Chapter 53
Drug Interactions Between Antimicrobial Agents and Common Immunosuppressive Drugs Used in Transplantation
| Antimicrobial drug | Interaction with: | Interactions/required dose adjustment |
| Antibacterial agents | ||
| Fluoroquinolones | ||
| Ciprofloxacin | CsA | Potential for mild increase in CsA levels. Not usually clinically significant |
| Macrolides | ||
| Erythromycin | CsA, Tac, SRL, EVL | Known significant increase in CsA, Tac, SRL and EVL levels. TDM required |
| Clarithromycin | CsA, Tac, SRL, EVL | Known significant increase in CsA, Tac, SRL and EVL levels. TDM required |
| Azithromycin | CsA | Potential for mild increase in CsA levels. TDM recommended |
| Aminoglycosides | ||
| Gentamicin, tobramycin, amikacin | CsA, Tac | Increased nephrotoxicity, avoid combination |
| Miscellaneous | ||
| Rifampin | CsA, Tac, SRL, EVL | Known significant decrease in CsA, Tac, SRL, EVL levels. Avoid combination if possible. TDM is required. Consider rifabutin as an alternative (less severe induction) |
| MMF | Possible moderate decrease in MMF exposure, mechanism unknown. Avoid combination if possible | |
| Quinupristin/dalfopristin | CsA, Tac | Possible moderate increase in CsA levels. TDM recommended |
| TMP-SMX | MMF, Aza | When used together, potential for synergistic increase in bone marrow toxicity |
| Vancomycin | CsA, Tac | Possible increased nephrotoxicity |
| Antifungals | ||
| Amphotericin B deoxycholate | CsA, Tac | Increased nephrotoxicity, avoid combination |
| Liposomal amphotericin B formulations | CsA, Tac | Increased nephrotoxicity, less profound as seen with amphotericin B deoxycholate |
| Echinocandins | ||
| Caspofungin | CsA | Possible increase in caspofungin exposure, clinical relevance not clear. Possible increase in liver enzymes in healthy volunteers but not shown in transplant patients |
| Tac | Possible decrease in Tac levels. May not be clinically significant. TDM recommended | |
| Micafungin | SRL | Possible increase in SRL levels. May not be clinically significant. TDM recommended |
| Anidulafungin | CsA | Possible increase in anidulafungin exposure, clinical relevance unknown |
| Azole antifungal | Inhibitors of CYP450 metabolism. Inhibitory potential: ketoconazole < itraconazole ≈ voriconazole < posaconazole < fluconazole | |
| Ketoconazole | CsA, Tac, SRL, EVL | Known significant increase in CsA, Tac, SRL and EVL levels. TDM required. Suggested dose reductions: CsA (70–80%), Tac (50–60%), SRL (80–90%), EVL (unknown minimum 50%) |
| Itraconazole | CsA, Tac, SRL, EVL | Known significant increase in CsA, Tac, SRL and EVL levels. TDM required. Suggested dose reductions: CsA (50–60%), Tac (50–60%), SRL and EVL (unknown, minimum 40%) |
| Voriconazole | CsA, Tac, SRL, EVL | Known significant increase in CsA, Tac, SRL and EVL levels. TDM required. Suggested dose reductions: CsA (50%), Tac (66%), SRL (contraindicated though reductions of 90% have been reported), EVL (unknown, minimum 40%) |
| Posaconazole | CsA, Tac, SRL, EVL | Known significant increase in CsA, Tac, SRL and EVL levels. Use of posaconazole with sirolimus is contraindicated. TDM required. Suggested dose reductions: CsA (up to 30%), Tac (75–80%), EVL (unknown, minimum 40%) |
| Fluconazole | CsA, Tac, SRL, EVL | Known significant increase in CsA, Tac, SRL and EVL levels. TDM required. Suggested dose reductions: CsA (20–50%), Tac (40%), SRL (50–70%) and EVL (unknown, minimum 40%) |
| Antivirals | ||
| Acyclovir/valacyclovir | MMF | Possible increase risk of acyclovir toxicity in the setting of renal insufficiency when co-administered with MMF |
| Ganciclovir/valganciclovir | Aza, MMF | Increased risk of cytopenia |
| Foscarnet | CsA, Tac | Probable increased nephrotoxicity |
| Cidofovir | CsA, Tac | Probable increased nephrotoxicity |
| Highly active antiretroviral therapy (HAART) | Significant drug–drug interactions exist with protease inhibitor containing HAART regimens. Collaboration with an infectious diseases-HIV specialist and transplant pharmacist is highly recommended | |
| Nucleoside reverse transcriptase inhibitors (NRTIs) | ||
| AZT, abacavir | MMF | MMF undergoes glucuronidation like AZT and abacavir. Potential for increased risk of mitochondrial toxicity when used together. TDM recommended |
| Tenofovir | CsA, Tac | Potential for synergistic nephrotoxicity, monitoring of renal function is recommended |
| Protease inhibitors | ||
| Atazanavir, darunavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir | CsA, Tac, SRL, EVL | Known significant increase in CsA, Tac, SRL and EVL levels. TDM required. Suggested dose modification when used in combination with PIs: CsA (15–25 mg BID), Tac (0.5–1 mg once to twice a week), SRL (0.5–1mg once to twice a week), EVL (unknown) |
| Non-nucleoside reverse transcriptase inhibitors (NNRTIs) | ||
| Delavirdine | CsA, Tac, SRL, EVL | Possible mild increase in CsA, Tac, SRL and EVL levels. TDM required |
| Efavirenz | CsA, Tac, SRL, EVL | Possible mild decrease in CsA, Tac, SRL and EVL levels. TDM required |
| Nevirapine | CsA, Tac, SRL, EVL | Possible mild decrease in CsA, Tac, SRL and EVL levels. TDM required |
| Etravirine | CsA, Tac, SRL, EVL | Possible alterations in CsA, Tac, SRL and EVL levels. TDM required |
AZT, zidovudine/azidothymidine; Aza, azathioprine; BID, twice daily; CsA, cyclosporine A; CYP 450 cytochrome P450; Tac, tacrolimus; EVL, everolimus; MMF, mycophenolate mofetil; PI, protease inhibitor; SRL, sirolimus; TDM, therapeutic drug monitoring.
Internet references: General reference: http://medicine.iupui.edu/clinpharm/ddis/; Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table, Indiana University School of Medicine (2007), http://medicine.iupui.edu/clinpharm/ddis/table.asp; HAART: http://www.hiv-druginteractions.org/; Micromedex® Healthcare Series [internet database], Thomson Healthcare, Greenwood Village, CO (updated periodically).
References: [1] AST Guidelines 2009; 9(s4): S263; [2] Circulation 2005; 111: 230; [3] J HIV Therapy 2007; 1: 24; [4] Semin Liv Dis 2006; 26: 273; [5] Pharmacotherapy 2006; 26(12): 1730; [6] Am J Transplantation 2007; 7: 2816; [7] Current Opinion in Nephrology and Hypertension 2009; 18: 404.