SOT7_ID_57 (1).pptx

Solid Organ Transplantati on Infections in Transplantati on Yasar Tasnif, PharmD, BCPS, FAST Associate Professor of Practice | UTEP School of Pharmacy Transplant Case HPI: JG is a 55-year-old Hispanic male, 5’6” and 81kg. He is on the transplant waitlist for a kidney. Today, the local organ procur...

Solid Organ Transplantati on Infections in Transplantati on Yasar Tasnif, PharmD, BCPS, FAST Associate Professor of Practice | UTEP School of Pharmacy Transplant Case HPI: JG is a 55-year-old Hispanic male, 5’6” and 81kg. He is on the transplant waitlist for a kidney. Today, the local organ procurement agency notifies the transplant team of a potential kidney donor. The donor is a 19 y/o, otherwise healthy male, who died in a car crash. He had no significant medical history (e.g., kidney or cardiovascular disease). The donor died in the area, and the kidney will have a minimal cold ischemia time since it is being procured locally. The crossmatch is negative, and JG has a PRA of 25%. The transplant surgeon and nephrologist reviewed the case and evaluated the recipient and donor. Based on the information given, they accept the organ for JG. Based on JG’s PRA, they determine him to be of moderate immunological risk. PMH: JG has a history of type 2 diabetes mellitus (currently controlled with a pre-transplant A1C of 5.9%) and end-stage renal disease. He is receiving 3x weekly hemodialysis. SH: Non-contributory. Transplant Case Transplant Case What anti-viral prophylaxis would you choose for this patient? • Valganciclovir • Valacyclovir • None What medications from the patient’s previous regimen would you continue, and which would you add? • Insulin glargine 20 units SubQ QHS; Insulin aspartate 10 TiD SubQ with Meals; Lisinopril 10mg PO daily; Carvedilol 6.25mg PO BID; Aspirin 81mg PO daily; Sevelamer 1600mg PO with meals • Insulin regimen to be determined; Lisinopril 10mg PO daily; Carvedilol 6.25mg PO BID; Aspirin 81mg PO daily; stop Sevelamer • Insulin regimen to be determined; Carvedilol dose to be determined; Aspirin 81mg PO daily; stop Sevelamer and hold lisinopril for now • Insulin regimen to be determined; Carvedilol dose to be Objectives • Recognize the common infections in transplant patients • • • • Bacterial Fungal Viral Opportunistic diseases • Understand the prophylaxis and Treatment regimens for these diseases Post-Transplant Complications • Vascular complications • Bleeding • Infections • Rejection • Adverse reactions • Disease recurrence Quiroga et. al. Radiographics. 2001; 21(5): 1085-102 Akbar et. al. Radiographics. 2005; 25(5): 1335-56 Immunosuppression https://www.sciencedirect.com/science/article/abs/pii/S0196439916300599 Overview of Infections • Common Viral infections • Cytomegalovirus (CMV) • BK Virus • Epstein Bar Virus (EBV) • Common Bacterial Infections • Skin and soft tissue • UTIs • Common Fungal Infections • Oral/Muco-Candidiasis • Opportunistic Diseases • PJP/PCP; Nocardiosis; Toxoplasmosis Infections Post-Transplant HSV – Herpes simplex virus CMV – Cytomegalovirus EBV – Epstein–Barr virus VZV – Varicella (Herpes) Zoster virus Papovaviruses – (BK and JC) TB – Tuberculosis • Timetable of infection after solid organ (renal) transplantation Marty, F. M., R. H. Rubin. Transpl Int. 2006; 19(1): 2-11 Incidence of Infections PostTransplant a b Data are from large studies in a variety of transplantation centers The numbers given reflect the range of the numbers found in the cited studies Patel, R., C. V. Paya. Clin Microbiol Rev. 1997 Jan;10(1):86-124 Infection Prophylaxis Infection Prophylaxis Surgical Cephalosporin (first generation +/- vancomycin, or third generation) Viral Ganciclovir, acyclovir, valganciclovir, valacyclovir Fungal Clotrimazole, nystatin, fluconazole, voriconazole Pneumocystis carinii, Listeria monocytogenes and Nocardia species TMP/SMX, pentamidine (aerosolized), dapsone, or atovaquone (G6PD deficiency) Bacterial Infections Skin and Soft Tissue Infections http://www.healthcarereportcard.illinois.gov/contents/view/ ASHP Clinical Practice Guidelines for Antimicrobial Prophylaxis in Surgery Type of Procedure Recommended Agent Alternative Agent (BLactam Allergy) Heart, lung, Heart–Lung transplantation Cefazolin Clindamycin, Vancomycin Liver transplantation Piperacillin– tazobactam, cefotaxime + ampicillin Clindamycin or vancomycin + aminoglycoside or aztreonam or fluoroquinolone Kidney Cefazolin Clindamycin or vancomycin + aminoglycoside or aztreonam or fluoroquinolone Pancreas and Pancreas– Kidney transplantation Cefazolin, Clindamycin or vancomycin + fluconazole (for aminoglycoside or aztreonam patients at high risk or fluoroquinolone of fungal infection [e.g., those with enteric drainage of the pancreas]) https://www.ashp.org/-/media/assets/policy-guidelines/docs/therapeutic-guidelines/therapeutic-guidelines* Guidelines are often updated. Refer to updated guidelines and text of article for Prophylaxis of Bacterial Infections • • • • • Transplanted organs facilitate transmission of bacterial, viral, fungal and parasitic infections Recently, estimated donor-derived infections (DDIs) in the United States occur in less than 1% of all transplant procedures Although the incidence of DDI is low, when a transmission does occur, significant morbidity and mortality can result Factors for transmission of infection by grafts are virulence, tissue tropism of the bacteria, recipient’s immune status, graft condition, clinical experience, laboratory technical support and extent of donor exposures Prophylactic treatment may begin when donor https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033458/ UTI Prophylaxis • UTI is common in the early and late period among solid organ transplant recipients • Data show that UTI was the most prevalent primary source of bacterial infection over 6 months post-transplant • Common Pathogens are E. coli, Enterococcus faecium, Klebsiella species, S. aureus, Enterobacter species, and Enterococcus faecalis • UTI are common sources of antibiotic resistant bacteria, such as ESBL producing Enterobacteriaceae, vancomycin-resistant enterococci, and methicillin-resistant staphylococci https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033458/ UTI Prophylaxis • Risk factors for UTI are age, diabetes, and longterm use of a urinary indwelling catheter • Many centers introduce prophylactic use of TMP/SMZ for the prevention of Pneumocystis jirovecii pneumonia as well as UTIs • However, UITs are considered less preventable because of the increasing rate of TMP/SMZ resistance https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033458/ Treatment of Bacterial Infections • Post-transplant bacterial infections are treated per guideline recommendation of that specific disease • Ex. Empiric MRSA bacteremia or UTIs will be treated per IDSA guidelines • Care must be taken to use recommendations for immunocompromised persons (drug, doses and duration) • Drug therapy should be streamlined when culture and sensitivity reports return (blood/urine cultures and sensitivities etc.) • Care is taken to preserve graft function if possible • Ex. Avoidance of aminoglycosides and amphotericin in kidney transplant patients to prevent nephrotoxicity to the graft • Immunosuppression is decreased to allow the body to fight the disease • 25% in mild infections, 50% in moderate, 75-100% in life- Fungal Infections Fungal Prophylaxis • Because immunosuppressed transplant recipients are at risk for mucocutaneous fungal infections, prophylactic oral or topical antifungal agents may be indicated in these patients • Use of corticosteroids also increases risk • Liver, pancreas, and small bowel transplant recipients are clearly at high risk for invasive fungal infections and should receive prophylaxis with fluconazole • Prophylaxis has also been suggested for lung and heart–lung transplant recipients due to the high incidence of invasive fungal infections in these patients Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Fungal Prophylaxis • Prophylaxis with inhaled LAMB, high-dose fluconazole, itraconazole, voriconazole and echinocandins have all been reported • However, data supporting either the general recommendation for prophylaxis or choice of specific agent are largely lacking and center-tocenter variability is great • Concentrations of immunosuppressant drugs should be monitored closely in transplant patients receiving azole-type antifungal agents • When starting AND when stopping therapy Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Anti-fungal Agents • Many centers give anti-fungal in kidney and liver transplant patient for 1 month with: • Nystatin Suspension (swish and swallow): 500,000 units 4 times/day; swish in the mouth and retain for as long as possible (several minutes) before swallowing • Fluconazole Oral: 200-400 mg given perioperatively and continued once daily postoperatively • Clotrimazole Troche: 10 mg dissolved slowly 3 times daily. • Prophylaxis is usually given when steroids are at high doses and stops when reduced to maintenance levels (ex. Prednisone Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2020; April 11, 2020. Monitoring Azole Anti-Fungal Agents • Periodic liver function tests • AST • ALT • Alkaline phosphatase • Renal function tests • CrCl >50 mL/minute: No dosage adjustment necessary for Fluconazole • CrCl ≤50 mL/minute: Reduce fluconazole dose by 50% • Potassium PCP, Nocardia and Toxoplasma PCP/PJP Pneumonia Chest radiograph on presentation: bilateral reticular markings with no pleural effusions. b) Computed tomography scan of chest (third day): diffuse bilateral ground glass opacities consistent with Pneumocystis pneumonia (PCP). https://erj.ersjournals.com/content/35/4/927 PCP/PJP Pneumonia c) Pneumocystis jirovecii (arrow) with Gömöri methenamine silver (shown in greyscale here) stain on bronchoalveolar lavage fluid (third day). d) Bone marrow analysis (ninth day): marked megakaryocytic hypoplasia. Increased monocytes and atypical lymphocytes. https://erj.ersjournals.com/content/35/4/927 PCP/PJP Pneumonia Prophylaxis Drug Dose and Comments Trimethoprim/ • Primary choice for PCP prevention. Single-strength sulfamethoxa (80/400 mg) daily or double-strength (160/800 mg) zole 3x weekly • Side effects: Rash, nausea, vomiting, neutropenia, pancytopenia, nephrotoxicity, hyperkalemia. Pentamidine • 300 mg once/month by inhalation, special equipment for aerosolization such as Respirgard II® (GE Healthcare) is required. • Should be administered in a separate room • Pre-treatment with albuterol aids in delivery of drug • Side effects: Coughing and wheezing (prn albuterol should be on hand) Dapsone • 50 mg twice daily or 100 mg daily • Side effects: Drug-related hemolytic anemia and methemoglobinemia • Should not be given to patients with G6PD deficiency Atovaquone • 1,500 mg/day with fatty food (increases https://www.researchgate.net/figure/PCP-prophylaxis-after- Nocardia asteroides appear as red-stained, long, branching filaments in a smear of a lesion (modified acidfast stain). Nocardia asteroides appear as red-stained, long, branching filaments in a smear of a lesion (modified acidfast stain). https://www.merckvetmanual.com/generalized-conditions/nocardiosis/ Lifecycle of Toxoplas ma gondii https://en.wikipedia.org/wiki/Toxoplasmosis Toxoplasmosis and Nocardia • Transplant patients, especially heart and heart and lung recipients, without serologic evidence of prior exposure to T. gondii who receive organs from seropositive donors are at high risk for toxoplasmosis. • Many of these patients will be receiving trimethoprim– sulfamethoxazole for prophylaxis of P. jiroveci infection. • This agent will also provide effective prophylaxis against T. gondii as well as N. asteroides. • Patients will often be asked to have their pets be taken care of by others during the first 6 months to 1year post transplant. • Of note, pentamidine does not provide protection against T. gondii and N. asteroides. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Viral Infections Cytomegalovirus (CMV) • CMV is a serious infection caused by a virus called cytomegalovirus (CMV). • This virus is related to the herpes viruses that cause chicken pox and mononucleosis (mono). • CMV is one of a number of infections that can develop in immunocompromised patients (opportunistic infections). • Prophylaxis with IV ganciclovir or oral valganciclovir is effective in reducing the incidence of both primary and reactivated CMV infection. • Acyclovir is less efficacious in high-risk renal transplant patients (donor positive, recipient negative for CMV serum antibodies) and other Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Cytomegalovirus (CMV) • Preemptive ganciclovir or valganciclovir (initiated after actual isolation of CMV from blood, urine, bronchoalveolar lavage fluid, or other site) is more effective than acyclovir in preventing CMV disease in liver transplant recipients. • Preemptive ganciclovir effectively prevents CMV disease in other types of solid-organ transplants as well. • Ganciclovir-related bone marrow suppression is not as problematic in solid-organ transplant recipients as in HSCT patients; most studies report that the drug is reasonably well tolerated. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Cytomegalovirus (CMV) • Whether prophylaxis or preemptive therapy is the best approach to preventing CMV disease is controversial. • Prophylaxis is effective and easy to administer without the need for careful discrimination among suitable patients. • However, universal prophylaxis results in unnecessary exposure of low-risk individuals to adverse effects of drugs, and there are concerns that prolonged exposure may increase the risk of viral resistance to drugs. • Preemptive therapy is effective and results in exposure of fewer patients to drugs. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Cytomegalovirus (CMV) • Prophylactic therapy is recommended primarily in patients at highest risk of disease (i.e., seronegative patients receiving organs from seropositive donors), whereas other lower-risk patients are often recommended to receive only preemptive therapy. • However, the risk of CMV infection and disease in lung transplant recipients is so high and is associated with such severe consequences (i.e., chronic graft dysfunction, decreased survival) that prophylaxis is routinely recommended for all lung transplant recipients. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Valganciclovir vs. Ganciclovir • Oral valganciclovir is rapidly absorbed and hydrolyzed to ganciclovir. • The oral bioavailability of ganciclovir after oral valganciclovir administration is high. • Oral valganciclovir 900 mg provides a daily exposure of ganciclovir comparable to that of intravenous ganciclovir 5 mg/kg. • Oral valganciclovir may be suitable in many circumstances currently requiring intravenous ganciclovir, allowing for more convenience. https://www.uptodate.com/contents/ganciclovir-and-valganciclovir-an- CMV Universal Prophylaxis Fishman, JA. Infection in Organ Transplantation. Am J Transplant 2017; 17: Valganciclovir Dosage Adjustment • Maintenance/prevention dose: • CrCl ≥60 mL/minute: No dosage adjustment necessary • CrCl 40 to 59 mL/minute: 450 mg once daily • CrCl 25 to 39 mL/minute: 450 mg every 2 days • CrCl 10 to 24 mL/minute: 450 mg twice weekly • CrCl <10 mL/minute: • Manufacturer labeling: Use not recommended; ganciclovir (with appropriately specified renal dosage adjustment) should be used instead of valganciclovir. BK Virus • Polyomaviruses are a growing family of common, small, nonenveloped, doublestranded DNA viruses that infect multiple species including humans • BK polyomavirus (BKPyV) infection: In renal transplant recipients, BKPyV is associated with viruria and viremia, ureteric ulceration and stenosis, and polyomavirus-associated nephropathy Fishman, JA. Infection in Organ Transplantation. Am J Transplant 2017; 17: BK Virus • There is no accepted treatment other than reduction in the intensity of immune suppression for those with sustained viral loads. • It is reasonable, and controversial, to reduce dosing of both calcineurin inhibitors and antimetabolites in a stepwise fashion (25–50% per step) to allow anti-BK T cell activity while monitoring BKV plasma loads. • Some centers use cidofovir for BK nephropathy in low doses (0.25–1 mg/kg every 2 weeks). • Significant renal toxicity is common with cidofovir; lipid-conjugated cidofovir is under study for this indication. • Leflunomide, an agent with some antiviral Fishman, JA. Infection in Organ Transplantation. Am J Transplant 2017; 17: Epstein Bar Virus (EBV) • EBV is a gamma herpesvirus • In immunocompetent individuals, infection presents as a childhood febrile respiratory illness or as infectious mononucleosis of young adults • After transplantation, EBV seronegative individuals are at risk for primary infection, which is associated with greatly increased risk of PTLD Fishman, JA. Infection in Organ Transplantation. Am J Transplant 2017; 17: Epstein Bar Virus (EBV) • There are insufficient data to support routine use of antiviral prophylaxis in the donor positive, recipient negative population • Reduction in the intensity of immunosuppression risks rejection • Viremic patients are candidates for reduction in immunosuppression; failure to clear viremia should raise concerns for PTLD • Insufficient data exist to support routine use of antivirals, anti-B cell therapies, or adoptive immunotherapy in such individuals Fishman, JA. Infection in Organ Transplantation. Am J Transplant 2017; 17: Transplant Case HPI: JG is a 55-year-old Hispanic male, 5’6” and 81kg. He is on the transplant waitlist for a kidney. Today, the local organ procurement agency notifies the transplant team of a potential kidney donor. The donor is a 19 y/o, otherwise healthy male, who died in a car crash. He had no significant medical history (e.g., kidney or cardiovascular disease). The donor died in the area, and the kidney will have a minimal cold ischemia time since it is being procured locally. The crossmatch is negative, and JG has a PRA of 25%. The transplant surgeon and nephrologist reviewed the case and evaluated the recipient and donor. Based on the information given, they accept the organ for JG. Based on JG’s PRA, they determine him to be of moderate immunological risk. PMH: JG has a history of type 2 diabetes mellitus (currently controlled with a pre-transplant A1C of 5.9%) and end-stage renal disease. He is receiving 3x weekly hemodialysis. SH: Non-contributory. Transplant Case Transplant Case What anti-viral prophylaxis would you choose for this patient? • Valganciclovir; Patient is a CMV mismatch (D+/R-) therefore at high risk of infection What medications from the patient’s previous regimen would you continue, and which would you add? • Insulin glargine 20 units SubQ QHS; Insulin aspartate 10 TiD SubQ with Meals; Lisinopril 10mg PO daily; Carvedilol 6.25mg PO BID; Aspirin 81mg PO daily; Sevelamer 1600mg PO with meals • Insulin regimen to be determined; Lisinopril 10mg PO daily; Carvedilol 6.25mg PO BID; Aspirin 81mg PO daily; stop Sevelamer • Insulin regimen to be determined; Carvedilol dose to be determined; Aspirin 81mg PO daily; stop Sevelamer and hold lisinopril for now; missing statin • Insulin regimen to be determined; Carvedilol dose to be determined; Aspirin 81mg PO daily; stop Sevelamer and hold lisinopril for now; add on a statin since patient has a ASCVD Question s • Please contact me at: [email protected] u