Impact of Tacrolimus Trough Variability on Acute Rejection Following Lung Transplantation.

BACKGROUND: Acute rejection is a risk factor for the development of chronic lung allograft dysfunction, the leading cause of morbidity and mortality in lung transplant recipients. Calcineurin inhibitors are the cornerstone of immunosuppression regimens after lung transplantation. METHODS: We retrospectively evaluated the association of tacrolimus level variability with total acute rejection score at 12 months post-transplant. Secondary outcomes included the development of chronic lung allograft dysfunction and antibody-mediated rejection at 24months post-transplant. There were 229 lung transplant recipients included. RESULTS: The mean (standard deviation) total rejection score of the cohort was 1.6 (1.7). Patients with high tacrolimus variability at 0 to 3, 3 to 6, and 6 to 12 months on average scored 0.18 (mean 1.6 vs 1.5; 95% CI): -0.3 to 0.66, P =.46), 0.14 (mean 1.7 vs 1.5; 95% CI: -0.32 to 0.6, P = .55), and 0.12 (mean 1.6 vs 1.5; 95% CI: -0.34 to 0.58, P = .62) point higher in 12-month total acute rejection scores, respectively; however, these differences were not statistically significant. The incidences of chronic lung allograft dysfunction and antibody-mediated rejection were numerically greater in the high variability group throughout certain periods; however, this was not consistent throughout all study timeframes and statistical significance was not evaluated. CONCLUSIONS: High tacrolimus variability was not associated with increased 12-month total acute rejection score. Further studies are needed to assess long-term outcomes with tacrolimus level variability.

Cytomegalovirus prevention in thoracic organ transplantation: A single-center evaluation of letermovir prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) infection is common following thoracic organ transplantation and causes substantial morbidity and mortality. Letermovir is a novel antiviral agent used off-label in this population for CMV prevention. Our goal was to understand patterns of letermovir use and effectiveness when applied for CMV prophylaxis after thoracic transplantation. METHODS: We retrospectively evaluated letermovir use among thoracic transplant recipients at an academic transplant center who initiated letermovir from January 2018 to October2019 for CMV prophylaxis. We analyzed indication, timing, and duration of prophylaxis; tolerability; and occurrence of breakthrough CMV DNAemia and disease. RESULTS: Forty-two episodes of letermovir prophylaxis occurred in 41 patients, including 37 lung and 4 heart transplant recipients. Primary prophylaxis (26/42, 61.9%) was utilized mainly due to myelosuppression (25/26, 96.2%) and was initiated a median of 315 days post-transplant (interquartile range [IQR] 125-1139 days). Sixteen episodes of secondary prophylaxis (16/42, 38.1%) were initiated a median of 695 days post-transplant (IQR 537-1156 days) due to myelosuppression (10/16, 62.5%) or prior CMV resistance (6/16, 37.5%). Median duration of letermovir prophylaxis was 282 days (IQR 131-433 days). Adverse effects required letermovir cessation in 5/42 (11.9%) episodes. Only one episode (2.4%) was complicated by clinically significant breakthrough CMV infection. Transient low-level CMV DNAemia (<450 IU/ml) occurred in 15 episodes (35.7%) but did not require letermovir cessation. CONCLUSIONS: Letermovir was well tolerated and effective during extended prophylactic courses with only one case of breakthrough CMV infection in this cohort of thoracic transplant recipients. Further prospective trials of letermovir prophylaxis in this population are warranted.

Clinical pharmacy programmatic perspectives on use of direct-acting antivirals for acquired hepatitis C infection in solid organ transplant recipients.

PURPOSE: An institutional workflow developed by clinical pharmacists for initiation of directing-acting antiviral (DAA) therapy for patients who receive solid organ transplants from hepatitis C (HCV)-positive donors is described; programmatic challenges in providing pharmaceutical care to these patients are reviewed. SUMMARY: In recent years the introduction of new oral DAAs, coupled with faster screening of donor organs for HCV infection through use of a nucleic acid test (NAT), has facilitated transplants of organs from HCV-seropositive donors to HCV-seronegative recipients. The solid organ transplant program of a North Carolina health system began performing such transplants in December 2017. In the pharmacist-developed workflow, patients are initiated on DAA therapy in the outpatient clinic setting, and clinic pharmacists are consulted regarding drug selection. Prescriptions for DAA therapy are sent to an on-site specialty pharmacy, where pharmacists and pharmacy technicians work to obtain prior authorization and, if necessary, payment assistance through manufacturer-sponsored programs. The medical team is notified at the time of patient approval to begin treatment. Pharmacists provide counseling at the time of DAA therapy initiation and follow up with patients every 2 weeks to confirm adherence. As of June 2019, about 100 transplants of HCV NAT-positive organs had been performed (approximately 50% were kidney transplants; 15%, lung transplants; 20%, heart transplants; and 15%, liver transplants). Many challenges are encountered in the process of providing pharmaceutical care to this patient population, including challenges in patient selection and counseling, overcoming financial barriers and insurance restrictions, and coordinating with an internal specialty pharmacy to ensure timely delivery of medication to patients. CONCLUSION: Within a solid organ transplantation program, clinical pharmacists and other pharmacy personnel can play vital roles in ensuring safe and effective DAA therapy for recipients of transplanted HCV NAT-positive organs.

Clinically Relevant Drug-Drug Interactions in Primary Care.

Drug interactions are common in the primary care setting and are usually predictable. Identifying the most important and clinically relevant drug interactions in primary care is essential to patient safety. Strategies for reducing the risk of drug-drug interactions include minimizing the number of drugs prescribed, re-evaluating therapy on a regular basis, considering nonpharmacologic options, monitoring for signs and symptoms of toxicity or effectiveness, adjusting dosages of medications when indicated, and adjusting administration times. Inhibition or induction of cytochrome P450 drug metabolizing isoenzymes is the most common mechanism by which clinically important drug interactions occur. The antimicrobials most likely to affect the international normalized ratio significantly in patients receiving warfarin are trimethoprim/sulfamethoxazole, metronidazole, and fluconazole. An empiric warfarin dosage reduction of 30% to 50% upon initiation of amiodarone therapy is recommended. In patients receiving amiodarone, limit dosages of simvastatin to 20 mg per day and lovastatin to 40 mg per day. Beta blockers should be tapered and discontinued several days before clonidine withdrawal to reduce the risk of rebound hypertension. Spironolactone dosages should be limited to 25 mg daily when coadministered with potassium supplements. Avoid prescribing opioid cough medicines for patients receiving benzodiazepines or other central nervous system depressants, including alcohol. Physicians should consider consultation with a clinical pharmacist when clinical circumstances require the use of drugs with interaction potential.

Gastric Mucormycosis in a Renal Transplant Patient Treated with Isavuconazole Monotherapy.

Gastrointestinal mucormycosis is a rare infection in solid organ transplant recipients. Our patient, a 79-year-old male, presented with severe dysphagia and odynophagia about 2 weeks after receiving a renal transplant. An upper gastrointestinal (UGI) endoscopy revealed esophagitis and gastric ulceration, the cultures from which grew Rhizopus species. A usual treatment strategy should include Amphotericin B as monotherapy or in combination with Posaconazole or Isavuconazole for such infections. Our patient was treated with Isavuconazole monotherapy, in an effort to minimize renal toxicity from Amphotericin B to the new allograft. Unique to our case was a successful clinical response and resolution of UGI lesions with Isavuconazole monotherapy. Due to the vagueness of presenting symptoms, such infections can be easily missed in an immunocompromised patient which can have tragic outcomes. Prompt diagnosis and modulation of immunosuppression are essential to decrease mortality and morbidity. Isavuconazole is a novel agent and can be used as a monotherapy for such infections, especially in renal transplant recipients.