Infection continues to be a major cause of morbidity and mortality in transplant recipients. Risk factors for the development of infection include T- and B-cell depletion by induction agents, T- and B-cell dysfunction caused by the use of calcineurin inhibitors, and neutropenia associated with purine antagonists [25]. Infections due to T cell-mediated defects include cytomegalovirus, herpes simplex virus, Pneumocystis jiroveci pneumonia, mucosal candidiasis, cryptococcus, and mucormycosis. Neutropenia-related infections include gram-positive and gram-negative bacterial infections, aspergillosis, and disseminated candidiasis [26–28].

The incidence of invasive fungal infections has become increasingly common in organ transplant recipients, ranging from 11 to 42 %, with the highest incidence reported in liver transplant patients [29–31]. Current options for the treatment of fungal infections include azole antifungals, amphotericin B, and the newest class of antifungals, echinocandins.

The azole antifungals have been extensively used in transplant recipients. All the azole antifungals have varying CYP3A4 inhibitory potencies, with ketoconazole being the most potent followed by itraconazole, posaconazole, voriconazole, and lastly fluconazole. Ketoconazole has been shown to increase the AUC of cyclosporine by almost threefold, requiring up to an 80 % reduction in cyclosporine dose [32]. Because of this interaction, clinicians have combined ketoconazole with a calcineurin inhibitor-based regimen for cost reduction benefit [32–35]. In a 10-year follow-up study by El-Agroudy and colleagues, the long-term use of ketoconazole for cyclosporine dose reduction was found to be safe, cost sparing, and associated with a significantly lower incidence of chronic allograft nephropathy [36]. Newer triazole antifungals, voriconazole and posaconazole, have an extended spectrum of activity against the Candida species, including C. krusei and C. glabrata, Aspergillus, and Cryptococcus. A randomized, double-blind, cross-over study in kidney transplant recipients found that the addition of voriconazole increased the mean cyclosporine AUC by 1.7-fold [37, 38]. It is recommended that the dose of cyclosporine be cut in half when voriconazole is added to the regimen. Voriconazole has also been shown to inhibit the metabolism of tacrolimus. In healthy volunteers, the addition of voriconazole has been shown to triple the AUC of tacrolimus, thus leading to the recommended 66 % dose reduction of tacrolimus when voriconazole is added to the regimen [38]. A retrospective study, which examined the impact on tacrolimus trough concentration after switching from fluconazole to voriconazole in allogenic hematopoietic stem cell transplant recipients, showed that the mean concentration/dose ratio of tacrolimus was increased 4.5-fold, prompting a 75 % dose reduction of tacrolimus [39]. Posaconazole has also been shown to significantly increase tacrolimus maximum blood concentration and area under concentration-time curve by 121 % and 358 %, respectively [40]. A study in four adult heart transplant recipients found that concomitant administration of posaconazole with cyclosporine increased cyclosporine exposure, requiring a 14–29 % cyclosporine dose reduction [40]. The manufacturer recommends reducing the cyclosporine dose by 25 % and tacrolimus dose by 66 % at the initiation of posaconazole treatment [41]. At the initiation and discontinuation of azole antifungals, dosage adjustment and close monitoring of calcineurin inhibitor concentration are recommended.

The echinocandins, caspofungin, micafungin, and anidulafungin, have good in vitro and in vivo activities against Aspergillus and Candida species. Data from in vitro and clinical studies indicate that caspofungin is not an inhibitor or inducer of the CYP450 enzyme system [42]. However, in a phase 1 clinical study, concomitant administration of caspofungin with cyclosporine resulted in an abnormal elevation of alanine aminotransferase (ALT) [42]. A limited number of subsequent studies examined this potential drug–drug interaction [43–47]. Marr et al. reported the hepatic safety profile in 40 patients concomitantly treated with caspofungin and cyclosporine. Transaminase elevation, >5 times the upper limit of normal or >3 times baseline, occurred in 14 patients (35 %) receiving concomitant therapy during a 14-day follow-up period [44]. Five patients had aspartate aminotransferase (AST) elevations that were considered possibly related to concomitant therapy, although no clinical evidence of hepatotoxicity or serious hepatic events was reported. In a retrospective study, Saner et al. reported the safety profile of concomitant administration of caspofungin in 12 liver transplant recipients receiving cyclosporine (N = 7) or tacrolimus (N = 5) [43]. No hepatotoxicity or liver enzyme elevation was reported. Due to the limitation of the size of these studies, when considering adding caspofungin to a cyclosporine regimen, the potential risk and benefit should be considered and hepatic function should be closely monitored. Early studies evaluating drug interactions found no effect of single or multiple doses of micafungin on the pharmacokinetic parameters of cyclosporine or tacrolimus [48]. An in vitro study did not find anidulafungin to be a CYP450 inhibitor or inducer and was not metabolized by the CYP450 enzyme system. In clinical studies, co-administration of anidulafungin did not significantly alter the pharmacokinetics of cyclosporine or tacrolimus [49, 50].

Amphotericin B remains an important antifungal, especially in the treatment of invasive mycoses [51]. Amphotericin B-induced nephrotoxicity, due to reduced renal blood flow and renal tubular dysfunction, continues to be an important dose-limiting side effect, especially in transplant recipients that may have some degree of renal dysfunction. Calcineurin inhibitors may also increase the nephrotoxicity of amphotericin B. Several lipid-based formulations of amphotericin B have been introduced to the market. Among these formulations, liposomal amphotericin B (Ambisome^®) was reported as the least nephrotoxic [52]. To prevent nephrotoxicity, patients should be hydrated with 200–500 mL of 0.9 % normal saline before and after administration of amphotericin B [52].

The macrolide antibiotics are frequently used in the treatment of various infections, including atypical bacteria such as Legionella pneumophila and Mycoplasma pneumoniae. Erythromycin and clarithromycin share a 14-membered macrocyclic lactone ring structure. These macrolides form inactive complexes with CYP3A enzymes and thus inhibit the metabolism of drugs requiring this enzyme, including tacrolimus and cyclosporine. In contrast, azithromycin has a 15-membered ring structure that does not complex with CYP3A enzymes and is thought to have little effect on the metabolism of the calcineurin inhibitors [53]. Therefore, when plausible, it may be beneficial to use azithromycin as the macrolide of choice to avoid this interaction. Concomitant use of calcineurin inhibitors and erythromycin or clarithromycin requires empiric dose reduction and close monitoring of calcineurin inhibitor plasma concentrations.

Rifampin is a potent CYP3A4 enzyme inducer, increasing hepatic and intestinal metabolism of CYP3A4 substrates, including the calcineurin inhibitors. Rifampin has been found to decrease cyclosporine trough concentrations by 73 % after administration of a single dose [54]. Kim et al. investigated the pharmacokinetic profile of cyclosporine in kidney transplant recipients before and after the administration of rifampin and found a significant decrease in cyclosporine concentration. A dose increase of 2.5–3 times was needed in order to maintain optimal cyclosporine trough concentrations [55]. Other studies also confirmed that, in addition to an increase in dosing frequency, a 3–5-fold increase in cyclosporine dose is required when using rifampin in order to achieve satisfactory trough concentrations [56, 57]. Similar findings were observed in heart transplant recipients when rifampin was co-administered with cyclosporine [58]. The same interaction is also seen when rifampin was administered with tacrolimus in kidney transplant recipients. A tacrolimus dose increase of up to tenfold is often needed [59, 60].

HIV protease inhibitors are known to cause significant drug interactions through inhibition of the CYP3A4 enzyme and P-glycoprotein efflux pump, leading to an increase in systemic blood levels of CYP3A4 or P-glycoprotein substrates. Pharmacokinetic studies have consistently shown that when administered in conjunction with HIV protease inhibitors, calcineurin inhibitor doses need to be reduced significantly to maintain similar trough concentrations. When co-administered, the lopinavir/ritonavir combination significantly increases tacrolimus exposure, with a tenfold increase in half-life. This pronounced effect results in the need for significant tacrolimus dose and administration frequency reduction [61–63]. Case reports in kidney transplant patients have shown that the combination of saquinavir or darunavir with tacrolimus resulted in an increase in tacrolimus trough concentrations, necessitating a 96.5 % reduction in dose to maintain stable trough levels [64, 65]. In liver transplant patients, the addition of nelfinavir to a tacrolimus-based regimen required a 16–70-fold decrease in tacrolimus dose to maintain similar trough concentrations [66, 67]. Similarly, in kidney transplant patients, an 85 % dose reduction of cyclosporine was required when cyclosporine and nelfinavir and indinavir were concomitantly administered [68]. Vogel et al. observed a need for a 5–20 % cyclosporine dose reduction when lopinavir/ritonavir was administered in liver transplant patients receiving cyclosporine [69]. To avoid drug-induced toxicity, close therapeutic drug monitoring and dose adjustment are necessary when immunosuppressants are co-administered with protease inhibitors.

Seizures are common in both the pre- and post-transplant population. Calcineurin inhibitors have been associated with lowering the seizure threshold.

Barbiturates markedly reduce cyclosporine and tacrolimus levels. Doses up to two or three times the previous regimen may be required to maintain adequate levels. Carbamazepine may also decrease cyclosporine or tacrolimus levels, but the effect is less pronounced. Similarly, oxcarbazepine may decrease levels as well. Benzodiazepines and valproic acid do not affect drug levels, but valproic acid has been associated with hepatotoxicity, which may result in alterations in metabolism. Modafinil can cause a reduction in calcineurin inhibitor levels up to 50 %. Phenytoin, a common first-line therapy used in the treatment of many types of seizures, causes CYP 3A4 enzyme induction [70, 71]. Due to the upregulation of metabolism, calcineurin inhibitor therapeutic drug concentrations are difficult to maintain [72, 73]. On average, two times the previous dose of cyclosporine or tacrolimus is required for patients receiving phenytoin. Levetiracetam, a newer anticonvulsant, does not undergo hepatic metabolism. Due to negligible effects on CYP450 system, levetiracetam is a safe option for transplant patients receiving calcineurin inhibitors.

Cardiovascular disease is the leading cause of mortality in the kidney transplant population. Patients with kidney disease often have hypertension pre-transplant that is worsened by maintenance immunosuppression regimens [74]. Calcineurin inhibitors induce hypertension through endothelin-mediated vasoconstriction, decreased nitric oxide production, and increased renal tubular sodium reabsorption [74]. To confound the situation, corticosteroids also increase blood pressure primarily through increased sodium retention [75]. Non-dihydropyridine calcium channel blockers, diltiazem and verapamil, are effective in treating hypertension and maintaining normal sinus rhythm in the setting of atrial fibrillation. However, these agents are potent CYP3A4 inhibitors, thereby increasing calcineurin inhibitor concentrations [76–78]. Cautious monitoring is required when initiating these agents, with a suggested empiric calcineurin inhibitor dose decrease of 25 % [76]. The dihydropyridine calcium channel blockers are relatively devoid of this interaction with the exception of nifedipine, which undergoes similar enzymatic metabolism [79].

Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are effective in decreasing both blood pressure and proteinuria. However, hyperkalemia may be a dangerous consequence when calcineurin inhibitors and ACEIs or ARBs are used concomitantly with sulfamethoxazole/trimethoprim, a common post-transplant prophylactic medication [80].

Despite exacerbation of comorbid diseases such as depression and erectile dysfunction, beta-blockers have been generally regarded as safe and effective for the treatment of hypertension in the post-transplantation setting. Notably, a retrospective study showed a significant increase in cyclosporine trough concentrations with the addition of carvedilol [81]. However, this interaction was absent when cyclosporine was co-administered with metoprolol. Carvedilol administration with cyclosporine increased the cyclosporine bioavailability by 40 % in one laboratory study [82]. As more data is needed regarding the effects of P-glycoprotein on cyclosporine and tacrolimus levels, caution should be taken when initiating carvedilol. Ultimately, the risk and side effects must be balanced with the management of hypertension and decreased mortality rates when choosing an appropriate agent.

Gout is a common condition that plagues not only the general population but solid organ transplant recipients as well. The calcineurin inhibitors, especially cyclosporine, have been associated with hyperuricemia [83]. Colchicine, commonly used in gout prophylaxis and acute attacks, must be used cautiously when administered concomitantly with the calcineurin inhibitors. Cyclosporine is thought to decrease the metabolism of colchicine through inhibition of P-glycoprotein, resulting in an increase in colchicine plasma concentrations and the potential for serious toxicity. In addition, concomitant use may result in increased cyclosporine plasma concentration and subsequent nephrotoxicity through competition for CYP3A4 metabolism. Appropriate dosage adjustments per colchicine package labeling must be followed to use this combination safely [84].

Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been associated with nephrotoxicity and should be avoided with calcineurin inhibitors if possible. However, NSAIDs can be given for short periods under close observation.

Any drug with the potential to cause nephrotoxicity should be used with caution in combination with calcineurin inhibitors because the vasoconstrictive effect of calcineurin inhibitors tends to potentiate other nephrotoxic mechanisms.

HMG-CoA reductase inhibitors are the most commonly used agents for the treatment of dyslipidemia in transplant recipients. Studies have shown that administration of cyclosporine, in combination with an HMG-CoA reductase inhibitor, can increase the systemic exposure to statins leading to an increase in incidence of rhabdomyolysis [85–93]. This interaction was initially thought to be due to competitive inhibition of CYP3A4-mediated drug metabolism by cyclosporine, increasing exposure of fluvastatin and pravastatin. However, interactions with the non-CYP3A4-dependent statins have also been reported, indicating a more complex interaction. It is recommended that when used in combination with cyclosporine, the statin dose should be significantly reduced to prevent serious adverse reactions. In contrast to cyclosporine, Lemahieu et al. reported no significant impact on the pharmacokinetics of atorvastatin and its metabolites when used in combination with tacrolimus [94]. Further studies are necessary to evaluate if this lack of interaction can be applied to the other HMG-CoA reductase inhibitors. When statins are co-administered with calcineurin inhibitors, patients should be closely monitored for any signs and symptoms of myopathy and/or rhabdomyolysis.

Depression is common in both the pre-transplant and post-transplant periods. Factors such as chronic illness, lethargy, anxiety associated with waiting for transplant, medications, including post-transplant immunosuppressive agents, as well as post-transplant complications have been associated with the development of depression [95]. Selective serotonin reuptake inhibitors (SSRI) are the most commonly prescribed class of medications used to treat depression. Nefazodone and fluvoxamine are known CYP3A4 inhibitors. While case reports of significant drug interactions with fluvoxamine are lacking, nefazodone has been shown to increase both cyclosporine and tacrolimus trough levels tenfold after initiation [96–100]. Based on the in vitro potential for CYP3A4 inhibition, sertraline should exhibit the least effects, followed by fluoxetine and citalopram [101]. While conflicting reports have been published regarding sertraline’s effects on cyclosporine concentrations, fluoxetine, paroxetine, and citalopram do not alter cyclosporine trough concentrations, which may in part be due to their diminished effects on CYP3A4 [100, 102–105]. Ultimately, nefazodone should be avoided in the transplant population and vigilant therapeutic drug monitoring should be considered when a new SSRI is initiated. Venlafaxine, the serotonin–norepinephrine reuptake inhibitor, is an attractive alternative to SSRI. It has been proven to have little effect on the CYP3A4 enzyme system and is metabolized through the CYP2D6 pathway [106]. To date, desvenlafaxine and duloxetine have not been reported to interact with the calcineurin inhibitors. However, desvenlafaxine has been shown to undergo CYP3A4 metabolism; therefore, caution should be taken since safety data is lacking surrounding this class of medications.

In addition to the pharmacokinetic interactions, the potential for toxicity of antidepressants and antipsychotics must be considered when choosing appropriate therapy. Lithium, a known cause of renal failure, may have its nephrotoxic effects potentiated by calcineurin inhibitors. Drugs that may cause QT prolongation, such as haloperidol, quetiapine, and olanzapine, may be potentiated in the setting of high calcineurin inhibitor trough concentrations.

MPA, a fermentation product of Penicillium brevicompactum, is a noncompetitive, reversible inhibitor of IMPDH and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation to DNA [107, 108]. After oral or intravenous administration, mycophenolate mofetil is rapidly absorbed and converted to MPA [109]. MPA is eliminated through glucuronidation via uridine diphosphate glucuronosyltransferases (UGT) to the pharmacologically inactive 7-O-MPA-glucuronide (MPAG) in the gastrointestinal tract, liver, and kidney [110, 111]. After the first peak (C _max), intra-intestinal bacterial breakdown of MPAG to MPA and enterohepatic recirculation resulted in a second plasma concentration peak observed 8–12 h post dose [14, 109].