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Pharmacology of Prophylactic Agents After Transplantation

Tam Khuu, PharmD, BCPS
UCLA Medical Center, Los Angeles, CA, USA

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tam khuuAntimicrobial chemoprophylaxis is becoming increasingly important in the setting of advanced immunosuppressants, extended criteria donors, and a progressively older recipient population. Common targets of antimicrobial chemoprophylaxis include; Pneumocystis, Cytomegalovirus, and various fungi.

Anti-Pneumocystis prophylaxis continues to be recommended for all transplant recipients. Duration ranges from six months to lifelong, depending upon organ type and risk factors. Trimethoprim-sulfamethoxazole (TMP/SMX) continues to be the drug of choice as it is readily available, well tolerated, and has great breadth of coverage, including toxoplasma, listeria, and many respiratory and gastrointestinal microbes. Effective TMP/SMX prophylaxis regimens vary from a single-strength tablet daily to a double strength tablet once or twice daily, two to three times weekly.1 The most common side effects of TMP/SMX include gastrointestinal upset (nausea, vomiting, loss of appetite) and rash or urticaria. Bone marrow suppression, Stevens-Johnson syndrome, hepatitis, and interstitial nephritis are also possible. TMP and SMX are metabolized by the liver and excreted via the kidneys. SMX is an inhibitor of CYP450 2C9 and will potentiate the effects of drugs such as warfarin.2 TMP inhibits renal tubular secretion of potassium and creatinine, creating laboratory abnormalities that may not be indicative of true renal function.3 However, increased half-life and/or reduced clearance of TMP/SMX in the elderly and those with reduced renal function have been shown, in which cases dose reductions may be necessary.2

Second-line agents for PCP prophylaxis include dapsone, atovaquone, and inhaled pentamidine. Dapsone is associated with hemolytic anemia and methemoglobinemia, and patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at increased risk.4 While dapsone does not contain the classic sulfonamide moiety, it does contain an arylamine group and should be avoided in patients experiencing anaphylaxis or other severe reactions to sulfonamides.5 Atovaquone is only available as a suspension and should be given with food to enhance absorption. The most common adverse effects seen with atovaquone include rash and gastrointestinal upset (diarrhea, nausea, vomiting, abdominal pain). Atovaquone is minimally metabolized and primarily excreted via feces, so dose adjustments are not generally required.6 Inhaled pentamidine therapy is usually last-line due to special administration requirements and reduced effectiveness compared to TMP/SMX and dapsone.

Cytomegalovirus (CMV) infection post-transplantation remains a pervasive concern. Oral valganciclovir (VGCV), oral ganciclovir (GCV), and intravenous GCV are the recommended agents for CMV prophylaxis. Duration of universal prophylaxis for CMV generally ranges from three months to one year.7 VGCV is the valine ester prodrug of GCV; both inhibit viral DNA synthesis. VGCV 900mg orally provides systemic exposure similar to 5mg/kg IV GCV.8 VGCV provides the benefits of increased oral bioavailability, reduced pill burden, and reduced dosing frequency over oral GCV. VGCV and GCV require dose adjustment for renal dysfunction. VGCV is not recommended in patients on hemodialysis, and GCV should be used in these patients. Furthermore, dosing in pediatric patients should never exceed the normal adult dose. VGCV and GCV are associated with diarrhea, tremor, increased serum creatinine, and may induce significant myelosuppression (anemia, thrombocytopenia, neutropenia). VGCV should be given with food to enhance absorption.8 Pharmacodynamic interactions include increased risk of seizure when used with imipenem and increased risk of myelosuppression with drugs like mycophenolate mofetil or TMP.8,9 Late-onset CMV in the setting of prolonged prophylaxis is an evolving issues that will benefit from further study.

Antifungal prophylaxis varies depending upon transplant organ and center. Heart transplant recipients with endemic fungal exposure often receive antifungal prophylaxis.10 Aspergillus infection is of particular concern in the lung transplant population, and thus voriconazole and/or amphotericin are frequently utilized in this group. Duration of prophylaxis varies widely from two weeks to lifelong.11 Amphotericin B and its various lipid formulations have a broad spectrum of activity, binding ergosterol in fungal cell membranes, altering permeability and ultimately leading to cell death.12 Inhaled amphotericin B or lipid complex amphotericin B are both used prophylactically in lung transplant recipients. Inhaled amphotericin regimens vary from 6-30mg/day of amphotericin B to 50mg lipid complex amphotericin B once weekly.11 Systemic exposure with inhaled amphotericin is limited, thus limiting the risk of nephrotoxicity. However, cough, bronchospasm, and nausea are frequently observed.13

Systemic antifungal prophylaxis with fluconazole, voriconazole, or itraconazole is also used. Azoles damage fungal cell walls by disrupting ergosterol biosynthesis.12 Voriconazole, with or without inhaled amphotericin, is often the drug of choice for aspergillus prophylaxis in lung transplant recipients. Adverse effects unique to voriconazole include transient visual changes and hallucinations, both possibly linked to elevated drug concentrations.14 Itraconazole may be used in place of voriconazole if susceptibility permits. However, itraconazole administration is limited by poor bioavailability due to its lipophilicity. Itraconazole absorption is also dependent upon formulation: capsules require food or an acidic environment to increase absorption, and thus cannot be taken with antacids, histamine-2 receptor blockers, or proton pump inhibitors. On the other hand, itraconazole suspension provides 30% greater absorption and should be taken on an empty stomach.15

Fluconazole is commonly utilized for targeted prophylaxis against dimorphic fungi such as blastomyces, histoplasma, or coccidioides in heart transplant recipients. Drug-drug interactions are of significant concern with azole antifungals. Fluconazole is a potent inhibitor of CYP2C9 and potentiates the effects of warfarin to a much greater degree than itraconazole or voriconazole. Voriconazole and itraconazole, on the other hand, inhibit CYP3A4 more than fluconazole.16

Therapeutic drug monitoring (TDM) for azole antifungals themselves (voriconazole, itraconazole) is increasingly being utilized11 to ensure adequate drug exposure. It is recommended to begin TDM once drug concentrations are at steady state, approximately two weeks after drug initiation.

Disclosure Statement: The author has no conflicts of interest to disclose.

References:

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