More than 90,000 patients per year undergo heart valve replacement in the United States (29). Prosthetic valves are either mechanical that are constructed of carbon alloys, a balland-cage, single tilting disk, or more common, bi-leaflet tilting disk configuration or bioprosthetic valves that include porcine heterografts, bovine pericardium constructed into three cusps mounted on a stent, and the rarely used homografts, which are preserved human aortic valves or pulmonary autografts (30).

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 from a secondary source, such as a central venous catheter. 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 (31); however, there is ongoing discussion at CDC that may redefine the length of the surveillance period for device-associated SSIs.

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% to 0.6% annually thereafter (32,33,34). A recent study on early PVE (i.e., occurring <12 months after valve surgery) of 77 patients reported decreasing rates comparing two periods, 1.5% in 1992 to 1994 versus 0.7% in 1995 to 1997 (35). A long-term study of the Veterans Affairs population in the 1990s reported the incidence of PVE to increase from 3% to 5.7% at 5 years to 13% at 15 years (36).

The risk factors associated with PVE include implantation of multiple prostheses (32), longer cardiopulmonary bypass time (36), 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 BSI (HA-BSI) (34,39,40,41,42). Three studies reviewed the risk of PVE in patients who developed HA-BSI and reported rates between 11% and 50%. Investigators in 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 (43,44)) 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. The hallmark features of definite PVE in this study were persistent fever and sustained BSI (45). 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 were attributed to BSI due to intravascular devices, and skin infections accounted for another 30%; the mitral valve site and Staphylococcus spp. BSI were significantly associated with the development of PVE (46). 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 (47). The studies highlight the importance of preventing BSI and skin infections following PV implantation.

To better assess the risk of PVE in healthcare settings, a prospective cohort study conducted by the International Collaboration on Endocarditis of 556 patients, HAI, acquired in both inpatient and outpatient settings, the latter defined as identification of PVE within 48 hours of admission, but with extensive healthcare contact, had a relative frequency of 37%, with 70% occurring as inpatients and the remaining 30% acquired as outpatients. Most of the healthcare-acquired PVE were diagnosed within the first 60 days of implantation, with 70% occurring within the first year. S. aureus was the most common organism in 34% of patients (48).

Early studies comparing mechanical with bioprosthetic valve and aortic versus mitral valve 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 owing to the platelet-fibrin thrombus deposition on aging leaflets that can become a nidus for infection (33). 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 replacement (37,38).

Although outbreaks of healthcare-associated PVE are uncommon, they have been described for Mycobacterium chelonae because of contamination of the bioprosthetic valve (49); Staphylococcus epidermidis in association with surgical staff carriage (50,51,52,53); Legionella pneumophila and Legionella dumoffii from exposure of wounds and chest/mediastinal tubes to tap water in a healthcare facility (54); and Candida parapsilosis possibly related to torn gloves used by the surgical team (55). 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% to 70%. A recent multicenter study reported a 23% PVE mortality rate, possibly a reflection of earlier detection, more optimal use of combination antimicrobial therapy, and prompt surgical intervention (48). The risk factors for higher mortality rates resulting from PVE include early PVE (≤1 year of onset), infection with Staphylococcus spp., 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 (56). American Society of Anesthesiology (ASA) class IV and bioprosthetic valves were independent predictors of mortality when subjected to multivariable analysis. A subset of medically treated 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. Comparing surgical treatment of native to PVs, the 30-day outcomes were better for the former; however, long-term outcomes of the two groups were similar. S. aureus infections were associated with a significantly higher mortality when compared with other pathogens (57).

Within the first 12 months of implantation, the predominant organisms, in decreasing order of frequency, are CONS, S. aureus, fungi/yeast, gram-negative bacilli, and enterococci (Table 39.2). Further stratification of the time period to the first 60 days of implant identified S. aureus (36%), followed by CONS as the predominant organisms (48). Of the 16% of 537 patients with CONS-PVE in non-drug-injecting patients, 48% were diagnosed after 60 days of valve implantation (58). In late PVE (>12 months), non-enterococcal streptococcus was the most common pathogen, a finding similar to native valve endocarditis (excluding the intravenous drug-using population).

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 on the basis of clinical suspicion. However, in patients with PVs, it is a good practice to obtain blood cultures before initiating empiric antimicrobials to avoid missing a diagnosis of PVE. The 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 to 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, or 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 antimicrobial exposure, it is estimated that blood cultures would be positive in ≥90% of patients with PVE (33). 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 or diphtheroids, can 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 (59).

As with native valve endocarditis, the modified Duke criteria are used to establish a diagnosis of PVE (43,44). Echocardiographic findings, therapy (i.e., need for bactericidal antimicrobial agents, issues with combination therapy, treatment of MDROs, and optimal use of pharmacodynamic strategies), and indications for surgical intervention are beyond the scope of this chapter and discussed elsewhere (33).

Heart failure compromises the health of >5.7 million Americans. About 670,000 new episodes are diagnosed each year, and 282,000 persons die because of heart failure annually. The attributable financial impact of the treatment of heart failure is estimated at >39 million dollars. While the incidence and prevalence of heart failure continue to increase, the donor pool has remained static over time. The 2,000 heart transplants performed each year contrast with the 3,000 patients awaiting transplant at any given time (60,61).

The introduction of the LVAD catapulted the management of severe end-stage cardiomyopathy refractory to inotropic therapy, intra-aortic balloon counterpulsation, or both, into a new era. LVADs were originally approved in 1994 by the Food and Drug Administration (FDA) as a bridge to transplantation. Subsequent studies demonstrated that 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. An impressive 70% of patients survived until heart transplantation (62,63). Furthermore, following transplantation, the survival at 3 years was 95% ± 4% for the LVAD group and 65% ± 10% years for the control inotropesalone group (64). Even in the presence of LVAD-associated infections, heart transplantation recipients had similar outcomes, including long-term survival, when compared with patients without LVAD infections (65,66,67), although there was a doubling of LVAD-support days that delayed transplantation with a trend toward longer hospital stays posttransplant and increased early mortality resulting from a newly acquired infection in the cohort with LVAD-related infection (68,69). These important observations quieted the unease of subjecting LVAD-associated infected patients to intense immunosuppression following their transplants for fear of aggravating their infections (68).

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 (63). In LVAD recipients, sepsis from any cause accounted for 41% of deaths, whereas the mortality was 17% in patients without sepsis. Within 3 months after implantation, the probability of an HAI related to the LVAD was 28%. 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. The LVAD recipients who did not develop sepsis had superior survival rates of 60% at 1 year and 38% at 2 years compared to 39% and 8%, respectively, in LVAD patients who developed sepsis. Localized infections, such as percutaneous site or pocket infection, did not have an adverse impact on survival (71). 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 (72). The current survival rates with the continuous-flow LVADs for the bridge-to-transplant population is at least 80% at 1 year and 70% at 2 years (72).

The LVAD infection attack rate is estimated to be around 30% (range, 16% to 37%) and likely reflects the population and device studied (73,74,75). 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% (eight patients) with (five of eight) infected patients dying from sepsis before transplantation (76). 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 (77). Zierer reviewed the first-generation LVAD late-onset driveline infections between 1995 and 2005. Late driveline infections developed in 17 or 23% of patients that occurred at a median of 158 days after implantation. Although the number and duration of readmissions to the hospital greatly increased, there was a nonstatistical decrease in survival, 41% versus 70% at 5 years (78).

Refinement in the design and technology of LVADs led to the introduction of the second-generation, continuous-flow devices that include the HeartMate II (Thoractec), MicroMed DeBakey (MicroMed), Jarvik 2000 Heart (Jarvik Heart), and VentrAssist (Ventracor). With an improved design that includes a more compact device that is simpler with fewer moving parts, a smaller percutaneous driveline, and that has eliminated the use of polyurethane membranes or PVs that would increase the risk of infections, along with the experience gained with time, the recipients of the continuous-flow LVADs had significantly better survival rates and lower incidence of infectious complications compared to those who had received the first-generation pulsatile devices.

Despite improvement in survival advantage and durability of the second-generation continuous-flow LVADs, infection and sepsis continue to be a major complication that occur in patients undergoing implantation as a bridge to transplantation and for destination therapy.

In the HeartMate II bridge-to-transplantation trial, a significant proportion of patients had local non-LVAD infections (28%), sepsis (20%), or LVAD driveline infections within 1 year (14%) after LVAD implantation (79). More recently, the HeartMate II destination therapy trial has demonstrated even higher rates of infection, including local non-LVAD infections (49%), sepsis (36%), and LVAD-related infections (35%) in the HeartMate II therapy arm (80). Even so, this study also concluded that the HeartMate II had better survival rates, lower incidences of LVAD-related infections, local non-LVAD-related infections, and sepsis compared to its earlier counterpart. Topkara reported his experience with 81 patients who underwent implantation of the second-generation (continuous-flow) LVADs. Forty-two (51.9%) patients developed at least one type of infection. Additionally, the patients who developed sepsis had increased mortality (61.9% septic vs. 18% nonseptic patients) at 2 years, whereas patients who developed driveline or pocket infections had no effect on survival, although all infections resulted in a significantly prolonged hospital stay and a trend toward increased mortality (81).

The national database, the Interagency Registry for Mechanical Circulatory Support (INTERMACS), reported data on 1,158 LVADs that were implanted between June 2006 and March 2009. There were 1,092 primary implants and 66 nonprimary implants, of which 564 were second-generation devices. The survival rates of 83% at 6 months, 74% at 1 year, and 55% at 2 years were reported. Infections following implantation developed in 16% of patients with an overall rate of 17.46 infections per 100 patient-months during the first 12 months after implant. Beyond the first 30 days after implantation, infection was second to heart failure as the most common cause of death in this cohort of patients, with rates of 12.9%, 17.4%, and 15.4% of deaths (N = 122) occurring from infections in the bridge-to-transplantation, bridge-tocandidacy, and destination patients, respectively. There was a significant decrease (p < .0001) in infectious complications, comparing the first-generation pulsatile LVAD (28.9 infectious complications/100 months of device use, 406 patients) and the second-generation continuous-flow LVAD (11.8/100 months of device use, 548 patients) (82). Other investigators also have concluded that there was a reduction in LVAD-associated and nondevice-associated infections in patients ineligible for transplantation (80,83,84).

A report on healthcare-associated 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 (69). 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 five episodes of LVAD endocarditis and 17 localized LVAD infection (i.e., exit site, LVAD pocket infections) (68). In a study of 109 consecutive patients supported by LVADs as a bridge to transplant, 65 patients (60%) during 584 ± 389 device-days developed a BSI that resulted in a significant adverse impact on survival after LVAD implantation. The risk factors associated with death included postoperative right heart failure and BSIs caused by pathogens other than gram-positive cocci. The investigators concluded that urgent cardiac transplantation should be considered in these patients. None of the 22 patients who were transplanted had a recurrence of their BSI and all were alive at 3 years posttransplant (85).

The microbiology of LVAD-associated infections is fairly consistent with gram-positive organisms predominating and likely resulting from the disruption of the cutaneous barrier with the subsequent biofilm formation, followed by P. aeruginosa and enteric gram-negative rods. 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 [MRSA]), Candida sp., and P. aeruginosa. Although the enterococci accounted for only about 8% of BSIs, 50% of the isolates were vancomycin-resistant (69). A more recent review reported that of 221 BSIs that occurred in 65 patients, the majority was caused by gram-positive cocci (159 or 72%), with 101 caused by S. aureus (MRSA, 65 or 29%; methicillin-susceptible [MSSA], 36 or 16%) and 50 or 23% caused by CONS followed by gram-negative rods (17%) and fungi (6%) (85). Of the 300 patients who received a VAD, 108 (36%) developed VAD infection, including 85 bacterial and 23 fungal infections. The most common
bacterial causes of infection were S. aureus, CONS enterococci, and P. aeuruginosa. The most common fungal etiologic agent was C. albicans. Only the use of total parenteral nutrition was associated with the development of a fungal VAD infection in multivariate analyses (odds ratio, 6.95; 95% confidence interval, 1.71 to 28.16; p = .007). Patients who experienced a fungal VAD infection were less likely to be cured (17.4% vs. 56.3%; p = .001) and had greater mortality (91% vs. 61%; p = .006), compared with those who experienced a bacterial VAD infection (75).

Of 47 isolates from 76 LVAD patients who developed LVAD-associated infections, 78% and 19% of LVAD-associated infections were due to gram-positive organisms and gram-negative rods, respectively, with only one 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 posttransplantation-invasive vancomycin-resistant Enterococcus faecium (VREF) infections in six patients with an associated mortality of 67%. This is in marked contrast to LVAD-support patients who did not develop LVAD-associated infections, and there were no postoperation-invasive VREF infections (68). Resistant Staphylococcus and P. aeruginosa were the most common pathogens leading to device- and nondevice-related local infections (81).

Patients who require implantation of an LVAD to treat terminal heart failure have inherent risk factors that predispose them to infectious complications as with other postoperative SSIs. These include cardiac cachexia, age (84), renal disease (77), diabetes (68

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