected portion(s) of the device. Clinical manifestations of infected intravascular or endovascular portions of a device are similar to those seen in infective endocarditis or endarteritis.3,4 Fever is present in most cases. Embolic events are also commonplace and involve either the pulmonary or systemic vasculature, according to the location of the infected device. Sepsis with shock and organ dysfunction is present in some acute presentations caused by virulent pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. Subacute to chronic presentations are characteristic of infections produced by less aggressive microorganisms. Immune-mediated events are occasionally seen with chronic infections and include immune complex–mediated nephritis and vasculitis. These infections can present as bacteremia with fever and no other clinical findings. For devices that have infection involving percutaneous drivelines, there can be local pain, erythema, induration, warmth, and purulent drainage at the percutaneous exit site, often in association with bacteremia. For devices that are implanted subcutaneously, infection at the site can present with local findings of cellulitis or abscess formation, with or without bacteremia (Figure 1). Pseudoaneurysms develop in some cases of infection at vascular graft anastomosis sites and present as pulsatile masses. Occlusion of a graft may lead to distal manifestations of ischemia or necrosis. Download figureDownload PowerPointFigure 1. Vascular graft site infection in a hemodialysis patient due to methicillin-resistant S aureus. The patient suffered bacteremia in addition to focal skin and soft tissue changes at the graft site, including erythema, swelling, warmth, and pain.MicrobiologyStaphylococci account for the majority of device-related infections. Either coagulase-negative staphylococci or S aureus is the most common pathogen identified, according to the case series reported. Other types of skin flora produce infection less frequently. Distinguishing skin flora, particularly coagulase-negative staphylococci, as either pathogen or culture contaminant is a frequent diagnostic dilemma. Multiple sets of blood cultures should yield the pathogen if endovascular infection is present. Skin flora that grow in culture from percutaneous aspirates of fluid or abscess collection should be considered as pathogens. Recovery of skin flora at driveline transcutaneous exit sites or in open wounds in proximity to a device is more difficult to define as pathogen versus contaminant; a Gram’s stain may be helpful. Other Gram-positive cocci, Gram-negative bacilli, and fungi, particularly Candida species, cause a minority of device-related infections. Multidrug resistance is common and reflects the nosocomial origin of many of these infections.PathogenesisThree factors should be considered when addressing the pathogenesis of medical device–related infections: (1) pathogen virulence factors, (2) host response to the presence of an artificial device, and (3) the physical and chemical characteristics of the medical device. During the past decade, many published studies have detailed the complexities of the pathogenesis of medical device–related infections. These are a result of advances in molecular biology techniques that have facilitated the study of purported virulence determinants among both bacterial and fungal pathogens.Pathogen Virulence FactorsTwo major areas of investigation of microbial virulence factors are (1) tissue and foreign body adherence molecules and (2) foreign body surface biofilm formation. There are several S aureus adhesins5–9 that are operative in the binding of microorganisms to extracellular and host plasma proteins that coat the surface of indwelling medical devices. These host proteins are exposed in areas where endothelium has been denuded by contact with or attachment to indwelling devices. The adhesins, known as extracellular matrix-binding proteins or microbial surface components recognizing adhesive matrix molecules (MSCRAMM), have been studied in a number of in vitro adherence assays and in animal models of infection and have demonstrated their importance in microbial virulence. Much of the work has examined S aureus surface proteins, including fibronectin-binding protein A or B, clumping factor A or B, and collagen-binding protein. The only experimental model of cardiovascular infection that has been used to examine these putative virulence factors is the animal endocarditis model.10 Findings derived from experimental endocarditis investigations may be applicable to cardiovascular device–related infections in humans.A number of studies6,7 suggest that binding to fibrinogen is critical in the pathogenesis of catheter-induced experimental endocarditis in rats. Other work5 suggests that binding of staphylococci to collagen is advantageous. There are temporal aspects of binding; fibrin(ogen) binding early in the infection process seems to be important with S aureus. Fibronectin binding may be more important later, when bound fibrin degradation occurs because of plasmin.9 Other investigations7,8 that used recombinant techniques demonstrated that fibronectin binding was also important in virulence in the animal endocarditis model. In a rat model of experimental endocarditis examining the role of fibronectin binding in virulence, conflicting results were seen. In one investigation, fibronectin binding by S aureus seemed important,8 whereas in another, it did not.9 There has been limited investigation of the role of collagen-binding protein.4Another area of interest in microbial pathogenesis of cardiovascular medical device infections is biofilm formation.11–13 Biofilm, consisting of infecting microorganisms and extracellular matrix, forms on the surface of an indwelling medical device and serves as a protected environment for microorganisms. It is believed that mature biofilm formation is predominantly responsible for the inability of the host immune response and antimicrobial therapy to clear device-related infections. Because of this protected environment, device removal to achieve cure of infection is usually required.Staphylococcus epidermidis13 has received the most investigative attention among the variety of microorganisms that can produce biofilm-related medical device infections. The polysaccharide intercellular adhesin that is responsible for cellular aggregation and biofilm formation has been characterized, and the gene cluster (ica) that contains all genes required for polysaccharide intercellular adhesin production has been described.14,15 Notably, similar genes that are present in other coagulase-negative staphylococci and in S aureus are responsible for the production of the polysaccharide intercellular adhesin and biofilm.14Host Response to Medical DevicesMany of the critical host elements that affect the risk for device infection, including the endothelium, white blood cells, platelets, and microorganisms within the bloodstream, react to the specific quality of blood flow to which they are exposed. Normal cardiovascular flow is regularly pulsatile and dynamic. Each region of the cardiovascular system has a characteristic normal shear stress (the frictional force due to the flowing blood in contact with the wall) and circumferential strain (the distending force of the intraluminal pressure). Normal flow at physiological shear rates is antistimulatory to the endothelium16,17; the endothelial cells align and flatten with the flow, and apoptotic and inflammatory mediators are suppressed.Many of the devices discussed in detail in this Statement, including electrophysiological devices, left ventricular assist devices (LVADs), ventriculoatrial shunts, total artificial hearts, stents, grafts, and balloon pumps, create or reside within sites of very abnormal cardiovascular blood flow. The flow changes may augment the infective potential of the devices and impede response to therapy. Some important characteristics of abnormal flow are abnormally high or low shear stress and increased gradient in shear, alterations in circumferential strain, and abnormal boundary surfaces. Examples of abnormal flow conditions and devices often associated with them are turbulence caused by tricuspid regurgitation due to a pacemaker lead18,19 that interferes with valve closure, high shear caused by a LVAD valve, and abnormal circumferential strain produced by vascular grafts.Turbulence is not a prominent component of normal cardiovascular flow. It occurs alongside high-velocity jets, such as along the edges of jets of tricuspid regurgitation or prosthetic valve hinges. Some turbulence may occur at arterial branch points, creating characteristic zones where flow becomes disorganized, with low velocities and random fluctuations in flow. Low shear stresses in turbulent regions increase the reactivity of the endothelial cells and circulating platelets and have been closely associated with regional progression of atherosclerosis and thrombosis. Platelets and microorganisms caught in the turbulent zones are exposed to adverse shear conditions. These conditions strongly promote regional endothelial activation, increase platelet aggregation, and provide opportunities for platelet and microbial adherence.16,20 The spatial and temporal disorganization in a turbulent zone thwarts any compensatory endothelial realignment that the cardiovascular system would normally invoke to minimize the adverse effects of abnormal flow.High shear stress, beyond the 14 dyne/cm2 that is the normal upper limit for the arterial tree, occurs with luminal stenosis. The high shear at vascular stenotic sites, including those due to constriction from grafts or intraluminal devices, affects neutrophil and monocyte adherence and phagocytosis21,22 without impeding, and possibly increasing, microbial adherence.23 These deleterious effects on endothelial cells, platelets,24 and cell-mediated immunity may have important etiologic roles with regard to establishment and maintenance of device infection.All devices present an artificial surface to the blood. Neutrophil and monocyte function has also been shown to be adversely affected by contact with some prosthetic surfaces,21 and antibiotic penetration into areas of medical devices may be diminished. The abnormal material properties of some vascular grafts, which change the circumferential strain experienced by the endothelium within the grafts, may similarly increase endothelial activation and platelet and microbial adherence.25 In addition, T-cell function may be influenced by the presence of some of these devices.26 Endothelialization of an implanted device is a key factor in the prevention of subsequent infection. In animal studies of explanted devices, endothelialization has been noted to occur as early as 1 month after implantation and to be complete by 3 months.27 The “healing response” to device implantation in humans has been much less studied, but in a recent report of human cases involving explanted devices, similar results were found.28 The development of a nonthrombotic fibroelastic pseudointima was apparent in these cases by 2.7 months and was not affected by the site of implantation.Physical and Chemical Characteristics of Medical DevicesMany authorities believe that the occurrence of infection is related to the ability of red blood cells, platelets, and fibrinogen to adhere to prosthetic material. Fibrinogen is one factor that promotes “sticking” to a prosthetic device. It is a highly hydrated macromolecule and precedes platelet attachment to biomaterial. Biomaterials with lower critical surface tension, including Teflon and other fluorocarbon polymers, do not attract platelets. The biomaterials with higher critical surface tension, such as Dacron polyethamine, attract platelets and fibrinogen, both of which aggressively bind to these materials. Clumps of fibrinogen and platelets attract white blood cells, and a surface-bound mass develops around the biomaterial.DiagnosisLaboratory, radiological, and echocardiographic procedures are helpful in making a diagnosis of cardiovascular device–related infection. In untreated patients with bacteremia, blood cultures are usually positive. Culture of purulent drainage from a percutaneous driveline exit site or from a subcutaneous pocket or other site identifies a specific pathogen. Gram’s stain of the drainage material is useful in demonstrating neutrophils and infecting bacteria.Despite collection of clinical specimens for microbiological examination, stains and cultures fail to demonstrate a pathogen in some patients with nonvalvular cardiovascular device–related infections. These culture-negative cases, much like those seen with infective endocarditis, are often due to recent antibiotic administration, which may diminish the sensitivity of subsequent microbiological studies. Unlike infective endocarditis, fastidious and uncommon microorganisms that do not grow or stain positive by routinely used laboratory methods have not been identified as pathogens in nonvalvular device-related infections. These groups of rare pathogens that are now being identified as causes of culture-negative endocarditis by technical advances in the laboratory29 have not accounted for culture-negative nonvalvular infections.Role of ImagingAll imaging modalities (Table 2) discussed in the following section are useful only as aids in diagnosis and treatment. Findings from these studies have to be interpreted for the individual patient and with the results of other diagnostic testing to assist the clinician in forming a diagnosis of device-related infection. TABLE 2. Imaging for Nonvalvular Cardiovascular Device–Related InfectionsManifestation of InfectionInitial Imaging ModalityImaging with a complementary modality may be required in addition to the initial evaluation.EndocarditisTEE Pacemakers (temporary and permanent) Defibrillators LVADs Ventriculoatrial shunts Pledgets Patent ductus arteriosus occlusion devices Atrial septal defect closure devices Conduits PatchesPericarditisTTE or TEE Coronary artery stents PledgetsPerivasculitisCT or MRI Peripheral vascular stents Vascular grafts, including hemodialysis Angioplasty/angiography-related bacteremias Coronary artery stents PatchesAneurysm or pseudoaneurysmAngiography Pledgets Coronary artery stents Patches Angioplasty/angiography-related bacteremias Vascular grafts, including hemodialysisInfected thrombosisUltrasound Vena caval filter Vascular grafts, including hemodialysisPocket site infectionsUltrasound Pacemakers (permanent) Defibrillators LVADs Total artificial heartsPlain radiographic films play a minor and indirect role in diagnosing infections of nonvalvular implanted cardiovascular devices but can provide important information when used judiciously. Infections may be related to misplacement or displacement of devices. For example, a port catheter in the superior vena cava or high right atrium, as intended, is less likely to thrombose and develop an infection than is a catheter that is displaced into the internal jugular vein or is left with its tip in the less capacious subclavian vein.Computed tomographic (CT) scanning can give similar information. The advantage of CT scanning is that it is less operator dependent than ultrasonographic scanning, in both acquisition and interpretation of images. Furthermore, particularly with newer multislice units, images can be obtained very rapidly, often obviating the need for breath holding and limiting the degree to which patient cooperation is necessary. Even relatively large areas, such as vascular grafts and stent-grafts, can be quickly and accurately imaged. On the negative side, contrast injection may be necessary, and this is a concern in patients with compromised renal function. Also, stents cause metallic artifacts so that visualization within the stented lumen is limited. Devices such as wires, catheters, and stent-grafts (with Nitinol stents [Nitinol Devices and Components], as opposed to stainless steel alloys) do not produce such artifacts.Angiography has little role in diagnosing infections. Cardiac catheterization may, however, offer therapeutic options that decrease the risk of infection. It may be useful in confirming and correcting malpositioned lines or wires. Percutaneous stripping of thrombus from catheters with a snare has been widely used to restore function. It may also decrease the risk of infection, although this has not been well investigated. Angiographic dye-related renal toxicity is another concern.Ultrasound may be helpful in several ways; however, its efficacy is dependent on the proficiency of the technician. It can identify abnormal fluid collections around a device. By demonstrating septations or inhomogeneity of the fluid in such collections, it can provide clues as to whether or not the fluid is likely to be infected. Ultrasound is also very useful in guiding aspiration, for both diagnosis and treatment of fluid collections. Ultrasound can detect pseudoaneurysm formation. The addition of Doppler flow studies provides physiological information that can give indirect evidence of infection—eg, slowed or turbulent flow through a graft due to thrombus formation.Transthoracic and transesophageal echocardiography have proven useful in visualizing abnormalities such as valvular vegetations, pericardial effusion, abnormal position of a device such as a pacemaker wire, or thrombus on or related to a device.Magnetic resonance imaging (MRI) does not have a major role. Its use is contraindicated in patients with electrophysiological cardiac devices. Current information should be obtained from an institution’s MRI safety committee when considering MRI use in patients with other types of cardiovascular devices. Metallic implants such as stents produce artifacts that significantly degrade image quality. It may be a more sensitive technique than CT scanning in evaluating subtle perigraft inflammatory changes.Radionuclide studies can be valuable in difficult cases in determining whether there is a focal infection or which area is infected. Both Tc99m-labeled white blood cells and gallium can be used. The advantage of the Tc99m white blood cell scan is that results are available within a few hours of white blood cell injection. Gallium scans require 1 to 2 days after nuclide injection before scan results are interpretable.Antimicrobial Therapy—General PrinciplesInitial antimicrobial treatment of nonvalvular cardiovascular device–related infections should incorporate certain goals. These goals represent the consensus opinion of the authors and are not based on data obtained from prospectively conducted clinical trials. Antimicrobial therapy should be directed against an identified pathogen and guided by the in vitro antimicrobial susceptibility testing results for the isolate. In some cases, however, because of negative cultures or an inability to collect cultures, no pathogen is recovered, and empiric broad-spectrum therapy should be selected to treat many potential nosocomial and skin-colonizing organisms. Therapy should be bactericidal (for bacterial infections) and should be administered parenterally in patients with known or suspected bacteremia. Removal of the medical device, if feasible, is preferable. Without prompt removal, risk of morbidity and mortality may increase. The duration of antimicrobial therapy should be individualized for each patient. If there is associated bacteremia, particularly if due to S aureus, then a minimum of 14 days of antimicrobial treatment is necessary after removal of the device and the first negative blood culture. Other experts suggest 4 weeks of antimicrobial therapy after the device is removed for patients with S aureus bacteremia (SAB) due to an infected cardiovascular device or if vegetations are present. If bacteremia is due to staphylococcal endocarditis of a LVAD valve, 6 weeks of antimicrobial therapy is suggested, with a regimen similar to that suggested for prosthetic cardiac valve infection.30A regimen including vancomycin is recommended as initial empiric therapy because staphylococci are frequently identified as pathogens, and methicillin resistance is common among these strains. Alternative antimicrobial regimens are limited for patients who do not respond to or who cannot tolerate vancomycin. Two newer agents, linezolid and the combination of quinupristin/dalfopristin, offer treatment options for methicillin-resistant staphylococcal infections and infections due to vancomycin-resistant enterococci. Both agents should be used only when vancomycin is not a treatment option, such as in the case of vancomycin-resistant enterococci infection or patient history of true vancomycin allergy.Local administration of antibiotics at the device infection site has been used. In the case of vascular graft infection, antibiotic-bonded prosthetic grafts have been implanted for in situ revascularization after resection of infected aortic prosthetic grafts.Long-term suppressive therapy is a useful treatment option for selected patients with cardiovascular device–related infection in whom surgical removal of a device is not possible. These patients should be stable from a cardiovascular standpoint, have responded to antimicrobial therapy, and not be candidates for surgical removal of the indwelling device. Two recently published case series31,32 discuss the use of long-term (lifelong) suppressive antimicrobial therapy in patients with cardiovascular device–related infection. Five patients who had undergone abdominal aortic aneurysm repair developed proven or suspected graft infection.31 Because of severe concomitant medical conditions, none of the 5 patients were considered appropriate surgical candidates for graft replacement. All 5 were infected with Gram-positive cocci and received long-term suppressive antibiotics after initial treatment with a course of parenteral therapy. The patients were followed up for a median period of 32 months (range, 30 to 72 months) on chronic suppressive oral antibiotic therapy with no clinical evidence of graft site infection and reportedly tolerated therapy.Members of the Infectious Diseases Society of America’s Emerging Infections Network were queried in January 2000 to contribute data for patients who received chronic suppressive antimicrobial therapy for cardiovascular device–related infection.32 Data for 51 patients were provided. Vascular graft infections were present in 30 cases (58.8%). Five patients had pacemaker-related infections, 3 had central venous catheter infections, and 1 had an infected venous filter. The remaining 12 patients (23.5%) had infected prosthetic cardiac valves; in 3 of these, aortic grafts were also present. Sixty-three percent of infections were due to Gram-positive cocci.Duration of antimicrobial therapy ranged from 3 to 120 months; duration was 1 year or longer in 51% of cases. Three patients (7.3%) suffered relapse of infection, with one of these relapses due to P aeruginosa that had become resistant during ciprofloxacin monotherapy. Adverse drug events were described in 3 (6.52%) of 46 cases for which information was provided.PreventionBecause of the proclivity for indwelling medical devices to become infected and the general requirement for device removal when they are infected, prevention of infection is a primary goal. Prevention interventions include primary and secondary prophylaxis, antimicrobial impregnation of devices, appropriate infection-control measures, and careful surgical technique for device implantation. Primary or preimplantation antimicrobial prophylaxis is modeled after that used to prevent surgical site infection. In contrast to that used to prevent surgical site infections, primary prophylaxis for the prevention of device-related infection has not been examined in prospective randomized trials. This is due, in large part, to the infrequency of infection. Nevertheless, primary prophylaxis is routinely given to patients who undergo placement of electrophysiological cardiac devices (pacemakers, cardioverter-defibrillators), ventricular assist devices, total artificial hearts, ventriculoatrial shunts, cardiac pledgets, vascular grafts, and arterial patches. One dose of antibiotic, usually cefazolin, is administered to prevent methicillin-susceptible staphylococcal infection of the cardiovascular device. A single dose of vancomycin should be considere