White paper on antimicrobial stewardship in solid organ transplant recipients.

Antimicrobial stewardship programs (ASPs) have made immense strides in optimizing antibiotic, antifungal, and antiviral use in clinical settings. However, although ASPs are required institutionally by regulatory agencies in the United States and Canada, they are not mandated for transplant centers or programs specifically. Despite the fact that solid organ transplant recipients in particular are at increased risk of infections from multidrug-resistant organisms, due to host and donor factors and immunosuppressive therapy, there currently are little rigorous data regarding stewardship practices in solid organ transplant populations, and thus, no transplant-specific requirements currently exist. Further complicating matters, transplant patients have a wide range of variability regarding their susceptibility to infection, as factors such as surgery of transplant, intensity of immunosuppression, and presence of drains or catheters in situ may modify the risk of infection. As such, it is not feasible to have a "one-size-fits-all" style of stewardship for this patient population. The objective of this white paper is to identify opportunities, risk factors, and ASP strategies that should be assessed with solid organ transplant recipients to optimize antimicrobial use, while producing an overall improvement in patient outcomes. We hope it may serve as a springboard for development of future guidance and identification of research opportunities.

Impact of asymptomatic bacteriuria incidence and management post-kidney transplantation.

OBJECTIVE: Urinary tract infections (UTIs) are the most commonly occurring infectious complication following kidney transplantation. Questions remain regarding whether asymptomatic bacteriuria (ASB) should be treated. The aim was to evaluate the incidence and management of ASB in kidney transplant recipients at a large academic medical center. METHODS: All subjects receiving an isolated kidney transplant between September 2012 and October 2016, and with at least one ASB episode were included. Demographics, symptomatology, and urine culture data were collected on subjects with bacteriuria in the first year post-transplant. Cultures were classified by symptoms, ASB treatment trends were analyzed, and ASB-to-UTI progression was compared between ASB treatment and non-treatment. RESULTS: A total of 527 subjects were transplanted with 64 developing at least one ASB episode. The incidence of ASB was 12.1% and treated 74.6% of the time. Neither lack of ASB treatment (P = 0.463) nor ASB within the first month post-transplant (P = 0.303) were associated with ASB-to-UTI progression. CONCLUSION: Despite high ASB treatment rate, this was not found to be protective against ASB-to-UTI progression. ASB within the first month post-transplant also did not correlate with increased progression risk. These results suggest minimization of ASB treatment in kidney transplant recipients remains an important antimicrobial stewardship target.

Infectious diseases pre-transplant evaluation improves vaccination rates for liver transplant candidates.

Immunization rates in pre-liver transplant patients have been historically below rates for immunocompetent patients. At Cleveland Clinic, an infectious diseases (ID) consult is required for all patients during the liver transplant evaluation and may beneficially impact vaccination rates. The goal of this study was to evaluate pre-transplant vaccination rates in pre-liver transplant candidates. This single-center, retrospective chart review included adults transplanted between January 1, 2013, and December 31, 2016. Prior to transplant, rates of vaccination and/or documented seropositivity were 35% for hepatitis B vaccine, 92% for hepatitis A vaccine, 57% for pneumococcal conjugate vaccine, 62% for pneumococcal polysaccharide vaccine, and 77% for influenza vaccine. Vaccination rates were higher than to previously reported. Rates were also higher for several vaccines compared to transplant candidates for other organs without ID consult. With ongoing ID consult requirements for liver transplant candidates, combined with standardization of vaccine recommendations via technology, and increased multi-disciplinary collaboration, vaccination rates should improve further.

Single-dose rituximab for recurrent glomerulonephritis post-renal transplant.

BACKGROUND/AIMS: Post-renal transplant recurrent glomerulonephritis (GN) contributes to allograft loss. Rituximab treatment has been used in a multidose strategy with variable efficacy and toxicity. We investigated a novel single-dose approach. METHODS: A single center, retrospective, cohort study was conducted between January 1998 and April 2012 among renal allograft recipients with recurrent GN treated with rituximab (cases) or without (controls). The primary outcome was complete response (CR, urine protein/creatinine ratio (UP/C) <0.3). Secondary outcomes included partial response (PR >50% reduction in UP/C), response relapse, treatment-response by GN type, acute rejection incidence, time to graft loss, and infection incidence. RESULTS: The median dose of rituximab was 200 mg per patient. Of 20 rituximab cases and 13 controls, CR was achieved in eight (40%) versus four (31%), respectively (p = 0.72). Three subjects in each group achieved PR (p = 0.66). Response relapse was similar between the two groups (p = 0.47). Significantly more subjects with recurrent membranous nephropathy (MN) achieved CR with rituximab treatment (p = 0.029). Acute rejection was lower in the rituximab group versus controls (n = 0 vs. 4; p = 0.046). The mean time to graft loss was much later in the rituximab group (35 months, (95% CI 33-37)) versus controls (29 months, (95% CI 24-35)) at 36 months (p = 0.04). There was no infection increase in rituximab-treated subjects (p = 0.16). CONCLUSION: Single-dose rituximab for treatment of recurrent GN was associated with less subsequent rejection and longer time to graft loss without increased infection, but was no more effective than regimens not using rituximab at 36-months except those with recurrent membranous GN.

Recommended foscarnet dose is not associated with improved outcomes in cytomegalovirus salvage therapy.

BACKGROUND: Cytomegalovirus (CMV) infection causes significant morbidity and mortality in transplant recipients. Ganciclovir and valganciclovir have proven efficacy but are limited by resistance and toxicity, whereas foscarnet typically retains activity when CMV has become resistant to other antivirals. Foscarnet dosing used in practice may be discordant with what is recommended in product labeling, as the result of an unconventional dosing nomogram or prescriber preference; however, it is unknown how discordant foscarnet dosing affects outcomes. OBJECTIVE: Our purpose was to characterize the relationship between initial foscarnet dosing intensity (relative to product labeling) and key effectiveness and safety endpoints. STUDY DESIGN: This single-center, retrospective study included immunosuppressed adults with CMV viremia who received foscarnet between January 2012-July 2017. Subjects were divided into low dose (LD) and non-low dose (NLD) groups, according to foscarnet dose intensity. The primary endpoint was time-to-CMV eradication. Secondary endpoints included time-to-CMV clearance, acute kidney injury, hematologic toxicity, and mortality. RESULTS: Of 87 subjects, 38 met inclusion. Primary immunosuppression reasons were solid organ (63%) or hematopoietic cell transplant (29%). Seventeen and 21 subjects were in the LD and NLD groups, respectively. Median time-to-CMV eradication was 17 days (LD group) versus 13 days (NLD group), p = 0.823. Median time-to-CMV clearance was also non-significant (p = 0.505). There was no association between initial foscarnet dosing intensity and acute kidney injury, hematologic toxicity, or mortality (24% in both groups). CONCLUSIONS: These findings suggest outcomes may be sensitive to other factors and underscore the need for further studies to improve understanding of foscarnet dosing in immunosuppressed patients.

P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model.

Accumulation of amyloid-beta (Abeta) within extracellular spaces of the brain is a hallmark of Alzheimer disease (AD). In sporadic, late-onset AD, there is little evidence for increased Abeta production, suggesting that decreased elimination from the brain may contribute to elevated levels of Abeta and plaque formation. Efflux transport of Abeta across the blood-brain barrier (BBB) contributes to Abeta removal from the brain. P-glycoprotein (Pgp) is highly expressed on the luminal surface of brain capillary endothelial cells and contributes to the BBB. In Pgp-null mice, we show that [I]Abeta40 and [I]Abeta42 microinjected into the CNS clear at half the rate that they do in WT mice. When amyloid precursor protein-transgenic (APP-transgenic) mice were administered a Pgp inhibitor, Abeta levels within the brain interstitial fluid significantly increased within hours of treatment. Furthermore, APP-transgenic, Pgp-null mice had increased levels of brain Abeta and enhanced Abeta deposition compared with APP-transgenic, Pgp WT mice. These data establish a direct link between Pgp and Abeta metabolism in vivo and suggest that Pgp activity at the BBB could affect risk for developing AD as well as provide a novel diagnostic and therapeutic target.

Renal Transplant Acute Rejection with Lower Mycophenolate Mofetil Dosing and Proton Pump Inhibitors or Histamine-2 Receptor Antagonists.

BACKGROUND: Pharmacokinetic data show reduced mycophenolic acid levels in renal transplant recipients taking mycophenolate mofetil (MMF) and proton pump inhibitors (PPIs) concomitantly. This reduced exposure could increase rejection risk. The typical initial MMF dose post renal transplantation is 2 g/day, which often requires dose reduction secondary to side effects. Existing studies have not shown significant acute rejection differences for patients taking MMF-PPI versus patients taking MMF-ranitidine. OBJECTIVE: The purpose of this study was to evaluate clinical outcomes in renal transplant recipients receiving a lower MMF dose than previously studied (1.5 g/day) and either a PPI or histamine-2 receptor antagonist (H2RA). METHODS: This retrospective cohort study included adult subjects receiving a renal transplant between January 1, 2009, and June 30, 2013. Comparison groups were defined based on acid-suppressing therapy class prescribed at discharge from transplantation. The primary outcome was acute rejection incidence within 1 year posttransplantation. RESULTS: Of 728 renal transplant recipients screened, 522 were included: 183 taking a PPI and 339 taking an H2RA. There was no significant difference in acute rejection within 1 year (H2RA 19% versus PPI 14%, p=0.12) or 3 months (4% vs 5%, p=0.44, respectively) posttransplantation. Maintenance immunosuppression (MMF dose and tacrolimus troughs) was similar between groups at 3 months and 1 year. Graft and patient survivals were favorable (> 95%), and graft function at 1 year was stable and similar between groups. CONCLUSION: Despite taking lower MMF doses than previously studied, subjects on a PPI compared to an H2RA were not at increased risk of acute rejection within 1 year posttransplantation.

Pharmacology of testosterone replacement therapy preparations.

The goal of testosterone replacement therapy (TRT) is to return serum testosterone levels to within physiologic range and improve symptoms in hypogonadal men. Some of the symptoms aimed to improve upon include decreased libido, erectile dysfunction, infertility, hot flashes, depressed mood, and loss of muscle mass or hair. Clinical use of testosterone for replacement therapy began approximately 70 years ago. Over the decades, numerous preparations and formulations have been developed primarily focusing on different routes of delivery and thus pharmacokinetics (PKs). Currently the routes of delivery approved for use by the United States Food and Drug Administration encompasses buccal, nasal, subdermal, transdermal, and intramuscular (IM). Many factors must be considered when a clinician is choosing the most correct formulation for a patient. As this decision depends highly on the patient, active patient participation is important for effective selection. The aim of this review is to describe and compare all testosterone preparations currently available and approved by the United States Food and Drug Administration. Areas of focus will include pharmacology, PKs, adverse effects, and specifics related to individual delivery routes.

Impact of prophylactic versus preemptive valganciclovir on long-term renal allograft outcomes.

BACKGROUND: Both prophylactic and preemptive oral valganciclovir therapy are effective for the management of cytomegalovirus (CMV) postrenal transplantation in the short term. The long-term effect of either strategy is less well defined. METHODS: We analyzed the data on 115 adult recipients previously enrolled in a prospective randomized controlled trial of prophylaxis versus preemptive therapy for CMV. The primary outcome was a composite of freedom from acute rejection, graft loss, or death. Secondary outcomes included individual primary outcomes, posttransplant cardiovascular events, new-onset diabetes mellitus after transplantation, achievement of goal blood pressure, change in body mass index, interstitial fibrosis/tubular atrophy, and change in renal function. The analysis period was a minimum of 48-month posttransplant or a date of death or graft loss, whichever was earlier. RESULTS: The primary outcome was similar between groups (83% prophylactic vs. 81% preemptive, P=0.754). The secondary outcomes showed similarities between the prophylactic and preemptive groups. Four patients in the prophylactic group (8%) compared with none in the preemptive group (0%) died with a functioning graft, P=0.043. CONCLUSIONS: Within the limitations of sample size, our data suggest that either strategy for the management of CMV immediately after transplantation seems effective for patient and graft survival in the long term. CMV management is one of the many therapeutic strategies incorporated into a renal transplantation protocol, which often differs among institutions, and the decision as to which approach to use remains center- and resource-specific. The increased incidence of death in the prophylactic group requires further investigation.

Amyloid-beta dynamics correlate with neurological status in the injured human brain.

The amyloid-beta peptide (Abeta) plays a central pathophysiological role in Alzheimer's disease, but little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human brain. We used intracerebral microdialysis to obtain serial brain interstitial fluid (ISF) samples in 18 patients who were undergoing invasive intracranial monitoring after acute brain injury. We found a strong positive correlation between changes in brain ISF Abeta concentrations and neurological status, with Abeta concentrations increasing as neurological status improved and falling when neurological status declined. Brain ISF Abeta concentrations were also lower when other cerebral physiological and metabolic abnormalities reflected depressed neuronal function. Such dynamics fit well with the hypothesis that neuronal activity regulates extracellular Abeta concentration.

Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans.

OBJECTIVES: Amyloid-beta(42) (Abeta(42)) appears central to Alzheimer's disease (AD) pathogenesis and is a major component of amyloid plaques. Mean cerebrospinal fluid (CSF) Abeta(42) is decreased in dementia of the Alzheimer's type. This decrease may reflect plaques acting as an Abeta(42) "sink," hindering transport of soluble Abeta(42) between brain and CSF. We investigated this hypothesis. METHODS: We compared the in vivo brain amyloid load (via positron emission tomography imaging of the amyloid-binding agent, Pittsburgh Compound-B [PIB]) with CSF Abeta(42) and other measures (via enzyme-linked immunosorbent assay) in clinically characterized research subjects. RESULTS: Subjects fell into two nonoverlapping groups: those with positive PIB binding had the lowest CSF Abeta(42) level, and those with negative PIB binding had the highest CSF Abeta(42) level. No relation was observed between PIB binding and CSF Abeta(40), tau, phospho-tau(181), plasma Abeta(40), or plasma Abeta(42). Importantly, PIB binding and CSF Abeta(42) did not consistently correspond with clinical diagnosis; three cognitively normal subjects were PIB-positive with low CSF Abeta(42), suggesting the presence of amyloid in the absence of cognitive impairment (ie, preclinical AD). INTERPRETATION: These observations suggest that brain amyloid deposition results in low CSF Abeta(42), and that amyloid imaging and CSF Abeta(42) may potentially serve as antecedent biomarkers of (preclinical) AD.

The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice.

Apolipoprotein E (apoE), a chaperone for the amyloid beta (Abeta) peptide, regulates the deposition and structure of Abeta that deposits in the brain in Alzheimer disease (AD). The primary apoE receptor that regulates levels of apoE in the brain is unknown. We report that the low density lipoprotein receptor (LDLR) regulates the cellular uptake and central nervous system levels of astrocyte-derived apoE. Cells lacking LDLR were unable to appreciably endocytose astrocyte-secreted apoE-containing lipoprotein particles. Moreover, cells overexpressing LDLR showed a dramatic increase in apoE endocytosis and degradation. We also found that LDLR knock-out (Ldlr-/-) mice had a significant, approximately 50% increase in the level of apoE in the cerebrospinal fluid and extracellular pools of the brain. However, when the PDAPP mouse model of AD was bred onto an Ldlr-/- background, we did not observe a significant change in brain Abeta levels either before or after the onset of Abeta deposition. Interestingly, human APOE3 or APOE4 (but not APOE2) knock-in mice bred on an Ldlr-/- background had a 210% and 380% increase, respectively, in the level of apoE in cerebrospinal fluid. These results demonstrate that central nervous system levels of both human and murine apoE are directly regulated by LDLR. Although the increase in murine apoE caused by LDLR deficiency was not sufficient to affect Abeta levels or deposition by 10 months of age in PDAPP mice, it remains a possibility that the increase in human apoE3 and apoE4 levels caused by LDLR deficiency will affect this process and could hold promise for therapeutic targets in AD.