Steven M. Gordon

Diagnosis and Management of Infections Involving Implantable Electrophysiologic Cardiac Devices

Worldwide, there are approximately 3.25 million functioning pacemakers and 180 000 functioning implantable cardioverter defibrillators (Warkentin D. Personal communication). Infection rates for these devices range from 1% to 7% (1-4), and the optimal method for management of such infection has yet to be defined (5-16). Since 1988, the Cleveland Clinic Foundation in Ohio has been a referral center for treatment of device-related infections because of the tools and techniques used there to extract leads for transvenous pacemakers and implantable cardioverter defibrillators (17). To define optimal management of these infections, we examined our recent experience at the Foundation. Methods We reviewed information on all patients treated at the Cleveland Clinic Foundation between 1 January 1995 and 31 August 1998 who had explantation of pacemakers or implantable cardioverter defibrillators. Only patients who satisfied the case definition of infection were included. Infection was defined as the presence of local warmth, erythema, swelling, edema, pain, or discharge from the device pocket along with a positive culture from the device, device pocket, blood, or lead. Device-associated endocarditis was defined as the presence of lead or valvular vegetation on surface or transesophageal echocardiography. Relapse was defined as the recurrence of infection with a similar type of organism documented by antibiogram within 1 year of treatment of the original infection. Statistical calculations were performed by using EpiInfo, version 6 (Centers for Disease Control and Prevention, Atlanta, Georgia). Results Four hundred sixty-seven consecutive patients had explantation of their devices, leads, or both because of mechanical or infectious complications. Three hundred forty-four patients were excluded because no organisms were isolated from the device pocket or explanted hardware. One hundred twenty-three patients satisfied the criteria for device-related infection. Ninety-nine patients (81%) had had their device placed at another institution. One hundred nineteen patients (97%) had transvenously implanted leads, and 3% (n =4) had leads implanted through the epicardium. The study included 87 men and 36 women (mean age, 66 16 years [range, 14 to 93 years]). Comorbid conditions included coronary artery disease in 64% of patients (n =79), coronary bypass surgery in 32% (n =39), diabetes mellitus in 26% (n =32), anticoagulation in 19% (n =23), atrial fibrillation in 19% (n =23), malignant conditions in 6% (n =7), oral corticosteroid use in 5% (n =6), and hemodialysis in 2% (n =3). Corticosteroid use and diabetes mellitus occurred more frequently in patients with polymicrobial infections (12% and 38%, respectively). Infection occurred early (0 to 28 days after device placement) in 25% of patients (n =31), occurred late (29 to 364 days after device placement) in 33% of patients (n =41), and was delayed (at least 365 days after device placement) in 42% of patients (n =51). Patients most commonly presented with erythema and pain over the pocket (Table 1). Sixty-nine percent of patients (n =85) presented with symptoms localized to the pulse generator pocket, 20% (n =25) presented with a combination of local and systemic symptoms, and 11% (n =13) presented with systemic signs and symptoms alone. Table 1. Clinical Presentation Thirty-three percent of patients (n =40) were bacteremic, but of these, only 24 (60%) had systemic symptoms. Eighty-one percent of pulse generator pocket cultures (n =99) were positive, and of patients with positive cultures, 24% (n =24) had bacteremia. The most common pathogens were coagulase-negative staphylococci in 68% of infections (n =83), Staphylococcus aureus in 24% (n =29), and enteric gram-negative bacilli in 17% (n =21). Thirteen percent of infections (n =16) were polymicrobial. Antibiotics were given to 76% of patients (n =94) before they presented for device extraction. Twenty-three percent of patients (n =28) received intravenous antibiotics alone (median, 5 days), 33% (n= 40) received intravenous antibiotics (median, 8 days) followed by oral antibiotics (median, 20 days), and 20% (n =25) received oral antibiotics alone (median, 15 days). One patient received topical antibiotic treatment for 30 days. Sixty-three percent of patients (n =78) had been previously hospitalized for a mean duration of 11 days (range, 1 to 100 days), and 33% (n =40) had had a previous surgical intervention without full removal of all hardware. Echocardiography was performed on 64 patients (52%). Forty-five patients (37%) received transthoracic echocardiography, 8 (7%) received transesophageal echocardiography, and 11 (9%) received both types. Thirteen patients, 12 with a pacemaker and 1 with an implantable cardioverter defibrillator, had vegetations on valves, leads, or both. The device and all lead material were completely removed in 95% of patients (117 of 123). Six of 123 patients did not have removal of all hardware. One hundred nineteen patients received antibiotics after hardware was removed. Fifty-eight percent of patients (n =71) received intravenous antibiotics alone (median, 28 days), 35% (n =43) received intravenous antibiotics (median, 7 days) followed by oral antibiotics (median, 16 days), and 4% (n =5) received oral antibiotics alone (median, 24 days). The mean interval from the date of explantation of the infected device to reimplantation of a new device was 7 days (median, 5 days [range, 0 to 68 days]) (Table 2). Of 13 patients with vegetations, 7 underwent reimplantation a median of 7 days (range, 5 to 25 days) after extraction, 5 did not require further device therapy, and 1 had a new device implanted at another institution. Thirty percent of patients (n =37) did not have their devices reimplanted during the index hospitalization. Eighteen percent (n =22) did not require further device therapy, and 6% (n =7) had their devices reimplanted at other institutions. Two patients were treated with antibiotics alone, 2 had lead removal only, and 1 left the treatment center against medical advice. One patient was treated with ablation, 1 died of congestive heart failure, and 1 declined to undergo reimplantation for the long QT syndrome. Table 2. Analysis of Results according to Subgroup The median hospital stay was 8 days (range, 1 to 65 days). One patient died of congestive heart failure before discharge. Follow-up information was available for 115 patients (94%) at a mean interval of 56 weeks after discharge (range, 1 to 194 weeks). Eighty-six percent of patients (n =106) were still alive at the last follow-up. The relapse rate was 3% (n =4). Relapse occurred in 1 of 117 patients who had all hardware removed and in 3 of 6 patients who did not have complete hardware removal. The patient who experienced relapse despite complete hardware removal was the only patient to have a new device reimplanted in the old pocket. All other patients had new devices reimplanted at a new site at a later date. The crude mortality rate was 8% (n =10), and causes of death were not related to surgery or infection (respiratory failure [n =3], congestive heart failure [n =3], multiorgan failure [n =1], pneumonia [n =1], myocardial infarction [n =1], and renal failure [n =1]). Discussion Although our study of our clinical experience in the treatment of device-related infection was not randomized, it provides substantial insight into an effective approach in a large group of patients. Our study also describes the management delivered by the community at large and documents numerous unsuccessful attempts to treat infections without removing all hardware. The length of hospital stay for these unsuccessful attempts at device salvage was similar to if not longer than that for complete extraction of all hardware. Some authors (5-11) have advocated conservative therapythat is, antibiotic therapy with hardware in placefor device-related infections. However, conservative therapy has a limited role in the treatment of such infections and was effective for only three patients in our study group. Forms of conservative treatment, such as partial device removal, pocket debridement, and repositioning of the device, are best used as a bridge to full explantation. Complete explantation, as recommended by other studies (12-16) and supported by our study, is an effective form of management for device-related infections. Conservative therapy may be tried for a short period but should generally be reserved for patients who cannot tolerate any surgical procedure (13). Table 2 summarizes the various clinical conditions, duration of antibiotic treatment, date of reimplantation, and treatment outcome for our patients. Bacteremia or endocarditis on presentation was not a contraindication for ultimate reimplantation. Successful reimplantation was accomplished when patients were afebrile and cleared of bacteremia after extraction. Some authors have recommended reimplantation as early as 36 hours after explantation in patients with only local symptoms of device-related infection (18). In our study, 19% of bacteremic patients presented with only local symptoms. Therefore, because most blood cultures turn positive within 48 hours, it is prudent to wait for results before considering reimplantation (19). Also, 18% of our patients no longer required device therapy or had reasonable alternatives after their devices were removed. Therefore, the need for reimplantation in patients with infected devices should be reassessed. Our study has important limitations. Eighty-one percent of our patients initially presented to other institutions, and 33% had previous failed treatment attempts. This study therefore has a potentially significant referral bias because treatment of referred patients was difficult, complicated, and high risk. Optimal treatment of infected pacemaker and implantable defibrillator devices involves complete explantation of all hardware, followed by antibiotic the

Lactobacillus Bacteremia and Endocarditis: Review of 45 Cases

Lactobacilli are part of normal gastrointestinal and genitourinary flora but are an uncommon cause of bacteremia. We reviewed the cases of 45 patients with clinically significant lactobacillus bacteremia occurring over 15 years. Underlying conditions were common, including cancer (40%), recent surgery (38%), and diabetes mellitus (27%). Twenty-two patients were in the intensive care unit at the time of onset of lactobacillus bacteremia. Eleven of the 45 patients were receiving immunosuppressive therapy, 11 were receiving total parenteral nutrition, and 23 had received antibiotics without activity against Lactobacillus prior to the occurrence of bacteremia. Bacteremia was polymicrobial in 27 patients and developed during hospitalization in 39. Thirty-one patients died, but only one death was attributable to lactobacillus bacteremia. Lactobacilli are relatively avirulent pathogens that produce bacteremia in patients with serious underlying illnesses, many of whom have received prior antibiotic therapy that may select out for the organism. While rarely fatal in itself, lactobacillus bacteremia identifies patients with serious and rapidly fatal illness.

The incidence of invasive aspergillosis among solid organ transplant recipients and implications for prophylaxis in lung transplants

Abstract: Background. Invasive aspergillosis (IA) is associated with significant morbidity and mortality in solid organ transplant recipients but data on the incidence rates stratified by type of solid organ are limited. Objective. To describe the attack rates and incidence of IA in solid organ transplant recipients, and the impact of universal Aspergillus prophylaxis (aerosolized amphotericin B or oral itraconazole) in lung transplant recipients. Patients. The 2046 patients who received solid organ transplants at the Cleveland Clinic Foundation from January 1990 through 1999 were studied. Methods. Cases were ascertained through computerized records of microbiology, cytology, and pathology reports. Definite IA was defined as a positive culture and pathology showing septate hyphae. Probable IA was clinical disease and either a positive culture or histopathology. Disseminated IA was defined as involvement of two or more noncontiguous anatomic sites. Results. We identified 33 cases of IA (28% disseminated) in 2046 patients (attack rate = 1.6%) for an incidence of 4.8 cases per 1000 patient‐years (33 cases/6813 pt‐years). Both the attack and the incidence rates were significantly higher for lung transplant recipients vs. other transplant recipients: lung 12.8% (24 cases/188 patients) or 40.5 cases/1000‐pt year vs. heart 0.4% (3/686) or 1.4 per 1000‐pt year vs. liver 0.7% (3/439) or 2.1 per 1000‐pt year vs. renal 0.4% (3/733) or 1.2 per 1000‐pt year (P < 0.01). The incidence of IA was highest during the first year after transplantation for all categories, but cases occurred after the first year of transplantation only in lung transplant recipients. The attack rate of IA in lung transplant recipients was significantly lower after institution of routine Aspergillus prophylaxis (4.9% vs. 18.2%, P < 0.05). Conclusions. The highest incidence and attack rate of invasive aspergillosis among solid organ transplant recipients occurs in lung transplant recipients and supports the routine use of Aspergillus prophylaxis for at least one year after transplantation in this group.

Cytomegalovirus Infection Is a Risk Factor for Invasive Aspergillosis in Lung Transplant Recipients

Invasive aspergillosis (IA) remains a major cause of morbidity and mortality following solid organ transplantation. To assess the incidence of IA following lung transplantation and to identify risk factors for its occurrence, we performed a case-control study involving 101 patients undergoing lung transplantation at our institution from 1990 to 1995 and reviewed the findings. Fourteen patients (14%) developed IA. The mean time from transplantation to diagnosis was 15 months. Nine patients died; the mean time to death from diagnosis was 13 days. Risk factors associated with developing IA included concomitant cytomegalovirus (CMV) pneumonia or viremia and culture isolation of Aspergillus species from a respiratory tract specimen after lung transplantation. Optimal strategies to prevent IA in lung transplant recipients remain to be determined, but prevention of aspergillus airway colonization and CMV viremia and disease after transplantation may be important targets for prophylactic interventions.

The Response of Symptomatic Neurosyphilis to High-Dose Intravenous Penicillin G in Patients with Human Immunodeficiency Virus Infection

BACKGROUND Infection with the human immunodeficiency virus (HIV) may affect both the natural course of syphilis and the response to treatment. We examined the response to treatment with high-dose penicillin G in HIV-infected patients with symptomatic neurosyphilis. METHODS Neurosyphilis was defined by reactivity in serum treponemal tests for syphilis, neurologic manifestations consistent with neurosyphilis, and a positive Venereal Disease Research Laboratory (VDRL) test on cerebrospinal fluid. We identified 11 HIV-infected patients with symptomatic neurosyphilis; 5 had been treated previously for early syphilis with penicillin G benzathine. Patients were treated with 18 million to 24 million units of penicillin G per day administered intravenously for 10 days. Cerebrospinal fluid was examined approximately 6 and 24 weeks after treatment, when the polymerase chain reaction and rabbit inoculation were used to detect Treponema pallidum. RESULTS In four of the seven patients studied 24 weeks after treatment, the serum titers on rapid plasma reagin (RPR) testing decreased by at least two doubling dilutions, and four patients had reductions in the cerebrospinal fluid titers on VDRL testing or reverted to nonreactive results. In two patients there was no normalization or improvement in serum titers on RPR testing or cerebrospinal fluid titers on VDRL testing, cell counts, or protein concentrations. One patient relapsed with meningovascular syphilis six months after therapy. T. pallidum was detected by the polymerase chain reaction in cerebrospinal fluid from 3 of 10 patients before treatment, but in none of the 10 post-treatment specimens. CONCLUSIONS In patients with early syphilis who are also infected with HIV, therapy with penicillin G benzathine may fail, and neurosyphilis may develop. The regimen of high-dose penicillin recommended for neurosyphilis is not consistently effective in patients infected with HIV.

Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued

Solid organ transplant recipients are at risk for Pneumocystis carinii pneumonia (PCP), but the risk of PCP beyond 1 year is poorly defined. We identified 25 cases of PCP in 1,299 patients undergoing solid organ transplantation between 1987 and 1996 at The Cleveland Clinic Foundation (4.8 cases per 1,000 person transplant-years [PTY]). Ten (36%) of 28 PCP cases (transplantation was performed before 1987 in three cases) occurred > or = 1 year after transplantation, and no patient developed PCP while receiving prophylaxis for PCP. The incidence of PCP during the first year following transplantation was eight times higher than that during subsequent years. The highest rate occurred among lung transplant recipients (22 cases per 1,000 PTY), for whom the incidence did not decline beyond the first year of transplantation. We conclude that the incidence of PCP is highest during the first year after transplantation and differs by type of solid organ transplant. Extending the duration of PCP prophylaxis beyond 1 year may be warranted for lung transplant recipients.

Cardiac implantable electronic device infections: Presentation, management, and patient outcomes

BACKGROUND Indications for cardiac implantable electronic devices (CIEDs) are increasing. Although CIED infections occur infrequently, the impact of this outcome is expected to be substantial. OBJECTIVE The purpose of this study was to the evaluate the outcome of patients undergoing removal of infected CIEDs. METHODS A retrospective study was conducted of all patients with proven or suspected infected CIEDs who were referred to the Cleveland Clinic for system removal from January 2002 through March 2007. RESULTS A total of 412 patients (age 68 +/- 15 years) were included in the study. The majority of patients (241 [59%]) presented with localized infection involving the device pocket. The remaining 171 patients (41%) presented with endovascular infection but no evidence of inflammation of the device pocket. Of the total 414 pathogens isolated, 366 (88%) were aerobic gram-positive organisms, of which 90% were Staphylococcus species, and almost half of these were methicillin resistant. In-hospital mortality was 4.6% (19 patients). Only 2 deaths were extraction related. One-year mortality was 17%. Among the total cohort, 8 (1.9%) patients had relapsing infection within the first year. Among patients who had device replacement during the same hospitalization, 6 (2.6%) had relapsing infections within 1 year of reimplantation; 5 of these patients had systemic symptoms and were bacteremic upon initial presentation. CONCLUSION CIED infections are most often caused by Staphylococcus species, half of which are methicillin resistant. Percutaneous lead and device removal along with antibiotic therapy are effective as primary interventions. The overall relapse rate is 1.9%, and the relapse rate among patients who had reimplantation during the same hospitalization is 2.6%.

Emergence of fluoroquinolone-resistant Escherichia coli as cause of postprostate biopsy infection: implications for prophylaxis and treatment.

OBJECTIVES To report the sensitivity and resistance of Escherichia coli in patients with infectious complications after prostate biopsy in a North American cohort. Increasing antibiotic-resistant E. coli has been observed worldwide. METHODS Data were available for 1446 patients who had undergone transrectal ultrasound-guided prostate biopsy from 2001 to 2010. Of the 1446 patients, 932 were administered 500 mg of ciprofloxacin 1 hour before prostate biopsy and 514 were administered a 3-day course of ciprofloxacin starting 1 day before biopsy plus an enema the night before. The sensitivity and resistance of E. coli were attained through the analysis of the blood and urine cultures of patients with suspected infection. RESULTS Of the 1446 patients, 40 (2.77%) developed an infection after biopsy. Of these 40 patients, 31 (2.14%) had a febrile urinary tract infection and 9 (0.62%) were diagnosed with sepsis requiring hospitalization. Of the 40 patients, 20 (50%) had urine cultures positive for E. coli. Of these 20 patients, 11 (55%) had fluoroquinolone-resistant infection and 9 had fluoroquinolone-sensitive E. coli. Of the remaining 20 patients, culture was not obtained for 9, and 5 had negative urine culture findings. Of the 7 patients (78%) with sepsis had blood cultures positive for E. Coli; 4 (57.1%) of which were fluoroquinolone-resistant and 3 were fluoroquinolone-sensitive. CONCLUSIONS In the present study, a significant risk of fluoroquinolone-resistant E. coli was observed in patients with both febrile urinary tract infection and sepsis after prostate biopsy. Alternative prophylactic antibiotics should be researched further, and postbiopsy infections developing after standard quinolone prophylaxis should be treated with cephalosporins until culture findings are available to guide therapy.

Hypogammaglobulinemia in lung transplant recipients

Background. Infectious complications continue to represent a significant source of morbidity and mortality in lung transplant recipients.Identifying specific, remediable immune defects is of potential value. After one lung transplant patient with recurrent infections was noted to be severely hypogammaglobulinemic, a screening program for humoral immune defects was instituted. The objectives were to define the prevalence of hypogammaglobulinemia in lung transplant recipients, assess levels of antibody to specific pathogens, and correlate infectious disease outcomes and survival with immunoglobulin levels. Methods. All lung transplant recipients followed at a single center between October 1996 and June 1999 underwent a posttransplant humoral immune status survey as part of routine posttransplant follow-up. This survey consists of total immunoglobulin levels (IgG, IgM, IgA), IgG subclasses (IgG1–4), and antibody titers to Pneumococcus, diphtheria, and tetanus. Since February 1997, this survey has been incorporated into the pretransplant evaluation as well. Humoral survey results for October 1996 through July 1999 were recorded, and clinical information on major infectious disease outcomes was obtained from chart reviews, discharge summaries, the Cleveland Clinic Unified Transplant Database, and review of all microbiological studies and pathology results for each patient. Results. Of 67 patients with humoral immune surveys drawn posttransplant, 47 (70%) had IgG levels less than 600 mg/dl (normal 717-1410 mg/dl), of which 25 (37%) had IgG levels less than 400 mg/dl (“lowest IgG group”) and 22 (33%) had IgG levels between 400 and 600 mg/dl (“moderately low IgG group”). A total of 20 patients (30%) had IgG levels of more than 600 mg/dl (“normal IgG group”). Infections that were significantly more common in the lowest IgG group, and more common in the moderately low IgG group than the normal IgG group, included: number of pneumonias (P =0.0006), bacteremias (P =0.02), total bacterial infections (P =0.002), tissue-invasive cytomegalovirus (P =0.01), invasive aspergillosis (P =0.001), total fungal infections (P =0.001), and total infections (P =0.006). Median hospital days per posttransplant year was significantly different in the three groups (11.0 vs. 7.4 vs. 2.8 days, P =0.0003.) Invasive aspergillosis occurred in 44% of the lowest IgG group, 9% of the moderately low IgG group, and 0% of the normal IgG group (P <0.001). Survival was poorest in the lowest IgG group and intermediate in the moderately low IgG group. IgG subclass deficiencies occurred in a variety of patterns. Hypogammaglobulinemic patients lacked protective responses to Pneumococcus in 14/47 (30%), diphtheria in 15%, and tetanus in 19%. In a group of 48 patients screened pretransplant, 90% had normal immunoglobulin levels. Conclusions. Hypogammaglobulinemia in lung transplant recipients is more common than has been previously recognized. An IgG level of less than 400 mg/dl identifies a group at extremely high risk of bacterial and fungal infections, tissue-invasive cytomegalovirus, and poorer survival. Immunoglobulin monitoring may offer an opportunity for intensive surveillance, tapering of immunosuppression, and preemptive therapy for infection.

Nosocomial bloodstream infections in patients with implantable left ventricular assist devices.

BACKGROUND Implantable left ventricular assist devices (LVAD) are used as a bridge to transplantation but are associated with a high risk of infection including nosocomial bloodstream infections (BSI). METHODS We retrospectively reviewed the medical records of all patients with implantable LVAD at the Cleveland Clinic with 72 hours or longer of LVAD support from January 1992 through June 2000, to determine the attack rate, incidence, and impact of nosocomial BSI in patients with LVAD. A nosocomial BSI was defined using Centers for Disease Control and Prevention definition. An LVAD-related BSI was defined as one where the same pathogen is cultured from the device and the blood with no other obvious source. Two hundred fourteen patients were included in the study (17,831 LVAD-days). RESULTS One hundred forty BSI were identified in 104 patients for an attack rate of 49% and incidence of 7.9 BSI per 1000 LVAD-days. Thirty-eight percent of the BSI were LVAD associated. The most common pathogens causing BSI were coagulase-negative staphylococci (n = 33), Staphylococcus aureus, and Candida spp. (19 each), and Pseudomonas aeruginosa (16 each). A Cox proportional hazard model found BSI in patients with LVAD to be significantly associated with death (hazard ratio = 4.02, p < 0.001). Fungemia had the highest hazard ratio (10.9), followed by gram-negative bacteremia (5.1), and gram-positive bacteremia (2.2). CONCLUSIONS Patients with implantable LVAD have a high incidence of BSI, which are associated with a significantly increased mortality. Strategies for prevention of infection in LVAD recipients should focus on the drive line exit site until technical advances can achieve a totally implantable device.