An example is the use of CNI in combination with ACE inhibitors. Because both
classes of agents can cause hyperkalemia and potentially decrease renal function,
toxicity may be more pronounced when given in combination.
drug interactions are usually more difficult to identify and require a thorough
knowledge of the pharmacologic effects of the agents. Often, little or no information
in the literature on these types of interactions exists to guide the clinician in
determining whether this drug interaction will occur. As a general rule, if an agent is
known to cause a particular toxicity that is similar to a toxicity associated with the
immunosuppressant agent, then there is a high likelihood that a pharmacodynamic
interaction will occur. Another example is an interaction between metoclopramide
and MMF. Both agents are known to cause diarrhea, and a higher incidence or
severity of diarrhea likely occurs when these agents are used together.
Immunosuppressant Drug Interactions
Immunosuppressant Interacting Drugs Mechanism Consequence
Azathioprine Allopurinol Inhibit metabolism
aThese are considered either potent inhibitors or inducers.
AUC, area under the curve; CYP, cytochrome P-450; IS, immunosuppressant.
It is important to be alert for drugs with pharmacologic effects that may alter the
efficacy of an immunosuppressant.
77 For example, a drug with immunosuppressant
properties, such as cyclophosphamide, could lead to overimmunosuppression of the
transplant recipient and a higher incidence or severity of opportunistic infections.
Conversely, a drug with immunostimulant properties, such as the herbal medication
echinacea, may reduce the efficacy of the immunosuppressant agent and increase the
risk of rejection in the transplant recipient.
76,77 Although agents that have
pharmacodynamic drug interactions with the immunosuppressants are not absolutely
contraindicated, transplant recipients should be closely monitored for either
increased risk of drug toxicity or decreased drug efficacy when these agents are used
in combination. When a transplant recipient adds any new medication—whether
prescription, over-the-counter, or herbal—it should be thoroughly researched to
determine whether there is a potential interaction with the immunosuppressant
In C.C., the addition of fluconazole will lead to a pharmacokinetic drug interaction
by inhibiting the cytochrome P-450 3A4 system and may significantly increase
tacrolimus concentrations. This interaction is usually evident within 2 to 5 days, and
a maximal effect is seen within a week of initiating fluconazole. Therefore, C.C.’s
tacrolimus dose should be reduced when fluconazole is started. Tacrolimus blood
levels should be monitored, as should signs and symptoms of toxicity. Fluconazole
could also influence steroid metabolism, but specific recommendations are not
available. In general, drug interactions can be managed and, in some cases, may
require only separate administration times. In other cases, an alternative agent can be
used within a pharmacologic class that does not interact with these agents.
Infection continues to be a major source of morbidity and mortality. Transplant
recipients have the same risk of infection from transplant surgery as any other patient
having a surgical procedure. The incidence of infections or organ transplant
recipients has decreased since the advent of cyclosporine. Infection rates, however,
remain high—upwards of 50% in transplant recipients.
Prophylactic antimicrobial therapy decreases the risk of surgical infections;
however, prophylactic regimens and antibiotic therapies are highly institutiondependent.
80 Kidney transplant recipients typically receive a first-generation
cephalosporin, such as cefazolin, to cover uropathogens and staphylococci. Usually,
antibiotic prophylaxis is given preoperatively, prior to skin incision and continued
for one to three doses post-transplant. Due to how severely ill a cirrhotic is going
into transplant and the fact that the surgery requires multiple anastomoses in an
nonsterile environment (the bowel), liver transplantations are associated with the
highest rate of life-threatening bacterial infection. Piperacillin–tazobactam commonly
is used to cover staphylococci, enterococci, and Enterobacteriaceae. Duration of
therapy in these patients is individualized, based on the patient’s postoperative
recovery, but usually lasts from 24 for 96 hours post-transplant.
occur at any time after transplantation, but there are predictable time patterns for
79 The time of highest risk for infection in transplant
recipients is during the first 6 months, because they are receiving the highest doses of
immunosuppressive agents during this period. Another time of high risk is during and
after treatment of acute rejection with high-dose immunosuppression. Patients can
acquire new infections (Pneumocystis jiroveci pneumonia [PJP], CMV), reactivate
old infections (e.g., CMV, BK virus), or experience recurrence of underlying disease
(hepatitis B or C). Opportunistic infections are common during this time, as shown in
Table 34-3. Because the infections shown in Table 34-3 occur at such a high rate, it
is routine to provide specific prophylaxis for many of them. For example, nystatin
suspension 500,000 IU by “swish and swallow” 3 to 4 times a day is commonly used
for 1 month post-transplant in kidney recipients, and fluconazole 100 mg every day is
used to reduce fungal colonization of the GI tract in liver and pancreas transplant
recipients; acyclovir, ganciclovir, valacyclovir, valganciclovir, and
immunoglobulins can be used for CMV and/or herpes virus infections; and TMP–
SMX is used for Pneumocystis prophylaxis. For patients with sulfa allergies,
alternatives, such as dapsone 50 to 100 mg PO daily, inhaled monthly doses of
pentamidine 300 mg and atovaquone are used. These generally are given for the first
3 to 6 months after transplantation and, in some cases, up to 1 year or even for life.
S.C. needs prophylaxis with TMP–SMX for PJP prevention; valganciclovir for CMV
prevention; and HBIG and lamivudine, adefovir, entecavir, tenofovir, or telbivudine
to prevent recurrence of hepatitis B.
Common Opportunistic Infections After Transplantation
Organisms Usual Time of Onset After Transplantation
Herpes simplex virus 2 weeks–2 months
Varicella-zoster virus 2–6 months
Pneumocystis jiroveci pneumonia 1–6 months
Cryptococcus 4 months–indefinitely
A major concern for S.C. would be recurrence of hepatitis B in his new liver. If
hepatitis B recurs, it is associated with a poorer outcome. Strategies that have been
effective are the use of lamivudine, adefovir, entecavir, telbivudine, and tenofovir
preoperatively and HBIG, with or without oral antiviral therapy, postoperatively.
S.C. was started on lamivudine and HBIG postoperatively because monotherapy with
HBIG is associated with recurrence in 10% to 50% patients, whereas HBIG with
lamivudine has been associated
with a lower incidence of recurrence compared to HBIG monotherapy. Lamivudine
resistance rates are reported in 15-30% of patients taking this agent per year. In
patients who develop a resistant form of hepatitis B to lamivudine, adefovir,
entecavir, telbivudine, and tenofovir have been shown to be effective. After the first
week of HBIG, S.C. will continue to receive 10,000 IU IV as a 1-hour to 2-hour
infusion weekly for 4 weeks, then 10,000 IU monthly for the first 6 to 12 months after
transplantation. During this time, anti-HBs titers are monitored and kept greater than
500 IU/L. Because HBIG is expensive (up to $50,000 per patient per year) and with
the newer, more potent, oral antivirals available, more transplant centers now target
lower titers (>100 IU/L) and HBIG doses of 1,500 IU intramuscularly every 3 to 4
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