Long-Term Infectious and Noninfectious Outcomes of Monthly Alemtuzumab as a Calcineurin Inhibitor- and Steroid-Free Regimen for Pancreas Transplant Recipients.

Multiple doses of alemtuzumab for immunosuppressive therapy of patients with hematologic malignancies and hematopoietic stem cell transplant have been associated with a high rate of infection. In transplantation, limited alemtuzumab dosing has been successfully used as induction immunosuppression. The effect of multiple doses of alemtuzumab, used as maintenance therapy to minimize steroid and/or calcineurin inhibitor toxicity in solid organ transplant recipients, is unknown. We evaluated the infectious and noninfectious outcomes of 179 pancreas transplant recipients treated with alemtuzumab for induction and maintenance therapy (extended alemtuzumab exposure (EAE)) from 2/28/2003 through 8/31/2005, compared with 159 pancreas transplant recipients with standard induction and maintenance (SIM) therapy performed before (1/1/2002 until 12/31/2002) and after (1/1/2006 until 12/31/2006) the implementation of EAE. EAE was associated with higher risk of overall infections (hazard ratio (HR) 1.33 (1.06-1.66), P=0.01), bacterial infections (HR 1.33 (1.05-1.67), P=0.02), fungal infections (HR 1.86 (1.28-2.71), P < 0.01), and cytomegalovirus infections (HR 2.29 (1.39-3.77), P < 0.01). In addition, EAE was associated with higher risk of acute cellular rejection (HR 2.09 (1.46-2.99), P < 0.01). In conclusion, while a limited alemtuzumab dosing is safe and effective for induction therapy in pancreas transplantation, EAE combined with steroid and calcineurin minimization is associated with a high risk of infectious complications and acute cellular rejection.

Intestinal pathophysiological and microbial changes in sickle cell disease: Potential targets for therapeutic intervention.

There is a large therapeutic gap in the treatment of sickle cell disease (SCD). Recent studies demonstrated the presence of pathophysiological and microbial changes in the intestine of patients with SCD. The intestinal microbes have also been found to regulate neutrophil ageing and possible basal activation of circulating neutrophils. Both aged and activated neutrophils are pivotal for the pathogenesis of vaso-occlusive crisis in SCD. In this paper, we will provide an overview of the intestinal pathophysiological and microbial changes in SCD. Based on these changes, we will propose therapeutic approaches that could be investigated for treating SCD.

Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors.

We carried out a retrospective cohort study on patients with advanced cancer treated with immune checkpoint inhibitors (ICIs) to determine whether antibiotics affect treatment outcome. Sixty consecutive patients were identified, and 17 received systemic antibiotics within 2 weeks before and/or after first dose of ICI. Antibiotic-treated patients were significantly younger (p = 0.0008) and less likely to receive nivolumab (p = 0.08) or had neutrophil:lymphocyte ratio < 5 (p = 0.08). They had a lower response rate (RR) (29.4% vs 62.8%) (p = 0.024) and more inferior progression-free survival (PFS) (p = 0.048). Narrow-spectrum antibiotics did not affect the RR. However, broad-spectrum antibiotics were associated with a lower RR (25% vs 61%) (p = 0.02) and a trend towards longer time to response (median: 14 weeks vs 12 weeks) (p = 0.1). They also had shorter PFS (p = 0.012). Multivariate analysis identified antibiotics as the only factor affecting RR (p = 0.0038) and PFS (p = 0.01). We next examined the 21 patients whose PFS lasted for 12 weeks or more. Five of the 21 patients received broad-spectrum antibiotics within 10 weeks before disease progression. There was a trend towards shorter PFS in these patients (p = 0.1). Finally, antibiotic-treated patients experienced shorter overall survival (OS) (median: 24 months vs 89 months) (p = 0.003). Multivariate analysis found age (p = 0.035) and antibiotics (p = 0.038) to be the only factors affecting OS. Our results point to a detrimental effect of broad-spectrum antibiotics on treatment outcome to ICI therapy.

Invasive non-typhoidal Salmonella in sickle cell disease in Africa: is increased gut permeability the missing link?

Non-typhoidal Salmonella usually induces self-limiting gastroenteritis. However, in many parts of Africa, especially in individuals who are malnourished, infected with malaria, or have sickle cell disease, the organism causes serious and potentially fatal systemic infections. Since the portal of entry of non-typhoidal Salmonella into the systemic circulation is by way of the intestine, we argue that an increased gut permeability plays a vital role in the initiation of invasive non-typhoidal Salmonella in these patients. Here, we will appraise the evidence supporting a breach in the intestinal barrier and propose the mechanisms for the increased risks for invasive non-typhoidal Salmonella infections in these individuals.

Infections in patients on BCR-ABL tyrosine kinase inhibitor therapy: cases and review of the literature.

The introduction of BCR-ABL-tyrosine kinase inhibitors (TKI) for treatment of hematologic malignancies has made a significant impact on patient outcome. Contingent upon their targeted and off-target activity, therapy-associated infectious complications may occur. We present a case of cytomegalovirus pneumonitis and a case of adenovirus hemorrhagic cystitis in two patients with Philadelphia chromosome-positive acute lymphoblastic leukemia on BCR-ABL TKI treatment and review the literature to summarize the infectious complications based on clinical data. As life-threatening infections may occur, treating physicians should maintain a heightened awareness in patients treated with BCR-ABL TKIs. Based on the frequent reports of hepatitis B virus (HBV) reactivation under the treatment BCR-ABL TKIs, screening for and prophylactic therapy of chronic HBV infection should be considered. Similarly, patients would benefit from screening for and treatment of latent tuberculosis.

Relapsing EBV encephalitis in a renal transplant recipient.

In solid organ transplant recipients, Epstein-Barr virus (EBV) can cause active central nervous system (CNS) infection or malignant transformation of latently infected cells in the CNS, known as post-transplant lymphoproliferative disease (PTLD). Reduction of T-cell immunosuppression is the cornerstone of management. The role of antivirals with in-vitro activity against herpesviruses in EBV-related CNS syndromes is controversial, as they have no effect on latent virus. We report an unusual case of relapsing EBV encephalitis in a donor-positive, EBV-negative renal transplant recipient, with response to valganciclovir. Our report supports the utility of antiviral treatment for EBV encephalitis, as adjunct to reducing immunosuppression, and highlights the need for a systematic approach and long-term, multi-disciplinary follow-up of such patients.

Resolution of diarrhea in an immunocompromised patient with chronic norovirus gastroenteritis correlates with constitution of specific antibody blockade titer.

Norovirus gastroenteritis in immunocompromised hosts can result in a serious and prolonged diarrheal illness. We present a case of chronic norovirus disease during rituximab-bendamustine chemotherapy for non-Hodgkin's lymphoma. We show for the first time a correlation between norovirus strain-specific antibody blockade titers and symptom improvement in an immunocompromised host.

Transfusion-transmitted anaplasmosis from a leukoreduced platelet pool.

BACKGROUND: Human granulocytic anaplasmosis is an emerging tick-borne illness. Anaplasma phagocytophilum resides intracellularly, can cause asymptomatic infection, and can survive blood component refrigeration conditions for at least 18 days. To date, eight cases of transfusion-transmitted anaplasmosis (TTA) have been reported: seven attributed to red blood cell (RBC) units, five of which were prestorage leukoreduced using RBC leukoreduction filters, and one involving a process leukoreduced apheresis platelet (PLT) unit. Here, we report a case of TTA from a whole blood-derived PLT pool. STUDY DESIGN AND METHODS: Donation segments from the 7 units of RBCs and two PLT pools transfused were examined. Fast protocol multiplex real-time A. phagocytophilum polymerase chain reaction (PCR) and serologic testing for immunoglobulin (Ig)M and IgG antibodies to A. phagocytophilum by enzyme immunoassay were performed. RESULTS: Transmission was confirmed by positive A. phagocytophilum PCR and serology in one of 16 donors and by positive PCR and seroconversion in the recipient. CONCLUSION: This is the first confirmed case of TTA from a whole blood-derived PLT pool prepared from PLT concentrates leukoreduced by in-line filtration of PLT-rich plasma.

Antibacterial bioagents based on principles of bacteriophage biology: an overview.

Bacteriophages were discovered almost a century ago. With the advent of antibiotics, the use of bacteriophages for treatment of infections fell out of favor in Western medicine. In light of the rise of antibiotic resistance, phages and their products (lysins) are rediscovered as antibacterial bioagents. This overview summarizes principles of phage biology and their translation for therapeutic and preventive applications. Examples are presented to highlight their therapeutic promise for prophylaxis and treatment of bacterial infections including multidrug-resistant organisms in humans and animals, and their use as decontaminants of food supplies and environments. Besides research on the in vivo behavior of phages and lysins, dialogues between researchers and regulatory agencies are necessary to publish guidelines for bacteriophage manufacturing and formulation for human use. Only well-designed, double-blind randomized controlled trials will determine if phages and lysins are safe and effective adjuncts or alternatives to antibiotic therapy for infections with multidrug-resistant organisms.

Vancomycin-resistant Enterococcus faecium meningitis in adults: case series and review of the literature.

BACKGROUND: Vancomycin-resistant Enterococcus faecium (VR E. faecium) is a rare cause of meningitis and is associated with substantial mortality. Limited therapeutic options are available for the treatment of VR E. faecium meningitis. The optimum therapy has not been established. METHODS: We retrospectively identified adult cases of meningitis due to VR E. faecium that occurred at the Massachusetts General Hospital from 1999 to 2011 and performed a literature search for published adult cases using Medline and Embase. RESULTS: At our institution, 4 cases of meningitis due to VR E. faecium were identified. Three out of our 4 cases were successfully treated with linezolid in combination with rifampicin, or with daptomycin in combination with quinupristin-dalfopristin (QD), and 1 out of 4 with linezolid monotherapy. The literature search yielded 18 cases published to date. Published cases showed bacterial cure with linezolid, chloramphenicol or QD (intravenous (IV) and intrathecal (IT)) monotherapy, or linezolid in combination with ampicillin, gentamicin, rifampicin or chloramphenicol, or daptomycin in combination with gentamicin or QD. CONCLUSIONS: Bacterial cure of meningitis due to VR E. faecium can be achieved with various antimicrobial drugs used as monotherapy or in combination. IT in addition to IV therapy should be considered dependent on the pharmacological properties of the drugs. We also reported the successful treatment of a case with a vancomycin-resistant, linezolid-intermediate isolate with QD and daptomycin. The paucity of cases with this clinical syndrome does not allow the identification of an optimal treatment regimen.

Reduction of inappropriate urinary catheter use at a Veterans Affairs hospital through a multifaceted quality improvement project.

BACKGROUND: Foley catheter (FC) use is a modifiable risk factor for hospital-acquired urinary tract infection, the most common type of nosocomial infection. It is unknown whether sustained, hospital-wide reductions in FC use are achievable by combining interventions with demonstrated short-term effectiveness in selected units. METHODS: A multifaceted quality improvement project to decrease unnecessary FC use and increase order documentation was instituted throughout the Minneapolis Veterans Affairs Medical Center in March 2005, after a >2-year baseline period. Bundled interventions included multiple types of education, system redesign, rewards, and feedback (phases I and II), plus, in phase III, involvement of a dedicated FC nurse. RESULTS: The daily prevalence of FC use dropped steeply during intervention phase I (5.5 months), from a 15.2% baseline mean to a 9.3% nadir, but rebounded quickly during the subsequent hiatus phase (1.2 months). It dropped again (mean, 13.6%) during intervention phase II (27.3 months) and even further (mean, 12.0%) during intervention phase III (22.8 months) (P ≤ .001, phase II or III vs baseline). Compared with baseline, during phase III (with the dedicated FC nurse) the mean daily percentages of nonordered and nonindicated FCs dropped from 17% to 5.1% and from 15% to 1.2%, respectively. During phases II and III combined, an estimated total of 6691 FC days were avoided. CONCLUSIONS: Significant hospital-wide reductions in total and inappropriate FC use and improved FC order documentation were achieved through a multicomponent campaign. The greatest and most sustained improvements accompanied the involvement of a dedicated FC nurse.

R753Q single-nucleotide polymorphism impairs toll-like receptor 2 recognition of hepatitis C virus core and nonstructural 3 proteins.

BACKGROUND: Hepatitis C virus (HCV) core and nonstructural (NS) 3 proteins induce inflammation and immunity through a toll-like receptor (TLR) 2-dependent pathway. Individuals with the R753Q single-nucleotide polymorphism (SNP) in the TLR2 gene have increased the risk of allograft failure after liver transplantation for chronic hepatitis C. METHODS: To test the hypothesis that R753Q SNP impairs TLR2 recognition of HCV proteins, a series of in vitro experiments were performed wherein stable clones of wild-type TLR2-deficient human embryonic kidney (HEK) 293 cells and HEK293 cells transfected with wild-type (HEK293-TLR2) or variant TLR2 genes (HEK293-TLR2-R753Q) were stimulated with HCV core and NS3 proteins. Cellular activation was assessed by nuclear factor-kappa B-driven luciferase activity, cytokine secretion, and gene upregulation. RESULTS: Compared with TLR2-deficient HEK293 cells, HEK293-TLR2 cells had marked nuclear factor-kappa B-driven luciferase activity, had modest to marked upregulation in TLR2 signaling-associated genes, and secreted large quantities of interleukin-8 during exposure to HCV core and NS3 proteins. In contrast, HEK293-TLR2-R753Q cells did not respond to stimulation with HCV and behaved similarly like TLR2-deficient HEK293 cells. CONCLUSION: R753Q SNP impairs TLR2-mediated immune recognition of HCV core and NS3 proteins. This biologic defect may account for the predisposition of patients to develop allograft failure after liver transplantation for chronic hepatitis C.

Temporal trends in the incidence of Staphylococcus aureus bacteremia in Olmsted County, Minnesota, 1998 to 2005: a population-based study.

BACKGROUND: There is a paucity of population-based studies on Staphylococcus aureus bacteremia (SAB) in the United States. We determined the incidence of and trends in SAB in Olmsted County, Minnesota, over an 8-year period. METHODS: A retrospective, population-based, cohort study was done to evaluate the initial episodes of SAB occurring in adult residents of Olmsted County, Minnesota, from 1 January 1998 through 31 December 2005, using the microbiology databases at Mayo Clinic and Olmsted Medical Center in Rochester, Minnesota. RESULTS: Of 247 evaluable adult patients with SAB who were included in the incidence calculation, 143 (57.9%) were males, and the median age was 72.1 years (range, 19.5-98.5 years). Episodes of bacteremia were classified according to acquisition type: 58 (23.5%) were nosocomial (N-SAB), 145 (58.7%) were healthcare-associated (HCA-SAB), and 44 (17.8%) were community-acquired (CA-SAB). Methicillin-resistant S. aureus (MRSA) constituted 31.6% of the cases. No community-acquired MRSA bacteremia was noted. The age-adjusted incidence of SAB was 28.3 episodes/100,000 person-years for females and 53.5 episodes/100,000 person-years for males, with an age- and sex-adjusted rate of 38.2 episodes/100,000 person-years. The age- and sex-adjusted incidence of N-SAB, HCA-SAB, and CA-SAB was 9.0, 22.6, and 6.6 episodes/100,000 person-years, respectively. The age- and sex-adjusted incidence of methicillin-susceptible S. aureus was 25.4 episodes/100,000 person-years, and that of MRSA was 12.4 episodes/100,000 person-years. Overall, the incidence rate increased with age but not over the calendar year. The exception was MRSA bacteremia, which increased at a rate of 19.8% (standard error, +/-5.5%) per year during the study. CONCLUSIONS: The incidence of SAB in adults remained stable in Olmsted County, Minnesota, from 1998 to 2005, but the proportion of episodes due to MRSA significantly increased over the 8-year period.