Drug-Drug Interactions and Most Commonly Used Drugs in Renal Transplant Recipients

Ali J. Olyaei

Angelo M. deMattos

William M. Bennett^*

Division of Nephrology and Hypertension, Oregon Health Sciences University, Portland, Oregon 97201; and ^*Solid Organ and Cellular Transplantation, Legacy Good Samaritan Hospital, Portland, Oregon 97210

INTRODUCTION

The field of transplantation has witnessed a significant improvement in allograft and patient survival in the last three decades. Introduction of potent and selective immunosuppressive drugs, improvements in surgical techniques, enhanced allograft preservation and optimal post-operative patient care have impacted allograft and patient survival significantly. Drug therapy following kidney transplantation is often the most challenging aspect of care. Improved graft survival requires selection of the best possible agents with close monitoring of pharmacokinetics, pharmacodynamics, adverse drug reactions and cost of different agents (1, 2, 3, 4, 5, 6, 7, 8).

In general, adverse drug-related events present a challenging and expensive public health problem in the US. Approximately 3% to 10% of all hospital admissions or prolonged hospital stays are caused by drug-drug interactions or adverse drug reactions (9, 10, 11, 12, 13, 14). Transplant patients are at greater risk of drug-drug interactions, because most patients have several comorbid conditions resulting in administration of multiple agents. Most drug-drug interactions in transplant patients have proven to be highly clinically significant resulting in an increased risk of morbidity and mortality following transplantation (15, 16, 17).

Several studies have demonstrated that most clinicians under-appreciate the frequency and significance of drug-drug interactions (17,18). Drug-drug interactions should be routinely screened for in all transplant patients initially or whenever a new medication is added to pre-existing immunosuppressive regimens (19,20).

Either cyclosporine or tacrolimus is commonly used with one or two other agents (azathioprine, mycophenolate mofetil, sirolimus, corticosteroids) to prevent acute rejection. To avoid drug-drug interactions both pharmacokinetic properties and pharmacodynamic interactions should be considered. Since most transplant patients have several risk factors for cardiovascular and infection complications following transplantation, effective immunosuppressant management is a vital issue to enhance allograft and patient survival. The significant reduction of acute allograft rejection and graft loss from immunological factors has been paralleled with an observed increase in predominantly cardiovascular complications (hypertension, hypercholesteremia, obesity, and post-transplant diabetes), connective tissue diseases, psychiatric diseases and osteoporosis (21, 22, 23, 24, 25, 26). The success of renal transplantation also has broadened the indications of transplantation. Today, selected HIV patients with
end stage renal disease, obese (BMI >35) and patients with pre-existing cardiovascular conditions are already transplanted or listed for transplantation (27, 28, 29, 30, 31). As the number of prescribed drugs among these patients for the treatment of these complications increases, adverse drug reactions and drug-drug interactions leading to hospitalization will increase as well.

Finally, transplant patients are not equal in biological composition (32, 33, 34, 35, 36). A remarkable heterogeneity in genetic make up has been preserved or created through evolution and environmental factors. A significant polymorphism in P-glycoprotein and cytochrome P450 has been observed in different individuals (Table 34.1) (37,38). Polymorphism of cytochrome P isoenzyme and P-glycoproteins may directly and/or indirectly influence drug-drug interactions in transplant patients (39,40). For example, a significant heterogeneity is present in the oral doses required to achieve pharmacokinetic goals (eg. cyclosporine level) or pharmacodynamic targets (blood pressure or LDL levels) among individual transplant patients. African American patients require higher oral doses to achieve the same target blood concentrations of tacrolimus and cyclosporine than other ethnic groups (41). These differences can be partly related to polymorphism expression of intestinal P-glycoprotein (the product of the multiple drug resistance genes MDR-1) and cytochrome P450III A (42, 43, 44).

The objective of this chapter is to discuss two aspects of drug-drug interactions in transplant patients: pharmacokinetic and pharmacodynamic drug-drug interactions. Drug-drug interactions are classified according to drug absorption, distribution, metabolism, elimination, or decreased efficacy or enhanced toxicity. This chapter reviews clinically relevant drug-drug interactions and provides a guideline for pharmacological management of the most commonly complications of drug-drug interaction in the transplant patient. Tables in this chapter are intended to provide only an initial attempt/guideline for drug dosing of the most commonly used drugs in transplant recipients. Transplant patients may respond differently to each drug therapy. Clinicians should use clinical judgment, intuition and experience to individualize drug therapy for each transplant patient. The magnitude of each drug interaction is different in each patient. Noninteracting drugs are also recommended in Tables 34.2, 34.3 and 34.4. The most commonly used agents in transplant patients are arranged by pharmacologic or therapeutic classification in each tables. It is also important to formulate a dosage adjustment, if necessary for impaired renal function. An appropriate starting dose and maximum dose is included in addition to some guidelines for drug administration in patients with impaired renal function (Tables 34.5, 34.6, 34.7, 34.8 and 34.9).

TABLE 34.1. Factors Influencing Cytochrome P450 Activities

	1A2	2C	2D6	2E1	3A4
Nutrition	+			+	+
Smoking	+
Alcohol				+
Drugs	+	+	+		+
Genetics		+	+

DRUG-DRUG INTERACTIONS

Drug-drug interactions can be devastating in transplant patients. It is crucial for transplant practitioners to recognize any potential drug-drug interactions (17). It is also equally important not to over react when facing a drug-drug interaction. Most drug-drug interactions are manageable and toxicity can be avoided. Therapeutic drug monitoring and assessment of the side effect profile remains the single most important strategy to minimize any adverse outcomes of drug-drug interactions. Half-life, dosage, route of administration and drug metabolism may affect the time course of drug-drug interactions.

Pharmacokinetic Drug-Drug Interactions

Drug-drug interactions are classified as pharmacokinetic or pharmacodynamic. In pharmacokinetic drug interactions, the administration of one drug may affect the pharmacokinetic behavior of another agent. In this setting, drug absorption, distribution, metabolism and elimination are altered because of the administration of two agents concomitantly. Since most transplant patients receive several drugs during the first year post-transplant to prevent of acute rejection or infection, drug-drug interactions are common.

For drugs with narrow therapeutic indices, clinically important drug-drug interactions can be detected by using therapeutic drug monitoring. Drugs like phenytoin enhances metabolism of sirolimus and calcineurin inhibitors (45,46). When phenytoin is initiated in a transplant patient, the blood concentration of calcineurin inhibitors and sirolimus should be monitored very closely and dosage should be adjusted accordingly. An immunosuppressant can alter the pharmacokinetic profile of another immunosuppressant. There appears to be some alteration in cyclosporine pharmacokinetics, when used with basiliximab (47). Combined use of basiliximab and cyclosporine may increase the risk of cyclosporine toxicity. Basiliximab is the only IL-2 receptor antagonist that inhibits the metabolism of cyclosporine. Therefore, a lower dosage of cyclosporine should be considered (20% less). What about drugs with wide therapeutic windows? Since clinically significant drug-drug interactions cannot be detected by using therapeutic drug monitoring, it does not indicate a lack of drug-drug interaction. For example most transplant physicians do not adjust prednisone or other immunosuppressive agents when a patient is started on phenytoin. However, It has been well established that phenytoin increases metabolism of prednisone in transplant patients and increases the risk of acute rejection following transplantation (48). Although the interaction of iron products and most drugs has been extensively reviewed, most clinicians do not adjust the dose of immunosuppressive drugs when iron products are co-administered in transplant patients. Simultaneously, oral administration of iron products with mycophenolate leads to a decrease in bioavailability of mycophenolate mofetil by approximately 90% (49). Because mycophenolate has bioavailability of 94% with a fast absorption rate and a rapid time to maximum concentration, iron preparations can be given 4 hours after mycophenolate without expecting a significant change in the area under of curve or overall rate of absorption. Steroids also enhance the metabolism of mycophenolate through induction of hepatic glucuronyltransferase enzyme system. Cattaneo et al have shown following discontinuation of steroids, mean AUC of MPAG was decreased from 50 to 33 mcg/ml, which suggest a dose reduction is necessary when steroids are considered to be withdrawn (50). Van Gelder et al studied the relationship between cyclosporine and tacrolimus and changes in mycophenolate pharmacokinetics. A higher MPA was detected when tacrolimus and mycophenolate were co-administrated. This elucidates the need for a lower mycophenolate dose in combination with tacrolimus. However, cyclosporine interferes with MPGA excretion into the bile and higher doses of mycophenolate are needed to achieve a therapeutic plasma concentration (51).

TABLE 34.2. Cyclosporine and Tacrolimus Drug-Drug Interactions

Drug	Mechanism	Effects	Severity	Comments
Acetazolamide	Decrease clearance	Increase CSA/FK level	3	May cause acidosis
Acyclovir	Crystallization in renal tubules	Nephrotoxicity	4	Avoid dehydration. Infuse over 1 hour.
Amikacin	Synergistic nephrotoxicity	Nephrotoxicity	3	Monitor Aminoglycoside level very close. Target Amikacin level peck 30-40 and trough less than 10.
Amiloride	Decrease K+ secretion	Hyperkalemia	3	Avoid in transplant recipients
Amiodarone	Decrease clearance	Nephrotoxicity	3	Very slow onset and offset.
Amlodipine	Decrease clearance	Increase CSA/FK level	4	10-15% increase in CSA/FK level
Amphotericin B	Synergistic nephrotoxicity	Nephrotoxicity	3	Require hydration and electrolyte monitoring.
Atrovastatin	CSA decreases clearance of statins	Myopathy, rhabdomyolysis	3	Monitor CPK carefully
Carbamazepine	Increase clearance	Decrease CSA/FK level	3	Slow onset (may take up to 7 days)
				Monitoring of CSA/FK level
Carvedilol	Decrease clearance	Increase CSA/FK level	3	Can cause toxicity
Cervastatin	CSA decreases clearance of statins	Myopathy, rhabdomyolysis	3	Require Close CPK monitoring
Chloroquine	Decrease clearance	Increase CSA/FK level	3
Cholestyramine	Increase clearance	Decrease CSA/FK level	4	Sperate Doses by 3 hrs
Cimetidine	Inhibit creatinine secretion	Increase serum creatinine	4	Use other H2 antagonist agents (ranitidine, famotidine and nizatidine)
Ciprofloxacin	Decrease CSA effects on IL-2	Pharmacodynamic antagonism	4	May increase risk of rejection
Cisapride	Decrease gastric emptying time	Increase CSA/FK level	2	Metoclopramide is the preferred agent
Clarithromycin	Decrease clearance	Increase CSA/FK level	2	Azithromycin is the preferred agent gastrointestinal dysfunction and neuromyopathy
Colchicine		Increase neurotoxicity	3
Cotrimoxazole	Inhibit creatinine secretion	Increase serum creatinine	4	Preferred agent for PCP
Digoxin	CSA may decreases clearance of digoxin	Increase digoxin level	3	Monitor Digoxin level closely
Diltiazem	Decrease clearance	Increase CSA/FK level	3	Monitor CSA/FK level closely
Enalapril	Renal dysfunction in RAS	Increase serum creatinine	3	May cause anemia. Use for treatment of Post-Transplant Erythrocytosis.
Erythromycin	Decrease clearance	Increase CSA/FK level	2	Azithromycin is the preferred agent
Fluconazole	Decrease clearance	Increase CSA/FK level	3	Increase LFTs, Monitor levels carefully
Fluvoxamine	Decrease clearance	Increase CSA/FK level	2	Monitor levels carefully
Fosinopril	Renal dysfunction in RAS	Nephrotoxicity	3	Can cause elevation of Scr
Fosphenytoin	Increase clearance	Decrease CSA/FK level	3	Monitor levels carefully
Ganciclovir	Synergistic nephrotoxicity	Nephrotoxicity	3	Avoid dehydration
Gentamicin	Synergistic nephrotoxicity	Nephrotoxicity	3	Monitor blood concentrations very closely
Griseofulvin	Unknown	Decrease CSA/FK level	3	Decreased cyclosporine effectiveness
Itraconazole	Decrease clearance	Increase CSA/FK level	3	Monitor levels carefully, Decrease dosage 50-85%
Ketoconazole	Decrease clearance	Increase CSA/FK level	3	Monitor levels carefully, Decrease dosage 25-75%
Lovastatin	CSA decreases clearance of statins	Myopathy, rhabdomyolysis	3	Require Close CPK monitoring
Methylprednisolone	Decrease clearance	Increase CSA/FK level	3	Only high doses
Methyltestosterone	Decreased cyclosporine metabolism	Increase CSA/FK level	3	Can cause toxicity
Metoclopramide	Decrease gastric emptying time	Increase CSA/FK level	3	Increase peak and AUC by 25-50%
Metronidazole	Decrease clearance	Increase CSA/FK level	4	Monitor CSA/FK levels
Mibefradil	Decrease CSA/FK clearance	Increase CSA/FK level	3	Monitor CSA/FK levels
Nafcillin	Increase CSA/FK clearance	Decrease CSA/FK level	3	Monitor CSA/FK levels
Nefazodone	Decrease CSA/FK clearance	Increase CSA/FK level	3	Monitor CSA/FK levels
Nicardipine	Decrease CSA/FK clearance	Increase CSA/FK level	3	Monitor CSA/FK levels
NSAIDs	Synergistic nephrotoxicity	Nephrotoxicity	3	CSA/FK induced vasoconstriction is influenced by prostaglandins inhibition
Octreotide	Decrease intestinal absorption of CSA/FK	Decrease CSA/FK level	3	Monitor CSA/FK levels
Phenobarbital	Increase CSA/FK clearance	Decrease CSA/FK level	3	Slow onset, slow offset
Phenytoin	Increase CSA/FK clearance	Decrease CSA/FK level	3	Monitor cyclosporine/FK levels
Pravastatin	CSA decreases clearance of statins	Myopathy, rhabdomyolysis	3	Monitor CPK carefully
Rifabutin	Increase CSA/FK clearance	Decrease CSA/FK level	3	Monitor CSA/FK levels, rifabutin is a less potent hepatic enzyme inducer than rifampin
Rifampin	Increase CSA/FK clearance	Decrease CSA/FK level	2	Monitor cyclosporine/FK levels
Sildenafil	Increase FK level	Decrease CSA/FK level	4
Simvastatin	CSA decreases clearance of statins	Myopathy, rhabdomyolysis	4	Monitor CPK carefully
Spironolactone	Decrease K+ secretion	Hyperkalemia	3	Avoid
Terbinafine	Decrease CSA/FK clearance	Increase CSA/FK level	3	Monitor CSA/FK levels
Ticlopidine	Increase CSA/FK clearance	Decrease CSA/FK level	3	Monitor CSA/FK levels
Tretinoin	Inhibit tretinoin metabolism	Increase tretinoin toxicity	3
Triamterine	Decrease K+ secretion	Hyperkalemia	3	Avoid
Troglitazone	Increase CSA/FK clearance	Decrease CSA/FK level	3	Hepatotoxicity
Valacyclovir	Hemolytic anemic syndrome	Renal dysfunction	3	Acyclovir or Famciclovir are preferred agents for treatment of HSV and VZV
1) Avoid combination 2) Usually avoid (use only no other alternative agents available) 3) Monitor closely 4) No action needed (the risk of ADR is small)

TABLE 34.3. Sirolimus Drug-Drug Interactions

Drug	Mechanism	Effects	Severity	Comments
ACE-inhibitors	Synergistic myelosuppression	Anemia, neutropenia	3	Increase bone marrow toxicity
Amprenavir	Increase plasma level	Hyperlipidemia, anemia, neutropenia	3	Monitor sirolimus level
Bromocriptine	Increase plasma level	Hyperlipidemia, anemia, neutropenia	3	Monitor sirolimus level
Carbamazepine	Decrease intestinal absorption	Decrease sirolimus level	2	Monitor sirolimus level
Cholestyramine	Decrease intestinal absorption	Decrease sirolimus level	3	Monitor sirolimus level
Clarithromycin	Increased plasma level	Hyperlipidemia, anemia, neutropenia	2	Monitor sirolimus level
				Azithromycin is the preferred agent
Cyclosporine	Increase plasma level when taken at the same time	Hyperlipidemia, anemia, neutropenia	3	Monitor sirolimus level, Give 4 hours after the dose
Danazol	Decrease intestinal absorption	Decrease sirolimus level	3	Monitor sirolimus level
Diltiazem	Increase plasma level	Hyperlipidemia, anemia, neutropenia	2	Monitor sirolimus level
				Amlodipine is the preferred agent
Erythromycin	Increase plasma level	Hyperlipidemia, anemia, neutropenia	2	Monitor sirolimus level
				Azithromycin is the preferred agent
Fluconazole	Increase plasma level	Hyperlipidemia, anemia, neutropenia	2	Monitor sirolimus level
Ganciclovir	Synergistic myelosuppression	Anemia, neutropenia	3
Indinavir	Increase plasma level	Hyperlipidemia, anemia, neutropenia	2	Monitor sirolimus level
Itraconazole	Increase plasma level	Hyperlipidemia, anemia, neutropenia	2	Monitor sirolimus level
Metoclopramide	Increase plasma level	Hyperlipidemia, anemia, neutropenia	3	Monitor sirolimus level
Nicardipine	Increase plasma level	Hyperlipidemia, anemia, neutropenia	2	Monitor sirolimus level
				Amlodipine is the preferred agent
Phenobarbital	Increase metabolism	Decrease sirolimus level	2	Monitor sirolimus level
Phenytoin	Increase metabolism	Decrease sirolimus level	2	Monitor sirolimus level
Rifabutin	Increase metabolism	Decrease sirolimus level	2	Monitor sirolimus level
Rifampin	Increase metabolism	Decrease sirolimus level	2	Monitor sirolimus level
Ritonavir	Increase plasma level	Hyperlipidemia, anemia, neutropenia	2	Monitor sirolimus level
TMP/SMX	Synergistic myelosuppression	Anemia, neutropenia	3
Verapamil	Increase plasma level	Hyperlipidemia, anemia, neutropenia	2	Monitor sirolimus level
Voriconazole	Increase plasma level	Hyperlipidemia, anemia, neutropenia	2	Monitor sirolimus level
1) Avoid combination 2) Usually avoid (use only if no other alternative agents available) 3) Monitor closely 4) No action needed (the risk of ADR is small)

TABLE 34.4. Azathioprine and Mycophenolate Drug-Drug Interactions

Drug	Mechanism	Effects	Severity	Comments
ACE-inhibitors	Synergistic myelosuppression	Anemia, neutropenia	3	Increase bone marrow toxicity
Acyclovir	Increase AUC of MMF	Not significant	4
Allopurinol	Inhibit xanthene oxidase	Severe neutropenia	2	Decrease azathioprine dose by 75%
Antacids	Decrease absorption of MMF	Decrease efficacy	3
Cholestyramine	Decrease absorption of MMF		3	Increase bone marrow toxicity
Ganciclovir	Synergistic myelosuppression	Anemia, neutropenia	3
TMP/SMX	Synergistic myelosuppression	Anemia, neutropenia	3
1) Avoid combination 2) Usually avoid (use only no other alternative agents available) 3) Monitor closely 4) No action needed (the risk of ADR is small)

TABLE 34.5. Dosing Antimicrobial Agents in renal Impairment

			Dosage Adjustment in Renal Failure
Drugs Normal Doses		% of Renal Excretion	GFR >50	GFR 10-50	GFR <10	Comments
ANTIMICROBIAL AGENTS
Aminoglycoside						Nephrotoxic, ototoxic, may prolong the neuromuscular blockade effect of muscle relaxants
Gentamicin	2 mg/kg q8hrs	95%	60-90% q12hrs	30-70% q24hrs	20-30% q24hrs	Peak 6-8, Trough <2
Tobramicin	2 mg/kg q8hrs	95%	60-90% q12hrs	30-70% q24hrs	20-30% q24hrs	Peak 6-8, Trough <2
Netilmicin	2 mg/kg q8hrs	95%	60-90% q12hrs	30-70% q24hrs	20-30% q24hrs	Peak 6-8, Trough <2
Amikacin	7.5 mg/kg q12hrs	95%	60-90% q12hrs	30-70% q24hrs	20-30% q24hrs	Peak 20-30, Trough <5
CEPHALOSPORIN						Coagulation abnormalities, Transitory elevation of BUN, rash and serum sickness-like syndrome
Oral Cephalosporin
Cefaclor	250-500 mg tid	70%	100%	100%	50%
Cefadroxil	500 to 1 gm bid	80%	100%	100%	50%
Cefixime	200 to 400 mg q12h	85%	100%	100%	50%
Cefpodoxime	200 mg q12hrs	30%	100%	100%	100%
Ceftibuten	400 mg q24hrs	70%	100%	100%	50%
Cefuroxime	250-500 mg tid	90%	100%	100%	100%
Cephalexin	250-500 mg tid	95%	100%	100%	100%
Cephradine	250-500 mg tid	100%	100%	100%	50%
IV Cephalosporin
Cefamandol	1-2 gm IV q6-8hrs	100%	q6hrs	q8hrs	q12hrs
Cefazolin	1-2 gms IV q8hrs	80%	q8hrs	q12hrs	q12-24hrs
Cefepime	1-2 gms IV q8hrs	85%	q8-12hrs	q12hrs	q24hrs
Cefmetazole	1-2 gms IV q8hrs	85%	q8hrs	q12hrs	q24hrs
Cefoperazone	1-2 gms IV q12hrs	20%	No renal adjustment is required
Cefotaxime	1-2 gm IV q6-8hrs	60%	q8hrs	q12hrs	q12-24hrs
Cefotetan	1-2 gm IV q12hrs	75%	q12hrs	q12-24hrs	q24hrs
Cefoxitin	1-2 gms IV q6hrs	80%	q6hrs	q8-12hrs	q12hrs
Ceftazidime	1-2 gms IV q8hrs	70%	q8hrs	q12hrs	q24hrs
Ceftriaxone	1-2 gms IV q24hrs	50%	No renal adjustment is required
Cefuroxime	750-1.5 gms IV q8hrs	90%	q8hrs	q8-12hrs	q12-24hrs
PENICILLIN						Bleeding abnormalities, hypersensitivity
Oral Penicillin
Amoxicillin	500 mg po tid	60%	100%	100%	50-75%
Ampicillin	500 mg po q6hrs	60%	100%	100%	50-75%
Dicloxacillin	250-500 mg po q6hrs	50%	100%	100%	50-75%
Penicillin V	250-500 mg po q6hrs	70%	100%	100%	50-75%
IV Penicillin
Ampicillin	1-2 gms IV q6hrs	60%	q6hrs	q8hrs	q12hrs
Nafcillin	1-2 gms IV q4hrs	35%	No renal adjustment is required
Penicillin G	2-3 million Units IV q4hrs	70%	q4-6hrs	q6hrs	q8hrs
Piperacillin	3-4 gms IV q4-6hrs		No renal adjustment is required
Ticarcillin/clavulanate	3.1 gm IV q4-6hrs
Piperacillin/tazobactam	3.375 gm IV q6-8hrs
QUINOLONES						Photosensitivity, Food, dairy products, tube feeding and Al (OH)3 may decrease the absorption of quinolones
Ciprofloxacin	200-400 mg IV q24hrs	60%	q12hrs	q12-24hrs	q24hrs
	400 mg po/IV q24hrs	88%	100%	50%	50%
Levofloxacin	500 mg po qd	70%	q12hrs	250 q12hrs	250 q12hrs
Moxifloxacin	400 mg qd	20%	No renal adjustment is required
Norfloxacin	400 mg po q12hrs	30%	q12hrs	q12-24hrs	q24hrs
Ofloxacin	200-400 mg po q12hrs	70%	q12hrs	q12-24hrs	q24hrs
Trovafloxacin	200-300 mg po q12hrs	10%	No renal adjustment is required
MISCELLANEOUS AGENTS
Azithromycin	250-500 mg po qd	6%	No renal adjustment is required		NO drug-drug interaction with CSA/KF
Clarithromycin	500 mg po bid	20%	No renal adjustment is required		Pseudomembranous colitis
Clindamycin	150-450 mg po tid	10%	No renal adjustment is required		Increase CSA/FK level,
Dirithromycin	500 mg po qd		No renal adjustment is required
Erythromycin	250-500 mg po qid	15%	No renal adjustment is required		Increase CSA/FK level, avoid in transplant patients
Imipenem/Cilastatin	250-500 mg IV q6hrs	50%	500 mg q8hrs	250-500 q8-12hrs	250 mg q12hrs	Seizure
Meropenem	1 gms IV q8hrs	65%	1 gms q8hrs	0.5-1gms q12hrs	0.5-1 gms q24hrs
Metronidazole	500 mg IV q6hrs	20%	No renal adjustment is required		Peripheral neuropathy, increase LFTs, disulfiram reaction with alcoholic beverages
Pentamidine	4 mg/kg/day	5%	q24hrs	q24hrs	q48hrs	Inhalation may cause bronchospasm, IV administration may cause hypotension, hypoglycemia and nephrotoxicity level.
Rifampin	300-600 mg po qd	20%	No renal adjustment is required		Decrease CSA/FK
Trimethoprim/Sulfamethoxazole	one po bid	70%	q12hrs	q12hrs	q24hrs	Increase serum creatinine
Vancomycin	1 gm IV q12hrs	90%	q12hrs	q24-36hrs	q48-72hrs	Nephrotoxic, ototoxic, may prolong the neuromuscular blockade effect of muscle relaxants
						Peak 30, trough 5-10
Vancomycin po qid	125-250 mg	0%	100%	100%	100%	Oral vancomycin is indicated only for the treatment of C. diff
ANTIFUNGAL AGENTS
Amphotericin B	0.5 mg-1.5 mg/kg/day	<1%	No renal adjustment is required		Nephrotoxic, infusion related reactions, give 250 cc NS before each dose
Amphotec	4-6 mg/kg/day	<1%	No renal adjustment is required
Abelcet	5 mg/kg/day	<1%	No renal adjustment is required
AmBisome	3-5 mg/kg/day	<1%	No renal adjustment is required
Azoles and other antifungals						Increase CSA/FK level
Fluconazole	200-800 mg IV qd/bid	70%	100%	100%	50%
Itraconazole	200 mg q12hrs	35%	100%	100%	50%	Poor oral absorption
Ketoconazole	200-400 mg po qd	15%	100%	100%	100%	Hepatotoxic
Miconazole	1200-3600 mg/day	1%	100%	100%	100%
Terbinafine	250 mg po qd	>1%	100%	100%	100%
ANTI-VIRAL AGENTS
Acyclovir	200-800 mg po 5x/day	50%	100%	100%	50%	Poor absorption
Amantadine	100-200 mg q12hrs	90%	100%	50%	25%
Famciclovir	250-500 mg po bid to tid	60%	q8hrs	q12hrs	q24hrs	VZV: 500 mg po tid HSV: 250 po bid
Foscarnet	40-80 mg IV q8hrs	85%	40-20 mg q8-24 hrs according to ClCr		Nephrotoxic, neurotoxic, hypocalcemia, hypophosphatemia, hypomagnesemia and hypokalemia
Ganciclovir IV	5 mg/kg q12hrs	95%	q12hrs	q24hrs	2,5 mg/kg qd	Granulocytopenia and thrombocytopenia
Ganciclovir PO	1000 mg PO tid	95%	1000 mg tid	1000 mg bid	1000 mg qd	Oral Ganciclovir should be used ONLY for prevention of CMV infection. Always use IV ganciclovir for the treatment of CMV infection
Lamivudine	150 mg po bid	80%	q12hrs	q24hrs	50 mg q24hrs	For hepatitis B
Ribavirin	500-600 mg q12hrs	30%	100%	100%	50%	Hemolytic uremic syndrome
Rimantadine	100 mg po bid	25%	100%	100%	50%
Oseltamivir	75 mg po bid	10%
Valacyclovir	500-1000 mg q8hrs	50%	100%	50%	25%	Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome
						Avoid in transplant recipients
Zanamivir	2 puffs bid × 5 days