Interactions Between Anti-Infective Agents and Immunosuppressants in Solid Organ Transplantation
Corresponding author: Jennifer Trofe-Clark, Jennifer.firstname.lastname@example.org
area under the curve
enteric coated mycophenolate sodium
human immunodeficiency virus
mammalian target of rapamycin
Infectious diseases are among the leading complications of immunosuppression for solid organ transplantation . The first few months posttransplant are particularly critical because immunosuppression is usually at high levels, acute rejection episodes are most likely to occur during this time frame requiring further increases in immunosuppression, and patients are receiving anti-infective prophylaxis . However, it is essential for the clinician to consider drug interactions and infectious complications for the life of the recipient. Although the risk of infection is highest in the first year posttransplant, the risk of infection may increase at any time during the posttransplant course when the patient's cumulative immunosuppressive state is enhanced (e.g. during treatment of rejection episodes when immunosuppression is intensified; Ref. ). In addition, infectious diagnosis may be complicated by lack of signs and symptoms of inflammation, alterations in anatomy as a result of transplant surgery, denervation of the transplanted graft and preexisting diseases . Optimal treatment of specific infections, therefore, should be guided not only by knowledge of the pathogen's susceptibility to antimicrobial agents but also by the effects the agents will have on the pharmacokinetics and/or pharmacodynamics of the immunosuppressants that the patient is receiving.
Drug–drug interactions with immunosuppressants and anti-infective agents can be divided into two categories: pharmacokinetic and pharmacodynamic interactions. Pharmacokinetic drug–drug interactions may lead to altered drug concentrations of immunosuppressants, anti-infective agents or their metabolites through interactions in stages of absorption, distribution, metabolism or elimination. Some of the more frequently used immunosuppressive agents used in organ transplantation are metabolized via the cytochrome (CYP) 3A4 system. For example, immunosuppressive drug interactions can be caused by an anti-infective agent directly inhibiting CYP3A4 or via drug competition for CYP3A4 substrate sites. Both of these mechanisms may result in increased immunosuppressive concentrations. In contrast, CYP3A4 induction via increased synthesis or decreased breakdown of CYP isoenzymes may result in decreased immunosuppressive concentrations  Another type of interaction is through the membrane transporter P-glycoprotein . Drugs that inhibit or induce P-glycoprotein activity can ultimately result in increased or decreased bioavailability in the intestine. Moreover, due to genetic polymorphisms, patients may express variation in CYP3A4 enzymes and P-glycoprotein, which also can influence drug levels. The reader is referred to the following published reviews for a more detailed review of the pharmacokinetic principles of immunosuppressive agents and mechanisms of drug–drug interactions [5, 6].
Pharmacodynamic interactions may occur as a result of drugs increasing or decreasing the efficacy or toxicity of each other. This may lead to detrimental or beneficial drug interactions. For example, the administration of calcineurin inhibitors with aminoglycosides, amphotericin, cidofovir, foscarnet, intravenous acyclovir or higher dose sulfamethoxazole-trimethoprim may result in the detrimental effect of additive nephrotoxicity. Alternative therapies without nephrotoxicity should be used whenever possible. When nephrotoxic therapies are essential to treatment, calcineurin inhibitors should be minimized whenever possible. Renal function must be carefully monitored and changes in renal function may necessitate decreasing or discontinuing anti-infective therapies.
Administration of mycophenolate mofetil (MMF), enteric coated mycophenolate sodium (ECMS) or azathioprine (AZA) with leflunomide for BK virus nephropathy may result in additive myelosuppression. Therefore, these antiproliferative agents should be discontinued upon initiation of leflunomide. Antiviral agents such as ganciclovir and valganciclovir and antibacterials such as linezolid and sulfonamides may result in myelosuppression when combined with MMF, ECMS or AZA too. Careful monitoring of white blood cells, platelets and hematocrit is necessary as well as consideration of dose adjustments of immunosuppressive and anti-infective agents as applicable. Pharmacodynamic interactions may also work in synergy. For example, CSA, (but not TAC) has been shown to inhibit hepatitis C virus in vitro, and may have a beneficial effect when combined with antiviral therapy . In addition, the mTOR inhibitors may decrease the incidence and severity of cytomegalovirus posttransplant  and MMF has been reported to potentially be associated with a decreased incidence of Pneumocystis jiroveci pneumonia [9, 10].
Another consideration in dosing anti-infective agents is that many are renal-eliminated. Doses may need to be continually adjusted to maximize efficacy and limit toxicity, particularly in patients with fluctuating renal function. It is important to note that although MDRD is available to estimate GFR in transplant recipients, renal drug dosing recommendations are still based on Cockcroft-Gault calculations unless otherwise specified in the product information .
Table 1 provides summary information on interactions between anti-infectives and immunosuppressants, an indication of their severity, suggested actions by the clinician, the weight of evidence supporting these effects and suggested actions. For completeness, we have also included anti-infective agents in the table that may not always result in significant interactions in clinical practice, but have either in vitro data showing an interaction with immunosuppressants, or case reports showing evidence of an interaction. The following discussion describes these interactions in more detail focusing on the most severe and suggests approaches to alternative treatment.
Interactions That Significantly Raise Calcineurin Inhibitor and mTOR Inhibitor Plasma Levels
All macrolide antibiotics, with the exception of azithro-mycin, are moderate to strong inhibitors of CYP3A4 and thus decrease the metabolism of calcinerin inhibitors: cyclosporine (CSA) and tacrolimus (TAC), and mammalian target of rapamycin (mTOR) inhibitors: sirolimus (SRL) and everolimus (EVR; Ref. ). The magnitude of this effect varies between the macrolides, with erythromycin and clarithromycin having the greatest impact. Variations in immunosuppressive agent drug half-life can also impact the duration of the interaction. For example, SRL is dosed once daily and has a longer half live than EVR or calcineurin inhibitors, which are often dosed twice daily. In all cases, however, these combinations result in very significant (3- to 10-fold) increases in immunosuppressant concentration or area under the curve (AUC). The availability of clarithromycin and azithromycin, which have fewer gastrointestinal side effects, has resulted in diminished use of erythromycin in the community, thereby diminishing the chance of inadvertent co-administration. However, some surgical and medical intensive care units have adopted the use of erythromycin for gastrointestinal motility in patients with poor gastric emptying or ileus. The co-administration of erythromycin with calcineurin inhibitors, and especially mTOR inhibitors should be avoided in this situation when feasible; however, if the combination is used, at least a 50% reduction of calcineurin inhibitors should be considered early, because the effect is rapid. Daily drug level monitoring with calcineurin inhibitors is recommended and every third day level monitoring with mTOR inhibitors is recommended. Similar considerations apply to clarithromycin, which is widely used in the community and may be required for the treatment of transplant recipients with nontuberculous mycobacterial infections. However, this agent should be avoided whenever possible due to the interactions previously noted. The majority of in vitro and in vivo data indicate there is no pharmacokinetic interaction between azithromycin and calcineurin inhibitors or mTOR inhibitors. However, two case reports describe elevation of CSA concentrations with several days of concomitant administration of azithromycin [13, 14]. Elevation of TAC levels have also been reported with co-administered azithromycin . Therefore, monitoring drug levels may be appropriate.
All of the azole derivative antifungal agents decrease the metabolism of calcineurin inhibitors and mTOR inhibitors resulting in modest to profound increases in serum concentration and AUC. The potency of the interaction is different for each agent. For example, itraconazole and posaconazole have been shown to be more-potent inhibitors of CYP3A4 than are fluconazole or voriconazole .
Ketoconazole has also been shown to be the most potent inhibitor of CYP3A4 and has been co-administered with calcineurin inhibitor or mTOR inhibitor based immunosuppression in an effort to decrease immunosuppressive dose requirements and cost to transplant recipients [17-20]. If undertaken, this drug combination must be carefully monitored as inadvertent discontinuation of ketoconazole by the patient or an outside health provider will dramatically decrease immunosuppressive levels.
The interaction of fluconazole with calcineurin inhibitors is both dose-dependent and drug-dependent . At modest doses (100–200 mg/day) of fluconazole used for nonsystemic candidiasis, effects on CSA are minor, whereas moderate to significant increases are seen with TAC. At doses of fluconazole required for systemic fungal infection (e.g. 400 mg for cryptococcosis or candidemia) significant dose reductions of immunosuppressants are required.
Voriconazole prescribing information recommends empiric dose reduction of TAC by two-thirds and CSA by 50% of the original maintenance dose when voriconazole is initiated [21-23]. The combination of voriconazole and SRL is contraindicated as SRL levels may rapidly rise 10-fold . However, a small case series reported that voriconazole and SRL could potentially be used together if low doses of SRL are used (0.5–1.0 mg/day; Ref. ). Similarly, EVR prescribing information recommends that it not be administered with voriconazole , but case reports have detailed their concurrent use with EVR dose reduction [26, 27]. Like voriconazole, posaconazole prescribing information also recommends empiric dose reduction of TAC by two-thirds and to decrease CSA dose by one-fourth of the original maintenance dose when posaconazole is initiated [28, 29]. The combination of posaconazole and SRL is contraindicated as SRL rise 9-fold [28, 30]. No information is available on the use of EVR and posaconazole in prescribing information of either agent [25, 28], but one case report in a renal transplant recipient found a 3.8-fold increase in everolimus levels with posaconazole . Close drug monitoring is recommended at initiation, during and after discontinuation of voriconazole or posaconazole.
In addition, oral clotrimazole troches used for oral mucocutaneous candidiasis prophylaxis or treatment has also been shown to increase TAC blood levels significantly, doubling levels in some studies [31-34]. The mechanism of this interaction is thought to be related to cytochrome (CYP) 3A4. Calcineurin inhibitor and m TOR inhibitor levels should all be monitored during initiation or discontinuation of clotrimazole.
The new echinocandin antifungal agents provide alternatives to the use of azole derivatives. None of the echinochandins are significantly metabolized by CYP3A and are available only in intravenous formulations. Although the original studies that resulted in approval of caspofungin suggested increased hepatotoxicity when used in conjunction with CSA, and noted that CSA increase caspofungin AUC by 35% , subsequent studies found no significant increase in hepatotoxicity nor a major change in CSA or TAC pharmacokinetics [36, 37]. A previous review article also noted that TAC AUC, peak and 12 hour concentrations are decreased by 20% in presence of caspofungin , but current product information for caspofungin recommends to follow standard TAC dosing and level monitoring and has no interaction with the active metabolites of MMF either . No data are available on interactions with mTOR inhibitors. Micafungin has not been shown to interact with TAC . The micafungin product information notes that there was no effect of a single dose or multiple doses of micafungin on MMF, prednisolone, TAC or CSA . However, one study has shown micafungin to decrease CSA concentrations by 16% in one study and hence monitoring of CSA levels is recommended . Micafungin product information also notes that SRL AUC was increased by 21% with no effect on maximum concentration, in the presence of steady-state and recommends SRL dose monitoring with dose adjustment as needed . A 22% increase in anidulafungin concentrations and drug exposure has been observed with CSA, but is not considered to be clinically relevant, and dose adjustments are not recommended for either agent . Of note, this interaction has not been observed with anidulafungin and tacrolimus . No data are available regarding interactions with mTOR inhibitors.
Patients chronically infected with human immunodeficiency virus-1 (HIV-1) are increasingly being transplanted for end organ disease . Many of the antiretroviral medications are substrates of CYP3A4; therefore, the interactions between these medications can be severe, particularly when used with calcineurin inhibitors or mTOR inhibitors in combination with protease inhibitors . All HIV-1 infected transplant recipients need close monitoring of immunosuppression levels to avoid underimmunosuppression or toxicity related to these medications. A summary of these interactions is provided in Table 1, but the reader is referred to the chapter in these guidelines on Solid Organ Transplant in the HIV-Infected Patient for further specific information on outcomes and drug interactions.
HCV protease inhibitors
The hepatitis C virus (HCV) protease inhibitors, boceprevir and telaprevir, are important new therapies for HCV treatment and are likely to be increasingly used in the liver transplant population. Both drugs are substrates and inhibitors of CYP3A4, with the main effect being elevated blood levels of the calcineurin inhibitors in healthy volunteers [46-48]. Empiric CSA dose reduction of 75% or holding calcineurin inhibitors when boceprevir or telaprevir are introduced with drug level monitoring has been recommended by some authors . However, in three liver transplant recipients receiving co-administered CSA and boceprevir, only a minor increase in CSA blood levels were noted . A series of six liver transplant patients treated with telepravir required dosing of TAC once weekly or EVR every three days with close monitoring of drug levels . It seems based on several small case series in liver transplant recipients that boceprevir and telaprevir can be safely given with concomitant calcineurin inhibitors with close monitoring of drug levels [49-53]. No data are yet available on the use of SRL with HCV protease inhibitors, but drug interactions are expected to be similar to those with TAC .
Interactions That Significantly Decrease Calcineurin Inhibitor and mTOR Inhibitor Plasma Levels
All of the rifamycins are strong inducers of CYP3A4. For rifampin and rifabutin, clinical data confirm the dramatic increases in clearance and resultant decreases in plasma levels of the calcineurin inhibitors and mTOR inhibitors [54-60]. This effect has been reported to remain even in the presence of multiple CYP3A4 inhibiting medications . No data are available for rifapentine but a similar effect is likely. This combination should be avoided if at all possible because of the severe difficulty of maintaining therapeutic levels of calcineurin inhibitors, mTOR inhibitors. In those situations where a rifamycin derivative must be used, as in patients with tuberculosis, increased doses of calcineurin inhibitors or mTOR inhibitors should be initiated with onset of combined therapy. A twofold dose increase is recommended at the initiation of therapy, with rapid subsequent increases (up to 10-fold reported) and frequent drug level monitoring until stable dosing is achieved. Similar vigilance is required when rifamycin therapy is discontinued.
A much less dramatic effect on MMF pharmacokinetics has been reported with rifampin . Although the increase in MMF dosing requirements seems to be moderate compared with those for calcineurin inhibitors, the manufacturer's prescribing information recommends avoiding this combination when possible and monitoring drug levels closely if it is used . There is no information available for use with ECMS , but based on the mechanism of interaction, we recommend closely monitoring drug levels if used. Of note, ethambutol and isoniazid, which are sometimes used in combination with these agents, do not seem to interact with immunosuppressive agents.
The artemether component of the new antimalarial artemether/lumefantrine is an inducer of CYP3A4 . Although there is no currently available data on drug–drug interactions with immunosuppressants, it would be expected to potentially decrease calcineurin levels, as well as mTOR inhibitor levels (Table 1).
Table 1. Antiinfective drug interactions
|Antibacterials|| || || || || |
|Fluoroquinolones|| || || || || |
|Ofloxacin||CSA, TAC||++||↑ Imm levels||Choose alternate||B|
|Ciprofloxacin||CSA, TAC||+/–||May ↑ Imm levels||No adjustment/consider monitoring Imm levels||B|
|Levofloxacin||CSA||+/–||May ↑CsA||No adjustment/consider monitoring Imm levels||A|
|Moxifloxacin||CSA, TAC, SRL, EVR||–||None||No adjustment||B|
|Macrolides|| || || || || |
|Erythromycin||CSA, TAC, SRL, EVR||+++||↑ Imm levels||Avoid||A|
|Clarithromycin||CSA, TAC, SRL, EVR||+++||↑ Imm levels||Avoid/↓ Imm by1/2||A|
|Telithromycin||CSA, TAC, SRL, EVR||+++||↑ Imm levels||Avoid||A|
|Azithromycin4||CSA, TAC, SRL, EVR||+/–||↑ Imm levels||No adjustment/consider monitoring Imm levels||A|
|Rifamycins|| || || || || |
|Rifabutin||CSA TAC, SRL, EVR||++||↓ Imm levels||Monitor Imm Levels||A|
|Rifapentine5||CSA, TAC, SRL, EVR, Prednisone||++||↓ Imm levels||Monitor Imm Levels||N/A|
|Rifampin||CSA, TAC, SRL, EVR, MMF, ECMS||+++||↓ Imm levels||Avoid/Monitor Imm Levels||A|
|Aminoglycosides|| || || || || |
|Gentamicin||CSA, TAC||+++||Enhanced nephrotoxicity||Avoid/Monitor Imm Levels and renal function||A|
|Tobramycin|| || || || || |
|Amikacin|| || || || || |
|Streptomycin|| || || || || |
|Other antibacterials|| || || || || |
|Nafcillin||CSA, TAC, SRL, EVR||+||↓Imm levels||Monitor Imm Levels||B|
|Quinupristin/Dalfopristin||CSA||+++||↑ CsA||Monitor Imm Levels||B|
|Linezolid||MMF, ECMS, AZA||++||Myelosuppression||Monitor WBC and platelets||B|
|Sulfonamides||MMF, ECMS, AZACSA, TAC||++++||MyelosuppressionNephrotoxicity||Monitor WBC, hematocrit, platelets and renal function||B|
|Tetracycline6||CSA, TAC, SRL, EVR||+||↑Imm Levels||Monitor Imm Levels||B|
|Tigecycline||CSA||+||↑Imm Levels||Monitor Imm Levels||C|
|Metronidazole||CSA, TAC, SRL, EVR||+/–||May ↑Imm Levels||No adjustment/consider monitor levels||B|
|Chloramphenicol||CSA, TAC, SRL, EVR||++||↑Imm Levels||↓CSA or TAC by 25%||B|
|(intravenous)|| || || || || |
|Clindamycin||CSA, TAC, SRL, EVR||+/–||May ↓Imm levels||No adjustment/consider monitor levels||C|
|Antimalarial|| || || || || |
|Artemether5/Lumefantrine||CSA, TAC, SRL, EVR||++||↓Imm levels||Monitor Imm Levels||N/A|
|Antifungals|| || || || || |
|Azoles|| || || || || |
|Ketoconazole||CSA, TAC, SRL, EVR||+++||↑ Imm levels||Avoid/↓Imm by 1/2||A|
|Voriconazole||CSA, TAC, SRL, EVR||+++||↑ Imm levels||↓CsA by 1/2, ↓Tac by 2/3||A|
|Itraconazole||CSA, TAC, SRL, EVR||++||↑ Imm levels||Monitor Imm Levels||A|
|Posaconazole||CSA, TAC, SRL, EVR||+++||↑ Imm levels||↓CsA by 1/4, ↓Tac by 2/3||A|
|Fluconazole||CSA, TAC, SRL, EVR||++||↑ Imm levels||Dose dependent ↓CsA and Tac by 1/3||A|
|Clotrimazole||CSA, TAC, SRL, EVR||++||↑ Imm levels||Monitor Imm Levels||A|
|Echinocandins|| || || || || |
|Caspofungin7||TAC||+/–||May ↓TAC levels||None||B|
| ||CSA||++||↑ Caspofungin Levels||Monitor AST/ALT||B|
| ||MMF (no data on ECMS)||–||None||None||N/A-product info|
| ||No data on SRL, EVR|| || || || |
|Micafungin||TAC, MMF, Prednisone (no data on ECMS)||–||None||None||N/A-product info|
| ||CSA||++||↓ CSA levels||Monitor Imm Levels||A|
| ||SRL (no data on EVR)||++||↑SRL levels||Monitor Imm Levels||N/A product info|
|Anidulafungin||CSA||+||↑ Anidulafungin levels||None||A|
| ||TACNo data on SRL, EVR||–||None||None||A|
|Polyenes|| || || || || |
|Amphotericin|| || || || || |
|Lipid formulation||CSA, TAC||++||Nephrotoxicity||Monitor Imm Levels and renal function||A|
|Amphotericins|| || || || || |
|Antiviral agents|| || || || || |
|Antiviral agents (non HIV)|| || || || || |
|Acyclovir||MMF, ECMS||+/–||↑ACV, ↓MPA||None||C|
|Intravenous acyclovir||CSA, TAC||+++||Nephrotoxicity||Monitor renal function||A|
|Ganciclovir||MMF, ECMS, AZA||++||Neutropenia||Monitor WBC||B|
|Valganciclovir||MMF, ECMS, AZA||++||Neutropenia||Monitor WBC||B|
|Foscarnet||CSA, TAC||+++||Nephrotoxicity||Monitor renal function, Ca, Mg,||A|
| || || ||↓Ca ↓Mg||CNI levels, decrease foscarnet|| |
|Cidofovir||CSA, TAC||+++||Nephrotoxicity||Monitor renal function||A|
|Boceprevir||CSA, TAC, SRL, EVR||+++||↑ Imm levels||Imm dose reductions vary (see text)||A|
|Telaprevir||CSA, TAC, SRL, EVR, systemic prednisone and methylprednisolone||+++||↑ Imm levels||Imm dose reductions vary (see text)||A|
|Leflunomide||MMF, ECMS, AZA, SRL, EVR||+++||Myelosuppression||Hold MMF, ECMS, AZA and monitor WBC, hematocrit and platelets||A|
|Oseltamivir||CSA, TAC, MMF||+/–||13% increase in TAC trough only||Monitor Imm Levels||A|
| ||SRL||–||None|| ||C|
| ||No data with ECMS, EVR|| || || || |
|Zanamivir4||CSA, TAC, SRL, EVR||–||None||None||N/A-product info|
| ||MMF, ECMS|| || || || |
|Antiretroviral agents|| || || || || |
|NNRTIs8|| || || || || |
|EFV||CSA, TAC, SRL, EVR||++||↓CSA, ↓ TAC||Monitor Imm Levels||A|
|NVP||CSA, TAC, SRL, EVR||+/–||May ↓ Imm levels||Monitor Imm Levels||N/A|
|ETR5||CSA, TAC, SRL, EVR||+/–||May ↓ Imm levels||Monitor Imm Levels||N/A|
|DLV5||CSA, TAC, SRL, EVR||++||↑ Imm levels||Monitor Imm Levels||N/A|
|PIs9|| || || || || |
|(ATV, DRV, FPV, IDV, LPVr, NFV10, RTV, SQV, TPVr)||CSA, TAC, SRL, EVR not recommended for use with RTV-regimens||+++||↑CSA||CSA 25-50 mg daily||A|
| || ||+++||↑TAC/SRL/EVR||TAC 1 mg once or twice a week||A|
| || || || ||SRL 1 mg once or twice a week||A|
| || || || ||When using RTV-PI boosted regimen||B|
| || || || ||TPVr interaction unpredictable|| |
|NRTIs11|| || || || || |
|AZT||MMF/ECMS||+||In vitro antagonism||None||C|
|D4T||MMF/ECMS||+||In vitro antagonism||None||C|
This manuscript was modified from a previous guideline written by LD Thomas and Geraldine Miller published in the American Journal of Transplantation 2009;9(Suppl 4): S263–S266, and endorsed by American Society of Transplantation/Canadian Society of Transplantation.
Funding source: The authors have not accepted funding or support for preparation of this manuscript.
The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Dr. Trofe-Clark is a consultant for LexiComp, is a Transplant Medical Review Board Member for CMS, and attended a transplant pharmacy advisory board meeting for Novartis Pharmaceuticals.