Keywords

The treatment of patients with transplant-related infections requires close attention to the host in order to ensure adequate and safe dosing of anti-infective medications. Solid organ transplant recipients are at risk for synergistic toxicities due to drug–drug interactions between anti-infective agents and immunosuppressive medications. These toxicities relate to consequences of high exposures to the immunosuppressive and/or the anti-infective medication. While perhaps less frequent, the risk of inadequate anti-infective drug exposure and resulting treatment failure due to drug–drug interactions must also be avoided. This chapter presents a summary of the clinically significant drug–drug interactions encountered in providing anti-infective chemotherapy to solid organ transplant recipients.

Medications used for immunosuppression after organ transplantation can be split into seven categories (Table 4-1): polyclonal antibodies, monoclonal antibodies, calcineurin inhibitors, antimetabolites, mammalian target of rapamycin (mTOR) inhibitors, corticosteroids, and selective T-cell costimulation blockers. The reader is referred to Chap. 3 for more detailed information regarding the mechanism of action of these commonly used immunosuppressive agents. The risk of drug interactions is high, particularly within the calcineurin inhibitor and mTOR inhibitor drug classes.

Table 4-1. Immunosuppressive agents [7]
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Cyclosporine (Neoral, Sandimmune, Novartis Pharmaceuticals) and tacrolimus (Prograf, Astagraf XL, Astellas Pharmaceuticals) are calcineurin inhibitors. They suppress the immune system by blocking IL-2 signaling between immune cells. Major toxicities include electrolyte disturbances (i.e., hypophosphatemia, hypomagnesemia, hyperkalemia), hypertension, hyperlipidemia, hyperglycemia, nephrotoxicity, neurotoxicity, and others [1, 2]. Doses are adjusted to obtain target whole blood cyclosporine or tacrolimus levels and the target range is patient-specific.

Sirolimus (Rapamune, Pfizer Inc.) and everolimus (Zortress, Novartis Pharmaceuticals) are mTOR inhibitors whose actions inhibit T-cell activation and proliferation. Major toxicities include impaired wound healing, hypertriglyceridemia, hyperlipidemia, oral ulcers, proteinuria, and noninfectious pneumonitis [3–6]. Sirolimus and everolimus doses are adjusted to obtain target whole blood trough concentrations, and the target range is patient-specific. Sirolimus has a long half-life and it will take 1–2 weeks to reach steady state after initiating therapy and/or after dose changes.

Cyclosporine, tacrolimus, sirolimus, and everolimus are substrates for both cytochrome P-450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Drugs and substances that induce CYP3A4 and/or P-gp may decrease cyclosporine/tacrolimus/sirolimus/everolimus concentrations, whereas inhibitors of CYP3A4 and/or P-gp may increase cyclosporine/tacrolimus/sirolimus/everolimus concentrations. Cyclosporine also inhibits CYP3A4 and P-gp and may have additional unique drug interactions not present with tacrolimus, sirolimus, and everolimus.

Azathioprine (Imuran; Prometheus Laboratories) is an antimetabolite. Major toxicities include bone marrow suppression manifesting as leukopenia, thrombocytopenia, and anemia. Standard, weight-based dosing is used for azathioprine; serum drug concentrations are not utilized [7].

Mycophenolate mofetil (MMF , CellCept; Genentech) and mycophenolic acid (MPA , Myfortic; Novartis Pharmaceuticals) are also antimetabolites, but, compared with azathioprine, their mechanism of action is more targeted to the white blood cell lines. Major toxicities include leukopenia and gastrointestinal adverse effects, most notably diarrhea [8]. Although these drugs are generally used at standard doses, therapeutic drug monitoring may be useful for MMF.

MMF is a prodrug that, after absorption, is quickly hydrolyzed to MPA. Myfortic is an enteric coated formulation of MPA, which is the active moiety of both these drugs. The major metabolite of MPA, an MPA glucuronide known as MPAG, is excreted into urine and bile. Once in the GI tract, MPAG is converted back into MPA and reabsorbed, resulting in enterohepatic recirculation.

MMF and MPA are believed to have similar drug interactions. Indeed, most MPA drug interactions are derived from the MMF literature. The clinical impact may not be exactly the same, however, because each of these medications has a unique pharmacokinetic profile. In addition to the interactions listed in Table 4-2, drugs that alter the GI flora may disrupt enterohepatic recirculation of MPA. This is because natural GI flora is responsible for conversion of MPAG to MPA [75].

Table 4-2. Common immunosuppressant drug interactions
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There is scant evidence suggesting that corticosteroids may have clinically relevant drug interactions with other immunosuppressive agents [76]. Corticosteroids induce the CYP3A4 and P-gp pathways to varying degrees; cyclosporine, tacrolimus, sirolimus, and everolimus rely on these pathways for metabolism. Corticosteroids also induce uridine diphosphate glucuronosyltransferase enzymes and multidrug resistance-associated protein 2; the mycophenolate products rely on these pathways for metabolism. When possible, therapeutic drug monitoring can be used to ensure appropriate immunosuppressive exposure while initiating or tapering corticosteroids [7].

Relevant drug interactions have not been noted for the polyclonal/monoclonal antibodies or selective T-cell costimulation blockers. These drugs do, however, pose the risk of pharmacodynamic interactions and additive toxicities.

Since our last update, several new anti-infective medications have been approved for marketing. These include the antibacterial drugs tedizolid, ceftaroline, dalbavancin, oritavancin, ceftolozane–tazobactam, fidaxomicin, and ceftazidime–avibactam. New antiviral agents include antihepaciviral protease inhibitors (telaprevir, boceprevir, simeprevir), polymerase inhibitors, and NS5A inhibitors as well as antiretroviral integrase inhibitors (raltegravir, elvitegravir, dolutegravir). The new azole antifungal agent isavuconazole was also introduced and is marketed as the prodrug isavuconazonium sulfate. New immunosuppressant agents include everolimus and belatacept. The tables highlight only drugs with potential interactions in transplant recipients. Table 4-1 lists the immunosuppressive agents according to their class; Table 4-2 shows common immunosuppressant interactions; and Table 4-3 presents common interactions between anti-infective and immunosuppressant drugs.

Table 4-3. Common interactions between anti-infective agents and immunosuppressive agents
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