Raymond Chinn
Introduction
In response to the Centers for Disease Control and Prevention (CDC) report that heart disease is the leading cause of death for both men and women in the United States, strategies to prevent and manage cardiovascular disease have become national healthcare priorities [1]. Significant technological advances have made it possible to circumvent the natural history of cardiovascular disease by providing implantable devices that replace or bypass the failing components of the cardiovascular system. Doing so, these devices can salvage a limb or sustain life by maintaining hemodynamic and electrical stability. Prosthetic valves, permanent pacemakers, implantable cardioverter-defibrillators (ICD), left ventricular assist devices (LVAD), total artificial hearts, vascular stents, vascular patches, and vascular grafts are included in this group of devices.
The incidence of device associated-infection (DAIs) varies and depends on the type of implanted device (Table 38-1). In most instances, DAIs are rare (the notable exception are LVADs with infection rates between 25–75%), but their occurrence is associated with significant morbidity and mortality.
Most patients who develop implantable cardiac or vascular DAIs are in older age groups; have required frequent hospitalizations; have significant comorbid conditions, such as diabetes and renal failure; and often are subjected to intense antibiotic pressure, the latter resulting in oxcolonization and subsequent healthcare-associated infection (HAI) with multidrug-resistant organisms. The implanted devices are made of inert materials with inherent properties to overcome immunologic barrier that would confer a survival advantage for patients. However, exposure of the foreign body to microbes results in the elaboration of a biofilm that contributes to the persistence of DAIs. Mechanical failure, thromboembolic events, and anticoagulation-associated bleeding also compromise DAIs' longevity and functional capabilities and such complication increase with the duration of device use.
This chapter examines the pathogenesis common to all implantable cardiac and vascular DAIs in healthcare settings, reviews specific DAIs, discusses the strategies to prevent HAIs, and identifies further research needs. The chapter does not discuss DAIs related to central lines or vascular access for dialysis settings, which are reviewed elsewhere.
Pathogenesis
Following the implantation of a medical device, successful integration occurs when host cells adhere to the surface of the device, multiply, and form granulation tissue that envelops the device and renders it resistant to invasion by microorganisms. However, in a permissive host, this normal event is replaced by adhesion of microbes onto the
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device. The majority of implanted DAIs are caused by the staphylococci; Staphylococcus aureus produces a number of adherence molecules collectively known as the microbial surface components recognizing adhesive matrix molecules (MSCRAMM). These molecules bind the microorganisms onto the surface of medical devices after interacting with host plasma proteins such as fibronectin and fibrinogen, a process similar to the implicated pathogenesis for infective endocarditis [2,5,6]. The exposure of host plasma proteins results from increased turbulence due to an alteration of the normal cardiovascular flow and from the physiologic shear rates caused by the implanted device. An in vitro model suggests that the shear stress induces apoptosis of neutrophils, thereby preventing the host's first line of immunologic response from fully activating [7,8,9]. In this setting, elaboration of microbial virulence factors overcomes the host's immunologic barrier and initiates a cascade of events that culminates in the formation of an intricate extracellular matrix, the biofilm. Within the confines of the biofilm, the microbes reside and create an environment that is relatively impervious to antimicrobials and resistant to the innate host defenses. The presence of an avascular foreign body enhances the risk of surgical site infections (SSIs), by reducing the infecting dose of microorganisms that cause SSIs.
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TABLE 38-1 |
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Microorganisms attach to medical devices in the free-floating (plaktonic) form, divide, interact, become embedded in a biofilm and then transforming into the surface-associated form. An adhesive matrix then creates a protective complex that becomes heterogenous with multiple channels providing transporting nutrients and oxygen to the microorganisms within the biofilm. The surface cells divide, and as the thickness of the biofilm increases, the host's normal immune response to microbiologic challenge is blunted, and the capacity of the host neutrophil's ability to phagocytize, affect intracellular killing, and proliferate is diminished. Microorganisms embedded in biofilms are much more resistant than planktonic cells to antimicrobials and can survive despite concentrations 10–1,000 times what is necessary to eradicate plaktonic forms. In a suspended state of activity, these forms become resistant to the cell wall, growth-phase-dependent antimicrobials, such as penicillin, cephalosporins, and vancomycin. In the deeper layers of the biofilm, microorganisms require less nutritional support and are better able to tolerate environments of lower oxygen tension, a characteristic that renders the microorganism resistant to the aminoglycosides, agents maximally effective in aerobic conditions [10,11]. Clinically, the persistence of DAIs caused by S. aureus and Staphylococcus lugdunensis has been attributed to small colony variant phenotypes that can exchange genetic material codes for an antimicrobial-resistant phenotype that ensures their survival [12,13]. Biofilms have been most studied in S. aureus; however, emerging evidence suggests their role in the pathogenesis of DAIs due to coagulase-negative staphylococci (CoNS), Pseudomonas aeruginosa, and other gram-negative rods, enterococci, and Candida albicans [14,15,16,17,18,19,20].
Comorbid conditions, such as diabetes mellitus, have deleterious effects on chemotaxis, phagocytosis, and adherence of granulocytes, components in the initial line of defense against invading microbes [21,22]. Hyperglycemia, especially in the immediate postoperative period, is a risk factor for SSIs as described in the cardiac bypass literature [23,24,25,26].
Microbial exposure can occur with intraoperative contamination, as a result of hematogenous seeding from a secondary bloodstream infection (BSI) and from an extension of a local infection as occurs with pacemaker or ICD infections. Whether microbial exposure results in infection depends on microbial virulence factors and the host's response to the implanted device. Once the protective biofilm forms, eradication of the infection requires not only appropriate antimicrobial therapy but also, more importantly, explantation of the implanted cardiac or vascular device.
Prosthetic Valve Endocarditis
Epidemiology
More than 60,000 patients per year undergo heart valve replacement in the United States [7]. Prosthetic valves are either mechanical that are constructed of carbon alloys, a ball-and-cage, single tilting disk, or bi-leaflet tilting
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disk (most common) configuration or bioprosthetic valves that include porcine heterografts, bovine pericardium constructed into three cusps mounted on a stent, and the rarely used homografts, that are preserved human aortic valves or pulmonary autografts [28].
Traditionally, prosthetic valve endocarditis (PVE) is classified as early (occurring <60 days of implantation), intermediate (2–12 months), or late (>12 months). CoNS is the pathogen commonly isolated in early PVE and attributed to intraoperative contamination or hematogenous seeding during BSI from other sites such as central venous catheters. However, patients infected with CoNS, a fairly indolent organism, may not have clinical manifestations until the intermediate period. Therefore, for surveillance purposes, the CDC's National Healthcare Safety Network (NHSN; formerly the National Nosocomial Infections Surveillance, or NNIS, system) defines a healthcare-associated postoperative SSI as any SSI that occurs within 1 year of device implantation [29].
The incidence of PVE varies according to the duration of the follow-up period and is estimated to be around 3.1% (data from 1980s) during the first 12 months. The risk of infection is highest within the first 3 months and declines to a fairly constant rate of 0.3–0.6% annually thereafter [30,31,32,33,34]. A recent early PVE study (occurring <12 months after valve surgery) of 77 patients reported decreasing rates comparing two periods, 1.5% in 1992–1994 versus 0.7% in 1995–1997 [35]. A long-term study of the Veterans Affairs population in the 1990s reported the incidence of PVE to increase from 3–5.7% at 5 years to 13% at 15 years [36].
Risk Factors
Risk factors associated with PVE include implantation of multiple prostheses [30], longer cardiopulmonary bypass time [37], valve replacement in the setting of infective endocarditis, New York Heart Association (NYHA) functional class III or IV, alcohol consumption, fever in the intensive care unit, gastrointestinal bleeding, and healthcare-associated blood stream infection (HA-BSI) [32,37,38,39,40]. Three studies reviewed the risk of PVE in patients who developed HA-BSI and reported rates between 11–50%. Investigators of one study of 51 patients reported that approximately half of the patients with a prosthetic valve (PV) or a ring who developed S. aureus BSI (SA-BSI) had definite evidence of PVE at the time of the BSI (using the modified Duke criteria [41,42]) and that the risk was independent of the type, location, or age of the PV or ring. The most common source of early (<12 months of valve placement) SA-BSI was SSIs (59%), whereas patients with late SA-BSI (>1 year after valve placement) had an unidentified source of BSI in 48% of patients. Hallmark features of definite PVE in this study were persistent fever and sustained BSI [43]. In the second study of 171 patients with PVs (excluding 33% of patients who had a diagnosis of PVE at the time of the BSI), 15% of patients developed PVE with a mean of 45 days after documentation of the BSI despite having received antimicrobial therapy. Thirty-three percent was attributed to BSI due to intravascular devices, and skin infections accounted for another 30%; the mitral valve site and Staphylococcal spp. BSI were significantly associated with the development of PVE [44]. The third study describes 37 patients with PV who had no evidence of PVE during the initial 4-week follow-up period after documentation of postoperative candidemia; 11% of patients who had sustained fungemia developed fungal PVE [45]. The studies highlight the importance of preventing BSI and skin infections following PV placement.
Early studies comparing mechanical with bioprosthetic valve and aortic versus mitral site on the incidence of PVE were inconclusive; however, a recent study reported that the incidence of early PVE (occurring <12 months of implantation) was similar in mechanical and bioprosthetic valves. After a longer observation period, the incidence of PVE was higher with bioprosthetic valves due to the platelet-fibrin thrombus deposition on aging leaflets that can become a nidus for infection [31]. In early PVE, infection develops along the suture lines of the prosthesis-annulus interface and perivalvular tissue with resultant dehiscence of sutures. Late infection is similar to native valve endocarditis and begins with platelet-fibrin thrombi deposition on the prosthesis followed by adherence of microorganisms. Early PVE was significantly lower for prosthetic mitral valve than for aortic valve placement [31,35].
Although outbreaks of healthcare-associated PVE are uncommon, they have been described for Mycobacterium chelonei due to contamination of the bioprosthetic valve [46];Staphylococcus epidermidis in association with surgical staff carriage [47,48,49]; Legionella pneumophila and L. dumoffii from exposure of wounds and chest/mediastinal tubes to tap water in a healthcare facility [50]; and Candida parapsilosis possibly related to torn gloves used by the surgical team [51]. Refinements in molecular typing techniques have enabled investigators to link outbreaks to a common source.
In early studies, PVE was associated with mortality rates of 10–70%. Recent reports indicate that the PVE mortality rates are between 4–20% and likely reflect earlier detection, more optimal use of combination antibiotic therapy, and prompt surgical intervention [4]. Risk factors for higher mortality rates resulting from PVE include early PVE (≤1 year of onset), Staphylococcal spp. infection, presentation or development of heart failure, infections involving the aortic valve, and medical management alone. Management of S. aureus PVE with surgical intervention was associated with a 28% mortality rate in contrast to 48% in the medical group in one study [52]. American Society of Anethesiology (ASA) class IV and bioprosthetic valves were independent predictors of mortality when subjected to multivariable analysis. A subset of medically treated
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patients characterized by age <50 years, ASA score III, and the absence of cardiac, central nervous system, and systemic complications was cured without surgical intervention.
Microbiology
In early PVE, the predominant organisms (in decreasing order of frequency) are CoNS, S. aureus, fungi/yeast, gram-negative bacilli, and enterococci (Table 38-2). In contrast, the nonenterococcal streptococci are the most common pathogens in late PVE, similar to native valve endocarditis (excluding the intravenous drug–using population). In late PVE, CoNS remains a common pathogen while the HACEK bacteria, uncommon in early PVE, emerge as pathogens.
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TABLE 38-2 |
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Clinical Manifestations, Diagnosis, and Therapy of Prosthetic Valve Endocarditis
Fever is a common manifestation of PVE, and the presence of sustained fever in a patient with a PV, regardless of the timing of implantation, should prompt a clinical investigation to confirm or exclude the diagnosis. Often it is tempting in clinical practice to attribute fever in the postoperative patient to a urinary tract infection or early pneumonia and initiate empiric antibiotic therapy based on clinical suspicion. However, in patients with PVs, it is a good practice to obtain blood cultures before initiating empiric antibiotics to avoid missing a diagnosis of PVE. Salient clinical features of PVE show similarities with native valve endocarditis and are determined by the time of onset, the virulence of the pathogen, and host responses. Patients with PVE due a pathogen such as S. aureus can present with fulminant sepsis in association with central nervous system emboli and hemorrhagic events with intracardiac manifestations (e.g., acute valvular failure, conduction abnormalities, and progression of perivalvular infection) resulting in rapid cardiac decompensation and with septic peripheral emboli. In contrast, infections caused by the more indolent organisms, such as CoNS, are associated with a subacute presentation characterized by peripheral stigmata of endocarditis (autoimmune arthralgias/arthritis, Osler nodes, Janeway lesions).
In the absence of antibiotic exposure, it is estimated that blood culture would be positive in ≥90% of patients with PVE [4]. Isolation of organisms such as S. aureus and Candida spp. without evidence of a secondary source of infection is likely due to PVE. However, ascertaining the significance of the isolation of skin organisms, such as CoNS and diphtheroids could be difficult unless there is demonstration of persistent BSI with suggestive clinical and echocardiographic features. With refinements of molecular typing techniques, confirmation of the presence of clonality is possible and helpful when it is important to distinguish pathogens from contaminants; however, the possibility of polymicrobial infections also should be considered [4,53].
As with native valve endocarditis, the modified Duke criteria are used to establish a diagnosis of PVE [41,42]. Echocardiographic findings, therapy (need for bactericidal antimicrobial agents, issues with combination therapy, treatment of multidrug-resistant pathogens, and optimal use of pharmacodynamic strategies), and indications for surgical intervention are beyond the scope of this chapter and discussed elsewhere [4,31].
Left Ventricular Assist Devices
Introduction
Heart failure compromises the health of >5,000,000 Americans; 550,000 new patients are diagnosed with this disease each year. Each year, approximately 250,000 persons in the United States develop severe, end-stage heart failure (NYHA Class IV) and are candidates for transplantation. Limited donor availability has narrowed the therapeutic options for this group of patients, estimated to be up to 5,000 at any one time for heart transplantation, a staggering figure when one considers that only about 2,400 heart transplants are performed each year [54].
The introduction of the LVAD catapulted the management of severe end-stage cardiomopathy refractory to ionotropic therapy, intraaortic balloon counterpulsation, or both into a new era. The device was originally approved in 1994 by the Food and Drug Administration as a bridge to transplantation. Subsequent studies demonstrated that
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the use of the LVAD was associated with improvement in hemodynamic and end-organ function and conferred a meaningful survival benefit in implanted patients as compared with controls managed with medical therapy alone, with an impressive 70% of patients surviving until heart transplantation [55,56]. Furthermore, following transplantation, the survival at 3 years was 95% ± 4% for the LVAD group and 65% ± 10% years for the control group managed with inotropes alone. The survival for LVAD-implanted patients was 95% at 3 years compared with 65% in the control group [57]. Even in the presence of LVAD-associated infections, heart transplantation recipients had similar outcomes when compared with patients without infection [58,59,60]. A later study detected a doubling of LVAD-support days that could delay transplantation, a trend for longer hospital stays posttransplant and increased early mortality resulting from a newly acquired infection in the cohort with LVAD-related infection [61,62,63]. The long-term survival was not statistically significant when compared with patients on LVAD support who developed an LVAD-associated infection. These important findings quiet the unease of subjecting LVAD-associated infected patients to intense immunosuppression following their transplants for fear of aggravating their infections [61].
When it became apparent that patients managed with the LVAD had better outcomes compared to their medically treated counterparts, the indications for LVAD implantation broadened to include those ineligible for transplantation (destination therapy). The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial investigated the use of LVADs for destination therapy: 41% of deaths in the LVAD recipient group resulted from sepsis of any cause; within three months after implantation, the probability of an HAI-related to the LVAD was 28% [56]. The Kaplan-Meier survival analysis did show a 48% reduction in the risk of death from any cause in those patients randomized to LVAD implantation during the first year. However, the aggregate adverse event rate was twice as likely to occur in LVAD patients. By the second year of study, the survival rate of 23% between the two groups was not statistically significant. Those LVAD patients who did not have sepsis had superior survival rates of 60% at 1 year and 38% at 2 years compared with 39% and 8%, respectively, in LVAD patients who developed sepsis. Localized infections such as percutaneous site and pocket infection did not have an adverse impact on survival [64]. An additional 2 years of observation in the REMATCH trial revealed that patients randomized to LVAD implantation in the period after 2000 had a statistically significantly higher survival rate of 59% at 1 year and 38% at 2 years when compared to the 44% and 21% rates, respectively, for the medically treated group. The improved survival rate in patients implanted during the second study period was attributed to the experience gained in areas of patient care and device modifications [65].
A review of 46 patients with LVAD-associated infections (the most common being the driveline site) noted that infections developed at an average of 65 days postimplantation with a mortality rate of 17% (8 patients) with (5/8) infected patients dying from sepsis before transplantation [63]. Postoperative LVAD-associated infections were identified in 46% of 35 patients in whom 36 LVADs were implanted for a mean of 73 days. Deep SSIs were associated with the requirement for postoperative hemodialysis [66].
Epidemiology
The LVAD infection attack rate is about 34% and likely reflects the population studied (Table 38-3).
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TABLE 38-3 |
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A report on nosocomial LVAD-associated BSIs in 214 patients revealed an incidence of 38%; the BSI was statistically significantly associated with death (the overall incidence of BSI in recipients of LVADs from any cause was 49%). Fungemia had the highest hazard ratio (10.9) followed by gram-negative (with Pseudomonas aeruginosa predominating) and gram-positive bacteremia. The duration of LVAD support before the onset of any BSI was 19.5 days for gram-negative bacilli, 28 days for yeast, and 242 days for gram-positive cocci [62]. Forty-six LVAD-associated infections were described in 50% (38/76) of patients who underwent LVAD implantation as a bridge to transplantation. Twenty-nine LVAD-associated BSIs included 5 LVAD endocarditis and 17 localized LVAD infection (exit site, LVAD pocket infections) [61].
The Jarvik 2000 LVAD designed for permanent use was compared to the more conventional HeartMate® [Thoratec] LVAD; although only 17 patients were studied, implantation of the HeartMate® was associated with a 0.43 device-related infections per 100 patient-days compared with 0.08 device-related infections per 100 patient-days when the Jarvik 2000 was implanted. The authors postulated that the decrease in infection risk could be due to the smaller size of the Jarvik 2000 and the unique power cable that is tunneled to the retroauricular skull area connected to the power supply [67].
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Microbiology
The microbiology of LVAD-associated infections is fairly consistent with gram-positive organisms predominating and likely resulting from disruption of the cutaneous barrier with the subsequent biofilm formation. S. aureus was the most common organism isolated in one series followed by gram-negative rods, candida, Enterococcus sp., and CoNS [63]. Another series found that CoNS was the most frequent pathogen isolated in BSIs in LVAD-implanted patients from any cause followed by S. aureus (of which 36% were methicillin resistant),Candida sp., and Pseudomonas aeruginosa. Although the enterococci accounted for only about 8% of BSIs, 50% of the isolates were vancomycin resistant [62].
A recent report of 76 LVAD-patients noted that of 47 isolates, 78% and 19% of LVAD-associated infections were due to gram-positive organisms and gram-negative rods, respectively, with only 1 infection due to yeast. Diabetes mellitus was identified as a risk factor for the 30 BSIs in this cohort. There was a striking incidence of post-transplantation invasive vancomycin-resistant Enterococcus faecium (VREF) infections in 6 patients with an associated mortality of 67%. This is in marked contrast to LVAD-support patients who did not develop LVAD-associated infections in whom there was no postoperative invasive VREF [61].
Emerging evidence suggests that LVAD implantation is associated with progressive defects of cellular immunity by inducing an aberrant activation of T-cells, resulting in program CD4 cell death [68,69,70]. Ankersnitt et al. concluded that defects in cellular immunity predisposes patients to infections caused by Candida sp., and the risk of developing disseminated candidiasis in that study was 28% in LVAD recipients compared to 3% of controls [68]. This finding coupled with the fact that advanced age (patients on destination therapy) also is associated with decreased cellular immunity [14] introduces major challenges ahead for mechanical circulatory support [71].
Types of Left Ventricular Assist Device-Associated Infections, Diagnosis, and Management
The components of the LVAD (e.g., HeartMate) consist of an intracorporeal blood pump encased in titanium (placed in the abdominal cavity or preperitoneal pocket), an inflow cannula (inserted into the apex of the left ventricle) an outflow cannula (inserted into the ascending aorta), and porcine valves within the inflow and outflow cannulas to maintain unidirectional flow. Implantation of the LVAD requires an extended median sternotomy. A driveline connects the blood pump to an external power source that exits through the abdominal wall, usually contralateral to the side of the pump (Figure 38-1).
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Figure 38-1 HeartMate™ left ventricular assist device (LVAD). |
Although the driveline is tunneled before exiting the abdomen, its size and the bulk of the battery pack increase the risk of skin trauma resulting in the loss of the protective skin barrier and permits invasion by microorganisms.
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Figure 38-2 Driveline exit site infection. |
The spectrum of LVAD-associated infections is categorized according to the anatomical site and are not mutually exclusive: (1) driveline exit site (Figure 38-2), (2) pump pocket (Figure 38-3), and the least frequent (3) endocarditis [2,4,61,62]. Pathogens causing LVAD infections can result from intraoperative inoculation from entry through the percutaneous driveline exit site or from hematogenous seeding from central venous catheter-associated BSIs, catheter-associated urinary tract infection, and ventilator-associated
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pneumonia. In driveline exit site infections, there often is evidence of localized inflammation at the exit site accompanied by poor tissue healing; seropurulent/purulent drainage can be present with variable systemic manifestations of infection. In the early phases of driveline exit site infection, it could be difficult to differentiate irritation from an inadequately immobilized driveline from infection because pain and erythema are common features to both situations.
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Figure 38-3 Pump pocket infection. |
Pump pocket infections can result from secondary infection of a localized hematoma and seroma from the operative procedure or inadvertent trauma. The clinical presentation depends on the pathogenicity of the microorganism. Characteristic features of infection could be absent, and infection could be suspected on the basis of unexplained leukocytosis, generalize malaise, and low-grade fevers. In some instances, palpation over the incision can lead to discovery of an abscess [72].
LVAD-associated endocarditis is characterized by involvement of the surface components of the mechanical device that is in contact with blood: the blood pump and the inflow or outflow tracts. It shares many of the clinical features diagnostic of infective endocarditis (i.e., persistent BSI, systemic signs and symptoms [e.g., fever, toxicity, emboli, immune complex disease, valvular incompetence]).
Radiographic studies (e.g., echocardiography, computed tomography, and nuclear imaging for abscess localization) are of limited value in the presence of hardware and the absence of standards for interpretation but could be helpful identifying a fluid collection(s) that could lead to a diagnostic aspiration.
Distinguishing LVAD-related BSI from a non-LVAD-related BSI can be difficult; however, identical microorganisms recovered from the device (e.g., valves, internal pump surface, and pump pocket) and the bloodstream would suggest an LVAD-associated BSI. Single positive blood cultures for cutaneous organisms (e.g., CoNS, diphtheroids) should be interpreted with caution because these organisms are common causes of pseudobacteremia; therefore, multiple cultures are necessary to interpret results correctly.
Management
The therapy of LVAD-associated infections depends on the infected site. Driveline exit site and pocket infections are managed by (1) aggressive wound care, (2) immobilization of the driveline to avoid further tissue trauma, (3) gentle debridement of devitalized tissue and cleansing of exit site, and (4) exploration of the pump pocket as indicated. Use of polymethylmethacrylate (PMMA) beads containing vancomycin and tobramycin (and potentially other antimicrobial agents) that coat the external surface of the LVAD is an experimental approach to managing pocket infection [72,73], but more research is warranted to determine optimum bead material, size, shape, and positioning. Placement of a KCI vacuum-assisted closure (VAC) device (WoundVac™) is reported to be beneficial after appropriate drainage and debridement of large wounds [74].
LVAD-associated endocarditis usually requires device removal, urgent transplantation, and bactericidal antibiotics [59,75,76]. A report by Nurozler et al. on fungal endocarditis in which early diagnosis, prompt institution of antimicrobials, and device removal and replacement followed by transplantation was associated with a 80% favorable outcome in 5 patients [77].
Culture results dictate the choice of systemic bactericidal antibiotics. Continuous antimicrobial treatment before, during, and after transplantation was associated with fewer relapses when compared to limited courses of antibiotics (p < .001). Discontinuing antibiotics after a 2–6 week course was associated with relapse or a secondary infection; however, the survival rates for the two groups at 1 year were similar [61]. Treatment strategies include the use of a suppressive component for destination therapy patients with recalcitrant infections in whom device exchange is associated with prohibitive risks. However, with increasing duration of device utilization, pathogens tend to be multidrug-resistant, and therapy relies on parenteral and potentially nephrotoxic agents.
To minimize the sequelae of intraoperative contamination during device implantation, some centers use a combination of five different perioperative antibiotics including vancomycin, a quinolone, rifampin, fluconazaole, and a β-lactam or a monobactam for 48–72 hours [66]; other institutions recommend a quinolone or β-lactam plus vancomycin [61]. Preoperative colonization (e.g., tracheal aspirates from ventilated patients or wounds) and infection should be considered when choosing preoperative prophylactic agents. The impact of broadspectrum antimicrobial prophylaxis on the emergence of multidrug-resistant organisms has not been formally evaluated but is a perceived risk.
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Total Artificial Hearts
The total artificial heart (TAH) was designed to provide the necessary mechanical support for patients with severe biventricular failure that is refractory to inotropic therapy and replaces both native cardiac ventricles and all cardiac valves. Indications for use include aortic insufficiency, severe ventricular arrhythmias, left ventricular thrombus, and calcified left ventricular aneurysm. It is also considered for those patients who are not transplant candidates by virtue of their underlying disease, such as amyloidosis and cardiotoxicity from chemotherapy, diffuse cardiac tumors, failure, heart transplants from graft failed and rejection, the latter group being candidates for destination therapy [78].
Two TAHs, the CardioWest Total Artificial Heart and Abiocor, are currently under investigation. The CardioWest Total Artificial Heart uses pneumatic drives and shares the same characteristics with the LVAD in terms infection risk (i.e., the presence of an external drive line). A bridge to transplantation study of 81 patients reported a 79% survival rate in the study group compared with 46% in the control, medically treated group. The 1-year survival for TAH recipients was 70%. This cohort included 17 driveline infections, 7 BSIs (6 associated with an infusion catheter), and 5 mediastinal infections. In 68 patients, there were no delays to transplantation or deaths due to infection. Transplantation was delayed in 5 patients due to any infection; when further stratified, 3 infections were related to the TAH: 2 drivelines and 1 mediastinum. Seven deaths were attributed to infection from any cause; one was from mediastinitis [79].
The AbioCor TAH, targeted for destination patients, uses an electrohydraulic actuator system. The 30-day survival for the first 7 patients was 71% compared to 13% predicted survival for patients medically treated; at 60 days, the survival was 43%. When reviewed in 2004, two patients were still alive at 234 and 181 days. No DAIs were reported in this small cohort, and it is believed that the absence of a percutaneous external access decreases the risk of infection significantly in eliminating a portal of entry for microorganisms. The large size of this TAH, however, increases the risk for increase thrombosis [80].
Cardiac Rhythm Management Device Infections
Cardiac rhythm management devices (CRMD) include permanent pacemakers and implantable cardioverter defibrillators (ICD) that provide electrical stability to patients with ischemic cardiomopathy or other conditions that place them at risk for fatal ventricular arrhythmias. Implantation of CRMDs involves subcutaneously inserting a generator or defibrillator into the chest (most common) or abdominal wall; lead wires are threaded into the soft tissues, enter at the subclavian vein, and gain access to the right side of the heart; the electrodes are implanted in the right atrium and/or right ventricular endocardium.
It is estimated that 3.25 million pacemakers worldwide and 180,000 cardioverter defibrillators with 300,000 CRMDs are implanted in the United States annually with reported infection rates that vary from 1–7% [2,3,81], the lower rates due to device refinement and improved technique.
A variety of CRMD-associated infections have been described and are not mutually exclusive: (1) device pocket infection that can or cannot involve the lead wires, (2) infection that is limited to the lead wires in the subcutaneous space, and (3) endocarditis that involves the transvenous component of the electrode with consequent infection of the endocardium at the tip of the electrode or at the tricuspid valve [82,83]. In a study of 33 episodes of pacemaker-associated endocarditis, three settings were noted with equal distribution: (1) infection localized to the pacemaker, (2) pacemaker lead infection combined with the involvement of either the right or left side, and (3) infection of the valve independent of the pacemaker leads. In two-thirds of the episodes, endocarditis involved the valvular structures that surprisingly included the left side [84]. Of 123 patients with CRMD-associated infections, 25% occurred in the first 4 weeks, and 42% occurred 1 year following implantation. Infections that develop >60 days tend to be more indolent [81].
Host-related issues, comorbid conditions, and procedure-related challenges associated with pacemaker infections are similar to those described for other cardiovascular surgical procedures and include diabetes mellitus, advanced age, use of steroids/immunosuppressive agents, malnutrition, chronic skin conditions, underlying malignancy, anticoagulant use, and multiple manipulations rather than complicated implantations [2,84,85]. Secondary BSI can seed the implanted device, and localized trauma resulting in hematomas can cause tension along the suture line, disrupt the skin barrier, and expose the implant.
The predominant pathogen causing CRMD-associated infections is Staphylococci spp. [83]; other skin pathogens that have been implicated in pocket infections include Corynebacteriasp., Propionibacterium acnes, and Micrococcus which result when the device erodes through the skin. In one series of 87 pacemaker-associated and 36 ICD-associated infections, the most common pathogens were CoNS (68%), S. aureus (23%), and enteric gram-negative bacilli (13%) [81]. Instances of Candida sp. and fungi such as aspergillus are rare [86,87,88]. Fungal infections occurred at the rate of 0.1% (3,648 procedures); associated risk factors include abdominal placement, local versus systemic infection, and longer duration from original implant to presentation.
Chamis studied a cohort of patients with CRMD and S. aureus BSI (SA-BSI) over a 6-year period. The total number of confirmed CRMD infections was 45.4% (15/33) episodes of SA-BSI. Nine of 12 patients (75%) were
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found to have CRMD infection with SA-BSI within a year of CRMD implantation or manipulation; in 6/9 patients, SA-BSI resulted from CRMD infection, and the remaining 3 patients developed CRMD infection as a result of hematogenous seeding. In the 21 patients who developed SA-BSI >1 year following CRMD implantation, the device was rarely implicated as the initial source of SA-BSI; however, as a result of SA-BSI, CRMD infection developed in 28% of the patients [89]. In contrast, a 7-year retrospective cohort study of 49 patients with gram-negative BSI (GN-BSI) showed that 6% (3) had definite/possible CRMD GN-BSI at presentation; hematogenous seeding of CRMD was not encountered. Thirty-four patients with retained CRMD were observed for 3 months; only 3% (2) developed relapsing BSI, but alternative sources for the relapse were present [90].
Symptoms of CRMD infection depend on the anatomical area of infection. Localized inflammatory changes over the device pocket are fairly diagnostic, although with indolent pathogens, such as CoNS, signs can be absent even with an exposed device. One series noted that of the patients, <1/3 presented with fever and one-fourth had occult BSI without systemic symptoms. The Duke criteria [41,42] can be used to diagnose CRMD infections; the inclusion of device abnormalities (use of ultrasound or computed tomography [CT) for fluid) and the presence of septic pulmonary emboli by CT increases the diagnostic yield [91]. Blood cultures should be obtained even in the absence of systemic symptoms to detect occult bacteremia. Transesophageal echocardiography (TEE) has a sensitivity of >95% compared to <30% for transthoracic echocardiography (TTE) in identifying vegetations [81] (see Figure 38-4).
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Figure 38-4 Large vegetation on tricuspid valve adjacent to pacemaker wire. |
Optimal management requires the institution of bactericidal antimicrobials and the removal of the CRMD, but device removal itself can result in complications such as arrhythmias and tearing or perforation of myocardial wall as the lead is removed. An operative mortality of zero was reported in a series of 123 patients; of these, 95% (117) underwent CRMD removal with an 8% (1/117) relapse rate versus a 50% (3/6) relapse rate in the medically treated group. In a study of 31 patients with CRMD endocarditis, the only prognostic factor identified with failure of therapy or mortality was the absence of surgical intervention; however, the mortality rate despite surgical and medical therapy was still 12.5% (3/24) [92].
A meta-analysis found preoperative antimicrobial prophylaxis to be beneficial in preventing pacemaker infections [93]. A study of 2,564 patients identified no significant impact on CRMD-associated pocket infection rates using local povidone-iodine solution pocket irrigation of the subcutaneous pocket before wound closure [94].
Coronary Arterial Stents
In the United States, >700,000 percutaneous transmluminal coronary angioplasty (PTCA) procedures are performed annually [2]; coronary artery stents are placed to decrease the risk of restenosis following PTCA. There is a paucity of reports on coronary artery stent–associated infections. To date, only 10 infections occurring between 2 days to 4 weeks following stent placement (age distribution between 38–80 years) have been reported in the world's literature [95]. It is notable that all patients had positive blood cultures, with S. aureusrecovered in 70% of them, the other pathogens were Pseudomonas aeruginosa in 2 patients and CoNS in 1 patient. Clinical features included fever, chest pain in 50% of patients with 2 patients sustaining myocardial infarction, and multiple systemic septic emboli. Four patients were diagnosed by coronary angiography; 4 false aneurysms were identified, the fatality rate was 40%. Only 1 patient in this series underwent placement of a drug-eluting stent to prevent restenosis by its immunomodulating and antiproliferative effects [96]. Additional reports describe 2 patients who developed DAIs following placement of rapamycin-eluting and paclitaxel-eluting coronary stents [97,98].
Endocascular Stents and Prosthetic Vascular Grafts
Vascular Prosthetic Grafts
Prosthetic graft infections are uncommon, and their rate of occurrence is determined by the anatomic location of the graft with reported incidences of <1% for abdominal grafts, increasing to 1.5–2% for aortofemoral grafts and to 6% for infrainguinal grafts [99]. Significant morbidity is associated with peripheral graft infection because of the threatened loss of limb and high mortality rates associated with aortic graft infections. Identified risk factors include groin incision, wound complications (e.g., hematoma, wound
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separation), emergent and repeated procedures, diabetes mellitus or suboptimal glycemic control, obesity, and operative time [4,100,101,102,103,104]. The majority of infrainguinal graft infections occur within 1–2 months postoperatively and therefore are attributed to intraoperative contamination or extension from an adjacent postoperative SSI. Early infections can be marked by inflammatory soft tissue changes over the graft, sinus tract formation, peripheral emboli, development of pseudoaneurysms, and graft malfunction. However, an increasing number of infections are caused by cutaneous organisms such as CoNS, Corynebactereium sp. and Propionibacterium acnes that result in abdominal graft infections; their indolent course explains their subacute presentation with aortoenteric fistula or enlarging inguinal mass presenting years after implantation [2]. Pounds et al. reported a high number of SSIs following vascular reconstruction surgery including aortic, extraanatomic, and infrainguinal procedures [105]. A retrospective case-control study of 410 procedures identified 45 infections including graft infection in 67% (30/45). Of these patients, 27% (12/45) presented with anastomotic disruption. Multivariate regression analysis identified previous hospitalization, younger age, and groin incision as risk factors. The emergence of methicillin resistant S. aureus (MRSA) as the predominant pathogen causing 53% of the SSIs was disturbing a trend also noted by Taylor in vascular surgery infections [106].
Radiographic studies (e.g., ultrasonography, Indium-labeled white cell scan, CT) are used to identify pseudoaneuryms and perigraft fluid and to detect the presence of air beyond what is expected in the early postoperative period [106]. Magnetic resonance imaging (MRI) in patients suspected of having a prosthetic graft infection with CT-negative studies can reveal subtle inflammatory changes [107].
The guiding principles of therapy for vascular graft infections include (1) excision of the foreign body, (2) debridement of infected or devitalized tissue, (3) and establishment and maintenance of vascular supply, and (4) institution of appropriate antibiotic therapy [4,108]. Estimated overall mortality and limb amputation of lower extremeties are 14–58% and 8–52% respectively [102].
The value of preoperative antibiotics in preventing early graft infection has not been studied. Rifampicin bonding to Dacron grafts had no beneficial effect [109].
Peripheral Vascular Stents
It is estimated that >400,000 patients undergo stent placement in the United States as a strategy to prevent vessel restenosis following PTCA for the nonsurgical management of artherosclerotic vascular disease. The reported infection rate is <1/10,000 patients [110]. Potential risk factors include (1) prolonged use of indwelling vascular catheter or sheath and reuse of the sheath after 24 hours, (2) thrombolytic therapy, for patients, (3) recurrent use of the same femoral artery for vascular access within a week, (4) local hematoma formation, (5) prolonged stent insertion time, (6) use of same site for interventions, and (7) iliac artery access [111]. In addition to death and loss of limb, other complications include pseudoaneurysms, mycotic aneurysms, and cutaneous fistulae [112,113].
A review of 65 aortioiliac stent graft infections involving 50 aortic and 15 iliac artery grafts identified the following: (1) the frequency of infection was 0.43%, (2) 23% had immunodeficiency issues, (3) the male:female ratio was 1.4, (4) 31% of patients had associated aortoenteric fistulae, (5) S. aureus was recovered in 54.5% of patients, (6) the overall mortality was 18%; when stratified according to conservative treatment versus surgical treatment, the rates were 36.4% and 14%, respectively, and (7) risk factors were poorly defined [114].
The majority of infections of endovascular stent and stent/grafts implanted through the groins are caused by S. aureus. The preponderance of these organisms has been attributed to the high concentration of bacteria harbored within the many eccrine sweat glands within the intertriginous zones of the groin [115].
Other Vascular Devices
Arterial Closure Devices
The discomfort and time necessary to achieve hemostasis at the femoral puncture site accessed for cardiac catheterization by conventional means led to the development of percutaneous arterial closure devices in the1990s. However, when compared with traditional manual and mechanical compression, there is an increased risk of infection. Although the risk is relatively low, infections related to arterial closure devices require multiple surgical procedures and, at times, amputation of the limb; high mortality rates have been reported [116,117]. In one study, the reported infection rate was 1.6%, 80% (4/5) of which were due to S. aureus (2 were methicillin resistant) and resulted in groin abscesses and mycotic aneurysms; the crude mortality rate was 40% [118]. Over a 4-year time period, 46 patients with a mean age of 64 with diabetes mellitus and obesity as comorbidities had a documented mortality rate of 6% were reviewed. Mycotic pseudoaneurysm was encountered in 22 patients, and S. aureus accounted for 75% of the isolates [119].
Prosthetic (Dacron) Carotid Patches
Until the introduction of Dacron carotid patches, carotid arterotomies were primarily closed or “patched” with autologous saphenous veins, the purpose of which was to decrease patient morbidities such as thrombosis and restenosis after primary closure. The use of Dacron carotid
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patches ensured successful closure of arterotomies with ease and predictability, but infectious complications were inherent in their use as they are for any foreign body. Over a period of 4 years, 8 patients were described with an infection rate of 0.5% in 1,258 procedures with no mortality and a zero relapse rate. Gram-positive pathogens were recovered in 7 patients (4 staphylococci, 3 steptococci)[120,121]. A subsequent study that described 4 subacute episodes of pseudoaneursyms (3 related to Dacron) confirmed these observations [122]. Treatment consisted of removing the foreign body, debriding infected tissue, performing autologous saphenous vein patch angioplasty or interposition grafting, and using appropriate antimicrobial therapy.
Cardiac Suture Line Pledget
The 1998 review on infections of the cardiac suture line after left ventricular surgery is the most recent. It describes 3 patients from one institution and includes a literature review on 22 other patients [123]. While distinctly rare and occult in presentation, such infections are associated with a long incubation period, at an average 16 months after surgery. Clinical features include cardiocutaneous fistulae with bleeding, pleuropulmonary symptoms with hemoptysis, chest wall abscess, BSIs that mimick endocarditis, and left ventricular false aneurysms that developed in 60% (15/25) of patients. The most frequent pathogens encountered were the staphylococci and gram-negative bacilli. Optimal treatment included appropriate antibiotics and excision of all infected sutures, pledgets, and infected tissue. The overall survival rate was 79%.
Prevention of Cardiac and Vascular Device-Associated Infections
The devastating consequences of cardiac and vascular DAIs highlight the importance of implementing prevention strategies. These include (1) the appropriate use of prophylactic antibiotics, (2) a reduction of intraoperative risk by adhering to infection control guidelines, (3) glycemic control, and (5) prevention of secondary BSI.
Prophylactic Antibiotics
While there are data to support the use of perioperative antibiotics for cardiac bypass surgery [124,125], no randomized prospective trials have been conducted to assess whether antimicrobial prophylaxis confers benefit to prevent implantable cardiac and vascular DAIs, meta-analysis of seven randomized trials involving 2,023 patients that showed a reduction of permanent pacemaker-associated infections when prophylactic antibiotics were administered before implantation [93]. No randomized studies are projected for the future, largely due to the infrequent occurrence of these infections and the large number of patients required to demonstrate benefit [3] as well as some concern as to whether performing such studies is ethical. Despite the absence of direct scientific data, systemic antimicrobial prophylaxis is recommended for implantation of cardiac and vascular devices, and guidance is extrapolated from recommendations for cardiac bypass surgery and orthopedic implants. Included are prosthetic valves, CRMDs, LVADs, TAHs, cardiac pledgets, vascular grafts, and arterial patches [2].
The choice of antibiotics is dictated by epidemiologic data that suggest that intraoperative contamination with cutaneous microorganisms resulted in early infections. Generally, a cephalosporin is recommended to target methicillin-susceptible S. aureus; it should be administered within an hour (2 hours if vancomycin is used due to the lengthy infusion time) of incision to ensure therapeutic concentrations at the surgical site and continued no longer than 24–48 hours following the procedure. Intraoperative bleeding >1.5 liters (assuming 25% of blood volume) or operative time >2.5 times the half-life of prophylactic agent(s) require redosing of the antibiotic (for cefazolin, about 3–4 hours) [124,125]. Preoperative colonization (e.g., tracheal aspirates from ventilated patients) and concurrent antibiotic therapy for infection could have an impact on the choice of preoperative prophylactic antibiotics.
Continuing antimicrobial prophylaxis >48 hours in cardiovascular surgery does not confer additional benefits but does increase the development of antimicrobial resistance (isolation of cephalosporin-resistant enterobacteriaceae and vancomycin-resistant enterococci) [124,125]. Prolonged prophylactic antibiotic use also has been associated with Clostridium difficile-associated disease [124,125]. The microbiologic landscape of SSIs is ever changing and reflects an increasing number of MRSA isolates [62,105,106] and the emergence of vancomycin-resistant Enterococcus faecium as pathogens in LVAD patients [61,62].
The use of secondary antimicrobial prophylaxis (i.e., for dental, respiratory, gastrointestinal, genitourinary cases) is recommended for patients with valvular heart disease [126]; however, because the majority of pathogens causing DAIs originate from the cutaneous flora, secondary prophylaxis is not generally recommended [2].
Clinical practice uses four local antimicrobial measures to prevent implantable DAIs: local irrigation, antimicrobial carriers, dipping of implants in antibiotic solution, and antibiotic coating of prosthesis. Use of such strategies in cardiovascular surgery has not been studied [127]. Antibiotic irrigation of the surgical site is an accepted standard among surgeons. Antimicrobial carriers such as the silver-impregnated dressings (Silverlon®, Argentum Medical LLC,) that provide local antisepsis to LVAD driveline sites are being used to prevent site-associated infection; however, clinical studies are needed to define
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their utility and efficacy. While antibiotic-coated beads have been used for treatment, their role in prophylaxis has not been studied [73]. Rifampicin bonding to Dacron grafts (dipping in solution before implantation) had no beneficial effect [109]. Studies demonstrating efficacy in the prevention of line-related BSI by using antibiotic-impregnated or antiseptic-coated catheters [128] led to the development of a silver-coated sewing ring for mechanical valves, but clinical trials were terminated due to early paravalvular leaks in the study patients [129].
The impact of intranasal mupirocin on cardiac and vascular device–associated S. aureus infections is not well characterized, especially because an estimated 60% of the S. aureusinfections at surgical sites appear not to have originated from the patient's nose [130]. The conclusions of clinical studies somewhat discordant [131,132]. One study of 3,864 patients undergoing various types of surgical procedures reported that S. aureus HAIs were significantly reduced in nasal carriers treated with mupirocin. The study reported a tendency toward lower S. aureus SSI rates, but significance was not achieved when compared to those nasal carriers who did not receive mupirocin [133]. A meta-analysis concluded that the use of perioperative mupirocin was associated with a reduction in SSIs in nongeneral surgery patients (i.e., those undergoing cardiothoracic, orthopedic, and neurosurgery) [134]. More studies are needed to better define the role of intranasal mupirocin for SSI prevention, especially related to implantable cardiac and vascular devices; however, conducting such studies could be difficult because of the requirements for a large study sample size. One proposed strategy is to treat S. aureus nasal carriers who are to undergo nongeneral surgical procedures (i.e., cardiac surgery and implants).
Glycemic Control
There is ample evidence that strict perioperative glycemic control reduces SSIs in patients undergoing cardiac bypass surgery [23,24,25,26]. The favorable impact of this strategy can be applied to patients undergoing implantation of cardiac and vascular devices because some studies indicate that diabetes often is a comorbid condition or is a risk factor for DAIs as discussed previously.
Intraoperative Contamination
The predominance of gram-positive organisms causing early DAIs is attributed to intraoperative contamination. CDC has outlined strategies to decrease the risks of SSIs [29] that include: optimal aseptic technique, appropriate environmental controls, and reduction of the risk of bacterial shedding. Airborne dispersal of MRSA and CoNS of nasal carriers with experimental rhinovirus as a potential transmission means in the nonsurgical setting has been described; surgical masks were reportedly effective in decreasing MRSA shedding but not CoNS [135,136]. Additionally, individuals with dermatitis shed an increased number of squamous cells that contain cutaneous microorganisms [29].
In-situ air-sampling studies conducted during an 18-month period involving 70 separate vascular surgical procedures; samples obtained from 0.5–4 meters from the surgical wound reported recovery of CoNS and S. aureus from 86% and 64% procedures, respectively. Of these, 51% and 39% respectively, were from within 0.5 meters of the surgical wound. Pulse-field gel electrophoresis confirmed that the origin of these isolates was from the surgical team. In separate studies, the surgical mask did not protect against shedding [137]. Another potential source of intraoperative contamination is the vertical air curtain used to provide ultraclean air directed downward toward the patient. In experimental studies during simulated surgical activity, the surgeon shed particles into the wound model, but the number shed decreased when ventilation was directed away from the wound [138].
Prevention of Secondary BSIs
Secondary BSIs, especially those due to S. aureus, can result in hematogenous seeding of the implanted device [43,90,139]; careful attention to CVC insertion practices and site management [128] along with prompt removal of devices, including ventilators and indwelling urinary catheters, reduced BSI risks.
Conclusion
Implantable cardiac and vascular devices have been integrated into the fabric of modern medicine and allow for the reconstruction of the heart and vessels. Doing so restores hemodynamic and electrical stability to patients afflicted with valvular heart disease and medically refractory end-stage cardiomyopathy. Improving circulation to limbs of patients with severe peripheral vascular disease is a way to salvage limbs. The incidence of DAIs is relatively low (except for LVADs), but when infections develop, they are associated with considerable morbidity and mortality, especially among the frail and elderly who have a variety of comorbid conditions. Furthermore, cure in conjunction with antimicrobial therapy requires device explantation, and prolonged hospitalization, repeated operations, and substantial costs have significantly adverse impact on quality of life. These observations highlight the importance of adhering to infection prevention strategies to maximize the cost-effective use of these implantable devices and offer the host the advantage in the ongoing conflict between man and microbe.
Areas of future research that could increase the survival benefit of patients with implantable cardiac and vascular devices include (1) nonsurgical treatment of chronic biofilm-associated infections with antimicrobials (experimental in vitro data suggest that certain ones
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[e.g., rifampin, daptomycin, and linezolid] in a vascular graft model for staphylococci [140], tigercycline for S. epidermis [141], and caspofungin for Candida albicans could be effective in penetrating the biofilm [142]; (2) introduction of smaller devices and drive lines of LVADs and TAHs or complete internalization of the device and lines, thereby decreasing SSI risk; (3) development of devices that would resist biofilm formation (possibly by incorporating antiseptic/antimicrobials without having a significant impact on the emergence multidrug-resistant microorganisms); (4) the environment as a source of intraoperative contamination; and (5) the reversal of defects of the immune system, specifically CD4 bearing T-lymphocytes that are sequelae of age and implanted devices such as the LVAD.
References
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