Perioperative daptomycin for prophylaxis of vancomycin-resistant Enterococcus infection in colonized liver transplant recipients.

BACKGROUND: Infection with vancomycin-resistant Enterococcus (VRE) in liver transplant recipients (LTR) has been associated with extended hospital stays, increased readmission rates, graft failure, and death. A tailored perioperative surgical prophylaxis regimen targeting VRE may reduce postoperative infections in VRE-colonized patients. This study investigated the outcomes of perioperative daptomycin in this patient population. METHODS: This retrospective, single-center cohort study included LTR ≥ 18 years old who were VRE-colonized from June 2018 to November 2022. VRE colonization was identified by a VRE rectal swab screen or a positive VRE culture prior to transplant. Two groups were analyzed: daptomycin versus no daptomycin. All LTR received perioperative piperacillin-tazobactam for 24 h. If VRE-colonized, one dose of daptomycin (6 mg/kg) was given pre- and postoperatively. Demographics, clinical characteristics, risk factors for VRE infection, and daptomycin dose were collected. The primary outcome was VRE infection at 14 days and 90 days post-transplant. RESULTS: There were 36 VRE-colonized LTR; 19 received daptomycin and 17 did not. Baseline characteristics and risk factors for VRE infection were similar between groups. More VRE infections occurred in the no daptomycin group within 14 days post-transplant (24% vs. 0%, p = .04), but at 90 days posttransplant there was no significant difference (29% vs. 16%, p = .43). The average daptomycin dose was 7.1 mg/kg. CONCLUSION: Perioperative daptomycin reduced the rate of VRE infections in VRE-colonized LTR within 14 days posttransplant but not at 90 days. Future studies should evaluate if higher doses and/or longer duration of perioperative daptomycin can reduce VRE infections beyond 14 days post-transplant.

Improved Medication Adherence with the Use of Extended-Release Tacrolimus in Liver Transplant Recipients: A Pilot Randomized Controlled Trial.

Background: Nonadherence to immunosuppression in liver transplant recipients (LTRs) leads to deterioration in health outcomes. Once-dailyextended-release tacrolimus (TAC-ER) may improve adherence when compared to twice-dailyimmediate-release tacrolimus (TAC-IR). Methods: We conducted a randomized controlled study to evaluate medication adherence, clinical efficacy, and safety of TAC-ER in stable LTR. All patients >18 years who underwent liver transplantation before 6 months were eligible. Patients were randomized 1 : 1 to continued TAC-IR or conversion to TAC-ER. The primary outcome was change in medication adherence from baseline to 9 months, assessed using BAASIS. Secondary outcomes were tacrolimus trough levels, safety, and quality of life. Results: Thirty-one patients were consented and randomized to either of the two groups: conversion to TAC-ER (n = 15) or continued TAC-IR (n = 16). Six patients in the TAC-ER group withdrew after randomization due to apprehension about switching medication (n = 2), unwillingness to travel (n = 2), and increased liver tests after conversion (n = 2, both were acute rejections despite therapeutic tacrolimus levels and were considered unrelated to TAC-ER). We compared the results of nine patients in the TAC-ER group that completed the study with those of sixteen in the TAC-IR group. At baseline, there was no difference in tacrolimus trough levels between groups. Improved adherence was observed in the TAC-ER group as 100% of patients reported at least one period of full adherence during the study period (100% vs. 62.6%, p = 0.035). Tacrolimus trough levels and liver tests were comparable between groups throughout the study. There were no differences in eGFR, HbA1c, or QoL between the groups. Conclusion: TAC-ER improved medication adherence while maintaining comparable trough levels, liver function, and QoL as TAC-IR in LTR.

Impact of Removing the Race Coefficient in Renal Function Estimate Equations on Drug Dosage Recommendations.

BACKGROUND: The appropriateness of including the race coefficient in glomerular filtration rate (GFR) equations in Black patients is debated, and the impact on drug dosing is unknown. OBJECTIVE: This study explored the impact of removing the race coefficient on drug dosing in Black patients in comparison to conventional methods. METHODS: This was a retrospective study of hospitalized patients who self-identified as Black/African American and were prescribed an antimicrobial that includes renal dosage recommendations in the product labeling. The primary end point was the discordance between drug dosing recommendations derived by body surface area deindexed GFR estimated by the CKD-EPI equation (Chronic Kidney Disease Epidemiology study) with and without race versus recommendations derived from Cockcroft-Gault (CG). RESULTS: A total of 210 Black patients were included. There was an 18% rate of discordance when GFR was estimated with the race coefficient (GFR w/Race) versus without the race coefficient (GFR w/out Race). GFR w/out Race had a higher level of agreement with dosing by creatinine clearance (CrCl; κ = 0.779) than GFR w/Race versus CrCl (κ = 0.651). GFR w/out Race had less within-patient difference than GFR w/Race in comparison to CrCl (mean difference: -6.3 vs -18.0 mL/min). CONCLUSIONS AND RELEVANCE: This represents the first report to examine the removal of the race coefficient and its implication on drug dose discordance. GFR w/out Race had a higher level of agreement and less drug dose discordance than GFR w/Race, in comparison to CrCl estimates. If GFR equations are considered comparable to CrCl for the purposes of guiding drug dosing, GFR w/out Race should be considered.

Evaluating Factors Associated With Blood Pressure Control in the Early Post-Kidney Transplant Period.

Background: Shortened allograft survival, and cardiovascular morbidity and mortality are consequences of inadequate control of hypertension for kidney transplant recipients (KTRs). Literature suggests the risk is multifactorial, although few studies have evaluated risk factors in relation to guideline recommended blood pressure (BP) goals in the early post-kidney transplant period. This study will elucidate factors associated with controlled BP in KTRs. Methods: Adult KTRs who were transplanted between January 1, 2013, and October 31, 2018, were evaluated. Coprimary outcomes included the proportion of patients who had controlled BP at postoperative day (POD) 30 and identification of the covariates associated with controlled BP at POD 30. Additional outcomes included the proportion of patients who had controlled BP at POD 60 and 90; the difference in the average number of antihypertensive medications taken pretransplant vs POD 30, 60, and 90 for patients with controlled BP at POD 30; antihypertensive use rates pretransplant vs POD 30 and 90; and class of antihypertensive used pretransplant vs POD 30 and 90. Results: At POD 30, 44% (100/226) of patients had controlled BP. The proportion of patients with controlled BP at POD 60 and 90 were 37% (82/220) and 40% (79/196), respectively. In bivariate analyses, lack of recipient hypertension (75% vs 42.5%, P = .04); fewer days on dialysis (1684 vs 2189 days, P = .005); absence of delayed graft function (51.2% vs 35.6%, P = .02); younger donor age (30 vs 40 years, P < .001); absence of donor hypertension (46.9% vs 29.3%, P = .004); and a lower median kidney donor profile index (29% vs 40%, P = .03) were associated with controlled BP at POD 30. In a multivariate analysis, donor age was independently associated with controlled BP at POD 30 (P = .03). Conclusions: This study suggests that younger donor age is associated with controlled BP, and conversely, older donor age is associated with uncontrolled BP in KTRs in the early post-kidney transplant period. Patients receiving a graft from older donors should have their BP closely monitored.

Impact of Clotrimazole Fungal Prophylaxis on Tacrolimus Exposure in Kidney Transplant Recipients: A Retrospective Study.

Tacrolimus, an immunosuppressant prescribed to reduce the risk of organ rejection, is metabolized by cytochrome P450 and is a substrate for P-glycoprotein. Many medications affect tacrolimus concentrations, making it difficult to maintain exposure within its narrow therapeutic index. Clotrimazole troches, prescribed to posttransplant recipients immediately for the first 30 days for oral candidiasis prevention, are considered nonsystemic. However, data suggest a potential drug interaction, affecting tacrolimus exposure. To assess the magnitude of the effect of clotrimazole on tacrolimus trough levels, 97 kidney transplant recipients, on a stable dose of tacrolimus, were retrospectively evaluated. Tacrolimus trough concentrations were analyzed 7 and 14 days before and after discontinuation of clotrimazole. The median change in tacrolimus trough level was -1.3 ng/mL (confidence interval, -2.5, -1.0; P < .001) at day 7 and -2.8 ng/mL (confidence interval, -3.3, -1.6; P < .001) at day 14 after clotrimazole discontinuation, from a median baseline of 8.9 ng/mL. Overall, a reduction in tacrolimus level was observed in 60% of patients after discontinuation of clotrimazole. When assessing the effect of race and sex, no influence was found on the degree of change in tacrolimus level after clotrimazole discontinuation. In conclusion, clotrimazole exerts a significant interaction on tacrolimus where close monitoring of tacrolimus trough levels after discontinuation of clotrimazole is warranted.

A single dose of pre-operative pregabalin reduces post-operative opioid use after orthotopic liver transplantation.

Multimodal pain management strategies including pregabalin (PGB) have been shown to reduce pain and opioid use after many types of surgeries. This was a single-center, retrospective study aimed to determine whether a single pre-operative dose of PGB reduces opioid requirements and post-operative pain after orthotopic liver transplantation (OLT). Outcomes included the mean morphine milligram equivalents used; the proportion of patients with no pain documented; and the maximum level of pain documented within the first 24h and in the 24-72h following OLT. A total of 44 patients received PGB vs 57 who received standard of care. Baseline demographics were comparable between groups. Patients who received PGB required 70% and 54% less opioids within the first 24h and subsequent 24-72h post-OLT, respectively (p-values < .001). In the first 24h post-OLT, there were more patients with no documented pain, and fewer with severe pain in the PGB group, but these were not significant. A greater proportion in the PGB group reported a maximum of mild pain (p = .039). This study demonstrated that a single dose of pre-operative PGB significantly reduced opioid use in the first 72 h after OLT. Larger studies will help determine the safety and efficacy of PGB in this setting.

Tocilizumab in patients with severe COVID-19: A single-center observational analysis.

Patients with coronavirus disease 2019 (COVID-19) may develop severe respiratory distress, thought to be mediated by cytokine release. Elevated proinflammatory markers have been associated with disease severity. Tocilizumab, an interleukin-6 receptor antagonist, may be beneficial for severe COVID-19, when cytokine storm is suspected. This is a retrospective single-center analysis of the records of patients diagnosed with COVID-19 who received tocilizumab. Outcomes, including clinical improvement, mortality and changes in oxygen-support at 24, 48, and 72 hours, and 7, 14, and 28 days post-tocilizumab, are reported. Patients were evaluated by baseline pre-tocilizumab oxygenation status and changes in proinflammatory markers within 7 days post-tocilizumab are reported. Sixty-six patients received tocilizumab at a mean dose of 724 mg (7.4 mg/kg), 3.7 days from admission. At baseline, 53% of patients were on ventilation support and all had elevated proinflammatory markers, including c-reactive protein (CRP). Common comorbidities were diabetes mellitus (43%) and hypertension (74%). Most patients received concomitant glucocorticoids and hydroxychloroquine. Seven days after tocilizumab, ten patients (15.2%) had clinical improvement in their oxygenation status, and there was a 95% decrease in CRP. Within 14 days of treatment, 29% of patients had clinical improvement, 20% had minimal or no improvement, 17% worsened, 27% died, and 7% were transferred to an outside hospital. Ultimately, 42% of all patients that received tocilizumab expired and 49% were discharged. This study found limited clinical improvement in patients that received tocilizumab in the setting of severe COVID-19. Clinical trials are ongoing to further evaluate tocilizumab's benefit in this patient population.

De Novo Thrombotic Microangiopathy Immediately After Kidney Transplant in Patients Without Apparent Risk Factors.

Thrombotic microangiopathy refers to a spectrum of conditions that share a common underlying pathologic mechanism that result in endothelial damage and microangiopathic hemolytic anemia. De novo thrombotic microangiopathy after kidney transplant is often triggered by immunosuppressive drugs, and studies most often implicate calcineurin inhibitors and/or mammalian target of rapamycin inhibitors; however, muromonab and alemtuzumab also reportedly cause thrombotic microangiopathy. In addition, thrombotic microangiopathy may be triggered by acute antibody-mediated rejection and infections like cytomegalovirus and parvovirus. Here, we present a case series of 3 patients without any apparent risk factors (eg, acute antibody-mediated rejection) who developed de novo thrombotic microangiopathy immediately following kidney transplant, but before the introduction of calcineurin inhibitors. Two of these 3 patients were successfully managed with plasma exchange, and calcineurin inhibitors were successfully introduced without the recurrence of thrombotic microangiopathy.

Severe Interferon/Ribavirin-Induced Hyperuricemia and Urate Nephropathy Requiring Rasburicase and Hemodialysis in a Liver Transplant Recipient.

INTRODUCTION: Hyperuricemia caused by pegylated-interferon-α2a and ribavirin therapy has been rarely reported. We report a case of severe hyperuricemia and urate nephropathy in a liver transplant recipient with recurrent hepatitis C, which required discontinuation of therapy, rasburicase, and hemo-dialysis. CASE REPORT: A 64-year-old female liver transplant recipient was begun on treatment of fibrosis cholestatic hepatitis with pegylated-interferon-α2a and ribavirin therapy. She received a one-time dose of pegylated-interferon-α2a 135 mcg subcutaneously, and ribavirin was initiated. Within 24 hours of treatment initiation, she developed an acute kidney injury with serum creatinine increased from a baseline 132.6 µmol/L (1.5 mg/dL) to 459.7 µmol/L (5.2 mg/dL) within 72 hours. Ultrasound and computed tomography of the kidneys were normal with no stones and urinalysis showed no crystals. Her ribavirin dosage was adjusted based on her changing renal function. Within 72 hours after treatment initiation, her serum uric acid level was 1392 µmol/L (23.4 mg/dL), for which she received rasburicase 3 mg intravenously. Ribavirin was discontinued at this time. The next day, her serum uric acid level and remained elevated at 1166 µmol/L (19.6 mg/dL) and she received a second dose of rasburicase 7.5 mg and hemodialysis. Her serum uric acid level decreased to 131 µmol/L (2.2 mg/dL) and remained within normal limits; however, she continued to require intermittent hemodialysis until she died from complications of sepsis 38 days after admission. After discontinuation, she was not rechallenged with pegylated-interferon-α2a /and ribavirin. CONCLUSIONS: A liver transplant recipient with recurrent hepatitis C developed severe hyperuricemia and urate nephropathy shortly after receiving pegylated-interferon-α2a and ribavirin therapy. The patient's hyperuricemia was managed with rasbu-ricase and hemodialysis. This rare but potentially serious adverse reaction can limit the use of these agents in patients with recurrence of life threatening hepatitis C after liver transplant.

Concomitant proton pump inhibitors with mycophenolate mofetil and the risk of rejection in kidney transplant recipients.

BACKGROUND: Recent pharmacokinetic studies have demonstrated that proton pump inhibitors (PPI) reduce exposure of mycophenolic acid. However, the clinical significance of this drug-drug interaction on transplantation outcomes has not been determined. METHODS: This was a retrospective cohort study in kidney transplant recipients who were prescribed rabbit antithymocyte globulin, calcineurin inhibitor, mycophenolate mofetil, and steroids. We evaluated the impact of PPI use on the 1-year rates of biopsy-proven acute rejection (BPAR). RESULTS: Two hundred thirteen patients who were prescribed PPI were compared with 384 patients who were on standard acid-suppressive therapy with ranitidine. BPAR occurred in similar rates in both groups (15% vs. 12%; P=0.31). In a multivariable analysis, black race was associated with a higher risk of rejection (risk ratio [RR], 2.38; 95% confidence interval [CI], 1.41-4.03). While controlling for rejection risk factors, PPI exposure was associated with an increased risk of rejection in black patients (RR, 1.93; 95% CI, 1.18-3.16) but not in non-black patients (RR, 0.54; 95% CI, 0.19-1.49). At 1 year, BPAR type, BPAR grade, patient and graft survival, graft function, and time to BPAR were not associated with PPI exposure. CONCLUSION: In this retrospective study, PPI use in the first transplant year was associated with an increased risk for BPAR in black patients but not in non-black patients. It is possible that a reduction in mycophenolic acid exposure contributed to the increased risk.

Evaluating safety and efficacy of rabbit antithymocyte globulin induction in elderly kidney transplant recipients.

OBJECTIVES: The optimal immunosuppression regimen for elderly kidney transplant recipients is poorly defined. We sought to evaluate the short-term efficacy and safety of thymoglobulin in geriatric recipients of deceased-donor kidneys. MATERIALS AND METHODS: A single-center, retrospective analysis was undertaken between elderly (≥ 65 years) (n=137) and nonelderly (n=276) kidney transplant recipients who received rabbit antithymocyte globulin induction and calcineurin inhibitor, mycophenolic acid, and prednisone maintenance. RESULTS: The mean age was 70 versus 52 years. Fewer elderly patients had an earlier transplant or panel reactive antibodies > 20%, but had more machine perfused, older, and extended criteria donor kidneys. Elderly patients received lower rabbit antithymocyte globulin (5.4 vs 5.6 mg/kg; P = .04) and initial mycophenolic acid doses (1620 vs 1774 mg; P = .002), and experienced less delayed graft function (31.1% vs 50.0%; P < .001). Death-censored graft survival and graft function at 3 years and biopsy-proven acute rejection at 1 year were comparable; however, there was lower 3-year patient survival in elderly patients. Donor age was the only factor associated with reduced patient survival. Rates of malignancy, infection, or thrombocytopenia were similar; however, leukopenia occurred less frequently in elderly patients (11.7% vs 19.9%; P = .038). CONCLUSIONS: Elderly kidney transplant recipients receiving rabbit antithymocyte globulin did not experience different short-term graft survival, graft function or rates of infection, malignancy or hematologic adverse reactions than did nonelderly patients; they experienced fewer episodes of delayed graft function, but had lower 3-year patient survival.

Metronidazole-induced encephalopathy in a patient with end-stage liver disease.

Purpose. Metronidazole-induced encephalopathy (MIE) has been rarely reported. We report a case in a patient with end-stage liver disease (ESLD). Summary. A 63-year-old male with ESLD secondary to hepatitis C virus presented with progressively worsening fatigue, slurred speech, aphasia, vomiting, and left-sided facial droop after completing a 2-week course of metronidazole for recurrent Clostridium difficile-associated diarrhea. He completed a previous course of metronidazole 3 weeks prior to presentation. He is on the liver transplant waiting list and has known hepatic encephalopathy. MRI revealed hyperintense T2 signals involving the bilateral dentate nuclei, inferior colliculi and splenium of the corpus callosum, and increased diffusion restriction at the splenium of the corpus callosum. His neurological function improved over the next several days. He underwent liver transplantation 6 days after admission. A follow-up MRI 6 weeks after presentation revealed resolution of abnormalities; however, paresthesias persisted 6 months after MIE diagnosis. Conclusion. An ESLD patient with hepatic encephalopathy developed MIE after a relatively short course of metronidazole. Metronidazole has been shown to accumulate in patients with ESLD. Increased awareness for neurotoxicity when using metronidazole in ESLD patients is warranted, especially in those with potentially confounding hepatic encephalopathy.

Falsely elevated tacrolimus levels caused by immunoassay interference secondary to beta-galactosidase antibodies in an infected liver transplant recipient.

Careful interpretation of tacrolimus levels is essential to ensure optimal immunosuppressive therapy while avoiding toxicity. Interference with tacrolimus assays may be an underreported event that has the potential to result in negative patient outcomes through unnecessary modifications of therapy. We describe a 55-year-old liver transplant recipient who had falsely elevated tacrolimus levels that led to the eventual disruption of his immunosuppressive therapy and subsequent rejection of his allograft.Although his increased tacrolimus levels did not correlate with clinical signs and symptoms of tacrolimus toxicity, interruption of therapy in this patient was supported by an acute infection and a slight elevation in serum creatinine concentration. Tacrolimus levels were analyzed by using an antibody conjugated magnetic immunoassay method, and levels as high as 79.7 ng/ml were observed, despite discontinuation of tacrolimus. We conducted an evaluation for assay interference by using an alternative assay method(microparticle enzyme immunoassay), by testing plasma samples that were not hemolyzed, and by analyzing levels of an unrelated drug that uses the same technology as the initial tacrolimus assay. beta-galactosidase antibodies were ultimately confirmed as the cause of the immunoassay interference. Inpatients receiving tacrolimus, spuriously high tacrolimus levels should be carefully evaluated, and drastic adjustments to therapy should be made only within the context of clinical toxicity.

Ciprofloxacin-induced Q-T interval prolongation.

PURPOSE: A case of Q-T interval prolongation in a pediatric patient with no known risk factors for the development of a long Q-T syndrome is reported. SUMMARY: A 16-year-old boy arrived at a children's hospital reporting mucous diarrhea that had lasted two weeks, light-headedness with two blackouts on the day before his arrival to the hospital, and a 4.3-kg weight loss over the previous three weeks. He had a 3.5-year history of Crohn's disease and had been hospitalized for two months with a diagnosis of colitis with cryptitis. He was admitted for the treatment of an acute flare of Crohn's disease and a perirectal abscess. The patient was started on i.v. ciprofloxacin 400 mg twice daily and metronidazole 500 mg every six hours. The selected agents provided adequate empirical coverage of the suspected organisms and would not be contraindicated with the patient's allergy to penicillin. Within 48 hours of administration of ciprofloxacin, the patient became bradycardic. The cardiology service was consulted, and an electrocardiogram showed a mildly prolonged Q-T interval (corrected Q-T interval, 486 msec) and low heart rate (42 beats/min). Antimicrobial therapy was changed to ampicillin and then to linezolid. The patient's Q-T interval normalized within seven days of ciprofloxacin discontinuation. The patient had no further cardiac anomalies. Two weeks later, he was discharged on linezolid and aztreonam for the treatment of his abscess and was responding to treatment. CONCLUSION: A pediatric patient with Crohn's disease and colitis with cryptitis developed a prolonged Q-T interval within 48 hours of treatment with ciprofloxacin.