Successful treatment of donor-derived hepatitis C infection in a lung transplant recipient.

Data are limited regarding the use of direct-acting antivirals for treatment of hepatitis C infection post lung transplant, especially in a donor-derived infection. We present a case of a lung transplant recipient with donor-derived hepatitis C that was successfully treated with a 12-week regimen of simeprevir and sofosbuvir. This case reiterates the importance of screening recipients of increased-risk donor organs for disease transmission and the value of early therapy.

Infections after Transplantation of Bone Marrow or Peripheral Blood Stem Cells from Unrelated Donors.

Infection is a major complication of hematopoietic cell transplantation. Prolonged neutropenia and graft-versus-host disease are the 2 major complications with an associated risk for infection, and these complications differ according to the graft source. A phase 3, multicenter, randomized trial (Blood and Marrow Transplant Clinical Trials Network [BMT CTN] 0201) of transplantation of bone marrow (BM) versus peripheral blood stem cells (PBSC) from unrelated donors showed no significant differences in 2-year survival between these graft sources. In an effort to provide data regarding whether BM or PBSC could be used as a preferential graft source for transplantation, we report a detailed analysis of the infectious complications for 2 years after transplantation from the BMT CTN 0201 trial. A total of 499 patients in this study had full audits of infection data. A total of 1347 infection episodes of moderate or greater severity were documented in 384 (77%) patients; 201 of 249 (81%) of the evaluable patients had received a BM graft and 183 of 250 (73%) had received a PBSC graft. Of 1347 infection episodes, 373 were severe and 123 were life-threatening and/or fatal; 710 (53%) of these episodes occurred on the BM arm and 637 (47%) on the PBSC arm, resulting in a 2-year cumulative incidence 84.7% (95% confidence interval [CI], 79.6 to 89.8) for BM versus 79.7% (95% CI, 73.9 to 85.5) for PBSC, P = .013. The majority of these episodes, 810 (60%), were due to bacteria, with a 2-year cumulative incidence of 72.1% and 62.9% in BM versus PBSC recipients, respectively (P = .003). The cumulative incidence of bloodstream bacterial infections during the first 100 days was 44.8% (95% CI, 38.5 to 51.1) for BM versus 35.0% (95% CI, 28.9 to 41.1) for PBSC (P = .027). The total infection density (number of infection events/100 patient days at risk) was .67 for BM and .60 for PBSC. The overall infection density for bacterial infections was .4 in both arms; for viral infections, it was .2 in both arms; and for fungal/parasitic infections, it was .04 and .05 for BM and PBSC, respectively. The cumulative incidence of infection before engraftment was 47.9% (95% CI, 41.5 to 53.9) for BM versus 32.8% (95% CI, 27.1 to 38.7) for PBSC (P = .002), possibly related to quicker neutrophil engraftment using PBSC. Infections remain frequent after unrelated donor hematopoietic cell transplantation, particularly after BM grafts.

Human leukocyte antigen type and posttransplant lymphoproliferative disorder.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is an infrequent but serious complication of solid organ transplantation. Early detection and initiation of therapy may improve outcomes. The purpose of this study was to identify human leukocyte antigen (HLA) type as risk and prognostic factors for PTLD. METHODS: A review was undertaken to identify PTLD cases treated at our institution over the past 25 years. Logistic regression and Cox Proportional Hazards were used to model risk factors for PTLD and clinical outcomes in patients with PTLD. RESULTS: One hundred six cases of PTLD were identified with 1392 solid-organ transplant recipient controls. Epstein-Barr virus (EBV) seronegative status pretransplant (odds ratio [OR] = 7.61, 95% confidence interval [95% CI] = 3.83-15.1) and receipt of a nonkidney transplant were associated with an increased risk of PTLD. Being African American and receipt of a living-related kidney transplant were associated with a decreased risk of PTLD. The HLA-B40 group was a risk factor for PTLD in EBV-seronegative individuals (OR = 8.38, 95% CI = 2.18-32.3), whereas HLA-B8 was a risk factor for PTLD in EBV-seropositive individuals (OR = 3.29, 95% CI = 1.52-7.09). Specific HLA types were not associated with graft failure or mortality after PTLD diagnosis. In PTLD patients, central nervous system (CNS) involvement, bone marrow involvement, T-cell PTLD, and age were associated with increased mortality. CONCLUSION: Human leukocyte antigen-B40 group and HLA-B8 were identified as novel susceptibility factors for PTLD in EBV-seropositive and EBV-seronegative individuals, respectively. Multicentered, large prospective studies of PTLD with correlative immunologic work are needed to test the significance of these observed associations.

Infectious Complications of Mechanical Circulatory Support (MCS) Devices.

Left-ventricular assist devices and other forms of mechanical circulatory support are increasingly important in the routine therapy of patients with end-stage congestive heart failure. Technology may help to decrease the rate of infections associated with these devices, but with larger numbers of implants being utilized across the globe, infections overall are becoming more commonplace. Becoming familiar with appropriate techniques for prevention and with the ideal approach to diagnostic and therapeutic strategies is key to managing mechanical circulatory support infections in this unique, but growing, patient population.

The impact of lecture attendance and other variables on how medical students evaluate faculty in a preclinical program.

PURPOSE: High-quality audiovisual recording technology enables medical students to listen to didactic lectures without actually attending them. The authors wondered whether in-person attendance affects how students evaluate lecturers. METHOD: This is a retrospective review of faculty evaluations completed by first- and second-year medical students at the Ohio State University College of Medicine during 2009-2010. Lecture-capture technology was used to record all lectures. Attendance at lectures was optional; however, all students were required to complete lecturer evaluation forms. Students rated overall instruction using a five-option response scale. They also reported their attendance. The authors used analysis of variance to compare the lecturer ratings of attendees versus nonattendees. The authors included additional independent variables-year of student, student grade/rank in class, and lecturer degree-in the analysis. RESULTS: The authors analyzed 12,092 evaluations of 220 lecturers received from 358 students. The average number of evaluations per lecturer was 55. Seventy-four percent (n = 8,968 evaluations) of students attended the lectures they evaluated, whereas 26% (n = 3,124 evaluations) viewed them online. Mean lecturer ratings from attendees was 3.85 compared with 3.80 by nonattendees (P ≤ .05; effect size: 0.055). Student's class grade and year, plus lecturer degree, also affected students' evaluations of lecturers (effect sizes: 0.055-0.3). CONCLUSIONS: Students' attendance at lectures, year, and class grade, as well as lecturer degree, affect students' evaluation of lecturers. This finding has ramifications on how student evaluations should be collected, interpreted, and used in promotion and tenure decisions in this evolving medical education environment.

Critical appraisal of ceftaroline in the management of community-acquired bacterial pneumonia and skin infections.

Ceftaroline is a novel broad-spectrum cephalosporin ß-lactam antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA) as well as multidrug-resistant Streptococcus pneumoniae among other routine Gram positive and Gram negative organisms. It has been approved by the US Food and Drug Administration for treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections (ABSSSIs). Ceftaroline is approved for treatment of ABSSSI due to MRSA, however currently there are no data for pneumonia due to MRSA in humans. Herein we review the major clinical trials as well as ceftaroline microbiology, pharmacokinetics, and safety, followed by a look at further directions for investigation of this new agent.

Newer beta-lactam antibiotics: doripenem, ceftobiprole, ceftaroline, and cefepime.

This article reviews the new beta-lactam (ß-lactam) antibiotics doripenem, ceftobiprole, and ceftaroline. It covers pharmacokinetic and pharmacodynamic properties, dosing, in vitro activities, safety, and clinical trial results. Doripenem (Doribax) has been approved by the US Food and Drug Administration (FDA) for the treatment of complicated intra-abdominal and urinary tract infections. Ceftaroline has received FDA approval for the treatment of skin and soft tissue infections and community acquired pneumonia. Ceftobiprole has not received FDA approval. The article also reviews recent data suggesting increased overall mortality with Cefepime (Maxipime) use compared with other beta-lactam antibiotics and the potential risk for neurotoxicity in the setting of renal failure.

Effect of body mass index and device type on infection in left ventricular assist device support beyond 30 days.

Infection as a complication of long-term left ventricular assist device (LVAD) support leads to significant morbidity and mortality. Obesity, a possible risk factor for other postoperative cardiovascular surgical site infections, is an increasingly prevalent condition among recipients of LVAD devices. We retrospectively analyzed 145 LVADs that remained in place beyond 30 days over a nine-year period at a single medical institution. Statistical analysis was carried out using univariate and multivariable logistic regression and chi(2)-testing where indicated. Body mass index (BMI) had no effect on the incidence of infectious outcomes regardless of age, gender, underlying pathogen or device type. This included the morbidly obese population as well (BMI >or=40). Independent of BMI, device type did have an effect, with the HeartMate XVE increasing the risk for infections [odds ratio (OR) 4.3 with 95% confidence interval (CI) 2.1-8.8, P=0.0001] and the HeartMate II reducing the risk (OR 0.21 with 95% CI 0.09-0.50, P=0.0001). The risk for infection after LVAD placement for long-term support is likely to be a multi-factorial phenomenon. BMI, including morbid obesity, does not appear to be a statistically significant relevant factor in determining that risk. Device type may have an effect, however, on risk of infection in long-term support.

Newer beta-lactam antibiotics: doripenem, ceftobiprole, ceftaroline, and cefepime.

This article reviews the new beta-lactam (beta-lactam) antibiotics doripenem, ceftobiprole, and ceftaroline. It covers pharmacokinetic and pharmacodynamic properties, dosing, in vitro activities, safety, and clinical trial results. Doripenem (Doribax) has been approved by the US Food and Drug Administration (FDA) for the treatment of complicated intra-abdominal and urinary tract infections. At this writing, ceftobiprole is under review by the FDA for approval based on results of phase 3 clinical trials, whereas at least one phase 3 clinical trial of ceftaroline has been completed. The article also reviews recent data suggesting increased overall mortality with Cefepime (Maxipime) use compared with other beta-lactam antibiotics and the potential risk for neurotoxicity in the setting of renal failure.

Multidrug-resistant Acinetobacter baumannii pneumonia in lung transplant recipients.

We present 6 cases of multidrug-resistant (MDR) Acinetobacter baumannii pneumonia in lung transplant recipients. All cases were treated with imipenem and/or non-traditional antibiotics, such as tigecycline and colistimethate, and had different microbiologic and clinical outcomes. Prior treatment with broad-spectrum anti-microbial therapy was the single most likely risk factor for the development of infection due to MDR Acinetobacter baumannii. Ideal preventive and therapeutic strategies for this pathogen in lung transplant recipients require further study.

Gene expression of porcine lymphotrophic herpesvirus-1 in miniature Swine with posttransplant lymphoproliferative disorder.

Porcine lymphotropic herpesvirus-1 (PLHV-1) is a gamma-herpesvirus related to Epstein-Barr virus (EBV) and associated with development of posttransplant lymphoproliferative disorder (PTLD) following allogeneic stem cell or spleen transplantation in miniature swine. Oligonucleotide microarrays were designed based on known open reading frames (ORFs) of PLHV-1. Expression was compared by cohybridization of cDNA from lymph nodes of PLHV-1+ swine after allogeneic spleen transplantation between either: 1) PTLD-affected and PTLD-unaffected swine; or 2) PTLD-affected swine vs. samples from the same animal prior to diagnosis. In PTLD-affected animals, consistent upregulation (nine ORFs) and downregulation (four ORFs) of PLHV-1 mRNA was observed in comparison to those without PTLD. No differences in gene expression were discovered at the time of clinical PTLD diagnosis compared to six to nine days prior to diagnosis in the same animals. This model provides insights into the pathogenesis of PTLD and, by extension, potential diagnostic and therapeutic tools for human EBV-associated PTLD.

Genomic presence of recombinant porcine endogenous retrovirus in transmitting miniature swine.

The replication of porcine endogenous retrovirus (PERV) in human cell lines suggests a potential infectious risk in xenotransplantation. PERV isolated from human cells following cocultivation with porcine peripheral blood mononuclear cells is a recombinant of PERV-A and PERV-C. We describe two different recombinant PERV-AC sequences in the cellular DNA of some transmitting miniature swine. This is the first evidence of PERV-AC recombinant virus in porcine genomic DNA that may have resulted from autoinfection following exogenous viral recombination. Infectious risk in xenotransplantation will be defined by the activity of PERV loci in vivo.

Infectious complications associated with alemtuzumab use for lymphoproliferative disorders.

BACKGROUND: Alemtuzumab is an emerging therapy for refractory lymphoproliferative disorders. The associated long-term risks of infection remain poorly defined. METHODS: From July 2001 through December 2003, all patients who received alemtuzumab for the treatment of lymphoproliferative disorders at 1 institution underwent a retrospective evaluation to document infectious complications until death or end of follow-up in October 2004. Alemtuzumab recipients who underwent allogeneic hematopoietic stem cell transplantation were compared with a concurrent cohort who also underwent allogeneic hematopoietic stem cell transplantation but did not receive alemtuzumab. RESULTS: Twenty-seven patients were identified (21 with chronic lymphocytic leukemia and 6 with plasma cell disorders). The overall mortality was 37%, with 7 of 10 deaths being related to infection. Significant opportunistic infections occurred in 9 patients (43%) with chronic lymphocytic leukemia, including cytomegalovirus, progressive multifocal leukoencephalopathy, adenovirus, toxoplasmosis, and acanthamaebiasis. Thirty nonopportunistic infections in 22 patients (82%) were also identified. The 3 deaths related to nonopportunistic infections all involved Enterococcus species bacteremia. When compared with a concurrent chronic lymphocytic leukemia cohort that underwent allogeneic hematopoietic stem cell transplantation, alemtuzumab recipients had an incidence of cytomegalovirus reactivation of 66.7% (6 of 9 patients), compared with 37% in the non-alemtuzumab group (10 of 27 patients; P = .15), and an incidence of post-transplant opportunistic infections (excluding herpesviruses) of 44.4% (compared with 29.6% in the non-alemtuzumab group; P = .41). CONCLUSIONS: Despite the use of herpesvirus and Pneumocystis pneumonia prophylaxis, serious infectious complications occur in patients receiving alemtuzumab for lymphoproliferative disorders. Infectious complications are more varied and diverse in patients receiving alemtuzumab than has been reported in trials to date.

Reactive Epstein-Barr virus-related polyclonal lymphoproliferative disorder in a patient with AIDS.

Reactivation of Epstein-Barr virus infection and polyclonal expansion of lymphocytes is well-documented in solid organ and hematopoietic stem cell transplant recipients and is considered a potential precursor to lymphoma. We report an analogous case of posttransplantation polyclonal lymphoproliferative disorder in a patient with human immunodeficiency virus infection who was successfully treated with antiretroviral therapy.

Beta-lactam antibiotics: newer formulations and newer agents.

beta-Lactam antibiotics share a common structure and mechanism of action, although they differ in their spectrum of antimicrobial activity and utility in treating different infections. The current classes include the penicillins, the penicillinase-resistant penicillins, the extended- spectrum penicillins, the cephalosporins, the carbapenems, and the monobactams. This article discusses some of the newest beta-lactams available for use in the United States: ertapenem, cefditoren, and cefepime. A new formulation of amoxicillin-clavulanate, which contains higher doses of amoxicillin, is also discussed.