›Ganciclovir IV for severe or tissue-invasive disease, or when oral absorption is unreliable
›5 mg/kg IV every 12 hours for induction in normal renal function
›Dose reduced per creatinine clearance
›Neutropenia is the dose-limiting toxicity, monitor CBC twice weekly during induction
›Verify against current pediatric guideline before use in a pediatric recipient
›Foscarnet IV for ganciclovir-resistant disease or significant myelosuppression precluding ganciclovir
›60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours
›Requires vigorous IV hydration and infusion over at least 1 hour
›Monitor calcium, magnesium, and phosphate, hypocalcemia and hypomagnesemia are common and can precipitate seizures and QT prolongation, obtain an ECG when significant electrolyte derangement is found
›Cidofovir IV as a further alternative for multidrug-resistant CMV
›Requires concurrent probenecid and IV saline hydration to reduce nephrotoxicity
›Nephrotoxicity is dose-limiting, monitor renal function closely
›Pneumocystis jirovecii pneumonia
›Trimethoprim-sulfamethoxazole IV or PO, first line
›TMP component 15 to 20 mg/kg/day divided every 6 to 8 hours
›Renal dose adjustment per creatinine clearance
›Monitor potassium mmol/L and creatinine, hyperkalemia is common
›Adjunct corticosteroids for moderate to severe disease
›If PaO2 < 70 mmHg on room air or A-a gradient significantly widened, prednisone 40 mg PO twice daily days 1 to 5
›Prednisone 40 mg PO daily days 6 to 10
›Prednisone 20 mg PO daily days 11 to 21
›Alternatives for TMP-SMX intolerance or allergy
›Clindamycin plus primaquine, exclude G6PD deficiency before primaquine
›IV pentamidine, monitor glucose and QT interval, hypoglycemia and torsades de pointes are recognized risks
›Atovaquone for mild disease only
›Invasive aspergillosis and other moulds
›Voriconazole, first line for aspergillosis
›6 mg/kg IV every 12 hours for the first 24 hours, then 4 mg/kg IV every 12 hours
›Oral maintenance 200 to 300 mg PO every 12 hours based on weight
›Strong CYP3A4 inhibitor, raises calcineurin inhibitor and mTOR inhibitor levels substantially, empiric CNI dose reduction with level monitoring is required at initiation
›Visual disturbances and hepatotoxicity are recognized effects, monitor liver enzymes
›Isavuconazole as an alternative with a more favorable interaction and QT profile
›Loading 200 mg IV or PO every 8 hours for 6 doses, then 200 mg once daily maintenance
›Liposomal amphotericin B for mucormycosis or when azole therapy is not tolerated
›5 to 10 mg/kg IV daily depending on the site of infection and organism
›Nephrotoxicity and electrolyte wasting are dose-limiting, monitor potassium and magnesium, and obtain an ECG if significant hypokalemia develops given arrhythmia risk
›Posaconazole as an alternative agent or for step-down/salvage therapy
›Delayed-release tablet 300 mg PO twice daily on day 1, then 300 mg once daily
›Also a strong CYP3A4 inhibitor requiring calcineurin inhibitor dose adjustment
›Nocardiosis
›Trimethoprim-sulfamethoxazole, first line for susceptible isolates
›TMP component 10 to 15 mg/kg/day divided every 6 to 12 hours for severe disease, including CNS involvement
›Combination therapy for severe or disseminated disease pending susceptibilities
›Imipenem IV plus amikacin IV as an initial combination in critically ill patients
›Linezolid PO or IV 600 mg every 12 hours as an alternative agent with good CNS penetration
›Duration is prolonged, months rather than weeks, coordinate with infectious diseases
›Listeria monocytogenes
›Ampicillin IV, first line
›2 g IV every 4 hours for meningitis or bacteremia
›Plus gentamicin IV for synergy in severe disease
›5 to 7 mg/kg IV once daily dosing strategy
›Therapeutic drug monitoring and nephrotoxicity/ototoxicity risk, compounded by concurrent calcineurin inhibitor nephrotoxicity
›Trimethoprim-sulfamethoxazole IV as an alternative for penicillin allergy
›High dose regimen per meningitis dosing, coordinate with infectious diseases
›Cephalosporins have no reliable activity against Listeria and must not be relied on as monotherapy
›Cryptococcosis
›Induction therapy for CNS or disseminated disease
›Liposomal amphotericin B IV 3 to 4 mg/kg daily
›Plus flucytosine PO 25 mg/kg every 6 hours, dose-adjusted for renal function
›Monitor CBC for cytopenias from flucytosine and renal function and electrolytes from amphotericin
›Intracranial pressure management
›If opening pressure ≥ 25 cmH2O, therapeutic CSF drainage
›Repeat drainage daily if symptoms of elevated ICP persist
›Consolidation and maintenance
›Fluconazole PO 400 to 800 mg daily for consolidation, then 200 mg daily maintenance
›Isolated pulmonary cryptococcosis without dissemination
›Fluconazole PO 400 mg daily may be sufficient, confirm absence of CNS or disseminated disease first
›Reactivation tuberculosis
›Isolation
›Airborne precautions pending rule-out
›Standard four-drug induction when active disease is confirmed or highly likely, initiated with infectious diseases and public health involvement
›Isoniazid PO 5 mg/kg daily, maximum 300 mg daily
›Rifabutin PO substituted for rifampin
›Rifampin is a strong CYP3A4 inducer that lowers calcineurin inhibitor and mTOR inhibitor levels dramatically and risks acute rejection, rifabutin has weaker induction and is preferred in transplant recipients
›Calcineurin inhibitor dose typically requires substantial increase with frequent level monitoring even on rifabutin
›Pyrazinamide PO weight-based dosing per standard regimen
›Ethambutol PO weight-based dosing per standard regimen, monitor visual acuity and color discrimination
›Latent tuberculosis treatment before or after transplant per exposure and testing history, coordinated with the transplant center
›BK virus
›No specific antiviral therapy has proven efficacy, immunosuppression reduction is the primary intervention and is a transplant team decision
›Cidofovir low dose or leflunomide used off-label in refractory nephropathy at some centers, coordinate with transplant infectious diseases
›IVIG considered as an adjunct in select refractory cases
›EBV and post-transplant lymphoproliferative disorder
›Immunosuppression reduction is first line and often produces regression of early lesions
›Rituximab for CD20-positive disease not responding to immunosuppression reduction alone
›Chemotherapy regimens for aggressive or monomorphic PTLD are directed by oncology in coordination with the transplant center
›Endemic mycoses
›Histoplasmosis, moderate to severe or disseminated disease
›Liposomal amphotericin B IV 3 to 5 mg/kg daily for induction
›Step-down to itraconazole PO once improved, with itraconazole levels monitored for absorption adequacy
›Coccidioidomycosis, severe or disseminated disease
›Liposomal amphotericin B IV for severe disease, fluconazole PO for milder disease
›Blastomycosis, severe or disseminated disease
›Liposomal amphotericin B IV for induction, itraconazole PO for step-down and mild disease
›Azoles used for endemic mycoses share the same calcineurin inhibitor interaction as azoles used for mould infection, monitor levels
Late period community and continued opportunistic risk management
›Beyond six months, low immunosuppression burden
›Manage community-acquired infections using standard immunocompetent-host regimens, adjusted only for renal and hepatic graft function
›Beyond six months, augmented immunosuppression
›Apply the one to six month opportunistic pathogen-directed therapy above if the patient has had recent pulse steroids, lymphocyte-depleting therapy, or a lapse in prophylaxis
›Troubleshooting when therapy is not working
›Persistent fever or clinical decline after 96 hours of appropriate antimicrobial therapy
›Reconsider a resistant organism and repeat cultures
›Look for an undrained source or infected device requiring removal
›Reconsider the diagnosis, PTLD and drug fever both mimic ongoing infection
›Confirm the drug is reaching adequate levels, check interacting medications and renal or hepatic dosing
Drug interactions between antimicrobials and calcineurin inhibitors
›CYP3A4 inhibitors that raise calcineurin inhibitor and mTOR inhibitor levels
›Azole antifungals (voriconazole, posaconazole, isavuconazole, fluconazole at higher doses)
›Macrolides (clarithromycin, erythromycin), azithromycin has minimal interaction and is preferred when a macrolide is needed
›Consequence if unadjusted
›Calcineurin inhibitor toxicity, nephrotoxicity, neurotoxicity, and hemolytic uremic syndrome-like microangiopathy
›Action
›Empiric calcineurin inhibitor dose reduction at the time the interacting drug is started, with trough level rechecked within days rather than waiting for the next scheduled level
›CYP3A4 inducers that lower calcineurin inhibitor and mTOR inhibitor levels
›Rifampin is the most potent, rifabutin substantially weaker and preferred when rifamycin therapy is required
›Consequence if unadjusted
›Subtherapeutic immunosuppression and acute rejection
›Action
›Anticipatory calcineurin inhibitor dose increase with frequent level monitoring
›Additive nephrotoxicity
›Aminoglycosides, amphotericin formulations, and vancomycin each add to calcineurin inhibitor nephrotoxicity
›Monitor renal function closely and avoid combinations when a safer alternative exists